By

Industrial Pharmacy I Jitakshara Das

Preformulation studies Assistant Professor

The Assam Kaziranga University, SOP

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Preformulation
• Prebefore/Prior
• Formulation made into product.
• Before the development of a formulation or dosage
form, it is essential that certain properties of a drug
molecule are to be determined.
• Preformulation - phase of research and development
in which a drug molecule's physical and chemical
properties are developed to develop a safe, effective,
and stable dosage form.
• Preformulation commences when a newly synthesized
drug shows sufficient pharmacological promise in animal
models to warrant evaluation in man.
• First step in rational development of a dosage form of a
drug substance.
OBJECTIVES
Main objective is to generate information useful to the
formulation in developing the most stable and
bioavailable dosage form that can be prod produced.
Establish necessary physico-chemical parameters of new
drug substance that can affect the drug performance and
development of an efficacious stable and safe dosage
Determine kinetic rate profile.
form.
Establish physical characteristics.

Establish compatibility with common excipients.

Provide insights into how drug products should be

processed and stored to ensure quality.
To develop an optimal drug delivery system.

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Major Area of Preformulation Research
Bulk
Solubility Studies Stability Analysis
Characterization

• pKa • Crystallinity and • Solution Stability

Determination polymorphism • Solid-State
• pH Solubility • Hygroscopicity Stability
• Drug Excipient
Organoleptic Profile and • Micromeritic Compatibility
Studies Common Ion Properties
Effects Particle
• Effect of Charaterizatio
temperature n
• Solubilizaion Density and
• Partition porosity
Coefficient Powder Flow
• Dissolution properties

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 Organoleptic Characteristics
Colour Odour Taste

Organo Sensory
Organ Off white Pungent Bitter
Leptic Loving
Cream yellow Fruity Sweet

Tan Aromatic Tasteless

shinny Odourless Salty

Sulphorous Sour

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Solubility Studies
• 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:
→ taste masking products.
→ Production of sustained release
products.

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 Solubility Studies
The equilibrium solubility is based on the phase solubility techniques proposed by
Higuchi-Connors

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

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 Solubility Studies

•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

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

Henderson-Hasselbalch equation
For Basic compounds
pH=pKa + log
For Acidic compounds
pH=pKa + log
% Ionisation=×100

• Determined by uv spectroscopy, potentiometric titration, titrimetric method.

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 pKa Determination
• 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 very weakly acidic drug with pKa value greater than 8, or very basic
drug (pKa less than 5),the unionized form is present throughout the GIT.
• As example, for a weakly acidic drug with pka value greater than 3-7, 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.
• What happens for weakly basic drugs?
• What happens for strong acidic/basic drugs?

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 pKa Determination
• 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 very weakly acidic drug with pKa value greater than 8, or very basic
drug (pKa less than 5),the unionized form is present throughout the GIT.
• As example, for a weakly acidic drug with pka value greater than 3-7, 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.
• What happens for weakly basic drugs?
• Whar happens for strong acidic/basic drugs?

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 pH solubility profile and common
ion effect

• Solubility of an acidic or basic drug dependson-

• pKa of the ionizing functional group &
• intrinsic solubilities for both the ionized & unionized forms.
• Common Ion affect
A Drug, CH3COONa, is added to a a solution containing CH3COOH.

CH3COONa +
Sodium Acetate
acetate (ionized)
(unionized)

CH3COOH +
Acetic acid

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 Effect of temparature
• The solubility of a solute in a solvent is dependent on
temperature, nature of solute and nature of solvent.
• Heat of solution represents the heat released or absorbed
when a mole of solute is dissolved in a large quantity of
solvent.
• Most of the substances are endothermic, absorbing heat in
the process of dissolution.
• For endothermic solutions, is positiveincreasing
temperature increases drug solubility.
• For exothermic solutions, is negative increasing
temperature decreases drug solubity

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 Solubilization
How we can increase the solubility extent in
water?
Addition of co-solvent (depending on chemical
structure of drug?).disrupts hydrophic interaction
at the non-polar solute/water interface.
depands on the chemical structure of drug, non-
polar the solute solubilization achieved by
cosolvent addition.
Addition of
surfactant
Complexation

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 Partition Coefficient
• P.C is the ratio of the concentration of solute in two immiscible or slightly
miscible liquids, when it is in equilibrium across the interface between them.
• Generally refers to the concentration ratio of un-ionised species of a compound.
• Po/w= ; P>1 Lipophilic, P<1 Hydrophilic
• Measures how hydrophilic or hydrophobic a drug substance is.
• Hydrophobic drugs distribute in the hydrophobic areas such as lipid bilayers of
the cells.
• Hydrophilic drugs are found in the hydrophilic areas such as blood
• serum.
• Determined experimentally by shake shake flask flask method, high
performance liquid chromatography.

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 Shake Flask Method

• Liquid XOctanol/Phenol
• Liquid YWater.
• Solute ZDrug.

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 Dissolution
• Rate of Drug dissolution bioavailability and drug delivery aspects.
• Controlled by several factors chemical form, particle size, surface area, wetting properties.
• The modified Noyes-Whitney equation describes drug dissolution in which surface area is
constant during disintegration.
=×(CS-C)

• Where, D=diffusion coefficient of the drug in dissolution medium

h=thickness of diffusion layer at solid liquid interface
A=surface area of drug exposed to dissolution medium
V=volume of medium
Cs=Concentration of saturated solution in the dissolution medium at the experimental
temperature.
C=a concentration of drug in solution at time t.
Where A=Constant and Cs>>C

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BULK CHARACTERIZATION
Crystallinity
• Crystal habit & internal structure of drug can affect bulk & physicochemical
property of molecule.
• Crystal habit is description of outer appearance of crystal.
• Internal structure is molecular arrangement within the solid.
• Change with internal structure usually alters crystal habit.
Eg. Conversion of sodium salt to its free acid form produce both change in
internal structure & crystal habit.

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Different
shapes
of
crystals

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• Depending on internal structure compounds is classified as
1. Crystalline
2. Amorphous
• Crystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three
dimensional array.
• In amorphous form atom or molecule are randomly placed.
• Solubility & dissolution rate are greater for amorphous form than crystalline, as amorphous form has
higher thermodynamic energy.

Eg. Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption.

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 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.
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Eg. Glyceryl stearate.
 Polymorphism
• Polymorphs differ from each other with respect to their physical property such as
• Solubility
• Melting point
• Density
• Hardness
• Compression characteristic
Eg. 1)Chloromphenicol exist in A,B & C forms, of these B form is more stable & most
preferable.

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ANALYTICAL METHODS FOR THE
CHARACTERIZATION OF SOLID FORMS

• Microscopy
• Hot stage microscopy
• Thermal analysis
• X-ray diffraction
• Infrared (IR) spectroscopy
• Proton magnetic resonance (PMR)
• Nuclear magnetic resonance (NMR)
• Scanning electron microscopy (SEM)

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Microscopy

• Material with more than one refractive index are anisotropic & appear bright with brilliant colors
against black polarized background.
• The color intensity depends upon crystal thickness.
• Isotropic material have single refractive index and this substance do not transmit light with
crossed polarizing filter and appears black.
• Advantage :
By this method, we can study crystal morphology & difference between polymorphic form.
• Disadvantage :
This require a well trained optical crystallographer, as there are many possible crystal habit &
their appearance at different orientation.
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Hot stage microscopy

• The polarizing microscope fitted with hot

stage is useful for investigating
polymorphism, melting point & transition
temp.

• Disadvantage :
In this technique, the molecules can degrade
during the melting process.

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 Thermal analysis

• Differential scanning calorimetry (DSC) & Differential thermal analysis are

(DTA) are particularly useful in the investigation of polymorphism.
• It measures the heat loss or gain resulting from physical or chemical changes
within a sample as a function of temp.
• For characterizing crystal forms, the heat of fusion can be obtained from the
area under DSC- curve for melting endotherms.
• Similarly, heat of transition from one polymorph to another may be calculated.
• A sharp symmetric melting endotherm can indicate relative purity of molecule.
• A broad asymmetric curve indicates presence of impurities.
• Endothermic reactions-Melting, boiling, sublimation
• Exothermic- Cystallization
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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

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 Hygroscopicity is tested by:

Samples are exposed to the moisture

exposed to controlled relative humidity environments

moisture uptake is monitored at different time points

Analytical methods which is used are :
Gravimetry
Karl Fischer Titration
Gas chromatography

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PARTICLE SIZE

• Particle size is characterized using these terms :

• Very coarse, Coarse, Moderately coarse, Fine ,Very fine .
• Particle size can influence variety of important factors :
- Dissolution rate: eg P.S Solubility Dissolution.; Circular shape S.A Dissolution
- Suspendability: eg P.SRemains suspended in solution for longer time. (for liq)
- Uniform distribution.
- Penetrability
- Lack of grittiness

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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)

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 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 due to surface roughness.
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
3. Adhesion between particles and wall of container.

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Determination of Powder Flow
Properties
• By determining Angle of
Angle of Repose Type of Flow Repose.
( In degree) • A greater angle of repose
indicate poor flow.
<25 Excellent
• It should be less than 30°. & can
be determined by following
25-30 Good equation.
• tan θ = h/r.
30-40 Passable
• where, θ = angle of repose.
>40 Very poor • h=height of pile.
• r= radius.
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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

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Determination of Powder Flow Properties

 Measurement of free flowing powder by compressibility.

 Also known as Carr's index.

CARR’S INDEX(%) =(TAPPED DENSITY – BULK DENSITY) X 100

TAPPED DENSITY
HAUSNER’S RATIO= TAPPED DENSITY
BULK DENSITY

 It is simple, fast & popular method of predicting powder flow characteristics.

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Determination of Powder Flow
Properties

Carr’s Index Hausner’s ratio Type of flow

5-15 1.05-1.18 Excellent
12-16 1.14-1.20 Good
18-21 1.22-1.26 Fair To Passable
23-35 1.30-1.54 Poor
33-38 1.50-1.61 Very Poor
>40 >1.67 Very, Very Poor

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STABILITY ANALYSIS
1. Solution stability
2. Solid state stability
SOLUTION STABILITY
 The decomposition of drug occurs through hydrolysis, oxidation, photolysis.
 Hydrolysis (anaesthetics, vitamins etc )
a) Ester hydrolysis
R’-COOR + H+ + OH- RCOOH + ROH
ester acid alcohol
b) Amide hydrolysis
RCONHR’ + H+ + OH- RCOOH + H2N-R’
amide acid amine

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Oxidation

used to evaluate the stability of pharmaceutical preparations

Eg : steroids, vitamins, antibiotics, epinephrine

Autoxidation

Materials + molecular oxygen

homolytic fission

Free radicals are produced.

Oxygen sensitivity is measured by bubbling air through the compound or adding hydrogen peroxide.

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Photolysis

pharmaceutical compounds

exposure to uv light

absorbs the radiant energy

undergoes degradative reactions

SOLID-STATE STABILITY

1o objective: identification of stable storage conditions.

identification of compatible excipients.

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Solid-state stability depends on the temperature , light, humidity, polymorphic changes, oxidation .
Solid-State Stability profile of a new compound
Samples are placed in open vials and are exposed directly to a variety of temperatures,
humidities, and light intensities for up to 12 weeks.
Vials exposed to oxygen and nitrogen to study the surface oxidation and chemical stability ,
polymorphic changes and discolouration.
Stability data obtained at various humidities may be linearized with respect to moisture using
the following apparent decay rate constant (K H )
k H
[ gpl ]. k 0

gpl= concentration of water in atmosphere in units of grams of water per liter of dry air .
ko = decay rate constant at zero relative humidity
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Mole fraction of the solid that has liquefied (F m ) is directly proportional to its decay rate.
  H fus 1 1
ln k app  ln Fm  [  ]
R T T m

 H fus
-molar heat of fusion
Tm - absolute melting point
T - absolute temperature
R - gas constant

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Drug- excipient compatibility

• Compatibility test play a very important role in the preformulation studies of

oral dosage forms
• An incompatibility in the dosage form can result in any of the following
changes:
 Changes in organoleptic properties
 Changes in dissolution performance
 Physical form conversion
 An decrease in potency

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 Drug- excipient compatibility
Drug + Excipients
(1:1)
Powder samples dispersed into glass
ampoules
1 ampoule 1 ampoule (sample +
water)

stored at a particular temperature (500 C) and analysed

• In emulsions the studies include measuring the critical micelle concentration of the formulations
• For oral use preparations compatibility of the ingredients (ethanol, glycerine, syrup, sucrose,
buffers and preservatives)

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Drug- excipient compatibility

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 CONCLUSION
• Preformulation studies on a new drug molecule provide useful information for
subsequent formulation of a physicochemically stable and biopharmaceutically
suitable dosage form.

• Preformulation work is the foundation of developing efficacious and economical

formulations.

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 REFERENCE
• Leon Lachman, Liberman. The theory and practice of Industrial pharmacy, Edn
4. CBS publishing house, New Delhi.2013 p:217-307.
• Banker GS, Rhodes CT. Modern pharmaceutics, Edn 4. Marcel Dekker, New
York. 2002 p:167-184.
• Loyd V. Allen, Nicholas [Link], Howard C. Ansel. Ansel’s pharmaceutical
Dosage forms & Drug delivery systems, Edn 8. [Link] pvt. Ltd, p:187-
193,42 & 43,126-133.
• Brahmankar D.M, Jaiswal BS. Biopharmaceutics and
pharmacokinetics a Treatise, Edn 2. Vallabh Prakashan, Nagpur.
2009; p: 37-45.

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Thank You

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