PREFORMULATION STUDIES

1. PREFORMULATION STUDIES
Reshma Fathima K
Assistant Professor
Grace College of Pharmacy, Palakkad

2. S.No Parameters Evaluation parameters
1. Stability
 Solid State
 Solution
Temperature, Light, humidity,
Solvent,pH
2. Solid State Compatibility TLC FTIR
3. Physico-chemical Properties Color, odor, particle size,
shape crystallinity
Molecular Structure and Weight, melting point
4. Thermal Analysis Profile Solubility
Water and other solvent, pH
DTA, DSC,TGA
Salt forms, co-solvent, Complexation, pro-drug
5. Absorbance Spectra UV, IR
6. Other properties Hygroscopicity Potential Bulk characterization Volatility, optical activity, solvate
formation Crystallinity and polymorphism
7. Physico-mechanical Properties Bulk and Tapped density, compressibility Photomicrograph
8. In Vitro Availability Properties Rat Everted Gut
Technique
Dissolution and analysis of Drug Crystal, pallets
9. Other Studies Plasma Protein-Binding, Ionization
Constant
Effect of Compatible Excipients on dissolution, Kinetic Studies
of Solution Degradation, Use of Radio-labeled Drug
Preformulation is defined as the phase of research and development in which preformulation studies
characterize physical and chemical properties of a drug molecule in order to develop safe, effective and
stable dosage form.
Table 1 describes some evaluation parameters used in preformulation of drug development.

4. • OBJECTIVES
• To generate useful data needed in developing stable and safe dosage forms that can be manufactured on a
commercial scale.
• To provide a complete knowledge and understanding of charateristics of a drug molecule before
development of a dosage forms.
• To improve bioavailability.
• GOALS
• To establish the physico-chemical parameters of a new drug entity
• To determine its kinetic rate profile of drug substances.
• To establish its compatibility of drug molecule with common excipients
• To choose the correct form of a drug substance.

5. PRINCIPLE AREAS OF PREFORMULATION
ORGANOLEPTIC PROPERTIES
i. Color
ii. Odour and taste
BULK CHARACTERIZATION
i. Crystallinity and polymorphism
ii. Hygroscopicity
iii. Fine particle characterization
iv. Powder flow
SOLUBILITY ANALYSIS
i. Ionization constant –pKa
ii. pH solubility Profile
iii. Common ion effect- Ksp
iv. Thermal effects
v. Solubilization
vi. Partition coefficient
vii. Dissolution

6. STABILITY ANALYSIS
i. Stability in toxicology formulations
ii. Solution stability
a) pH stability profile
i. Solid state stability
a) Bulk stability
b) Compatibility
Organoleptic properties:
Color: It should be Unappealing to the eye and determined by
either instrumental methods or visible method that varies from
batch to batch. Record of early batches and establishing “specs”
is very useful for later production. Coating of body in variable
color can be done if found undesirable.
Odor and taste:
For unpalatable drug use of less soluble chemical form or
suppress it by flavors, excipients, coating etc. Drug substances
which irritating to skin should be handle with precautions.
Flavors, dyes, excipients used will affect stability and
bioavailability. Color may be off-white, cream yellow, tan,
shiny. Odor may be pungent, sulfurous, fruity, aromatic and
odorless. Taste may be acidic, bitter, bland, intense, sweet and
tasteless.

7. Bulk characterization studies
It is needed to identify all the solid forms that may exist as a consequence of the synthetic stage such as the presence of
polymorphs. Bulks properties such as particle size, bulk density, surface morphology may be changed during the
development process and to avoid mislead predictions of solubility and stability which depends on a particular crystalline
form. Bulk characterization testing includes
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.

8. • Different shapes of crystals
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.

9. • 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.

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

12. 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)

13. 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.

14. • 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.

15. • 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. Abroad asymmetric curve indicates presence of impurities.

17. • 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
• - Suspendability
• - Uniform distribution
• - Penetrability
• - Lack of grittiness
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)

18. 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
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

19. Fine particle characterization
Certain physical and chemical properties of drug substances are affected by the particle size distribution, including
drug dissolution rate, bioavailability, content uniformity, taste, texture color, and stability. In addition, properties
such as flow characteristics and sedimentation rates, among others, are also important factors related to particle
size. It is essential to establish as early as possible how the particle size of the drug substance may affect formulation
and product efficacy. Methods of evaluation of particle size and distribution includes light microscope with a
calibrated grid, Sedimentation techniques, Stream scanning, Coulter counter and Surface area determination by
BET nitrogen adsorption method.
Bulk density = Weight of sample/Bulk volume (Vb)
Tapped density = Weight of sample/ Tapped volume (Vt)
Powder flow properties
The flow properties of powders are critical for an efficient
tablet operation.During the pre-formulation evaluation of the
drug substance, therefore, its flow ability characteristic should
be studied, especially when the anticipated dose of the drug is
large.Powders may be free flowing or cohesive (non free
flowing).Flow properties are affected by changes in particle
size, density, shape, electrostatic charges, and adsorbed
moisture. It is characterized by Carr’s index and Hausner ratio,
Angle of repose, rheology and thixotropy etc.

20. • Angle of repose
• The static angle of repose “Ө” was measured according to the fixed funnel and free standing cone method. It
is the maximum angle possible between the surface of a pile of powder and the horizontal plane. The funnel
was clamped with its tip 2 cm above a paper placed on a flat horizontal surface. The tablet granules were
poured through the funnel until the apex of the cone thus formed just reached the tip of the funnel. The
mean diameters of the base of the powder cones were determined and the tangent of the angle of repose
calculated using the equation,
• tan Ө = h/r
• h = height of granule pile
• r = radius of tablet granules
• Angle of repose (Ө) = tan1(h/r).
Hausner’s ratio
This was calculated as the ratio of tapped density to the bulk
density
Hausner’s ratio= Tapped density/Bulk density
Compressibility index (Carr’s Index)
Compressibility index was calculated using the equation
Compressibility index = (Tapped density-Bulk density)/tapped
density × 100