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Definition:
It is a stage of formulation development where
Objective:
To generate information useful to formulator in
developing stable and bioavailable dosage forms
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Preformulation
Bulk
characterisation
Solubility
characterisation
Stability
characterisation
Description
pKa
Solid state
stability
Crystallinity
pH solubility
profile
Solution
stability
Polymorphism
Common ion
effect
Bulk stability
Particle size
Thermal effect
Compatibility
Bulk density
Partition
coefficient
pH rate profile
Powder flow
properties
Dissolution
Stability in
formulation
Hygroscopicity
BULK
CHARACTERISATION
Description
The colour, odour, and taste of the drug is recorded
Molecular structure
External
Chemical
structure
Habit
Amorphous
Overall appearance of
the compound
Single entity
Internal
Crystalline
Molecular
adduct
(pseudopoly
morphism)
Salt forms
Solvates/
hydrates
Internal structure
Higher energy state High solubility, Less
stability
Amorphous form: Highest energy state
greatest solubility
Crystalline form polymorphism
ENANTROPIC polymorphs can be reversibly
changed into another stable form by changing the
temperature or pressure. RARE
MONOTROPIC one polymorph is stable at all
temperatures and pressures and others will
eventually convert to the stable form. COMMON 8
Solubility:
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Pseudopolymorphim
Crystalline form of drug can exist as a molecular
adduct.
If water molecules are incorporated into the drug
molecules hydrate and water is know as water of
crystallisation
If any other solvent solvates and solvent of
crystallisation
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Crystal habit
1. cubic system is one where all sides
equal one another and where all
angles are 90.
2. orthorhombic system all angles are
90 but the side lengths are
unequal.
3. monoclinic system is one where all
sides are different, where two of the
angles are 90 but one is not
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Ca Oxalate Thermogram
Change in weight with change in temperature is monitored
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UV-Vis spectroscopy
UV spectrum of theophylline
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FTIR spectroscopy
Chromatography
TLC
Paper chromatography
Thin layer of silica, alumina, cellulose etc on glass plates
HPLC
Normal phase
Polar stationary phase
Non polar mobile phase
Reverse phase
Non - Polar stationary phase
polar mobile phase
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Melting point
Requires minute amount of substance
Information regarding
1. Thermal properties of substance
2. Stability of the compound
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Hygroscopicity
Hygroscopic-absorb moisture from the atmosphere
when exposed but does not change its state. eg
anhydrous CuSO4.
Deliquescent-it absorbs moisture from the
atmosphere when exposed and changes its state.
eg. NaOH, KOH
Efflorescent-lose their moisture to the atmosphere
when exposed and changes into amorphous form
from crystalline hydrated state.
Na2CO3.10H2O ---> Na2CO3.H2O+9H2O
(crystalline)
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TEST
Powder is exposed to a range of controlled
humidity environment and moisture uptake is
recorded
Any compound that takes up more that 5%
moisture should be stored at low humidity
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Particle size
Fine particle characterization
Various methods like:
Coulter counter method
SEM
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Density
Absolute and bulk densities of the drug substance decides size
granulation of tablet
High- dose capsule formulation
Filling of tablet dies
Density of solids affects their flow properties
Significant difference in the absolute densities of components
leads to segregation
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Flowability
Flow properties of powders are critical for efficient tableting
operation
Angle of repose
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Type of flow
<20
Excellent
20-30
Good
30-34
Passable*
>40
Very poor
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Compactibility/ Compressibility
"Compressibility" of a powder is the ability to decrease
in volume under pressure. (Carrs ratio)
"Compactibility is the ability of the powdered material
C 100 1
T
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Carrs index
Is an indication of the compressibility of a powder
Frequently used as an indication of flowability of powder
A Carrs index >33 (equivalent to 1.5 of Hausners ratio)
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Carrs ratio
Type of flow
5-15
Excellent
12-16
Good
18-21
Fair to passable*
23-25
Poor*
33-38
Very poor
>40
Extremely poor
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Solubility Characterisation
Solubility
Solid drugs administered orally for systemic activity must
dissolve in GI fluids prior to absorption
Dissolution of drugs in gastrointestinal fluids influences the
rate and extent of their absorption
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Intrinsic Solubility C0
Definition: Fundamental solubility of any substance when it is
completely unionized
ie the solubility of an acid in acid and the solubility of a
base in base
If solubility of a substance increases in aqueous basic
solution in comparison to water is known as a weak acid
Measurement of solubility
Solubility is measured at two temperatures
4oC - Substances possess minimum solubility due to max
density of water
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Water
2.
3.
0.01M HCl
4.
0.1M HCl
5.
0.1M NaOH
6.
pH 7.4 buffer
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Semi-quantitative determination
Add solute in small amounts to fixed volume of solvent
Shake the system vigorously
Quantitative analysis
pH dependent solubility
Most drugs (75%) are weak bases, 20% are
weak acids and 5% are non ionic
Weakly acidic drugs pKa > 3 unionised in
stomach
Weakly basic drugs pKa 8 9 ionised in
stomach and intestine (duodenum)
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A
pH pK a log 10
HA
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pH solubility profile
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pKa
Solubility is influenced by the degree of
ionization of the substance.
Many drugs are either weak acids or weak
bases.
In solutions of these drugs equilibrium exist
between undissociated molecules and their
ions
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Effect of temperature
The solubility of any substance is a function of
temperature.
Most substances are endothermic, absorbing
heat in the process of dissolution.
For these substances, an increase in temperature
results in an increase in solubility.
A few substances, such as calcium hydroxide and
sodium carbenicillin, are exothermic and give off
heat in the process of dissolution.
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Partition coefficient
Measure of relative solubility of a drug in other
solvents as compared to water
Solvent: water quotient of drug distribution.
Coil
Po
w
Cwater
Equilibriu m
Biopharmaceutical Classification
System
Class I
Class II
Solubility
Solubility
Permeability
Permeability
e.g. Paracetamol,
metoprolol
e.g. Atenolol,
ranitidine
BCS
classification
e.g. Cinnarizine,
Famotidine
e.g. Griseofulvin,
spironolactone
Class III
Class IV
Solubility
Solubility
Permeability
Permeability
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Class
I
II
Solubility
High
Low
Permeation
High
High
Absorption
Good
Variable
III
IV
High
Low
Low
Low
Variable
Poor
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Dissolution
Intrinsic Dissolution
Definition:
The intrinsic dissolution rate (IDR) of a pure substance
is the rate at which it dissolves from a constant surface area
whilst the temperature, agitation, pH, and ionic strength of
the dissolution medium are kept constant.
or
medium.
Expressed as mg/min/cm2.
Knowledge of this value helps in predicting if absorption would be
dissolution rate-limited
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conditions)
Intrinsic dissolution rate is defined by the equation
Where
A : surface area of the dissolving solid
D : diffusion coefficient
h :diffusion layer thickness
V :volume of the dissolution medium
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Determination of IDR
Preparation of compressed pellet:
1.
about 500 gm of pure drug is loaded in a stainless steel punch and die
2.
3.
disc
The base plate is then detached to expose a smooth and constant pellet
surface at the face of the die
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Dissolution procedure
1. Die is inverted and screwed onto a customized shaft on a
dissolution tester
2. Shaft is lowered into dissolution medium until the face pellet
is 3.8 cm from the bottom of the vessel
Calculation
Plot a graph of cumulative amount dissolved per unit
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Stability
As a general rule all drug products should have a shelf life of atleast
3 years
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1.
2.
3.
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Solid-State Stability
Refers to physical as well as chemical stability
1. Pyrolysis (temperature)
2. Hydrolysis and solvolysis
3. Oxidation,
4. Photolysis,
5. Hygroscopicity
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Temperature
Pyrolysis is chemical decomposition of substances that occurs
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Hydrolysis
Water from atmosphere may be absorbed
Get hydrolyzed
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(4) Heat
Oxidation
Degree of oxidation is influenced by
environment
Light
Trace metals
Oxygen
Oxidizing agents
Photolysis
Many drug substances fade or darken on exposure to light
Usually the extent of degradation is small
Degradation is limited to the exposed surface area
Hygroscopicity
A substance that absorbs enough moisture to dissolve itself is
deliquescent.
A substance may loose water to form a lower hydrate or become
anhydrous is called efflorescent.
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Excipient compatibility
Drug is in intimate contact with one or more excipients;
Binders
Disintegrants
Lubricants
Fillers
Compatibility screening for new drug must consider two or more
excipients from each class
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Drug
No interaction
50% mixture
DSC
Recommend excipient
interaction
Excipient
TLC
Alternative
Excipient
Yes
Significant
breakdown
No
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