Exipient development halm 115

Water
Excipients both typically contain water and are required to interact with it. The
water associated with excipients can exist in various forms. Studies with
different
materials have shown that water can exist in association with excipients in at
least
four forms that may be termed free water, bound water, structural
water,
and water of crystallization. Water associated with a particular excipient may
exist
in more than one form (26). The type of water will govern how it is implicated
in
interactions between the excipient and the API or another excipient. The so-
called
free water is the form that is most frequently implicated in excipient
interactions.
Bound water is less easily available for interaction, and structural water is
usually
the least available one. Water of crystallization can be very tightly bound into
the
crystal structure; however, there are some comparatively labile hydrates, e.g.,
dibasic
calcium phosphate dihydrate (see above). If water of crystallization remains
tightly
bound within the crystal structure, it is unlikely to participate in an excipient
interaction.
However, any material that is in equilibrium with air above 0% RH will have
some free moisture associated with it. In reality, below about 20% RH, the
amount of moisture will probably be insufficient to cause problems. However,
if sufficient
moisture is present (e.g., at a higher RH), it can facilitate the interaction
between components of the formulation.
The dibasic calcium phosphate dihydrate example discussed above is probably
an extreme example of the instability of an excipient relating to the release of
water.
But many excipients exist in a hydrated state, and heating them for the
purposes of
compatibility studies, or accelerated stability testing, can cause any free
water, and
sometimes other types of water, to be released, which can then influence any
potential
interaction, or even interact itself with the drug.
Excipient Interactions 103
2006 by Taylor & Francis Group, LLC

The interaction of many excipients with water is an important property

because the physiological fluids the medicine will encounter after
administration
are based on water. For example, we use the interaction between the tablet
disintegrant
and water to facilitate the breakup of a conventional immediate release tablet
or capsule in the stomach, and thereby aid the dissolution of the API.
Certain APIs are administered topically, e.g., topical anti-inflammatory steroids
and topical anti-fungal agents. The release of these APIs from their formulation
was thought to be maximized when the solution of the drug in the vehicle is
just saturated
(27). However, Davis and Hadgraft (28) have shown that supersaturation can
increase the penetration even further. The interaction of the moisture present
in the
skin with the topical formulation can be used to change the degree of
saturation of
the formulation and thereby enhance the release of the API from the
formulation
into the skin.
Oxygen
Like water, oxygen frequently interacts with pharmaceutical materials, both
APIs
and excipients. Antioxidants are included in many formulations to inhibit
oxidation
reactions. Oxidation reactions do not necessarily require molecular oxygen.
For
example, the oxidation of cytidine analogues to the equivalent uridine
analogues
can occur in the presence of water even in the absence of oxygen. But oxygen
is
implicated, for example, in the breakdown of unsaturated fatty acids
(rancidity).
Oxygen can also react with, e.g., polyethylene glycols (PEGs). These materials
are
stabilized, during manufacture, by either the addition of antioxidants, or
manufacturing
under a nitrogen blanket to exclude oxygen. It is important to know which
material is stabilized, because a change in source might lead to unexpected
stability
problems because of the presence or absence of the antioxidant, and thus
changes in
the potential for interaction.

PHYSIOLOGICAL/BIOPHARMACEUTICAL INTERACTIONS
By this we mean interactions that occur after the medicine has been
administered to
the patient. For the most part, they are physical interactions. However, the
major
distinctions are that the interaction is between the medicine (including
excipients)
and the body fluids, primarily comprising aqueous solutions, and that they
have
the potential to influence the rate of absorption of the drug. They will vary
depending
on the route of administration. Because physiological and biopharmaceutical
interactions are so important, and they are not specifically linked, for example,
to
the stability of the medicinal product, and also because they occur after the
medicine
has been administered to the patient, they have been included as a special
category
for the purposes of this discussion. The importance and potential impact of
biopharmaceutical
interactions of excipients has been recognized for some years (see for
example Ref. 29).
All excipients interact in a physiological sense when they are administered as
part of the medicine. For example, we can get dilution of the vehicle leading to
changes in viscosity or precipitation of the drug, disintegration of a tablet or
capsule,
activation of a controlled release mechanism, etc. This may be stating the
obvious to
many, but in many instances this interaction with physiological fluids is not
actively
considered; although it may be understood or assumed to be occurring.
However these physiological interactions are very important for the correct
functioning of the
product, and it is thus important to understand when other interactions occur
and
what the physiological impact will be. For example, we consider the physical
properties
of magnesium stearate as a tablet or capsule lubricant, but, as was discussed
in
Physical Interaction section, it is well documented in the literature that
when magnesium
stearate is used incorrectly these same physical properties can lead to
problems
that can impact dissolution, and thus could possibly affect bioavailability.
We include certain excipients in a formulation specifically because they
interact
with the physiological fluids and the bodily functions in a certain way. For
example,
as discussed above, we include disintegrants in immediate release tablet and
capsule
formulations, because we know that when they encounter the aqueous
environment
of the stomach, they will cause the tablet or capsule to disintegrate and
thereby aid
dissolution of the API. Another example is the general case of hydrophilic
colloid
matrices used as prolonged release drug delivery systems. We know that
when these
materials contact the aqueous environment of the GIT they swell and create a
diffusion
barrier that slows the rate of dissolution of the dissolved drug.
One physiological interaction that can potentially cause serious problems for
the patient is the interaction between enteric coatings and antacids. Enteric
coatings
on tablets or capsules are intended to allow the formulation to pass though
the stomach
into the duodenum before dissolution and then rupture of the enteric coating,
disintegration of the tablet core, and release of the drug. Certain products
may be
enteric coated to protect the API from degradation in the stomach, e.g., pro-
drugs.
Other APIs are enteric coated to protect the stomach from the API, e.g.,
nonsteroidal
anti-inflammatory drugs (NSAIDs). The enteric-coating polymers, e.g.,
cellulose
acetate phthalate and hydroxypropyl cellulose acetate phthalate, rely on their
pHsolubility
profile for their function; they are soluble at a more basic pH, but insoluble
at acid pH. Antacids raise the pH of the stomach contents and thus cause the
enteric
coating to begin to dissolve in the stomach. The enteric coating thus begins to
breakdown
allowing the premature release of the API in the stomach. For the pro-drugs,
this might mean that more of the drug is degraded than is desirable and the
patient
would receive a suboptimal dose. For the NSAIDs, the premature breakdown of
the
enteric coat may cause unwanted side effects, such as gastric bleeding.
A classic biopharmaceutical incompatibility is the interaction between
tetracycline
antibiotics and calcium and magnesium ions (30). A complex is formed that is
not absorbed from the GIT. This is a well-known interaction, and tetracycline
antibiotics
usually carry a warning against taking them with certain types of food. But
magnesium and calcium salts are quite common excipients, in terms of both
the
range of formulations containing them and the level of inclusion in those
formulations.
How many of us would think about not including magnesium stearate in a
formulation of medicine intended to be an adjunct therapy to treatment with a
tetracycline?
The point is that the design of a formulation cannot be undertaken in
isolation, and the possibility of excipient interactions on final administration to
the patient must be considered, not only with the formulation being
developed,
but also with other medicines administered concomitantly.
Some drugs, such as aspirin, appear to be well absorbed along the length of
the
lower GIT (the ileum and colon). Certain other drugs, e.g., metoprolol, have a
limited
absorption window in the GIT. That is to say that they are not absorbed along
the whole length of the lower GIT but only to a small segment of it. For these
drugs,
it is clear that the speed with which the drug passes down the GIT
(gastrointestinal
motility) will influence absorption of the drug. Certain excipients can increase
gastrointestinal motility, i.e., speed up the passage of material down the GIT,
and
thereby reduce the time available at the site of absorption for drugs such as
metoprolol.
Excipients that can increase gut motility include the polyols [e.g., sorbitol and
xylitol(31)]. The effect is very much dependent on the amount of the polyol
administered
at one time. PEG 400 has also been reported to influence the absorption of
ranitidine in a similar fashion (32). These are examples of physiological
interactions
between an API and an excipient.
As our understanding of the mechanisms whereby drugs are absorbed
increases, we have come to understand that not only are there mechanisms of
drug
absorption, but also mechanisms whereby drugs are actively secreted back
into the
lumen of the GIT. These are known as efflux mechanisms, and a major efflux
system
concerns p-glycoprotein (there may be others). The significance of p-
glycoprotein is
that if a drug is a p-glycoprotein substrate (or a substrate for any other efflux
mechanism), it may not matter how well absorbed the drug is, the efflux
mechanism
is likely to pump the drug back out into the GIT. In the past it has been
assumed that
certain drugs were just not well absorbed, and that may have been the case,
but there
is now another possible explanationthat they are substrates for an efflux
mechanism.
There are recent reports in the literature that at least one excipient, a-
tocopheryl
PEG 1000 succinate, appears to inhibit the p-glycoprotein efflux pathway
(33,34). If
confirmed, generally, this potentially beneficial biopharmaceutical interaction
may
have important implications for the oral delivery of certain drugs.

SUMMARY
Excipient interactions are what make the formulations work, or not work in
some
cases. In one sense, pharmaceutics might be described as the science and
investigation
of excipient interactions. Excipient interactions may be classified as physical,
chemical, or physiological/biopharmaceutical. They can also be beneficial or
detrimental.
Not all excipient interactions are detrimental, and many interactions
between two or more excipients are used to enhance the performance
attributes of
the medicinal product, or to improve the manufacturing process. However,
prediction
of excipient interactions and relating them to product stability is complex,
particularly for physical interactions. Excipient compatibility studies can
provide
information on which excipients to avoid because of a probable chemical
interaction.
Interactions between excipients and active drugs, or between two excipients,
can
occur during administration of the medicine to the patient. Excipient
interactions
can also occur throughout the development life cycle. Formulation design
relies
on excipient interactions, but the formulator must take into account all the
known
potential interactions of the excipient to realize a robust formulation that will
make
it to market. It is often as important to understand the limitations of a system,
as it is
to understand its advantages, and this applies very much to excipients and
pharmaceutical
formulation.
Water is an essential component of many excipient interactions, whether
chemical,
physical, or physiological/biopharmaceutical.
Our understanding of the biopharmaceutical and physiological processes that
occur during drug absorption is rapidly increasing. It is clear that excipients
can
influence some of these processes, and the formulation scientist needs to be
aware
of the potential of these effects. Not all effects are detrimental, but many are.
They
can mean the difference between success and failure of a development
project. As
106 Moreton
2006

stated in the Introduction section, we need to consider three components in

order
to design a successful formulation: the advantages and limitation of the API,
the
excipients, and the manufacturing process. We can now add a fourth
component
how they all interact? Perhaps this is the key to understanding the science
of pharmaceutical formulation.
REFERENCES

Halm 129

MATERIAL CHARACTERISTICS AND FLOW PROPERTIES

Powder flow is typically determined by particle size, particle size distribution,
and
particle shape (39). Particle size and its distribution have a critical effect on
the mixing
of powders and the resulting content uniformity of the solid dosage form. Wide
differences in particle size result in product segregation during manufacturing.
Irregularly
shaped particles also contribute to poor flow properties (40,41). Particles
having a more regular shape (nearly spherical) are easy to flow and pose
minimal
hurdles during dosage form production. Coprocessing overcomes all these
limitations
and provides excipients with predefined attributes.
Halmn 148

Microcrystalline Cellulose
Physical Properties
Examination of these materials reveals that many have similar particle
morphology
particle shape, aspect ratio, etc.but they differ significantly in their particle
size
ranges. SEM images in Figure 3A show Avicel PH102, which has a particle
morphology
representative of several MCC grades, and Avicel PH105, a specialty grade
with a more unique morphology. The particles of Avicel PH102 appear very
rough, with many wrinkles and folds, and irregular in shape, with aspect ratios
from
1.5 to 3. Other grades with similar morphology include Avicel PH101, PH200,
PH301, and PH302, but they differ significantly by particle size. Both SEM
images
and laser diffraction particle size data indicate that the PH102 grade particle
diameters
ranged from under 10 mm to about 200 mm, while Avicel PH200, a coarser
grade, had about 10% of particles under 50 mm diameter with 300 mm
diameter particles
being not uncommon. Avicel PH101, a finer grade than PH102, showed about
40% of particles under 50 mm, with the largest approaching 140 mm. Avicel
PH302
showed a size range very similar to PH102. The particles of Avicel PH105, a
very fine
grade, generally show a flake-like morphology with typical length-to-width
aspect
ratios from 2 to 3 and diameters from less than 5 mm to about 30 mm. Laser
diffraction
particle size data indicate that about 95% of particles were under 50 mm.
Overall,
these materials showed narrow particle size distributions (BMID80<2).
In summary, MCC products are offered in a wide range of particle sizes
and they typically show very rough particle morphology. Based on these
properties,
one would expect a wide range of handling behavior with these materials,
from poor flowing and very cohesive to freely flowing, and a range of
mechanical
properties.