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Preformulation

Definition:
It is a stage of formulation development where

physical and chemical properties of drugs alone and


when combined with excipients are studied

Objective:
To generate information useful to formulator in
developing stable and bioavailable dosage forms
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Stages in formulation development

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:

AMORPHOUS > METASTABLE > STABLE


FORMULATORS PREFER THE METASTABLE FORM.
Chloramphenicol palmitate: 3 polymorphic forms
A, B and C
B metastable form, best BA
A most stable, biologically inactive
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Polymorphs have different physical properties like


1. Melting point
2. Density
3. Compaction behaviour
4. Vapour pressure
5. Solubilities
6. Flow properties
7. X-ray diffraction patterns
8. Crystal and optical behaviour
9. Different stabilities

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Distinguishing amorphous and


crystalline forms
Powder X~ray
diffraction patterns
of amorphous and
crystalline
trihydrate forms of
epicillin

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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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Anhydrous form > hydrate form


eg. Ampicillin has more solubility than
ampicillin trihydrate
Solvates > non-solvates
eg. Chloroform solvate of griseofulvin is more
soluble than griseofulvin

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Distinction between solvate and true


polymorph
Observing melting behavior of substances
Hot stage micrometer
Drug dispersed in silicone oil using hot stage
microscopy

Hydrates and solvates evolve a gas causing


bubbling of oil

The temperature of bubbling is close to


boiling point of solvent

True polymorphs melt without gas evolution


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Salt form of the drug


Most drugs exist as weak acids or weak bases, thus making
salt forms improves solubility
Acidic drugs ppt in stomach eg. Pentobarbital, hexobarbital
sodium or potassium salts
Pentobarbital sodium, Warfarin sodium

Basic drugs ppt in intestine eg. Codeine, theophylline


hydrochloride or sulphate salts
Codeine hydrochloride, Ranitidine hydrochloride

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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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Crystal characteristic and stability


For drugs prone to degradation in solid state, physical form of drug

influences rate of degradation


Eg: Aztreonam, a monobactam antibiotic exists in needle like and dense
spherical -crystalline forms
In presence of high humidity (37C/75% RH),

form undergoes -lactam hydrolysis more readily


Half life of 6 months

form under identical conditions is stable for several


years
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Polymorphic transformations can occur during grinding,


granulating, drying, and compressing operations.
Eg: Digoxin, spironolactone, and estradiol undergo
polymorphic transformations during comminution process
During granulation use of a solvent can lead to a solvate
formation

Drying may cause transformation to an amorphous form

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Crystal characteristics and tableting


behavior
Eg: different polymorphs of sulfathiazole,
barbitone. and asprin differ significantly in
their compression characteristics
Crystalline indomethacin yields tablets with
better hardness than amorphous form

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How to study Purity?


Generally determined by the analytical department
1.
2.
3.
4.

Thermal analysis DTA, DSC and TGA


Spectroscopy UV and FTIR
Chromatography TLC and HPLC
Melting point

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Differential thermal analysis (DTA)


Material under study and an inert reference are made
to undergo identical thermal cycles, and temperature
difference between them are recorded.

Differential temperature is plotted against time.


Changes in sample, either exothermic or endothermic,
can be detected relative to inert reference.

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Differential scanning calorimetry (DSC)


Measures amount of
energy required to
keep the sample at
the same
temperature as the
reference. i.e.
measures the
enthalpy of transition
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Thermo-gravimentric Analysis (TGA)

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

FTIR spectra of cinnarizine


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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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Chemical stability, flowability and compatibility


are affected if moisture is absorbed
Mechanical processing of solids such as grinding,
milling, micronization, compaction, etc., can
induce changes in their reactivity toward water
vapor
Preformulation study should be conducted with
the form of material to be used in the final
formulation
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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

of the final dosage form.


Very critical for
Drugs of low potency - constitute the bulk of final

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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Measurement of bulk densities

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Flowability
Flow properties of powders are critical for efficient tableting

operation

to assure efficient mixing and acceptable weight


uniformity
Bad flow is improved by selecting appropriate excipients i.e.
glidants

Measured by angle of repose, flow through an orifice or


compressibility index
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When a heap of powder is


allowed to stand with only
gravitational force acting on
it, the angle between free
surface of the static heap of
horizontal plane achieves a
certain maximum value for a
given powder and is known as
static angle of repose

Angle of repose

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Angle of repose as an indication of


flow properties
Angle of repose

Type of flow

<20

Excellent

20-30

Good

30-34

Passable*

>40

Very poor

* May be improved by adding glidant; Eg:0.2% Aerosil

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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

to be compressed into a tablet of specified tensile


strength.

C 100 1
T

Hausners ratio is related to Carrs ratio by the formula


1
H 100 1
C

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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)

indicates poor flow,


Carrs ratio <20 (equivalent to 1.25 of Hausners ratio)

indicates good flow

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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

May be improved by glidant Eg: 0.2% Aerosil

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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

compounds with an aqueous solubility of greater than 1%


w/v do not present dissolution-related absorption
problems
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However, a highly insoluble drug administered in


small doses can exhibit good absorption
Drug that has high solubility but is unstable in the

highly acidic environment of the stomach could


result in a decreased bioavailability.

For these reasons aqueous solubility is a useful


biopharmaceutical parameter.
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Drug candidates are becoming more lipophilic


and poorly soluble

Recent trends in aqueous solubility of discovery compounds


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Formulation Challenges with Poorly


Soluble Compounds
Poor dissolution rate
Low and variable bioavailability
Inability to deliver high doses for toxicity
studies

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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

Similarly increase in solubility in alkaline solutions suggests


weakly acidic drug
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Measurement of solubility
Solubility is measured at two temperatures
4oC - Substances possess minimum solubility due to max
density of water

Ensures physical and chemical stability on short


term storage till more data is available
37oC Indicates solubility of substance at physiological
temperature

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Solubility is measured in different solvents


1.

Water

2.

0.9% NaCl solution

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

Examine visually for any undissolved solute particles

When some solute remains undissolved, the total


amount added up to that point serves as a good and
rapid estimate of solubility
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Quantitative analysis

Suspension of solute in solvent is shaken at constant


temperature.
Samples are withdrawn periodically and filtered
Concentration of the solute in the filtrates is
determined by a suitable method.

Sampling is continued until consecutive samples show


the same concentration.
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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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Handerson - Hasselbach equation provides an


estimate of unionized and ionized drug conc.
at a particular pH
for ac idic drugs

A
pH pK a log 10
HA

for basic drugs


B
pH pK a log 10
BH

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pH solubility profile

Determined by Shake Flask Method


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These equations are used to


1. Determine pKa by following changes in solubility
2. Predict solubility at any pH provided Co and pKa are known

3. Facilitate selection of suitable salt forming compounds


and predict solubility and pH of salts

Determination of pKa is by Potentiometric titration

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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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The solubility of such substances would


decrease with an increase in temperature.
The application of this aspect of solubility is of
limited use to us, since pharmaceutical
solutions must be administered at or near
room or body temperature.
It is more a factor to be considered for
product storage than for formulation.
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Common ion effect


Salting-out is the precipitation of organic
solutes from aqueous solution by the addition
of an electrolyte or salt.
This is attributed to competition between
solute molecules for the solvent and is
dependent upon the size and valence of the
ion.
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Salting-in is the increase in solubility of an


organic solute upon addition of an electrolyte
Complex ion formation occurs when an
insoluble solute reacts with a soluble substance
to form a soluble complex.
An example is the addition of the soluble
potassium iodide (KI) to the insoluble iodine
molecule (I2) to form a soluble triiodide
complex (KI3).
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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.

Drugs lipophilicity and ability to cross the cell


membrane is due to o/w partition coefficient
Generally
n-Octanol/water or Chloroform/water systems are used to
study the partition coefficient
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Defines as ratio of unionized drug distributed


b/n organic and aqueous phases

Coil
Po
w
Cwater

Equilibriu m

When the ratios are larger log P values are


used
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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

Kd = dissolution rate constant


Ka = absorption rate constant

When dissolution is significantly slower of the two processes (ie , kd


ka) absorption is described as dissolution rate-limited.
Since dissolution precedes absorption in the overall scheme, any
change in the process of dissolution would influence the absorption.
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When solubility of drug exceeds 10mg/mL at


pH <7 no bioavailability problems due to
dissolution are observed

Below 1mg/mL such problems are possible


and salt formation could modify them
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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

It is characteristic of each solid compound in a given solvent


under fixed hydrodynamic conditions.
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For a drug substance, IDR is independent of formulation factors


and measures the inherent solubility of the drug in dissolution

medium.

measured in preformulation tests by the rotating


disk method or Woods apparatus

Expressed as mg/min/cm2.
Knowledge of this value helps in predicting if absorption would be
dissolution rate-limited

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When dissolution is completely controlled by diffusion,


the rate of diffusion is directly proportional to the
saturated concentration of the drug in solution (sink

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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Constant-surface assembly for the determination


of intrinsic dissolution rates (Woods Apparatus)

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Schematic of rotating disk intrinsic


dissolution rate apparatus

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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.

die is mounted onto a smooth polished base plate

3.

High compression pressure of (500MPa )and long dwell time (1 minute)


is applied

This gives a non disintegrating zero porosity pellet

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

3. Rotated at 100rpm containing 1 L fluid at 37OC.

If possible sink conditions should be maintained

4. Cumulative amount released is calculated


5. Plot a graph of CAR vs. time
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Calculation
Plot a graph of cumulative amount dissolved per unit

area of exposed pellet surface against time


Plot until 10% of the drug pellet has dissolved.

Linear regression is applied to data points


Slope of the regression line is calculated.
This gives the IDR of the substance under test in
mg/min/cm2.
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Kaplan (1972) suggested that if the IDR was


greater than 1 mg/cm2/min, then absorption
was unimpeded.
Dissolution rates less than 0.1 mg/cm2/min
were likely to give dissolution rate-limited
absorption.
This tenfold difference in dissolution rate
translates to a lower limit for solubility of 1
mg/ mL
A solubility of less than 1 mg/ mL indicates the
need for a salt
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Stability

As a general rule all drug products should have a shelf life of atleast
3 years

Potency does not fall below 95%


Without generation of toxic products

Product should look like and perform the same as


when it was manufactured

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Stability of drug is evaluated under three categories:

1.

Solid-state stability of drug alone;

2.

Compatibility studies (stability in the presence of excipients);

3.

Solution phase stability (including stability in gastrointestinal fluids


and granulating solvents).

Results rely on availability of stability-indicating analytical method


HPLC and TLC methods are used

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Solid-State Stability
Refers to physical as well as chemical stability

Solid-state reactions are slow,

Hence stress conditions are used for study


pharmaceutical solids degrade as a result of

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

spontaneously at high temperatures


A 10o C rise in temperature leads to 2-5 times increase in
degradation process
Most often Arrhenius relationship is followed
A plot of log of reaction rate vs. reciprocal of absolute temperature gives a straight
line (1/T)

Chemical reactions change at a temperature of 50oC


NOTE: High temperature may remove moisture from drug and make it more stable

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Hydrolysis
Water from atmosphere may be absorbed

Onto solid particles


Partial drug may dissolve in absorbed water

Layer of saturated solution is formed


Dissolved drug may

react with other substance

Get hydrolyzed

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Factors contributing to hydrolysis


(1) Presence of OH-

(2) Presence of H3O+

(3)Presence of divalent metal ions


(5) Light

(4) Heat

(6) Solution polarity

(7) High drug concentrations

Breakdown of compounds due to reacting


solvents other than water is termed solvolysis
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Oxidation
Degree of oxidation is influenced by
environment
Light
Trace metals
Oxygen
Oxidizing agents

In organic molecules oxidation is same as


dehydrogenation (loss of hydrogen)
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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

presents an aesthetic problem


controlled by using amber glass or an opaque
container
Oxidation and hydrolysis may be catalyzed by light
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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.

Materials unaffected by moisture are non-hygroscopic


Those in equilibrium with water in atmosphere are hygroscopic
Drug salts should be so chosen that they are non hygroscopic

They should take up less than 0.5% even in 95% RH

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1. Moisture content influences

1. flow and compression characteristics of powders


2. hardness of final tablets and granulations
2. Hygroscopic compounds should be stored in a well-closed
container, preferably with a desiccant
3. Mechanical processing of solids such as grinding, milling,
micronization, compaction, etc., can induce changes in their
reactivity toward water vapor
4. Preformulation study should be conducted with the form of
material to be used in the final formulation.

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Excipient compatibility
Drug is in intimate contact with one or more excipients;

Excipients could affect the stability of the drug


Knowledge of drug-excipient interactions is useful in selecting appropriate
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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