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IAJPS 2015, 2 (10), 1399-1407 Prasanna Kumar et al ISSN 2349-7750

CODEN (USA): IAJPBB ISSN: 2349-7750

INDO AMERICAN JOURNAL OF

PHARMACEUTICAL SCIENCES

Available online at: http://www.iajps.com Review Article

AN OVERVIEW ON PREFORMULATION STUDIES


Prasanna Kumar Desu*, G.Vaishnavi, K. Divya, U.Lakshmi,
Department of Pharmacy, St.Marys Group of Institutions, Guntur.

Abstract:
Every drug has intrinsic chemical and physical properties which has been consider beforedevelopment of
pharmaceutical formulation. This property provides the framework for drugscombination with pharmaceutical
ingredients.Preformulation studies carried out by various research scientists is reviewed. Preformulationstudies
conduct for newly synthesiedcompounds or extracted compound and it gives the information regarding the
degradation process, any adverse conditions relevant to the drug, bioavailability, pharmacokinetics and
formulation of similar compound and toxicity. Preformulation studies strengthen the scientific foundation of the
guidance, provide regulatory relief and conserve resources in the drug development and evaluation process,
improve public safety standards, enhance product qualityin the fabrication of dosage form.
Key words: Preformulation, dissolution, oxiadation, computability studies
Corresponding Author:
D. Prasanna Kumar, QR code
Department of Pharmacy,
St.Marys Group of Institutions,
Guntur.
Email.id: Prasanna.desu@gmail.com
Mbl.No:9966916329

Please cite this article in press as Prasanna Kumar et al, An Overview on Preformulation Studies, Indo Am.
J. Pharm. Sci, 2015;2(10).

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IAJPS 2015, 2 (10), 1399-1407 Prasanna Kumar et al ISSN 2349-7750

INTRODUCTION
Preformulation studies were evolved in 1950 & 3. PREFORMULATIONPARAMETERS:
early 1960.Preformulation testing is the first step in A. PHYSICAL CHARACTERISTICS.
the rational development of dosage forms of a drug 1) Organoleptic properties
substance. It can be defined as an investigation of 2) Bulk characteristics
physical and chemical properties of a drug a) Solid state characteristics
substance alone and when combined with b) Flow properties
excipients. The overall objective of preformulation c) densities
testing is to generate information useful to the d) compressibility
formulator in developing stable and bioavailable e) crystalline
dosage forms that can be mass produced. f) polymorphism
Preformulation investigations are designed to g) hygroscopicity
deliver all necessary data especially
physicochemical, physico- mechanical and bio 3) Solubility analysis
pharmaceutical properties of drug substances, a) Ionization constant(Pka)
excipients and packaging materials [1,2]. b) Partition co-efficient
c) Solubilization
Preformulation during Drug Discovery d) Thermal effect
Apart from helping formulation development, e) Common ion effect(Ksp)
preformulation studies also help in lead f) Dissolution
identification during drug discovery phase. A new
chemical entity should possess optimal 4) Stability analysis
biopharmaceutical properties to become a drug a) Solution-state stability
molecule. Mere possession of potency and b) Solid-state stability
selectivity does not ensure drug ability. c) Drug-excipients compatibility
Preformulation studies help in assessing the drug B. CHEMICAL CHARACTERISTICS
ability of a molecule. Preformulation can thus be 1) Hydrolysis
considered as critical decision-making tool during 2) Oxidation
both drug discovery and development phase. A 3) Photolysis
comprehensive understanding of physicochemical 4) Recemization
properties and its effect on biological performance, 5) Polymerization
allows selection of potential lead molecules and in 6) Isomerization
identification of drug delivery challenges. 1. ORGANOLEPTIC PROPERTIES
A typical preformulation program should begin
Objectives with the description of the drug substance. The
color, odour and taste of the new drug must be
To develop the elegant dosage forms recorded using descriptive terminology. The color,
(stable, effective & safe} odour and taste of the new drug must be recorded
It is important to have an understanding of using descriptive terminology. It is important to
the physical description of a drug establish a standard terminology to describe these
substance before dosage form properties in order to avoid confusion among
development. scientists using different terms to describe the
It is 1st step in rational development of a same property. A list of some descriptive terms to
dosage form of a drug subt before dosage describe the most commonly encountered colors,
form development. tastes and odours of pharmaceutical powders is
Goals provided in table. The color of all the early batches
of the new drug must be recorded using the
To establish the physico-chemical descriptive terminology. A record of color of the
parameters of new drug substance. early batches is very useful in establishing
To establish the physical characteristics appropriate specifications for later production.
To establish the kinetic rate profile. When the color attributes are undesirable or
To establish the compatibility with the variable, incorporation of a dye in the body or
common excipient. coating of the final product could be
To choose the correct form of a drug recommended.
substance.

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Table 1: Terminology to describe organoleptic


properties of pharmaceutical powders. Table .2: Common Techniques for Measuring
Fine Particles of Various Sizes
Colour Odour Taste Technique Particle size
Off-white Pungent Acidic (micro meters)
Cream Sulfurous Bitter Microscopic 1-100
yellow Sieve >5
Tan Fruity Bland Sedimentation >1
Shiny Aromatic Intense Elutriation 1-50
Odouerless Sweet Centrifugal <50
Tasteless Permeability >1
light scattering 0.5-50
2. BULK CHARACTERISTICS:

a) Solid state characteristics: b) POWDER FLOW PROPERTIES :

Powders are masses of solid particles or granules The flow properties of powders are critical for an
surrounded by air (or other fluid)and it is the solid efficient tableting operation. A good flow of the
plus fluid combination that significantly affects the powder or granulation to be compressed is
bulk properties of the powder. It is perhaps the necessary to assure efficient mixing and acceptable
most complicating characteristic because the weight uniformity for the compressed tablets. If a
amount of fluid can be highly variable.Powders are drug is identified at the preformulation stage to be
probably the least predictable of all materials in "poorly flowable, the problem can be solved by
relation to flow ability because of the large number selecting appropriate excipients. In some cases,
of factors that can change their rheological drug powders may have to be precompressed or
properties. Physical characteristics of the particles, granulated to improve their flow properties. Some
such as size, shape, angularity, size variability and of these methods are angle of repose, flow through
hardness will all affect flow properties. External an orifice, compressibility index, shear cell, etc.
factors such as humidity, conveying environment, Changes in particle size and shape are generally
vibration and perhaps most importantly aeration very apparent; an increase in crystal size or a more
will compound the problem. uniform shape will lead to a smaller angle of repose
and smaller carrs index [3,4].
Particle size and size distribution:
Various chemical and physical properties of drug Angle of Repose:
substances are affected by their particle size The maximum angle which is formed between the
distribution and shapes. The effect is not only on surface of pile of powder and horizontal surface is
the physical properties of solid drugs but also in called the angle of repose.
some instances on their biopharmaceutical
behaviour.For example, the bioavailability of For most pharmaceutical powders, the angle-of-
griseofulvin and phenacetin is directly related to repose values range from 25 to 45, with lower
the particle size distributions of these drug. It is values indicating better flow characteristics.
now generally recognized that poorly soluble drugs
showing a dissolution rate- limiting step in the Tan = h / r
absorption process will be more readily
bioavailable when administered in a finely sub h = height of heap of pile, r = radius of base of
divided state than as a coarse material.Size also pile
plays a role in the homogeneity of the final tablet. c) Densities:
When large differences in size exist between the The ratio of mass to volume is known as density
active components and excipients, mutual sieving Types of density:
(de- mixing) effects can occur making thorough (a) Bulk density: It is obtained by measuring
mixing difficult or if attained difficult to maintain the volume of known mass of powder that
during the subsequent processing steps. passed through the screen.
(b)Tapped density: It is obtained by
mechanically tapping the measuring
cylinder containingpowder.
(c)True density: It actual density of the solid
material.
(d)Granule density: may affect
compressibility, tablet porosity, disintegration,
dissolution

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d) Compressibility: g) Hygroscopisity:
"Compressibility" of a powder can be defined as Many compounds and salts are sensitive to the
the ability to decrease in volume under pressure presence of water vapour or moisture. When
and "compactability as the ability of the powdered compounds interact with moisture, they retain the
material to be compressed into a tablet of specified water by bulk or surface adsorption, capillary
tensile strength. condensation, chemical reaction and, in extreme
It can be used to predict the flow properties based cases, a solution (deliquescence). Deliquescence is
on density measurement. where a solid dissolves and saturates a thin film of
Tapped density pored density * 100 water on its surface. It has been shown that when
Carrs index= moisture is absorbed to the extent that
Tapped density deliquescence takes place at a certain critical
relative humidity, the liquid film surrounding the
e) Crystallinity [5-8]: solid is saturated. This process is dictated by
Generally most of drugs exist in solid state. Very vapour diffusion and heat transport rates.
few are in liquid state like valproic acid and even
less in gaseous form like some general Moisture is also an important factor that can affect
anesthetics. A crystal structure is a unique the stability of candidate drugs and their
arrangement of atoms in a crystal. Physical formulations. Sorption of water molecules onto a
properties affected by the solid-state properties candidate drug (or excipient) can often induce
can influence both the choice of the delivery hydrolysis.In this situation, by sorbing onto the
system and the activity of the drug, as determined drug-excipient mixture, the water molecules may
by the rate of delivery. Chemical stability, as ionize either or both of them and induce a reaction.
affected by the physical properties, can be For example, we have found that a primary amine,
significant. A crystalline particle is characterized when mixed with lactose was apparently stable
by definite external and internal structures. even when stored at 90C for 12 weeks. However,
Crystal habit describes the external shape of a when the experiment was carried out in the
crystal, whereas polymorphic state refers to the presence of moisture, extensive degradation by way
definite arrangement of molecules inside the of the well-known Mailliard reaction took place.
crystal lattice. Crystallization is invariably Other properties such as crystal structure,
employed as the final step for the purification of a powderflow, compaction, lubricity, dissolution rate
solid. The use of different solvents and processing and polymer film permeability may also be affected
conditions may alter the habit of recrystallized by moisture adsorption.
particles, besides modifying the polymorphic state Table 2: Different classes of hygroscopic
of the solid. substances
f)Polymorphism: Hygroscopicity Classification
Class 1 Non- Essentially no
Many drug substances can exist in more than one Hygroscopic moisture increases
crystalline form with different space lattice occur at relative
arrangements. This property is known as humidities below
polymorphism. The different crystal forms are 90%.
called polymorphs.When polymorphism occurs, the Class 2 Slightly Essentially no
molecules arrange themselves in two or more hygroscopic moisture in occur at
different ways in the crystal; either they may be relative humidity
packed differently in the crystal lattice or there may below 80%
be differences in the orientation or conformation of
Class 3 Moderately Moisture Content
the molecules at the lattice sites.
hygroscopic does not increase
more than 5% after
Methods to identify polymorphism storage for 1 week
at relative humidity
Optical crystallography
below 60%
Hot 0stage microscopy
Class 4 Very Moisture content
X- Ray Diffraction method
hygroscopic increase may occur
NMR technique
at relative humidity
FTIR technique.
as low as 40 to
Microcalorimetry
50%
Thermal methods
Melting point determination

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3. Solubility Analysis: [Un- ionized form]


An important Physical-chemical property of a drug pH = pKa + log ----------------------------- for bases
substance is solubility, especially aqueous [ionized form]
solubility. A drug must possess some aqueous
solubility for therapeutic efficacy in the [Ionized form]
physiological P H range of 1 to 8. For a drug to pH = pKa + log------------------- for acids
enter into systemic circulation, to exert therapeutic [un ionized form]
effect, it must be first in solution form. If solubility Weakly acidic compounds (pKa< 4.3) were
of drug substance is less than desirable, than absorbed relatively rapidly;Those with pKa values
consideration must be given to increase its ranging between 2.0 and 4.3 were absorbed more
solubility. Poor solubility (< 10mg/ml) may exist slowly; and strong acids (pKa> 2.4) were hardly
incomplete or erratic absorption over PH rang 1-7 at absorbed.For bases, those with pKa values smaller
37C. However, knowledge of two fundamental than 8.5 were absorbed relatively rapidly; those
properties is mandatory for a new compound with a pK a between 9 and 12 were absorbed more
i) Intrinsic solubility(Co) slowly; and completely ionized quaternary
ii) Dissociation constant (Pka). ammonium compounds were not absorbed. In
i) Intrinsic Solubility (Co) pharmacokinetic area, the extent of ionization is
The intrinsic solubility should be measured at two imp. affect of its extent and absorption,
temp: 4 to 5C to ensure good physical stability distribution, elimination. The extent of P ka , in
and to extend short term storage and chemical many cases, highly dependent on PH of the medium
stabilityuntil more definite data is available. 37 C containing the drug.
to support biopharmaceutical evaluation. The
solubility of weakly acidic and weakly basic drug Determination of Pka:
as function of PH can be predicted with help of
equation, Potentiometric Titration
Spectrophotometric Determination
S = So {1 + (K1/ [H+])} For weak Dissolution rate method
acid. Liquid-Liquid Partition method
S = So {1+ ([H+]/ K2)} For weak base.
b). Partition Coefficient:
The lipophilicity of an organic compound is
usually described in terms of a partition coefficient;
Where, S = solubility at given PH. log P, which can be defined as the ratio of the
concentration of the unionized compound, at
So = intrinsic solubility of neutral form. equilibrium, between organic and aqueous phases:
K1 = dissociation constant for the weak acid.
K2 = dissociation constant for weak base. Po/w = ( C oil/water)equilibrium

a) Ionization Constant(PKA) [9-12]: Or


Many drugs are either weakly acidic or basic
compounds and, in solution, depending on the pH (un ionized compound)org
value, exist as ionized or un-ionized species. The logP =
un- ionized species are more lipid-soluble and (un ionized compound)aq
hence more readily absorbed. The gastrointestinal
absorption of weakly acidic or basic drugs is thus This ratio is known as the partition coefficient or
related to the fraction of the drug in solution that is distribution coefficient and is essentially
un- ionized.The conditions that suppress ionization independent of concentration of dilute solutions of
favor absorption. The factors that are important in a given solute species. logP = 0 means that the
the absorption of weakly acidic and basic compound is equally soluble in water and in the
compounds are the pH at the sit e of absorption, the partitioning solvent. If the compound has a log P =
ionization constant, and the lipid solubility of the 5, then the compound is 100,000 times more
un- ionized species. These factors together soluble in the partitioning solvent. A log P = 2
constitute the widely accepted pH partition theory. means that the compound is 100 times more
The relative concentrations of un-ionized and soluble in water, i.e., it is quite hydrophilic. Drugs
ionized forms of a weakly acidic or basic drug in a having values of P much greater than 1 are
solution at a given pH can be readily calculated classified as lipophilic, whereas those with
using the Henderson-Hasselbalch equations: partition coefficients much less than 1 are
indicative of a hydrophilic drug. Although it
appears that the partition coefficient may be the

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best predictor of absorption rate, the effect of dissolution rate, pKa, and solubility on absorption
Must not be neglected. Lipids occurring in living Where, S = molar solubility at temp. T ( K)
membranes are complex and difficult to obtainin R = gas constant.
pure form. An indication of the relative lipid Heat of solution represents the heat released or
solubility, however, can be obtained by absorbed when mole of solute is dissolved in large
determining how a drug substance distributes itself quantity of solvent. It is determined from solubility
between water and an immiscible organic solvent. value for saturated solution equilibrated at
When a solute is added to two immiscible liquids controlled temperature over the range of interested.
that are in contact with each other, it will distribute Typically the temperature range should include 5
itself between the two phases in a fixed ratio. This C, 25C, 37C and 50C.If heat of solution is
ratio is known as the partitioncoefficient,or positive (endothermic process) thus, increasing
distribution coefficient, and is essentially solution temp. Increased the drug solubility. For
independent of concentration of dilute solutions of non-electrolyte and un-ionized form of weak acid
a given solute species. Various organic solvents and weak bases dissolved in water, heat of solution
such as chloroform, ether, amyl acetate, range from 4 to 8 Kcal/mol.
isopropylmyristate, carbon tetrachloride, and n - e) Common Ion Effect:
Octanol can be used in the determination of the A common interaction with solvent, which often
partition coefficient, with the latter gaining overlooked, is the common ion effect. The addition
increasing acceptance. of common ion often reduces the solubility of
Methods of finding Partition coefficient: slightly soluble electrolyte. This salting out results
1) Shake-flask method from the removal of the water molecule as the
2) Chromatographic method. solvent due to competing hydration of other ions.
3) Counter current and filter probe method. So, weakly basic drug which are given as HCL
4) Tomlinsons filter probe method. salts have decreased solubility in acidic (HCL)
5) Microelectrometrictitratation method solution.
6) Automated instrument is now available.
Applications of Partition coefficient: Eg.Chlortetracycline, methacyclin, papaverine,
Measure of Lipophilic character of molecules. cyproheptadine, bromhexine,Triamterene
Recovery of antibiotics from fermentation broth. To identify a common ion interaction, the intrinsic
Extraction of drug from biological fluid for dissolution rate of hydrochloride salt should be
therapeutic monitoring. compared between, Water and water containing
Absorption of drug from dosage forms. (Ointments, 1.2%W/V NACL 0.05M HCL and 0.9%W/V
Suppositories, Transdermalpatches). NACL in 0.05M After this, if solubility is not
Study of distribution of flavouring oil between oil decreased than we can give drug in chloride salt,
& water in emulsion. otherwise it should be eliminated.
c). Solubilization: f) Dissolution:
For drug candidates, with either poor water In many instances, dissolution rate in the fluids at
solubility or insufficient solubility for projected the absorption site, is the rate limiting steps in the
solution dosage form, preformulation study should absorption process. This is true for the drug
include limited experiments to identify possible administered orally in the solid dosage forms such
mechanism for solubilization. as tablet, capsule, and suspension as well as drug
Methods for Increasing Solubility: administered I.M. in form of pellets or
suspension.Dissolution is of 2 types.
Change in pH
Co-Solvency a) Intrinsic dissolution
Dielectric Constant b) Particulate dissolution
Solubilization by Surfactant
Complexation a)Intrinsic Dissolution
Hydrotropy
Chemical Modification of drug The dissolution rate of a solid in its own solution is
adequately describedby the Noyes-Nernst equation:
d) Thermal Effect:
We determine the effect of temp. on the solubility AD (Cs C)
of drug candidate. This can be determined by dC / dt =-------------------------
measuring heat of solution i.e. HS hv
lnS = - HS ( 1 ) + C
R T

Where, A = surface area of the dissolving solid


dC / dt = dissolution rate D = diffusion coefficient

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C = solute concentration in the bulk medium Then sample is physically observed for (1)
h = diffusion layer thickness caking (2) liquefaction (3) Discoloration (4)
V = volume of the dissolution medium odor (5) gel formation.
Cs = solute concentration in the diffusion layer It is then assayed by TLC or HPLC or DSC.
During the early phase of dissolution, Cs C and is Whenever feasible, the degradation products
essentially equal to saturation solubility S. Surface are identified by MASS SPECTROSCOPY,
area A and volume V can be held constant.Under NMR or other relevant analytical techniques.
these conditions and at constant temperature and (B) Solution State Stability Studies [13]:
agitation, Equation reduces to It is easier to detect liquid state reactions as
dC / dt = KS compared to solid state reactions. For detection of
Where unknown liquid incompatibilities, the program set
K =AD/hV = constant. up is same as solid dosage forms. Now according to
Dissolution rate as expressed in Equation is termed Stability guidelines by FDA states that:
the intrinsic dissolution rate and is characteristic of Following conditions be evaluated in studies on
each solid compound in a given solventunder fixed solutions or suspensions of bulk drug substances:
hydrodynamic conditions. The intrinsic dissolution 1) Acidic or alkaline pH.
rate in a fixed volume of solvent is generally 2) Presence of added substances- chelating
expressed as mg dissolved x(min-1 cm- Z). agents, stabilizers etc.
Knowledge of this value helps the preformulation 3) High Oxygen and Nitrogen atmospheres.
scientist in predicting if absorption would be 4) Effect of stress testing conditions
dissolution rate-limited.
Particulate dissolution: Methodology:-
It will determine dissolution of drug at different Place the drug in the solution of additives.
surface area.It is used to study the influence on Both flint and amber vials are used.
dissolution of particle size, surface area and mixing Autoclave conditions are employed in many
with excipient. So, if particle size has no influence cases. This will provide information about
on dissolution than other method like addition of Susceptibility to oxidation.
surfactant will be considered. Susceptibility to light exposure.
4. STABILITY STUDIES: Susceptibility to heavy metals.
Incompatibility- general aspects In case of oral liquids, compatibility with
When we mix two or more API and / or excipient ethanol, glycerine, sucrose, preservatives and
with each other & if they are antagonistic & affect buffers are usually carried out.
adversely the safety, therapeutic efficacy,
appearance or elegance then they are said to be (C) Drug-Excipient Compatibility Studies:
incompatible. In the tablet dosage form the drug is in intimate
(A). Solid State Stability Studies: contact with one or more excipients; the latter
Solid state reactions are much slower and more could affect the stability of the drug. Knowledge of
difficult to interpret than solution state reactions, drug-excipient interactions is therefore very useful
due to a reduced no. of molecular contacts between to the formulator in selecting appropriate
drug and excipient molecules and to the occurrence excipients. This information may already be in
of multiple phase reactions. existence for known drugs. For new drugs or new
excipents, the preformulation scientist must
generate the needed information. A typical tablet
Sample A Sample B Sample C contains binders, disintegrants, lubricants, and
Prepare a small Sample Drug itself fillers. Compatibility screening for a new drug
mixture of drug preparation without any
method is same as excipient is
must consider two or more excipients from each
and excipient.
Place above mix sample A but 5% taken as a class. The ratio of drug to excipient used in these
in vial. moisture is added sample for tests is very much subject to the discretion of the
Palce a rubber in mixture. solid state preformulation scientist.
closure on vial stability
and dip the study.
stopper in molten
Importance of Drug Excipient Compatibility
carnuba wax to Study:-
render it Stability of the dosage form can be
hermetically
maximized. Any physical or chemical
sealed.
interaction between drug and excipient can
affect bioavailability and stability of drug.
All the samples of drug-Excipient blends are
kept for 1-3 weeks at specified storage It helps to avoid the surprise problems.
conditions. By performing DECS we can know the
possible reaction before formulating final
dosage form.

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It bridges the drug discovery and drug It is a very commonpathway for drug degradation
development. Drug discovery can emerge in liquid and solid formulations. Oxidation occurs
only new chemical entity. It becomes in two ways
drug prod uct after formulation and 1. Auto- oxidation
processing with excipients. 2. Free radical chain process.
By using DECS data we can select the Reaction of any material with molecular oxygen
suitable type of the excipient with the producing free radicals by hemolytic bond fission
chemical entities emerging in drug of a covalent bond. These radicals are highly
discovery programs. DECS data is unsaturated and readily accept electron from other
essential for IND (investigational new substance causing oxidation is called Auto-
drug ) submission. Now, USFDA has oxidation. Free radical chain process involves
made it compulsory to submit DECS data Initiation, Propagation, Hydro peroxide
for any new coming formulation before decomposition and Termination. Factors affecting
its approval. oxidation process are Oxygen concentration, light,
Analytical techniques used to detect Drug- heavy metals particularly those having two or more
Excipient Compatibility: valence state (copper, iron, nickel, cobalt),
hydrogen and hydroxyl ion, temperature. Oxidation
1) Thermal methods of analysis can be Prevented by Reducing oxygen content-
I. DSC- Differential Scanning Calorimetry oxidative degradation of drug takes place in an
II. DTA- Differential Thermal Analysis aqueous solution, so the oxygen content can be
2) Accelerated Stability Study decreased by boiling water or by storing the
3) FT-IR Spectroscopy formulation in in a dark and cool condition or by
4) DRS-Diffuse Reflectance Spectroscopy addition of an antioxidant/reducing agent /chain
5) Chromatography inhibitors of radical induced decomposition.
I. SIC-Self Interactive Chromatography Antioxidants are of two types based on Solubility.
II. TLC-Thin Layer Chromatography Oil soluble and Water soluble. Oil Soluble
III. HPLC-High Pressure Liquid Antioxidants are Free radical acceptors and inhibit
Chromatography free radical chain process eg: hydroquinone,
6) Miscellaneous propylgallate, lecithin whereas Water soluble
I. Radiolabelled Techniques Antioxidants Oxidizes itself and prevents oxidation
II.Vapour Pressure Osmometry of drug Eg: sodium metabisulphate, sodium
III. Fluorescence Spectroscopy bisulfate, thioglycolic acid, thioglycerol.
c) Reduction: is a relatively morecommon pathway
B. CHEMICAL CHARACTERISTICS [14] of drug metabolic process. Hepatic
a) Hydrolysis-It involves nucleophilicattack of microsomescatalyze diverse reductive chemical
labile groups eg: lactam ester amide imide. When reaction* and require NADPHfor this purpose. Azo
the attack is by the solvent other than water, then it and nitro reduction is catalyzed by cytochrome P-
is known as solvolysis. It generally follows 2nd 450.Chloral hydrate is reduced to its active
order kinetics as there are two reacting species, metabolite trichloroethanol by alcohol
water and API. In aqueous solution, water is in dehydrogenase. Reduction of prednisolone and
excess so the reaction is 1st order. Conditions that cortisone results in the formation of their active
catalyze the breakdown are Presence of hydroxyl metabolites hydrocortisone. Azo dyes used as
ion, hydride ion, divalent ion and heat, light, ionic coloring agents in pharmaceutical products or food
hydrolysis, solution polarity and ionic strength, are reduced to form amines in the liver and by the
high drug concentration. Hydrolysis can be intestinal flora.
prevented by Adjusting the PH.As most of the d)Photolysis: Mechanism of photodecomposition:
potent drugs are weakly acidic or weakly basic in Electronic configuration of drug overlaps with the
nature. Formulate the drug solution close to spectrum of sunlight or any artificial light where
itsPHof optimum stability or by Addition of water energy is absorbed by the electron resulting in
miscible solvent in formulation or by Using excitation. As they are unstable, they release the
Optimum buffer concentration to suppress acquired energy and return to the ground state by
ionization or by Addition of surfactant such as non- decomposing the drug. The phenomenon where
ionic, cationic and anionic surfactant stabilizes the molecules or excipients which absorb energy but
drug against base catalysis or the solubility of donot participate themselves directly in the reaction
pharmaceuticals undergoing ester hydrolysis can be but transfer the energy to others which cause
reduced by forming less soluble salts or ester of cellular damage by inducing radical formation is
drug. eg: phosphate ester of Clindamycin or Store known as photosensitization. Photosentizer Convert
with desiccants, using complexing agents. oxygen from its ground state to singlet excited state
and Generate superoxide molecule which is an
b) Oxidation: anion radical and acts as a powerful oxidizing

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agent.
Photo Decomposition Pathway REFERENCES
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CONCLUSION 14. D.Swathi, Sowjanya et al, Various aspects of
Preformulation studies have a significant part to Pharmaceutical Preformulation: A Review,
play in anticipating formulation problems and PHARMANEST: An International Journal of
identifying logical paths in both liquid and solid Advances in Pharmaceutical Sciences. ISSN: 2231-
dosage form Technology. By comparing the 0541, Vol(4),Issue(2), Pages:171-190, Mar 2013.
physicochemical properties of each drug candidate
within a therapeutic group, the Preformulation
scientist can assist the synthetic chemist to identify
the optimum molecule, provide the biologist with
suitable vehicles to elicit pharmacological
response. Stability studies in solution will indicate
the feasibility of parental or other liquid dosage
form and can identify methods of stabilization. In
parallel solid-state stability by DSC, TLC and
HPLC in the presence of tablet and capsule
excipient will indicate the most acceptable vehicles
for solid dosage form. This review article gives
details of above studies with respect to any
sustained release dosage forms can be developed
without preformulation studies.

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