Preformulation

Studies
 Outline of topic

Study of physical properties of
drugs like physical form, particle
size, shape, density, wetting,
dielectric constant, solubility,
 Study of chemical properties of drugs like
hydrolysis, oxidation – reduction,
dissolution, racemisation,
organoleptic
polymerization and their influence on formulation
and stability of properties
products. and their effect on
formulation, stability and
 Study of prodrugs in solving problems related to
bioavailability.
stability, bioavailability and elegancy of
formulation.
 Introduction
Preformulation:
• a stage of development during which the
physicochemical properties of drug substance are
characterized.

When???
• If the drug shows sufficient activity in animals & is
to be evaluated in humans.

Focus……
• On physicochemical properties of a new compound
which may affect the drug performance &
development of efficacious dosage form.
Drug Development Cycle
 The Drug Development Cycle ~ An
Overview
The process of developing a new drug can take between
10 and 15 years with an estimated average cost of $800
million
Discovery/Pre-Clinical Testing
 Time: 6.5 Years

Phase I
 Time: 1.5 Years

Phase II: Safety and Efficacy

 Time: 2 Years

Phase III
 Time: 3.5 Years

Marketing Approval Process

 Time: 1.5 Years
 Introduction
Project team – Representative from
different disciplines
Different Disciplines
 Medicinal Chemistry and Pharmacology
 Pre-formulation Research
 Formulation development
 Process R&D
 Analytical R&D
 Toxicology and drug metabolism
Why preformulation studies are
required?
Preformulation studies are an important foundation
tool early in the development of both API and drug
products.
They influence….
Selection of the drug candidate
itself Selection of formulation
components
API & drug product manufacturing
processes
Determination of the most appropriate
container / closure system
Development of analytical
methods Assignment of API retest
 Preformulation Characterization
Stability
Bulk properties
•solid state (RH, oxygen, light, compatibility)
 Organoleptic
 crystallinity and polymorphism •solution (pH, buffers, solvent, temperature)
 water adsorption •compatibility with excipients (other additives)
 particle size, shape, and
surface area
 bulk density
 Adhesion Biopharmaceutical properties
 powder flow •absorption (route, rate, extent, mechanism,
 compressibility
absorption windows, food effects)
•metabolism (first pass metabolism, enzyme
Physico-chemical properties induction, metabolism in GIT)
 solubility analysis •duration of action (dosing, controlled
 Ionization release)
 partition coefficients •dose
 dissolution
Investigative Procedures on
Pre-formulation
Characteristic contents as
Examples
 Objective
 Quantitation of physical chemical
properties that will assist in developing a
stable, safe and effective formulation with
maximum bioavailability
 Principal areas of
Pre-
formulations
 Bulk
Characterization

 Solubility Analysis

 Stability Analysis
 Principal areas of Preformulations
 Bulk Characterization

 Crystallinity and polymorphism

 Hygroscopicity

 Fine particle characterization

 Bulk density

 Powder flow properties

 Bulk Characterization
 Synthetic process simultaneously developed
 A drug candidate – Solid form not identified –
emerge of new polymorphs
 Solid form – particle size, bulk density and
surface morphology – Process development
 Comprehensive characterization – To avoid
misleading predictions of stability or solubility,
which depends on a particular crystalline
form
Crystallinity and polymorphism
Crystal habit and the internal structure
affects the bulk and physiochemical
properties
 Flowability to chemical stability
Habit – Description of the outer
appearance of a crystal
 Eg:Acicular or needle, platy, massive,
tabular etc
Internal structure : Molecular
arrangement within the solid
 Crystallinity and polymorphism
 Changes in internal structure for a compound – Alter
change in the crystal habit.
 Characterisation Involves –
 Verifying the solid is the expected chemical compound
 Characterization of the internal structure
 Describing the habit of the crystal

Prismatic

Bladed
Habit and Crystal chemistry of a
compound
Chemical Compound

Habit Internal structure

Crystalline Amorphous

Molecular Adducts
Single entity
Polymorphs Stoichiometric
Non Stoichiometric
inclusion compounds Solvates
(Hydrates)
Cage ,
Layer Channel
(Clathrate)
 Polymorphism
Classification-
1. Monotropic polymorphs - one stable crystal form and
one meta stable regardless of temperature change
OR
Only one polymorph is stable at all reasonable Temp.
 Eg. Glyceryl stearates, metalazone

2. Enantiotropic polymorphs - One polymorph is stable

over one temperature range, another polymorph is
stable over a different temperature range
 E.g. carbamazepine and acetazolamine,Sulfur
 Analytical method for
characterization of polymorph
1.
Microscopy-
 Hotstage microscopy
Micrographs taken at a heating rate of 108C/min
(a) 30.08C, (b) 156.58C, (c) 162.58C, (d) 166.28C,
(e) 168.58C and (f) 170.58C.
Scanning electron microscopy
(SEM)
 Hygroscopicity
 Factors
 Adsorption & equilibrium moisture content depends upon
 Atmospheric humidity
 Temperature
 Surface Area
 Exposure & mechanism for moisture uptake
 Types
 Deliquescent: adsorbs sufficiently water to dissolves completely

 Hygroscopic: adsorb water and forms

hydrate
 Changes in moisture level affects
 Chemical stability
 Flow ability
 Compactibility
 Fine Particle Characterization
Bulk flow, formulation homogeneity and surface area
controlled processes such as dissolution.
Microscopy

 Coulter counter
Sieve method
 BET method (Surface area)
 SEM method
 Bulk Density
 Bulk density :
Varieswith Method of crystallization, milling or
formulation
 High dose – Size of capsules
 Low dose - homogeneity
 Drug and excipients
 Tapped density
 True density
 Powder Flow properties

Powder Flow properties: Free flowing

or
cohesive
Factors affecting are-
particle size, density, shape,
moisture content, electrostatic
charge

-Flow rates (g/sec)

Way to improve flow properties
-Granulation

-Slugging/ compaction

-Glident
Principal areas of Pre-formulations-
Solubility Analysis
 Ionization constant –pKa
 pH solubility profile
 Common ion effect – Ksp
 Thermal effects
 Solubilization
 Partition co-efficient
 Dissolution
 Solubility Analysis
Very soluble less than 1 part
Freely soluble from 1 to 10
parts

Soluble from 10 to 30 parts

Sparingly soluble from 30 to 100 parts

Slightly soluble from 100 to 1000 parts

Very slightly soluble from 1000 to 10,000 parts

Practically insoluble more than 10,000 parts

 Solubility Analysis
 Solubility study done in various
solvents
-Aqueous solvent
- water, buffers
-Nonaqueous
solvents
- Organic solvents
- Glycerol, PEG
 Solubility Analysis
 Focus on drug-solvent system that
could occur during the delivery of the
drug candidate
 Provides basis for formulation work.
 Determination of
 pKa

 Temperature dependence
 pH solubility profile
 Solubility products
 Solubilization mechanisms
 Solubility Analysis
 Analytical methods useful include
 HPLC

 UV Spectroscopy
 Fluoroscence Spectroscopy
 Reverse Phase gas chromatography

 Factors to be defined for solubility and

Dissolution study -
 pH

 Temperature
 pKa Determination
 Dissociation constant is capability of
drug to ionize within pH range of 1 to 10
 Solubility & absorption altered
 Henderson-Hasselbalch equation

 Acidic compounds

 Basic
Compounds
 pKa Determination
contd..
 Absorption
Principles
 Weakly acidic drug pka > 3, unionized form in the
stomach , Drug is ionized predominantly in
intestine.

 Basic drug pka=8-10, ionized form predominantly

in stomach & intestine
Eg. Erythromycin

- Other factors like lipid solubility, dissolution rate,

common ion effects, metabolism also affects
 Partition Coefficient

 Ratio of unionized drug distributed

between the organic & inorganic aqueous
phase at equilibrium.

 Importance
 Screening for biological activity
 Drug delivery
 System used are
 Octanol/water and Chloroform/water
 pH Solubility Profile & Common Ion
Effects
 Solubility of an
depends on acidic or basic drug
 pKa of the ionizing functional group &
 intrinsic
solubilities for both the ionized &
unionized forms.

 Experimental determination of a
solubility product should include
measurement of pH as well as assays of
both drug & counter ion concentrations.
 Dissolution
 Release of drug from a dosage form involves diverse factors
as:
 A drug is expected to be release from the solid dosage forms
(granules, tablets, capsules etc) & immediately go into
molecular solution. This process is called dissolution.
 Dissolution (molecular dispersion) is a prerequisite for the
drug absorption.

 APPLICATION
 The dissolution test is used as a quality control tool to monitor
routinely the uniformity & reproducibility of production batches.
 The test is utilized as a research tool for optimizing the parameters
& ingredients in new formulations.
 Whenever in vitro & in vivo correlation are observed, the dissolution
studies are used as tools to substitute the frequent studies of
bioabsorption.
 Dissolution contd…

 Dissolution is expressed in terms of a rate process.

 Greater the rate, faster the dissolution.
 Dissolution rate may be defined as “the amount of drug
substance that goes into solution per unit time under
standardized conditions of liquid/solid interface,
temperature & solvent composition”.
 Noyes-Whitney’s equation is useful for estimating the
rate of dissolution.
dC / dt = DA/ hV (Cs -C)
DISSOLUTION TESTING CONDITIONS
 Apparatus
 Dissolution Medium
 Agitation
 Validation
 DISSOLUTION APPARATUS
The most commonly employed dissolution test methods
are (1) the basket method (Apparatus 1)
(2)the paddle method (Apparatus 2)
The basket and the paddle methods are simple, robust,
well standardized, and used worldwide. These methods
are flexible enough to allow dissolution testing for a variety
of drug products.
Apparatus 1 and Apparatus 2 should be used unless
shown to be unsatisfactory.
The in vitro dissolution procedures, such as
(3) the reciprocating cylinder (Apparatus 3) and
(4) a flow-through cell system (Apparatus 4)
described in the USP, may be considered if
needed.
These methodologies or other
alternatives/modifications
should be considered on the basis of their proven
superiority for a particular product.
Dissolution

Paddle method
(Apparatus 2)

basket method
(Apparatus 1)

reciprocating cylinder flow-through cell

(Apparatus 3) system (Apparatus 4)
 Stability
 Analysis
Preformulation studies give first quantitative
assessment of chemical stability of a new drug.

Solution State Solid

State
Handling, formulation, storage and administration
of a drug candidate
 Test protocols & experimental methods
 Assay – intact drug and degraded product
Evaluation – HPLC, Gas Chromatography
 Stability in toxicology
formulations
 Since toxicological studies typically commence early in drug
development, it is often advisable to evaluate samples of
toxicology preparations for Stability and potential
homogeneity problems
 Drug administered – Feed or oral gavage of solution
or suspension of drug in an aqueous vehicle
 Minerals, vitamins, enzymes , a multitude of functional
groups present in feed – reduces shelf life of drug
 Fresh sample of feed to be used
 Solution or suspension – Checked for ease of
manufacture
 Stored in a flame sealed ampoules at various

temperatures
 Solution Stability
 Aim- Identification of conditions necessary to form a
stable solution
 Study Includes – effects of pH, Ionic strength, Co-solvent, light ,
temperature and oxygen
 Probing experiments at extremes conditions of pH and
temperature (0.01N HCl , water ,0.01N, NaOH all at
90°C).
 Assay specificity and Maximum rates of degradation
 Complete pH rate profile – pH of max stability.
 Aq. Buffers are used to provide wide range with constant levels of
drug, co solvent and ionic strength
 Compatible with physiological media
 Eg.: Ionic strength ( µ) of 0.9% NaCl is 0.15
 Equation: µ = ½ ∑miZi
2
 Solid state
Aim: Identifications of stable storage
stability
conditions for drug in the solid state
and
identification of compatible excipients
for a formulations.

 Affected by change in purity and crystallinity

 Initial bulk lots and newer lots– to be studied
 Solid state is slower and difficult to interpret than solution
state
 TLC, UV-Vis, fluorescence
 Polymorphic changes – DSC, IR or appearance changes like
oxidation – surface discoloration

Procedure: Open screw cap vials – Exposed to various

 Solid State
Stability
 Storage conditions
1.Refrigerator- 5°C
2.Room temp.- 22°C
3.Ambient humidity, 70% RH, 90%RH
4. 25°C/60% RH, 40°C/75% RH,

5.Light- Clear, Amber, yellow-green glass,

control sample

6. Ambient humidity- O2 headspace, N2

headspace
 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 changes is seen after 30 days at 60°C , the stability
prognosis is excellent.
 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
 Photolytic
 Many drugsstability
fade or dorpen on exposure light.
 Increased Impurity level
 Samples should be exposed to light providing an overall
illumination of not less than 1.2 million lux
hours and an integrated near ultraviolet energy of not
less than 200watt hours/square meter
 If protected samples (e.g., wrapped in aluminum foil)
are used as dark controls to evaluate the contribution of
thermally induced change to the total observed change,
these should be placed alongside the authentic sample.
 Resulting data may be useful in determining if an amber
colored container is required or if color masking bye should
be used in the formulation
 Stability to Oxidation
 Drug’s sensitivity to oxidation can be examined
by exposing it to atmosphere of high oxygen
tension.
 Usually a 40% oxygen atmosphere allows for
rapid evaluation.
 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
 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 for
physicochemical properties like appearance,
Assay and degradation products.
Formulation Recommendation
 Upon the completion of preformulation
evaluation of a new drug candidate, it is
recommended that a comprehensive report
to be prepared
highlighting the pharmaceutical problems
associated with this molecule.
 This report should conclude with
recommendations for developing phase I
formulations.
 These reports are extremely important in
preparing regulatory documents & aid in
developing subsequent drug candidates.
Study ofchemical properties
of drugs like

 Hydrolysis
 Oxidation – Reduction
 Photolysis
 Racemisation
 Polymerization

Mechanisms of degradation and their influence

 OBJECTIVE
 Initial investigation on chemical properties
 Knowledge about the chemical and
physical stability of a candidate drug 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
 Degradation Pathway
Hydrolysis: Drug interact with water
molecule to yield breakdown product.
 Susceptible to the hydrolytic process: esters,
substituted amides, lactones, and lactams.
Eg: Anestheics, antibiotics , vitamins and barbiturates
1. Ester hydrolysis:
 Ester Acid + Alcohol (involves rupture of
Hydrolysis

a covalent linkage between a carbon atom and an oxygen

atom).
 Acid or alkali catalysed hydrolysis
Ester
Hydrolysis
 Factors to be considered in Hydrolysis
 pH
 Type of solvent : solvent lower dielectric constant
 Eg.: ethanol,glycols, mannitol etc.
 Complexation : steric or polar effects. Eg.: caffeine with
benzocaine – electronic influence of complexing agent –
alters affinity
 Surfactants: nonionic , cationic , anionic stabilizes drug
against base catalysis. Eg: 5% SLS – 18folds increase in
t1/2 of benzocaine
 Modification of chemical structure
 Salts and esters
 Amide
 hydrolysis
Hydrolytic reaction results :
Amide Acid +Amine
 Eg.: Chloramphenicol
Niacinamides

 Ring alterations: hydrolysis proceed as a result

of ring cleavage.
 Eg. Pilocarpine
 Oxidation -
 Substance isreduction
oxidized when :
 If electrons are removed from it
 Gains electronegative atoms or radicals or loses
electropositive atoms or radicals
Addition of oxygen and removal of hydrogen
 Most common : autoxidation (free radical
chain process)
 Involves homolytic bond fission of a covalent
bond
– each atom retains one of the electrons of original
covalent bond:
 Photolysis
 Photochemical
 Photosensitizer
 UV- violet portions – more active
( shortet wavelength ,more energy)
 Racemizatio
 n
Racemization – compound changes optical
activity without changing the chemical
composition.
 Levo and dextro form
 Eg: l-adrenaline is 15-20times more active
than dextro form
Racemic mixture
 Stability and therapeutic activity
 Principal areas of Preformulations

Prodrugs
 Study of prodrugs in solving problems related
to

Stability,

Bioavailability and

Elegancy of formulation
 Prodrugs-
Intoduction
Drugs – Undesirable

physicochemical and biological
How do one improve therapeutic efficacy?
properties
Biological, Physical and Chemical means
 Biological approach – Alters the ROA – may
or may not be acceptable by the patient
 Physical approach – Modify the design of
the dosage form Eg.: CDDS
 Chemical Approach – Best to enhance the
drug selectivity by minimizing the toxicity
 Prodrug
 3 Chemical means – To optimize the
drug therapeutics
1.Design and development of new drugs with
desirable features
Screening of chemicals for biological activity-
Clinically useful
2.Design of hard and soft drugs with desirable
characterisitcs
3. Design of prodrugs
 Prodru
 g to biotransformation -
Hard drugs :Resistant
Long biological half life, no toxic metabolite
formation.
Disadv.: Accumulation
 Soft drugs: A biologically active drug compound
i.e biotransformed in vivo in a rapid and
predictable manner into non- toxic moieties.
Relatively inert metabolites
Disadv.: Short Duration Of Action
Ex. Insulin, adrenaline
Replacement of alkyl chain of drug – ester group
 Prodru
A prodrug is chemically modified
inert g
drug precursor which
upon biotransformation
liberates the pharmacologicallyactive
parent compound
Pro-agent, bioreversible derivative or latentiated

drug
Design approach – Drug latentiation

Classification
Depends on constitution, lipophilicity and method
of bioactivation and catalysts involved in
 Carrier linked prodrugs
Simple prodrugs
 Areones where the active drug is covalently
linked to an inert carrier or transport
moiety
Esters or amides
Greatly modified lipophilicity due to the
attached carrier
Active drug released by hydrolytic cleavage
either chemically or enzymatically
Carrier linked
prodrugs
 Bioprecursors
Known as Metabolic precursors
 Are inert molecules obtained by chemical
modifications of active drug but do not
contain a carrier
 Moiety has same lipophilicity as the parent
drug
Bioactivated by redox biotransformation only
enzymatically
 Eg.: Arylacetic acid NSAID – fenbufen from
aroylpropionic acid precursors.
Bioprecursors
 Pro-
Prodrug
Few cases of carrier type prodrugs to be formulated as
ophthalmic, parenteral or oral liquid preparations, the
conversion to active drug –- Chemically ( non
enzymatically) triggered by change in pH –- Stability
problems

Overcome by :
 Double prodrug or pro-prodrug concept
Further derivatized in a fashion – Only
enzymatically conversion of prodrug is possible
before the latter can cleave to release the active
drug
 Mutual
 Prodrug
In contrast to simple prodrugs where the
carrier used is biologically inert,
 Prodrug comprises of 2 pharmacological active
agents coupled together to form a single
molecule that each acts as carrier for the other
 Prodrugs of two active compounds are
called as mutual prodrugs
 Eg.: Benorylate : For NSAID’s of aspirin and
paracetamol
 Examples of Prodrug
Aspirin – Produg of salicylic acid- decrease
GI irritation
Hexamine – Excreted in urine is converted to
formaldehyde in the acidic urine pH -
Urinary tract antibacterial
 Ideal characteristics of Prodrug
 Shouldn’t have intrinsic pharmacological
activity- Inert
 Rapidly transform, chemically or enzymatically
into the active form where desired
 The metabolic fragments, apart from the active
drug should be nontoxic
 Applications -
 Prodrug
Pharmaceutical Applications:
Improvement of taste
Improvement of odor
Change of physical form for preparation of solid
dosage forms
Reduction of GI irritation
Reduction of pain on injection
Enhancement of drug solubility and dissolution
rate
Enhancement of chemical stability of drug
 Applications -
ProdrugApplications
Pharmacokinetic

Enhancement of bioavailability
(lipophilicity)
Prevention of pre-systemic
metabolism
Prolongation of duration of
action
Reduction of toxicity
 Site specific drug delivery (drug