Industrial

Pharmacy-I
BPH5002
PREFORMULATION
Industrial Pharmacy – I

A STEP BEFORE BPh5002

PRODUCT
Introduction

Preformulation studies are synonymously known as “Learning before doing”.

Preformulation is the interface between new chemical entities (NCE) and the
formulation development phase therefore it is the sole study to provide a complete
pathway of drug formulation development.

Key preformulation factors are thermal particle size, shape, dissociation and partition
coefficient, drug/API stability, absorption behaviour, and solid-state characters like
polymorphism, the structural, degradable, biophysical, and physicochemical
characteristics of the macromolecules are also evaluated at the preformulation stage
https://www.youtube.com/watch?v=h8zY-V3lSt4
Early drug development
Stages of preformulation studies.
Preformulation studies performed post-scientific literature
survey of some type of drug molecules to recognise the
following parameters
• Chemistry of API, the synthetic pathway of API, drug product
manufacturing processes.
• Degradation process and metabolites.
• Development of analytical methods.
• Distribution kinetics and bioavailability of same kind molecules.
• Toxicity profile of candidate drug.
• Preformulation influences, drug candidate selection, formulation
adjuvants.
• Optimum storage containers and conditions selection.
Definition

Preformulation studies can therefore be defined as; Laboratory studies to

determine the characteristics of active substance and excipients that may
influence formulation and process design and performance.
• Preformulation research is performed to generate data related to
biopharmaceutical, physicochemical, and physic-mechanical
properties of molecules, and adjuvants.

• Various regulatory guidelines like the ICH and US-FDA support and
recommend basic concepts for preformulation development.
Preformulation studies are advised by NDA, IND, and ANDA and
released by the ICH and the US FDA regulatory agencies.

• ICH guidelines state that all technical requirements for drug approval
applications should be submitted in a standardised e-CTD format.
Preformulation study
schematic
representation.
 Provide comprehensive and detailed knowledge
of the product to the company’s product
pipeline.

Determine the product specifications

Pharmaceutic
continuously within the purview of the regulatory
framework and know about product
specifications.

al drug
product life
Determine batch variability by trend analysis
resulting from differences in the raw materials
and ageing of the equipment, and establish the

cycle
proper preventive maintenance and corrective
action and preventive action. T

Manage post-commercialization data related to

regulatory approvals, change management, data
publication from other sources and sales.
Preformulation: objectives
To produce the helpful data required for the development of desired,
convenient, stable, efficacious, and products produced at a large
level.
Establish a fine understanding of the physicochemical properties of
new drug substances before being developed into a final dosage
form.

Physical characteristics establish the selection of the appropriate

form of a drug substance.

Selection of accurate excipients and additives which are compatible

with drug substances.
Pharmacokinetics Vs Pharmcodynamics
 Preformulation: goals

The establishment of the physicochemical properties leads to a drug

candidate.

Establish pharmacokinetics and biodistribution profile of selected

drug molecule.

Establishment of drug molecule common excipients compatibility.

Significant roadblocks to the development of successful

pharmaceutical products
List of drug product development challenges and strategies to overcome the challenges.

Discovery Developmen Strategies to overcome drug discovery challenges

team
tal
challenges
Discovery unit Poor drug Apply SAR to get drugs with low IC50 (nmol/L) values for lower toxicity
potency and improved effectiveness. STR-mediated structural modifications are
and useful for clinical efficacy, and safety dose selection in clinical studies.
specificit
y
Clinical Lack of The top leading candidate for clinical trials is identified by the ratio of
clinical their IC50 value and kinase profile selectivity which is 10-fold higher for
efficacy disease vs. other kinases.
Safety Off- Toxicogenomics as a tool for early toxicity determination
(clinical target
toxicity) toxicity
Safety On- Inhibition of disease-related targets and required titration of dose,
(clinical target toxicogenomics used for early assessment of potential toxicity.
toxicity) toxicity
Business Poor Industries have a multidisciplinary business development team which
developmen strategic make a detailed roadmap and milestone for new compound
t planning development
from laboratory to market authorization. Nowadays, Artificial Intelligence
with the help of large data analytics enables pharma industries to
• Physicochemical parameters:
• Organoleptic properties:
• Bulk characterization studies:
• Crystallinity and polymorphism
• Hygroscopicity
• Fine particle characterization
• Bulk density
• Powder flow properties
• Compression properties
• Physical description
• Solubility analysis:
• Intrinsic solubility determination
• PKa determination
• Partition coefficient
• Dissolution study
• Common ion effect
• Stability analysis:
• In toxicology formulations
• Solution stability
List of various organoleptic
properties.
Sub classification of internal structure of a compound
Polymorphic forms of drugs can prove interesting for drug developers
because their thermodynamic and physicochemical properties, such as
energy, melting point, density, stability, and in particular solubility, may
offer an improvement on the original form.
DSC analysis involves subjecting a sample to a controlled temperature program
while quantifying the heat exchange with the surroundings. The technique
measures how much heat is absorbed or released during phase transitions or
chemical reactions, offering a glimpse into the material's thermal behavior.

Fusion, sublimation, solid‐solid transition & water loss generally produce

endothermic effects while crystallization produces exothermic effects
DSC analysis could give application w.r.t
•Melting Point/Melting Range
•Heat Capacity
•Crystallization
•Glass Transition
•Thermal Stability
•Decomposition Temperature
•Oxidative Induction Times (OIT)
•Purity

In thermo-gravimetric analysis, the sample is heated in a given environment

(air, N2, CO2, He, Ar, etc.) at controlled rate. The change in the weight of
the substance is recorded as a function of temperature or time.
Other techniques named Photon magnetic resonance and nuclear magnetic
resonance are also been applied for evaluating a polymorphic form.
• Hygroscopicity
• A substance that absorbs sufficient moisture from the atmosphere to
dissolve itself is deliquescent.
• A substance that loses water to form a lower hydrate or becomes anhydrous
is termed efflorescent.
• These are extreme cases, and most pharmaceutical compounds are usually
either impassive to the water available in the surrounding atmosphere or
lose or gain water from the atmosphere, depending on the relative
humidity (RH).
• Materials unaffected by RH are termed non-hygroscopic, whereas those in
dynamic equilibrium with water in the atmosphere are hygroscopic.
• Ambient RH (0% poles and desert, 55% temperate and 87% tropics) can
vary widely and continually depending on the weather and air temperature,
and these cyclic changes lead to constant variations in the moisture content
of unprotected bulk drug and excipients.
• The constant sinusoidal change in day and night temperatures is the major
influence. For this reason pharmaceutical air conditioning is usually set
below 50% RH, and very hygroscopic products, e.g. effervescents, which are
• particularly moisture sensitive, are stored and made below 40% RH.
 Hygroscopicity Classification

Class 1 Non Hygroscopic Essentially no moisture increases occur at

relative humidities below 90%.

Class 2 Slightly Hygroscopic Essentially no moisture in occur at

relative humidity below 80%

Class 3 Moderately Moisture Content does not increase more

Hygroscopic than 5% after storage for 1 week at
relative humidity below 60%

Class 4 Very Hygroscopic Moisture content increase may occur at

relative humidity as low as 40 to 50%
 Particle size
• Various chemical and physical properties of drug substances are affected by
their particle size distribution and shapes.
• The effect is not only on the physical properties of solid drugs but also in some
instances on their biopharmaceutical behaviour
• .For example, the bioavailability of griseofulvin and phenacetin is directly
related to the particle size distributions of these drug.
• It is now generally recognized that poorly soluble drugs showing a dissolution
rate- limiting step in the absorption process will be more readily bioavailable
when administered in a finely sub divided state than as a coarse material.
• Size also plays a role in the homogeneity of the final tablet. When large
differences in size exist between the active components and excipients, mutual
sieving (de- mixing) effects can occur making thorough mixing difficult or if
attained difficult to maintain during the subsequent processing steps.
 Coulter Counter

• Particle size affects particle size, shape and surface morphology.

• Optical microscopy, Stream counting devices like coulter counter and HIAC
counter are different methods for characterizing the size distribution.
The Coulter principle states that particles pulled through an orifice, concurrent with an electric current,
produce a change in impedence/ resistance for the particles against electrical flow proportional to the
volume of the particle traversing the orifice. This pulse in impedance originates from the displacement
of electrolyte caused by the particle.
The Coulter principle relies on the fact that particles moving in an electric field cause measurable
disturbances in that field. The magnitudes of these disturbances are proportional to the size of the
particles in the field. Coulter identified several requirements necessary for practical application of this
phenomenon:
• The particles must be suspended in a conducting liquid.
• The electrical field must be physically constricted so that the movement of particles in the field
causes detectable changes in the current.
• The particles must be dilute enough so that only one at a time passes through the physical
constriction.
Limitations:
• Not adequate for nonspherical particles
• Needle or irregular shaped particles cold cause blockage to the orifice
Particle surface area

The BET method measures the specific surface area which relates to the
reactive surface of the sample, including the pore size distribution.
Brunauer–Emmett–Teller (BET) theory aims to explain the physical
adsorption of gas molecules on a solid surface and serves as the basis for an
important analysis technique for the measurement of the
specific surface area of materials.
Tilting box
This method is appropriate for fine-grained, non-cohesive materials with individual
particle size less than 10 mm. The material is placed within a box with a transparent side
to observe the granular test material. It should initially be level and parallel to the base
of the box. The box is slowly tilted until the material begins to slide in bulk, and the
angle of the tilt is measured.

Rotating cylinder
The material is placed within a cylinder with at least one transparent end. The cylinder
is rotated at a fixed speed and the observer watches the material moving within the
rotating cylinder. The effect is similar to watching clothes tumble over one another in a
slowly rotating clothes dryer. The granular material assumes a certain angle as it flows
within the rotating cylinder. This method is recommended for obtaining the dynamic
angle of repose, and may vary from the static angle of repose measured by other
methods.
How particle flow properties can be improved?
Using Glidants-Increase flowability of powders by reducing particle-particle
friction
Examples- Talc and others (Find on your own)

Using lubricants- reduces friction between particles as well as between the

particle and punch wall
Examples-Magnesium stearate and others (Find on your own)

Anti adherents- avoids sticking of the tablets to the dies

Examples- Croscarmellose sodium (Ac-di-sol),Crospovidone (Polyplasdone), and
Sodium starch glycollate, Starch etc.
 Drug solubility
• Solubility of a drug substance is a fundamental property that should be evaluated early in
the discovery phase. In reality, it is difficult to predict the aqueous solubility due to the
complicated solubilization procedure and solid-phase chemistry of the drug candidate.
• A variety of approaches are employed at different phases of drug discovery and
development such as in silico, kinetic and equilibrium solubility.
• Thermodynamic or equilibrium solubility has been considered as the ‘gold standard’ for
solubility determination, but kinetic solubility is more appropriate for early phase drug
discovery.
• A direct relationship exists between solubility of a molecule and its dissolution rate. Drug
penetration through lipid membranes depends on the lipophilicity of the molecule and,
thus, may be correlated with the partition coefficient value.
• Absorption of a drug depends on the correct balance between these two opposite
properties.
• A lack of solubility affects the ability of drug to achieve efficacious and toxicologically
relevant exposures in animals.
Ionization Constant
• Many drugs are either weakly acidic or basic compounds and, in solution, depending on the pH value,
exist as ionized or un-ionized species.

• The un- ionized species are more lipid-soluble and hence more readily absorbed. The gastrointestinal
absorption of weakly acidic or basic drugs is thus related to the fraction of the drug in solution that is un-
ionized. The 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 lipid solubility of the un- ionized species. These
factors together constitute the widely accepted pH partition theory.

• The relative concentrations of un-ionized and ionized forms of a weakly acidic or basic drug in a solution
at a given pH can be readily calculated using the Henderson-Hasselbalch equations:

Low pKa demonstrates powerful acid

 Significance of pKa
• From the pKa of a weak acid or weak base the unionized fraction of a drug
can be determined at a certain pH.
• The unionized fraction has greater absorption rate through any biological
membrane. So while designing a dosage form how a weak acid or weak
base will behave in any biological fluid and its rate of absorption and the
site of absorption can be guessed from the pKa.
• Ibuprofen, a weak acid is absorbed maximum from stomach and
Nitrazepam, a weak
base will be absorbed preferrentially from duodenum.
• The solubility of a weakly acidic and weakly basic drug can be increased if
the drug remains in ionized state. So the solubility vs. pH is plotted to get
pH-solubility profile of a drug. While designing a dosage form (oral,
ophthalmic or parenteral) the pH the solution is buffered to that pH
where the solubility is maximum and the drug is reasonably stable.
B.pH‐solubility profile & Common Ion Effect
Compounds with acidic/basic functionalities show pH dependent solubility
profile.
pH=pKa+log[Cs]/[Ca]
pKa—negative log of the ionization const.
[Cs]—molar conc. Of salt form in water
[Ca]—molar conc. Of free acid in water.
Total solubility can be givenas
St=[Ca]+[Cs].
• Determination of Pka:
– Potentiometric Titration
– Spectrophotometric Determination
– Dissolution rate method
– Liquid-Liquid Partition method
Common Ion Effect

Le Châtelier’s principle states that when an equilibrium is out of balance, the reaction will change to put
it back in balance. An equilibrium between a weak acid or base and a common ion will shift in favour of
the reactants. The common ions suppress the ionisation of a weak acid in the presence of a weak base
or acid by producing more comparable product ions. Hence, adding common ions to the solution may
shift the reaction toward the reactant to dismiss excess product stress in the form of precipitation
leading to a decrease in the solubility. For example, the solubility of weakly basic drugs in acidic (HCl)
solution is diminished when they are administered as HCl salts due to Cl common ions. Hydrochloride
salt’s intrinsic dissolution rate evaluation between water, and water containing 1.2% w/v NaCl, and 0.9%
w/v NaCl in 0.05 M HCl medium suggest a common ion interaction pathway. Following this, if the drug’s
solubility has not decreased, the drug can suitable to administer as a chloride salt; otherwise, it should
be discarded. Hence, to get optimum solubility common ions effect must be avoided
Common Ion Effect

• A common interaction with solvent, which often overlooked, is the common ion effect.

• The addition of common ion often reduces the solubility of slightly soluble electrolyte.

• This salting out results from the removal of the water molecule as the solvent due to competing hydration of

other ions.

• So, weakly basic drug which are given as HCL salts have decreased solubility in acidic (HCL) solution.

 Eg.Chlortetracycline, methacyclin, papaverine, cyproheptadine, bromhexine,Triamterene

• To identify a common ion interaction, the intrinsic dissolution rate of hydrochloride salt should be compared

between, Water and water containing 1.2%W/V NACL 0.05M HCL and 0.9%W/V NACL in 0.05M After this, if

solubility is not decreased than we can give drug in chloride salt, otherwise it should be eliminated.
 Thermal effect
We determine the effect of temp. on the solubility of drug candidate. This can
be determined by measuring heat of solution i.e. HS

Where,
dC / dt = dissolution rate
Where, S = molar solubility at temp. T (° K)
R = gas constant.
Heat of solution represents the heat released or absorbed when mole of solute is dissolved in large quantity of solvent.
It is determined from solubility value for saturated solution equilibrated at controlled temperature over the range of
nterested. Typically the temperature range should include 5°C, 25°C, 37°C and 50°C.If heat of solution is positive
(endothermic rocess) thus, increasing solution temp. Increased the drug solubility. For non-electrolyte and un-ionized
form of weak acid and weak bases dissolved in water, heat of solution range from 4 to 8 Kcal/mol.
• Solubilization
• For drug candidates, with either poor water solubility or insufficient
solubility for projected solution dosage form, preformulation study should
include limited experiments to identify possible mechanism for
solubilization.
• Methods for Increasing Solubility:
– Change in pH
– Co-Solvency- use of co solvents like ethanol, PEG, glycerine to increase the
solubility
– Dielectric Constant
– Solubilization by Surfactant
– Complexation
– Hydrotropy
– Chemical Modification of drug
 Addition Of Co-Solvent

• Weak Electrolyte :- Phenobarbitone

• Non polar :- Nitro Cellulose
These are poorly soluble in given solvent.
For such poorly soluble materials, to enhance their solubility, the
water miscible solvents are used in which the drug has good solubility.
This process of improving solubility is known as co-solvency and the
solvent used is known as co- solvents.
 Addition Of Co-Solvent

e.g. Phenobarbitone is insoluble in water. A clear solution is obtained

by dissolving in mixture of Alcohol, Glycerin, Propylene glycol.

e.g. Of Cosolvents:-
PG, glycerin, sorbitol, PEG, Glyceryl formal, glycofurol,
ethyl carbamate, ethyl lactate and dimethyl acetamide.
 pH change Method
Weak base:- Alkaloids, Local Anaesthesia Weak acid:-
Sulphonamides, Barbiturates
In aqueous medium they dissociate poorly and
undissociated portion is insoluble.
e.g. Benzoic acid, Phenobarbitone
So, solubility of the undissociated portion is
improved by pH control.
For weak acidic drug:- increase pH, solubility
is increase.
For weakbase drug:- decrease pH, increase
solubility.
 Reduction Of Particle size

Reduction in Particle size improve solubility of

drug.

Basically reduction in particle size increase contact

surface area of the particle, there by ultimately it
increase rate of solubility of drug.
 Temperatre Change Method

In endothermic reaction by increasing temperature

solubility is increase.

In exothermic reaction by increasing temperature solubility is

decrease.

e.g. Methyl Cellulose when mixed with water and temperature is raised, it
becomes insoluble. To dissolve it cold water is added.
 HYDROTROPHY

The term Hydotrophy has been used to designate the increase in

solubility in water of various substances due to the presences of large
amount of additives.

e.g. Solubilization of Benzoic acid with Sodium benzoate.

 Addition of Surfactant

Surfactants are molecules with well defined polar and non-polar region
that allow them to aggregate in solution to form micelles. Non polar drugs
can partition into micelles and be solubilized.

e.g.Surfactant based solution of Taxol, that is solubilized in 50%

solution of Cremophor.
 Dielectrical Constant

Dielectrical Constant is the effect that substances has, when it acts as a

solvent on the case with which it separates oppositely charged atoms.

e.g. DEC of Water- 80

Kerosene- 2
Glycerine- 48
Benzene- 2.2
 Complexation

For the Complexation occur both drug and ligand molecule should be
able to donate or accept electrons.
The solubility of compound is the sum of solubility of the compound and
its complex.

e.g. HgI2 (Mercuric Iodide) is sparingly soluble in water. Its solubility in

water is increased by forming complex with KI.

HgI2 +2KI K2HgI4 (water soluble)

Applications of solubilization
Drugs with limited aqueous solubility can be solubilized. These
include vitamins, oil-soluble steroid hormones and antimicrobial agents
etc.

Solubilization of orally administered drugs results in an improved

appearance and improves unpleasant taste.

Both oil-soluble and water-soluble compounds can be combined in a

single phase system as in case of multivitamin preparations.
 Applications of solubilization

• Solubilization may lead to enhanced absorption and increased

biological activity.
• Improves the intestinal absorption of vitamin A.
• Drug absorption from ointment bases and suppositories also increased.
• Liquid preparations with small quantity of preservative can be
prepared by solubilization.
Partition Coefficient:
The lipophilicity of an organic compound is usually described in terms of a partition coefficient; log P, which can be
defined as the ratio of the concentration of the unionized compound, at equilibrium, between organic and
aqueous phases:

Methods of finding Partition coefficient:

• Shake-flask method
• Chromatographic method.
• Counter current and filter probe method.
• Microelectrometric titratation method
• Automated instrument is now available.
• This ratio is known as the partition coefficient or distribution coefficient and
is essentially independent of concentration of dilute solutions of a given
solute species.
• logP = 0 means that the compound is equally soluble in water and in the
partitioning solvent. If the compound has a log P = 5, then the compound is
100,000 times more soluble in the partitioning solvent. A log P = –2 means
that the compound is 100 times more soluble in water, i.e., it is quite
hydrophilic.
• Drugs having values of P much greater than 1 are classified as lipophilic,
whereas those with partition coefficients much less than 1 are indicative of
a hydrophilic drug.
• Applications of Partition coefficient:
– Measure of Lipophilic character of molecules.
– Recovery of antibiotics from fermentation broth.
– Extraction of drug from biological fluid for therapeutic monitoring.
– Absorption of drug from dosage forms. (Ointments, Suppositories, Transdermalpatches).
– Study of distribution of flavouring oil between oil & water in emulsion.
 Dissolution rate

The dissolution rate is defined as the quantity of drug substances dissolve per unit of time with
specific circumstances of temperature and solvent conditions for liquid or solid interface. The
process is termed dissolution.
The dissolution rate can be determined with the help of the Noyes-Whitney Equation. The
dissolution rate is the rate-limiting step at the site of absorption for drugs in solution. At the
preformulation stage, scientists understand, how excipients, surface area, and particle size affect
the dissolution behavior of drug substances and ascertain whether the rate-limiting behaviour is
dissolution mediated. The drug dissolution is followed by reaching into the systemic circulation and
is dependent on the type of dosage forms like solid oral (tablets, capsules, and suspensions) and
intramuscular (pellets or suspensions); the rate-limiting factor governs which type of drug
administration route is optimum for a selected dosage form
Dissoltion is of two types:
1. Intrinsic
2. Particulate
Intrinsic Dissolution
The dissolution rate of a solid in its own solution is adequately describedby the Noyes-Nernst equation:

Where,
dC / dt = dissolution rate
A = surface area of the dissolving solid
D = diffusion coefficient
C = solute concentration in the bulk medium
h = diffusion layer thickness
V = volume of the dissolution medium
Cs = solute concentration in the diffusion layer
During the early phase of dissolution, Cs » C and is essentially equal to saturation solubility S. Surface area A and
volume V can be held constant. Under these conditions and at constant temperature and agitation, Equation
reduces to
dC / dt = KS
Where
K =AD/hV = constant.
Dissolution rate as expressed in Equation is termed the intrinsic dissolution rate and is characteristic of each solid
compound in a given solvent under fixed hydrodynamic conditions. The intrinsic dissolution rate in a fixed volume
of solvent is generally expressed as mg dissolved x(min-1 cm- Z). Knowledge of this value helps the
preformulation scientist in predicting if absorption would be dissolution rate-limited.
Particulate dissolution:
It will determine dissolution of drug at different surface area. It is used to study the influence
on dissolution of particle size, surface area and mixing with excipient. So, if particle size has no
influence on dissolution than other method like addition of surfactant will be considered.
 Biopharmaceutical classification(BCS) classification of drugs
• Amidon et al. suggested a Biopharmaceutical classification Scheme which has been used as a preliminary
indication of bioavailability.
• This categorization can be used to establish whether candidate compounds possess physicochemical
properties that are likely to be inferior in terms of bioavailability and hence suggest that further medical
chemistry should be conducted to achieve potentially better bioavailability whilst retaining potency. It also
forms the basis of FDA Regulatory Guidance on the need for bioavailability and bioequivalence studies
Biopharmaceutical Classification System

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.
 Biopharmaceutical Classification System
(BCS)
of drug• substances
Example: metoprolol,
Class I
High Permeability • paracetamol
Those compounds are well absorbed and their
High Solubility absorption rate is usually higher than excretion.

• Example: glibenclamide, bicalutamide,

Class II ezetimibe, aceclofenac
• The bioavailability of those
High permeability
limited
productsby their solvation
is rate. A
Low solubility correlation the in vivo bioavailability
between
and
the in vitro solvation can be found.
Class III • Example: cimetidine
Low • The absorption is limited by the
permeability formulation
permeation does not change
permeability
rate but the drug
the or is solvated very
gastro-
High solubility time,
fast. Ifthen
the class
intestinal I criteria can be
duration
Class IV • applied.
Example:
• Those
Bifonazolecompounds have a
Low bioavailability. Usually they are not
permeability, poor
well absorbed over the intestinal
Low solubility mucosa and a high variability is
 Biopharmaceutical Classification System
(BCS) (as defined by the FDA after Amidon
et al.)
 High Solubility Low Solubility

Cl ass Im ip ra m in e Cl ass
1 I
Ket or ol 2 S,
Abacavir Am i o d a r o I Itr
ac I
A ceta m ino p he n Ator
n e vas ta ti n S , I aKceot n
oac zoonl ea z o l e
Ketoprofen I
Ac y c lo v ir b Az i t h r o m y c i n S , I Lansopr
I
Labetolol S,
Amiloride S , I Carbamazepin Lovastatin
azole
Levodopa S I
A m itryp ty lin e S , e S, I Mebendazole
Le vo flo
I
Chlorpromazine
C a r ve d i l o l I Nap ro x en
xac in S Nelfinavir SI ,
Antipyrine Lidocaine Cisapr ide S
High Permeability

Atropine I Ciprofloxacin S Ofloxacin

Buspir one c Lomefloxac C yc l o s p o r i n S, I
Caffeine e Danazol Oxa p ro z i n
Phenazopyridine
in
C
Captopril S,
Dapson Phenytoin S
I M eper
C hro
hlo lor
q uph
ine e Piroxicam
idine
eniramine Dic lo fe na c R a lo xife n e S
Metoprolol
Ni fedi pi ne S
C y c lo p h o s p h a mid e Digo xin S
Diflunisal Ritonavir S ,
M e t ro nid a z o
Phenobarbital
Desipramine Er y th ro my c in S , I Saqui navi Ir SI ,
le M idazo
Phenylalanine S
D il a
Di z eem
ti az pam S,
Flurbiprofen Sir olim
I la m S, I M
Prednisolone
D i p h e n h yd r a m Glipizide Spironolactone
us I
i nrim
P o c yc
a ql i u
n ei n e S,
ine Gl ybur i d e S , Ta c r o l i m
Misoprostol
S
S
I
Disopyramide I
Griseofulvin Talinolol
us
Promazine
Doxepin Ibuprofen Ta m o x i f I
Propranolol I Te I
Do xyc y c lin e Indinavir S e nr
Q u ini d i n e
Enalapril Indomethacin fenadine
S,I
R
Ephedrine Warfarin
o sig lita z o ne
Ergonovine Salicylic acid
Theophylline
Ve r ap am i I
Etha mb u t o l
lValproic acid
Ethinyl
Zidovudine
 High solubility Low solubility
Class 3
Acyclovir Fexofenadi Class 4
Amiloride ne Folinic aci
Amphotericin
Amoxicillin Furosemide d
B
Atenolol Ganciclovir
Chlorthalidone
Atropine Hydrochlorothiazi
Chlorothiazide
Low Permeability

Bisphosphon de
Colistin
ates Lisinopril
Ciprofloxacin
Bidisomide Metformin Furosemide
Hydrochlorothi
Captopril Methotrexa
de
azi
Cefazolin te Nadolol
Mebendazole
Methotrex
Cetirizine Pravastatin
ate
Cimetidine S Penicillins
Neomycin
Ciprofloxacin Ranitidine
Cloxacillin Tetracycline
Dicloxacillin
Erythromycin Trimethopr
Famotidine im
Valsartan
 Class–I High Solubility High Permeability

• Drugs dissolved rapidly

• Drugs absorbed rapidly
• Rapid therapeutic action
• Excellent property
• Ideal for oral route
• e.g. Metoprolol, Diltiazem, Verapamil,
Propranolol,
 Class – II Low Solubility High Permeability
• Drugs dissolve slowly
• Drugs absorbed rapidly
• Controlled released drugs
• Oral / IV route for administration
• E.g. Glibenclamide, Ezetimibe, Phenytoin,
Nifedipine
Class – III High Solubility Low
Permeability
• Dissolved rapidly
• Absorbance is limited
• Incomplete bioavailability
• Oral / IV route for
administration
• Ex. Cimetidine, Acyclovir,
Captopril
 Class – IV-Low Solubility Low Permeability

• Low dissolution rate

• Low permeability
property
• Slow or low therapeutic
action
• IV or other routes are
required
• Ex. Hydrochlorothiazide
 BCS can be used as a key component to guide drug
delivery system design for any route of administration
 Significance of BCS Class

• Regulatory tool for replacement of certain BE studies.

• It can save both time and money—if the immediate -release, orally
administered drug meets specific criteria, the FDA will grant a waiver for
expensive and time-consuming bio- equivalence studies.
• Valuable tool for formulation scientist for selection of design of formulated drug
substance.
• When integrated with other information provide a
tremendous tool for efficient drug
development.
• Reduces cost and time of approving Scale- up and post approval challenges.
• Applicable in both pre-clinical and clinical drug development process.
Stability Studies
Clearly, the stability of a drug (and of formulation excipients) is critically important to ensure that the patient
receives the correct dose of the active ingredient. Furthermore, for those drugs that can degrade to produce
toxic materials, it is essential to determine the conditions under which this might occur so as to find methods
of prevention or stabilization and/or to determine limitations in terms of shelf life and storage conditions. In
addition, the stability of excipients and their stability in combination with other excipients and drug substances can
be a critical factor in achieving a stable marketable product, e.g. the stability of antimicrobial or antioxidant
preservatives in liquid formulations. Degradation can occur through a number of chemical/physiochemical and
biological pathways.
e.g.
● hydrolysis
● isomerisation
● oxidation
● polymerisation
● solid-state phase transformation
● dehydration or desolvation
● cyclization
● photolytic degradation
● microbial attack
ICH (International Conference on Harmonisation of Regulatory Requirements) Drug stability test
guideline Q1A (R2) requires that the drug substance be tested under different stress conditions. It is
suggested that stress testing include the effect of
● pH
● Temperature
● Humidity
● Light
● Oxidizing agents
Chemical degradation in Solution

1. Temperature
The chemical stability of a drug substance in the solid state can be evaluated under various temperature
and humidity stress conditions. Pre-weighed samples are stored in stability cabinets in open vials or thin
layers for periods of up 8 weeks under conditions such as:
● 40 °C
● 60 °C
● 80 °C
● 25 °C 85% RH
● 40 °C 75% RH
 Chemical Properties of Drug Substances
a)Oxidation & Reduction
b)Hydrolysis c)Photolysis
d)Racemisation

e)Polymerization
f)Isomerisation
Oxidation:
It is very common pathway for drug degradation in both
liquid and solid formulation.
Oxidation is the gain of oxygen, loss of hydrogen and/or
loss of electrons.

When iron reacts with oxygen it forms a chemical called

rust. The iron is oxidized and the oxygen is reduced.

Oxidation occurs in two ways

 Auto oxidation
 Free radical oxidation
 Functional group having high susceptibility towards
oxidation:-
• Substituted aromatic group (Toluene, Phenols,
Anisole).
• Alkenes
• Ethers
• Thioethers
• Amines
Factors affecting oxidation process

1) Oxygen concentration
2) Light
3) Heavy metals particularly those having
two or more
valence state
4) Hydrogen & Hydroxyl Ion
5) Temperature
How to prevent oxidation?

1.Reducing oxygen content

2.Storage in a dark and cool condition
3.Addition of chelating agent (Eg. EDTA, Citric acid,
Tartaric acid)
4.Adjustment of pH
5.Changing solvent (Eg. Aldehydes, ethers, Ketones, may
influence free radical reaction)
6.Addition of an antioxidant or reducing agent (e.g. H2,
CO, Zn etc)
 Hydrolysis
o It is the cleavage of chemical bonds by the addition of water.
o The reaction of water with another chemical compound to form two or
more products, involving ionization of the water molecule usually
splitting the other compound.

• Examples include :
o the catalytic conversion of starch to glucose,
o saponification, and
o the formation of acids or bases from dissolved ions.
• When this attack is by a solvent other than water then it is known as
solvolysis.
 Conditions that catalysis the breakdown are:
1. Presence of hydroxyl ion
2. Presence of hydride ion
3. Presence of divalent ion
4. Heat
5. Light
6. Ionic hydrolysis
7. Solution polarity and ionic
strength
8. High drug concentration
 Prevention of hydrolysis:
 pH Adjustment

o Formulate the drug solution close to its pH of optimum stability.

o Addition of water miscible solvent in formulation.
o Optimum buffer concentration.

 Addition of surfactant

o Nonionic, cationic, and anionic surfactant stabilizes the drug against

base catalysis.

 Salts and Esters Eg. Phosphate esters of clindamycine

o The solubility of pharmaceuticals undergoing ester hydrolysis can be

reduced by
forming less soluble salts.

o By use of complexing agent.

 Photodecomposition pathway

• N-Dealkylation
Di-phenylhydramine, Chloroquine, Methotrexate

• Dehalogination
Chlorpropamide, Furosemide

• Dehydrogenation of Ca++channel blocker

Solution of Nifedipine

• Oxidation
Chlorpromazine & other Phenothiazines give N- &
S- oxides in the presence of sunlight
 Prevention of Photodecomposition
o Suitable packing.
Yellow-green glass gives the best protection in U.V. region while Amber
gives
considerable protection against U.V. radiation but little from I.R.
o Protection of drug from light
Nifedipine is manufactured under Na light.
o Avoiding sunbath
 Racemization
• It is the process in which one
enantiomer of a compound, such as
an L-amino acid, converts to the
other enantiomer.

• The compound then alternates

between each form while the ratio
between the (+) and (–) groups
approaches 1:1, at which point it
becomes optically inactive.

• If the racemization results in a mixture

where the enantiomers are present in
equal quantities, the resulting sample
is described as racemeric or a
 The inter-conversion from one isomer to another can lead to different
pharmacokinetic
properties (ADME) as well as different pharmacological & toxicological effect.

 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.

 It depends on
• Temperature,
• Solvent,
• Catalyst &
• Presence or absence of light
• Biological significance:
• Many psychotropic drugs show differing activity or efficacy between isomers,
e.g. Amphetamine is often dispensed as racemic salts while the more active
dextro- amphetamine is reserved for severe indications;
• Another example is Methadone, of which one isomer has activity as an opioid
agonist and the other as an NMDA antagonist.
 Polymerization

• Polymerization is a process of reacting monomer molecules together in a chemical reaction

to form polymer chains or three-dimensional networks.

• It is a continuous reaction between molecules.

• More than one monomer reacts to form a polymer.

• Darkening of glucose solution is due to polymerization of breakdown product [5- (hydroxyl

methyl)
furfural. (a colorless liquid used in synthetic resin manufacture).
• Eg. Shellac on aging undergoes polymerization & hence prolongs disintegration time &
dissolution time.
 Isomerization
 Is the process by which one molecule is transformed into another
molecule which has
exactly the same atoms, but the atoms have a different arrangement.
e.g. A-B-C → B-A-C (these related molecules are known as isomers).

Examples:-
o Tetracycline & its derivatives can undergo reversible Isomerization at pH
range 2-6.

o Trans-cis Isomerization of Amphotericin B.

 Significance

Isomerism finds its importance in the field of clinical pharmacotherapeutics, as

pharmacology and isomers
differ in their pharmacokinetic and pharmacodyanmic
• Cetrizine to levocetrizine is one of such examples, where effective and safer drug has been
properties.
made available.
• Levocetrizine has smaller volume of distribution than its dextroisomer.
• Esomeprazole is more bioavailable than racemic omeprazole;
• STABILITY STUDIES
– Solid State Stability Studies:
Solid state reactions are much slower and more difficult to interpret than solution state reactions, due
to a reduced no. of molecular contacts between drug and excipient molecules and to the occurrence of
multiple phase reactions.
– Solution State Stability Studies :
It is easier to detect liquid state reactions as compared to solid state reactions. For detection of unknown
liquid incompatibilities, the program set up is same as solid dosage forms. Now according to:
– Stability guidelines by FDA states that:
• Following conditions be evaluated in studies on solutions or suspensions of bulk drug substances:
– Acidic or alkaline pH.
– Presence of added substances- chelating agents, stabilizers etc.
– High Oxygen and Nitrogen atmospheres.
– Effect of stress testing condition
• Drug-Excipient Compatibility Studies
– Stability of the dosage form can be maximized. Any physical or chemical
interaction between drug and excipient can affect bioavailability and stability of
drug.
– It helps to avoid the surprise problems. By performing DECS we can know the
possible reaction before formulating final dosage form.
– It bridges the drug discovery and drug development. Drug discovery can emerge
only new chemical entity. It becomes drug product after formulation and
processing with excipients.
– By using DECS data we can select the suitable type of the excipient with the
chemical entities emerging in drug iscovery programs. DECS data is essential for
IND (investigational new drug ) submission. Now, USFDA has made it compulsory
to submit DECS data for any new coming formulation before its approval.
Drugs are often made into their chemical salt forms to enhance how the drug dissolves,
boost its absorption into your bloodstream, and increase the effectiveness. Without
absorption, a drug cannot have a therapeutic effect, so some forms require a salt. Many
medications also need a salt attached to be water-soluble.
Like Diclofenac sodium is more soluble than diclofenac
 Crystal habit

• Crystal engineering studies are important in the pharmaceutical industry to

develop stable and robust solid dosage forms.
• Solid-state properties have a great impact on physicochemical and
biopharmaceutical properties of drugs.
• The solid state is important as it affects filtration, flow, tableting and
dissolution.
• Although there may not be significant differences in bioavailability of drugs
with different crystal habits, it is of importance from a technological point of
view.
• The injection of a suspension-containing drug in crystal form is influenced by its
habit. Crystal habit also influences the ease of compression of the tablet and
the flow properties of the solid form of the drug.
• For example, plate-like crystals of tolbutamide created powder-bridging in
the hopper of the tablet machine and also led to capping problems during
tableting.
• Bristol-Myers Squibb recalled antihypertensive combination of
hydrochlorothiazide and irbesartan due to problems associated with
dissolution of irbesartan. This reduced solubility of irbesartan in certain
batches was the result of formation of a secondary crystal form of
irbesartan.
• The formation of the less soluble crystal form was due to tablet
manufacturing changes. Detailed investigations revealed that an increase in
granulation time resulted in formation of these secondary crystals.
Crystal habit can be modified by

• Excessive supersaturation, which tends to transform a prism or isodiametric

(granular) crystals to a needle shape.
• Cooling rate and agitation, which changes habit as it changes the degree of
supersaturation. Naphthalene gives thin plates (platy) if rapidly
recrystallized in cold ethanol or methanol, whereas slow evaporation yields
prisms.
• The crystallizing solvent affects habit by preferential absorption on to
certain faces, inhibiting their growth. Resorcinol produces needles from
benzene and squat prisms from butyl acetate.
• The addition of cosolvents or other solutes and ions which change habit by
poisoning crystal growth in one or more directions. Sodium chloride is
usually cubic, but urea produces an octahedral habit.
 Technique Particle size (micro meters)
Microscopic 1-100
Sieve >5
Sedimentation >1
Elutriation 1-50
Centrifugal <50
Permeability >1
light scattering 0.5-50

Powder flow properties

Angle of repose Density Compressibility

Need of Dosage forms
 To provide mechanism for the safe & convenient delivery of accurate dose.

 To protect from environment i.e. destructive effect of oxygen or humidity.

 To protect from the destructive effect of gastric acid after oral

administration Ex. Enteric coated tablet.
 To conceal the bitter, salty, nauseous odor of drug substance. Ex. Capsule,
Coated tablet.
 To provide liquid preparation which are unstable or insoluble in vehicle. Ex.
Suspension
 To provide clear dosage forms of substance. Ex. Syrups , Solutions

 To provide rate controlled drug action. Ex. Sustained Release & Controlled
release Tablets
 To provide optimal drug action from topical administration. Ex. Ointments,
 What we identify
• The preformulation study gave the ideas for characteristics new drug.

• It’s behavior with other excipients and materials.

• Stability of drug in different environments.

• Physical and chemical nature of the drug

• Ideas for probable dosage form and it’s delivery system

 Steps for preformulation study:-

• Pre formulation study • Analytical Study

• Compound identity o HPLC Assay
o TLC Assay
• Formula &amp; Molecular
o UV/ VIS Sprectroscopy
Weight o Synthetic Routes
• Therapeutic Indication o Probably decay product
o Probable Humane Dose • Key dates
o Desired Dosage form o Bulk scale up
o Bioavailability Model o Toxicology study
o Competitive Products o Clinical supplies
• Potential Hazards preparation
• Initial Bulk study o IND filling
– Lot number o Phase I testing
– Crystallization solvents
– Particle size
• Critical development steps
– Melting Point
– % Volatilities
– Observation
Flow diagram of the multidisciplinary development of drug
 Main Principal area of Preformulation study

• Bulk characterization: • Stability analysis

 Crystallinity & polymorphism,  Solution stability
 Hygroscopicity,  pH rate profile
 Fine particle characterization,  Solid state stability
 Powder flow properties.  Bulk stability
• Solubility analysis:  Stability in toxicology
 Ionization constant –Pka formulation
 pH solubility profile
 Common ion effect-Ksp
 Solubilization
 Dissolution,
 Partition co-efficient
2.pH-dependent Stability
Stability tests should also be performed under several physiological and formulation pH
conditions in order to understand the characteristics of the drug candidate under physiological
conditions and to provide key information for the formulation of solution dosage forms.
Typically this would involve measuring stability at 37 °C in a range of buffer solutions e.g. pH 1,
pH 4, pH 7 and pH 9 at intervals from 1 day up to 1 month. The studies should be designed using
reasonable concentration of drug or excipient to detect even minor decomposition products in the
range of detection.

3. Hydrolytic Degradation
• Hydrolysis can occur in many molecular species but particularly for carboxylic acid derivatives
or substances containing a functional group based on carboxylic acid, e.g. ester, amide, lactone,
lactam, imide and carbamate.
• To identify and quantify potential degradation by this route, samples of the compound should
be subject to stress testing in acidic and alkaline conditions, e.g. refluxing the drug in 0.1 N HCl
and 0.1 N NaOH for 8–12 hours.