Preformulation

Solid Dispersion
The term solid dispersion is applied to those systems in which a drug is homogeneously distributed
throughout a solid matrix. Depending on whether the matrix is water soluble, the drugs dissolution can
be decreased or enhanced. In terms of increasing its solubility the matrix material must be water
soluble.
The term solid dispersion may also be defined as the dispersion of one or more active ingredients in an
inert carrier or matrix at solid state prepared by the melting (fusion), solvent or melting solvent method.
Selection of carriers
It is important that the carrier chosen for the solid dispersion system should be readily soluble in water.
Additionally, it should be stable at the processing temperature, easily form one or the other type of
dispersion and chemically and pharmacologically inert.
Commonly used carriers include PEG-4000, PEG-6000, urea, citric acid, tartaric acid, succinic acid,
pentaerythritol, various sugars, povidone etc.
Polyethylene glycols are expected to form interstitial solid solutions with many drugs. Their super
cooling and viscous effects are considerable for the formation of solid dispersions. They are transparent
in the UV and visible region and hence do not interfere with the analysis of the drug.
Urea melts with decomposition at 132.70C. Hence it cannot be used as a carrier in the preparation of
solid dispersion by fusion method, if the fusion temperature of the physical mixture of drug and carrier
exceeds the melting point of the carrier. Such decomposition has been reported in chlorpropamide-urea
system.
Citric acid is capable of glass formation while succinic acid with similar physicochemical properties as
citric acid, does not exhibit this property.
METHODS OF PREPARATION
There are three general methods of preparation described in a comprehensive review by Chiou and
Riegelman.
1. Melting method
This method, also known as fusion method was first proposed by Sekiguchi and obi. In this method,
the physical mixture of a drug and a water soluble carrier was heated directly until it melted which
was then cooled and solidified rapidly in an ice-bath under rigorous stirring. To facilitate faster
solidification, homogeneous melt was poured in the form of a thin layer onto a stainless steel plate
and cooled by blowing air or water on the opposite side of the plate. This modification was
employed by Goldberg et al, Chiou and Riegelman. The final solid mass is then crushed, pulverized
and sieved.
The main advantages of this method are its simplicity and economy. In addition, a super saturation
of a solute or drug in a system can often to be obtained by quenching the melt rapidly from a high
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temperature. Under such conditions, the solute molecule is arrested in the solvent matrix by the
instantaneous solidification process. The solidified masses required hardening in desiccators. Often
systems are fond to harden more rapidly if kept at 370C or higher temperature.
The disadvantages of this method are decomposition or evaporation of drugs or carriers as fusion
occurs usually at higher temperatures. Evaporation problem can be avoided if the physical mixture is
heated in sealed containers. Melting under vacuum or a blanket of an inert gas such as nitrogen may
be employed to prevent oxidation of the drug or carrier.
It is observed that the melting point of a system may be much lower than the melting points of its
two components, which is of advantageous if the pure drug undergoes decomposition at or near its
melting points. This principle has been used to prepare solid dispersion of steroids and cardiac
glycosides in PEG-6000. Solid dispersion systems of salicylic acid urea have been prepared using a
fusion method and two different methods of cooling namely rapid cooling in liquid nitrogen and
slow cooling in air. Rapid cooling resulted in a much faster drug dissolution rate.
2. Solvent method:
Solid solution or mixed crystals could be prepared by dissolving a physical mixture of two solid
components in a common solvent, followed by evaporation of the solvent. Solvent dispersions of carotene-PVP, Griseofulvin-PVP, Reserpine-deoxycholic acid, Tolbutamide-PVP, Methisazone-PVP,
Digitoxin-deoxycholic acid are few examples. In this method the thermal decomposition of drugs or
carriers can be prevented because of the low temperature involved. The higher cost of production,
incomplete removal of liquid solvent, adverse effect of the solvent on the chemical stability of the
drug, selection of a common volatile solvent and possible polymorphic changes are the drawback of
this method. In addition, a super saturation of the solute in the solid system cannot be attained.
Solid dispersions of an aspirin-acetaminophen-urea ternary system were prepared by the solvent
method because of possible aspirin decomposition in samples prepared by the melt method.
3. Melting-solvent method
Liquid compounds up to 5 to 10% (w/w) could be incorporated into PEG-6000 without significant
loss of solid property. The drug is first is dissolved in a solvent and then the solution is incorporated
directly into the melt of the carrier. This method possesses the advantage of both the melting and
solvent methods although it is limited to drugs with the low therapeutic dose. The method ha s been
employed to prepare solid dispersions of spiranolactone-PEG6000 and Griseofulvin-PEG6000. A
liquid drug such as Methyl salicylate, Vitamin-E, Clofibrate could be formulated as a solid dosage
form by mixing it with the melted liquid of PEG6000 and cooling the mixture.
TYPES AND MECHANISMS OF FAST RELEASE
Chiou and Riegelman have classified various systems of solid dispersions of drugs on the basis of their
major fast release mechanisms. They are simple eutectic mixture, solid solutions, glass solutions and
glass suspensions, amorphous precipitations of a drug in crystalline carrier, compound or complex
formations between the drug and carrier among the previous systems.

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a). Simple Eutectic Mixtures:
Rapid solidification of the fused liquid of two components which show complete liquid
miscibility and negligible solid-solid solubility usually yields a simple eutectic mixtures. It is an
intimately blended physical mixture of two crystalline components, when a eutectic is exposed
to gastro-intestinal fluids, both the poorly soluble drug and the carrier may simultaneously
crystallize out in very small particulate sizes. A eutectic is formed by some sort of loose
molecular or atomic interactions which do not involve the formation of a chemical bond.
Between slow processes of cooling and rapid quenching the latter yields a fine dispersion of
phases. Further, the composition of a eutectic also governs the particle size of the crystallites. A
low weight fraction of the drug yields finer crystalline size of its precipitate.
The factors contributing to the faster dissolution rate of a drug dispersed in the eutectic are:1. Reduction of particle size and increase in specific area
2. An increase in drugs solubility
3. A solubilization effect exerted by the carrier which completely dissolves in a short time in
the diffusion layer around the drug particle.
4. Absence of aggregation and agglomeration between the fine crystallites of the pure
hydrophobic drug because these particles are surrounded in the matrix by carrier particles.
5. Excellent wettability and dispersasbility of a drug as the encircling soluble carrier readily
dissolves and causes the water to contact and wet the drug particle.
6. Crystallization of the drug in a metastable form after solidification from the fused solutions
which has a higher solubility
b) Solid Solutions:
A solid solution is made up of a solid solute dissolved in a solid solvent. The two components crystallize
together in a homogeneous one phase system and hence they are referred to as mixed crystals.
According to Goldberg, et al a solid solution achieves faster dissolution rate than a eutectic mixture,
because in the former the drug particle is reduced to its molecular size and dissolution of the drug takes
places in solid state itself prior to exposure to the liquid medium. In addition to above phenomenon,
factors such as increase in drug solubility, solubilization effects exerted by the carrier, absence of
aggregation and agglomeration, and excellent wettability and dispersibility of the drug may also come
into play to improve the dissolution rate.
Some time, a drug may precipitate due to high supresaturation of the bulk fluid if compensatory
processes to remove the drug are inadequate.
According to the extent of miscibility between the two components, the solid solution can be divided
into two groups, continuous (or isomorphous, unlimited, complete) solid solutions and discontinuous (or
limited, restricted, partial, incomplete) solid solutions.

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1) Continuous solid solution
The strengths of the bond between the two different at the solid-state should be greater than that
between the same species of the molecules, in ordered to form continuous solid solutions. The two
components are miscible or soluble at solid state in all proportions.
2) Discontinuous solid solutions
In this system, there is only a limited solubility of a solute in a solid solvent. Each component is
capable of dissolving the other component to a certain degree above the eutectic temperature.
Based on the crystalline structure of the solid solution can be divided into two groups: substitutional
solid solutions and interstitial solid solutions.
a) substitutional solid solutions
Here, the solute molecule substitutes for the solvent molecule in the lattice of the solid solvent. It
can form a continuous or discontinuous solid solution. The size of the solute and the solvent
molecule should be as close as possible. Timmerman calculated the degree of molecular
isomorphism to express the degree of similarity of the shape of the two components. The solubility
of the solute increases until the distortion of the lattice field of the solvent by the solute molecules
can no longer be tolerated. Globular or plastic compounds form a wide range of solid solutions.
Crystals of these compounds are usually of cubic or hexagonal symmetry, clear, tacky and easily
deformed. They will more easily accommodate all kinds of molecules in there crystal lattice. Solid
dispersions of Griseofulvin have been prepared using pentaerythritol, a typical plastic compound.
b) Interstitial Solid Solutions:
In this type, the solute molecule occupies the interstitial space of the solvent lattice and forms only
discontinuous solid solutions. Obviously, the size of the solute is critical. Thus, water soluble
crystalline polymers of high molecular like PEG4000, 6000 become excellent choices for this type of
solid solutions of insoluble drugs. Besides, these polymer carriers are of low toxicity and are not
absorbed from the GIT. A fast rate of dissolution has been obtained when Griseofulvin, Digitoxin,
Steroids and Indomethacin were dispersed in PEG6000.
High viscosity, super cooling and the difficulty in nucleation of the drug in the viscous medium favor
the formation of thermodynamically stable interstitial solid solutions. PEG polymers also exert a
solubilisation effect in the aqueous medium on insoluble drugs. It is also likely that they will form
metastable solid solutions.
c) Glass solutions and glass suspensions:
Glass solution is yet another potential modification of dosage forms in increasing drug dissolution
and absorption. It is a homogeneous, glassy system in which a solute dissolves in a glassy solvent.
Abrupt quenching of the melt usually results in a glassy or vitreous state. It is characterized by
transparency and brittleness below the glass-transforming temperature. On heating, it softens
progressively and continuously without a sharp melting point. Glass solution is metastable and has a
structure only with a short range order. It is also amorphous to X-ray diffraction. Poly hydroxyl
molecules such as sugars form glasses. This may be due their strong hydrogen bonding which may
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prevent crystallization. The in-situ dissolved drug in a glass solution is released into the aqueous
medium rapidly because the carrier quickly dissolves upon exposure to the aqueous medium. The
strength of the chemical binding in a glass solution is much less compared to that in solid solutions.
It is more similar to a liquid solution. Therefore the dissolution rate of drugs in the glass solution is
faster than that in the solid solution.
Citric acid melt is highly viscous and can be drawn into a thread or sheet and forms a hard, brittle
and transparent glass on standing at 370 c, for a few days. Glassy solutions were obtained with
Griseofulvin-citric acid, Primidone-citric acid, methisazone-PVP, barbiturates-citric acid systems.
Glass suspensions referred to a mixture in which precipitated particles are suspended in a glassy
solvent.
Glass solution is also obtained when a solution of PVP and the drug in a common solvent is
evaporated to dryness. Precipitation of drugs introduced into the system is inhibited due to the
increase in viscosity ass the solvent evaporates. The enhancement of dissolution rate is the function
of molecular weight of Povidone and the concentration of the drug incorporated in the co
precipitate.
d) Amorphous precipitations In a crystalline carrier:
The drug may also precipitate out in an amorphous form in the crystalline carrier from a melting or
solvent method of preparation. Amorphous form produces faster dissolution rates than the
crystalline forms. Amorphous Novobiocin has ten-fold higher solubility than its crystalline form.
Increased oral absorption of Sulfathiazole in man was found with amorphous Sulfathiazole dispersed
in the crystalline Urea. A drug with high super cooling property possibly has more tendencies to
solidify as an amorphous form in the presence of a carrier.
e) Compound or complex formation:
Dissolution and absorption of a drug into the body can occur from a complex or a compound formed
between the drug and an inert soluble carrier. Complexation also implies that the dissolution could
be retarded as observed with the Povidone-hexyl resorcinol and PEG6000-phenobarbitone.
However, the formation of a soluble complex with low association constant results in increased
rates of dissolution and absorption. Complex formation between Nitrofurantoin and Povidone
25,000 has been established. The above dispersion provides a far more rapid dissolution than the
pure drug alone. Although the solubility of Griseofulvin was increased markedly by succinic acid in
water their interaction or compound formation could not be detected in the solid state. It may be
observed that the utility of a compound or complex formation depends on the particular drug under
study.
f) Combinations and miscellaneous mechanisms:
Quiet often the observed increase in dissolution and absorption rates with solid dispersions may be
due to interplay of different mechanism discussed earlier. Griseofulvin at high concentrations in
Griseofulvin-PEG system may exist as individual molecules and as micro crystalline particles.
Sulfathiazole dispersed at high concentration in Povidone may be present as individual Sulfathiazole,
complex molecules with Povidone, amorphous and polymorphic sulfathiazole and possibly as
amorphous sulfathiazole-Povidone complex. Increased dissolution of Reserpine from co precipitates
with bile steroids was proposed to be due to the decrease in the particle size of Reserpine, increased

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wetting of the dispersed particles and Clathrate and inclusion compound formation between the
steroids and the drug.
CHARACTERIZATION OF SOLID DISPERSION SYSTEMS:
Many methods are available which would provide an insight into the physical nature of a solid
dispersion systems and the nature of interaction between the components. Characterization normally
requires pooling of data from several methods of study to finally arrive at conclusions regarding the
nature of the solid dispersion.
1) TLC
To test whether the drugs are decomposed by the processes, TLC characteristics of the pure and the
processed samples are studied. A single spot with the same Rf value is expected for both, the pure
and processed samples on the thin layer plates. In a study of Digitoxin-PEG6000 system, the samples
fused above 1700c showed two additional spots indicating some decomposition. TLC studies on
Nitrofurantoin-PEG6000 fused samples, ruled out any interactions.
2) Spectroscopic studies:
In the UV study, the spectra of the pure and the dispersed drugs are scanned. Assay of the solid
dispersions and calculation of the molar extinction co-efficient provides evidence of any
decomposition of the drug. The spectrum of the dispersed -Carotene in Povidone resembles with
that of the drug dissolved in organic solvents but not that of drug particles indicating molecular
dispersion of the drug in the polymer.
Similarly, IR spectral analysis is also employed. The undetected shift of IR band of the dispersed Carotene was thought to indicate the absence of the marked interaction of the drug and povidone.
IR spectrometry has provided evidence that there was complex formation between povidone25,000
and nitrofurantoin, probably via hydrogen bonding.
3) Short term stability studies:
A short term stability study of the dispersions at ambient or slightly elevated temperatures could be
of value in exposing a slow interaction occurring in the system.
4) Solubility determinations:
Results from aqueous solubility studies of the drug in various concentrations of the carrier would
further indicate interactions between the drug and the carrier. Such studies indicated weak or
insignificant interaction between Griseofulvin and PEG6000. Increased rate of dissolution due to
solubilisation of the drug by the carrier is also better understood by this technique.
5) Dissolution Rate Method:
This method was proposed by Allen and K Wan to study the degree of crystallinity in solid solid
equilibria. The in-vitro dissolution rate of the drug from a constant surface tablet of the solid
dispersion is compared with the physical mixture of the same chemical compositions. This method
has been shown to be applicable to simulated systems of iIndomethcain-PEG6000.

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6) Microscopic Method:
Morphology of the solid dispersions and the study of the polymorphism could be undertaken with
the help of microscopic techniques. The fine particles of crystallization in the glassy Povidone matrix
can be readily detected by the polarizing microscope. High resolution electron microscope can be
used to estimate the particle size of the dispersed drug in the carrier matrix.
7) Thermal Analysis:
The principle of change of thermal energy as function of temperature is utilized to study the
physicochemical interaction of two or more component system.
a)Cooling Curve Method:
The physical mixtures of various compositions are heated until a homogeneous melt is obtained and the
temperature of the mixture is then recorded as function of time. The phase diagrams can be constructed
from such temperature-time curves. Phase diagrams of deoxycholic acid-Menadione and caffeine and
phenobarbitone have been established through this method.
b) Thaw-Melt Method:
The sample is heated gradually in a capillary tube and thaw point is noted. The thaw point is the
temperature on crossing a solidus line. In differentiating between a simple eutectic systems and a
limited solid solution, the thaw point provides the diagnostic point.
c) Thermo Microscopic Method:
A polarizing microscope with a hot stage was employed by Goldberg to study phase diagrams of binary
systems. The physical Mixture is heated on a slide until it completely liquefies. After cooling, the
mixture is heated at a rate of 40 per minute. The thaw and melting points are visually observed.
d) Differential Thermal Analysis :
DTA is an effective method to study phase equilibria. The substance is heated at a uniform rate and the
differential effects associated with physical or chemical changes are automatically recorded as a
function of time or temperature. Two eutectic temperatures and a complex formation were shown in
the phase diagram study through DTA of Papaverine- succinic acid systems.
e) Zone melting method:
A molten zone affected by heater traverses a cylindrical ingot or solidified melt. After zone melting is
finished, the bar is analyzed for its chemical composition. The phase diagrams can be constructed from
the chemical composition and freezing temperature. The exact chemical composition of eutectic and
low solid-solid solubility could be easily detected.
F) X-Ray Diffraction method:
The intensity of the X-ray diffraction from a sample is measured as function of diffraction angles.
Counter and film methods detect the diffraction intensity. Counter method provides the better

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resolution of diffraction peaks and the relative diffraction intensity of the different peaks is easily
compared. The X-ray diffraction method was used to characterize the physicochemical properties of
Griseofulvin dispersed in PEG6000 and PEG4000.
Stability Analysis
Preformulation stability studies are usually the primary quantitative assessment of chemical stability of a
new drug which includes both solid and solution liquid state experiments under difficult conditions for
handling. During drug development , several bulk lots are produced first , which are used for stability
studies may not be the representative of the whole bulk but it acts as a baseline for the consequent lots
to be analysed.
Solution stability
The objsective of carrying out solution stability studies is to identify conditions necessary to
form a stable solution. This includes effects of ph, ionic strength, co-solvent light
temperature and oxygen on solution
Studies are carried out to confirm decay at the extremes of ph and temperature i.e. Ex: 0.1
N HCl, water, 0.1 N NaOH all at 90
These degraded analyses are carried out to confirm assay specified as well as to provided
estimated for maximum rates of degradation.
-ph profile rate is generated to identify then ph of maximum stabilIty. Aqueous buffers (
wide range of ph are used, this do not effects the drug content and ionic strength

For parentral route ph studies conducted at a constant ionic strength that is compacted with the
physiological medium
Ionic strength( )

- molar concentration the ion,

valency
Co solvents :
Needed to achieve drug concentration that are required for analytical sensitivity and these selected
from alcohol family are beneficial . Stable solution produced are placed in the fint glass ampoules and
stored at constant temperatures. Therefore not exceeding the boiling point of the most volatile
co=solvent. Some ampoules are stored at different temperature to provide data for calculating
activation energies ( Arhenious plot ) and shelf life. Some of these will be subjected to light stability test
Rate PH profile:

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Number of solutions undergoes accelerated decomposition upon the addition of acid or bases. Solutions
when buffered no decomposition accompanied by an appreciable change in concentration of acid or
bases. These reactions are catalysed by hydrogen and hydroxyl ions therefore tey are aid to be as
specific acid base catalysis. They are of two types.
(1) Hydrogen ion catalyzed reactions
(2) Hydroxyl ion catalysed reactions
Hydrogen ion catalysed reactions:
1) Hydrolysis of ester:
In acid solution

ion he esters is in equilibrium with

of acid

S
It combines with water to form

SH+ + R

Therefore rate of product formation is

= R (SH+)
K = SH+/ [S][H+]
So substituting (SH+) We get

K [s] [H] [R]

A ph rate profile can be obtained by plotting the PH at various concentration of hydrogen ion so,
K [S] [H] = K [H]
Under buffer condition, at a given PH, the first order reaction is observed as

obs

K [H] = Kobs
Log = -[-log [H+]] + log K1
Log obs = - PH + log k1

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The log of KabsVs pH in this case gives a line of slope -1
Incase of alkaline solution the plot of straight line with a slope +1
The rate pH profile of the reaction is affected by
1. Effect of pH
2. Effect of catalysis by one or more species of the buffer
3. Changes in ionic strength
4. Changes in pKa
Ex : Degradation of thiamine in acetate buffer solution is unaffected at pH 3.9 but at higher pH
degradation rate increases . Minimum of the pH rate profile is a maximum of drug stability . If the
oxidation potential or reaction with other gases are unknown . ample solution is injected and subjected
to several tests .
1. With oxygen
2. With helium and nitrogen
3. Inorganic antioxidants Ex ; Sodium metabisulfite
4.With an organic antioxidant such as BHT, BHA
Theses tests are carried out for injection vials . Which are capped with Teflon coated rubber . Caps are
being penetrated with needle the head space is flooded with desired atmosphere and the needle hole
are sealed with wax to prevent degassing . These sample solution are assayed for the drug content to
find stability.
Solid state stability :
Objectives To find out stable storage conditions for the drug in the solid state and identification of
compactable excipients for formulation , on contrary to the liquids / solutions stability this studies are
affected by changes in purity and crystallinity and the solid state reactions are much slower and more
difficult to interpret than solution state stability studies .
Determination of solid state stability of newer drug : The weighed samples are placed in open screw
capped vials and exposed directly to various temp. humidities and light intensities for upto 12 weeks .
(Only if the drug is not hygroscopic ) Three 5-10mg weighed samples at each data point for HPLC analysis
in approximately 10-15mg of sample for polymorph evaluation by differential scanning colorimetry or
IR(2mg in KBr and 20mg in Nujol) Samples stored in large 25ml vials for injections which are capped with
Teflon lined rubber stopper and the head space flooded with dry oxygen (Dry oxygen to confirm that
decay absorbed is purely due to oxygen rather than that to reduced humidity). Second test should be

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carried out in vials for injection flooded with nitrogen in the head space . After fixed exposure time the
samples are removed and analysed by multiple methods to check for chemical stability , polymorphic
change and discoloration . If the humidity doesnt effect the drug stability then by arhenium plot is used
to produce the shelf life but if the humidity effects the stability a comparison with solution state stability
and hygroscopicity may suggest an aqueous reaction occurring in the drug saturated water layer on the
crystal surface . An important relationship in solid state stability assumes that the durg compound must
partially liquefy prior to decomposition . Its given by

K=Decay rate,Fm=Mole fraction of solid that has liquefied,-Hfus = Molar heat of fusion,T= Absolute
temperature,Tm= Absolute melting point,R= gas constant.
Compatibility with excipients used in solid dosage form are studied
A bulk quantity compound having low stability should be formulated with anhydrous excipients and pH
maximum of the drug stability should match with ph of an aqueous solution or suspension of the drug
and the excipients . Solid formulation requires granulation , stability should be checked by excess wet
down process and drying (50 C forced hot air oven for 48hrs )besides chemical stability of granules ,
unformulated bulk ample exposed to each granulation solvent should be checked for crystallinity ,
polymorph conversion etc. ,which alters bioavailability of sample for finding bulk stability profile for a
new drug candidate .
Storage conditions :
1. 5 C refrigerator
2. 22 C Room temp.
3. 37 C Ambient humidity
4. 37 C per 75% RH
5. Light box clear glass , amber glass , yellow green glass
6. 50 C ambient humidity with oxygen , nitrogen head space
7. 70 C ambient humidity
8.90 C ambient humidity
Compatibility
Compatibility is the ability of powdered material to be compressed into a tablet of specified tensile
strength. Hydraulic press offers one of the simplest ways to obtain such data. Compactable form is
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powder that hard compacts under applied pressure without exhibiting any tendency to cap or to chip
can be considered a readily compactable. Other studies performed are tensile strength hardness etc are
the characteristic features. Compaction of powder involved two processes .
(1) Cold welding
(2)Fusion welding
Cold welding:When the surface of two particles approach each other closely ( i.e., separation of less that 50 ) their
force surface energy results in a strong attractive force and this process is called as cold welding
Fusion weldilng
On considering a bed of granules most of the particles have irregular shapes so that there will be many
ponts contacts on that particles in a bed of granules. Any applied load to the bed is transmitted through
these particles contacts. This transmitted result in generation of considered heat due to friction

Mechanism that effect tablet stability

1. oxidation:
This is one of the major cause for tablet instability. Main reason for oxidation is that , only traces of
oxygen is needed for oxidation and oxidative reactions are influenced by light and metal ion (
iron,Cu,Co,Ni etc ) this causes the tablet to produce coloured products or produce objectionable odours.
Oxidation cannot happen with out reduction i.e. transfer of electron inorganic compounds
Oxidation loss of electron
Reduction gain of electron
Fe2+

Fe3+ + e-

In organic compounds, oxidation is governed by the number by the number of bonds from cation to
oxidation. Greater the number of bonds the more highly oxidized
Ex: Aldehyde is more oxidizable than that of alcohol. A change n molecular structure also effect
oxidation.
Auto oxidation which involves a free radical chain process is most common form of oxidative
degradation in tablets. (free radical atoms or molecules that have one or more unshared valences
electrons CH3CH3-------- Ch3)since they are unshared they take up electrons readily from other
substance causing oxidation. The auto oxidation of hydrogen (RH) by a free radical chain process can be
written as
1. RH

Ro + H+(initation or induction )

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2. R0 + O2

RO20

RO20 + R0H
ROOH

ROOH + R10

RO0 + OH0

3.the final step, the chain breaks RO20 + X

RO20 + RO20

inactive products

inactive product (termination) coupling

Here x free radical inhibitor, such as sulphate or aromatic avins.

Auto oxidation requires only a small amount of O2 to initiate the reaction, which is catalyzed by the
heavy metal ions processing valances of 2 or more electrons. These heavy metals reduce the length of
induced ions step and increase the maximum rate of oxidation by increasing the formation of free
radicals. Ex: 0.0002 M cu ion is enough to increase the rate of vitamin C oxidation. To reduce this effect
water used must be free of heavy metals and manufacture practices which prevent cases of direct
contact of the granules with the metals are recommended. Protection from the light also reduces
oxidation. The rate of these reactions depends on temperature. Radiation, oxygen and drug
concentration in addition to the catalyst. Ex of auto oxidation reaction during tablet formulation
Steroids Prednisolone
Vitamins C ,BL ,A ,E
Phenothiazine derivatives Chlorapromazine
Alkaloids Physostigmine
Antibiotics tetracycline

2. Hydrolysis
Although the solid dosage form stabiles hydrolysis by limiting the acceptability of drug to water ,
compounds with ester , amide acid, acid chloride, acid anhydride acetum groups are prone to hydrolysis
even in tablet form. the hydrolysis of ester for either acid or alkaline catalyzed reactions involves the
linkage between C = 0 to form an acid and alcohol
Hydrolysis of amide is similar to that of ester except that it forms an aid and amine. Even the hydrolysis
is catalysed by both hydrogen and hydroxyl ions, hydroxyl ions has stronger effect on hydrolysis, PH also
effect the reaction. so the reaction of excipients should be done only after a through evaluation of these
stability studies.
Ex: Atropine sulphate is most stable at PH 4 and excipients which impart alkalinity should be avoided

3. Photolysis (break down in presence of photons)

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Photolysis is a surface phenomenon and in most cases it. Affect the interior of the tablet. Free radicals
are important in photolysis as they undergo subsequent reactions. The various factors in the photolysis
degradation are
a) Intensity and wavelength o light.
b) Size, shape, composition and colour of container
a substances exhibit photolysis when it absorbs radiation at a particular wavelength of above threshold.
Not all the absorbed radiation exhibit photolysis , so some part may change to heat which causes a
thermal reaction , which is identical or opposite to the original photolysis reaction. Sometimes catalysis
may induce a thermal degradation. the radiation which has the greatest energy supply, effects the
photolysis more. The commonly used method to permit photolysis is the use of coloured or plastic
containers. Drug that are prone to photolysis reaction s are folic acids, ascorbic acids sulphonamide,
steroids.

4.Racimization
I9t is the reaction where by an optically active drug substance changes to an optically inactive mixture of
corresponding dextro or levo forms. Ex: Hysocyamine is three times as effective as the dextro levo form,
atropine. Recemization do not depend on temperature, solvent, catalyst and light. This depends on the
functional group bound to the asymmetrical carbon atom. And aromatic group tends to accelerate the
recemization.

Nagaraja y s Dept of Pharmaceutics,