Preformulation studies(unit 1)

PREFORMULATIONstudies and bcs
classification
Prepared By:
MOHAMMAD KHALID
(Assistant Professor)
Krishna Pharmacy College, Bijnor (UP)

INTRODUCTION
Preformulation studies are the investigations of
physical and chemical properties of a drug
substance, alone and in combination with other
excipients,
Characterization of physical, chemical and
mechanical properties of new drug molecule in
order to develop safe, effective , and stable
dosage form.
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Preformulation is branch of Pharmaceutical
science that utilizes biopharmaceutical principles
in the determination of physicochemical properties
of the drug substance.
Prior to the development of any dosage form new
drug , it is essential that certain fundamental
physical & chemical properties of drug powder are
determined .
This information may dictate many of subsequent
event & approaches in formulation development.
This first learning phase is called as preformulation.

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Objectives of preformulation studies
To generate useful data needed in developing stable and
safe dosage forms that can be manufactured on a
commercial scale.
To provide in-depth knowledge and understanding of
the physical characteristics of a candidate drug molecule
prior to dosage form development.
To generate useful information on how to design a drug
delivery system with good bioavailability.
Preparation of safe, effective and stable dosage form
with better therapeutic values.

Goals of Preformulation studies
To establish the physicochemical
parameters of a candidate drug molecule.
To determine the kinetic rate profile of drug
substances.
To establish the compatibility of a candidate
drug molecule with common excipients.

Classes of preformulation studies
a. Fundamental preformulation studies:
These studies are specific to candidate drug molecules and it include
solubility analysis (e.g., ionization constant, partition coefficient,
solubilization, thermal effect, common ion effect, dissolution etc.),
solid state properties (e.g., polymorphism, solvated forms and
amorphous form ), stability analysis (e.g., solution-state stability and
solid-state stability) and permeability studies. These studies are
dependent on the chemical structure of the candidate drug molecule.
b. Derived preformulation studies:
These studies include characterization of particle properties (e.g.,
particle size and particle shape), bulk density, powder flow
properties, compaction behaviour etc. They are carried out on the
intended dosage form.

What to consider before starting a preformulation study
Before embarking on preformulation studies, scientists
must consider-
The available physicochemical data including chemical
structure, different salts, potency relative to the
competitive products and the dosage form etc.
Anticipated dose and the proposed route of drug
administration.
Supply situation and development schedule.
Availability indicating assay.

Evaluated parameters in preformulation
studies
a. Physical characteristics
Organoleptic properties of the candidate drug molecule e.g.,
colour, odour and taste.
Bulk characterization e.g., particle size and surface area,
powder flow properties, density, compressibility, crystallinity,
polymorphism and hygroscopicity.
Solubility analysis e.g., ionization constant/ drug Pka, partition
coefficient, solubilization, thermal effect, common ion effect
(Ksp) and dissolution.
Stability analysis e.g., solution-state stability testing, solid-state
stability testing, and drug-excipient compatibility studies.

Continue…
b. Chemical characteristics
Hydrolysis
Oxidation
Reduction
Racemization
Polymerization
Isomerization
Photostability

ORGANOLEPTIC CHARACTERS
“Organoleptic properties are those properties
which are evaluated after an impression on
the organs of sense.”
Colour,odour, taste of the new drug must be
recorded.

Colour
Colour can be useful, while describing different
batches of drug, it can sometimes be used as an
indicator of solvent presence or more importantly
of degradation.
In addition minute difference in colour due to
particle size distribution.
Colour of various drug formulation may indicate
the degradation process, the colour of certain types
of formulation can be improved by adding certain
dyes

odour

Physical form (crystal & amorphous)

Different types of crystal

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Difference between crystalline and amorphous form
Crystalline form Amorphous form
 Have fixed internal structure. Do not have any fixed internal
structure.
More stable than its amorphous
forms.
Less stable than its crystalline
forms.
Has lesser solubility than its
amorphous form.
Have greater solubility than its
crystalline forms.
Lesser tendency to change its
form during storage.
Tend to revert to more stable
forms during storage.

Continue….

Polymorphism
It is the ability of the compound to crystallize as more than
one distinct crystalline species with different internal
lattice.
Different crystalline forms are called polymorphs.
Polymorphs are of 2 types 1. Enatiotropic 2. Monotropic
The polymorph which can be changed from one form into
another by varying temp or pressure is called as
Enantiotropic polymorph. Eg. Sulphur.
One polymorph which is unstable at all temp. & pressure
is called as Monotropic polymorph. Eg. Glyceryl stearate.

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Polymorphs differ from each other with
respect to their physical property such as
Solubility
Melting point
Density
Hardness
Compression characteristic
Eg. Chloromphenicol exist in A,B & C forms, of
these B form is more stable & most preferable.

Methods to identify polymorphism
Optical crystallography
Hot 0stage microscopy
X- Ray Diffraction method
NMR technique
FTIR technique.
Microcalorimetry
Thermal methods
Melting point determination

PROPERTIES OF POLYMORPHS
Polymorphs show the same properties in liquid or gaseous state but
they behave differently in solid state.
Polymorphs differ from each other with respect to physical
properties like
Melting and sublimation temperature
Vapour pressure
Solubility and dissolution rate
Stability
Optical and electrical properties
Crystal habit
Hygroscopicity
Heat capacity
Solid – state reactions
Conductivity
Compression characteristics

Particle size and shape
Not only effect only physical properties of
solid drug but also, in some instances effect
on the biopharmaceutical behavior
Size, shape & surface morphology of drug
particles affect
Flow property
Dissolution
Chemical reactivity of drugs

Significance of particle size
1. Particle size of drug may affect formulation and product efficacy
2. Particle size can influence variety of important factors
a. The particle size
b. Drug dissolution rate
c. Content uniformity
d. Texture
e. Stability
f. Flow characteristics
g. Sedimentation rates
h. Penetrability
i. Suspendability
3. Particle size significantly influences the oral absorption profile of certain drugs
4. Satisfactory content uniformity in solid dosage forms depends to a large degree
on particle size and the equal distribution of active ingredients throughout the
formulation25 August 2020 Krishna Pharmacy College, Bijnor 26

particle size continue….
Particle size is characterized using these terms :
Very coarse, Coarse, Moderately coarse, Fine ,Very
fine .
Methods to Determine Particle Size :
Sieving (5µ-150µ)
Microscopy (0.2µ-100µ)
Sedimentation rate method (1µ-200µ)
Light energy diffraction (0.5µ-500µ)
Laser holography (1.4µ-100µ)

HOWEVER SIZE REDUCTION IS NOT REQUIRED
IN FOLLOWING CASES
When drug is unstable.
Degrade in solution form.
Produce undesirable effects.
When sustained effect is desired

POWDER FLOW PROPERTIES
Powder flow properties can be affected by change in
particle size, shape & density.
The flow properties depends upon following-
1. Force of friction.
2. Cohesion between one particle to another.
Fine particle posses poor flow by filling void spaces
between larger particles causing packing &
densification of particles.
By using glident we can alter the flow properties. e.g.
Talc

Determination of Powder Flow Properties
By determining Angle of
Repose.
A greater angle of repose
indicate poor flow.
It should be less than 30°. &
can be determined by
following equation.
tan θ = h/r.
where, θ = angle of repose.
h=height of pile.
r= radius.

Methods to determine angle of repose
Static angle of repose
Fixed-funnel method
Fixed-cone method
Kinetic or dynamic
method
Rotating cylinder
method
Tilting box method

Determination of Powder Flow Properties

HYGROSCOPICITY
Many drug substances, particularly water –soluble salt forms,
have a tendency to adsorb atmospheric moisture.
Adsorption and moisture content depend upon the atmospheric
humidity, temperature, surface area, exposure and the
mechanism of moisture uptake.
The degree of Hygroscopicity is classified into four classes:
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 adsorbed to form a solution

solubility
Solution phase equilibrium with solid phase at a stated temperature and
pressure .
Determines amount of drug dissolved , amount of drug available for
absorption.
Solubility reduction is carried out in certain conditions:
Enhancement of chemical stability.
taste masking products.
Production of sustained release products.
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Continue….
The equilibrium solubility is based on the phase-solubility
technique proposed by Higuchi-Connors.
Method
Drug dispersed in solvent in a closed container
agitated at a constant temperature using shakers
samples of the slurry are withdrawn as a function of time
clarified by centrifugation and assayed by HPLC, UV, GC etc

Continue….
 It is important for orally administered drugs or
drugs needed to be converted into solutions.
 It includes:
 pKa determinations
 pH solubility profile and common ion effects
 Effect of temperature
 Solubilization
 Partition coefficient
 Dissolution

General Method of Increasing the Solubility
Addition of co-solvent
pH change method
Reduction of particle size
Temperature change method
Hydotrophy
Addition of Surfactant
Dielectrical Constant
Complexation

pKa determination
pKa is the dissociation constant of a drug
The un-ionized drug is lipid soluble thus permeates through lipid
membrane.
The ionized substance is lipid insoluble therefore permeation is slow
Degree of ionization depends on pH
38

Continue….
It is important for drugs capable of ionization within a pH range
(1-10), since solubility and then absorption can be changed by
pH changes.
As example, for a weakly acidic drug with pka value greater than
3, the unionized form is present within the acidic contents of the
stomach, but the drug is ionized predominantly in the neutral
media of the intestine.
for basic drugs such as erythromycin, (pka ˜ 8-9), the ionized
form is predominant in both the stomach and intestine.

Partition Coefficient
Ratio of unionized drug distributed between the
organic & inorganic aqueous phase at equilibrium.
Importance
Screening for biological
Drug delivery
System used are
Octanol/water and Chloroform/water

Methods of finding Partition coefficient:
Shake-flask method
Chromatographic method.
Counter current and filter probe method.
Tomlinson’s filter probe method.
Micro electro-metric titratation method
Automated instrument is now available.
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.

pH Solubility Profile & Common Ion
Effects
Solubility of an acidic or basic drug depends
on-
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
Dissolution is an important step during preformulation
studies because the rate of drug dissolution of a drug will
exert a direct impact on bioavailability and drug delivery
aspects (Bergstrom et al., 2014).
Dissolution can be defined as the process through which
drug particles tend to dissolve in the body fluids. Any
change in drug dissolution will significantly affect the
bioavailability.
Dissolution of a drug particle is controlled by several
physicochemical properties, including chemical form,
crystal habit, particle size, surface area, solubility and
wetting properties.

Continue….
The modified Noyes–Whitney equation describes the drug
dissolution in which surface area is constant during disintegration.
Dc/dt=DA/hV x (CS−C)
where,
D=diffusion coefficient of the drug in the dissolution medium.
h=thickness of the diffusion layer at the solid/liquid interface.
A=surface area of drug exposed to dissolution medium.
V=volume of the medium.
CS=Concentration of saturated solution of the solute in the
dissolution medium at the experimental temperature.
C=Concentration of drug in solution at time t.
When A=constant and CS≫C

Permeability
Once in solution in physiological fluids e.g. gastric juices or plasma, a
drug must permeate cells and tissues to reach its target site of action.
This will involve passive and/or active transport mechanisms. For
passive diffusion the drug will need to partition with the lipid
components of cells and/or diffuse through aqueous pores in tissues.
An index of its permeability can be obtained in vitro by measuring the
permeability across a model membrane at a constant temperature,
Typically the drug in solution is placed in one side of a two-
compartment cell separated from the second compartment by a
polymeric membrane, the second compartment containing a
physiological representation fluid, e.g. normal saline.
The amount of drug permeating through the membrane can be measured
at various time intervals. A variety of membranes may be chosen each
differing in their lipid composition.

Hydrolysis
Hydrolysis involves reaction of a molecule with
water resulting in cleavage of a chemical bond
within the molecule.
If readily hydrolyzable functional groups are
available, then reaction proceeds even at faster
rates, making the molecule ineffective.
Molecules containing esters and amide functional
groups are prone to hydrolysis and especially the
ester derivatives, which may lead to formation of
carboxylic acid or an alcohol.

Effectiveness of molecule therefore depends on hydrolytic
stability of molecule.
For example, lidocaine is amide derivative of procaine, which is ester
derivative used as local anesthetic. As ester derivative is more readily
hydrolyzed; its duration of action is short while amide derivative is more
stable and hence used as long-acting local anesthetic.
Beta-lactam antibiotics are susceptible to hydrolysis and hence they are
supplied as dry powder injection where they are reconstituted before
intravenous administration.
Continue….

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

oxidation
It is a very common pathway for drug degradation in liquid and solid
formulations. Oxidation occurs in two ways
1. Auto- oxidation
2. Free radical chain process.
Reaction of any material with molecular oxygen producing free radicals
by hemolytic bond fission of a covalent bond. These radicals are highly
unsaturated 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.
Factors affecting oxidation process are Oxygen concentration, light,
heavy metals particularly those having two or more valence state
(copper, iron, nickel, cobalt), hydrogen and hydroxyl ion, temperature.

Continue….
Oxidation can be Prevented by Reducing oxygen content-oxidative
degradation of drug takes place in an aqueous solution, so the oxygen
content can be decreased by boiling water or by storing the
formulation in in a dark and cool condition or by addition of an
antioxidant/ reducing agent /chain inhibitors of radical induced
decomposition.
Antioxidants are of two types based on Solubility.
Oil soluble and Water soluble.
Oil Soluble Antioxidants are Free radical acceptors and inhibit free
radical chain process
eg: hydroquinone, propylgallate, lecithin whereas
Water soluble Antioxidants Oxidizes itself and prevents oxidation of
drug
Eg: sodium metabisulphate, sodium bisulfate, thioglycolic acid, thioglycerol.
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Reduction
Reduction is a relatively morecommon pathway of drug
metabolic process.
Hepatic microsomescatalyze diverse reductive chemical
reaction* and require NADPHfor this purpose. Azo and nitro
reduction is catalyzed by cytochrome P-450.
Chloral hydrate is reduced to it’s active metabolite
trichloroethanol by alcohol dehydrogenase.
Reduction of prednisolone and cortisone results in the
formation of their active metabolites hydrocortisone.
Azo dyes used as coloring agents in pharmaceutical products
or food are reduced to form amines in the liver and by the
intestinal flora.

Racemization
It is an event where optically active molecule becomes inactive without any
change in molecular composition.
Such study is of highest importance when racemic mixture form is used.
The interconversion from one 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 activity
ofracemic mixture is just one half of the L-form.
It follows first order kinetics.
It depends on temperature, solvent, catalyst & presence or absence of light.
Racemization is mostly affected by the conditions like pH, type of solvents,
presence of light, and temperature.
So main goal in this study is to design optimum condition in which
molecule can remain stable

Polymerization
It is a continuous reaction between molecules.
More than one monomer reacts to form a
polymer.
Eg. Darkening of glucose solution is attributed to
polymerization of breakdown product [5-
(hydroxyl methyl) furfural].
Eg. Polymerization of HCHO to para-HCHO
which crystallizes out from the solution.

Photolysis
Electronic configuration of drug overlaps with the spectrum of
sunlight or any artificial light where energy is absorbed by the
electron resulting in excitation.
As they are unstable, they release the acquired energy and return
to the ground state by decomposing the drug.
The phenomenon where molecules or excipients which absorb
energy but donot participate themselves directly in the reaction
but transfer the energy to others which cause cellular damage by
inducing radical formation is known as photosensitization.
Photosentizer Convert oxygen from its ground state to singlet
excited state and Generate superoxide molecule which is an anion
radical and acts as a powerful oxidizing agents.

Photo Decomposition Pathway
N-dealkylation: eg:Dipenhydramine, Chloroquine, Methotrexate
Dehalogenation: eg:-Chlorpropamide, Furesemide
Dehydrogenation of ca++ channel blockers
Decarboxylation in anti-inflammatory drugs: Naproxen,
Flurbiprofen, Benzoxaprofen
Oxidation:- Chlorpromazine and other phenothiazines give n-
oxides in the presence of sunlight.
Isomerization and cyclization:-Noradrenaline, Doxapine
Rearrangement: Metronidazole and oxidiazine yellow color
Photodecomposition canbe Prevented by-suitable packing,
antioxidant, protection of drug from light, avoiding sunbath,
photostabilizer, coating

Testing scope for Solid dosage (Tablet & Capsule)
Physical-chemical properties –
Appearance
Elasticity
Mean mass
Moisture
Hardness
Disintegration
Dissolution
Chemical properties –
Assay
Degradation
Microbial properties
Container closure system properties –
Functionality tests (e.g. extraction from blister)

Testing scope for Oral liquid form
pH
Color & clarity of solution
Viscosity
Particle size distribution (for oral suspensions only)
Assay
Degradation products
Degradation preservatives
Content antioxidants
Container closure system properties
Functionality tests

Testing scope for LIQUID FORMS ( injection and
PARENTRAL)
pH
Loss on weight
Color & clarity of solution
Chemical properties
Assay
Degradation products
Degradation preservatives
Content antioxidants
Functionality tests

Testing scope for
(SEMI LIQUID FORMS)
Appearance, odor, homogenesity, consistency
Loss on weight, Viscosity
Content uniformity (within the container)
Assay
Degradation products & preservatives
Content preservatives
Degradation-Content antioxidants
Functionality tests

Why stability analysis/ testing?
To generate useful information on how
environmental factors e.g., temperature, humidity,
light etc. influence the quality of drug products over
time.
To establish the how physical, chemical and
microbiological changes influence the effectiveness,
safety and stability of the final drug product.
To recommend storage conditions, establish a retest
period, and shelf life of drug products

Factors influencing drug stability
Temperature or thermal effect
Moisture and relative humidity
Light and radiation energy
pH
Presence of reacting solvents
Order of reaction
Microorganisms
Chemical nature of the drug or excipient
Ionic strength
General acid-base catalysis
Presence of trace metals, oxygen, and oxidizing agents

Significant changes that might occur during stability
analysis
Physical changes – changes in the physical
appearance of the drug product, melting point,
clarity and color of solutions, crystal modification
(polymorphism) and particle size, etc.
Chemical changes – increased degradation and
decrease API (Active Pharmaceutical Ingredient)
assay
Microbial changes – increased microbial load/
microbial contamination.

Stability analysis
 Is usually the first quantitative assessment of
chemical stability of a new drug.
 It includes both solution and solid state experiments
under conditions typical for the handling,
formulation, storage and administration of a drug
candidate.
 Generally, it includes:
1. Stability in toxicology formulations
2. Solution stability
3. Solid state stability25 August 2020 Krishna Pharmacy College, Bijnor 63

Stability in toxicology formulations
 A drug is administered to the animal in their feed,
or by oral gavage of a solution or suspension of the
drug in an aqueous vehicle.
 Water, vitamins, minerals (metal ions), enzymes and
a multitude of functional groups are present in feed,
which can severely reduce the shelf- life of a drug.
 Solution and suspension formulations are checked
for ease of manufacture and then stored in flame-
sealed ampoules at various temperatures.

Solution stability
 It is important for identification of conditions necessary to
form a stable solution including the effects of (pH, ionic
strength, co-solvent, light, temperature and oxygen).
 pH for maximum stability is determined using different
types of buffers at constant conditions(?).
Rate(K)
Acid-base catalysis
(pH rate profile)

 Ionic strength depends on the molar concentrations
of ion (with valency), it must be constant specially
for injectable solutions (about 0.15).
 Co-solvent can affect solubility and stability
(hydrolysis prevention), solvents effects originated
from dielectric constants values?, toxicity and
compatibility. So the selected cosolvent must be
selected at controlled conditions like (temperature
not causes evaporation, sealing/packaging).
 The studies include photodegradation and oxidation
depending on the drug, so if found (must be
prevented ? how).

 Then, Arrhenius equation ? is used for studying
the effect of temperature on solution at controlled
conditions.
 The fractions of remaining drugs are assayed
using UV, HPLC (the best?).
 After determination of the rate constant at 25°C,
the shelf life can be calculated using the equation:
t10% = 0.105/K25
 Depending on the results, we can decide if, the
drug can prepared in soluble, stable and effective
form or not.

Solid state stability
 Includes identification of the suitable conditions for storage
of solid drugs and drug-excipients compatibility.
 Solid state changes may include changes in the bulk
properties.(so must be assayed as before)
 The reaction rates are much slower and more difficult to
interpret.(why?)
 Generally, it involve placing of a new drug (certain weight)
in open screw cap vials and then exposed directly to a
variety of temperatures, humidities, and light intensities for
long period of time.

 Effect of oxygen and light can be studied for
effected drugs and then protected within study at
various (T and RH).
 RH has its reaction rate constant (KH), so as
increased by increasing of water in atmosphere as
the degradation increased.
 Solid drug-excipient compatibilities (physical or
chemical ) must be evaluated using different assay
methods for pure drug alone, physical mixtures (at
certain ratio) and formulas.

Purpose of stability study
To ensure the efficacy.
To ensure the safety.
To ensure the quality of active drug substance and dosage
forms.
To establish shelf life or expiration period and to support label
claims.
To gain information about its packaging.
Assess the condition of the product on storage on prolong period
of time.
To determine compatibility of drug with excipient and other
additives.
To determine the dosage form in which the drug is most
suitable.

BIOPHARMACEUTICS CLASSIFICATION
SYSTEM
INTRODUCTION:
The biopharmaceutics classification system is guidance for
Predicting the intestinal drug absorption provided by the
U.S. Food and Drug Administration. The fundamental basis
for the BCS was established by Dr. Gordon Amidon.
DEFINITION:
The Biopharmaceutical Classification System is a scientific
framework for classifying a drug substance based on its
aqueous solubility & intestinal permeability & dissolution
rate

OBJECTIVE OF THE BCS
To improve the efficiency of the drug development
and review process by recommending a strategy for
identifying expendable clinical bioequivalence test.
To recommend a class of immediate-release (IR)
solid oral dosage forms for which bioequivalence
may be assessed based on in vitro dissolution tests.
To recommend methods for classification according
to dosage form dissolution along with the solubility–
permeability characteristics of the drug product.

CLASSIFICATIAON
According to the BCS, drug substances are classified as follows:
A. CLASS I
High Permeability and high Solubility.
These are well absorbed and their absorption rate is
usually higher than excretion.
Drugs dissolved rapidly
Drugs absorbed rapidly
Rapid therapeutic action
Excellent property
Ideal for oral route
Ex. Metoprolol, Diltiazem, Verapamil, Propranolol,

Continue….
B. CLASS II
High Permeability and Low Solubility.
Bioavailability is limited by their solvation rate.
Drugs dissolve slowly
Drugs absorbed rapidly
Controlled released drugs
Oral / IV route for administration
Ex. Glibenclamide, Ezetimibe, Phenytoin,
Nifedipine.

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C. CLASS III
Low Permeability and High Solubility.
Dissolved rapidly
The absorption is limited by the permeation rate but drug
is solvated very fast.
Absorbance is limited
Incomplete bioavailability
Oral / IV route for administration
Ex. Cimetidine, Acyclovir, Captopril

Continue…..
D. CLASS IV
Low Permeability And Low Solubility.
Poor bioavailability and Not well absorbed over the
intestinal mucosa.
Low dissolution rate
Low permeability property
Slow or low therapeutic action
IV or other routes are required
Example- Hydrochlorothiazide

FACTOR AFFECTING ON BCS
The Biopharmaceutical Classification System has
been developed to provide a scientific approach to
allow for to prediction in vivo pharmacokinetics
of oral immediate release (IR) drug product by
classifying drug compound based on their,
SOLUBILITY
PERMEABILITY
DISSOLUTION

Continue….
1. 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 ).

Continue….
2. 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.

Continue….
3. DISSOLUTION
A drug product is considered to be RAPIDLY
DISSOLVING when > 85% of the labeled amount of
drug substance dissolves within 30 minutes using USP
dissolution apparatus I or II in a volume of 900 ml or
less in the following media:
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

IVIVC- in vitro in vivo correlation
IRP- immediate release product

SIGNIFICANCE OF BCS
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.
Works as a guiding tool in development of various oral drug delivery
systems.

Application of preformulation considerations
Objectives of the Preformulation Considerations are-
To provide and understand The degradation process,
Any adverse conditions relevant to the drug,
Bioavailability,
Pharmacokinetics and formulation of similar compound and
Toxicity

Continue….
Usefulness of Preformulation Consideration-
A. Selection of the drug candidate itself,
B. Selection of formulation components,
C. API& drug product manufacturing processes,
D. Determination of the most appropriate container
closure system,
E. Development of analytical methods,
F. Assignment of api retest periods
G. The synthetic route of the api,
H. Toxicological strategy.

solid dosage forms development
Solid dosage form acquires most of the pharmaceutical market.
The typical parameter studies for solid dosage forms relate to the
ability of a powder mix to flow well in manufacturing machines
and to the intrinsic characteristics that make it compressible.
Pre-formulation influences on 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
periods, the synthetic route of the API and toxicological strategy.

Continue….
The most important function of pre-formulation stage is
solid state characterization which determines the next step
in the formulation work of the studied API.
Solubility studies identify those drugs with a potential for
bioavailability problems.
E.g. Drug having limited solubility (7 %) in the fluids of GIT often
exhibit poor or erratic absorption unless dosage forms are tailored
for the drug.
Physical properties of the studied API influence on its
physical and chemical stability.
A drug for oral administrative should be examined for
solubility in an isotonic saline solution and acidic pH. This
solubility data may provide the dissolution profile in vivo.

Continue . . . .
It influences on the rout of administration,
delivery system and the drug activity.
Moreover, Chemical stability of the drug is
affected by the physical properties.
Crystal morphology, polymorphism, amorphous
forms and hygroscopicity are usually studied.
In addition, solubility, salt form, melting point,
dissolution of the API are also studied.

Liquid dosage form development
After solid dosage form second largest market is of liquid
dosage form.
Liquid dosage form has certain advantages like easy
administration, fast absorption and variety of dosage form
like syrup, emulsion, suspension etc.
During development of liquid dosage form formulation of
type of dosage form is based on preformulation studies, if
drug is aqueous soluble then it can be easily formulated in
solution dosage form, if drug is insoluble then it can be
formulated in suspension form, oily drug can be
formulated in emulsion form.

Continue . . . .
Solubility in various mediums is useful in developing
suspension or solution toxicological and pharmacological
studies.
Characterization of drug in solid form for particle size and
surface area during formulation of liquid dosage form is also
important as it affect various parameters of liquid dosage
form.
Stability concern is more in liquid dosage form as compared
to solid dosage form, as liquid provides media for various
degradation processes hence special concern should be
provided over stability in case of liquid dosage form.
Selection of container closure system is also important criteria
during preformulation of liquid dosage form.

Continue . . . .
Some of the examples studied during liquid
preformulation studied include organoleptic
characters like taste, colour, viscosity and flow
ability studies, stability studies, solubility of API,
selection of vehicle and proper excipients like
preservatives, antioxidants etc.

Parenteral dosage form development
Parenteral word means outside of intestine.
The drugs which are injected into the body come under
parenteral.
Preformulation studies of parenteral dosage forms include
bulk characterization like particle size, powder flow
properties, crystallinity and polymorphism, solubility study
including pka determination, partition coefficient, stability
study, spectroscopic studies, microscopic studies,
chromatographic studies.
Selection of container closure system is also important criteria
during preformulation studied of parenteral dosage form.

conclusion
Preformulation studies have a significant part to play in
anticipating formulation problems and identifying logical path in
both liquid and solid dosage form technology.
The need for adequate drug solubility cannot be overemphasized.
The most appropriate salt for development. Stability studies in
solution will indicate the feasibility of parental or other liquid
dosage form and can identify methods of stabilization.
In parallel solid-state stability by DSC, TLC and HPLC in the
presence of tablet and capsule excipient will indicate the most
acceptable vehicles for solid dosage form.
This review article gives details of above studies with respect to
any sustained release dosage forms can be developed without
preformulation studies.

References
https://www.pharmapproach.com/preformulation-studies
https://www.slideshare.net/makoye1954/preformulation-studies-62541046
vnd.mspowerpoint preformulation studies-1
https://www.slideshare.net/Protik007/preformulation-60288468
https://www.slideshare.net/makoye1954/preformulation-studies-62541046
https://www.researchgate.net/publication/324819639_Preformulation_lecture-
1/link/5ae43186a6fdcc3bea943cd7
https://www.intechopen.com/books/pharmaceutical-formulation-design-recent-
practices/preformulation-studies-an-integral-part-of-formulation-design
https://www.researchgate.net/publication/330193840_AN_OVERVIEW_ON_
PREFORMULATION_STUDIES
https://www.slideshare.net/venkateshdaggumati/1-preformulation
https://www.pharmapproach.com/preformulation-studies-stability-analysis/

continue.…
https://www.ijptonline.com/wpcontent/uploads/2009/10/2311-2331.pdf
http://www.ijpacr.com/files/07-04-2017/34.pdf
https://www.researchgate.net/publication/286453649_Preformulation_Stu
dies_of_Pharmaceutical_New_Drug_Molecule_Products_An_Overview
https://www.slideshare.net/sagarsavale1/bio-pharmaceutical-classification-
system-bcs
https://www.slideshare.net/azkagull1/skb-bcs-presentation
https://www.slideshare.net/PrinceDivyesh/biopharmaceutics-
classification-system-80736223
https://www.longdom.org/conference-abstracts-files/2153-2435.S1.025-
074.pdf
https://www.slideshare.net/ImranNurManik/preformulation-
considerations-ppt
https://www.slideshare.net/SarojMakwana/preformulation-80763095

Preformulation studies(unit 1)

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