B.Pharm - IP-I Unit I - Preformulation.pptxB

Industrial pharmacy -I
UNIT – I
PREFORMULATION
STUDIES

2
 A Preformulation study is an investigation of the physical,
chemical and mechanical properties of a drug substance to
develop a safe, effective, and stable dosage form.
 Thus, it forms an integral part of the drug development process.
Goals and objectives to accomplish the following:
 To establish the physicochemical properties of the new drug
substance
 To determine its kinetic profile and stability
 To determine its compatibility with inactive ingredients or
excipients
 To know the methods of drug processing and storage.

3
ORGANOLEPTIC PROPERTIES OF THE DRUG
 Organoleptic properties are the aspects that can be
experienced through one’s senses like taste, smell, sight
and touch.
 Thus, it includes a recording of the colour, odour, and
taste of the drug.

4
PHYSICOCHEMICAL PROPERTIES
 Organoleptic Properties – Colour, odour & taste
 Molecular structure & Molecular weight
 Melting point
 Thermal analysis - to analyze the time and temperature at which
physical changes occur when a substance is heated or cooled.
 Particle size & shape
 Hygroscopicity - the ability of solids to adsorb water onto their
surfaces microscopically.
 Ionization constant - a constant that depends upon the equilibrium
between the ions and the molecules that are not ionized in a solution
or liquid

5
 Optical activity - the ability of a substance to rotate the plane of
polarization of a beam of light that is passed through it.
 Solubility - the ability to be dissolved, especially in water.
 pH solubility – solubility increases with increase or decrease in
pH
 Polymorphism - the quality or state of existing in or assuming
different forms
 Absorption Spectra - that measure the absorption of radiation,
as a function of frequency or wavelength, due to its interaction
with a sample.
 Thermal Stability - the ability of the polymeric material to
resist the action of heat

6
PRINCIPLES AREAS OF
PREFORMULATION
1. Physical Properties:
a. Solubility Studies
 Effect of Temperature
 Compatibility studies
 Dissolution
 BCS Classification of drugs
b. Solubility Analysis
 pKa determination
 pH
 Partition coefficient
c. Bulk characterization
 Physical form – crystal & amorphous
 Polymorphism
 Micromeritics - Particle size & Particle shape
 Flow Properties – Angle of repose
 Density (true & bulk) and porosity

7
2. Chemical Properties
 Hydrolysis
 Oxidation – loss of electron
 Reduction – addition of an electron
 Racemisation – conversion of optically active
substance to racemic form
 Polymerization – creates polymers

8
BULK CHARACTYERIZATION
Physical form - Chemical substance
Habit
Internal structure - Crystalline & Amorphous
 The outer appearance of a crystal - Habit
 The arrangement of molecules within the solid -Internal
structure (crystalline or amorphous)
 The internal structure of a compound can be either crystalline
or amorphous.
 The compound is said to be crystalline if its atoms or
molecules are arranged repetitively in a 3-D array.

9
CRYSTAL HABITS
Habit Description
Acicular Elongated prism – needle like
Angular Sharp edged, roughly polyhedral
Bladed Flattened acicular
Crystalline Geometric shape fully developed in fluid
Dendritic Branched crystalline
Fibrous Regular or irregular thread – like
Flaky / Platy Plate or salt like
Granular Equidimensional irregular shape
Irregular Lacking any symmetry
Nodular Rounded irregular shape
Prismatic Columnar prism
Spherical Global Shape
Tabular Rectangular with a pair of parallel faces

11
 Solvate - a stoichiometric adduct is a molecular
complex in which the crystallizing solvent molecules
are incorporated within the crystal lattice.
 Hydrate - a stoichiometric adduct in which the
entrapped solvent is water
 Clathrate - a non-stoichiometric adduct entraps
solvent molecules within the crystal lattice.
 Anhydrous - A compound is said to be anhydrous if the
crystal structure does not contain water within it.

12
 Amorphous solids - the ones in which the atoms or molecules
are arranged in a random manner.
 In these solids, different bonds have different strength.
 There is no regularity in their external structure, and also they
do not have sharp melting points
Crystalline Amorphous
Have fixed internal structure No fixed internal structure
Have lower thermodynamic
energy
Have higher thermodynamic
energy
More stable Less stable
Lesser solubility Greater solubility
Lesser tendency to change Tend to revert to more stable
forms

13
POLYMORPHISM
 It is the ability of a compound to crystallize as more than one
distinct crystalline species with different internal lattices.
 Chemical stability and solubility changes due to polymorphism.
 Ex. Chloramphenicol palmitate exists in 3 crystalline polymeric
forms and amorphous form.
Types
 A. Enantiotropic – one polymorph can be reversibly changed
into another by varying temperature or pressure. Ex. sulfur.
 B. Monotropic – one polymorph is unstable at all temperatures
and pressure. Ex. Glyceryl stearates.

14
PARTICLE SIZE
Size, shape, and surface morphology of the drug particles
put a direct effect on the bulk flow, formulation homogeneity, and
surface area controlled processes such as dissolution and
chemical reactivity.
Methods to determine particle size
Sieving
Microscopy
Sedimentation rate
Coulter counter method
Scanning electron microscopy

15
BULK & TAPPED DENSITY
Bulk density (gm/ml) - The bulk drug which has been
sieved previously through a 40-mesh sieve is poured
into a graduated cylinder with the help of a large
funnel and the volume and weight is measured.
Tapped density (gm/ml) - A graduated measuring
cylinder with a known mass of drug or formulation is
placed on a mechanical tapper apparatus operating at
a fixed number of taps ( #1000). When the bed volume
of powder reaches minimum level, the weight and
volume of the drug in the cylinder is measured.

16
FLOW PROPERTIES
Angle of repose – angle between horizontal plane & pile
surface
θ = tan-1
(h/r)
Angle of repose Type of flow
< 25 Excellent
25 – 30 Good
30 – 40 Passable
> 40 Very poor

17
Hausner’s ratio Flow property Carr’s Index
1 – 1.11 Excellent 1 – 10
1.12 – 1.18 Good 11 – 15
1.19 – 1.25 Fair 16 – 20
1.26 – 1.34 Passable 21 – 25
1.35 – 1.45 Poor 26 – 31
1.46 – 1.59 Very poor 32 – 37
> 1.60 Very very poor > 37
Hausner’s ratio = Tapped density / Bulk density
Carr’s Index = [(Tapped density – Bulk density) / Tapped
density ] x 100
HAUSNER’S RATIO & CARR’S INDEX

18
THERMAL ANALYSIS
 Differential Scanning Calorimetry [DSC] &
differential thermal analysis [DTA] – measures
the heat loss or gain – which results in physical
or chemical changes.
 Endothermic processes – fusion, boiling,
sublimation, vapourization, desolvation, chemical
degradation etc
 Exothermic processes – degradation &
crystallization.

19
HYGROSCOPICITY
Hygroscopic – adsorption of atmospheric moisture.
 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 absorbed to form a solution.
 Changes in moisture level can greatly influence chemical
stability, flowability, compactibility etc.

20
SOLUBILITY STUDIES
 Solubility of a solid substance is defined as the
concentration at which the solution phase is in
equilibrium with the given solid phase at a stated
temperature and pressure.
 In order to be transported across biological membranes,
drug molecules are required to be present in dissolved
form.
 The bioavailability of an orally administered drug
depends primarily on its solubility in the GI tract and its
permeability.

21
SOLUBILITY ANALYSIS
A drug for oral administration should be examined for solubility in
media having isotonic chloride ion concentration and acidic pH.
Understanding drug's solubility profile and possible solubilization
mechanisms that provides a basis for later formulation work.
 Preformulation solubility studies usually include:
Determination of pKa
Temp. dependence
pH solubility profile
Solubility products
Solubilization mechanisms
Rate of dissolution

22
Analytical instruments used for solubility measurements include:
 HPLC
 UV spectroscopy
 Fluorescence spectroscopy
 Gas chromatography.
Factors affecting solubility and dissolution experiments:
pH
Temperature
Ionic strength
Buffer concentrations.

23
EFFECT OF TEMPERATURE
 The heat of solution, , represents the heat released or absorbed
when a mole of solute is dissolved in a large quantity of solvent.
Types of temp. effect on solubility:
1. Most commonly, the solution process is endothermic, or is
positive - increasing the solution temperature increases the drug
solubility.
2. For such solutes as lithium chloride and other hydrochloride
salts that are ionized when dissolved, the process is exothermic
(negative )such that higher temperatures suppress the solubility.
 Typically, the temperature range should include 5°C, 25°C, 37°C,
and 50°C.

24
SOLUBILIZATION
Increasing solubility is the addition of a cosolvent to the aqueous
system (For drug candidates with either poor water solubility or
insufficient solubility for projected solution dosage forms)
Ex: The solubility of poorly soluble nonelectrolytes can be improved
by orders of magnitude with suitable cosolvents (ethanol, propylene
glycol and glycerin)
Mechanism: These cosolvents solubilize drug molecules by disrupting
the hydrophobic interactions of water at the nonpolar solute/water
interfaces.
Depends on the chemical structure of the drug (more nonpolar the
solute, the greater is the solubilization achieved).

25
 For hydrocortisone and
hydrocortisone 21-heptanoate
(lipophilic ester) is solubilized to a
greater extent by additions of
propylene glycol than by the more
polar parent compound.
 Other ways of solubilizing poorly
soluble drugs:
1. Micellar solutions such as 0.0lM
Tween 20
2. Molecular complexes as with
caffeine.

26
DISSOLUTION
Dissolution of a drug particle is controlled by several physicochemical
properties including:
 Dissolution equilibrium solubility data
Identify potential bioavailability problem areas.
Chemical form
Crystal habit
Particle size
Solubility
Surface area
wetting properties

27
PKA DETERMINATIONS
 Determination of the dissociation constant for a drug capable of
ionization within a pH range of 1 to 10 is important since
solubility and consequently absorption can be altered by
orders of magnitude with changing pH.
 The Henderson-Hasselbalch equation provides an estimate of
the ionized and un-ionized drug concentration at a particular
pH.
For acidic compounds: For basic compounds:

29
PARTITION COEFFICIENT
 A measurement of a drug's lipophilicity and an indication of its
ability to cross cell membranes is the oil/water P.C. in systems such
as octanol/water and chloroform/water.
P.C. is defined as the ratio of un-ionized drug distributed between the
organic phases and aqueous phases at equilibrium.
 For drug delivery, the lipophilic/hydrophilic balance has been
shown to be a contributing factor for the rate and extent of drug
absorption.

30
BCS CLASSIFICATION
Class I: High solubility – High permeability
Class II: Low solubility – High permeability
Class III: High solubility – Low permeability
Class IV: Low solubility – Low permeability
 Absorption number: Ratio of mean residence time to
absorption time
 Dissolution number: Ratio of mean residence time to mean
dissolution time
 Dose Number: Mass / (250 ml of water / drug solubility)

32
SIGNIFICANCE OF BCS
 It is the regulatory tool for replacement of certain
bioequivalence studies.
 It is the valuable tool for formulation scientist for selection of
design of formulated drug substance.
 It is applicable in both pre-clinical & clinical drug
development process.
 Useful in development of various oral drug delivery systems.
 Acts as a framework for optimization of a new chemical
entity.

33
FACTORS AFFECTING BCS
1. Solubility:
 The maximum amount of solute dissolved in a given
solvent under std conditions of temperature, pressure &
pH.
 It is the ability of the drug to be in solution after
dissolution.
 The higher single unit dose is completely soluble in
250ml at pH 1 – 6.8 at room temperature (37 ).
℃

34
2. Permeability:
 It is the ability to pass the biological membrane which is
lipophilic.
 It is indirectly based on the extent of absorption of drug
substance.
 A drug is highly permeable if 90% of administered drug
is absorbed.

35
3. Dissolution
 Process in which solid substance solubilizes in
the given solvent.
 Solid phase to liquid phase using USP apparatus
II at 50 or 100 rpm.
 Highly dissolvable - 85% of drug should be
dissolved in 30 min.

36
CHEMICAL PROPERTIES
 Hydrolysis
 Oxidation
 Reduction
 Racemisation
 Polymerization

37
HYDROLYSIS
 Hydrolysis is the most common degradation pathway since
water plays an important role in many processes.
 It involves reaction of a molecule with water resulting in
cleavage of a chemical bond within the molecule.
 Hydrolysis occurs via nucleophilic attack of the water molecule
on labile bonds with susceptibility dependent on the bond type
and decreasing from lactam > ester > amide > imine - leading
to the formation of carboxylic acid or an alcohol.
 In case water is not used as the solvent, “solvolysis” occurs as
a result of reaction between the solvent and the compound.

38
Factors to be considered in Hydrolysis:
(i) pH
(ii) Type of solvent: Solvent lowers dielectric constant Eg.:
ethanol, glycols, mannitol etc.
(iii) Complexation: Steric or polar effects. E.g.: caffeine with
benzocaine – electronic influence of complexing agent - alters
affinity.
(iv) Surfactants: Non-ionic, cationic, anionic stabilizes drug
against base catalysis. E.g.: 5% SLS – 18 folds increase in t1/2 of
benzocaine modification of chemical structure salts and esters.

39
Preventive Measures against Hydrolysis:
1) Buffer: It is used for product stabilization.
2) Complexing Agent: It forms a complex with drug, prevents its
hydrolysis, and thus prolongs the shelf-life.
3) Suppression of Solubility: Less solubility reduces the drug
concentration in solution phase that reduces the hydrolysis rate.
4) Removal of Water: Presence of water should be avoided by
storing the drug in dry form & by using water immiscible vehicle.
Ester Hydrolysis: Acid + Alcohol
Amide Hydrolysis: Amide Acid + Amine

40
OXIDATION
 A process which involves the addition of oxygen or any
electronegative element or the removal of hydrogen or any
electropositive element.
 Electronic concept oxidation - the process in which an atom or
ion loses one or more electrons.
 Oxidising agent - a substance which brings about oxidation. Ex -
O2, S, Cl2, Br2, H2O2 .
 Oxidation also initiated by light or elevated temperature.
 Degree of oxidation - controlled by - avoiding exposure to lights,
storage at controlled temperatures, addition of antioxidants.

41
Oxidation reactions involve:
1. Addition of oxygen:
C + O2 → CO2 (oxidation of carbon)
2. Addition of electronegative element:
Fe + S → FeS (oxidation of Iron)
3. Removal of hydrogen:
H2S + Br2 → 2 HBr + S (oxidation of
sulphide)
4. Removal of electropositive elements:
2 KI + H2O2 → I2 + 2 KOH (oxidation
of iodide)

42
Preventive Measures against oxidation:
1) Using antioxidants (e.g. tocopherol), chelating agents & buffers
2) Preventing light exposure
3) Maintaining oxygen free environment
4) Storing the product at a low temperature
Photolysis:
 Photochemical
 Photosensitizer
 UV- violet portions – more active (shortest wavelength,
more energy).

43
PHOTOLYSIS
 It refers to decomposition of a molecule by absorption of
energy when exposed to light.
 Light causes photo degradation also trigger oxidation.
 Photochemical behaviour is studied in spectral regions of 200
– 290, 290 – 320, 320-400 & 400 – 700nm.
 Ex Riboflavin & Vitamin B12 are susceptible to photo
degradation directly and oxidation induced by light. So, it is
stored in amber color vials – which doesn’t allow UV
radiation to pass through.

44
REDUCTION
 Reduction is a relatively common pathway of drug metabolic process.
 Cytochrome P450 catalyses the azo and nitro reduction reaction.
 Prednisolone and cortisone reduces to hydrocortisone (their active
metabolites).
 The intestinal flora reduces the azo dyes (used as colouring agents in
pharmaceutical or food products) into amines in the liver.
 A process which involves the addition of hydrogen or any electropositive
element or the removal of oxygen or any electronegative element.
 Reducing agent is a substance which brings about reduction. Ex H2, HgCl2.
 A substance, which undergoes oxidation, acts as a reducing agent while a
substance, which undergoes reduction, acts as an oxidising agent.

45
Reduction reactions involve:
1. Addition of hydrogen:
N2 + 3 H2 → 2NH3 ( reduction of nitrogen)
2. Addition of electropositive element:
SnCl2 + 2HgCl2 → SnCl4 + Hg2Cl2 (reduction of mercuric
chloride)
3. Removal of oxygen
ZnO + C → Zn + CO (reduction of zinc oxide)
4. Removal of electronegative element
2FeCl3 + H2 → 2FeCl2 + 2HCl (reduction of ferric chloride)

46
RACEMIZATION
 Racemization involves the conversion of one enantiomer of a
compound, such as an L - amino acid, into the other enantiomer.
 It is an event where optically active molecule becomes inactive without
any change in molecular composition.
 Racemization leads to either loss of pharmacological action or toxic
effect may be enhanced by several folds.
 It can alter pharmacokinetic, pharmacological & toxicological
properties.
 It is affected by pH, type of solvents, presence of light & temperature.
 Optimum environmental condition can prevent racemization.
 Example: 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.

47
POLYMERIZATION
 In which 2 or more identical molecules joined to form large
complex or polymers.
 Ex. Degradation of aldehydes – formaldehyde solution
when subjected to cold may cause white deposit formation.
 Polymerization consists of three steps which include
initiation, propagation, and termination. As for the reaction
mechanism, the process of polymerization mainly involves
two different methods. These include the step-growth
mechanism and chain-growth mechanism.

48
TYPES BASED ON SOURCE
 Natural polymers: They are found naturally in plants and
animals. Resins, starch and rubber are examples of this.
 Semi-synthetic polymers: This is a modified version of
natural rubber. Natural rubbers are treated with chemicals to
make them semi-synthetic. Ex. Cellulose acetate and
cellulose nitrate.
 Synthetic polymers: Completely man-made are called
synthetic polymers. Ex Polythene, Nylon 66, synthetic
rubber.

49
BASED ON THE STRUCTURE OF
POLYMERS
 Linear polymers: Consists of a long and straight-chain of
monomers. PVC is a linear polymer
 Branched polymers: They are linear polymers containing
some branches. Low-density Polythene is an example.
 Network or cross-linked polymer: Polymers having
cross-linked bonds with each other is called cross-linked or
network polymer. They are formed from bi-functional or
tri-functional monomers. Ex -Bakelite and melamine.

50
BASED ON MODE OF
POLYMERIZATION
 Addition Polymers - formed by the repeated addition of
monomers by possessing the double or triple bonds.
Addition is of the same species they are called
homopolymers. Ex polythene
Addition is of different monomers they are called
copolymers. Ex Buna-s
 Condensation polymers: These polymers are formed by
repeated condensation of tri or bifunctional monomeric
units. Ex. Terylene and Nylon 6, 6.

51
IMPACT ON STABILITY OF DOSAGE
FORMS
 Preformulation stability analysis includes solid-state
stability analysis, solution-state stability analysis & drug-
excipients compatibility studies.
 The stability design will depend on the stage of the
development process & nature of the drug.
Need of stability analysis
 To generate information on how environmental factors
(temperature, humidity, light) influence the quality products
over time.
 To establish how physical, chemical & microbiological
changes influence the effectiveness, safety & stability of
the final drug product.
 To recommend storage conditions, retest period & shelf life
of drug products.

52
FACTORS AFFECTING DRUG
STABILITY
 Temperature or thermal effect
 Moisture & relative humidity
 Light & radiation energy
 pH
 Presence of reacting solvents
 Order of reaction
 Microorganisms
 Chemical nature of the drug excipients
 Ionic Strength
 General acid-base catalysis
 Presence of trace metals, oxygen & oxygen metals

53
CHANGES THAT OCCUR DURING
STABILITY STUDIES
1. Physical Changes – changes in physical
appearance, melting point, clarity, colour of
solutions, crystal modifications & particle size.
2. Chemical changes – increased degradation &
decrease API assay.
3. Microbial changes – increased microbial load /
microbial contamination.

54
APPLICATION OF PREFORMULATION STUDIES
IN DEVELOPMENT OF DOSAGE FORMS
Important in the development of various dosage forms as
follows:
 Helps in selection of drug candidate for development of
solid, liquid & parenteral dosage forms.
 Helps in selection of formulation additives for development
of dosage forms.
 Helps in development of analytical methods for development
of stable dosage forms.
 Helpful to formulate modified release dosage forms.

55
 Helps in selection of appropriate container closure system
for development of stable dosage forms.
 Helpful in minimizing the toxicities of different dosage
forms.
 Helpful in providing a safe & effective drug candidate for
various dosage forms.
 Correlation in pharmacokinetic & biopharmaceutical
properties of the drugs fro development of various dosage
forms.

56
REFERENCES
 Theory and Practice of Industrial Pharmacy by
Liberman & Lachman.
 Industrial Pharmacy – I by Dr B.Prakash Rao,
Dr. Beny Baby & S. Rajarajan.

B.Pharm - IP-I Unit I - Preformulation.pptxB

More Related Content

Similar to B.Pharm - IP-I Unit I - Preformulation.pptxB (20)

Recently uploaded (20)

B.Pharm - IP-I Unit I - Preformulation.pptxB