KUOPION YLIOPISTON JULKAISUJA A.

FARMASEUTTISET TIETEET 117

KUOPIO UNIVERSITY PUBLICATIONS A. PHARMACEUTICAL SCIENCES 117

RIIKKA LAITINEN

Physical Modification of Drug Release

Controlling Structures
Hydrophobic Matrices and Fast Dissolving Particles

Doctoral dissertation
To be presented by permission of the Faculty of Pharmacy of the University of Kuopio
for public examination in Auditorium, Mediteknia building, University of Kuopio,
on Saturday 27 th June 2009, at 12 noon

Department of Pharmaceutics
Faculty of Pharmacy
University of Kuopio

JOKA
KUOPIO 2009

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Series Editor :

Docent Pekka Jarho, Ph.D.

Department of Pharmaceutical Chemistry

Authors address:

Department of Pharmaceutics
University of Kuopio
P.O. Box 1627
FI-70211 KUOPIO
FINLAND
Tel. +358 40 355 3881
Fax +358 17 162 252
E-mail: Riikka.Laitinen@uku.fi

Supervisors:

Professor Jarkko Ketolainen, Ph.D.

Department of Pharmaceutics
University of Kuopio

Docent Eero Suihko, Ph.D.

Orion Oyj
Kuopio

Reviewers:

Professor Henderik W. Frijlink, Ph.D.

Department of Pharmaceutical Technology and Biopharmacy
Groningen University Institute for Drug Exploration (GUIDE)
The Netherlands

Professor Thomas Rades, Ph.D.

The New Zealand National School of Pharmacy
University of Otago
New Zealand

Opponent:

Professor Robert T. Forbes, Ph.D.

School of Life Sciences
University of Bradford
UK

ISBN 978-951-27-0855-0
ISBN 978-951-27-1148-2 (PDF)
ISSN 1235-0478
Kopijyv
Kuopio 2009
Finland

Laitinen, Riikka. Physical modification of drug release controlling structures hydrophobic matrices and
fast dissolving particles. Kuopio University Publications A. Pharmaceutical Sciences 117. 2009. 138 p.
ISBN 978-951-27-0855-0
ISBN 978-951-27-1148-2 (PDF)
ISSN 1235-0478
ABSTRACT
An oral drug delivery system (e.g. tablet or capsule) is required for administration, which must ensure
delivery to the site of absorption in the gastrointestinal (GI) tract and release control of the active drug
substance in a safe, effective and reliable way. However, many drug compounds are either ineffectively or
incompletely absorbed after oral administration. Fortunately, biopharmaceutical performance of drug
compounds suffering from such limitations can be effectively improved by modified-release formulation
technologies.
The objective of this study was to evaluate different modified-release technologies both for controlling
the drug release properties of a hydrophobic matrix system and for improving the dissolution properties of
a poorly soluble drug, in order to allow its intraoral delivery, i.e. to formulate an orally fast disintegrating
tablet (FDT). Matrix systems, which allow retarding the drug dissolution from the dosage form, are the
most commonly used controlled drug delivery dosage forms due to their robustness and low production
costs. This can beneficial in the case that the required dosing frequency is too high to enable once or twice
a day administration due to the excessively short pharmacokinetic half-life of the drug. On the other hand,
from a FDT the drug releases in the oral cavity and it can be absorbed through the oral mucosa and
delivered directly into the systemic circulation, avoiding first pass metabolism, by ensuring that the drug is
rapidly released and dissolved in the oral cavity. Another advantage of the intraoral route is the very fast
onset of drug action.
First, the ability of hydrophobic starch acetate (SA) and ethyl cellulose (EC) matrices for controlling the
release of water soluble model drugs was studied. In the study, the release properties of highly water
soluble saccharides were found to be similar with SA and commercially available EC. It was shown that
simply by altering tablet porosity and the relative amount of the excipient in the tablet, the release of
saccharides could be controlled over a wide time scale. Subsequently, a simple dry powder agglomeration
preparation process for drug/SA mixtures was developed. It was observed that changing the organization of
the powder mixture by this process, the release rate of water soluble model drugs from SA matrix and tablet
properties could be modified. The extent of the change in the mixture structure was found to be dependent
on the size and the surface roughness of the drug particles.
Finally, an extremely fast dissolution rate of a poorly water soluble drug in a small volume of liquid (pH
6.8) was obtained by utilizing a solid dispersion (SD) approach. The amorphous SD with the best
dissolution and stability characteristics was formulated as a FDT. The formulation prepared with direct
compression, underwent fast disintegration and displayed a fast and immediate onset of the release of the
drug and also possessed sufficient tensile strength.
In conclusion, simple formulation and processing modifications, which do not require any expensive and
complicated equipment or process stages, or new chemical entities, displayed a great potential in controlled
modification of release and dissolution of physicochemically diverse drugs. These simple methods may be
helpful in solving the future challenges of developing innovative formulations and dosage forms, e.g.
enhancing the drug solubility and dissolution rate of new, more hydrophobic lead molecules that otherwise
would have limited biavailabilities. The results can also be useful for developing dosage forms for elderly
patients and children, two patient groups who suffer problems in swallowing conventional dosage forms.
National Library of Medicine Classification: QV 785, QV 787, WB 350
Medical Subject Headings: Drug Delivery Systems; Administration, Oral; Dosage Forms; Delayed-Action
Preparations; Tablets; Solubility; Hydrophobicity; Starch/analogs & derivatives; Cellulose/analogs &
derivatives; Porosity; Excipients; Powders; Particle Size; Tensile Strength

Imagination is more important than knowledge

Albert Einstein

ACKNOWLEDGEMENTS

The present study was carried out in the Department of Pharmaceutics, University of
Kuopio during the years 2002-2009. This study was financially supported by the Finnish
Foundation for Technology and Innovation (TEKES), European Regional Development
Fund (ERDF), Kuopio University Pharmacy, The Finnish Cultural Foundation, Kuopio
University Foundation and The Finnish Pharmaceutical Society, which are gratefully
acknowledged.
I wish to warmly thank my principal supervisor, Professor Jarkko Ketolainen for giving
me the opportunity to work in his research group and for giving me the possibility to
grow into an independent scientist. I am also grateful to my second supervisor, Docent
Eero Suihko, for his invaluable contribution to my study and for always finding time for
me in his busy schedule.
Professors Kristiina Jrvinen and Arto Urtti, present and former heads of the
Department of Pharmaceutics, and Professor Jukka Mnkknen, dean of the Faculty of
Pharmacy, are acknowledged for providing facilities and pleasant working environment.
Kristiina, I highly appreciate your expertise and optimism which has been a great help,
especially in finishing the last two parts of my study.
I am grateful to my co-authors Mikko Bjrkqvist, Ph. D., Minna Heiskanen, M. Sc.
(Pharm.), Olli-Pekka Hmlinen, M. Sc., Ossi Korhonen Ph. D. (Pharm.), Docent VesaPekka Lehto, Marko Lehtonen M.Sc., Matti Murtomaa, Ph. D., Riku Niemi, Ph. D.
(Pharm.), Heli Pitknen, M.Sc. (Pharm.), Joakim Riikonen M.Sc., Ms. Susanne Rost and
Kaisa Toukola, M.Sc. (Pharm.) for their valuable collaboration. Ewen MacDonald, Ph.D.
is acknowledged for revising the language of my publications and this thesis. I also wish
to warmly thank all the personnel in the Faculty of Pharmacy who have contributed to
this work or helped me in any way during my career: especially Ms. Pirjo Hakkarainen
for her highly skillfull technical assistance and support at the beginning of my study; Ossi
Korhonen for introducing me to the research field of pharmacy and for guidance and
invaluable expert help during my work; Kristiina Heikkil M.Sc. (Pharm) for laboratory
assistance; Docent Pekka Jarho, Professor Tomi Jrvinen and Elina Turunen, M.Sc.

(Pharm.) for pleasant collaboration during the NOPPA-project and Tarja Toropainen,
Ph.D. (Pharm) for helping me with many practical things related to Ph.D. thesis project.
I am grateful to the official reviewers: Professor Henderik W. Frijlink from the
Groningen University Institute for Drug Exploration (GUIDE) and Professor Thomas
Rades from the University of Otago, for their useful comments to improve this thesis. I
also warmly thank Professor Robert T. Forbes from the University of Bradford for
agreeing to be the opponent in the public examination of my thesis.
My warmest thanks go to my friends and colleagues in the Department of
Pharmaceutics. Most of all I would like to thank the fabulous and highly talented TeTuteam: Katri Levonen, M. Sc. (Pharm), Juha Mnkre, M. Sc. (Pharm), Jari Pajander, M.
Sc. (Pharm) and Sami Poutiainen, M. Sc., for all of your cheer-ups and many
unforgettable moments during these years. Jari, it has been a privilege to be your
roommate. Your invaluable help and outstanding sense of humor will never be forgotten.
Cordial thanks for sharing the highs and lows of my Ph.D. studies, espresso breaks and
discussions varying from the scientific to the often very unscientific. I wish you the best
success with your own thesis.
I thank my parents Anja and Timo for always supporting the choices I have made. You
have given me a solid ground for life. I am also very grateful to my childhood friends and
the closest friends from the student days, that you have not forgotten me in spite of the
long distance between us.
Finally, I would like to express my sincere thanks to my beloved husband Mika.
Having you by my side has given me strength every single day. Your love and support
mean everything to me. Thank you for being there, you are my dearest!

Kuopio, May 2009

Riikka Laitinen

ABBREVIATIONS
A
ASES
ATR
C
Cp
Cs
CD
CP
CS
D
DEA
DMA
DS
DSC

EC
ELS
f2
FDT
FRET
FTIR
GAS
GI
H
h
HEC
HPC
HPLC
HPMC
HPMCAS
HSM
HTS
IGC
IMC
IR
k
m
Mt
M
MTDSC
n
NAG
NCE
NIR

surface area
aerosol solvent extraction system
attenuated total reflectance
concentration
heat capacity
solubility
cyclodextrin
crospovidone
calcium silicate
diffusion constant
dielectric analysis
dynamical mechanic analysis
degree of substitution
differential scanning calorimetry
solubility parameter
matrix porosity
ethyl cellulose
evaporative light scattering
similarity factor
fast disintegrating tablet
fluorescence resonance energy transfer
fourier-transform infrared
gas antisolvent
gastrointestinal
enthalpy
thickness of the diffusion layer
hydroxyethylcellulose
hydroxypropylcellulose
high performance liquid chromatography
hydroxypropylmethylcellulose
hydroxypropylmethylcellulose acetate succinate
hot-stage microscopy
high throughput screening
inverse gas chromatography
isothermal microcalorimetry
infrared
release rate constant incorporating the matrix structure
mass
amount of drug released at time t
amount of drug released at time t=
modulated temperature differential scanning calorimetry
diffusional exponent
N-acetyl-D-glucosamine
new chemical entity
near-infrared

MW
PAA
PE
PEG
PEO
PGSS
PLGA
PLS
PLS-DA
PP
PPZ
PVC
PVP
PVP/VA
Q

RESS
RH
SA
SAS
SAXS
SCF
SD
sd
SDS
SEDS
SEM
SS
ssNMR
t

TEM
Tg
TK
Tm
T50%
V
w
XRD
XRPD

molecular weight
polyacrylic acid
polyethylene
polyethylene glycol
poly (ethylene oxide)
particles from gas saturated solutions
copolylactic acid/ glycolic acid
partial least squares regression analysis
partial least squares discriminant analysis
polypropylene
perphenazine
polyvinyl chloride
polyvinyl pyrrolidone
poly (vinylpyrrolidone-co-vinylacetate)
the amount of drug released
density
rapid expansion of supercritical solution
relative humidity
starch acetate
supercritical antisolvent
small-angle X-ray scattering
supercritical fluid
solid dispersion
standard deviation
sodium dodecyl sulfate
solution enhanced dispersion by supercritical fluids
scanning electron microscopy
stainless steel
solid-state nuclear magnetic resonance
time
matrix tortuosity
mean molecular relaxation times
transmission electron microscopy
glass transition temperature
Kauzmann temperature (or temperature of zero mobility)
melting (fusion) temperature
time required for dissolution of 50% of the substance
(specific) volume
weight fraction
X-ray diffraction
X-ray powder diffractometry

LIST OF ORIGINAL PUBLICATIONS

This doctoral thesis is based on the following original publications referred in the text by
Roman numerals I-IV.

Mki R, Suihko E, Korhonen O, Pitknen H, Niemi R, Lehtonen M, Ketolainen J:

Controlled release of saccharides from matrix tablets. Eur J Pharm Biopharm 62:
163-170, 2006.

II

Mki R, Suihko E, Rost S, Heiskanen M, Murtomaa M, Lehto VP, Ketolainen J:

Modifying drug release and tablet properties of starch acetate tablets by dry
powder agglomeration. J Pharm Sci 96: 438-447, 2007.

III

Laitinen R, Suihko E, Toukola K, Bjrkqvist M, Riikonen J, Lehto VP, Jrvinen

K, Ketolainen J: Intraorally fast dissolving particles of a poorly soluble drug:
preparation and in vitro characterization. Eur J Pharm Biopharm 71: 271-281,
2009

IV

Laitinen R, Suihko E, Bjrkqvist M, Riikonen J, Lehto VP, Jrvinen K,

Ketolainen J: Perphenazine solid dispersions for orally fast disintegrating tablets:
physical stability and formulation. Drug Dev Ind Pharm, submitted

CONTENTS
1 INTRODUCTION ........................................................................................................... 17
2 BACKGROUND OF THE STUDY .............................................................................. 19
2.1 Oral drug delivery ...................................................................................................... 19
2.2 Matrix tablets for oral controlled release .................................................................. 21
2.2.1 Hydrophobic matrices ......................................................................................... 21
2.2.2 Hydrophilic matrices ........................................................................................... 23
2.2.3 Matrix tablet preparation ..................................................................................... 23
2.2.3.1 Tablet formation ............................................................................................... 23
2.2.3.2 Tablet structure and strength............................................................................ 24
2.2.3.3 Effect of solid state properties of the materials on tablet properties ............. 25
2.2.3.4 Importance of powder mixing on tableting and tablet properties.................. 26
2.2.4 Drug release mechanisms.................................................................................... 29
2.2.4.1 Diffusion ........................................................................................................... 29
2.2.4.2 Swelling............................................................................................................. 30
2.2.4.3 Erosion .............................................................................................................. 31
2.3 Intraoral drug formulations ........................................................................................ 31
2.3.1 Intraoral drug delivery ......................................................................................... 31
2.3.2 Orally fast disintegrating tablets ......................................................................... 33
2.3.2.1 Preparation by freeze-drying ........................................................................... 33
2.3.2.2 Preparation by compression ............................................................................. 35
2.3.2.3 Other preparation techniques ........................................................................... 36
2.3.2.4 Pharmacokinetic advantages of fast disintegrating tablets ............................ 36
2.4 Improvement of the dissolution rate of poorly soluble drugs .................................. 37
2.4.1 Solubility and dissolution rate ............................................................................ 37
2.4.2 Enhancement of the dissolution by using amorphous forms ............................ 40
2.4.2.1 Formation and properties of the amorphous state .......................................... 40
2.4.2.2 Characterization of the amorphous state ......................................................... 43
2.4.2.3 Stability of amorphous drugs ........................................................................... 46
2.4.3 Enhancing the dissolution by using solid dispersions ....................................... 48

2.4.3.1 Preparation of solid dispersions....................................................................... 50

2.4.3.2 Carrier materials ............................................................................................... 53
2.4.3.3 Physical characterization of solid dispersions ................................................ 56
2.4.3.4 Dissolution of solid dispersions....................................................................... 58
2.4.3.5 Stability and formulation of solid dispersions ................................................ 59
3 AIMS OF THE STUDY ................................................................................................. 63
4 EXPERIMENTAL .......................................................................................................... 64
4.1 Materials...................................................................................................................... 64
4.1.1 Excipients and model drugs (I-IV) ..................................................................... 64
4.1.2 Other chemicals (I-IV) ........................................................................................ 64
4.2 Methods ...................................................................................................................... 65
4.2.1 Particle and powder properties (I-IV) ................................................................ 65
4.2.2 Tableting (I, II, IV) .............................................................................................. 65
4.2.3 Tablet properties (I, II, IV).................................................................................. 66
4.2.4 Preparation of solid dispersions (III, IV) ........................................................... 67
4.2.5 Physicochemical characterization (I-IV) ............................................................ 67
4.2.5.1 Polarized light microscopy (I) ......................................................................... 67
4.2.5.2 Differential Scanning Calorimetry (I, III, IV) ................................................ 67
4.2.5.3 X-ray Powder Diffractiometry (III, IV) .......................................................... 69
4.2.5.4 Fourier Transform Infrared Spectroscopy (III, IV) ........................................ 69
4.2.5.5 Small-angle X-ray scattering (III, IV) ............................................................. 69
4.2.6 Solubility and dissolution testing (I-IV)............................................................. 70
4.2.7 Stability testing (IV) ............................................................................................ 72
4.2.8 Statistical analysis (I, II)...................................................................................... 72
5 RESULTS AND DISCUSSION..................................................................................... 74
5.1 Factors affecting release of highly water soluble compounds from hydrophobic
matrices (I) ................................................................................................................. 74
5.1.1 Dissolution characteristics of N-acetyl-D-glucosamine (I) .............................. 74
5.1.2 Dissolution characteristics of saccharides and oligosaccharides (I)................. 76

5.2 Effect of organization of powder mixture on the release rate of drugs from starch
acetate matrix (II) ...................................................................................................... 81
5.2.1 Triboelectrification of the materials (II)............................................................. 81
5.2.2 Dry powder agglomeration (II) ........................................................................... 82
5.2.3 Dissolution and tablet characteristics (II) .......................................................... 83
5.2.4 Summary and future prospectives (I, II) ............................................................ 88
5.3 Fast dissolving particles of a poorly soluble drug for intraoral preparations (III,
IV) ............................................................................................................................ 90
5.3.1 Improvement of drug dissolution by solid dispersion approach (III) ............... 90
5.3.1.1 Polymer selection by the solubility parameter approach (III) ....................... 90
5.3.1.2 Dissolution properties of the solid dispersions (III, IV) ................................ 91
5.3.2 Physical properties and stability of the solid dispersions (III, IV) ................... 93
5.3.3 Performance of fast disintegrating tablets containing solid dispersions (IV) 100
5.3.4 Summary and future prospectives (III, IV) ...................................................... 102
6 CONCLUSIONS............................................................................................................ 105
7 REFERENCES .............................................................................................................. 107
ORIGINAL PUBLICATIONS ........................................................................................ 138

17

INTRODUCTION
Solid oral dosage forms offer robustness, low manufacturing costs, ease of product

handling and convenience of use making them the most commonly used drug
administration systems (Rudnic and Kottke 1996, Venkatraman et al. 2000). However, in
oral drug delivery, as in all other categories of treatment, one major challenge for drug
development is to define optimal dose, time, rate and site of delivery in order to produce
safe and more efficient drugs. Thus, properties both of the drug and the delivery system
must be optimized.
The drugs bioavailability can be effectively optimized by modified-release formulation
technologies. Within the context of this doctoral thesis, by the term modified-release is
referred to oral controlled release systems, oral delivery systems for modifying the
release of poorly water soluble drugs as well as fast dissolving dosage forms from which
drug absorption may occur through the oral mucosa or the gastrointestinal (GI) tract.
Controlled drug delivery techniques are a feasible way of improving the efficacy of the
drug when the solubility, dose, stability and cell membrane permeability of the drug are
appropriate (Qiu and Zhang 2000). Typically, a controlled release system is designed to
provide a desired release rate for a certain drug over an extended period of time in order
to achieve constant drug levels in plasma. Hydrophobic or hydrophilic polymeric matrix
tablets are common controlled release dosage forms due to the ease and economy of their
production (Qiu and Zhang 2000). However, the drug release rate from simple polymeric
matrix systems tends to decrease as a function of time and to overcome this problem
various methods, such as geometric configurations (e.g. donut shaped systems (Kim
1995a, Sundy and Danckwerts 2004)) and multiple unit dosage forms (Kendall 1989),
have been developed. Unfortunately, the dosage form per se is not always sufficient to
produce desirable drug release properties.
High throughput receptor based screens (HTS) and combinatorial chemistry are
producing increasing amounts of drug candidates with high lipophilicity and thus, good
permeability, but poor aqueous solubility (Alsenz and Kansy 2007). This leads to slow
dissolution of the drug in GI fluids and a reduction in the rate of the first step in the oral
absorption process. After a certain point, the solubility limitations cannot be overcome

18
with dosage form design and thus strategies, such as micronization of the drug (McInnes
et al. 1982, Mosharraf and Nystrm 1995, Vogt et al. 2008), use of a faster dissolving
salt, polymorphic or amorphous form of the drug (Kobayashi et al. 2000, Huang and
Tong 2004, Blagden et al. 2007, Serajuddin 2007), complexation with cyclodextrins
(Rajewski and Stella 1996, Brewster and Loftsson 2007) and formation of a solid
dispersion (Chiou and Riegelman 1971, Leuner and Dressman 2000, Sethia and
Squillante 2003) are needed if one wishes to improve the solubility and dissolution rate of
the drug itself. Fast dissolution of the drug is also needed when formulating a drug for
dispensing in orally fast dissolving tablets from which the drug is released in the oral
cavity and absorbed through oral mucosa (Seager 1998).
In the present study, different modified-release technologies were applied for
improving the drug release properties of a controlled release drug delivery system and the
dissolution properties of a poorly soluble drug in order to enable its usage in orally fast
disintegrating formulations. First, the release rate and profile of highly water soluble
drugs from starch acetate matrix tablets were controlled by simple formulation
approaches. Then, the dissolution properties of a poorly soluble drug were improved with
a solid dispersion technique, after which the fast dissolving dispersion was formulated as
an orally fast disintegrating tablet.

19

BACKGROUND OF THE STUDY

2.1

Oral drug delivery

The majority of drug substances exist as crystalline or amorphous powders. A delivery

system (e.g. tablet or capsule) is required for delivering and releasing the drug substance
to its absorption site in the GI tract safely, effectively and reliably. In addition to the
delivery of the drug to its absorption site, transposition of a drug from an oral dosage
form into the bloodstream requires dissolving of the drug followed by movement of the
dissolved drug through the membranes of the GI tract into the general blood circulation.
Unfortunately, many drug compounds are either incompletely or ineffectively absorbed
after oral administration, i.e. they have low bioavailability due to low solubility or cell
membrane permeability, or because they are metabolized by the liver into an inactive
form (first-pass metabolism) (Lbenberg et al. 2000, Hillery 2001). On the other hand,
the required dosing frequency might be too high to enable once or twice a day
administration if the drug has a very short pharmacokinetic half-life. Nonetheless, the
biopharmaceutical performance of many drug compounds suffering from these kinds of
limitations can be effectively improved by resorting to modified-release formulation
technologies.
The term controlled drug delivery refers to dosage forms which provide a specifically
designed dissolution profile of the drug from the dosage form. Various physical and
chemical approaches can be applied to produce a dosage form displaying the desired
release profile and thereby control over the drugs absorption into the systemic
circulation (Qiu and Zhang 2000). Some of the systems utilized include: insoluble, slowly
eroding or swelling matrices; polymer-coated tablets, pellets or granules; osmotically
driven systems; systems controlled by ion exchange mechanisms and various
combinations of these approaches (Saikh et al. 1987a and b, Tahara et al. 1995, Charman
and Charman 2002, Jeong and Park 2008). With respect to controlled release dosage
forms, the focus in this thesis will be restricted to the matrix structures (Chapter 2.2).
Matrix systems are the most commonly used type of controlled drug delivery systems
due to their robustness and low production costs. A matrix system is simply a

20
homogenous mixture of drug particles within a polymer matrix, often manufactured by
direct compression. However, one disadvantage of a simple monolithic matrix is the
decrease in dissolution rate as a function of time, resulting from an increase in the
diffusion path length and a decrease in effective diffusion area, even when hydrophilic
polymers (swelling/erodible) are used. This leads to a square-root of time release profile
of the drug (Venkatraman et al. 2000, Charman and Charman 2002). However, zero-order
drug release is often desired since it offers several therapeutic advantages, such as
minimized peak plasma levels leading to reduced risk of adverse reactions and
predictable and extended duration of action (Breimer 1998). Therefore, numerous
approaches, such as matrices with modified geometry and the surface area available for
diffusion (Bayomi 1994, Kim 1995a, Chopra 2002, Zerbe and Kumme 2002, Sundy and
Danckwerts 2004) or multiple unit delivery systems consisting of small subunits such as
granules, pellets or minitablets (Efentakis and Koutilis 2001, Verhoeven et al. 2006,
Hayashi et al. 2007) have been examined as ways to modify the release rate of the drug.
Manufacturing of the multiple-unit preparations, however, is a relatively complicated and
expensive involving numerous process variables. Thus, the pharmaceutical industry
prefers to design of directly compressed monolithic delivery systems in controlling the
drug release. Furthermore, if one considers the pharmaceutical variables, then the
physicochemical properties of the drug are crucial, since after released from the dosage
form, the drug has to be dissolved into surrounding fluids in order to be absorbed. Drugs
that can be formulated to controlled release dosage forms have reasonable solubilities,
relatively low dose, short elimination half-lives, and low first pass metabolism (Qiu and
Zhang 2000, Chrzanowski 2008a,b). However, hydrophobic matrix systems are not
suitable for very poorly water-soluble compounds, since the concentration gradient
generated is insufficient for providing satisfactory drug release and in vivo exposure (Liu
et al. 2005). Instead, hydrophilic matrices may be designed where polymer erosion is
modulated to further aid release control of poorly soluble drugs (Liu et al. 2005).
Sufficient drug release is attained as long as the drug molecules dissolve before polymers
erode from the dosage form.
The physicochemical properties of the drugs, such as low solubility, might represent a
barrier for absorption. The ongoing trend in drug development towards lower solubility

21
drug candidates, attributed to HTS which was initiated in the late 1980s and the use of
combinatorial chemistry approaches to drug design and discovery of new targets
requiring more lipophilic molecules for target affinity (Lipinski 2000, Alsenz and Kansy
2007), poses challenges to development of controlled release dosage forms. It has been
estimated that over 40 percent of all new chemical entities (NCEs) entering drug
development programs have insufficient aqueous solubility to allow them to be absorbed
adequately from the GI tract in order to ensure therapeutic efficacy (Hauss 2007,
Stegemann et al. 2007). In addition, the previously mentioned first-pass effect can be
significant for some drug substances, leading to low bioavailability of the drug. In this
case, a dosage form redesign cannot improve the situation. Instead, only by changing the
absorption site or the entire administration route can the first-pass effect be avoided. If
one attempts intraoral drug delivery, e.g. with orally fast disintegrating/dissolving tablets
(Chapter 2.3), then the drug can be delivered directly into the systemic circulation, but
this requires that the drug is rapidly released and dissolved in saliva and can be absorbed
through the oral mucosa (Seager 1998, Kellaway et al. 2002, Bredenberg et al 2003). This
can represent an obstacle for lipophilic drugs and thus, facilitation of the solubility and/or
dissolution of poorly soluble compounds is required, and this can be approached by
several physical and chemical techniques, which are discussed in Chapter 2.4. Other
advantages of the intraoral route include fast onset of drug action and overcoming of
swallowing difficulties, which may be a real problem with pediatric and geriatric patients
(Kellaway et al. 2002, Strickley et al. 2008).

2.2

Matrix tablets for oral controlled release

Polymers from natural products, chemically modified natural products and synthetic
products are used in matrix-type dosage forms. Drugs are generally dispersed into
polymers which can be either hydrophobic or hydrophilic.

2.2.1

Hydrophobic matrices

In hydrophobic matrix tablets, the release rate controlling components are water
insoluble materials (Liu et al. 2005) such as waxes, glycerides, fatty acids and polymers

22
such as ethyl cellulose (EC) (Rekhi and Jambhekar 1995), starch acetate (SA) (Korhonen
et al. 2000) or ammonio methacrylate copolymers (Eudragit) (Caraballo et al. 1999).
Due to the insoluble nature of the matrix, the formulation maintains its dimensions during
drug release.
EC is a commercially available, inert polymer widely used for the preparation of matrix
tablets with both water soluble and poorly soluble drugs (Saikh et al. 1987a,b, Rekhi and
Jambhekar 1995). Starch acetates (SA) are prepared from native starch polymers by
esterification (Paronen et al. 1997). SAs with different degrees of substitution (DS) can
be produced by controlling the reaction conditions (Figure 2.1). SAs having the highest
DS values (i.e. 2.1-3) form a strong tablet matrix with sustained drug release properties
and they are suitable for direct compression (Korhonen et al. 2000). The drug release rate
from starch acetate tablets can be controlled by the DS value and the amount of SA in the
tablet.

CH2OR

CH2OR

CH2OR

n = 300 to 1000
R = COCH3

Figure 2.1. Native starch consists mainly of linear amylose, which is shown here, and
branched amylopectin units. Esterification replaces the hydrogen atoms with an acetyl
group producing SAs with DS values up to 3 (modified from Rowe et al. 2006).
In the case of a hydrophobic polymer matrix, such as EC and SA, the drug release
occurs by dissolution and diffusion of the drug through water-filled capillaries within the
matrixs pore network (Crowley et al. 2004, Pohja et al. 2004). According to the
percolation theory, the particle size of the hydrophobic polymer significantly affects the
drug release, since the more polymer particles present (i.e. the smaller the particle size)
the fewer drug clusters can be formed leading to slower drug release (Leuenberger et al.
1987, Holman and Leuenberger 1988, Crowley et al. 2004).

23

2.2.2

Hydrophilic matrices

The primary drug release rate controlling ingredients in a hydrophilic matrix are
polymers that swell on contact with the aqueous medium and form a gel layer on the
surface of the system. Polymers such as cellulose ethers (hydroxypropylmethylcellulose
(HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC)) (Colombo 1993,
Ferrero Rodriquez et al. 2000), xanthan gum (Talukdar et al. 1998), sodium alginate
(Efentakis and Buckton 2002) and poly(ethylene oxide) (Kim 1995b) are commonly used
in the production of compressed hydrophilic matrices. Due to their good compression
characteristics and adequate swelling properties, HPMCs are most widely used in
controlled release tablets (Ferrero Rodriquez et al. 2000). High viscosity grades of HPMC
are suitable for delaying the drug release from the matrix (Rowe et al. 2006). The
formulation variables which have the greatest impact on the release rate are matrix
dimension and shape, amount of polymer and its molecular weight, drug load and drug
solubility (Velasco et al. 1999, Liu et al. 2005). The release of a water soluble compound
from an HPMC matrix involves the successive processes of penetration of a liquid into
the matrix, hydration and swelling of the matrix, dissolution of the drug in the matrix and
diffusion of the drug through the channels in the matrix (Tahara et al. 1995, Colombo
1999).

2.2.3

Matrix tablet preparation

2.2.3.1 Tablet formation

Tablets are produced by applying a force on a powder material in a die, which
transforms the powder into a porous, coherent compact product with a well-defined
shape. The compression process can be considered to occur in four sequential or parallel
stages: particle rearrangement, deformation, fragmentation and bonding (Parrott 1981,
Nystrm and Karehill 1996, Patel et al. 2006). During compression, the particles are first
rearranged, resulting in closer packing. This particle movement is prevented at a certain
load by the packing characteristics of the particles or a high interparticulate friction and

24
thus the further reduction of the compaction volume occurs by elastic (reversible) and
plastic (irreversible) deformation of the particles. Subsequently, the particles are
fragmented into smaller parts which fill in the empty positions, decreasing further the
compact volume. Thus, the compaction process results in increased contact area and
interparticulate attraction or bonding occurs. The dominating bonding mechanisms in the
case of dry powders are: attraction between solid particles (molecular (van der Waals,
hydrogen bonding) and electrostatic forces), mechanical interlocking between irregularly
shaped particles and the formation of solid bridges (due to e.g. melting) (Nystrm and
Karehill 1996, Patel et al. 2006).
The properties of the produced tablets are strongly dependent on the mechanical
characteristics of the powder constituents and the particle-particle interactions (Patel et al.
2006). In addition, geometric factors such as surface rugosity, shape and size distribution
of the materials all contribute to tablet properties. These factors interact with the process
parameters applied during manufacturing, such as the compaction force, to govern the
tablet structure and strength (Sinka et al. 2009).

2.2.3.2 Tablet structure and strength

A tablet can be described as an aggregate of smaller particles which are strongly
adhered to each other. The gas phase in the compact (air) can be described as a three
dimensional network of connected pores. With normal compaction pressures (i.e. smaller
than 300-500 MPa), the porosity of the final compact is from 5% to 25%, depending on
the powder compressibility (Alderborn 1996). The strength of a tablet is dependent on
both the characteristics of the interparticulate pore system (e.g. porosity, pore size
distribution and pore surface area), the properties of the particles forming the compact
(e.g. surface area and morphology, particle size distribution and the packing
characteristics or relative positions of the particles) in conjunction with the interactions
between the particles (Alderborn 1996, Juppo 1996, Mattsson 2001, Wu et al. 2001, van
Veen et al. 2002).
In a tablet consisting of a mixture of two different materials, three different types of
interparticle bonding exist: cohesive forces between the particles of the same component

25
and adhesive forces between the particles of the two different components (Fell 1996).
When the ratio of the two components in a formulation is changed, also the
interparticulate bonding and the structure of the tablet will be altered (Fell 1996, van
Veen 2002). The structure of tablets consisting of a binary mixture can be described by
the percolation theory (Leuenberger et al. 1987, Holman 1991, Bonny and Leuenberger
1993, Fernndez-Hervs et al. 1996) according to which the particles either form a
continuous matrix or exist in separate clusters. At a certain component concentration in
the tablet (i.e. the percolation threshold), a continuous matrix is formed, instead of
clusters, leading to changes in tablet properties (e.g. strength) (Bonny and Leuenberger
1993, Amin and Fell 2004).
The strength of a tablet is also related to the particle size of the materials used and the
way they pack together under compaction (Alderborn 1996, Gane et al. 2006). Particle
dimensions affect both the degree of fragmentation and the degree of deformation during
compression and thus the number and strength of the interparticulate bonds (Alderborn
1996). In general, a decreased original powder particle size leads to increased tablet
strength (McKenna and McCafferty 1982). In contrast, the effect of particle shape is
relevant only when the material fragments to a limited degree during compression, and
then the more irregular shape of the particles will increase the strength of the tablets
(Alderborn 1996).
The dominant process parameter that determines tablet strength is the compression
pressure. As the compression pressure is increased, the tensile strength of a material
increases for most pharmaceutical materials due to the increased degree of fragmentation
and the number of interparticulate bonds or due to the increased degree of particle
deformation and the bonding force. This continues until a certain force threshold is
passed, after which cracking and lamination might occur (Alderborn 1996, Sinka et al.
2009).

2.2.3.3 Effect of solid state properties of the materials on tablet properties

In the solid state, a drug can exist in different physical forms. Two forms with the
same molecular structure but different crystal packing are called polymorphs.

26
Pseudopolymorphs (i.e. hydrates and solvates) differ from each other in terms of the
amount of solvent of crystallization (i.e. water in the case of a hydrate) incorporated into
the crystal lattice (Florence and Attwood 1998, Byrn et al. 1999a). Instead, amorphous
forms lack the long-range molecular order, but may possess some short-range order e.g.
due to hydrogen bonds (Byrn et al. 1999b). Amorphous forms are thermodynamically
unstable and they will eventually transform into the crystalline form by nucleation and
growth of crystals.
The different solid state properties of the physical forms of a drug or excipients can
have a significant effect on tableting and tablet properties, such as flow, densification or
binding properties (Fachaux et al. 1995, Bolhuis and Chowhan 1996, Sun and Grant
2001, Joiris et al. 2008, Sinka et al. 2009). In addition, metastable forms in
pharmaceutical products might crystallize, convert to another crystal form or change
between an unsolvated and a solvated form during processing or storage (Craig et al.
1999, Kaushal et al. 2004, Zhang et al. 2004, Tantry et al. 2007, Feng et al. 2008).
Furthermore, processes involving mechanical stress (i.e. grinding, milling, wet
granulation, drying and compression) can, intentionally or unintentionally, convert a
crystalline material into either fully or partially amorphous form (mechanical activation)
(Ketolainen et al. 1995, Guinot and Leveiller 1999, Yonemochi et al. 1999a, Morris et al.
2001, Mura et al. 2002), leading to development problems and altered product
performance (Httenrauch et al. 1985, Bhugra et al. 2008, Feng et al. 2008). Furthermore,
metastable forms of the drug might have considerably different dissolution rates from the
tablets than the stable form of a drug (Phadnis and Suryanarayanan 1997), and a rapid
phase transition during dissolution (e.g. from anhydrate to monohydrate) can negate the
potential dissolution advantage of the metastable forms (Debnath and Suryanarayanan
2004, Li et al. 2007).

2.2.3.4 Importance of powder mixing on tableting and tablet properties

Mixing of powders is an important operation in the production of tablets in order to
obtain a homogenous mixture of a drug and excipient(s). Powder mixing has been
described by several theories. In the random mixing theory, the mixing process is treated

27
as a statistical process where the bed of particles is repeatedly split and combined until a
binomial distribution is reached (Lacey 1954). This approach requires that all particles
are equal in every physical respect (except colour) and that all particles are noninteracting, i.e. particles in a random mix are mainly influenced by gravity. However, it is
well known that the materials involved in a mixing process interact with each other
through capillary, electrostatic and van der Waals forces (Zeng et al. 2000b) and may
produce ordered mixtures, where fine particles adhere or cohere to form ordered units
(Hersey 1974). In an ordered mix, it is the ordered units that are influenced by gravity.
Within the unit, the fine particles are bound to the coarse ones by interparticulate forces
which result from surface electrical attractions (Staniforth 1981). The force of gravity and
surface electrical forces vary with the particle size distribution of the materials; the
smaller the particles, the greater will be the influence of the surface electrical forces
(Staniforth 1981, Venables and Wells 2001).
The forces arising from the particle surfaces, along with gravity, define the organization
of a blend, not the bulk properties of the materials (i.e. parameters related to molecules)
(Barra et al. 1998). It has been observed that the adhesion force between two particles of
different materials will be maximum if they have same polarity and very different particle
sizes (Staniforth 1981, Barra et al. 1998). This causes adhesion of the small particles on
the surfaces of the larger particles. However in practice, rugosity of the particle surfaces
also affects adhesion (de Boer et al. 2005, Dickhoff et al. 2005). For example, if one of
the materials is porous, its surface will contain a large number of active adhesion sites
able to entrap smaller particles of the other material (Staniforth 1981, Barra et al. 1998).
Furthermore, the surface of contact available between the particles also depends on their
shapes (Venables and Wells 2001).
During mixing, powder particles come into contact with each other and with solid
surfaces (e.g. particle and a container wall) which leads to contact electrification of the
surface of the materials. The term triboelectrification is used when charges are transferred
between the contacting surfaces and the contact involves frictional effects e.g. due to
sliding and rolling (Staniforth 1981, Bailey 1993, Rowley 2001). The increasing number
of contacts and collisions between surfaces leads to accumulation of electrostatic charge
which in the case of a particle is positive or negative depending on the separation

28
energies, or work functions, of the outer electrons in the atoms of the powder particles
relative to those of the container wall (Staniforth and Rees 1981, Kulvanich and Stewart
1987). The particle size, shape, surface nature, purity and roughness, the electrical and
mechanical properties of the powder and the contact surface in addition to the
atmospheric conditions, e.g. relative humidity (RH), all affect the extent of
triboelectrification (Carter et al. 1992, Bennett et al. 1999, Rowley 2001, Murtomaa et al.
2004). Charging of powders, leading to agglomeration during processing is often
undesirable, but it can be also utilized e.g. in stabilizing ordered mixtures (Staniforth
1981, Staniforth and Rees 1981, Venables and Wells 2001). The increased electrostatic
attraction between oppositely charged drug and excipient particles brings two particles
into a close surface contact which might permanently increase van der Waals adhesion
forces compared to the situation with uncharged particles (Staniforth 1981).
Different organizations of the powder mixtures have been found to influence powder
compactibility and the tensile strength of the compacts. In the case of interacting
materials, the adhering material (i.e. the material with the lowest particle size) forms a
percolating network, and the mixture has the compactibility and the tensile strength of the
adhering material (Barra et al. 1999). This observation can be put into use in
pharmaceutical preparations by artificially increasing the compactibility of a mixture
without changing its composition. Furthermore, drug-excipient interactions can affect the
drug dissolution rate, i.e. it has been observed that inclusion of the drug in the excipient
agglomerates and adhesion of small-sized magnesium stearate on the surface of the drug
particles and agglomerates resulted in hydrophobic coating and reduced water
penetration, hindering the drug dissolution from the filled capsules (Chowhan and Chi
1986). In addition, by using ordered mixtures of fine drug particles attached to coarser
excipient carrier particles, optimal drug exposure and thus potentially immediate drug
dissolution can be achieved e.g. in the design of rapidly disintegrating tablets
(Bredenberg et al. 2003). Thus, the use of ordered mixtures might also provide a potential
way of controlling drug release rate from monolithic matrix formulations (Barra et al.
2000).

29
2.2.4

Drug release mechanisms

Factors affecting the drug release may vary depending on the drug release mechanism
of the delivery system. Thus knowledge of the mechanism of the delivery system is an
essential part of drug development process. The most important drug release controlling
mechanisms are diffusion, swelling and erosion which involve drug diffusion through
tortuous channels or a viscous gel layer, or drug dissolution due to system erosion.

2.2.4.1 Diffusion
Drug release from a porous monolithic matrix where the drug is dispersed in a
hydrophobic polymer, such as EC and SA, involves the simultaneous processes of
penetration of the surrounding liquid, dissolution of the drug and diffusion of the drug
through channels or pores of the matrix (Qiu and Zhang 2000, Crowley et al. 2004, Pohja
et al. 2004). The Higuchi model (Higuchi 1961) is the most frequently used model to
describe the drug release from such systems (Eq. 1):

Q = C s ( 2C C s ) Dt

(1)

where Q is the amount of drug released in time t, C s is the drug solubility in the matrix, C
is the initial concentration of the drug and D is the diffusion constant of the drug
molecules in the medium. Since the volume and length of the pores in the matrix must be
taken into account, Eq. 1 is further modified as:

Q = C s ( 2C C s )

Dt

(2)

where and are the porosity and the tortuosity of the matrix, respectively (Higuchi
1963). The assumptions when this equation is valid are that perfect sink conditions
prevail and swelling of the matrix is negligible, i.e. the matrix retains its dimensions.
Thus, according to Eq. 2, square-root of time kinetics is expected for drug release, since
there will be an increasing diffusion path length as drug release proceeds.

30
The Higuchi equation was originally developed for planar diffusion. Later, a simple
exponential equation was introduced by Korsmeyer and Peppas (Korsmeyer and Peppas
1983) for describing the general release behavior from hydrophobic matrices with other
geometries, such as slabs, spheres and cylinders (Eq. 3):

Q=

Mt
= kt n
M

(3)

where Q (Mt/M) is the fractional release, k is a constant and n is the diffusional

exponent. The n value can be used for characterization of different release mechanisms
(Costa and Sousa Lobo 2001). In the case of a cylinder, the exponent n has values of 0.45
for Fickian diffusion (leading to square root of time release kinetics), from 0.45 to 0.89
for non-Fickian anomalous transport (leading to first-order release kinetics) and 0.89 for
non-Fickian Case-II transport (leading to zero-order kinetics).

2.2.4.2 Swelling
Drug release controlled by swelling is a complex process due to diverse
macromolecular changes occurring in the polymer during release. Swelling controlled
systems consist of water soluble drugs dispersed in a glassy polymer matrix, such as
HPMC (Colombo 1993, Narasimhan 2000). Once it makes contact with water, the
polymer swells and transforms from a glassy to a rubbery state, forming a gel layer in
which the dissolved drug can be transported due to increased mobility of the polymeric
chains. The gel layer prevents matrix disintegration and controls additional water
penetration. Thus, water penetration, swelling, drug dissolution and diffusion, and matrix
erosion are the factors controlling formation of the gel layer and, consequently, drug
dissolution (Colombo et al. 1996, 2000). The drug release kinetics can be modified by the
gel layer thickness and the rate at which it is formed (Kanjickal and Lopina 2004). As the
proportion of the polymer in the tablet increases, the gel formed reduces diffusion of the
drug and delays the erosion of the matrix (Ford et al. 1985a).

31
2.2.4.3 Erosion
Also in erosion-controlled systems, the drug is dispersed uniformly throughout the
hydrophilic polymer matrix. Once in contact with water, these systems swell and this is
followed by polymer and drug dissolution. However, the diffusion of the drug in the gel
layer formed is slower than the polymer dissolution rate or erosion of the gel (Lee 1985,
Ford et al. 1987). In the erodible hydrophilic matrix, the drug release can be controlled
either by erosion in the case of poorly soluble drugs or by diffusion of the drug through
the gel layer and erosion of the gel in the case of highly water soluble drugs (Ford et al.
1985a, 1985b, 1987, Lee 1985). In addition, the strength of the gel layer influences drug
release: using polymers of low viscosity grades leads to erosion-controlled release and
zero-order kinetics (Zuleger and Lippold 2001). Instead, if one uses polymers of high
viscosity or high amounts of a polymer in the tablet then a stable matrix is created where
polymer dissolution is negligible, in which case the drug is released primarily by Fickian
diffusion following square-root of time kinetics (Pham and Lee 1994, Katzhendler et al.
1997, Zuleger and Lippold 2001). Often both diffusion and erosion contribute to the drug
release leading to anomalous transport, i.e. kinetics between zero-order and square-root
of time (Zuleger and Lippold 2001).
Two types of matrix erosion behavior, surface erosion and bulk erosion, can be
identified (Kanjickal and Lopina 2004). Polymers with highly reactive functional groups
(e.g. polyanhydrides) undergo faster degradation than the diffusion of water into the
matrix, leading to surface erosion. In contrast, in a bulk eroding system, degradation of a
polymer with less reactive groups (e.g. PLGA (copoly lactic acid/ glycolic acid)) is much
slower than the diffusion of water. Thus, water is present throughout the system and the
polymer erodes in a homogenous manner.

2.3
2.3.1

Intraoral drug formulations

Intraoral drug delivery

The per oral route has some considerable disadvantages in terms of effective drug
delivery. After absorption from the GI tract, the drug is subjected to first-pass
metabolism. For some drugs, the extent of first pass metabolism might be so considerable

32
as to substantially reduce the drugs bioavailability. Thus, there is a growing interest in
exploiting the oral cavity as a site for delivering drugs subject to extensive first-pass
metabolism since this is a way of gaining direct access to the systemic circulation (Sastry
et al. 2000, Kellaway et al. 2002). However, the differences in relative thickness of the
tissues as well as degree of keratinization of sublingual, gingival and buccal membranes
result in different permeability characteristics (Kellaway et al. 2002). It has been reported
that the sublinqual route is more permeable than the buccal or gingival routes (Harris and
Robinson 1992). In addition, even though oral administration of tablets is considered as a
convenient way of drug delivery, it has also been increasingly recognized that
compliance issues with solid oral dosage forms can be significant for those individuals
who have difficulty in swallowing conventional tablets or capsules (dysphagia).
Dysphagia is common among all age groups, but especially in elderly people and children
(Sastry et al. 2000, Kearney 2002, Strickley et al. 2008). The disorder can be associated
with many medical conditions, such as stroke, Parkinsons disease or radiation therapy to
the neck and head area (Sastry et al. 2000). It has been estimated that as much as 35% of
general population suffer from dysphagia (Sastry et al. 2000, Kearney 2002). In addition,
the inconvenience associated with administering conventional oral dosage forms
concerns people not having access to potable water. In this respect, modified-release
technology, viz. orally fast disintegrating tablets (FDTs), offers possibilities for avoiding
the abovementioned problems.
According to the European Pharmacopoeia (2007), FDTs should disintegrate or
dissolve in the oral cavity into the saliva in less than three minutes without chewing or
need of excess water. However, in many studies the limit for tablet disintegration in the
oral cavity has been considered as less than one minute (Habib et al. 2000, Fu et al. 2004)
or even less than 30 s (Shimizu et al. 2003). In addition to improving patient compliance,
FDTs produce rapidly concentrated saliva drug solutions, able to coat the oral mucosa
easily, and thus, to be absorbed directly into the systemic circulation avoiding the firstpass metabolism (Kellaway et al. 2002). Therefore, an added advantage of these
formulations is their rapid onset of action. However, unless the drug does not have an
undesirable taste, the use of taste-masking techniques becomes critical to patiet
acceptance. Taste-masking is accomplished simply by use of flavoring agents and

33
sweeteners or by microencapsulation, i.e. covering the drug particles by polymers
through spray-drying or coacervation (Habib et al. 2000, Sastry et al. 2000, Pather et al.
2002, Bora et al. 2008).

2.3.2

Orally fast disintegrating tablets

There are several formulation types of FDTs, e.g. fast melting, fast dispersing, rapid
dissolve and rapid melt. The fast disintegration is generally achieved either by choosing
fast dissolving tablet excipients, inclusion of effervescents in order to produce rapid
disintegration in contact with saliva or by using a freeze-drying process in order to
produce a highly porous tablet structure (Sastry et al. 2000, Dobetti 2001, Fu et al. 2004).
There are several technologies available for producing FDTs, however, not all of them
have succeeded in being applied in commercially marketed products. These technologies
utilize either freeze-drying, molding or compression as a production method, from which
compression supplemented with modifications is the most widely used (Dobetti 2001, Fu
et al. 2004). One common characteristic of all these methods is that selection of the
materials used is based on their rapid dissolution or ability to disintegrate in water, sweet
taste, low viscosity in order to provide a smooth texture in the mouth as well as
compressibility (Kearney 2002, Pather et al. 2002, Di Martino et al. 2005). This has led to
wide use of saccharides in FDTs. However, in order to attain fast disintegration, the
dosage forms need to be very porous and/or compressed at very low compression forces.
Thus, they are soft, friable and often require special packaging (Sugimoto et al. 2006). In
general, FDTs with tensile strength higher than 1 MPa (Takeuchi et al. 2005, Sugimoto et
al. 2006) are considered strong enough to be handled and packed normally.

2.3.2.1 Preparation by freeze-drying

In preparing FDTs by freeze-drying (i.e. lyophilization), the solvent is removed by
sublimation from a frozen drug solution or a suspension containing structure-forming
excipients (Dobetti 2001, Fu et al. 2004). The advantage of this technology is that the
tablets produced have a highly porous structure leading to extremely fast (< 5s)
dissolution/disintegration and release of the drug when the tablet is placed on the tongue

34
(Dobetti 2001). The process may also lead to formation of a glassy or rubbery amorphous
structure of excipients and the drug, further enhancing the dissolution rate. In addition,
tablet production is conducted at low temperatures, which may prevent stability problems
during processing. During the shelf life of the product, stability problems are avoided by
storing the tablets in a dry environment. The disadvantages of the method include the
poor stability of the formulation in elevated temperature and humidity, physical weakness
of the tablets (requiring special packaging) and high cost of the manufacturing process
(Dobetti 2001, Fu et al. 2004).
The Zydis technology is a pioneering technique and the most well known example of
the freeze-drying method (Habib et al. 2000, Kearney 2002). There are several
commercialized products based on this technology, such as Claritin RediTabs (an
antihistamine (loratadine) preparation from Schering Corporation), Maxalt-MLT (an
antimigraine (rizatriptan benzoate) preparation from Merck) and Zyprexa Zydis (an
antipsychotic (olanzapine) preparation from Eli Lilly).
In the Zydis process, the active incredient is dissolved or suspended in an aqueous
solution of water-soluble structure formers (typically gelatin and mannitol). The mixture
is poured into preformed blister pockets and freeze-dried. The Zydis process is most
suitable for low-solubility drugs in doses up to 400 mg. The suitable dose for a soluble
drug depends on the intrinsic properties of the drug and is usually less than 60 mg.
Generally the drug particle size should be limited to 50 m. Absorption from the oral
cavity can be achieved, if the characteristics of the drug are optimal (Kearney 2002,
Dobetti 2001).
Other techniques based on freeze-drying include Quicksolv, Lyoc and
NanoCrystal. Quicksolv, for example, is obtained by freezing an aqueous dispersion
or solution of the active-containing matrix and subsequently drying it by solvent
extraction (Dobetti 2001, Fu et al. 2004). The method produces a very rapidly
disintegrating tablet with uniform porosity and adequate strength for handling (Fu et al.
2004). A commercial product of a peristaltic stimulant cisapride monohydrate
(PropulsidQuicksolv from Janssen Pharma) is available based on this technology.

35
2.3.2.2 Preparation by compression
Conventional tablet processing methods and equipment can also be used in the
preparation of FDTs. However, achieving high porosity and adequate tablet strength
requires some modifications compared to the preparation of conventional tablets. Wet
granulation, dry granulation, spray drying and flash heating in addition to various aftertreatments, such as humidity treatment or sublimation, have been used in the preparation
of FDTs (Fu et al. 2004, Mizumoto et al. 2005). However, direct compression is still the
preferable technique due to its simplicity and cost efficiency and thus it is discussed here
in more detail.
Direct compression requires the incorporation of one or more superdisintegrants into
the formulation or the use of highly water-soluble excipients to achieve adequate tablet
disintegration (Dobetti 2001, Rawas-Qalaji et al. 2006). Saccharides are widely used as
excipients due to their solubility, sweetness and a pleasant oral texture (Fu et al. 2004).
The disintegration times achieved with this method are not as fast as can be obtained with
e.g. lyophilized tablets, and the disintegration and dissolution process is extremely
dependent on the tablet size, porosity and hardness, and the type(s) and amount(s) of the
disintegrants used (Dobetti 2001, Sunada and Bi 2002, DiMartino et al. 2005, RawasQalaji et al. 2006). In direct compression method the use of water or heat is not required
and therefore it is suitable for moisture and heat sensitive materials.
For example, OraSolv and DuraSolv technologies are based on direct compression
(Habib et al. 2000). In OraSolv technology, a pair of effervescent materials (i.e. an acid
source and a carbonate source) acts as a disintegrating agent, as well as assisting with
taste-masking and providing a pleasant fizzing sensation in the mouth (Pather et al.
2002, Fu et al. 2004). The fast disintegration (in 6 to 40 s) is achieved by compressing
water soluble excipients at lower compression forces than those used with conventional
tablets. Instead, in DuraSolv, it is the large amounts of fast-dissolving excipients (e.g.
dextrose, mannitol, sorbitol, lactose or sucrose) in fine particle form that are responsible
for the fast dissolution of the tablet (Pather et al. 2002, Fu et al. 2004). DuraSolv tablets
are harder and less friable than OraSolv tablets, thus they can be packed into bottles or
blisters (Habib et al. 2000). For example, Remeron SolTab, a product with the
antidepressant mirtazapine from Organon, is based on these technologies.

36

2.3.2.3 Other preparation techniques

In compression molding, the powder mixture of the drug and water-soluble excipients
is moistened with a solvent (ethanol or water) and then molded into tablets at low
compression forces (Bi et al. 1999, Fu et al. 2004). Instead, in heat molding, the drug is
dissolved or dispersed in a molten matrix or in no-vacuum lyophilization, the solvent
from a drug solution or suspension is evaporated at ambient pressure (Dobetti 2001, Fu et
al. 2004). In these cases, the drug remains dispersed as discrete particles or microparticles
in the matrix. These techniques produce relatively fast disintegrating (5-15 s), but weak
tablets. The manufacturing costs are high and the formulation may suffer from stability
problems (Dobetti 2001). In Flashdose technology, an amorphous candyfloss or
shearform matrix, formed from saccharides or polysaccharides by simultaneous flash
melting and centrifugal force, is partially recrystallized in order to provide a compound
with good flowability and compressibility suitable for tableting (Habib et al. 2000,
Dobetti et al. 2001, Fu et al. 2004). The floss fibers are blended with the drug and
conventional excipients and compressed into tablets. The drug can be added to the floss
also before the flash heat process (Sastry et al. 2000).

2.3.2.4 Pharmacokinetic advantages of fast disintegrating tablets

The drugs typically formulated as FDTs are often intended for treating of allergy, pain
or mental disorders (Sastry et al. 2000, Fu et al. 2004), where a rapid onset of action
and/or ease of administration due to the patients age (pediatrics or geriatrics) and/or
physical condition are crucial. Immediate absorption of the drug from FDTs through oral
mucosa into the systemic circulation also produces high bioavailability for the kinds of
drugs that are subjected to extensive first pass metabolism. Increased bioavailability has
been observed with FDTs (Fu et al. 2004). For example, the bioavailability of selegiline
has been improved when it is administered in a Zydis formulation due to the avoidance
of first-pass metabolism as a result of drug absorption in the pregastric region (Kearney
2002). Extremely fast tablet disintegration is required for rapid absorption of the drug
through the buccal or sublingual mucosa, but in addition to the formulation requirements,

37
the properties of the drug itself have to be appropriate. The drug has to be soluble, fast
dissolving and stable, but also small and lipophilic in order to pass through the oral
membranes (Bredenberg et al. 2003). Furthermore, due to the small volume of saliva in
the oral cavity, the therapeutic dose of an intraoral drug must be relatively small and in
most cases, dissolution enhancers must be applied (Jain et al. 2002). Thus, the difficulty
lies in resolving the problem of somehow dissolving a lipophilic drug rapidly in a small
volume of saliva. There are several approaches which can be utilized to overcome drug
solubility problems; these are discussed in the following sections.

2.4
2.4.1

Improvement of the dissolution rate of poorly soluble drugs

Solubility and dissolution rate

Solubility may be defined as the amount of a substance that dissolves in a given volume
of solvent at a specified temperature. Compound solubility can be defined as unbuffered
(i.e. in water), buffered (i.e. at a given pH) and intrinsic (i.e. solubility of the neutral form
of an ionizable compound) solubility (Alsenz and Kansy 2007). Dissolution is the process
by which the drug dissolves in a liquid and the rate at which this process takes place is
the dissolution rate. However, the difference between solubility and dissolution should be
noted: solubility implies that the dissolution process is completed and the solution is
saturated.
The relationship between the dissolution rate (dm/dt) and solubility (C s) can be
expressed by the Noyes-Whitney equation (Eq. 4):
dm
D
= A (Cs C )
dt
h

(4)

where m is the mass, t time, A the surface area of the dissolving solid, D the diffusion
coefficient, h the thickness of the diffusion layer and C the concentration in the
dissolution medium (Noyes and Whitney 1897). From Eq. 4, it can be seen that
parameters affecting the dissolution rate are the drug solubility, particle size of the drug
(since it affects the surface area of the drug solid) and the thickness of the diffusion layer.

38
Thus, increasing the dissolution rate of a drug can be achieved by increasing the
solubility of the drug or the surface area available for dissolution (i.e. decreasing the
particle size). Solubility is an intrinsic material property and it can only be influenced by
chemical modification of the molecule, i.e. by making salt form (Bogardus and
Blackwood 1979, Huang and Tong 2004, Serajuddin 2007) or prodrug formation (Stella
and Nti-Addae 2007). In contrast, dissolution which is an extrinsic material property, can
be affected by various chemical, physical or crystallographic techniques, such as
complexation, modification of particle size, surface properties or solid state, or
solubilization enhancing formulation strategies (Table 2.1). With respect to approaches
used in dissolution enhancement of poorly soluble drugs, the focus in this thesis will be
on amorphous forms, particularly amorphous solid dispersions.

Huang and Tong 2004, Kobayashi et

al. 2000, Murphy et al. 2002, Singhal
and Curatolo 2004, Zhang et al. 2004

Hancock and Parks 2000, Huang and

Tong 2004, Mosharraf et al. 1999,
Savolainen et al. 2009
Leuner and Dressman 2000,
Serajuddin 1999, Sethia and
Squillante 2003
Barich et al. 2005, Bogardus and
Blackwood 1979, Charman and
Charman 2002, Karavas et al. 2006,
Serajuddin 2007

Relatively small solubility benefit (less than 10-fold)

and the possible conversion to more stable and less
soluble forms during processing, storage or when in
contact with GI liquids limit the exploitability.
Toxicity issues with solvates.
Problems associated with physical and chemical
stability during storage. Dissolution rate advantage of
the amorphous drug form might be lost due to
solvent-mediated crystallization upon dissolution.
Scale up and stability issues (solvent-mediated
devitrification, crystallization upon processing and
storage).
Suitable only for weakly acidic/basic drugs. Common
ion effect may lower solubility/dissolution rate of
HCl salts. In vivo conversion of salt into acidic/basic
forms may inhibit the improvement of bioavailability.
A salt form repreresents a NCE, thus clinical trials
have to be performed.

Dissolution advantage due to different

lattice energies of drug physical forms.

Advantage up to several hundred times

in dissolution between amorphous and
corresponding crystalline form.

One of the most widely used and

successful strategies to improve the
dissolution of poorly soluble drugs.

Drugs with ionizable groups, such as

carboxylic acids or amines, form salts
with appropriate counterions. These
salts have higher solubilities than their
corresponding acid or basic forms.

Use of a polar promoiety may be useful

when usual approaches fail.

Modification of the
solid state
(polymorphs,
pseudopolymorphs)

Modification of the
solid state
(amorphous forms)

Drug dispersion in
carriers (solid
dispersions (SDs))

Formation of salts

Prodrugs

Stella and Nti-Addae 2007

Brewster et al. 2007, Brewster and

Loftsson 2007, Irie and Uekama
1997, Rajewski and Stella 1996

CDs increase the formulation bulk mass. The rate at

which the drug is released from CD might restrict
drug absorption.

Complexation
with
native
or
chemically modified CDs increases the
apparent solubility of drugs.

Complexation (e.g.
by cyclodextrins
(CDs))

A prodrug represents a NCE (clinical trials).

References
Farinha et al. 2000, Karavas et al.
2006, Kesisoglou 2007, Mller and
Peters 1998, Patravale et al. 2004

Limitations
Poor flow properties, generation of static charges and
particle adhesion. Micronization limit of 2-5 m
which is often not enough to to improve the drug
dissolution and bioavailability. Problems producing
particles smaller than 100 nm (nanosizing).

Advantages
Nanosizing (e.g. by high pressure
homogenization) might also increase
the saturation solubility of a drug,
further enhancing the dissolution rate.

Method
Reduction of
particle size
(micronization,
nanosizing).

Table 2.1. Approaches for improving solubility and/or dissolution and bioavailability of poorly soluble drugs.

39

40

2.4.2

Enhancement of the dissolution by using amorphous forms

2.4.2.1 Formation and properties of the amorphous state

There are two ways how a material may behave when a melt is cooled, which can be
seen from the enthalpy (H) (or specific volume (V)) temperature diagram (Figure 2.2).
At Tm, the liquid state usually crystallizes, which leads to a contraction of the system due
to decrease in V and H. Alternatively, if the cooling rate is too fast to permit
crystallization, H and V may follow the equilibrium line of the liquid beyond the T m into
the supercooled liquid region without showing any discontinuity in H and V. The
supercooled liquid is a nonequilibrium state relative to the crystalline state, but it is an
equilibrium state with respect to structural changes with temperature (Kawakami and
Pikal 2005). Thus, cooling causes direct corresponding changes in structure and
thermodynamic properties. As the viscosity of the material increases there is a reduction
in the molecular motions until the molecules move so slowly that they have no time to
rearrange themselves before the temperature is lowered further. Thus, a change in slope
(Figure 2.2) can be seen at the glass transition temperature (Tg), when the material enters
a glassy state where the disorder of the molecules is reduced (Hancock and Zografi 1997,
Craig et al. 1999, Kaushal et al. 2004). The real glass approaches the equilibrium glassy
state by spontaneous relaxation which decreases the energy (arrow a in Figure 2.2). When
the sample is heated near Tg (arrow b in Figure 2.2), the molecular mobility increases and
H recovers to the supercooled liquid state as shown by arrow c in Figure 2.2 (Kawakami
and Pikal 2005).
The amorphous state is characterized by the absence of the long-range three
dimensional molecular order. However, an amorphous solid may have a short-range
molecular order, i.e. a relationship between neighboring molecules (Hancock and Zografi
1997, Yu 2001). As a result of the higher internal energy, the amorphous state generally
has greater molecular motion and enhanced thermodynamic properties compared to the
crystalline state (e.g. solubility which can lead to enhanced dissolution and
bioavailability) (Hancock and Zografi 1997, Hancock and Parks 2000, Kaushal et al.
2004). The high internal energy and specific volume of the amorphous state are also
responsible for greater chemical reactivity and the tendency to crystallize (i.e. entry to a

41
lower energy state), possibly at different rates below and above T g (Hancock and Zografi
1997, Yu 2001).
Liquid

Enthalpy/volume

Supercooled
liquid
Real glass

a
b
Equilibrium glass
Crystal

TK

Tg Tm

Temperature
Figure 2.2. Schematic representation of enthalpy (or volume) versus temperature for a
liquid capable of crystallizing and glass formation, where T K is the Kauzmann
temperature (or temperature of zero mobility), Tg is the glass transition temperature and
Tm the fusion temperature (Modified from Kawakami and Pikal 2005). Arrows a, b and c
indicate the real glass approaching the equilibrium glassy state by spontaneous relaxation,
heating the sample near to Tg and subsequent enthalpy recovery to the supercooled liquid
state, respectively.
Amorphous drugs can be prepared by a variety of technologies (Table 2.2) such as
rapid cooling from the melt, rapid precipitation from solution and mechanical activation
of the crystalline material (Hancock and Zografi 1997, Craig et al. 1999, Yu 2001,
Kaushal et al. 2004). Rapid precipitation from solution can be made by freeze-drying
(Guo et al. 2000, Surana et al. 2004, Abdul-Fattah et al. 2007) or spray drying
(Yonemochi et al. 1999a, Surana et al. 2004, Ohta and Buckton 2005, Vogt et al. 2008),
where process conditions can strongly influence the amount of amorphous material in the
end product and the physical properties of the final product (Corrigan et al. 2003, Ohta
and Buckton 2005, Moran and Buckton 2007).

Amorphization mechanism

Crystallization is avoided since the cooling rate is too

fast or the crystallization itself is not favored because
of molecular shape, size or orientation (e.g. with
proteins).

Extremely low temperatures limit the molecular

mobility and prevent nucleation of the material.

Fast removal of solvent from droplets by hot air leads

to formation of amorphous material or rapid
crystallization of a metastable phase.

Mechanical stress induces defects in the crystal lattice.

Method

Cooling from the

melt

Freeze-drying

Spray drying

Grinding/milling

Descamps et al. 2007,

Httenrauch et al. 1985,
Mura et al. 2002,
Patterson et al. 2005,
Yonemochi et al. 1999a,
b

Moran and Buckton

2007, Ohta and Buckton
2005, Zeng et al. 2000a

Variations in process conditions, such as feed

solution concentration or inlet-air temperature, might
affect the particle size or surface properties and thus
physical stability of amorphous end products.
The effectiveness of ball milling is dependent on the
unit cell structure of the compound as shown with
carbamazepine. Milling performed far below T g (at
high enough intensity) has been observed to result in
amorphization while milling performed above Tg may
result in polymorphic transformations. In the T g
range, both types of transformations can occur
depending on the milling intensity.

Abdul-Fattah et al. 2007,

Morris et al. 2001, Zhang
et al. 2004

Amorphous celecoxib prepared in situ in DSC was

resistant to crystallization under the influence of
temperature and/or pressure, due to its protection
from the external environment during preparation.
Potential for chemical degradation of the drug is a
drawback.
Process conditions, such as annealing time and
temperature, might affect e.g. stability of the end
product.

References
Hancock and Zografi
1997, Gupta and Bansal
2005, Patterson et al.
2005

Specific information

Table 2.2. Methods for preparation of amorphous forms. The amorphization mechanisms and some details of the methods are
presented.

42

43

2.4.2.2

Characterization of the amorphous state

A wide selection of techniques is available for the physical characterization of

amorphous solids, though they do not all provide the same information (Table 2.3). Basic
characterization can be conducted by X-ray diffractometry (XRD) techniques and
differential scanning calorimetry (DSC). The specificity and accurate quantitative nature
of XRD in detecting long-range molecular order has made it a standard method for
studying amorphous/crystalline systems. Temperature and environmental control makes
it possible to follow the kinetics of phase transformations (e.g. crystallization) (Byrn et al.
1999d). DSC is widely used for studying fundamental thermodynamic properties, such as
glass transitions, heat capacities and enthalpy changes of the amorphous state. However,
the influences of several experimental variables (e.g. sample size, heating and cooling
rate) can effect the type and quality of the data obtained (Bhugra et al. 2006, Vyazovkin
and Dranca 2006, Bhugra et al. 2008).
If one wishes to study pharmaceutical systems containing a few weight percent of
amorphous material, then isothermal microcalorimetry (IMC), solution calorimetry and
water vapour sorption techniques are the preferred means (Saleki-Gerhardt 1994, Mackin
et al. 2002, Ramos et al. 2005). If one wishes to quantify of the degree of crystallinity,
also solid state nuclear magnetic resonance spectroscopy (ssNMR) can be used. Instead
of recognizing long-range molecular order (like XRD), ssNMR is more sensitive to local
or short-range order, thus differences between the results obtained with XRD and
ssNMR are to be expected (Stephenson et al. 2001). In addition to quantifying the degree
of

crystallinity,

Fourier-transform

infrared

spectroscopy

(FTIR),

near-infrared

spectroscopy (NIR) and Raman spectroscopy have been used for determining the glass
transition temperature and mean molecular relaxation times () as a function of
temperature (Oksanen and Zografi 1993, Taylor and Zografi 1998, Stephenson et al.
2001, Lubach et al. 2007, Imamura et al. 2008). Due to enhanced sensitivity of FTRaman spectroscopy and its advantages, such as minimum sample preparation and
greater specificity relative to NIR, its application in quantitative analysis is predicted to
increase in the future (Stephenson et al. 2001). However, interpretation of spectral data is
often quite complex and thus supporting information obtained by other techniques may

Lubach et al. 2007, Tiscmack et

al. 2003

Hancock and Zografi 1997,

Saleki-Gerhardt et al. 1994,
Saunders et al. 2004

Coleman and Craig 1996,

Guinot and Leveiller 1999,
Saklatvala et al. 1999

Non-destructive. Even whole tablets can

be studied without disrupting the tablet
structure and the physical state of its
contents.
Difficult to quantify low levels of
amorphous content (i.e. below 10%) with
conventional DSC. By using high speed
DSC (Hyper-DSC) amorphous contents as
low as 1.5% can be detected.
Enables the detection of hidden
phenomena, such as overlapping Tg and
crystallization. Able to detect and quantify
low amorphous contents.
Measurements in constant relative
humidity (RH) or linearly ramping the RH
from 0 to 100% are possible. Amorphous
contents as small as 0.5% can be detected.

Peaks are sharp for crystalline solids and broad for

amorphous solids. Quantitative analysis of
crystalline/amorphous mixtures can be achieved
without the need for standard curve preparation.

Sharp fusion endotherm is observed for crystalline

solids. Amorphous/partially amorphous samples
show glass transition (T g) with/without
recrystallization endotherm and fusion endotherm.

The heat flow signal is separated into reversing

(showing Tg) and non-reversing (showing relaxation
endotherm, recrystallization exotherm and fusion
endotherm) components.

No response for crystalline sample, for amorphous

material a recrystallization exotherm is observed.

Solid-state
Nuclear Magnetic
Resonance
Spectroscopy
(ssNMR)

Differential
Scanning
Calorimetry
(DSC)

Modulated
temperature DSC
(MTDSC)

Isothermal
Microcalorimetry
(IMC)

Lechuga-Ballesteros et al. 2003,

Mackin et al. 2002, Samra and
Buckton 2004

Bugay 2001, Stephenson 2001,

Taylor and Zografi 1998

Non-destructive. Often the spectral

features of different solid-state forms
overlap in which case special approaches
are needed in order to obtain a calibration
curve to quantify the degree of
crystallinity.

Sharp vibrational bands observed in the case of

crystalline material. For amorphous samples, the
bands are broader.

Vibrational
spectroscopy
(FTIR, NIR and
Raman)

References
Hancock and Zografi 1997, Men
et al. 2005, Pluta and Galeski
2007, Roe and Curro 1983,
Saleki-Gerhardt et al. 1994

Specific information
Conventional (with temperature and
environmental control, wide-angle and
small-angle techniques (SAXS) are
applicable. Nondestructive.

Observations
Sharp diffraction peaks are visible in the case of
crystalline material. Amorphous material shows a
halo pattern. Suitable for detecting and quantifying
molecular order down to levels of about 5%.

Method
X-ray Diffraction
(XRD)

Table 2.3. Techniques for physical characterization of amorphous solids.

44

An overall mass loss is observed as a clear hump in

the sorption diagram in the case of crystallization.

Birefringency in the case of crystalline material

under polarized light.

Gravimetric water
absorption

Polarized light
microscope

Polarized light is refracted from the crystal

planes and is seen as bright areas in the
inspection under the microscope.

Crystallization process can be studied by

monitoring the mass change of the material
as a function of time at given conditions,
since amorphous material adsorbs
relatively large amounts of water vapor
and, when crystallizing, gives up the extra
moisture due to decreased sorption
capacity of the crystalline material.

Andronis and Zografi 1997,

Hancock and Zografi 1997

Experimental difficulties have restricted

the use of the method.

Decrease in viscosity is continuous for crystalline

materials, while a sudden decrease in viscosity is
seen above T g for amorphous samples.
Density of a crystalline material is higher than that
of the corresponding amorphous form.

Viscometry

Byrn et al. 1999c

Burnett et al. 2004, Newman et

al. 2008

Yu 2001

Royall et al. 2005

Very sensitive technique for the

identification and characterization of glass
transitions, usually with polymers.

The mechanical properties of a sample are measured

as a function of temperature. Amorphous sample
shows a large change in these properties at T g.

Dynamical
Mechanic
Analysis (DMA)

Density

Craig 1996, Duddu and

Sokoloski 1995

Possible to monitor a range of low

temperature transitions associated with
changes in molecular mobility.

No response for crystalline sample, dielectric loss at

Tg for amorphous materials.

Dielectric
Analysis (DEA)

Hogan and Buckton 2000,

Ramos et al. 2005

Amorphous contents as small as 0.5% can

be detected. For example, for lactose
solution calorimetry has been reported to
give more precise results than IMC.

High heat of solution for crystalline materials and

low heat of solution for amorphous materials.

Solution
calorimetry

45

46
be needed (Bugay 2001). Raman spectroscopy is sensitive to changes in intramolecular
conformations and intermolecular interactions arising from changes in solid state
structure. The changes in the spectra between the different solid-state forms are often
very small, but when combined with suitable data-analysis method (e.g. partial least
squares discriminant analysis, PLS-DA, and partial least squares regression analysis,
PLS), Raman spectroscopy can be used for monitoring and quantifying the solid-phase
transition occurring during the dissolution of amorphous drugs (Savolainen et al. 2009).
Thus, there are many suitable methods available for the characterization of amorphous
materials. However, none of these methods is sufficient per se, instead a detailed
characterization of an amorphous material should always involve the combination of
spectroscopic, X-ray diffraction and thermal methods.

2.4.2.3

Stability of amorphous drugs

Since the amorphous forms are unstable, they tend to revert back to a crystalline form
with the passage of time. Prediction of the crystallization timescale is very important and
it can be achieved by understanding the physicochemical properties of the drug in
question combined with some knowledge of the general principles of crystallization.
Based on these parameters, optimized storage conditions can be determined and shelf-life
predicted.
Crystallization from the amorphous state is primarily governed by the same factors that
determine crystallization from the melt (Hancock and Zografi 1997). As can be seen from
Figure 2.3, in the case of amorphous materials, the rate of nucleation increases as the
temperature decreases due to increased viscosity. However, molecular motion decreases
as the temperature decreases (particularly below Tg), which slows the molecular diffusion
and reduces the crystallization rate. Thus, the maximum rate of crystallization occurs
somewhere between T m and Tg (Hancock and Zografi 1997, Craig et al. 1999). Storing
the amorphous material below T g should lower the risk of devitrification due to low
molecular mobility (Saleki-Gerhardt and Zografi 1994). However, this is far from a
guarantee of stability, since molecular mobility is present also below T g and it might be
sufficient to result in devitrification during the typical storage times for pharmaceutical
products (Craig et al. 1999). Furthermore, amorphous materials with similar T g values

47
might show different stability profiles when stored below their T g values, e.g. due to
variations in their steric structure and hydrogen bonding of the molecules within the
materials (Fukuoka et al. 1989). Furthermore, the presence of water in storage conditions
may plasticize the material sufficiently to lower the T g value to that of the storage
temperature, increasing the rate of crystallization and reducing the crystallization
temperature (Hancock and Zografi 1994, Ward and Schultz 1995, Jouppila et al. 1998). It
has been suggested that storage at T K, i.e. at the temperature of zero mobility, would
ensure sufficient physical stability for amorphous materials (Craig et al. 1999, Yu 2001,
Kaushal et al. 2004). For many fragile glasses, T K is approximately 50 K below T g and
for strong glass formers it is even lower (Yu 2001). Unfortunately, for the majority of
compounds, T K lies near to refridgeration temperature which is impractical for product
handling and storage (Craig et al. 1999, Kaushal et al. 2004). However, this approach can
be used as a way of estimating possible stability problems. A more concrete perspective
on stability characteristics of the material can be achieved by estimation of -values over
a range of conditions, which allows an insight into the relationship between molecular
mobility and temperature (Hancock et al 1995).
Nucleation
Molecular motion

Tg

Tm
Temperature

Figure 2.3. Schematic representation of the temperature dependence of the crystallization

process for an amorphous system (modified from Hancock and Zografi 1997).
The use of amorphous drugs in dosage forms is restricted by problems associated with
changes in physical and chemical stability during their storage. Furthermore, regardless

48
of possible stability in dry conditions, the solubility and dissolution rate advantage of the
amorphous drug form might be lost due to solvent-mediated crystallization upon
dissolution (Mosharraf et al. 1999, Hancock and Parks 2000, Savolainen et al. 2009).
Thus, one must find ways for stabilizing the amorphous drug forms during their shelf-life
and inhibiting their crystallization after administration. It is known that inclusion of
materials with high T g values may improve the physical stability of amorphous drugs by
raising the T g of the binary system (Yoshioka et al. 1995, Kakumanu and Bansal 2002).
Therefore, possibility of formulating the high-energy amorphous drugs in the form of
solid dispersions has generated huge interest. In addition to improved stability, solid
dispersion systems may demonstrate increases in solubility in the range of orders of
magnitude and provide markedly increased dissolution and absorption properties (Chiou
and Riegelman 1971, Serajuddin 1999, Leuner and Dressman 2000, Sethia and Squillante
2003, Vasconcelos et al. 2007).

2.4.3

Enhancing the dissolution by using solid dispersions

Solid dispersions (SDs) are defined as a range of pharmaceutical products with one or
more drugs homogenously dispersed in an inert carrier or matrix in a solid state, prepared
by the melting, solvent or melting-solvent methods (Craig 2002, Sethia and Squillante
2003, Kaushal et al. 2004).
SDs are divided into different types according to their physicochemical properties. A
broad distinction can be made based on the physical state of the drug within the system,
i.e. is it crystalline or amorphous. In eutectic and monotectic systems, both the drug and
carrier are present in the crystalline state. In eutectic systems, the drug and carrier are
completely miscible in the liquid (molten) state, and when cooling their mixture with the
eutectic composition they form a microfine physical mixture with a lower melting point
than the drug or the carrier alone (Leuner and Dressman 2000, Craig 2002, Vippagunta et
al. 2007). In monotectic systems, the melting point of the carrier does not change in the
presence of the drug (Vippagunta 2007). In eutectic drug/hydrophilic carrier systems, the
highly water soluble carrier dissolves quickly in an aqueous medium, releasing very fine
drug crystals and this drug size reduction has been noted to be responsible for improved

49
dissolution rate e.g. as observed for fenofibrate and loperamide in SDs with poly(ethylene
glycols) (PEGs) (Law et al. 2003, Weuts et al. 2005a).
In the second SD type, the drug may be dispersed as a separate amorphous or
crystalline phase (or some combination of the two) in a glassy matrix (i.e. solid
suspensions) (Craig 2002, Vasconcelos et al. 2007). These types of SDs are typically
formed with amorphous polymers, such as polyvinyl pyrrolidone (PVP) (Van den Mooter
et al. 1998, Sethia and Squillante 2004), or with semicrystalline materials, such as PEG
(Van den Mooter et al. 1998, Nair et al. 2002, Verheyen et al. 2002, Karavas et al.
2007b). In addition, complex formation might be possible with some carriers, such as
PVP (Garekani et al. 2003).
The third SD type is a solid solution in which the drug and carrier are totally miscible
with each other, and as a result of specific molecular interactions, the drug is present as a
molecular dispersion within the carrier (Leuner and Dressman 2000, Craig 2002, Sethia
and Squillante 2003, Kaushal et al. 2004, Vasconcelos et al. 2007). Solid solutions can be
further subdivided either according to their miscibility (continuous or discontinuous solid
solutions) or according to the way in which the drug molecules are distributed in the
matrix (substitutional, interstitial or amorphous) (Leuner and Dressman 2000). Few
drug/carrier systems have been observed to be continuous solid solutions, i.e. the
situation when the components are miscible with each other in all proportions (Shamblin
et al. 1998, Konno and Taylor 2006). Instead, discontinuous solid solutions are more
common, where the miscibility of the components with each other is limited (Craig 1990,
Leuner and Dressman 2000). For example, the solid solubility of trehalose in dextrose
has been found to be less than 10 % (w/w) (Vasathavada et al. 2004) and the solubility of
different drug molecules with PEGs has been reported as being less than 15% (Law et al.
2001, Urbanetz and Lippold 2005).
In addition to these classical SDs, "third generation" SDs, i.e ternary SDs, which
contain a mixture of polymers and/or surfactants as carriers (Mura et al. 1999, Mura et al.
2005, Vasconcelos et al. 2007) have been prepared. In these SDs, the carrier properties
are tailored to the needs of the drug in order to keep the drug molecularly dispersed at
higher drug loads (Janssens et al. 2008a-c).

50
2.4.3.1 Preparation of solid dispersions
The preparation methods of SDs can be roughly separated into two categories: melt
(fusion) methods and solvent evaporation methods (Table 2.4). Melt methods include
traditional hot melting, melt extrusion, direct capsule filling, compression moulding and
hot spin melting (Leuner and Dressman 2001). The solvent methods include traditional
solvent evaporation e.g. by spray or freeze-drying, supercritical fluid (SCF) technology,
co-precipitation and spin-coating. SDs prepared by solvent methods are often called
coprecipitates instead of coevaporates, even though this term is only correct for SDs
prepared by precipitation methods. The most widely used techniques in the small-scale
preparation of SDs are traditional melting or solvent evaporation methods, but their scaleup problems have led to the development of new methods which are suitable for largescale production, such as melt extrusion or SCF technology (Leuner and Dressman 2001).
There are only a few studies which have compared the traditional methods to the newer
ones, e.g. coevaporation has been observed to result in a higher amorphous content of the
drug than SCF technology, which in turn resulted in smaller amount of residual solvent
and thus more free flowing powders (Sethia and Squillante 2002, Majerick et al. 2007).
In addition to the methods reviewed in Table 2.4, simple kneading (Modi and Tayade
2006) and spray freeze drying, a potential method for incorporating labile drugs in a
stabilizing carrier (van Drooge et al. 2005), have been used in the preparation of SDs.
Furthermore, techniques such as a combustion dryer system (Xu et al. 2007) and a pulse
dropping method (Bashiri-Shahroodi et al. 2008) have been studied as novel, potential
preparation methods for SDs.

Specific information
Physical mixture of the drug and carrier is
melted or the drug is mixed with molten carrier,
the melt is cooled and then pulverized. Rapid
cooling leads to supersaturation of the drug in
the carrier matrix. Simple and economical
method.

The drug-carrier mixture is simultaneously

melted and homogenized, typically in a corotating twin-screw extruder, then extruded and
shaped as granules, pellets, sheet or tablets in a
shaping device. Short exposure to high
temperatures allows processing of relatively
thermolabile drugs. Absence of organic
solvents, continuous operation possibility,
minumun product wastage, good control of
operation parameters and thus good potential for
scale-up. Melt extrusion of miscible
components leads to formation of a solid
solution.

Direct filling of hard gelatin capsules with the

melt of solid dispersions. Possible grindinginduced changes in the crystallinity of the drug
are avoided. Large-scale manufacture
equipment commercially available.

Mixture of the drug and carrier is compressed

under elevated temperature. Produces an
intimate contact and mixing of the molten
components. Suitable for large-scale production
of SDs.

Method
Hot melting

Hot melt extrusion

Direct capsule
filling

Compression
moulding

Broman et al. 2001, Chokshi et al.

2005, Forster et al. 2001,
Ghebremeskel et al. 2007, Leuner
and Dressman 2000, Sethia and
Squillante 2002, Sethia and
Squillante 2003

Rowley et al. 1998, Sethia and

Sqillante 2003

Broman et al. 2001

Extrusion temperatures 10-20 C above the

Tg or Tm of the polymer are required to
assure proper material flow in the extruder
effective plastization of the polymer is a
challenge. Laboratory scale extruders
require large amounts of drug.

Not suitable for thermolabile drugs.

Solubility of the drug in the carrier is
required.

Not suitable for thermolabile drugs.

cont.

References
Aso and Yoshioka 2005, Broman et
al. 2001, Leuner and Dressman
2000, Mura et al. 1999, Sethia and
Squillante 2003, Urbanetz and
Lippold 2005, Vasconcelos et al.
2007, Verheyen et al. 2001

Limitations
Many drugs might be degraded or
evaporated at the high temperatures used.
Miscibility of the drug and carrier in the
molten form is necessary. Miscibility gaps
lead to a product that is not molecularly
dispersed. Not ideal for scale-up.

Table 2.4. An overview of preparation methods of solid dispersions.

51

Specific information
The drug and carrier are dissolved in a common
solvent followed by solvent evaporation, e.g. by
rotary evaporator, nitrogen stream, vacuum
drying, spray drying and freeze-drying, in order
to obtain a solid residue. Low operation
temperature prevents thermal degradation.
Allows for preparation of solid solutions.

CO2 is the most common SCF used since it is

nontoxic, non-flammable, inexpensive, and has
a low critical temperature which makes it
suitable for heat-labile molecules. Several
techniques, e.g. RESS, GAS, SAS, ASES,
SEDS and PGSS have been used for preparation
of SDs. Single step processing gives micronized
and solvent-free particles. Drugs sensitive to
heat, light oxidation or hydrolysis can be
processed. Scale up is possible.

A non-solvent is added dropwise to the drug and

carrier solution under constant stirring.
Eventually, the drug and carrier are coprecipitated as microparticles.

Solution of the drug and carrier in a common

solvent is evaporated by dropping the solution
on a spinning substrate. Heating is required to
remove residual solvent. The result is an
optically transparent thin film. Suitable for
moisture-sensitive drugs since it is performed
under dry conditions.

Method
Solvent
evaporation

Supercritical fluid
(SCF) technology

Co-precipitation

Spin-coating

Process design and scale-up requires

fundamental understanding of the
thermophysical process.The applicability of
RESS is limited by the very low solubility of
most drugs and polymers in CO2.

Limitations
Difficulties to find a common solvent. The
use of organic solvents and difficulties in
totally removing them (environmental and
toxicity issues). High preparation costs.
Small variations in processing conditions
may lead to large changes in product
performance.

Table 2.4. An overview of preparation methods of solid dispersions (cont.).

Konno and Taylor 2006, Marsac et al.

2006a, Vasconcelos et al. 2007

Vasconcelos et al. 2007

References
Ambike et al. 2005, Broman et al.
2001, Karavas et al. 2007b, Leuner
and Dressman 2001, Van den Mooter
et al. 1998, Sethia and Sqillante 2003,
Shah et al. 1995, Shamblin et al.
1998, van Drooge et al. 2004a,
Vasanthavada et al. 2004,
Vasconcelos et al. 2007
Jun et al. 2005, Juppo et al. 2003,
Ker et al. 1999, Lee et al. 2005,
Majerick et al. 2007, Moneghini et al.
2001, Sethia and Squillante 2003,
Won et al. 2005

52

53

2.4.3.2 Carrier materials

Carrier materials used in SDs are generally hydrophilic substances with varying
physicochemical properties, ranging from low molecular weight sugars to high molecular
weight polymers. Several factors should be considered when selecting a carrier, e.g. the
solubility of the drug in the carrier, mechanism of the inhibition of the crystal growth,
carrier's ability to enhance the dissolution rate and possible toxicity.
The carrier materials commonly used for preparation of SDs are presented in Table 2.5,
though different grades of PVP and PEG, either alone or in combinbation of surface
active ingredients, have become the most popular carriers (Leuner and Dressman 2001,
Sethia and Squillante 2003, Kaushal et al. 2004). In addition to the carriers shown in
Table 2.5, other polymers such as HPC (Ambike et al. 2004), poly (acrylic acid) (PAA)
(Broman et al. 2001, Weuts et al. 2005c), poly (vinylpyrrolidone-co-vinylacetate)
(PVP/VA) (Matsumoto and Zografi 1999, Weuts et al. 2005b), povidone (Nair et al.
2002); block copolymers such as Lutrol F127 (Poloxamer) and Pluronic F68 (Vippagunta
et al. 2002, Ahuja et al. 2007); sugars such as chitosan, inulin, mannitol and sorbitol
(Asada et al. 2004, van Drooge et al. 2004b, Ahuja et al. 2007); organic acids such as
citric acid and urea (Lu and Zografi 1998, Ahuja et al. 2007) have been used as carriers in
the preparation of SDs. In order to improve the miscibility of the drug in the carrier
matrix and the dissolution rate of the drug, ternary SDs with carrier combinations of e.g.
PEG and surfactants (sodium dodecyl sulfate (SDS), Tween 60, Tween 80) (Mura et al.
1999, 2005), and PEG and HPMC (Janssens et al. 2008a, 2008c) have been successfully
prepared.

Properties/advantages
PEGs in molecular weight range of 150020000 are usually empolyed. PEGs in this
MW range are semi-crystalline and water
soluble. The crystalline part may exist in
extended or folded forms. PEGs are suitable
for melting and solvent preparation methods.
Solubilization and improved wettability of the
drug improve dissolution.

Amorphous polymer, grades from K12 to K30

(MW 2500 to 50000) have been used for SDs.
Good solubility in water or organic solvents,
solubility in water decreases with increasing
MW. Good for preparation of SDs with
solvent method. Solubilization and improved
wettability of the drug improve dissolution.
Antiplastization and hydrogen bonding
interactions
stabilize
drug/PVP
SDs.
Molecular dispersions with many drugs have
been prepared.

The molecular weight ranges of HPMCs from

10000 to 1500000 are used. SDs both with
solvent and melt methods have been prepared.
Addition of short chain length PEGs to HPMC
has been observed to lead to a further
improvement of drug dissolution without
compromising stability.

Carrier
Polyethylene glycol
(PEG)

Polyvinyl pyrrolidone
(PVP)

HPMC/HPMCAS

Table 2.5. Carriers commonly used in solid dispersions.

Ambike et al. 2004, Crowley and

Zografi 2003, Karavas et al. 2005,
2007b, Konno and Taylor 2006,
Matsumoto and Zografi 1999, Van
den Mooter et al. 1998, Van den
Mooter 2001, Paradkar et al. 2004,
Perng et al. 1998, Sethia and
Squillante 2004, Shamblin et al.
1998, Tantishaiyakul et al. 1999,
Taylor
and
Zografi
1997,
Vasanthavada et al. 2004, 2005

Use in hot melt method limited due to high

Tg. The drug release is dependent on PVP
MW since increased viscosity with
increased MW retards drug dissolution, and
on the amount of PVP in the SD, since
higher proportion of PVP results in drug
amorphization and higher solubilization.

Janssens et al. 2008a, 2008c, Konno

et al. 2008, Six et al. 2003, Tanno et
al. 2004, Won et al. 2005

References
Anguiano-Igea et al. 1995, Craig
1990, Damian et al. 2000, Dordunoo
et al. 1997, Karavas et al. 2007b,
Khoo et al. 2000, Law et al. 2001,
2003, Moneghini et al. 2001, Van
den Mooter et al. 1998, Nair et al.
2002, Perng et al. 1998, Urbanetz et
al. 2005, Urbanetz 2006, Verheyen
et al. 2001, 2002, Weuts et al. 2005a

Limitations
Molecular dispersions with PEG (with
limited drug solubility in PEG) have been
prepared for only a few drugs. The drug
release is dependent on PEG MW and the
amount of PEG in the SD. Stability
problems during preparation or storage. Use
of low MW PEGs and/or a drug having
plasticizing effect might result in soft and
tacky product.

54

Saturated polyglycolized glycerides consisting

of a well-defined mixture of mono-, di- and
triglycerides and mono- and di-fatty acid
esters of PEG 1500. Grades of 44/14 and
50/13, have been used. Suitable for melting
and solvent methods. Solubilize lipophilic
drugs in contact with aqueous medium
facilitating drug absorption.

Prepared by esterification of the acid group of

d--tocopheryl acid succinate by PEG 1000.
Surface active and miscible with water in all
parts. Low critical micelle concentration and
melting point. Suitable for melting and
solution methods.

Crystalline, non-ionic hydrophilic polymer.

The chemical structure of the repeating unit is
identical to that of PEG, but the PEO
molecular weight is significantly higher. Low
processing temperature in melting method is
an advantage.

Gelucires

Vitamin E TPGS

Poly (ethylene oxide)

(PEO)

Broman et al. 2001, Li et al. 2006,

Schachter et al. 2004

Khoo et al. 2000, Sethia and

Squillante 2002, 2004, Shin and
Kim 2003

May require mixing with other carriers in

order to increase the melting point of the
SD.

Possible stability problems due to

crystalline nature of PEO.

Ahuja et al. 2007, Damian et al.

2000, Khoo et al. 2000, Sethia and
Squillante 2002, 2004, Shimpi et al.
2005, Vippagunta et al. 2002

Aging effect due to lipidic nature which can

be reduced by formulating Gelucires with
other carriers eg. PVP.

55

56

2.4.3.3 Physical characterization of solid dispersions

The basic questions in the physical characterization of SDs are: what are the changes
occurring in the physical state of the drug during preparation and storage of the SD, and
are there interactions present between the drug and the carrier? The methods for
characterization of the amorphous state, the basic features of which were discussed in
Table 2.3, are suitable and also widely used for general characterization of the SDs
(Leuner and Dressman 2000, Sethia and Squillante 2003). However, the sensitivities of
the methods are different, the obtained results might be conflicting and thus care is
required in their accurate interpretation. For example, a lack of drug melting endotherm
usually points to the presence of the drug in amorphous form in the SD. However, in PEG
SDs, PEG often has a lower melting point than the drug, and thus a crystalline drug might
dissolve in the melted PEG during the DSC scan (Damian 2000, Nair et al. 2002, Mura et
al. 2005). Thus, the lack of a drug melting endotherm might be misinterpreted as the
presence of an amorphous form. However, by performing hot stage-microscopy (HSM)
measurements, the possible drug dissolution in PEG can be visually confirmed (Mura et
al. 2005). In addition, the true drug physical state must be verified with XRPD (Nair et al.
2002).
IR-spectroscopy is mainly used for the assessment of molecular interactions (i.e.
hydrogen bonding) within the SDs (Taylor and Zografi 1997), since these interactions
give rise to band shifts and broadening of the peaks which are characteristic for the
interacting groups compared to the IR spectra of the corresponding physical mixtures.
For example, in the case of PVP SDs, shifts of the absorption band of the PVP carbonyl
group towards lower wavenumbers are evidence of hydrogen bonding interactions with
the drug molecule (Van den Mooter et al. 1998, Nair et al. 2001, Bansal et al. 2007).
Shifts towards higher wavenumbers, indicative of specific drug-PVP interactions, have
also been observed (Taylor and Zografi 1997, Khougaz and Clas 2000, Nair et al. 2001,
Karavas 2005). Instead, in the case of PEG SDs, the interactions have been more difficult
to demonstrate (Anguiano-Igea et al. 1995, Van den Mooter et al. 1998). In addition to
IR, interactions evoke band shifts also in Raman spectra (Taylor and Zografi 1997,
Shamblin et al. 1998, Li et al. 2006) and in ssNMR spectroscopy the interactions are

57
visualized by chemical shift variations (Aso and Yoshioka 2006, Van den Mooter et al.
2001, Schachter et al. 2004).
The miscibility of the drug and polymer can be predicted by the solubility parameter
approach (Hancock et al. 1997, Greenhalgh et al. 1999, Forster et al. 2001, Nair et al.
2001, Marsac et al. 2006b, Ghebremeskel et al. 2007). The solubility parameter () is one
way to quantify the cohesive energy of a material, which in turn determines many of the
critical physico-chemical properties (e.g. solubility, melting point) of drugs and
excipients. There are group contribution methods, such as the Hansens approach, by
which solubility parameters can be calculated. The Hansen solubility parameters for a
compound are calculated from its chemical structure using the approaches of
Hoftyzer/Van Krevelen and Hoy (Van Krevelen 1997) where the square root is taken of
the sum of squares of the contributions of dispersive, polar and hydrogen bonding. These
individual components are calculated using the contributions of the functional groups of
the molecule. The value of can also be determined experimentally e.g. by measuring the
solubility/miscibility of a material in liquids with known cohesive energies (ReutelerFaoro et al. 1988) or by inverse gas chromatography (IGC) experiments (Huu-Phuoc et
al. 1986, Adamska et al. 2008). Compounds with similar values for are likely to be
miscible, since the energy required for mixing of the components is compensated by the
energy released by the interaction between the components (Greenhalgh et al. 1999). It
has been estimated that if the difference between the solubility parameters of two
components () is smaller than 7 MPa1/2, then the components are likely to be miscible,
and when is smaller than 2.0 MPa1/2 the components might form a solid solution
(Greenhalgh et al. 1999, Forster et al. 2001, Ghebremeskel et al. 2007).
Differentiating whether a solid dispersion or a solid solution is formed, is generally
based on DSC analysis, where in the case of solid solutions, a single, compositiondependent Tg between the Tgs of the pure substances is observed as evidence of the
miscibility of the components (Matsumoto and Zografi 1999, Forster et al. 2001, Nair et
al. 2001, Vasanthavada et al. 2004, Marsac et al. 2006a). The T g value of the different
compositions can be predicted with Gordon-Taylor equation (Gordon and Taylor 1952,
Van den Mooter 1998, Nair et al. 2001) (Eq. 5):

58

Tg 12 =

w1Tg 1 + Kw2Tg 2
w1 + Kw 2

(5)

where T g12 is the glass transition temperature of the drug-polymer blend, w1, w2, Tg1 and
Tg2 are the weight fractions and glass transition temperatures (K) of the pure drug and
polymer, respectively. K is a constant describing the interaction between the components
and it can be approximated using the following equation (Simha-Boyer rule, Eq. 6):

1Tg 1
2 Tg 2

(6)

where 1 and 2 are the true densities of the components. Deviations of the
experimentally determined T gs from the theoretical T gs are indicative of differences in the
strengths of the intermolecular interactions between the individual components and those
of the blend (Nair et al. 2001).
However, there is a lack of a proper characterization tool which could determine the
actual dispersion of the drug and its particle size within a polymer matrix. Microscopic
methods, e.g. SEM, TEM, and MTDSC in combination to gravimetric water sorption
have been used for this purpose (Dordunoo et al. 1997, van Drooge et al. 2006b, Karavas
et al. 2007a,b), however they are not able to detect molecular dispersions. Instead,
alternative techniques such as micro-Raman and fluorescence resonance energy transfer
(FRET) might be capable of distinguishing between nanodispersions and solid solutions
(van Drooge et al. 2006a, Karavas 2007b).

2.4.3.4 Dissolution of solid dispersions

The mechanisms of dissolution enhancement in SDs are not yet completely understood
in spite of intensive research. There are several factors that are known to contribute to the
enhancement of drug solubility and dissolution rate from SDs. Reduced particle size and
thus increased surface area of the drug within the dispersion, especially in the case of
eutectics and solid solutions, leads to faster dissolution of the drug. In addition, improved

59
wettability of the hydrophobic drug particles, the absence of aggregation of the drug
particles and possible solubilization by the carrier are all factors that improve the drug
dissolution (Craig 2002, Sethia and Squillante 2003, Kaushal et al. 2004, Vasconcelos et
al. 2007). Furthermore, enhancement of drug solubility is achieved by converting the
drug to the amorphous state, since then no energy is required to break up the crystal
lattice during dissolution (Taylor and Zografi 1997, Kaushal et al. 2004). After
dissolution, the drug is present as a supersaturated solution which might precipitate with
the passage of time (Kaushal et al 2004, Vasconcelos et al. 2007). In addition,
intermolecular interactions between the drug and carrier promote drug dissolution from
SDs, since they control the physical state and the particle size of the drug in SDs (Bansal
et al. 2007, Karavas et al. 2007b). In the case where the effects of particle size reduction,
polymer hydrophilicity and wettability have been assumed to be the same, the major
contribution to the dissolution enhancement has appeared to be due to intermolecular
interactions between the drug and the polymer (Bansal et al. 2007). In addition, the
intensity of the interactions has been observed to modify the dissolution mechanism from
being carrier controlled to drug controlled for high polymer concentrations in the case of
felodipine/PVP dispersions (Karavas et al. 2006). However, the benefits attributed to
these factors are opposed by solvent-mediated devitrification and the overall solubility
benefit is a balance between these opposing forces (Bansal et al. 2007).
Enhanced in vitro dissolution by SD technique has been demonstrated to lead to
increased bioavailability of many drugs (Khoo et al. 2000, Ambike et al. 2005, Shimpi et
al. 2005, Piao et al. 2007). For example, SDs are more efficient than micronization in
increasing bioavailability. Micronization has a limited size reduction capacity and thus
might achieve only a marginal improvement of the drug solubility or release in the small
intestine (Serajuddin 1999, Dannenfelser et al. 2004).

2.4.3.5 Stability and formulation of solid dispersions

Improved stability has been observed for many drugs, which have been formulated in
amorphous SDs with different polymers, under accelerated conditions (Perng et al. 1998,
Khoo et al. 2000, Law et al. 2001, Ambike et al. 2004, 2005, Vasathavada et al. 2004,

60
Karavas et al. 2005, Shimpi 2005). In spite of extensive research into the stabilizing
effect of SDs, there is no consensus of what is the dominant mechanism of stabilization,
although it is generally considered that achieving miscibility between the drug and the
carrier is important (Marsac et al. 2006b).
Restricting molecular mobility by increasing the Tg of the system (antiplasticization) by
using carriers with high Tg values has been proposed to be the stabilizing mechanism for
SDs containing PVP (Van den Mooter et al. 2001). In addition, salt formation between
the polymer and the drug compound has resulted in high T g values of the system (Weuts
et al. 2005c). However, a significant reduction in crystallization rates or inhibition of
crystallization has been observed for many amorphous drugs at PVP amounts which were
too low to increase the Tg of the system or when the Tg of the SD was even lower than the
amorphous drug alone (Matsumoto and Zografi 1999, Khougaz and Clas 2000, Crowley
and Zografi 2003) suggesting that antiplasticization is not the only factor affecting the
physical stability of the SDs. Furthermore, two polymers might have different effects on
crystallization even when the T gs of the SDs with these polymers are similar (Miyazaki et
al. 2004). The stability of the SDs in these cases has been attributed to the interactions
formed between the drug and the polymer (Matsumoto and Zografi 1999, Khougaz and
Clas 2000, Miyazaki et al. 2004). Specific drug-polymer interactions have been observed
to lead to inhibition of drug crystallization in many cases (Perng et al. 1998, Karavas et
al. 2005), although it has been argued that interactions per se are not a prerequisite for
stabilization (Van den Mooter 2001). Since some level of adhesive interactions, such as
van der Waals forces, hydrogen bonds and ion-dipole interactions, is required between
the drug and the polymer to achieve the formation of a molecular level mixture of the
drug, the true role of these interactions in crystallization inhibition has been hard to
evaluate (Konno and Taylor 2006). However, hydrogen bonding (e.g. between the
carbonyl group of PVP and the drug) has been observed to reduce enthalpy relaxation
indicative of decreased molecular mobility of the system (Ambike et al. 2004, Aso and
Yoshioka 2006, Bansal et al. 2007). Furthermore, crystallization has been observed to be
effectively inhibited by a strong intermolecular interaction due to proton transfer between
acidic and basic functional groups of the drug and the polymer (polyacrylic acid (PAA))
(Weuts et al. 2005c, Miyazaki et al. 2006). However in some cases, the crystallization

61
tendency has been found to be dependent on the relative crystallization tendencies of the
pure substances (Marsac et al. 2006a). Thus, if an amorphous drug is stable in the
absence of the polymer, it will remain stable in the presence of polymer whether or not
there are any specific interactions present (Law et al. 2001).
In their studies with three chemically different polymers (PVP, HPMC and HPMCAS),
Konno and Taylor (2006) found these polymers to be equally effective in decreasing the
nucleation rate of amorphous felodipine at given weight percentages of the polymer. No
correlation between the nucleation rate and the Tgs of the pure polymers, the T gs of the
SDs or the strength of the hydrogen bond interactions could be established. Instead, the
stability was attributed to the polymers ability to increase the kinetic barrier to
nucleation with the scale of the effect being related to the polymer concentration and for
the three specific polymers studied, it was independent of the polymer physicochemical
properties.
From the above discussion, it is apparent that the physicochemical factors governing
the stability of SDs are not fully understood. Thus, crystallization of the amorphous drug
during processing (mechanical stress) or storage (temperature and humidity stress) can
not be fully controlled (Serajuddin 1999, Sethia and Squillante 2003, Kaushal et al. 2004,
Vasconcelos et al. 2007). Despite the clear advantages achieved by SD technology, the
above stability issues are one major reason why there are so few SD-based products on
the market. A striking example of the unpredictability of SD based products is the
ritonavir capsule (Norvir, Abbott) which was withdrawn from the market due to
crystallization of ritonavir from the supersaturated solution in a SD system during the
product's shelf life (Bauer et al. 2001). Furthermore, lack of predictability of the
dissolution behaviour of SDs due to lack of understanding of their molecular behavior,
manufacturing and scale up limitations, and cost of preparation are all factors that have
limited the commercialization of the SDs (Craig 2002, Sethia end Squillante 2003, Bansal
et al. 2007). Nonetheless, products of griseofulvin/PEG (Gris-PEG, Novartis),
nabilone/povidone (Cesamet , Lilly) and itraconazole/HPMC (Sporanox, Janssen
Pharmaceutica/Johnson and Johnson) are available on the US market.
Formulating SDs into tablets or capsules presents many formulation challenges. Solid
dispersions might be soft and tacky, making pulverization, sieving and tabletting difficult

62
(Serajuddin 1999, Sethia and Squillante 2003). In addition, often a high amount of carrier
is required in order to achieve fast dissolution of the drug from the SD which might mean
that the amount of SD required to administer the drug dose becomes too large to produce
a tablet of reasonable size (Leuner and Dressman 2000). This can be prevented by using
better carriers, e.g. gelucires, which are needed in smaller amounts in order to produce
satisfactory dissolution and stabilization of the drug (Shimpi 2007). However, direct
compression has been found to be suitable for tabletting of SDs, and there are ways to
avoid possible sticking problems e.g. by adding magnesium stearate to the powder
mixture (Liu and Desai 2005, Shibata et al. 2006). The improved dissolution by SD was
maintained in these tablet formulations, leading to better performance of the SD
containing tablets in comparison to conventional tablets.
In addition, rapidly disintegrating tablet formulations have been successfully prepared
using SDs. In these tablets, disintegration within the time range of 60 to 780 seconds is
effectively combined with a fast dissolution rate of the drug from the SDs, leading to a
fast release of the drug from the tablets (Valleri et al. 2004, Sammour et al. 2006,
Goddeeris et al. 2008). These SDs have been shown to be stable during preparation and
storage of these tablet formulations (Valleri et al. 2004, Shibata et al. 2006).

63

AIMS OF THE STUDY

I.

To examine the ability of hydrophobic excipients (starch acetate and ethyl

cellulose) to act as a release controlling matrix for highly water soluble
saccharides in order to design a tablet that would release the saccharides within 2
4 h, starting already in the stomach but mainly in the upper part of the small
intestine.

II.

To modify the drug release rate of water soluble model drugs without changing
the composition of the drug/starch acetate mixture. For this purpose, a dry powder
agglomeration, induced by triboelectrification on a mixing plate, was used for
drug and starch acetate mixtures prior to direct compression.

III.

To improve the release rate of a poorly water soluble drug by the solid dispersion
approach in order to allow usage of the drug in intraoral preparations from which
the drug would be released and dissolved fast enough to allow absorption through
oral mucosa.

IV.

To prepare a fast disintegrating tablet for intraoral administration, containing the

solid dispersion with acceptable dissolution properties, stability and size of the
product.

64

EXPERIMENTAL

4.1
4.1.1

Materials
Excipients and model drugs (I-IV)

N-acetyl-D-glucosamine

(NAG

(I,

II),

Sigma

Aldrich

Chemie,

Germany),

maltopentaose (I) and maltose monohydrate (I, sieved through a 1 mm sieve) (Seikagaku,
Japan) were used as highly water soluble model saccharides. Anhydrous caffeine (II) and
propranolol hydrochloride (II) (Sigma-Aldrich Chemie, Steinheim, Germany) were used
as water soluble model drugs. Perphenazine (III, IV) (PPZ, Sigma-Aldrich Chemie,
Steinheim, Germany) was used as a poorly water soluble model drug. Hydrophobic
matrix formers starch acetate (SA) with degree of substitution 2.7 (VTT, Rajamki,
Finland) (I, II) with sieve fractions of < 500 m (I), 500297 m (I), <149 m (I) and
<53 m (II) and ethyl cellulose (EC) (I) (Ethocel Standard 10 Premium, gift sample from
DOW Europe (Germany)); hydrophilic matrix former mannitol (IV) (Pearlitol 400 DC,
Roquette Frres, Lestrem, France); disintegrants crospovidone (CP) (II, IV),
(Polyplasdone XL-10, ISP Technologies, Inc.,Calvert City, KY, USA) and calcium
silicate (CS) (IV) were used in the tabletting studies.

4.1.2

Other chemicals (I-IV)

Chemicals used in the preparation of dissolution mediums and in HPLC analysis of the
model drugs were all obtained from commercial suppliers. Chemicals for HPLC analysis
(i.e. acetonitrile and triethylamine) were of HPLC grade, other chemicals were at least of
analytical grade.

65
4.2
4.2.1

Methods
Particle and powder properties (I-IV)

The particle size distribution of powders (I, II) was determined with a laser
diffractometer (Mastersizer 2000, Malvern Instruments Inc., Worchestershire, UK), either
by the particle in air method (I, II) or by the particle in liquid (ethanol) method (I).
Material densities (I-IV) were measured in five parallel determinations with a Multi
pycnometer (Quanta Chrome, NY, USA) using helium as the measuring gas.
Scanning electron microscopy was used for visual examination of powders (I-III). The
SEM micrographs were taken with a XL 30 ESEM TMP microscope (FEI Co., Czech
Republic).
The contact charging of powders with different materials was studied by performing
triboelectric measurements (II). The measurements were made by sliding the neutralized
powders through tubes of 50 cm in length into a Faradays cup where the generated
charge was measured using an electrometer (Keithley 6517A, Keithley Instruments Inc.,
USA) (Murtomaa and Laine 2000). Subsequently, the samples were weighed and the total
charge per unit mass, i.e. the specific charge, was calculated. The tube materials were
stainless steel (SS), glass, polyvinyl chloride (PVC), acrylic, polyethylene (PE) and
polypropylene (PP). The measurements were repeated five times per each powder/tube
material pair. For SA, a larger particle size fraction of SA (53-149 m) was used in these
measurements instead of cohesive fraction < 53 m (which was used in the tabletting
studies).

4.2.2

Tableting (I, II, IV)

Powder mixtures for tableting were prepared by mixing carefully in a mortar (I, II IV).
The relative amounts of the mixture components were calculated on a mass basis. Dry
powder agglomeration prior to tableting (II) was conducted on a stainless steel plate
(diameter 39 cm) which was attached to Erweka AR 400 apparatus (Erweka Apparatebau
G.m.b.H., Germany) where the mixture of drug and SA was placed. The plate was rotated
for 10 minutes at a rotation speed of 14 rpm. If CP was added to the formulation, it was
scattered on the agglomerated powder and the plate was rotated for an additional 5

66
minutes. The agglomeration process using a PP container (diameter 27 cm) was
conducted as described above with the PP container placed on the steel plate.
The powder mixtures were compacted with a compaction simulator (PCS-1, PuuMan
Ltd., Kuopio, Finland) (I, II, IV). Tablet formulations (I) were designed by using an
experimental design program (Design-Expert 5, StatEase Corp., Minneapolis, USA). The
tablets were cylindrical, with diameters of 8, 10 or 13 mm. Tablets were compressed to
the desired porosity. The compression profiles were sine waves for both punches or only
for the upper punch, in which case the lower punch was stationary. The compression
pressures varied between 42 and 345 MPa.
The compression profiles (II) were double sided sine waves. The tablets were
cylindrical, with a diameter of 13 mm and mass of 500 mg. The tablets were compressed
to the desired porosity (20 % for NAG and caffeine, and 15% for propranolol
formulations). The compression pressures varied between 72 and 293 MPa.
Four different formulations (IV), containing 10% of either 1/5 PPZ/PEG or 1/5
PPZ/PVP SD, mannitol and disintegrants (CS and/or CP) were prepared (i.e. each tablet
had 4 mg of PPZ). The compression profiles were double sided sine waves. The tablets
were cylindrical, with a diameter of 10 mm and a mass of 200 mg. The compaction
pressures were 64 or 127 MPa.

4.2.3

Tablet properties (I, II, IV)

Tablet volumetric dimensions and weights (I, II, IV) were measured 24 h after
compression. Crushing strengths of tablets (I, II, IV) were measured with a universal
tester (CT-5 tester, Engineering Systems, Nottingham, England). The tensile strengths of
the tablets (I, II, IV) were calculated according to Fell and Newton (1970).
Disintegration times for the tablets (IV) were determined on a petri dish without agitation
by immersing the tablet in 20 ml of distilled water and recording the time passing until
the tablet had visually disintegrated.

67
4.2.4

Preparation of solid dispersions (III, IV)

The carrier selection was based on a comparison of the solubility parameter of PPZ
(estimated according to the group contribution method (David and Misra 1999) using the
Matprop-program (Material Property Estimator and Database, SF Technologies,
Amherst, MA)) to the solubility parameters of different polymers and polymer grades,
found in the literature (Hancock et al. 1997, Greenhalgh et al. 1999, Forster et al 2001,
Marsac et al. 2006b).
SDs with different drug/polymer weight ratios (5/1, 1/5 and 1/20) were prepared by
freeze-drying. Thus, the SDs contained 80, 20 and 5 % (m/m) of PPZ, respectively. Also
pure PPZ was processed similarly. 0.1 N HCl-solutions with an overall solid
concentration (drug + polymer) of 5% (w/w) in the case of 1/5 and 1/20 dispersions were
prepared, 3% solutions in the case of 5/1 dispersions and 2% solutions in the case of pure
PPZ. After freezing, the samples were dried (Modulyod-230, Thermo Savant, Savant
NY) for 2-4 days. The prepared particles were stored in dessicator over silica gel at a
temperature below 10C.

4.2.5

Physicochemical characterization (I-IV)

4.2.5.1 Polarized light microscopy (I)

The existence of a crystalline part of maltopentaose was qualitiatively confirmed by
using polarized light microscopy (Nikon Microphot-Fxa, Nikon, Tokyo, Japan).

4.2.5.2 Differential Scanning Calorimetry (I, III, IV)

DSC was used in the determination of melting points (I, III, IV) and glass transition
temperatures (III, IV) of the materials. The measurements conducted with Perkin-Elmer
DSC7 (I) (Perkin-Elmer Co., Norwalk, CT, USA) were made in duplicate using a heating
rate of 10C/min and a temperature scale of 10-250C. Samples of 4-6 mg in weight were
crimped in 50 l aluminium pans with pierced lids. All runs were performed under an
atmosphere of dry nitrogen. The temperature axis was calibrated with Ga and In.

68
The cooling/heating programs when using a Mettler Toledo DSC823e equipped with an
intercooler (Mettler Toledo, Schwerzenbach, Switzerland) and an autosampler (Mettler
Toledo, TS080IRO, Sample Robot, Schwerzenbach, Switzerland) (III, IV) are shown in
Table 4.1. Sine-wave temperature modulation had to be used in the case of 1/5- and 1/20
PPZ/PVP-formulations in order to separate the overlying water evaporation endotherm
from the other thermal events, such as glass transition (Table 4.1).

Table 4.1. DSC cooling/heating programs for PPZ, PVP K30 and PEG 8000, freeze-dried
PPZ, the prepared solid dispersions (SDs) and the corresponding physical mixtures (PM).
Sample

Phase 1 (heating)

Phase 3 (heating)

from 115C
immediately to 40C, 15 min at 40C
from 140C
immediately to
25C, 10 min at
25C
from 100C to 75C, 10C/min, 15
min at -75C
-

from -40C to
120C, 10C/min

from 25C to
190C, 10C/min

from -75C to
100C, 10C/min

From 0C to
200C, 1C/min

Amplitude 1C,
frequency 1 min

at -40C 10 min

at -75C 30 min

from -40C to
55C or to 125C,
10C/min
from -75C to 10C or to 125C,
10C/min

PPZ

from 25C to
115C, 10C/min

PVP K30

from 25C to
140C, 10C/min,
10 min at 140C

PEG 8000

from 25C to
100C, 10C/min,
3 min at 100C
from 0C to
125C, 10C/min

freeze-dried PPZ,
5/1 PPZ/PVP PM
and SD
1/5 and 1/20
PPZ/PVP PM
and SD
5/1 PPZ/PEG PM
and SD
1/5 and 1/20
PPZ/PEG PM
and SD

Temperature
modulation

Phase 2 (cooling)

The samples were weighed (weight range 2-11 mg) with an analytical balance (Mettler
Toledo AT261, Mettler Toledo Ag, Schwerzenbach, Switzerland) and analyzed in sealed
40 l aluminium sample pans with a pierced lid. Measurements for each material were
performed in triplicate. H2O, In, Pb and Zn were used for temperature scale and enthalpy
response calibration, however for the temperature modulated runs, no further calibration

69
was done, thus the Cp-values could not be compared between the different materials.
The results were analysed with STARe software (Mettler Toledo Schwerzenbach,
Switzerland). Melting points were determined as onset-values and the glass transition
temperatures as midpoint-values. In the case of temperature modulated measurements,
the Tg-values were determined from the reversing heat flow signal as midpoint-values.

4.2.5.3 X-ray Powder Diffractiometry (III, IV)

X-ray powder diffraction analysis (XRPD) was performed using a Philips PW 1830
diffractometer (Philips, Amelo, The Netherlands) with Bragg-Brentano geometry (-2)
(III, IV). The radiation used was nickel filtered CuK, which was generated using an
acceleration voltage of 40 kV and a cathode current of 50 mA. The samples were scanned
over a 2 range of 3-30, step size being 0.04 and counting time 3s per step.
For the SDs stored in 40C/silica (IV), a Philips PW1050 diffractometer (Philips,
Amelo, The Netherlands) was used, since the measurements were conducted at 5% RH
(the measurement chamber contained silica). In that case, the acceleration voltage was
45 kV and the cathode current was 35 mA. The samples were placed into copper sample
holders and scanned over 2 range of 3-30, with the step size being 0.04 and counting
time 3s per step.

4.2.5.4 Fourier Transform Infrared Spectroscopy (III, IV)

A Nicolet Nexus 870 FTIR spectrometer (Thermo Electron Corp, Madison, WI)
equipped with an Attenuated Total Reflectance (ATR) accessory (Smart Endurance,
Single-reflection ATR diamond composite crystal) was used for obtaining the IR-spectra.
For each spectrum, 32 scans were performed with a resolution of 4 cm-1.

4.2.5.5 Small-angle X-ray scattering (III, IV)

SAXS permits the measurement of the size of inhomogeneity regions, arising from the
electron density inhomogeneities within the sample, in a range from 1 to 100 nm

70
(Guozhong 2004). In the measurements, the X-ray radiation generated by PW 1830 X-ray
generator (Philips, Amelo, The Netherlands, operated at 40 kV and 50 mA) was limited
to a narrow line. This permitted the determination of scattering of the radiation which
penetrated through the sample starting from small angles. The intensity of the scattered
radiation was measured by a proportional counter by changing the angle in a stepwise
manner (Kratky-camera, Anton Paar, Graz, Austria). The measuring times were
approximately 20 hours per sample (5 min/step). The measurements were carried out by
measuring the scattering of the transmitted radiation at small angles. When analyzing the
data, the shape of the areas of different electron densities (i.e. particles) was assumed to
be spherical and their size distribution was estimated to be from 0 to 100 nm. The pair
density distribution functions (particularly the location of the maximum (nm)),
determined from the original data, provide information on the size of the electron density
areas in the sample.

4.2.6

Solubility and dissolution testing (I-IV)

The drug release from tablets (I) was determined in triplicate by the USP XXVIII
rotating basket method, with a rotation speed of 100 rpm (Sotax AT6, Switzerland). The
dissolution medium was 900 ml of pH 1.2 HCl-solution for the first two hours, after
which the tablets were transferred into 900 ml of distilled water for the next 22 hours.
Both media were maintained at 37 0.5C. The amount of dissolved NAG was
determined with a Gilson HPLC system (Gilson, France) with UV-detection (UV/Vis151 detector Gilson, USA) at the wavelength of 210 nm (method adapted from Sashiwa
et al. 2002) using an amino column (Asahipak NH2P, 4.6x 250 mm, Shodex, Japan)
operating at 40C. The sample injection volume was 20 l, the mobile phase was
acetonitrile-water (70:30) and its flow rate was 1 ml/min. The retention time of NAG was
5 min.
The amount of dissolved maltose and maltopentaose was determined with a Merck
LaChrom HPLC system (Hitachi, Tokyo, Japan) with evaporative light scattering (ELS)
detection (Sedex 55 ELS detector, Sedere, Vitry-Sur-Seine, France) using the Asahipak
NH2P column. The sample injection volume was 10 l, the mobile phase was

71
acetonitrile-water (48:52) and its flow rate was 1 ml/min (method adapted from Shodex
2003). The detector temperature was 42C and the pressure of the nebulizing gas (dry and
filtered air) was 2.2 bar. The retention times of maltose and maltopentaose were 3.55 min
and 4 min, respectively.
The drug release from six parallel SA tablets (II) was determined by using the USP
XXVIII rotating basket method, with a rotation speed of 100 rpm. The dissolution
medium was 900 ml of simulated gastric fluid without enzymes (USP XXIV, pH 1.2),
maintained at 37 0.5 C. The amount of dissolved drug was determined by UVspectrophotometry (Genesys 10uv, ThermoSpectronic, Rochester, NY, USA). The
wavelengths used for NAG, caffeine and propranolol were 210, 272 and 289 nm,
respectively.
The PPZ equilibrium solubility (III) at pH 6.8 was determined by adding excess
amounts of the drug to 1 ml of buffer solution (pH unchanged during the experiment) at
room temperature. The suspensions were equilibrated in a shaker (at speed 300 rpm) for
three days and then filtered through a 0.45 m membrane filter. For the phase-solubility
studies, solutions containing 10, 7.5, 5, 2.5 and 1 % (w/v) of PVP or PEG in pH 6.8
phosphate buffer (pH was unchanged during the experiment) were prepared. Otherwise
the phase-solubility study was carried out similarly as the solubility studies, with the
exception that the solution volume was 10 ml. A 150 l sample of the filtered test
solution was taken, mixed with 350 l of ACN and analyzed with Gilson HPLC -system
with UV-detection at the wavelength of 254 nm. A reverse-phase column (Inertsil ODS3, 4.0x150 mm, GL Sciences Inc.,Tokyo, Japan) was used. The sample injection volume
was 20 l, the mobile phase was acetonitrile-water (70/30) with 0.03% (v/v)
triethylamine (TEA), and its flow rate was 1 ml/min. The retention time of PPZ was 3.75
min.
The dissolution rates of the materials (III, IV) were determined in a small volume (3 ml
of pH 6.8 phosphate buffer), in order to simulate the small liquid volumes present in the
mouth. The powder was weighed in the bottom of the test tubes in such a way that there
was always 4 mg of PPZ. Three parallel samples were prepared for each time point. The
test tubes were placed on a shaker at a speed of 300 rpm (KS125basic, IKA
Labortechnik, IKA-Werke Gmbh & Co., Straufen, Germany) and 3 ml of the pH 6.8

72
buffer was added to the test tube. The samples were taken at 15, 30 and 45 s, 1, 2 and 4
min time points by pouring the solution into a syringe equipped with a 0.45 m
membrane filter on the head, filtering it immediately and diluting it with phosphate buffer
prior to analysis with HPLC. The dissolution rates of PPZ (d(0.5) = 30 m) and PPZ
micronized (< 15 m) were also determined under sink conditions (i.e. the PPZ sample
amount was such that the maximum amount of the dissolved PPZ was 5% of its
equilibrium solubility) using the USP XXVIII rotating paddle method, with a rotation
speed of 50 rpm. The dissolution medium (900 ml of pH 6.8 phosphate buffer) was
maintained at 37.0 0.5 C.
The dissolution profiles of PPZ from the prepared tablet formulations (IV) were
determined using the USP XXVIII rotating basket method, with a rotation speed of 50
rpm. The dissolution medium was 500 ml of phosphate buffer pH 6.8, maintained at 37.0
0.5 C. Three parallel tablets from each formulation were tested. The amount of
dissolved PPZ was determined with HPLC as described above.

4.2.7

Stability testing (IV)

Fresh samples of solid dispersions were exposed to the following conditions: 40C/75%
RH and 40C/5% RH (silica) for four weeks after which the FTIR, DSC and XRPD
measurements and dissolution studies were conducted for the SDs. However, freeze-dried
PPZ, 5/1 PPZ/PEG and all of PPZ/PVP became deliquesced during the storage at
40C/75 % RH and no measurements for these samples could be conducted. In addition,
a total of 20 tablets from each formulation were stored at room temperature (21C)/60%
RH for four weeks. After that time, the tablet weights, crushing strengths and
disintegration times were measured and dissolution profiles of PPZ were determined.

4.2.8

Statistical analysis (I, II)

The experimental design program (Design-Expert 5, StatEase Corp., Minneapolis,

USA) was used for designing the tablet formulations (I) with a Plackett-Burman 2-level
factorial design. With this program the factors affecting the drug release rate (T50%) and

73
mechanism (n-value from Korsmeyer-Peppas model (Costa and Sousa Lobo 2001)) were
evaluated. Also a full 2-level factorial design was used for optimization of the drug
release.
Statistical significance for the differences between the melting points of maltose
monohydrate in the tablet prior to the dissolution test and after 2h of dissolution test (I),
and the tensile strengths of the unagglomerated and agglomerated formulations (II) were
evaluated by using Students t-test. Dissolution profiles were evaluated by calculating the
similarity factors (f2). Only one timepoint after 85% of drug released was included in f2value calculations. Should the f2-value be less than 50, then the dissolution profiles were
considered to be different.

74

RESULTS AND DISCUSSION

5.1

Factors affecting release of highly water soluble compounds from hydrophobic

matrices (I)

Generally, it is desirable that one has water-soluble drugs in the development of

immediate release dosage forms. However, retarding the release of these kinds of
molecules can be a challenging task (Pillay and Fassihi 2000, Liu et al. 2005). In this
study, SA and EC were used as hydrophobic matrix formers in order to obtain release of
model saccharides (NAG, maltose and maltopentaose) within 2-4 hours. The physical
properties of the drugs and excipients are shown in Table 5.1.

Table 5.1. Physical properties of tablet excipients (starch acetate with different particle
size fractions (I-II) and ethyl cellulose (I)) and model drugs (N-acetyl-D-glucosamine (I,
II), maltose monohydrate (I), maltopentaose (I), anhydrous caffeine (II) and propranolol
HCl (II)).
Volume mean particle
Melting point
Particle density
size (m)
(C)
(mean sd) (g/cm3)
SA < 500 m
1.326 0.004
131b
nd
SA 297-500 m
1.358 0.005
372b
nd
SA <149 m
1.310 0.011
23b
nd
12
nd
SA < 53 m
1.341 a
EC
nd
227b
1.192 0.005
NAG
1.483 0.008
141c
213.7 0.7
maltose monohydrate
125.5 0.6
1.525 0.004
138c
maltopentaose
1.481 0.008
nd
116 d
anhydrous caffeine
nd
1.452 0.003
46
propranolol HCl
1.211 0.003
14
nd
a
data from van Veen et al. 2005; b Particle in air method; c Particle in ethanol method; d Partially
amorphous (confirmed by polarized light microscopy), melting point of the crystalline part; nd = not
determined.
Material

5.1.1

Dissolution characteristics of N-acetyl-D-glucosamine (I)

In order to achieve controlled release of highly water soluble saccharides, the effect of
different formulation and process variables (Table 5.2) on the release rate and mechanism
of NAG from SA tablets were evaluated. Plackett-Burman 2-level factorial design of
experiment was used for designing eight different formulations (Table 5.2).

75
Table 5.2. Tablet formulations designed by Plackett-Burman design of experiment for
evaluation of the effect of six process and formulation variables on the release rate and
mechanism of N-acetyl-D-glucosamine (NAG) from the starch acetate (SA) tablets.
Formulation
Amount
Tablet
code
of NAG
mass
(NAG/SA)
(mg)
(mg)
A1 (25/75)
150
600
A8 (25/75)
150
600
B2 (50/50)
150
300
B7 (50/50)
150
300
C3 (17/83)
50
300
C6 (17/83)
50
300
D4 (8/92)
50
600
D5 (8/92)
50
600
a
-1 = one sided; 1 = double sided

Duration of
compression
(ms)
500
1500
500
1500
500
1500
500
1500

Type of
compressiona
-1
1
1
-1
-1
1
1
-1

Tablet
porosity
(%)
7.5
15
7.5
15
15
7.5
15
7.5

SA particle
size fraction
(m)
297-500
297-500
<149
<149
297-500
297-500
<149
<149

The dissolution studies of these formulations demonstrated that the dissolution rate of
the drug was fastest from formulation B7, which contained the higher amount of NAG in
the tablet and possessed a higher porosity of the tablet and lower tablet weight (T50%
values shown in Table 5.3). Three formulations studied (A8, B2 and B7) released NAG
within the desired time, i.e. within 2-4 hours.
The release rate (T50%) could be modeled (R2=0.999) and predicted (Q2=0.998) well
and the model showed that the four most significant factors affecting the release rate were
the amount of NAG in the tablet (P<0.0001), the porosity of the tablet (P<0.001), the
duration of compression (P<0.001) and the tablet mass (P<0.01).
In the case of high amount of drug in the tablet, the excipient was not able to form a
percolating network inside the tablet (Bonny and Leuenberger 1993, Amin and Fell 2004)
and thus, in the tablets of the formulations A1, A8, B2 and B7, the matrix was probably
formed by NAG, leading to lower tensile strengths and faster release (Table 5.3). The
higher porosity of the tables led to a weaker structure of the tablets and thus faster release
(Table 5.3). The longer duration of compression might have led to formation of a higher
amount of stronger bonds inside the tablet and thus to higher tensile strength and slower
release (Table 5.3). In the smaller tablet, the shorter diffusion path might have caused
faster release of the drug (Table 5.3). However, the particle size of SA did not seem to
have a significant effect on the drug release, which is in contradiction with general
observations about hydrophobic matrix formers (Leuenberger et al. 1987, Holman and

76
Leuenberger 1988, Crowley et al. 2004). This might be due to that the difference between
the two particle size fractions should have been larger in order to show a significant
effect on the release rate.
The release kinetics of NAG from the SA matrices was evaluated by using KorsmeyerPeppas model (Eq. 3). The resulting n values, indicative of drug release kinetics, are
shown in Table 5.3. It was found that according to Eq. 3, the release of NAG from three
formulations (B2, D5 and probably also B7) followed square root of time kinetics (i.e.
Q0.45), while with the other formulations, NAG release kinetics was anomalous
transport. In the B2 and D5 formulations, the smaller SA particle size fraction was used
and the tablet porosity was 7.5 % meaning that there was a tighter tablet structure and
purely diffusion-controlled release. Unfortunately, it was not possible to construct a
reliable model for predicting NAG release kinetics from the studied matrix tablets.

Table 5.3. Times required for 50 % of drug release (T50%), n values from the
Korsmeyer-Peppas equation and tensile strengths ( sd) of the tablets (Table 5.2).
Formulation
A1
A8
B2
B7
C3
C6
D4
D5

5.1.2

T50% (h)
2.5
1.1
1.2
0.7
3.8
8.0
4.4
9.2

Tensile strength (MPa)

4.15 0.11
2.87 0.20
4.60 0.31
1.86 0.12
2.73 0.60
5.97 0.51
4.17 0.24
5.04 0.09

n
0.55
0.63
0.49
0.40
0.53
0.56
0.63
0.46

Dissolution characteristics of saccharides and oligosaccharides (I)

After defining the most significant factors affecting NAG release, the release from SA
tablets was optimized by using a full 2-level factorial design, where the two variable
factors were the amount of drug in the tablet and tablet porosity (Table 5.4). The same
design was used for studying the release of NAG from hydrophobic EC matrices, and
also for studying the release of maltose monohydrate from SA and EC matrices.

77
Table 5.4. Formulations designed by a full 2-level factorial design for NAG and maltose
monohydrate in SA and EC matrices and the tensile strengths ( sd) of the prepared
tablets.
Tensile strength (MPa)
NAG

Maltose
Tablet
Amount of
Formulation porosity saccharide
SAb
EC
SAb
EC
a
(%)
(%)
1.16 0.08
0.50 0.02
2.16 0.20
1.05 0.07
1
20
50
0.17 0.06
0.37 0.04
0.22 0.03
2
25
75
nd
3.46 0.29
1.59 0.06
4.68 0.31
2.71 0.06
3
15
25
1.57 0.06
0.49 0.02
1.91 0.10
0.89 0.03
4
25
25
0.18 0.06
0.70 0.35
1.86 0.06
1.51 0.16
5
15
75
a
The amount of saccharide in the tablet was always 50 mg; b Since SA particle size found not to effect on
the NAG release, the SA fraction < 500 m was used; nd = not able to measure

In the dissolution studies with these formulations, two formulations, 2 and 5,

disintegrated in the dissolution bath and released the saccharide immediately (not shown).
Instead, formulations 1, 3 and 4 released the saccharides mainly within the desired 2-4
hours (Figure 5.1 a-d). Thus, for optimal release, either lower porosity and a higher
amount of the saccharide in the tablet or higher porosity and a lower amount of the
saccharide in the tablet was required. The release characteristics of EC were observed to
be very similar to SA (Figure 5.1 a-d). This is probably due to the fact that there were
identical mechanisms of drug release from these matrices in the case of water soluble
drugs, i.e. the release occurs by dissolution and diffusion of the drug through water-filled
capillaries of the pore network (Crowley et al. 2004, Pohja et al. 2004). Thus, in the case
of similar SA and EC formulations, the saccharide release rate depends mainly on the
properties of the molecule which was clearly shown by that the release of maltose
monohydrate was considerably slower from formulations 3 and 4 than NAG release from
similar formulations (Figure 5.1 a-d). This is probably due to the fact that maltose is a
hydrate and thus its dissolution rate in water is slower (Khankari and Grant 1995,
Florence and Attwood 1998, Murphy et al. 2002).
The release profiles of maltose monohydrate from SA/EC -formulations 3 and 4 (Figure
5.1 c, d) were found to consist of two linear phases with different release rates. The
release rate slowed at the time point of two hours, where the medium was changed.
However, also when the whole dissolution study was performed in pH 1.2 HCl-solution

78
or in water (not shown), a similar behavior was observed, indicating that the medium
change was not the reason for this behavior.

Figure 5.1. The dissolution profiles of NAG from; (a) starch acetate formulations 1 (),
3 () and 4 (); (b) ethyl cellulose formulations 1 (), 3 () and 4 (); and maltose
monohydrate released from; (c) starch acetate formulations 1 (), 3 () and 4 (); (d)
ethyl cellulose formulations 1 (), 3 () and 4 ().
It is well known that polymorphic transitions or the formation of amorphous regions on
particles can be induced by the application of mechanochemical stress, such as occurs
during tabletting (Chan and Doelker 1985, Saleki-Gerhardt et al. 1994), and that this can
have an effect on the dissolution rate of the drug (Phadnis and Suryanarayanan 1997).
During the tabletting process, maltose monohydrate could have been converted to a
metastable (more soluble) form and during the dissolution test it could have reverted back
to the monohydrate (less soluble) after a certain lag time, which could explain the initial
faster dissolution and consequent reduction of release rate at the two hour measurement
point. A biphasic dissolution caused by similar phenomenon has been previously reported
for calcium carbonate (Mosharraf et al. 1999). Evidence of activation of maltose
monohydrate during tablet compression was found by taking starch acetate tablets with

79
maltose monohydrate out of dissolution medium at 0.5, 1, 2, 2.5 and 4 hour timepoints
and analyzing 1) these tablets, 2) the corresponding physical mixture and 3) the tablet
before dissolution with DSC. There was a statistically significant difference (P<0.01 with
t-test) between the melting points of maltose monohydrate determined from dispersed
tablets prior to the dissolution test and after keeping the tablet for two hours in the
dissolution bath (average 130.2C) and those determined from the physical mixture and
from tablets taken out of the dissolution bath after 2.5 hours or later (average 131.3C)
(Table 5.5). The metastable solid-state structure, formation of which had been induced by
tabletting, had reverted or at least started to revert back to its original condition when the
tablets had been in the dissolution bath for more than two hours.

Table 5.5. Melting point ranges (n=2) of physical mixture of maltose monohydrate and
SA, tablets before dissolution and tablets removed from the dissolution bath at various
timepoints. Physical mixture and tablets are based on formulation 3 (Table 5.4).
Sample

Time in the dissolution bath (hours)

Melting point (C)a

Physical mixture

131.4 132.2

Tablet
Tablet
Tablet
Tablet
Tablet
Tablet
a
Peak-values were used
determination.

130.2 130.2

0.5
129.2 130.3
1
129.7 131.7
2
129.8 130.2
2.5
130.7 131.5
4
130.0 132.0
due to the large water dehydration peak, which interfered with onset-value

SA formulations 3 and 4 (Table 5.4) were also prepared by using maltopentaose, an

oligomer of maltose, in order to evaluate the effect of molecular size of the saccharides
on the release. Maltopentaose was observed to be released slightly faster than maltose
monohydrate (Figures 5.1 c and 5.2) presumably due to its mainly amorphous nature, this
being observed by using polarized light microscopy (Figure 5.3). In addition, the small
particle size (observed visually by SEM) could also mask the effect of molecular size on
the release rate. Once again, a biphasic release was seen, which could be due to the
existence of a small crystalline fraction in the maltopentaose particles (Figure 5.3, Table
5.1), dissolving slower than the amorphous component. In addition, the slowing of the

80
release rate of maltopentaose formulations could also be due to recrystallisation of the
amorphous maltopentaose in the dissolution medium during the dissolution test
(Mosharraf et al. 1999).

Figure 5.2. Dissolution of maltopentaose from SA formulations 3 () and 4 ().

Figure 5.3. Photographs of maltopentaose particles in polarized light microscope

showing the crystalline fractions as bright areas (left). When polarization is not in use, no
bright areas are seen (right).

81
5.2

Effect of organization of powder mixture on the release rate of drugs from

starch acetate matrix (II)

5.2.1

Triboelectrification of the materials (II)

It is known that ordered powder mixtures can be stabilized by charging the particles
with opposite polarity by triboelectrification (Chapter 2.2.3.4). In this study,
triboelectrification and the agglomeration tendencies of drugs with different particle sizes
(NAG, caffeine and propranolol HCl, Table 5.1) and a disintegrant (CP) with SA with a
small particle size fraction (Table 5.1) were studied. The triboelectric charging of the
powders in contact with different materials (Table 5.6) was measured. This revealed that
if NAG and caffeine were in contact with a stainless steel (SS) plate they became charged
with an opposite polarity to SA. In contrast, propranolol HCl was charged with the same
polarity as SA when it was in contact with all the tested materials. Thus, in the case of
NAG and caffeine, triboelectrification of powders might promote the drug-SA attraction,
i.e. increase in adhesion and agglomeration, but in the case of propranolol it would hinder
these processes. However, adhesion between caffeine and SA should be stronger than
between NAG and SA due to caffeines larger negative charge on SS. CP became
charged positively when it was in contact with SS, thus it might adhere similarly to SA to
the surfaces of negatively charged NAG and caffeine. Based on these results, the
agglomeration process was carried out on a SS plate. In addition, a PP plate was used in
the case of NAG, since on this material NAG charged with similar polarity to SA (which
was expected to hinder adhesion and agglomeration).

Table 5.6. Charging of powders (starch acetate (SA), crospovidone (CP), N-acetyl-Dglucosamine (NAG), caffeine and propranolol HCl) in contact with stainless steel (SS),
glass, polyvinyl chloride (PVC), acrylic, polyethylene (PE) and polypropylene (PP).
Charge of powders (nC/g)
Material
SS
PP
PE
SAa
12.27
3.53
-3.67
CP
15.57
12.32
NAG
-0.3
6
-1.09b
Caffeine
-3.72
8.39
-4.6
Propranolol HCl
16.28
16.11
-0.87
a
sieve fraction 53-149 m; b both polarities

PVC
21.11
8.92
2.43
22.98

Acrylic
-11.46
-1.1 b
-4.92
-5.2

Glass
14.64
6.64
-0.93
-4.21
14.97

82
5.2.2

Dry powder agglomeration (II)

The formation of agglomerates was carried out by mixing powders with different
compositions (Table 5.7) on a rolling plate placed at an angle, which created a "snowball"
effect, i.e. as the particles rolled along the slope on the surface of the powder, they
increased in size. The scanning electron micrographs of agglomerated powders (examples
shown in Figure 5.4) revealed that in both SS and PP-agglomerated NAG-SA
formulations, agglomerates of large, flaky NAG particles (mean particle size of 141 m,
Table 5.1) and small, round SA particles (mean particle size 12 m, Table 5.1) with small
CP particles (mean particle size 21 m, Table 5.1) on the surface were formed (Figure
5.4 a, d). Instead, in the case of caffeine formulations, the particle size of caffeine is only
slightly greater (mean particle size of 46 m, Table 5.1) than that of SA. Thus, the
adhesion of SA particles onto the surface of caffeine is not favored due to the rather small
difference in the particle size. This leads to to a weaker adhesion between the two
particles (Staniforth 1981) and the formation of smaller agglomerates with also some
caffeine particles on the surface (Figure 5.4 b). However, the opposite charging of
caffeine and SA on the SS plate favored agglomeration, as also is the case for NAG
(Table 5.6). In contrast, in the case of propranolol HCl, no agglomerates could be seen
(Figure 5.4 c). The mean particle size of propranolol (14 m, Table 5.1) and the charge
generated on SS was similar to those of SA, and therefore no adhesion promoted by a
particle size difference occurred in the mixture.
These results indicate that though the opposite polarities of the particle charges might
promote adhesion and agglomeration, the particle size difference between two materials
seems to be a more significant factor in determining the extent of particle interaction, as
is evidenced by the agglomeration of NAG and SA on the PP plate, in spite of the similar
charges of the particles (Figure 5.4 d). In addition, the particle distribution in a powder
mixture is affected by the surface properties of the particles. Surface roughness, surface
impurities and adhering moisture all contribute to the magnitude of the interparticulate
forces (Zeng et al. 2001). In general, large and irregular particles should exhibit higher
adhesion forces since they possess a higher contact area (Hersey 1975, Staniforth 1987).
The experimental results revealed that agglomeration was most effective with NAG in

83
spite of the polarity of tribocharging (Figure 5.4 a, d) due to its ability to store smaller SA
particles within the surface discontinuities (deBoer et al. 2005, Dickhoff et al. 2005).

Figure 5.4. Scanning electron micrographs of: (a) SS-agglomerated NAG formulation
A5, showing an agglomerate consisting of NAG, starch acetate and crospovidone on the
surface; (b) SS-agglomerated caffeine formulation B8, showing an agglomerate
consisting of SA, caffeine and CP; (c) SS-agglomerated propranolol HCl formulation C4
showing no agglomerates; (d) PP-agglomerated NAG formulation A, showing an
agglomerate consisting of NAG, starch acetate and crospovidone on the surface.

5.2.3

Dissolution and tablet characteristics (II)

The dissolution profiles of SS and PP-agglomerated NAG formulations and SSagglomerated caffeine and propranolol formulations together with the corresponding
unagglomerated formulations are shown in Figure 5.5 (formulation codes in Table 5.7).
In the case of NAG (Figure 5.5 a), it can be seen that the more CP present in the SSagglomerated formulation, the faster was the release of NAG. However, even with quite a
high amount of CP (i. e. 10%), NAG was not released immediately even though the tablet
disintegrated rapidly. In a comparison of the agglomerated formulation A5 with the

84
unagglomerated formulation A6 which had an identical material composition (containing
7.5 % of CP), it can be noted that agglomeration had slowed down the dissolution of
NAG (Figure 5.5 a). The calculated f2-value for formulations A5 and A6 was 35 which
indicates that they can be considered as being different. Furthermore, the initial burst
release, typical for uncoated SA matrix tablets (Pohja et al. 2004, Korhonen et al. 2005),
seen at the beginning of the dissolution curves, was less extensive with the agglomerated
formulation A5 than with the corresponding unagglomerated formulation A6. However,
these effects were not seen when comparing formulations A and A7, which did not
contain CP (Figure 5.5 a). The f2-value for these formulations was 72, indicating that the
formulations can be considered as being similar. When comparing the dissolution profiles
of PP-agglomerated formulations (A, A5) to the profiles of SS-agglomerated
formulations (Figure 5.5 b), no differences between SS and PP agglomerated
formulations were observed (f2-values 63 and 50, respectively). This confirms the
observation made with SEM (Figure 5.4), that NAG does form agglomerates with SA
despite the polarity of the charge generated on the particles.
In the case of caffeine (Figure 5.5 c), no significant difference was found between the
agglomerated (B5, B6) and unagglomerated (B1, B2) formulations when CP was present
in amounts of 0 and 1% (f2-values 73 and 59, respectively). However, much less CP
could be used in the formulations than in the case of NAG. The agglomerated
formulation B7 (contained 2% of CP) released caffeine slower than the corresponding
unagglomerated formulation B3. The formulations can be considered different, since the
f2-value was 47. However, the agglomerated formulation B8 (contained 3% of CP)
released caffeine faster than the corresponding unagglomerated formulation B4. The
difference is quite significant since the f2-value was 38. In addition, more extensive burst
release from the agglomerated formulation B8 compared to the unagglomerated B4 was
observed.
In the case of propranolol HCl SA formulations, the porosity of the tablets had to be
small (15%) and only very small amounts of CP (0.5%) could be used in order to achieve
sustained release of propranolol. The release profiles of propranolol HCl from the
agglomerated and the unagglomerated formulations were the same (Figure 5.5 d) with f2-

85
values of 94 (C1 vs. C3) and 96 (C2 vs. C4), supporting the results obtained by SEM
(Figure 5.4 c), evidence that no agglomeration had occurred.

Table 5.7. N-acetyl-D-glucosamine (NAG), caffeine and propranolol hydrochloride

formulations and tensile strengths ( sd) of the prepared tablets.
Drug

Formulation code

Amount of CP in the tablet

(%)

Aa
0
A1
2
A2
3
A3
5
A4
10
7.5
A5 a
A6 b
7.5
A7 b
0
0
caffeine
B1 b
B2 b
1
2
B3 b
B4 b
3
B5
0
B6
1
B7
2
B8
3
propranolol HCl
C1 b
0
0.5
C2 b
C3
0
C4
0.5
a
agglomerated also on a PP plate; b unagglomerated formulation
NAG

Tensile strength of the tablets

(MPa)
3.33 0.19
3.17 0.23
3.15 0.18
2.94 0.27
3.13 0.15
2.87 0.08
3.33 0.15
3.07 0.17
3.56 0.22
3.75 0.15
3.80 0.26
4.29 0.35
3.85 0.25
3.93 0.13
3.95 0.19
3.69 0.29
5.23 0.21
5.34 0.28
5.28 0.13
5.52 0.28

86

Figure 5.5. Dissolution profiles of: (a) agglomerated (A (), A1 (), A2 (), A3 (), A4
(+) and A5()) and unagglomerated (A6(), A7()) formulations of NAG; (b) SS
agglomerated (A (), A5 ()) and PP agglomerated (A (), A5 ()) formulations of NAG;
(c) agglomerated (B5 (), B6 (), B7() and B8 ()) and unagglomerated (B1(), B2
(), B3 () and B4()) formulations of caffeine; (d) (C3 () and C4 ()) and
unagglomerated (C1 () and C2 ()) formulations of propranolol HCl.
Thus, the most pronounced effects on dissolution were seen with NAG with a mean
particle size of 141 m, minor effects with caffeine (46 m) and no effects with
propranolol (14 m) (Figure 5.5). This can be explained by the differences in the
organization of the binary and tertiary powder mixtures, caused by the different particle
sizes of the drugs. The larger the particles, the more rough and the greater storage
capacity of the discontinuities of the drug particles (DeBoer et al. 2005, Dickhoff 2005).
In the case of NAG formulations, the SA particles were initially completely obscured in
the discontinuities of NAG and a percolating SA network could not be formed during
compaction of the tablet, since SA was only present in clusters in the NAG matrix

87
(formulation A7). The agglomeration process caused spreading of SA particles more
evenly over the large NAG particles and thus the particle contacts formed during
tabletting would be mainly SA-SA contacts, creating a continuous SA matrix inside the
tablet (observed also by SEM, not shown) (formulation A). This led to the formation of
stronger tablets than the tablets of unagglomerated A7 formulation (p < 0.05, Table 5.7).
In fact, as a consequence of the powder agglomeration, the tensile strengths of the tablets
A (Table 5.7) approached the values of pure SA tablets (3.62 0.37 MPa) which were
much higher than the tensile strengths of pure NAG tablets (0.52 0.09 MPa). This is in
accordance with the fact that the tensile strength and drug dissolution of a binary mix
have been observed to be dependent on its organization, i.e. governed by the adhering
material (Barra et al. 1999, 2000).
The effect of CP on the dissolution can be explained by the disruption of the SA matrix
in the tablet, which could be seen when 3% or more CP was present in the formulations
(Figure 5.5 a, c). Below this concentration, the SA matrix was not affected by the
presence of CP which was only present in minor clusters at lower concentrations (and had
only a minor effect on the tablet strength, Table 5.7). Thus, CP was unable to disrupt the
SA matrix during dissolution. In the agglomerated NAG formulations, SA and CP were
well distributed on the surfaces of the NAG particles (Figure 5.4 a) and the SA matrix
determined the strength of the tablets (Table 5.7). However, the addition of increasing
amounts of CP resulted in weaker tablets than the tablets of formulation A (contained 0%
of CP) and tablets of the unagglomerated A7 (Table 5.7), since it is known that SA-CP
binding is weaker than SA-SA binding (VanVeen et al. 2002, 2004). Interestingly,
despite the fact that as a result of the agglomeration process, the tensile strength values
decreased, there was still a reduction in the drug release rate (Figure 5.5). This might
indicate that, when the hydrophobic SA particles coated NAG particles, water penetration
and the subsequent contact with NAG was hindered and the release rate declined. This is
in accordance with that the dissolution properties of the tablet are governed by the
percolating material (Barra et al. 2000). The slowing of the dissolution rate as a result of
hydrophobic excipient coating of the drug particles has been previously observed with
filled capsules (Chowhan and Chi 1986).

88
In the case of caffeine, the storage capacity of the discontinuities was insufficient to
hide all SA and a percolating SA network was almost invariably formed when the tablets
were compressed. The agglomeration process only improved the SA network and thus
only minor effects were observed on dissolution (Figure 5.5 c) and tensile strength of the
tablets (Table 5.7). Finally, the propranolol particles were so small that the discontinuities
could not hide any SA particles and the mixtures were almost identical, whether or not an
agglomeration process had been carried out (Figure 5.5 d and Table 5.7).

5.2.4

Summary and future prospectives (I, II)

The study showed that controlling the release rate of highly water soluble saccharides
from hydrophobic matrices over a wide time scale is possible simply by altering the tablet
porosity and the relative amount of the matrix former in the tablet. Using these means in
the present study, the saccharide release type could be designed to be in the range of
intermediate to prolonged release. The desired saccharide release in 2-4 hours was
obtained with SA and EC matrices that had either relatively low porosity and a high
amount of saccharide in the tablet or high porosity and a low amount of saccharide in the
tablet. In addition, these hydrophobic matrices may be potential vehicles for oral delivery
of larger molecules (e.g. macromolecules), suggested by their ability to control the
release of an oligosaccharide (maltopentaose).
However, the physicochemical properties and process induced phase transformations
can affect significantly the dissolution rate of even highly water soluble substances, as
shown by the observed biphasic dissolution profile of maltose and maltopentaose,
attributable to water mediated phase transitions of the metastable phases present in these
materials. Thus, this observation emphasizes how important it is to understand crystal
forms and the amorphous phase of the drug (and excipients), since e.g. incorporation of a
metastable phase in the dosage form can lead to development problems.
Furthermore, in this study it has been shown that the dissolution characteristics and
tablet properties of a hydrophobic matrix tablet could be modified without changing the
composition of the powder mixture or other formulation parameters. A simple mixing
process prior to tabletting may be sufficient to change the mixture organization in a way

89
that the dissolution rate is modified, providing that certain conditions are fulfilled. By
choosing the right container material for the mixing, adhesion and agglomeration of the
drug with exipients can be promoted by triboelectic charging. However, drug-excipient
combinations that are sensitive to tribocharging can also be problematic in regular large
scale production since minor changes in the environmental humidity and powder
movements could lead to undesired variations in drug release. It is claimed that generally
excipient powders become negatively charged when they are in contact with metal or
glass and positively in contact with plastic (Staniforth and Rees 1982). However, in this
study, the excipients (SA and CP) became positively charged in contact with metal (SS),
glass and plastic materials of PP and PVC. SA charged negatively in contact with plastic
materials of PE and acrylic. Thus triboelectric measurements need to be conducted for
excipients and the drugs used in order to find a material where surface charges of
opposite signs are generated to allow interparticle attraction to occur. Unfortunately,
many pharmaceutical materials lose electrostatic charge through earth leakage relatively
quickly (Staniforth 1987). Thus, the stability of agglomerates generated by electrostatic
interactions may not be good.
However, the extent of particle organization in the tablets is dependent also on the size
and the surface roughness of the particles. In the present study, the most pronounced
effects were seen with the drug with the largest particle size (NAG) since initially, SA
particles were able to be stored within the discontinuities on the NAG surface and no SA
matrix was formed. Agglomeration caused spreading of SA particles over larger NAG
particles, promoting formation of the SA matrix and leading to slower dissolution rate of
NAG. In the case of drugs with smaller particle sizes (caffeine, propranolol), the storage
capacity of the surface discontinuities was insufficient to obscure all SA and the SA
matrix was almost invariably formed, leading to less pronounced changes in the tablet
properties.
For some time now, advances in oral-modified release technology have been largely
driven by significant improvements in manufacturing equipment and technologies as well
as the development of improved biocompatible and biodegradable polymeric materials
for controlling release rates (Charman and Charman 2002). It can be expected that this
trend will continue in the future. In the scientific literature, various examples of complex

90
oral-modified release systems can be found, but in many cases their commercial
applicability has not been proved. It needs to be remembered that the drug product
manufacturing process has to be both reproducible and capable of being conducted at
reasonable cost. It seems that the simple modifications and preparation processes for
tailoring the drug release properties of the hydrophobic matrices, examined in this study,
meet these criteria.

5.3

Fast dissolving particles of a poorly soluble drug for intraoral preparations

(III, IV)

5.3.1 Improvement of drug dissolution by solid dispersion approach (III)

As described in Chapter 2.3, there is a growing interest in developing dosage forms,
e.g. orally fast disintegrating tablets, which allow a rapidly dissolving drug to absorb
directly into the systemic circulation through the oral mucosa. The inherent advantages of
the SD approach in enhancing drug dissolution and stability (described in chapter 2.4.3)
might mean that even a poorly soluble drug could be administerd in such a formulation.
The model drug used (PPZ) was found to have poor dissolution properties in conditions
simulating the buccal cavity (i.e. low liquid volume (3 ml), with pH 6.8). The solubility
of PPZ was found to be 149 3 g/ml and its dissolution rate was poor, i.e. within 4
minutes only 2% of PPZ had dissolved (Figure 5.6 a). Reducing the particle size of PPZ
did not markedly change the situation, viz. only 13% of PPZ <15 m had dissolved
within 4 minutes (Figure 5.6 a). Furthermore, even when sink conditions prevailed, only
43 % of PPZ and 88 % of PPZ <15m had dissolved after 20 minutes (results shown up
to 4 min in Figure 5.6 a).

5.3.1.1

Polymer selection by the solubility parameter approach (III)

As described in section 2.4.3.3, two materials are considered to be miscible with each
other when is smaller than 2.0 MPa1/2 which might lead to the formation of a solid
solution. The value for PPZ was estimated to be 22.4 MPa1/2. Evaluation of a wide
selection of polymers and their different grades (Hancock et al. 1997, Greenhalgh et al.

91
1999, Forster et al. 2001, Marsac et al. 2006b) revealed that two hydrophilic polymers,
PVP K 30 and PEG 8000, possessed solubility parameter values nearest to that of PPZ,
i.e. 22.4 ( = 0) and 21.6 MPa1/2 ( = 0.8) respectively, and thus they were predicted to
provide the most favorable conditions for molecular level mixing with PPZ.

5.3.1.2 Dissolution properties of the solid dispersions (III, IV)

In phase solubility studies, increasing concentrations of PVP and PEG increased
linearly the PPZ solubility in pH 6.8 buffer, however PVP was considerably better than
PEG (Figure 5.6 b). PPZ solubility was increased over fivefold in 10% (w/v) PVP
solution whereas in 10% (w/v) PEG solution, the increase was a mere doubling. Similar
behavior has been observed previously for the other model drugs (Sethia and Squillante
2004, Mura et al. 2005, Ruan et al. 2005).
a

Figure 5.6. Dissolution curves of (a) PPZ (d(0.5) = 30 m) in supersaturated () and in

sink conditions (), and micronized (<15 m) PPZ) in supersaturated () and in sink
conditions (); (b) phase solubility diagrams of PPZ in solutions PVP () and PEG () in
pH 6.8 buffer solution at room temperature.
The dissolution rates of freeze-dried PPZ and PPZ from prepared PPZ/PVP and
PPZ/PEG dispersions were determined in supersaturated conditions due to the small
dissolution volume (3 ml), i.e. complete dissolution of PPZ would result in 9-times the
equilibrium solubility of crystalline PPZ (Table 5.8). With freeze-dried PPZ, a rapid
dissolution at the beginning of the experiment (over 70 % of PPZ dissolved already after
15 seconds) was seen leading to over 7-fold supersaturation of PPZ. The supersaturated

92
PPZ started to precipitate after one minute and the amount of dissolved PPZ declined
down to 60 %.
Instead, in the case of PPZ/polymer SDs, the ability of the polymers to inhibit
precipitation of PPZ was seen (Table 5.8). In the case of PPZ/PVP SDs, no precipitation
of supersaturated PPZ was observed. After 15 seconds, 20, 35 and 10 % of PPZ had
dissolved from 5/1, 1/5 and 1/20 PPZ/PVP, respectively, increasing up to 40, 90 and 40%
after four minutes. In the case of PPZ/PEG SDs, no precipitation of the supersaturated
PPZ was observed with 5/1 and 1/5-formulations. However, only 40% of PPZ dissolved
from the 5/1 PPZ/PEG after four minutes. The most remarkable improvement in the
dissolution rate was seen with 1/5 PPZ/PEG SD which dissolved within one minute
without precipitation of the supersaturated PPZ.
Thus, the dissolution rates of PPZ/PVP SDs were not as fast as those of PPZ/PEG SDs,
probably due to their surprisingly poor wettability which was observed visually
(PPZ/PVP powders remained floating on the liquid surface). On the other hand, at high
polymer contents, PVP might form a viscous layer during dissolution, hindering the
dissolution of the drug (Craig 2002) or it might act as a binder with some drugs which
could cause a decrease in the dissolution rate (Bansal et al. 2007).
The dissolution rates (in 3 ml of pH 6.8 buffer) of freeze-dried PPZ and PPZ/PVP SDs
were found to be changed after four weeks of storage at 40C/silica gel (Table 5.8). In the
case of fresh samples, freeze-dried PPZ and 1/5 PPZ/PVP had a faster dissolution, while
5/1 and 1/20 PPZ/PVP dissolved clearly more slowly. In contrast, the best dissolution
after storage was found with freeze-dried PPZ (50% of PPZ dissolved in 4 min) and 5/1
PPZ/PVP (60% of PPZ dissolved in 4 min), while the dissolution of 1/5 and 1/20
PPZ/PVP was considerably poorer that encountered with the fresh SDs. In fact, the
dissolution rate of PPZ from 1/20 PPZ/PVP had declined back to the level of crystalline
PPZ, i.e. 2% PPZ dissolved in four minutes.
In the case of PPZ/PEG SDs, the dissolution profiles were also found to be somewhat
different than the profiles of fresh samples (Table 5.8). After storage at 40C/silica gel,
1/5 PPZ/PEG formulation still had the best dissolution properties (i.e. over 60% of PPZ
dissolved in 4 min). The dissolution of 5/1 PPZ/PEG had remained almost unchanged,

93
but there was a reduction in the dissolution rate of 1/20 PPZ/PEG. After storage at
40C/75%, the dissolution of PPZ from 1/5 and 1/20 PPZ/PEG had further declined.

Table 5.8. The amount (%) of PPZ dissolved in the freeze-dried PPZ and from the SDs of
PPZ before and after four weeks storage at 40C/silica or 40C/75 % RH (n=3 sd.).
% of perphenazine dissolving at time t (min)
t=0.5
t=0.75
t=1
t=2
72 3
78 8
77 12
61 12

Storage
-

t=0.25
72 21

40/silica

40 6

52 1

57 11

52 5

66 3

51 6

40/silica

22 8
41 1

26 5
50 5

32 5
56 3

39 13
55 4

42 5
56 3

44 9
59 3

1/5 PPZ/PVP
1/5 PPZ/PVP

40/silica

35 3
8.4 2

36 5
9.6 3

46 6
9.5 3

60 10
12 1

75 11
13 1

86 6
15 1

1/20 PPZ/PVP
1/20 PPZ/PVP

40/silica

10 1
1.7 2.1

15 2
1.2 0.3

18 1
1.3 0.3

20 1
1.1 0.2

24 3
1.4 0.1

37 3
2.4 0.3

5/1 PPZ/PEG
5/1 PPZ/PEG

40/silica

26 6
22 5

33 4
25 1

36 5
38 5

45 4

36 3
43 9

38 3
57 3

1/5 PPZ/PEG
1/5 PPZ/PEG

40/silica

79 8
68 4

83 6
64 3

82 5
68 2

98 6
68 7

98 6
67 3

96 16
64 3

1/5 PPZ/PEG

40/75% RH

47 8

52 5

46 8

44 3

49 5

56 11

1/20 PPZ/PEG
1/20 PPZ/PEG
1/20 PPZ/PEG

40/silica
40/75% RH

72 2
48 2
39 1

76 2
47 7
50 1

75 1
54 4
53 6

107 1
56 6
45 1

73 7
63 4
54 3

77 8
53 1
53 2

Dispersion
freeze-dried
PPZ
freeze-dried
PPZ
5/1 PPZ/PVP
5/1 PPZ/PVP

5.3.2

t=4
61 9

Physical properties and stability of the solid dispersions (III, IV)

It has been suggested that in SDs, drug areas with dimensions of 50-100 nm can be
considered as drug particles that have not achieved molecular-level dispersion in the
polymer (Karavas et al. 2007a). When studying the distribution of PPZ in 1/5 and 1/20
PPZ/polymer SDs by SAXS using similarly processed PVP and PEG as references, there
was no evidence of these kinds of PPZ areas. In the pair density distribution curves of
PVP, PEG and their 1/5 and 1/20 SDs with PPZ (Figure 5.7 a, b), one large maximum
(approx. 25 nm) and another much smaller maximum (approx. 90 nm) can be seen, which
did not change in spite of addition of different amounts of PPZ (i.e. the case of 1/5 and

94
1/20 SDs). Thus, PPZ was uniformly distributed in the polymer matrices suggesting that
a molecular dispersion had been formed irrespective of the PPZ/polymer ratio.
However, the drug particle size in a SD might increase during storage due to phase
separation and crystallization of the drug (Dordunoo et al. 1997). After four weeks of
storage at 25C/60% RH, determination of the distribution of the inhomogeneity regions
revealed that with the PVP SDs, the maxima had been shifted from 24 nm to 26-27 nm
and from 89 nm to 70 nm (1/20 PPZ/PVP) (Figure 5.7 a). However, similar shifts were
visible with the freeze-dried PVP. In the case of PPZ/PEG SDs, the maxima were found
to be exactly the same in both the fresh and stored samples (i.e. 26 and 80 nm) (Figure
5.7 b). No increase in the size of the inhomogeneity regions (in the region up to 100 nm)
in the SDs had occurred during storage and thus, it was considered unlikely that phase
separation and crystallization had taken place.

Figure 5.7. Pair density distribution functions of (a) freeze-dried PVP () and 1/5 () and
1/20 (-) perphenazine/PVP fresh solid dispersions compared to the dispersions stored at
25C/60% RH for four weeks (corresponding symbols in grey); (b) freeze-dried PEG ()
and 1/5 () and 1/20 (-) perphenazine/PEG fresh solid dispersions compared to the
dispersions stored at 25C/60% RH for four weeks (corresponding symbols in grey),
determined from SAXS measurements.
The formation of solid solutions was confirmed by XRPD and DSC studies (Figures 5.8
a,b, Table 5.9) which revealed that PPZ was present in an amorphous form in the
dispersions in all mixture ratios and that all the SDs had a single T g, in contrast to many
studies with other drugs where amorphization of the drug has occurred only at higher
polymer contents (Shah et al. 1995, Lin and Cham 1996, Paradkar et al. 2004). This was
probably due to the complete miscibility of PPZ with the carriers, as indicated by the

95
similarity of their solubility parameters. Thus, in the case of PVP (initially amorphous,
Figure 5.8 a, Table 5.9), PPZ formed amorphous molecular dispersions with fully
amorphous PVP.
75000

60000

50000

25000

0
10000

Intensity (cts)

Intensity (cts)

d
40000

20000

a
5

10

15

20

25

0
5

30

2 theta ()

5000

c
b

10

15

20

25

d
PPZ

3000

PPZ PEG

PPZ
PEG
PPZ

2000

PPZ

a
c
b

1000

a
0
5

10

15

20

2theta ()

25

30

30

2theta ()

4000

Intensity (cts)

Intensity (cts)

5000

f
e
d
c
b
a

0
5

10

15

20

25

30

2theta ()

Figure 5.8. X-ray diffraction patterns of: (a) PPZ (a), PEG (b), PVP (c) and freeze-dried
PPZ (d); (b) fresh PPZ/polymer SDs (PVP a-c, PEG d-e); (c) freeze dried PPZ (a) and
PPZ/PVP SDs (b-d) stored at 40C/silica gel; (d) 1/5 PPZ/PEG SD before (a) and after
storage at 40C/silica gel (b) and 40C/75% RH (c).
However, the situation with PEG (initially crystalline, Figure 5.8 a, Table 5.10) was
found to be different. A decrease in PEG crystallinity as a function of the increasing PPZ
content indicative of lattice distortion of the carrier due to the formation of a solid
solution (Law et al. 2001), was seen in DSC (H values in Table 5.10). Furthermore, the
melting temperature of PEG was higher in the SDs compared to the physical mixtures
(Table 5.10) which might be attributable to the fact that the higher melting (extended
chain) form of PEG remained crystalline while the lower melting, once-folded
modification had transformed into the amorphous form (Craig 1990) during the SD
preparation process. The amount of amorphized PEG was found to be 94, 21 and 13 %

96
for 5/1, 1/5 and 1/20 dispersions, respectively, as can be calculated from the H values of
PEG in the dispersions and the H value for pure PEG, shown in Table 5.10. Thus, the
SDs consisted of two phases; one composed of crystalline PEG and one of amorphous
PPZ/PEG containing 19, 38 and 65 % of amorphous PEG, respectively.
Table 5.9. Glass transition (T g) and heat capacity (Cp) values (n= 3 sd) for freezedried perphenazine and the solid dispersions of perphenazine before and after the four
weeks of storage at 40C/silica gel.
Sample

Tg (C) before
storage

Cp (J/gK) before
storage

Tg (C),
after storage at
40C/silica gel

Cp ( J/gK)
after storage at
40C/silica gel

PPZ

15.3 0.3

0.49 0.06

PVP

172 0.3

0.22 0.03

PEG

nd.

nd.

freeze-dried PPZ

53.8 2.5

0.82 0.24

62.3 0.3

0.10 0.06

5/1 PPZ/PVP

58.9 0.6

0.68 0.14

60.9 0.8

0.46 0.10

1/5 PPZ/PVP

155.1 2.4

0.17 0.08

151.4 0.3

0.30 0.01

1/20 PPZ/PVP

170.3 1.4

0.13 0.03

165.7 1.6

0.26 0.02

5/1 PPZ/PEG

22.2 0.7

0.48 0.03

15.6 1.0

0.47 0.04

1/5 PPZ/PEG

-44.9 0.2

1/20 PPZ/PEG
nd.
- = not measured; nd. = not detected

0.02 0.01

nd.

nd

nd.

nd.

nd

Table 5.10. The melting points (T m,C) and enthalpies (H, J/g) (n= 3 sd) of PEG in
the prepared PPZ/PEG physical mixtures (PM), and solid dispersions (SD) before and
after the four weeks of storage at 40C/silica gel and 40C/75% RH.
Sample

Tm/C,
/J/ga
of PEG in PMb

Tm/C,
/J/ga
of PEG in SD

Tm/C,
/J/ga of PEG in
SD after storage at
40C/silica gel

Tm/C,
/J/ga of PEG after
storage at 40C/75%
RH

5/1 PPZ/PEG

59.7 0.1,
165 20

62.9 0.1,
9.4 2

64.0 0.4,
3.6 0.7

1/5 PPZ/PEG

59.3 0.1,
198 7

61.4 1.2,
157 6

60.8 0.7,
190 10

62.7 1.6,
190 5

1/20 PPZ/PEG

59.4 0.1,
193 1

61.2 0.3,
168 2

61.0 0.2,
196 2

63.3 0.3,
194 1

H is corrected for the amount of PEG in the mixture; b H of pure PEG is 186 3 J/g; - = not measured

97
The unexpectedly high Tg value observed for the amorphous, freeze-dried PPZ (Table
5.9) was attributed to the formation of an amorphous PPZ dihydrochloride salt due to the
preparation method, this being confirmed by the FTIR data. In fact, PPZ was found to be
present as an HCl salt in all of the SDs (example spectra in Figure 5.9 a, b), evidenced by
the appearance of a new absorption band at approx. 2400 cm-1 (HCl absorption) in freezedried PPZ and in the SDs.
The theoretical Tg-value for each of the PPZ/polymer blends was calculated according
to the GordonTaylor equation (Eq. 5) and Simha-Boyer rule (Eq. 6). The Tgs of the
freeze-dried PPZ and PVP measured by DSC (Table 5.9) and the T g value from literature
for PEG (Forster et al. 2001) were used for the calculations. The true density of the
components was measured by helium pycnometry, obtained values being 1.31, 1.17 and
1.48 g/cm3 for PPZ; PVP and PEG, respectively. In the calculations for PPZ/PEG SDs,
the true compositions of amorphous PPZ/PEG phase were used. The T g-values observed
by DSC (Table 5.9) were found to be in reasonable agreement with the values predicted
for the SDs by the Eq. 5 (74, 144 and 165C for 5/1, 1/5 and 1/20 PPZ/PVP, and 28, 5
and -24C for 5/1, 1/5 and 1/20 PPZ/PEG, respectively), except the value for 1/5
PPZ/PEG. Generally, deviation from ideal behavior would be caused by differences in
strength of intermolecular interactions between the individual components and those of
the blend (Nair et al. 2001).
a

Absorbance

Absorbance

e
b

d
c
b

a
4000 3500 3000 2500 2000 1500 1000
-1
Wavenumber (cm )

a
4000 3500 3000 2500 2000 1500 1000
-1
Wavenumber (cm )

Figure 5.9. The FTIR spectra of (a) 1/5 perphenazine/PVP solid dispersion before (a) and
after storage at 40/silica (b); (b) 5/1 perphenazine/PEG before (a) and after storage at
40/silica (b) and 1/5 perphenazine/PEG solid dispersions before (c) and after storage at
40/silica (d) and at 40/75% RH (e).

98
In addition, FTIR results revealed that hydrogen bonding between PPZ and PVP and/or
HCl was promoting the formation of PPZ/PVP solid solutions (Figure 5.9 a). In the SDs
of PVP, interactions between the OH-group of PPZ (band at approx. 3400 cm -1) and the
carbonyl group of PVP (band at approx. 1665 cm-1) were observed (example spectrum
shown in Figure 5.9 a) as shifts of the carbonyl band of PVP at to 1670, 1663 and 1662
cm-1 in the 5/1, 1/5 and 1/20 dispersions, respectively, compared to 1655 cm -1 in the
physical mixtures. Usually the carbonyl shift occurs to lower wave numbers (Nair et al.
2001), but similar shifts to higher wave numbers, indicative of specific drug-PVP
interactions, have been also observed (Taylor and Zografi 1997, Karavas et al. 2005). In
the case of SDs of PEG, interactions were present with the OH-group of PPZ and the
ether oxygen of PEG (band at approx. 1095 cm-1), observed as a small shift of the C-O
stretching band (2 cm-1 to the higher wavenumbers) in the case of 5/1 and 1/5
formulations compared to the physical mixtures (Figure 5.9 b). Hydrogen bonding
between PPZ and PEG was more difficult to demonstrate from the FTIR spectra than
between PPZ and PVP, in accordance with previous studies (Anguiano-Igea et al. 1995,
Van den Mooter et al. 1998).
These results indicate that the formation of a solid solution of PPZ and the presence of
PPZ HCl salt in the SDs, which created a microenvironment around the dissolving
particles leading to a high supersaturation of PPZ were the factors promoting the
dissolution of PPZ. Previously, simultaneous modulation of the microenvironmental pH
and drug crystallinity in solid dispersions has been claimed to be a useful way to increase
the dissolution rate of an ionizable drug (Usui et al. 1998, Tran et al. 2008). In
conjunction with hydrogen bonding between PPZ and polymers, these factors may also
improve the physical stability of the solid dispersions.
As a consequence of four weeks of storage of 1/5 and 1/20 PPZ/PEG SDs at accelerated
conditions (40C/75%), a breakdown of the stabilizing drug/polymer interactions was
observed by FTIR (Figure 5.9 b) which probably led to crystallization of the amorphous
part of PEG into a higher melting modification (Table 5.10, Figure 5.8 d), which has been
observed previously with PEGs (Dordunoo et al. 1997, Weuts et al. 2005). This led to at
least partial crystallization of PPZ which was observed by XRPD (Figure 5.8 d) and DSC
(i.e. no Tg was observed). Thus, the decline in dissolution rate after storage at 40C/75%

99
was most probably attributable to the increase in the amount of crystalline PPZ in the
SDs during storage. However, the capacity of PEG to create a local micro-environment
allowing more rapid dissolution probably compensated for the transformation of the drug
from an amorphous into the crystalline state, preventing the dissolution rate from
reverting back to the level of crystalline PPZ (Weuts et al. 2005). Furthermore, the
dissolution of PPZ from 1/5 and 1/20 PPZ/PEG had somewhat declined also after storage
at 40C/silica (Table 5.8), even though PPZ had remained in an amorphous state
according to XRPD (example diffractograms are displayed in Figure 5.8 d) and FTIR
demonstrated that the hydrogen bonding interactions between PPZ and PEG were stable
(example spectra shown in Figure 5.9 b). However, PEG had crystallized also in these
conditions (Table 5.10) from which it can be proposed that the ability of crystalline PEG
to preserve the supersaturated PPZ during dissolution is not as good as that of amorphous
PEG (Khougaz and Clas 2000, Konno and Taylor 2006). Regardless, it should be noted
that the dissolution properties after storage were still much better than those of the
crystalline PPZ with all PPZ/PEG formulations.
The PPZ/PVP SDs were found to be stable (observed by DSC and XRPD, Table 5.9
and Figure 5.8 c) during storage at 40C/silica, due to the antiplasticizing effect of PVP
and stabilizing hydrogen bonding interactions (observed by FTIR, Figure 5.9 a). In spite
of this, a significant decline was seen in the dissolution rate of PPZ from the 1/5 and 1/20
PPZ/PVP (Table 5.8). Similarly, a small decline in the dissolution rate of drugs has been
observed in other studies with PVP SDs when they are stored, in spite of the physical
stability of the SD (Ambike et al. 2004).
On the contrary, 5/1 PPZ/polymer SDs were found to be stable during storage at
40C/silica (Figures 5.8 c and 5.9 b, Tables 5.9 and 5.10) and the dissolution rate of PPZ
from these preparations was even slightly improved (Table 5.8). This phenomenon has
been claimed to be attributable to improved hydrogen bonding between the drug and
polymer due to increased molecular mobility during storage at elevated temperatures
(Gupta et al. 2002). In addition, freeze-dried PPZ remained stable during storage at
40C/silica (Table 5.9, Figure 5.8 c) but its dissolution rate became slightly slower (Table
5.8). The stability might be due to HCl salt formation, increasing the T g of the drug, and
it might promote the stability of PPZ also in the SDs, since the stability of some SDs has

100
been claimed to originate mainly from the physicochemical properties of the amorphous
drug (Law et al. 2001, Marsac et al. 2006).

5.3.3 Performance of fast disintegrating tablets containing solid dispersions (IV)

As discussed in chapter 2.3.2, FDTs can be prepared by variety of technologies, though
direct compression is relatively simple and economical. However, tabletting by direct
compression requires optimization of the type and amount of excipients and the
compression force in order to produce tablets which have sufficient hardness (i.e. > 1
MPa) but still disintegrate quickly (< 30s). In this study, this was examined by using a
combination of mannitol and disintegrants (CS and/or CP).
The 1/5 PPZ/PEG SD was selected for evaluation in the orally fast disintegrating tablet
formulation study considering the size of the dose (i.e. equivalent of 4 mg of PPZ) and
the results from physical characterization, dissolution rate and the stability studies. For
comparison, similar tablets were prepared with the 1/5 PPZ/PVP SD. Four different
formulations were prepared, the compositions and properties of which are shown in Table
5.11. A formulation containing 10% of 1/5 PPZ/PEG, 60% of mannitol, 15 % CS and
15% of CP (formulation 2) displayed a fast disintegration in 37 seconds even though it
had a tensile strength as high as 1.3 MPa (Table 5.11).
Furthermore, formulation 2 had the best PPZ dissolution properties (i.e. PPZ released
34 % in four minutes) (Figure 5.10 a), followed by formulations 1, 4 and 3, respectively.
Thus, PPZ release from the FDTs seemed to follow the order of the dissolution rates of
the SDs (Table 5.8). The tensile strengths of formulations 2 and 4 (containing CP and
CS) were higher (i.e. 1 MPa) than those of formulations 1 and 3 (containing only CS)
due to the higher compression force (Table 5.11). In spite of this, the disintegration times
of formulations 2 and 4 were considerably shorter than those of formulations 1 and 3.
This is due to CSs ability (alone or as a combination of superdisintegrants) to produce
tablets that retain their fast disintegration properties in spite of having being subjected to
a higher compression force (Rxcipients 2007). Furthermore, the disintegration time of
formulation 2, containing 1/5 PPZ/PEG, was 20 seconds shorter than the disintegration
time of the similar formulation 4, containing 1/5 PPZ/PVP, probably due to the lower

101
tensile strength of formulation 2 than that of formulation 4. This in turn might be
attributable to the SDs ability to resist deformation under the compaction force, which in
this case was better with PPZ/PEG, leading to the formation of weaker tablets (Sadeghi et
al. 2004).

Table 5.11. Formulation compositions, compression forces and resulting porosity (n=50)
of the FDTs containing either 10 % (w/w) 1/5 PPZ/PEG SD or 1/5 PPZ/PVP SD. In
addition, mass uniformity (n=50 (before) sd and n=20 sd (after)), tensile strength
(n=6 sd), disintegration time (n=6 sd) of the tablets before and after storage at
21C/60 % RH are shown.
Formulation
Property

SD
Mannitol % (w/w)
Calcium silicate % (w/w)
Crospovidone % (w/w)
Compaction force (kN)
Tablet porosity (%)

1/5 PPZ/PEG
60
30
5
29

1/5 PPZ/PEG
60
15
15
10
19

Mean weight (mg)

Tensile strength (MPa)
Disintegration time (s)

199.6 0.5
0.40 0.04
104 17

Mean weight (mg)

Tensile strength (MPa)
Disintegration time (s)

199.0 0.4
0.70 0.11
>120

1/5 PPZ/PVP
60
30
5
32
Fresh tablets

1/5 PPZ/PVP
60
15
15
10
22

200.5 0.6
1.28 0.06
37 3

198.7 0.5
0.62 0.07
>120
After storage

198.4 1.0
1.58 0.06
58 2

200.4 0.5
1.11 0.04
36 4

200.9 0.5
1.73 0.14
>120

204.8 1.1
1.29 0.07
68 4

Figure 5.10. Dissolution properties of the tablet formulations containing solid dispersions
1/5 of perphenazine with PEG (formulations 1 () and 2 ()) and PVP (formulations 3
) and 4 ()) (a) before and (b) after storage at 21C760% RH.

102
Formulation 2 was the best at maintaining its performance during storage at 25C/60%
RH (Table 5.1, Figure 5.10 b). The release properties of formulations 1 and 2 had
remained unchanged (or had become somewhat faster) throughout the storage (Figure
5.10 b), with formulation 2 still being the fastest releasing formulation. Instead, the
release of PPZ was slower from formulations 3 and 4 after storage (Figure 5.10 b). These
changes in dissolution properties were probably attributable to the changes in the tablet
properties occurring during storage (Table 5.11).
Due to the hygroscopicity of 1/5 PPZ/PVP, the weight of the tablets of formulations 3
and 4 had increased whereas the weight of the tablets containing 1/5 PPZ/PEG
(formulations 1 and 2) had remained constant during the storage (Table 5.11). The tensile
strength values had increased with formulations 1 and 3 but decreased with formulations
2 and 4 which can be attributable to several factors. The tensile strength during storage at
high relative humidity can decrease due to moisture uptake with a subsequent weakening
of the binder bridges (Carstensen 2000). Formulations 2 and 4 contained CP, for which
this behavior has been observed before (Engineer et al. 2004). In contrast, an increase in
tensile strength might occur when the sorbed moisture causes recrystallization of a tablet
component or its softening or deliquescence and subsequent filling of the pores of the
tablets (Serajuddin 1999, Carstensen 2000, Sunada and Bi 2002, Marsac et al. 2006a,
Sugimoto et al. 2006), which might be the case with formulation 3. This would also
account for the poorer release of PPZ from the tablet after storage. The increase in tensile
strength led to an increase in the disintegration time with formulation 1. The
disintegration time of formulation 2 remained the same whereas that of formulation 4
increased, in spite of the decrease in tensile strength, which might explain the slightly
slower release of PPZ.

5.3.4

Summary and future prospectives (III, IV)

In this study, freeze-drying of solutions of a poorly water soluble PPZ with 0, 20, 80 or
95% of a polymer led to an improved PPZ solubility and extremely fast dissolution rate
in a small liquid (pH 6.8) volume compared to crystalline or micronized PPZ. The most
remarkable improvement in the dissolution rate was seen with 1/5 PPZ/PEG formulation

103
which dissolved within one minute without precipitation of the supersaturated PPZ.
Dissolution of PPZ was enhanced by solid solution formation, which in turn was
promoted by hydrogen bonding interactions between the drug and polymers, and the
formation of HCl salt of PPZ in the SDs. These factors, in addition to hydrogen bonding
between PPZ and both polymers, probably promoted the stability of PPZ in all solid
dispersions when they were stored for four weeks at 40C/silica. Nonetheless, the
dissolution rate of PPZ from the solid dispersions was found to be changed, with 1/5
PPZ/PEG still exhibiting the fastest dissolution of PPZ.
When formulating the 1/5 PPZ/polymer SDs into FDTs, a fast and immediate onset of
the release of PPZ (i.e. 34 % of perphenazine in 4 minutes) was provided by the
formulation containing 10% of 1/5 PPZ/PEG, 60% of mannitol, 15 % CS and 15% of CP.
This might mean, however, that the remaining solid material (i.e. approx. 60% of the
drug) is not dissolved in the oral cavity as intended, but is simply swallowed and will be
absorbed via the GI-tract. The formulation showed a fast disintegration in 36 seconds and
had sufficient tensile strength (i.e. >1 MPa) to permit normal handling and packaging,
which is better than the disintegration times reported previously for FDTs containing
SDs, i.e. from 60 to 780 seconds (Valleri et al. 2004, Sammour et al. 2006, Goddeeris et
al. 2008). The formulation also maintained its performance during the four weeks of
storage at 25C/60% RH, as also in some previous studies with tablet formulations
containing SDs (Hirasawa et al. 2004, Valleri et al. 2004, Shibata et al. 2005).
The absorption of PPZ in vivo has been studied in rabbits after sublingual
administration of 1/5 PPZ/PEG SD powder, in addition to a solid PPZ/-CD complex,
plain micronized PPZ and after oral administration of an aqueous PPZ solution (Turunen
et al. 2008). The absorption of PPZ (AUC0-360min) was observed to decrease in the
following order: sublingual micronized PPZ > sublingual 1/5 PPZ/PEG SD > sublingual
solid PPZ/-CD complex > oral aqueous PPZ solution. Thus, the SD formation improved
more the sublingual absorption of PPZ in comparison to CD complexation, but was still
less effective than drug micronization, possibly due to larger bulk volume of the SD.
Today, approx. over 40% of the lead compounds have poor solubility, seriously
limiting their bioavailability (Hauss 2007, Stegemann et al. 2007). This figure is not
likely to decrease in the future, meaning that innovative dosage forms for enhancing the

104
solubility and dissolution rate, such as the amorphous systems, are increasingly needed.
In this study, the suitablility of the solid dispersion approach for formulation of a poorly
soluble drug (PPZ) into an intraoral FDT formulation was assessed. The need for
sophisticated drug delivery systems, such as those presented in this study, is expected to
increase in the future due to the increasing proportion of elderly patients. These types of
formulations are also suitable for pediatric patients (Danish and Kottke 2002). Moreover,
FDTs offer a means for extension of the patent life and market exclusivity for
pharmaceutical companies (Chandrasekhar et al. 2009).
In addition, as pointed out in this study, a thorough understanding of the way in which
solid state properties influence solubility, stability and other properties of the drug
substance is critical when developing drug formulations. In spite of intensive research
e.g. in the field of amorphous drugs and SDs there is still a lack of deep understanding of
the behaviour of these systems. In addition, optimized (new) manufacturing techniques
that are easily scalable remain a field where work is needed in the SD research. However,
control over the amorphous state represents a challenge also in the field of delivery of
macromolecules (e.g. peptides and proteins), since many of these formulations are at least
partially amorphous (Byrappa et al. 2008, Daugherty and Mrsny 2006, Shoyele and
Cawthorne 2006).

105
6

CONCLUSIONS
I.

Hydrophobic starch acetate and ethyl cellulose matrices were shown to be capable
of controlling the release of highly water soluble saccharides over a wide time
scale simply by altering tablet porosity and the relative amount of the excipient in
the tablet. The desired saccharide release was achieved with matrices that had
either relatively low porosity and a high amount of saccharide in the tablet or high
porosity and a low amount of saccharide in the tablet.

II.

The drug release rate of water soluble model drugs from starch acetate matrix was
modified by dry powder agglomeration. The agglomeration process affected the
particle distribution in the mixtures, this being dependent on the size and the
surface roughness of the drug particles, leading to changes in tensile strength and
drug release properties of the tablets.

III.

An extremely fast dissolution rate of a poorly water soluble perphenazine (PPZ)

in a small liquid (pH 6.8) volume was obtained by the formation of solid solutions
of HCl salt of PPZ with polyvinylpyrrolidone (PVP) or polyethyleneglycol
(PEG). The 1/5 PPZ/PEG solid dispersion powder, which dissolved within one
minute, was found to be the most promising candidate for usage in intraoral
formulations.

IV.

PPZ remained amorphous in the prepared PVP and PEG solid dispersions when
stored protected from humidity, but nonetheless the dissolution of PPZ had
declined to a greater or lesser extent. In the formulation study of an orally fast
disintegrating tablet, a formulation containing 10% of 1/5 PPZ/PEG, 60% of
mannitol, 15 % calcium silicate and 15% of crospovidone underwent fast
disintegration, displayed a fast and immediate onset of the release of PPZ and had
sufficient tensile strength. The formulation also maintained its performance
during four weeks of storage at 25C/60% RH.

106
V.

In this study, simple formulation and processing modifications, needing no

expensive and complicated equipment or process stages, or new chemical entities,
showed great potential in achieving controlled modification of release and
dissolution of physicochemically diverse drugs. These simple methods can be
helpful in solving the future challenges of developing innovative formulations and
dosage forms, e.g. enhancing the drug solubility and dissolution rate of new, more
hydrophobic lead molecules that otherwise would have limited bioavailability.
The results can also be useful for developing dosage forms for the increasing
proportion of elderly patients as well as for children, two patient groups who
experience problems in swallowing conventional dosage forms.

107
7

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138

ORIGINAL PUBLICATIONS
I

Mki R, Suihko E, Korhonen O, Pitknen H, Niemi R, Lehtonen M, Ketolainen J:

Controlled release of saccharides from matrix tablets. Eur J Pharm Biopharm 62:
163-170, 2006.

II

Mki R, Suihko E, Rost S, Heiskanen M, Murtomaa M, Lehto VP, Ketolainen J:

Modifying drug release and tablet properties of starch acetate tablets by dry
powder agglomeration. J Pharm Sci 96: 438-447, 2007.

III

Laitinen R, Suihko E, Toukola K, Bjrkqvist M, Riikonen J, Lehto VP, Jrvinen

K, Ketolainen J: Intraorally fast dissolving particles of a poorly soluble drug:
preparation and in vitro characterization. Eur J Pharm Biopharm 71: 271-281,
2009

IV

Laitinen R, Suihko E, Bjrkqvist M, Riikonen J, Lehto VP, Jrvinen K,

Ketolainen J: Perphenazine solid dispersions for orally fast disintegrating tablets:
physical stability and formulation. Drug Dev Ind Pharm, submitted

Kuopio University Publications A. Pharmaceutical Sciences

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