PREFORMULATION

M R . M E L ROY M E RV Y N D ’ SA
A S S I S TA N T P R O F E S S O R ( D E PA R T M E N T O F P H A R M A C E U T I C S )
O E S ’ S O R I E N TA L C O L L E G E O F P H A R M A C Y.

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 PREFORMULATION
2

➢ Pre-formulation is the stage in drug and dosage form development

before formulation.
➢ Pre-formulation testing is the first step in development of dosage form
of drug substance or drug substances.
➢ It is the process of investigation of physical and chemical properties of
drug substance alone and when combined with excipients.

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 WHY IS PREFORMULATION REQUIRED???
3

➢ Pre-formulation is a pre-requisite when a new drug or formulation has

to be developed.
➢ To test the formulation in the laboratory (in-vitro).
➢ To study the stability of the final finished product.
➢ If the drug shows sufficient pharmacological activity in animal models
and there is a need to warrant its evaluation in human subjects.

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 CONCEPT OF PREFORMULATION
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➢ Before the concept of preformulation study came into picture, developing the
dosage form depended on the formulator’s experience, knowledge of the
excipients used and the testing of basic functional products.
➢ The entire process of development of formulation was on trial and error
experimentation.
➢ The preformulation concept originated to impose scientific principles and
rationale on formulation of development processes to minimize the number of
trials and errors and to reduce cost during drug development process.
➢ It commenses when a newly synthesized drug shows sufficient pharmacologic
promise in animal models to warrant evaluation in man.

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 NEED/OBJECTIVE OF PREFORMULATION
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➢ To identify the physico-chemical properties of drug substance.

➢ To study the purity of drug substance.
➢ To study Drug-Excipient Compatibility (D+E Studies).
➢ Selection of excipients in the formulation.
➢ To determine the kinetic release profile.
➢ To focus on the physico-chemical properties of new compound which may affect the
drug performance and development of efficacious dosage form.
➢ The important objective of pre-formulation testing is to generate information useful
to the formulator in developing stable and bioavailable dosage forms which can be
mass produced.

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 NEED/OBJECTIVE OF PREFORMULATION
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➢ To establish proper and suitable analytical method for the given drug product as well
as dosage form for the purpose of quantification.
➢ To verify whether the standards of drug substance, meet the standards as mentioned
in COA by the given vendor.
➢ COA: Certificate of Analysis.

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 COA: CERTIFICATE OF ANALYSIS
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 ESSENTIAL INFORMATION FOR DESIGNING PRE-FORMULATION OF A NEW DRUG
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 Compound Identity (Solubility Profile, MP, BP, Organoleptic Properties)

 Structure (Different forms of API)
 Formula and Molecular Weight (Empirical Formula and Molecular Formula)
 Therpeutic Indication
➢ Probable Human Dose
➢ Desired Dosage Forms Drug Behaviour in Patients
➢ Bioavailability Models
➢ Competitive Products
Optimising Dosage Regimens

ADME

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 ESSENTIAL INFORMATION FOR DESIGNING PRE-FORMULATION OF A NEW DRUG
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 Potential Hazards
 Initial Bulk Lot Testing
➢ Lot Number
➢ Crystallisation Solvents
➢ Particle Size Range
➢ Melting Point
➢ Percent Volatile Observation
 Analytical Method: HPLC, UV, Probable Decay Products.

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 ESSENTIAL INFORMATION FOR DESIGNING PRE-FORMULATION OF A NEW
DRUG
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 Key Dates:
➢ Bulk Scale Up
➢ Toxicology Study Start Date
➢ Clinical Study Preparation
➢ IND Filing
➢ Phase I testing
 Critical Development Issues

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 FLASHBACK OF LECTURE 01,02
11

NEED AND OBJECTIVE OF

PREFORMULATION PRE-FORMULATION

ESSENTIAL
INFORMATION FOR
DESIGNING
PRE-FORMULATION OF LECTURE NO 03,04
A NEW DRUG

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 PREFORMULATION ASPECTS
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 Tablets are one of the most challenging of all pharmaceutical products with respect
to design and manufacture of the dosage form.
 Poor or Slow Dissolution of drug may result in low bioavailability.

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 PREFORMULATION ASPECTS
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 STEP I
➢ Stability:
 Solid State Stability: Light, Temperature, Humidity
 Solution State Stability: D+E Compatibility Studies, DSC Studies
➢ Physico-Mechanical Studies: Particel Size, Tapped Density, Bulk Density, MP, COT.
➢ Physico-Chemical Properties: Solubility (Solvent, pH, Co-Solvents)

Need of Co-Solvent
BCS Class II Drug: Low Solubility and High Permeability
BCS Class IV Drug: Low Solubility and Low Permeability

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 PREFORMULATION ASPECTS
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 STEP I
➢ Kinetic Profile:
 In-vitro Dissolution
 In-vitro Diffusion
 Drug Content

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 PREFORMULATION ASPECTS
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 STEP II
➢ Pharmaceutical Product Design:
➢ Optimization of Excipients: Type, Grade, Concentration
➢ Optimization Level of Excipients: By application of factorial design 22 , 32 , 33
and different other types of factorial designs.
➢ Targetted Drug Delivery
➢ Desired Release Profile

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 PREFORMULATION ASPECTS
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 Before beginning the pre-formulation the scientist should consider the

following factors:
➢ The Amount of drug
➢ The Physico-Chemical Properties of the drug.
➢ Therapeutic Indication.
➢ Dosage Form.
➢ Dose of the Drug.
➢ All the information that a formulator needs to have.

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 GOALS OF PREFORMULATION
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➢ To establish the physicochemical parameters of the new drug entity.

➢ To develop the most stable, safe and efficacious dosage form with maximum bioavailability.
➢ To establish the drug’s compatibility with common excipients and select the most suitable
excipients. (Eg. Milliard’s reaction)
➢ To help in adjustment of pharmacokinetic properties (ADME).
➢ To elucidate possible chemical and/or physical reactions leading to drug degradation and give the
solution to overcome this problem. i.e to determine its kinetics and stability.
➢ To produce necessary and useful data for development of analytical methods (assay).
➢ To determine most stable polymorph and salt forms that give maximum bioavailability.
➢ To minimize the time and money required for formulations.
➢ To confirm the absence of barriers for the development of a compound into a safe, marketable drug.

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 SCOPE OF PREFORMULATION
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➢ Preformulation studies focus on the physicochemical and properties of the new compound that
could affect drug performance and development of an efficacious dosage form.
➢ Athorough understanding of these properties may ultimately provide a rationale for formulation
design, or support the need for molecular modification. i.e these preformulation investigations may
merely confirm that there are no significant barriers to the compound's development.
➢ Preformulation studies may have a significant impact on manufacturing, storage, and performance
of drug products.
➢ It not only helps to guide dosage form selection, but also provides insights into how drug products
should be processed and stored to ensure their quality.
➢ A well designed preformulation study is therefore necessary to fully characterize molecules during
the discovery and development processes so that the new drug entities have the appropriate
properties, and there is an understanding of the shortcomings that must be overcome by the
formulation process.

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 PREFORMULATION
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Study of physical properties of Study of chemical properties of

drugs drugs

Hydrolysis, oxidation,
reduction, racemization,
Particle size and shape,
polymerization, drug
Density, wetting property,
excipient compatibility &
dielectric constant,
their influence on
solubility, dissolution
formulation and stability of
products

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PRINCIPAL AREAS OF PREFORMULATION RESEARCH
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Bulk Characterization Solubility Analysis Stability Analysis

• Organoleptic properties • Intrinsic solubility • Solution stability

• Crystallinity and • Ionization constant (pKa) • Solid state stability
polymorphism • Partition coefficient • Excipient
• Hygroscopicity (Ko/w) Compatibility
• Fine particle • Common ion effect (Ksp)
characterization • pH solubility profile
• Powder density & flow • Thermal effects
property • Solubility enhancement
• Compaction properties • Dissolution

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 BULK CHARACTERIZATION
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➢ Bulk properties of solid dosage forms such as particle size, bulk density and surface
morphology are likely to change during process development; therefore the
comprehensive characterization of all preformulation bulk is necessary to avoid
misleading predictions of stability or solubility.
➢ Organoleptic properties:
1. Appearance
2. Odor
3. Taste
4. Hygroscopicity

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 ORGANOLEPTIC PROPERTIES
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➢ Modern medicines require that pharmaceutical dosage forms are acceptable to the
patient.
➢ Unfortunately, many drug substances in use today are unpalatable and unattractive
in their natural state and dosage forms containing such drugs (particularly oral
preparations) may require the addition of approved flavors and/or colors.
➢ Taste: To improve palatability, flavors and additional excipients may be added.
➢ Odour: Degradation products, eg. Aspirin stable form of drug to be used, flavors
and excepients may be used.

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 APPEARANCE: COLOUR
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➢ Colour is generally a function of a drug’s inherent chemical structure relating to a certain level of
unsaturation.
➢ Colour intensity relates to the extent of conjugated unsaturation as well as the presence of
chromophores.
➢ Some compound may appear to have color although structurally saturated.
➢ Colours are used to standardise or improve an existing drug colour, to mask a colour change or
complement a flavour. while colours are obtained from natural sources (eg: Carotenoids) or
synthethized (eg: Amaranth), the majority used are synthetically produced.
➢ Dyes may be aqueous (eg: Amaranth) or oil soluble (eg: Sudan IV) or insoluble in both (eg:
Aluminium lakes).
➢ Lakes generally calcium or aluminium complexes of water -soluble dyes are particularly used in
tablets and tablet coatings because of greater stability to light than corresponding dyes.
➢ Change in Colour also indicates Stability problems, hence improve appearanceby including dye in
body or coating.

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 ODOUR AND TASTE
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➢ Odour:
 The substance may exhibit an inherent odor characteristic of major functional
groups present.
 Odor greatly affects the flavor of a preparation or food stuff.
➢ Taste:
 If taste is considered as unpalatable, consideration is to be given to the use of a less
soluble chemical form of the drug.
 The odour and taste may be suppressed by using appropriate flavors and excipients
or by coating the final product.

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 ODOUR AND TASTE
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➢ The use of flavors applies primarily to liquid dosage forms intended for oral administration.
➢ Available flavors are concentrated extracts, solutions, adsorbed onto powders or microencapsulated, they
are usually composed of mixtures of natural and synthetic materials.
➢ Unpleasant taste can be overcomed by using water-insoluble derivatives of drugs which have little or no
taste. eg. Amitriptyline pamoate (bioavailability should not change with change in derivative used).
➢ If an insoluble derivative is unavailable or cannot be used, a flavour can be used.
➢ However unpleasant drugs in capsules or prepared as coated particles or tablets may be easily
swallowed, avoiding the taste buds.
➢ Selection of flavor depends upon several factors but particularly on the taste of the drug substance.eg.
citrus flavours are frequently used to combat sour or acid-tasting drugs.
➢ Solubility and stability of the flavor in the vehicle are also important.
➢ In addition, the age of the intended patient should be considered, since children prefer sweet tastes, as
well as the psychological links between colours and flavors (eg: yellow colour is associated with lemon
flavour).
➢ Sweetening agents may also be required to mask the bitter tastes. sucrose continues to be used but
alternatives, such as sodium sachharine (200-700 times sweeter than sucrose), sorbitol recommended for
diabetic preparations.

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 SCOPE OF PREFORMULATION
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COLOUR ODOUR/ODOR TASTE

• Off white • Pungent • Acidic

• Cream Yellow • Fruity • Bitter
• Tan • Aromatic • Bland
• Shiny • Odourless • Intense sweet
• sulfurous • Tasteless

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 HYGROSCOPICITY
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➢ Many drug substances and other excipient materials have a tendency to adsorb atmospheric
moisture (especially water soluble salt forms). They are called hygroscopic, and this phenomenon is
known as hygroscopicity.
➢ Adsorption and equillibrium moisture content of any material depends upon its surface area,
atmospheric humidity, atmospheric temperature, atmospheric exposure time and mechanism of
moisture uptake.
➢ Deliquescent materials: They absorb sufficient amount of moisture to dissolve completely, eg:
anhydrous calcium chloride.
➢ The European Pharmacopoeia Technical Guide has classified the degree of hygroscopicity into four
classes based on the static method after storage at 250˚C for 24 hours at 80% Relative Humidity.
➢ 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.

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 EFFECT OF HYGROSCOPICITY ON PHARMACEUTICAL PARAMETERS
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Parameter Effect
Chemical stability Hygroscopic materials are more prone to hydrolytic degradation.
Flow property Hygroscopic compounds have poor flowability and cause weight variation problems.
Surface property Moisture in cohesive material causes formation of liquid and solid bridges between the
particles, which ultimately forms a hard cake.
Compaction property Hygroscopic compounds are generally sticky so they cause picking and sticking during
tablet compression.
Particle aerosulisation Moisture content of aerosols containing powders should be below 300 ppm.
Higher moisture level leads to particle agglomeration

Note: The amount of moisture in a drug can be determined by:

➢Gravimetry
➢Thermo Gravimetric Analysis (TGA)
➢Karl-Fischer Titration
➢Gas Chromatography (GC)
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 SIGNIFICANCE OF HYGROSCOPICITY TESTING
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1. To decide the storage conditions and packaging conditions.

2. To decide special handling procedures.
3. Moisture level in a powder sample may affect the flowability and compatibility, which are
important factors in preventing weight variation in tablet and capsule fillings.
4. After adsorption of moisture, if hydrates are formed, then solubility of that powder may change,
affecting the dissolution characteristics of the material.
5. Moisture may degrade some materials so humidity of a material must be controlled.

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 METHOD TO TEST HYGROSCOPICITY
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➢ To test for hygroscopicity, samples of bulk drug are placed in open containers with a thin powder
bed to assure maximum atmospheric exposure.
➢ These samples are then exposed to a range of controlled relative humidity environments prepared
with saturated aqueous salt solutions.
➢ Moisture uptake should be monitored at time points representative of handling (0 to 24 hours) and
storage (0 to 12 weeks).
➢ Analytical methods for monitoring the moisture level (i.e. gravimetry, TGA, Karl Fischer Titration, or
Gas Chromatography) depend upon the desired precision and the amount of moisture adsorbed
onto the drug sample.
➢ Normalized (mg H2O/g sample) or percentage-of-weight-gain data from these hygroscopic studies
are plotted against time to justify special handling procedures kinetically.
➢ A plot of normalized equilibrium versus relative humidity data may support the need for storage in
a low-humidity environment or for special packaging with a desiccant.

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RELATIVE HUMIDITY GENERATED BY VARIOUS SATURATED SALT SOLUTIONS
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Salt Solution % Relative Humidity at 25°C

Silica gel 0
Potassium acetate 20
Calcium chloride 32
Sodium bromide 58
Potassium bromide 84
Dipotassium hydrogen phosphate 92
Water 100

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 FLASHBACK OF LECTURE 03,04
32

PRE-FORMULATION ASPECT GOALS AND SCOPE OF

STEP I PREFORMULATION
STEP II

HYGROSCOPICITY
COLOUR DEFINITION
ODOUR IMPORTANCE/IMPACT
TASTE METHOD TO TEST
HYGROSCOPICITY
LECTURE NO 05,06

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 TAPPED AND BULK DENSITY
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➢ It is very useful to gain knowledge about the tap and bulk density of drug substance
and excipients, that helps to get an idea about the size of the final dosage form. The
density of the solid affects the flow properties.
➢ Bulk Density: In a 50 ml measuring cylinder, add 5-10 gm of material without
compaction. Note down the volume (bulk / untapped volume) occupied by the solid in
the measuring cylinder.
➢ It is given by the formula
➢ Bulk Density = (weight / untapped volume)
➢ Tap Density: It is determined by using a tap density testing apparatus, In a 50 ml
measuring cylinder, add 5-10 gm of material and mechanically tap the cylinder using
tap density testing apparatus, the cylinder is tapped for it is given by the formula 100
times and note the tapped volume.
➢ It is given by the formula
➢ Tap Density = (weight / tapped volume)

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 POWDER FLOW PROPERTIES
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 Determination of flow properties of podwer blend is important fro several

reasons.
 Flow property determinations help the formulation Pharmacist determine in
taking several decisions while designing a formulation.
 For Example:
 To choose among various methods of tablet compression.
 To choose a proper feeding device e.g. auger or vibrating feeding hopper.

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 POWDER FLOW PROPERTIES
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 Angle of repose is an important property that can be determined in order to an

idea about the flow property of the powder blend.
 Angle of repose: It is the maximum angle that can be obtained between the free
standing surface of a powder heap and the horizontal plane.
 Angle of repose determinations lacks precision and hence are less important in
determining powder flow rates.
 A useful emperical parameter is Carrs Compressibility Index.

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 POWDER FLOW PROPERTIES: ANGLE OF REPOSE
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Sr. No. Angle of repose (Degrees) Type of flow

1. 25-30 Excellent
2. 31-35 Good
3. 36-40 Fair (flow aid not needed)
4. 41-45 Passable (may hung up, flow aid might be needed)
5. 46-55 Poor (agitation or vibration needed)
6. 56-65 Very poor
7. Over 66 Very, very poor

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 CARRS INDEX
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Carrs Index: (Percentage Compressibility)

It relates the flow of powder with its compressibility. Higher the percent compressibility, the poorer is the
flowability.
Carrs Index is given by: (tapped density- bulk density/ tapped density) * 100

Sr. No. Carrs Index Type of Flow

1. 1-10 Excellent
2. 11-15 Good
3. 16-20 Fair (flow aid not needed)
4. 21-25 Passable (may hung up, flow aid might be needed)
5. 26-31 Poor (agitation or vibration needed)
6. 32-37 Very poor
7. More than 38 Very, very poor

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 HAUSNERS RATIO
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➢ Hausner found that the ratio of Tapped Density and Bulk Density is related to interparticulate friction. The
values obtained on determining the tap and bulk density helps in calculated Hausners ratio, which predicts the
flow property of the solid.
➢ Hausners Ratio is given by: (tapped density/ bulk density)

Sr. No. Hausner Ratio Type of Flow

1. 1.00-1.11 Excellent
2. 1.12-1.18 Good
3. 1.19-1.25 Fair (flow aid not needed)
4. 1.26-1.34 Passable (may hung up, flow aid might be needed)
5. 1.35-1.45 Poor (agitation or vibration needed)
6. 1.46-1.59 Very poor
7. More than 1.60 Very, very poor

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 SIEVE ANALYSIS
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1. Weigh 40 gm of the excipient, stack sieves from smallest to largest with a butter
paper below the smallest sieve.
2. 8#, 12#, 20#, 26#, 60#, 80#.
3. Add the powder sample to the top most sieve, powder should be free from
lumps. Tighten the equipment to ensure that the sieve stack is held firmly by the
shaker assembly.
4. Set the sieve shaker to vibrate for 15 minutes.
5. After 15 minutes, stop the equipment and carefully weigh the mass retained on
each sieve using abutter paper.

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 SIEVE ANALYSIS
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 STANDARD SCALE FOR SIEVE ANALYSIS
41

Sr. No. Type of Powder d50 Sieve Opening

1 Very Coarse >1000
2. Coarse 355-1000
3. Moderately fine 180-355
4. Fine 125-180
5. Very Fine 90-124

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 MICROSCOPY
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➢ The microscope has two major applications in Pharmaceutical Preformulation.

➢ Basic Crystallography: To determine Crystal Morphology, Polymorphism and
Solvates.
➢ Particle size and analysis
➢ Most pharmaceutical powders have crystals in the range of 0.5-300 μm. However
the distributions are often smaller typically 0.5-50 μm, to ensure good blend
homogeneity and rapid dissolution.
➢ For most preformulation work a 10X eye piece and a 10X objective lens are ideal.

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 PREFORMULATION STUDIES
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 PREFORMULATION STUDIES
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 PREFORMULATION STUDIES
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 PREFORMULATION STUDIES
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 POLYMORPHISM
47

Many Drug Substances can exist is more than

one form with different lattice arrangement
(Polymorphism) Enantiotropic
Change of one polymorph
to another by varying T and
P

Types of Polymorphs

Monotropic
Unstable at all
Temperature and Pressure

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 POLYMORPHISM
48

➢It can reversibly change into another form by ➢It is unstable at all temperatures and pressure,
altering the temperature and pressure, eg. Sulphur. Eg. Glyceryl stearates.
➢Reversible phase transition ➢Irreversible phase transition
(Metastable Stable). (Metastable Stable)
➢Transition is endothermic. ➢Transition is exothermic.
➢Higher melting form has lower heat of fusion. ➢Higher melting forms has higher heat of fusion.

➢During Preformulation, it is essential to identify if the polymorph is stable at room temperature or not, to
further determine formulation stability.
➢Polymorphs are also evaluated during preformulation studies to withstand temperature with drying and
milling during product formulation.

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 DIFFERENT POLYMORPHS
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 POLYMORPHISM
50

Low
Crystalline Solubility and
Powder Low
Form Dissolution
Rate

High
Amorphous Solubility and
Powder High
Form Dissolution
Rate

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 POLYMORPHISM
51

Chloramphenicol Palmitate

B . Meta-stable Polymorph
A. Stable Polymorph C. Un-stable Polymorph
(More Solubility)

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 POLYMORPHS OF ESTRONE
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 IR SPECTRA OF GLYCINE POLYMORPHS
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 IR SPECTRA OF PARACETAMOL POLYMORPHS
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EFFECT OF INTERNAL STRUCTURE ON PHARMACEUTICAL PARAMETERS
55

Parameter Example
Bioavailability Crystalline form of novobiocin (antibiotic) is inactive when administered orally;
whereas, Amorphous form is rapidly absorbed from GIT & shows 10 times more
bioavailability.
Stability Crystalline form of Penicillin G as potassium or sodium salt are more stable
compared to amorphous form of Penicillin G
Suspension Syringeability A suspension of plate shaped crystals may be injected through a needle with
greater ease than one with needle shaped crystals of same dimensions.
Effect on Granulation Use of amorphous form of calcium pantothenate in multivitamin tablets
prepared by wet granulation process, is not desirable because polymorphic
transformation makes the granulation mass sticky, making further granulation
virtually impossible.

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 Purity:
 Purity Studies are usually performed by analytical development and research
groups by using sophisticated analytical equipments.
 Techniques used for Characterizing Purity are:
 TLC
 UV
 HPLC
 GC
 Thermal Methods: DSC/TGA/DTA

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 UV Spectroscopy:
 The important requirement of any preformulation study is the
development of simple analytical method for quantitative estimation.
 Most of the drugs have an aromatic ring/double bond in their structures
and hence they absorb light in UV range.
 Chromophore: For drug substance not containing a chromophore they
have to derivatised, using a derivatising agent.

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➢ Chemical Stability Profile:

➢ In preformulation stability studies are usually the first quantitative assessment of
chemical stability of a new drug.
➢ Solid State Stability: To study the effect of pH, Temperature, Light on drug
stability is important in the development of oral dosage forms.
➢ Primary objectives are identification of stable storage conditions of for drug
product and identification of compatible excipients for the formulation.
➢ Solution State Stability: The stability of drug substance at various pH at ambient
and elevated temperature

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➢ ELEVATED TEMPERATURE STUDIES:

➢ The elevated temperatures commonly used are 40, 50, and 60 degree centigrade
with ambient humidity.
➢ The samples stored at highest temperature are observed weekly for physical
and chemical changes and compared to an appropriate control.
➢ If a substantial change is seen, samples stored at lower temperature are
examined.
➢ If no change is seen after 30 days at 60˚C, the stability prognosis is excellent.

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❑ STABILITY UNDER HIGH HUMIDITY CONDITIONS:

❑ Solid drug samples can be exposed to different relative humidity conditions
by keeping them in laboratory desiccators containing saturated solutions
of various salts.
❑ The closed desiccators in turn are kept in oven to provide constant
temperature.
❑ The preformulation data of this nature are useful in determining if the
material should be protected and stored in controlled low humidity
environment or if non aqueous solvent be used during formulation.

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 PHOTOLYTIC STABILITY:
 Many drugs fade or darken on exposure to light.
 Though the extent of degradations may be small and limited to the exposed
surface area, it presents aesthetic problems.
 Exposure of drug 400 and 900 footcandles of illumination for 4 and 2 week
periods, respectively is adequate to provide some idea of photosensitivity.
 Resulting data may be useful in determining if amber glass or opaque
containers can be used or if dye can be incorporated in the product to mask
the discoloration.

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 STABILITY TO OXIDATION
 Drug sensitivity to oxidation can be examined by exposing it to atmosphere of
high oxygen tension.
 Usually a 40% oxygen atmosphere allows for rapid evaluation.
 A shallow layer of drug exposed to a sufficient headspace volume ensures that
the system is not oxygen limited.
 Samples are kept in desiccators equipped with three-way stop cocks, which
are alternatively evacuated and flooded with desired atmosphere.
 The process is repeated 3 or 4 times to ensure 100% desired atmosphere.
 Results may be useful in predicting if an antioxidant is required in the
formulation or if the final product should be packaged under inert
atmospheric conditions.

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 COMPATIBILITY STUDIES
 The knowledge of drug excipients interaction is useful for the formulation
to select appropriate excipients.
 The described preformulation screening of drug excipients interaction
requires only 5mg of drug in a 50% mixture with the excipients to
maximize the likelihood of obscuring an interaction .
 Mixtures should be examined under nitrogen to limit oxidation and
paralytic effect at a standard heating rate on DSC, over a temperature
range, which will encompass any thermal changes due to both the drug and
excipient
 Appearance or disappearance of one or more peaks in thermograms
of drug excipient mixtures are considered as indication of interaction.

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 FLASHBACK OF LECTURE 05,06
64

ELEVATED
SOLID STATE STABILITY TEMPERATURE
SOLUTION SOLUTION STATE STUDIES, HIGH
STABILITY HUMIDITY
CONDITION

PHOTOLYTIC
STABILITY COMPATIBILITY
STUDIES LECTURE NO 7
STABILITY TO
OXIDATION

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65

➢ The most likely cause of drug instability is hydrolysis.

➢ Water plays a dominant role and in many cases it is impicated passively as a
solvent vector between two reacting species in solution.
➢ Hydrolytic reactions involve nucleophilic attack of labile bond, e.g. lactam ester
amide imide by water on the drug in solution and are first order.
➢ A umber of conditions catalyse the breakdown.
➢ Presence of OH-, H3O+ , divalent metal ions, heat, light.

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 ESTER HYDROLYSIS
66

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67

➢ Kinetic study of hydrolysis of Aspirin was done in various buffer solutions.

➢ It was observed that Aspirin is most stable at pH 2.4, at pH 5 to 7 degradation is
pH independent and above pH 10 stability decreases with increase in pH.

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68

➢ Racemization: It is a process wherein optically

active compounds (which consist of only one
enantiomer) are converted into an equal mixture of
enantiomers with zero optical activity (a racemic
mixture).
➢ Racemization rates are dependent on the molecule
and conditions such as pH and temperature.
➢ Levo and Dextro form.
➢ Eg: levo-Adrenaline is 15-20 times more active than
dextro-Adrenaline form
➢ Racemic mixture: Stability and therapeutic activity.

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69

➢ The degree of oxidation is influenced by the

environment i.e. light, trace metals, oxygen
and oxidising agent.
➢ Reduction is a complementary reaction and
there is a mutual exchange of electrons.
➢ Oxidation is a loss of electrons and an
oxidizing agent must be able to take
electrons.
➢ In organic molecules, oxidation is
synonymous with dehydrogenation and
this is the mode of action of poly-hydroxy-
phenol antioxidants e.g. hydroxquinone.

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“Preformulation: The multidisciplinary

interactions in development of a new drug
candidate”

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71

 A scientific framework for classifying drug substances based on their

aqueous solubility and intestinal permeability.
 Established by Gordon Amidon et al.
 BCS has gained importance worldwide as a drug product regulation tool
for scale-up and post-approval changes.
 The aim of the BCS is to provide a regulatory tool for the replacement of
certain BE studies by conducting accurate in-vitro dissolution tests.

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Mumbai:400705.
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 The Biopharmaceutical Classification BCS CLASS I BCS CLASS II

System is a scientific framework for High Solubility Low Solubility
classifying a drug substance based on
High Permeability High Permeability
its aqueous solubility & intestinal
permeability & dissolution rate Eg: Metoprolol Eg: Naproxen

BCS CLASS

BCS CLASS IV BCS CLASS III

Low Solubility High Solubility
Low Permeability Low Permeability
Eg: Curcumin Eg: Ranitidine

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Mumbai:400705.
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 HIGHLY SOLUBLE: the highest dose strength should be soluble in < 250
ml water over a pH range of 1 to 7.5. (The volume estimate, a glassful i.e.
8 ounce).
 HIGHLY PERMEABLE: when the extent of absorption in humans is
determined to be > 90% of an administered dose.
 RAPIDLY DISSOLVING: when > 85% of the labeled amount of drug
substance dissolves within 30 minutes using USP apparatus I or II in a
volume of < 900 ml buffer solutions.

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Mumbai:400705.
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 Solubility:
 The Maximum Amount of solute dissolved in a given solvent under
standard conditions of temperature, pressure and pH.
 Solubility is the ability of the drug to be solution after dissolution.
 The higher single unit dose is completely soluble in 250 ml at pH 1- 6.8 (
37˚C ).

OEs's Oriental College of Pharmacy, Sanpada, Navi- 10/25/2023

Mumbai:400705.
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75

 Permeability:
 Permeability of the drug to pass the biological membrane which is the
lipophilic.
 Permeability is indirectly based on the extent of absorption of a drug
substance.
 Drug substance is considered to be highly permeable, when the extent of
absorption in human determined to be 90% or more of administered
drug or compare to in vivo reference dose.

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Mumbai:400705.
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 It is process in which solid substance solubilises in given solvent i.e

mass transfer from solid surface to liquid phase.
 Using USP apparatus I at 100 rpm or USP apparatus II at 50 rpm.
 Dissolution Media [900 ml],
 0.1 N HCl or simulated gastric fluid (pH 1.2) without enzyme.
 pH 4.5 buffer & pH 6.8 buffer.
 Simulated intestinal fluid without enzyme.

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77

 To predict in vivo performance of drug product using solubility and

permeability measurements.
 Aid in earliest stages of drug discovery research.
 To use in biowaiver considerations.
 For research scientist to decide upon which drug delivery technology to
follow or develop.
 Also for the regulation of bioequivalence of the drug product during scale
up and post approval.

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Mumbai:400705.
 THANK YOU

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Mumbai:400705.