PHARMACEUTICAL PREFORMULATION STUDIES INCLUDING PHYSICHOCHEMICAL PROPERTIES IN DETAIL.

1. Unit 1
INDUSTRIAL PHARMACY 1

2.  Preformulation studies focus on those physicochemical properties of
the new compound that could affect the drug performance and
development of an efficacious dosage form.
 “It is the study of the physical and chemical properties of the drug prior
to compounding process”
 1st step in rational development of a dosage form of a drug substance
alone and when combined with excipients.
 This properties may provide;
• A rationale for formulation design
• Support the need for molecular modification
Definition:
It can be defined as an investigation of physical and
chemical properties of a drug substance alone or when combined
with excipients.
Preformulation
studies 2

3. GOALS AND OBJECTIVES
 To establish the physicochemical parameters of a new drug.
 To establish its kinetics and stability.
 To establish its compatibility with common excipients.
 Providing a scientific data to support the dosage form design and
evaluation of the product efficacy and stability.
PHYSICOCHEMICAL PROPERTIES :
The ability of a chemical compound to elicit a
pharmacological/therapeutic effect elated to the influence of various
physical and chemical properties of the chemical substance on bio
molecule that interacts with;
1) Physical properties: responsible for drug action
2) Chemical properties: The drug extracellularly according to simple
chemical reactions like neutralization, chelation , oxidation etc.
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4. I] Bulk characterization
1) Particle size
2) Particle shape
3) Crystallinity & polymorphism
4)Flow properties
5) Hygroscpicity
II] Solubility profile
i) pKa ii) pH iii) partition coefficient
III] Stability analysis
1) Particle size
Particle size is inversely proportional to the surface area. Properties such as
rate of absorption, dissolution, content uniformity and stability are
dependent to varying degrees on particle size, distribution and
interactions of solid surfaces.
Light microscopic method, Coulter counter method, HIAC counter are
methods for characterizing the size distribution of the compound
Sieve method for particle size ~ 100 microns.
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5.  Particle size is characterized using these terms:
Very coarse (#8)
Coarse (#20)
Moderately Coarse (#40)
Fine (#60)
Very fine (#80)
 Significance of Particle Size:
 Particle size of drugs may affect formulation and product efficacy.
 Certain physical and chemical properties of drug substances are affected
by the particle size distribution including; drug dissolution rate, content
uniformity, texture, stability, flow characteristics, and sedimentation rates.
 Particle size significantly influences the oral absorption profiles of certain
drugs.
 Satisfactory content uniformity in solid dosage forms depends to a large
degree on particle size and the equal distribution of the active ingredient
throughout the formulation
 Methods To Evaluate Particle Size And Distribution:
1. Sieving or screening 2. Optical microscopy
3. Sedimentation 4. Light energy diffraction.
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6.  Sieving method :
Range : 50 – 150 µm
Simple, inexpensive If powder is not dry, the apertures get clogged.
 Microscopy :
Range : 0.2 – 100 µm
Particle size can be determined by the use of calibrated grid
background . Most direct method. Slow & tedious method
Sedimentation method :
Range : µm
Andreasen pipette is used.
Light energy diffraction :
Range : 0.5 – 500 µm
Particle size is determined by the reduction in light reaching the
sensor as the particle, dispersed in a liquid or gas, passes through the
sensing zone. Quick & fast.
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7.  Apart from particle size, particle shape plays an important role during
preformulation phase as th shape of particle may influence surface area, flow
properties and compaction force.
A drug particle may exist in different forms such as spherical, angular, acicular,
needle , oval or rough. The spherical particle has the maximum area and
uniform flow property. The maximum surface area ensures better solubility.
 Egg: For topical products that are working as abrasives irregular particle
shape is more preferred.
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8. Crystallanity or drug form
 Drugs can be used therapeutically as solids, liquids and gases.
 Liquid drugs are used to a much lesser extent than solid drugs and even
less frequently than gases.
 Solid materials are preferred in formulation work because of their ease of
preparation into tablets and capsules.
 The majority of drug substances in use occur as solid materials.
 Most of them are pure chemical compounds of either: Amorphous or
Crystalline in nature
 Solid drug materials may occur as:
a. Amorphous (higher solubility) b. Crystalline (higher stability)
 The amorphous or crystalline characters of drugs are of great importance
to its ease of formulation and handling, its chemical stability and its
biological activity.
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9.  Amorphous drugs have randomly arranged atoms or molecules.
 These are typically prepared by ; precipitation, lyophilization, or rapid
cooling method.
Advantage:
 These forms have higher solubilities as well as dissolution rates as
compared to crystalline forms.
Disadvantage:
 Upon storage, sometimes amorphous solids tend to revert to more stable
forms. This instability can occur during bulk processing or within dosage
forms.
 E.g. Novobiocin : It is inactive when administered in crystalline form, but
when they are administered in the amorphous form, absorption from the
gastrointestinal tract proceeds rapidly with good therapeutic response.
 Crystals are characterized by repetitious spacing of constituent atoms or
molecules in a three dimensional array.
 Crystalline forms of drugs may be used because of greater stability than
the corresponding amorphous form.
E.g: the crystalline forms of penicillin G as potassium or sodium salt is
considerably more stable and result in excellent therapeutic response than
amorphous forms
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10. Polymorphism
Polymorphism is defined as the ability of compound to crystallize as more
than one crystalline species with different internal lattices
E.g. Chloramphenicol palmitate exists in three crystalline polymorphic
forms (A,B and C) and an amorphous form.
Crystal habit is the description of the outer appearance of the crystal
structure while internal structure is the molecular arrangement within the
solid. Hence a single internal structure can have several different habits
so the changes in internal structure cause external change of the crystal
habit.
Characterization of a solid form involves:
1) Verifying that the solid is the expected chemical compound
2) Characterization of the internal structure
3) Describing the habit of the crystal.
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11.  Different crystalline forms are called polymorphs.
Polymorphs are of two types
1) Enantiotropic
2) Monotropic
The polymorph which can be changed from one form to another by
varying temperature and pressure is called as Enantiotropic polymorph
E.g. Sulphur
One polymorph which is unstable at all temperature and pressure is
called Monotropic
E.g. Glyceryl stearate
Many drug substances can exist as more than one crystalline form with
lattice arrangements. Only one crystalline form of drug is stable at a given
temperature and pressure and others are metastable i.e. they convert to
metastable form
E.g.: Theophylline displays three polymorphs anhydrous I, II,III and
monohydrate and upon storage the anhydrous polymorphs convert to
monohydrate.
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12.  Polymorphism is the ability of a compound to crystallize as more
than one distinct crystalline species with different internal lattices or
crystal packing arrangement even they are chemically identical
depending on the variation in ;
a. Temperature
b. Solvent
c. Time
 Different polymorphs also lead to different morphology, tensile
strength and density of powder bed which all contribute to
compression characteristics of materials.
 Although a drug substance may exist in two or more polymorphic
forms, only one form is thermodynamically stable at a given
temperature and pressure.
 The other forms would convert to the stable form with time. In
general, the stable polymorph exhibits the highest melting point, the
lowest solubility, and the maximum chemical stability.
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13. 13

14. 14

15.  Metastable form is preferred as it has more aqueous solubility and
bioavailability.
E.g. : 1)Chloramphenicol palmitate B shows the best availability and A
form is virtually inactive biologically.
2) Polymorphic form III of Riboflavin is 20 times more water soluble
than the form I
 Amorphous form drugs represent highest energy state and can be
considered as supercooled liquids. They have higher aqueous
solubility than crystalline form because the energy required to
transfer a molecule from one crystal lattice is greater.
E.g.: Amorphous form of Novobiocin is 10 times more soluble than
crystalline form.
Thus the order of dissolution of different slid forms of drug is-
Amorphous> Metastable > Stable
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16.  Significance of polymorphism:
• Different polymorphs exhibit different solubilities, therapeutic activity
and stability.
• Chemical stability and solubility changes due to polymorphism can
have an impact on drug’s activity.
Polymorphs can be determined by following techniques:
Optical crystallography
X-ray diffraction
Differential scanning calorimetry
Polymorphic
form
Melting point Aqueous
solubility
stable High melting
point
Least aqueous
solubility
metastable Low melting
point
High aqueous
solubility
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17. 4) Flow properties:
 Powder flow properties can be affected by change in particle size,
shape & density. The flow properties depends upon following-Force of
friction. Cohesion between one particle to another.
Fine particle posses poor flow by filling void spaces between larger
particles causing packing & densification of particles..
By using glident we can alter the flow properties. E.g. Starch, Talc.
 It is a mechanical property Bulk powders are similar to non-Newtonian
liquids due to their plastic flow and sometimes dilatancy.
 Particles are influenced by attractive forces (vary in degrees).
 Pharmaceutical powders may be broadly classified into Free flowing
and Cohesive or sticky or non free flowing
 Factors influencing flow properties
1)Particle size
2)Particle nature
3)Porosity
4)Density of bulk powder
5)Moisture content
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18. 18
Methods to determine Flow Properties:
1) Angle Of Repose
 A greater angle of repose indicate poor flow.
 It should be less than 30°.
 The rougher and more irregular the surface of the particles, the
higher will be the angle of repose.
It is the maximum angle between the surface of a pile of powder and
horizontal plane and can be determined by following equation:
tan θ = h/r.
where, θ = angle of repose.
h=height of pile.
r= radius.

19. 2) Hausners Ratio
Density of powders
Density is defined as weight per unit volume (W/V).
• During tapping, particles gradually pack more efficiently, the powder
volume decreases and the tapped density increases.
Types of Density
1. True density: The true density or absolute density of a sample
excludes the volume of the pores and voids within the powder sample.
2. Bulk density: The bulk density value includes the volume of all of
the pores within the powder sample.
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20.  The compressibility index and Hausner ratio are measures of the products ability to
settle, and permit an assessment of the relative importance of interparticulate
interactions.
 In a free-flowing powder these interactions are less significant and the bulk and
tapped densities will be closer in value.
 For poorly flowing materials, there are greater interparticulate interactions and a
greater difference between the bulk and tapped densities will be observed.
 The differences are reflected in the compressibility index and Hausner ratio.
It is given by the formula:
Hausner ratio= tapped density
bulk density
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21. 3) Carr’s Compressibility index
 “Compressibility" of a powder can be defined as the ability to
decrease in volume under pressure and "compactability” as the
ability of the powdered material to be compressed into a tablet of
specified tensile strength.
 It can be used to predict the flow properties based on density
measurement.
A volume of powder is filled into a graduated glass cylinder and
repeatedly tapped for a known duration. The volume of powder after
tapping is measured.
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22.  Many drug substances, particularly water –soluble salt forms, have
a tendency to adsorb atmospheric moisture.
 Adsorption and moisture content depend upon the atmospheric
humidity, temperature, surface area, exposure and the mechanism
of moisture uptake.
 Changes in moisture level can greatly influence many parameters
such as ; chemical stability,flowability, and compatibility.
 The degree of Hygroscopicity is classified into four classes:
• Slightly hygroscopic: increase in weight is ≥ 0.2% w/w and < 2%
w/w
• Hygroscopic : increase in weight is ≥ 0.2 % w/w and < 15 % w/w
• Very hygroscopic : increase in weight is ≥ 15% w/w
• Deliquescent : sufficient water is adsorbed to form a solution
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23. For example, we have found that a primary amine, when mixed with
lactose was apparently stable even when stored at 90°C for 12 weeks.
However, when the experiment was carried out in the presence of
moisture, extensive degradation by way of the well-known Mailliard
reaction took place.
Hygroscopicity is tested by:-
Samples are exposed to the moisture exposed
to controlled relative humidity environments
moisture uptake is monitored at different time points
Analytical methods which is used are :
 Gravimetry
 Karl Fischer Titration
 Gas chromatography
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24. Solubility Analysis:
• An important Physical-chemical property of a drug substance is
solubility, especially aqueous solubility.
• A drug must possess some aqueous solubility for therapeutic efficacy
in the physiological pH range of 1 to 8. For a drug to enter into
systemic circulation, to exert therapeutic
effect, it must be first in solution form.
• The solubility of drug is an important physicochemical property
because it affects the rate of drug release into the dissolution medium
and consequently, the therapeutic efficacy of the pharmaceutical
product.
1. Polar solutes dissolve in polar solvents
2. Non-polar solutes dissolve in non-polar solvents
Methods for Increasing Solubility:
Change in pH Co-Solvency
Dielectric Constant Solubilization by
Surfactant
Complexation Hydrotropy
Chemical Modification of drug
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25.  A drug must possess aqueous solubility for therapeutic efficacy in
physiological pHrange of 1 to 8 at 37 ºC.
 Poor solubility (<10mg/ml) may result into bioabsorption problems.If
solubility of drug is less than 1 mg/ml it indicates the need for a salt,
particularly ifthe drug will be formulated as a tablet or capsule.
 In the range 1-10 mg/ml serious consideration should be given to
salt formation
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26.  Common solvents used for solubility determination are:
Water
Polyethylene Glycols
Propylene Glycol
Glycerine
Sorbitol
Ethyl Alcohol
Methanol
Benzyl Alcohol
Isopropyl Alcohol
Tweens
Polysorbates
Castor Oil ,Peanut Oil ,Sesame Oil
Buffers at various pHs
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27.  The solubility of weakly acidic and weakly basic drug as function of
pH can be predicted with the help of equation,
 Where, S = solubility at given pH.
So = intrinsic solubility of neutral form.
K1 = dissociation constant for the weak acid.
K2 = dissociation constant for weak base.
The intrinsic solubility must be measured at two temperatures
a) 4˚C- To ensure physical and chemical stability
b) 37˚C- To support biopharmaceutical evaluation
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S = So {1 + (K1/ [H+])} For weak acid
S = So {1+ ([H+]/ K2)} For weak base

28.  For a compound containing basic or acidic functional groups,
solubility at a given pH is influenced by the compound’s ionization
characteristics. The solubility of a compound in aqueous media is
greater in the ionized state than in the neutral state. Thus, solubility of
ionizable compounds is dependent on the pH of the solution
 The un-ionized species are more lipid-soluble and hence more
readily absorbed.
 The gastrointestinal absorption of weakly acidic or basic drugs is thus
related to the fraction of the drug in solution that is un- ionized.
 The factors that are important in the absorption of weakly acidic and
basic compounds are the pH at the site of absorption, the ionization
constant, and the lipid solubility of the un- ionized species.
These factors together constitute the widely accepted pH partition
theory.
 The relative concentrations of un-ionized and ionized forms of a
weakly acidic or basic drug in a solution at a given pH can be readily
calculated
using the Henderson-Hasselbalch equations:
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29.  The Henderson-Hasselbalch equation provides an estimate of the
ionized and un-ionized drug concentration at a particular pH
 For acidic compounds:
pH = pKa + log ([ionized drug]/[un-ionized drug])
 For basic compounds:
pH = pKa + log ([un-ionized drug]/[ionized drug])
The various methods for determination
of pKa are:
a) Potentiometric method
b) Spectrophotometric method
c) Solubility method
d) Conductivity method
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30. PARTITION COEFFICIENT
 The lipophilicity of an organic compound is usually described in
terms of a partition coefficient; log P, which can be defined as the
ratio of the concentration of the unionized compound, at equilibrium,
between organic and aqueous phases:
Po/w = ( C oil/water)equilibrium
Or
(un ionized compound)org logP = (un ionized compound)aq
 Drugs having values of P much greater than 1 are classified as
lipophilic, whereas those with partition coefficients much less than 1
are indicative of a hydrophilic drug.
• log P = 0 means that the compound is equally soluble in water and
in the partitioning solvent.
• If the compound has a log P =5, then the compound is 100,000
times more soluble in the partitioning solvent.
• A log P = –2 means that the compound is 100 times more soluble in
water, i.e., it is quite hydrophilic
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31.  When a solute is added to two immiscible liquids that are in contact
with each other, it will distribute itself between the two phases in a
fixed ratio. This ratio is known as the partition coefficient, or
distribution coefficient, and is essentially independent of
concentration of dilute solutions of a given solute species.
 Various organic solvents such as chloroform, ether, amyl acetate,
isopropylmyristate, carbon tetrachloride, and n -Octanol can be used
in the determination of the partition coefficient.
Methods of finding Partition coefficient:
1) Shake-flask method
2) Chromatographic method.
3) Counter current and filter probe method.
4) Tomlinson’s filter probe method.
5) Microelectrometric titratation method
6) Automated instrument is now available.
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32. Applications of Partition coefficient:
 Measure of Lipophilic character of molecules.
 Recovery of antibiotics from fermentation broth.
 Extraction of drug from biological fluid for therapeutic monitoring.
 Absorption of drug from dosage forms. (Ointments, Suppositories,
Transdermal patches).
 Study of distribution of flavouring oil between oil & water in emulsion.
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33. Incompatibility- general aspects
 When we mix two or more API and / or excipient with each other & if they
are antagonistic & affect adversely the safety, therapeutic efficacy,
appearance or elegance then they are said to be incompatible.
 (A) Solid State Stability Studies:
Solid state reactions are much slower and more difficult to interpret than
solution state reactions, due to a reduced no. of molecular contacts
between drug and excipient molecules and to the occurrence of multiple
phase reactions.
(B) Solution State Stability Studies :
It is easier to detect liquid state reactions as compared to solid state
reactions.
According to ―Stability guidelines by FDA states that: Following
conditions be evaluated in studies on solutions or suspensions of bulk
drug substances:
1)Acidic or alkaline pH.
2) Presence of added substances- chelating agents, stabilizers etc.
3) High Oxygen and Nitrogen atmospheres.
4) Effect of stress testing conditions
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34.  (C) Drug-Excipient Compatibility Studies:
 In the tablet dosage form the drug is in intimate contact with one or
more excipients; the latter could affect the stability of the drug.
Knowledge of drug-excipient interactions is therefore very useful
to the formulator in selecting appropriate excipients.
This information may already be in existence for known drugs. For
new drugs or new excipents, the preformulation scientist must
generate the needed information. A typical tablet contains binders,
disintegrants, lubricants, and fillers. Compatibility screening for a new
drug must consider two or more excipients from each class.
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35. Goals of understanding chemical properties
 Initial investigation on chemical properties
 Knowledge about the physical and chemical stability of a
drug candidate in the solid and liquid state-drug
development
 Stability of formulation-shelf life of marketed product
 Chemical properties, path of degradation, rate of
degradation
 Stability with temperature, pH, light and oxygen a
number of experiments need to be performed.
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36.  It is the cleavage of chemical bonds by addition of water.
 The reaction of water with another chemical compound to form two
or more products, involving ionization of the water molecule usually
splitting the other compound.
 Examples include : o the catalytic conversion of starch to glucose, o
saponification, and o the formation of acids or bases from dissolved
ions.
 It involves nucleophilic attack of labile groups.
E.g. Lactam > Ester > Amide > Imide.
 When this attack is by a solvent other than water then it is known
as solvolysis.
 It generally follows 2nd order kinetics as there are 2 reacting
species, water and API.
 In aqueous solution, water is in excess, the reaction is 1st order.
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37.  Conditions that catalyze the breakdown:-
(1) Presence of hydroxyl ion.
(2) Presence of hydride ion.
(3) Presence of divalent ion.
(4) Heat.
(5) Light.
(6) Ionic hydrolysis.
(7) Solution polarity & ionic strength.
HYDROLYSIS DEGRADATION PATHWAYS
1) Hydrolysis in esters:
37

38.  Esters on hydrolysis gives acid and alcohol by rupturing the
covalent linkage between a carbon atom and an oxygen atom.
 Catalysts include acids, alkalis or enzymes capable of supplying
H+ or OH-ions.
 EG:1)Aspirin on hydrolysis yields Salicylic acid
2)Clofibrate upon hydrolysis gives active acid metabolite
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39. 2) Hydrolysis in amides:
Amides on hydrolysis yield acids and amines
Eg 1) Procainamide on hydrolysis yields PABA
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40.  Carbamazepine to Iminostilbene reaction
 Prevention of hydrolysis:-
1) pH adjustment
 Most of the potent drugs are weakly acidic or weakly basic, which
are more soluble when ionized so their instability will increase.
 Remedy:-
- Formulate the drug solution close to its pH of optimum stability.
- Addition of water miscible solvent in formulation.
- Optimum buffer concentration to suppress ionization.
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41. 2) Addition of surfactant.
Nonionic, cationic & anionic surfactant stabilizes the drug against base
catalysis.
3) Salts & esters.
The solubility of p’ceuticals undergoing ester hydrolysis can be
reduced by forming less soluble salts or ester of drug.
Eg. Phosphate ester of Clindamycin.
4) Store with dessicants.
5) By use of complexing agent
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42.  It is a very common pathway for drug degradation in liquid & solid
formulation.
 Oxidation is gain of oxygen and loss of electrons.
Oxidation occurs in two ways:-
1. Auto oxidation.
2. Free radical chain process.
 Auto oxidation:-
It is defined as a reaction of any material with molecular oxygen which
produces free radicals by hemolytic bond fission of a covalent bond.
These radicals are highly unsaturated & readily take electron from other
substance causing oxidation.
 For auto oxidation to occur in solid molecular oxygen must be able to
diffuse through the crystal lattice to liable sites.
Hence crystal morphology & packing are important parameters for
determining oxidation kinetics.
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43.  Free radical chain process
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44.  Functional groups having high susceptibility towards oxidation:-
- Alkenes.
- Substituted aromatic groups. (Toluene, phenols, anisole).
- Ethers.
- Thioethers.
- Amines.
 Factors affecting oxidation process:-
1. Oxygen concentration.
2. Light.
3. Heavy metals particularly those having two or more valence state.
(Eg. Copper, iron,nickel, cobalt).
4. Hydrogen & Hydroxyl ion.
5. Temperature.
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45.  Prevention of oxidation:-
1) Reducing oxygen content.
Oxidative degradation of drug takes place in an aqueous solution, so
the oxygen content can be decreased by boiling water.
2) Storage in a dark & cool condition.
3) Addition of an antioxidant.
a) Reducing agent.
b) Chain inhibitors of radical induced decomposition.
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46. 4) Addition of chelating agent.
 It forms complexes with trace amount of heavy metal ion &
inactivate their catalyzing activity.
 Eg. EDTA, Citric acid, Tartaric acid.
5) Adjustment of pH.
 To optimum stability in order to reduce oxidation potential of the
system.
6) Changing solvent.
 Solvent other than water may have catalyzing effect on oxidation
reaction when used in combination with water or alone.
 Eg. Aldehydes, ethers, ketones may influence free radical reaction.
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47.  Bioreactions are capable of generating polar functional groups such
as hydroxy or aminoacids which can undergo biotransformation or
conjugation.
 A number of reductive reactions are exact opposite of oxidation .
 Bio reductions comprises of one half of reversible reactions. Such
reactions may be cataylised by-
Same enzyme (true reversible reaction)
Different enzyme (apparent reversible reaction)
These reactions generally lead to conversion of inactive metabolites
into active drug, that may lead to delay of drug removal from body
and hence prolongation of action
E.G. Methadone is reduced to methadol
Nitrazepam is reduced to 7- Amino metabolite
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48.  Racemization is another way in which the compound can change in
solution. In this optically active compound loses its optical activity
without changing its chemical composition and converted into its
inactive form that is racemic mixture
 The interconversion from one isomer to another can lead to
different Pharmacokinetic properties (ADME) as well as different
Pharmacological / toxicological effect.
 It depends on temperature, solvent
, catalyst & presence or absence of light.
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49.  It is the process in which one enantiomer such
as L-amino acid gets converted to other.
 The compound then alters between
each form while the ratio between
the (+) and (-) groups approaches 1:1,
at which point it becomes
optically inactive.
 If the racemization results in a
Mixture where the enantiomers
are present in equal quantities,
the resulting sample is described
as racemeric or a racemate.
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50. 50
E.g. l -epinephrine is 15 to 20 times more active than d-form while
activity of racemic mixture is just one half of the l -form.
E.g. Levo cetrizine is more active than the dextro form.
 It follows first order kinetics.
 It depends on temperature, solvent, catalyst / presence or absence
of light

51. POLYMERIZATION
Polymers are high molecular weight substances, fashioned by
aggregation of smaller molecules called monomers.
 It is a continuous reaction between molecules.
More than one monomer reacts to form a polymer.
 E.g. Darkening of glucose solution is attributed to polymerization of
breakdown product [5- (hydroxyl methyl) furfural].
 E.g. Shellac on aging undergoes polymerization & hence prolongs
disintegration time & dissolution time.
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