Pre-Formulation Studies

Pre- Formulation Studies
• Compiled By
• Vaibhav Tripathi Dr. Anil K. Sahu
Dr. Deepak K. Dash

Pre- formulation Studies
• Pre-formulation testing is the first step in the rational
development of dosage forms.
• It can be definedas an investigation of physical and chemical
property of a drug substance alone and when combined with
excipients.
• Drug performance, safety & stability are assessedby using pre-
formulation studies (PFS)
• PFS are an important foundation tool early in the development
of both API and drugproducts.

• Study of physical properties of drugs like physical form, particle
size, shape, density, wetting, solubility, dissolution, organoleptic
properties and
• their effect on formulation, stability and bioavailability.
• Study of chemical properties of drugs like hydrolysis, oxidation
– reduction, racemization, polymerization and
• their influence on formulation andstability of products.

Objectives
• To optimize the delivery of drug thoroughdetermination of
physical, chemical properties of new drugmoleculethat affect
drug performance and development of an efficacious stable and
safedosage form.
• PFS on a new drug molecule provide useful information for
subsequent formulation of a physico-chemically stableand bio-
pharmaceutically suitable dosage form.

Objectives
• To find out best possible synthetic routeof producing the API
withmaximumyield.
• To design the suitable Toxicological strategic management
protocol.
• To optimize API & drug product manufacturing processes
• To Develop analytical methods for QC & QA
• To Determine the most appropriate& compatible container /
closure systemfor formulation.

Parameters for PFS
Bulk Characterization Solubility Analysis
Crystallinity Intrinsic Solubility
Determination
Polymorphism pKa Determination
Hygroscopicity Partition Coefficient
Fine particle
characterization
Dissolution Studies
Bulk Density Common Ion Effect
Flow Property
Compression
Property
Physical Description
Stability
Analysis
Organoleptic
Properties
Toxicological
Studies
Colour
Solution
Stability
Odour
Solid State
Stability
Taste
Chemical Analysis
Hydrolysis
Oxidation
Reduction
Racemization
Polymerization

OrganolepticProperties
• A typical pre-formulation programshould begin with the
description of the drugsubstance.
• The color, odour and taste of the new drug must be recorded
using descriptive terminology.
• It is important to establish a standard terminology to describe
such properties in order to avoid confusion amongscientists
using different terms to describe the same property.

OrganolepticProperties
Colour odour Taste
Off white pungent Acidic
Cream yellow Sulfurous Bitter
Tan Fruity Blend
Shiny Aromatic Intense
Odourless Sweet
Tasteless

BulkCharacterization
• Crystallinity :
• Generally most of drugs exist in solid state.
• Very few are in liquid state like valproic acid and even less in
gaseous formlike some general anesthetics.
• A crystal structure is a unique arrangement of atoms in a
crystal.

• Crystallinity :
• Physical properties affectedby the solid-state properties can
influence boththe choice of the delivery systemand the activity
of the drug, as determined by the rate of delivery.
• A crystalline particle is characterized by definite external and
internal structures.
• Crystal habit describes the external shape of a solidmaterial.

• Crystallinity :
• Crystallization is invariably employed as the final step for the
purification of a solid.
• The use of different solvents and processingconditions may
alter the habit of recrystallizedparticles, besides modifying the
polymorphic state of the solid.

• Polymorphism:
• Many drug substances can exist in more than one crystalline
formwithdifferent space lattice arrangements.
• This propertyis known as polymorphism. The different crystal
forms are called polymorphs.

• Polymorphism:
• When polymorphismoccurs, the molecules arrange themselves
in two or more different ways in the crystal;
• either they may be packeddifferently in the crystal lattice or
there may be differences in the orientation or conformation of
the molecules at the lattice sites.

• Polymorphism:
• This propertydirectly influences the chemical stability and
solubilityof an API.
• Moreover, it alsoaffects the bioavailability parameter and
development scheme of a formulation.
• Identification methods of polymorphismare-
• Optical crystallography , Hot 0stage microscopy
• X- Ray Diffraction, NMR , FTIR Thermal analysis

• Hygroscopicity:
• Many compounds and salts are sensitive to the presence of
water vapour or moisture.
• When compounds interact withmoisture, they retain the water
by bulk or surface adsorption, capillary condensation, chemical
reaction and, in extreme cases, a solution (deliquescence).
• Deliquescence is where a soliddissolves and saturates a thin film
of water on its surface.

• Hygroscopicity:
• Moisture is also an important factor that can affect the stability
of candidate drugs and their formulations.
• Sorption of water molecules onto a candidate drug (or excipient)
can often induce hydrolysis.
• For example a primary amine, when mixed withlactose was
apparently stable even when stored at 90°C for 12 weeks.

• Hygroscopicity:
• However, when the experiment was carried out in the presence
of moisture, extensive degradation took place.
• Other properties such as crystal structure, powder flow,
compaction, lubricity, dissolution rate and polymer film
permeabilitymay also be affectedby moisture adsorption.

• Fine particle characterization :
• Various chemical and physical properties of drug substances are
affectedby theirparticle size distribution and shapes.
• The effect is not only on the physical properties of soliddrugs
but also in some instances on their biopharmaceutical
behaviour.
• For example, the bioavailabilityof griseofulvin and phenacetin is
directly related to the particle size distributions of these drug.

• Fine particle characterization :
• It is now generally recognizedthat poorly soluble drugs showing
a dissolution rate- limiting step in the absorption process
• will be more readilybioavailable when administered in a finely
sub divided statethan as a coarse material.
• Size also plays a role in the homogeneity of the final tablet.
• Optical & electron microscopy, sedimentation method, coulter
counter method

• Powder flowproperties :
• The flowproperties of powders are critical for an efficient
tabletingoperation.
• A good flowof the powder or granulation to be compressed is
necessary to assure efficient mixing and acceptable weight
uniformityfor the compressedtablets.
• If a drug is identifiedat the pre-formulation stage to be "poorly
flowable”

• The problemcan be solvedby selecting appropriateexcipients.
• The problemcan be solvedby selecting appropriateexcipients.
• In some cases, drug powders may have to be pre-compressedor
granulated to improve their flowproperties.

• Angle of Repose:
• The maximumangle whichis formedbetween the surface of pile
of powder and horizontal surface is called the angle of repose.
• For most pharmaceutical powders, the angle-of repose values
range from25 to 45°, with lower values indicating better flow
characteristics.
• Tan θ = h / r

• Densities:
• The ratio of mass to volume is known as density
• Bulk density: It is obtainedby measuring the volume of known
mass of powder that passedthrough the screen.
• Tapped density: It is obtained by mechanically tapping the
measuring cylinder containingpowder.
• True density: It actual density of the solid material.

• Densities:
• Granule density: may affect compressibility, tablet porosity,
disintegration, dissolution.
• Compressibility:
• "Compressibility" of a powder can be definedas the ability to
decrease in volume under pressure and "compactability

• Compressibility :
• as the abilityof the powdered material to be compressedinto a
tablet of specified tensilestrength.
• It can be usedto predict the flowproperties based on density
measurement.
• 𝑪𝒂𝒓𝒓′
𝒔 𝑰𝒏𝒅𝒆𝒙 =
𝒕𝒂𝒑𝒑𝒆𝒅 𝒅𝒆𝒏𝒔𝒊𝒕𝒚−𝒃𝒖𝒍𝒌 𝒅𝒆𝒏𝒔𝒊𝒕𝒚
𝒕𝒂𝒑𝒑𝒆𝒅 𝒅𝒆𝒏𝒔𝒊𝒕𝒚

SolubilityAnalysis
• Important goal of the pre-formulation effort is to devise a
method for making solutions of the drug
• Orally administered drug must dissolve in the fluidof the GIT
prior to absorption.
• A drug must possess some aqueous solubility for therapeutic
efficacy in the physiological P H range of 1 to 8.
• For a drug to enter into systemic circulation and to exert
therapeutic effect

SolubilityAnalysis
• it must be first in solution form.
• If solubility of drugsubstance is less than desirable, then
consideration must be given to increase its solubility.
• However, knowledge of 4 fundamental properties is mandatory
for solubility analysis of a new compound.
1. Intrinsic SolubilityDetermination
2. pKa Determination
3. Partition Coefficient 4. Common Ion Effect

SolubilityAnalysis
1. Intrinsic Solubility Determination (Co) :
•
The intrinsic solubility is the equilibriumsolubilityof the free
acid or base formof an ionizable compound at a pH where it is
fully unionized.
•
The intrinsic solubility shouldbe measured at two temperature
4 & 5°C to ensure good physical stability and to extend short
termstorage and chemical stability.

SolubilityAnalysis
1. Intrinsic Solubility Determination (Co) :
•
The solubility of weaklyacidic and weakly basic drugas function
of PH can be predicted with help of equation
•
S = solubility at given pH.
•
So = intrinsic solubility of neutral form.
•
K1 = dissociation constant for the weak acid.
•
K2 = dissociation constant for weak base.
S = So {1 + (K1/ [H+])} For weak acid.
S = So {1+ ([H+]/ K2)} For weak base.

SolubilityAnalysis
2. Dissociation Constant (pKa) :
•
Many drugs are either weakly acidic or basic compounds and, in
solution, depending on the pH value, exist as ionizedor un-
ionizedspecies.
•
The un- ionizedspecies are more lipid-solubleand 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.

SolubilityAnalysis
•
The conditions that suppress ionization favor absorption.
•
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 lipidsolubility of the unionized
species.
•
These factors together constitute the widelyacceptedpH
partition theory.

SolubilityAnalysis
•
The relative concentrations of un-ionized and ionizedforms of a
weakly acidic or basic drug in a solution at a given pH can be
readily calculatedusing the Henderson-Hasselbalchequations:
•
𝒑𝑯 = 𝒑𝑲𝒂 + 𝒍𝒐𝒈
𝑼𝒏𝒊𝒐𝒏𝒊𝒛𝒆𝒅 𝒇𝒐𝒓𝒎
𝒊𝒐𝒏𝒊𝒛𝒆𝒅 𝒇𝒐𝒓𝒎 for base
•
𝒑𝑯 = 𝒑𝑲𝒂 + 𝒍𝒐𝒈
𝒊𝒐𝒏𝒊𝒛𝒆𝒅 𝒇𝒐𝒓𝒎
𝒖𝒏𝒊𝒐𝒏𝒊𝒛𝒆𝒅 𝒇𝒐𝒓𝒎 for acid

SolubilityAnalysis
•
Weakly acidic compounds (pKa< 4.3) absorb relativelyrapidly;
Those with pKa values ranging between 2.0and 4.3 absorb more
slowly
•
and strong acids (pKa> 2.4) hardlyabsorb. For bases, those
withpKa values smaller than 8.5 absorb relatively rapidly
•
Those with a pK a between 9 and 12 absorb more slowly

SolubilityAnalysis
3. Partition Co-efficient :
•
Partition coefficient influences permeation of a drug across
biological membrane.
•
The lipophilicity of an organic compound is usually describedin
terms of a partition coefficient; log P,
•
which can be definedas the ratio of unionized compound, at
equilibrium, between organic and aqueous phases

SolubilityAnalysis
•
logP =
𝒖𝒏𝒊𝒐𝒏𝒊𝒛𝒆𝒅 𝒄𝒐𝒎𝒑𝒐𝒖𝒏𝒅 𝒊𝒏 𝒐𝒓𝒈𝒂𝒏𝒊𝒄 𝒔𝒐𝒍𝒗𝒆𝒏𝒕
𝒖𝒏𝒊𝒐𝒏𝒊𝒛𝒆𝒅 𝒄𝒐𝒎𝒑𝒐𝒖𝒏𝒅 𝒊𝒏 𝒂𝒒𝒆𝒐𝒖𝒔 𝒔𝒐𝒍𝒗𝒆𝒏𝒕
•
Drugs having values of P greater than 1 are classifiedas
lipophilic,
•
whereas those with partition coefficients less than 1 are
indicative of a hydrophilic drug.

SolubilityAnalysis
•
logP = 0 means that the compound is equally solublein water
and in the partitioningsolvent.
•
If the compound has a log P = 5, then the compound is 100,000
times more soluble in the partitioning solvent.
•
A logP = –2 means that the compound is 100 timesmore
soluble in water, that is quite hydrophilic

SolubilityAnalysis
3. Partition Co-efficient : Application
•
Recovery of antibiotics fromfermentation broth.
•
Extraction of drug frombiological fluid for therapeutic
monitoring.
•
Absorption of drug fromdosage forms. (Ointments,
•
Suppositories, Transdermal patches).
•
Study of distribution of flavoring oil between oil
•
& water in emulsion.

SolubilityAnalysis
4. Common Ion Effect:
•
The common ion effect describes the effect on equilibriumthat
occurs when a common ion (an ion that is already contained in
the solution) is added to a solution.
•
The common ion effect generally decreasessolubility of a solute.
•
So, weakly basic drug which are given as HCl salts have
decreasedsolubility in acidic (HCl) solution.

SolubilityAnalysis
4. Common Ion Effect:
•
To identifya common ion interaction, the intrinsic dissolution
rate of hydrochloride salt should be compared between,
•
Water and water containing1.2%W/V NaCl in 0.05MHCl and
0.9%W/V NaCl in 0.05MHCl
•
After this, if solubilityis not decreasedthen drudcan be desined
in chloride salt, otherwise it shouldbe eliminated.

SolubilityAnalysis
•
For drugcandidates, with either poor water solubilityor
insufficient solubility for projected solution dosage form, pre-
formulation study should include limitedexperiments to
identify possiblemechanism for solubilization.
•
Methods for Increasing Solubility:
•
Change in pH Co-Solvency
•
Solubilization by Surfactant
•
Chemical Modification of drug

ChemicalAnalysis
• Chemical property indicates the degree of stabilityof new drug
entity.
• Suchpropertyhelps to set theparameter for handling
formulation development, storage & mode of administration.
• Factors pertaining to chemical features of API
1. Hydrolysis 2. Oxidation
3. Racemization 4. Polymerization

ChemicalAnalysis
1. Hydrolysis:
• Splittingof bonds & the addition of H+ and /or OH− ion of
water.
• Hydrolysis involves nucleophilic attack of labile groups eg: ester
and amide.
• When the attack is by the solvent other than water, then it is
known as solvolysis.

ChemicalAnalysis
1. Hydrolysis:
• Conditions that catalyze the breakdown are Presence of
hydroxyl ion, hydride ion, divalent ion, heat, light, ionic
hydrolysis, solution polarity and ionic strength, high drug
concentration.
• Hydrolysis can be prevented by Adjusting the PH. As most of
the potent drugs are weakly acidic or weaklybasic in nature.

ChemicalAnalysis
1. Hydrolysis:
• Formulatethe drug solution close to it’s PH of optimumstability
or by Addition of water miscible solvent in formulation or
• by Using optimumbuffer concentration to suppressionization
or
• by Addition of surfactant such as nonionic, cationic and anionic
surfactant stabilizes the drug against base catalysis or

ChemicalAnalysis
1. Hydrolysis:
• the solubilityof pharmaceuticals undergoingester hydrolysis
can be reducedby forming less soluble saltsor ester of drug. eg:
phosphate ester of Clindamycin or Store withdesiccants, using
complexing agents.
• Other examples are aspirin, anaesthetics (ester), barbiturates,
chloramphenicol, ampicillin (amide)

ChemicalAnalysis
2. Oxidation:
• Second most common mechanismof degradation.
• Oxidation occurs in two ways
• I. Auto- oxidation
• II. Free radical chain process

ChemicalAnalysis
2. Oxidation:
• Reaction of any material with molecular oxygen producing free
radicals by hemolytic bond fission of a covalent bond. These
radicals are highlyunsaturated and readily accept electron from
other substance causing oxidation is called Auto-oxidation.
• Free radical chain process involves Initiation, Propagation,
Hydro peroxide decomposition and Termination.

ChemicalAnalysis
2. Oxidation:
• Factors affecting oxidation process are oxygen concentration,
light, heavy metals particularly those having twoor more
valence state(copper, iron, nickel, cobalt), hydrogen and
hydroxyl ion, temperature.
• Oxidation can be Prevented by reducing oxygen content
• Oxidative degradation of drugs takes place in an aqueous
solution

ChemicalAnalysis
2. Oxidation:
• so the oxygen content can be decreased by boiling water or by
storing the formulation in a dark and cool condition or
• By addition of an antioxidant/reducing agent /chain inhibitors
of radical induceddecomposition.
• Usually steroids, vitamins and antibiotics undergooxidative
degradation.

ChemicalAnalysis
3. Racemization:
• The inter conversion fromone isomer to another can lead to
different P’cokinetic properties (ADME) as well as different
P’cological& toxicological effect.
• Eg. L-epinephrine is 15 to 20 times more active than D-form,
while activityof racemic mixture is just one half of the L-form.
• It depends on temperature, solvent, catalyst & presence or
absence of light.

ChemicalAnalysis
4. Polymerization:
• It is a continuous reaction between molecules.
• More than one monomer reactsto forma polymer.
• Eg. Darkeningof glucose solution is attributed to
polymerization of breakdown product [5- (hydroxyl methyl)
furfural].
• Eg. Polymerization of HCHO to para-HCHO whichcrystallizes
out fromthe solution.

Biopharmaceutical ClassificationSystem(BCS)
• The Biopharmaceutical Classification Systemis a scientific
framework for classifying a drug substance basedon its aqueous
solubility & intestinal permeability under prescribed condition.
• The BCS is only applicable to immediate release, solidorally
administered dosage forms, emulsions or suspensions designed
to deliver drug to the systemic circulation.

• Drug products having a narrow therapeutic index are excluded
fromconsideration for a BCS guideline.
• The aimof the BCS is to provide a regulatory tool for the
replacement of certain BE studies by conducting accurate in
vitro tests.
• BCS has gained importance worldwide as a drug product
regulation tool For scale-up production and post-approval
changes

• Significant terms in BCS
1. Solubility:
• A drug substance is classifiedas highly soluble if the highest
single therapeutic dose is completely
• solublein 250 ml or less of aqueous media over the pH range of
1.2–6.8 at 37±1°C.

1. Solubility:
• In cases where the highest single therapeutic dose does not meet
this criterion but the highest strengthof the reference product is
solubleunder the aforementioned conditions, additional data
should be submittedto justifythe BCS-based approach.

1. Solubility:
• The sponsor is expectedto establish experimentally the
solubilityof the drug substance over the pH range of 1.2–6.8 at
37±1ºC.
• At least three pH’s within this range, including buffers at pH 1.2,
4.5 and 6.8, shouldbe evaluated.

2. Permeability:
• The assessment of permeability shouldpreferentially be based
on the extent of absorption derived from human
pharmacokinetic studies, e.g., absolute bioavailability or mass
balance.
• High permeabilitycan be concludedwhen the absolute
bioavailability is ≥85%.

2. Permeability:
• High permeability can also be concluded if ≥85%of the
administereddose is recovered in urine as unchanged (parent
drug), or as the sumof parent drug.
• Permeabilitycan be assessed by validatedand standardizedin
vitro method.

2. Permeability:
I. Cultured Caco-2 epithelial cell monolayers derivedfroma
human colon adenocarcinoma cell line are widelyusedto
estimateintestinal drug absorption in humans.
II. Human in vivo data derivedfrompublishedliterature
(bioavailability studies) may be acceptable.

2. Permeability:
III.

3. BCS BasedBio-waiver :
• A bio-waiver is an exemption fromconducting human
bioequivalence (in-vivo) studies.
• It is intended to reduce the need for in vivo bioequivalence
studies i.e., it can provide a surrogate for in vivo bioequivalence.

3. BCS BasedBio-waiver :
• In vivo bioequivalence studies may be exemptedif an
assumption of equivalence in in vivo performance can be
justified by satisfactory in vitrodata.

Class Solubility Permeability Examples
Class- I High High Metoprolol ,
Propranolol,
Diltiazem
Class- II Low High Nifedipine,
naproxen
Class- III High Low Cimitidine,
Metformin,
Insulin
Class- IV Low Low Taxol,
Clorthiazole,
Cefexime

• Class I
• Ideal for oral routeadministration.
• Drug absorbed rapidly.
• Drug dissolvedrapidly.
• Rapid therapeutic action.
• Bioavailability problemnot expectedfor immediate release drug
product.

• Class II
• Oral routefor administration.
• Drug absorb rapidly.
• Drug dissolve slowly.
• Bioavailability is controlled by dosage formand rateof release of
the drugsubstance.

• Class III
• Oral routefor administration.
• Drug absorbance is limited.
• Drug dissolve rapidly.
• Bioavailability is incomplete if drug is not release or dissolve in
absorption window.

• Class IV
• Poorlyabsorbed by orallyadministration.
• Bothsolubility& permeability limitation.
• Low dissolution rate.
• Slow or low therapeutic action.
• An alternate route of administration may be needed.

• Significance
• Regulatory toll for replacement of certain BE studies.
• It can save bothtime and money—if the immediate -release,
orally administereddrug meets specific criteria, the FDA will
grant a waiver for expensive and time-consuming
bioequivalence studies.
• Valuabletool for formulation scientist for selection of design of
formulateddrugsubstance.

• Significance
• When integratedwith other information; it provides a
tremendous tool for efficient drug development.
• For researchscientist to decide upon which drug delivery
technology to follow or develop.
• Aiduseful information in PFS if new drug entity.

References
1. Brahmankar, D. M and Jaiswal, Sunil. B (2009). Biopharmaceuticsand
Pharmacokinetics – A Treatise.2nd edition. Vallabh Prakashan, Page no. 27- 29
and 332 - 335.
2. WHOPrequalification of Medicines Programme; General noteson
Biopharmaceutics ClassificationSystem (BCS)-basedbiowaiver applications;
Guidance Document October 2012
3. KumarK.P. Sampath, A Text Bookof Industrial Pharmacy(2019), Nirali
PublicationAnd Distributors, Maharashtra.
4. ICHharmonized guideline “BiopharmaceuticsClassification System-based
Biowaivers M9”Adopted on 20 November2019

Pre-Formulation Studies

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