Introduction

• Preformulation study is the foundation of developing

robust formulation.
• Preformulation is branch of Pharmaceutical science that
utilizes biopharmaceutical principles in the
determination of physicochemical properties of the drug.
• 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
 Definition
• It can be defined as a phase of research &
development process for an investigation of
physical ,chemical properties and mechanical
of new drug substance alone or in
combination with other excipients in order to
development of safe and effective dosage
form
 Objectives
To generate useful information to the formulator to
design an optimum drug delivery system.
• To develop elegant dosage form( stable ,Safety and
effective)
• To increase drug stability
• To improve drug bioavailability
• To Reduce drug excipients incompatibility
• To establish the necessary physicochemical parameters
of new drug substances.
• To determine kinetic rate profile.
• To establish compatibility with common excipients.
 Stages of Preformulation studies
• Physicochemical properties and Analytical
Testing of drugs
• Data supporting Development of Dosage form
• Support for quality control and finished
product manufacturing.
 Outline of principal areas of
preformulation research
Principal areas

Stability analysis
Physico-chemical
properties Solution stability
Bulk
Solubility analysis Solid state
Organoleptic characterisation
Crystallinity and stability
properties Ionization constant pka
Particle size polimorphism Bulk stability
PH solubility profile
and shape Hygroscopicity Compatibilty
Common ion
Purity effect ksp
Particle size
characterization Thermal effects
Surface
Bulk density Partition co-efficient
area
solubilization
Powder flow Dissolution
properties
 Preformulation Parameters
PREFORMULATION PARAMETERS METHOD USED
Organoleptic Properties Colour and Odour Determination
Crystallinity & Polymorphyism X-ray Diffraction Studies (Lachman, 1991)

Fine Particle Characterization Microscopic Method (Lachman, 1991)

Solubility Profile Equilibrium Solubility Method (I.P. 2007)
Solubilization (Lachman, 1991)
Analytical Method Development UV Spectroscopic Method, HPLC Method
Ionization Constant, pKa Determination of Spectral Shifts by UV Spectroscopy
(Lachman, 1991)
Partition Coefficient Using octanol / water,(Lachman, 1991)

Bulk Density Tapping Method (Lachman, 1991)

Powder Flow Properties % Compressibility Determination, Angle of Repose (Lachman, 1991)

Compatibility With Excipients DSC (Stulzer and Rodriques et al., 2008)

Stability Solution and Solid State Stability (PCT/US03/35012)

Stability Indicating Method Development Forced Degradation Studies (Rao et al., 2009)
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Goals
Steps in Preformulation Process Pharmaceutical Research
1. Stability i. Solubility
a. Solid State (1) Water and Other Solvents
(1) Temperature (2) pH-Solubility Profile
(2) Light (3) Salt Forms
(3) Humidity (4) Cosolvents
b. Solution (5) Complexation
(1) Solvent (6) Prodrug
(2) pH j. Effect of pH on UV Spectra
(3) Light k. Ionization Constant
2, Solid State Compatibility l. Volatility
a. TLC Analysis m. Optical Activity
b. DRS Analysis n. Polymorphism Potential
3. Physico-chemical Properties o. Solvate Formation
a. Molecular Structure and Weight 4. Physico-mechanical Properties
b. Color a. Bulk and Tapped Density
c. Odor b. Compressibility
d. Particle size, Shape, and Crystallinity c. Photomicrograph
e. Melting Point 5. In Vitro Availability Properties
f. Thermal Analysis Profile a. Dissolution of Drug Crystal Per se
(1) DTA b. Dissolution of Pure Drug Pellet
(2) DSC c. Dissolution Analysis of Pure Drug
(3) TGA d. Rat Everted Gut Technique
g. Hygroscopicity Potential 6. Other Studies
h. Absorbance Spectra a. Plasma Protein Binding
(1) UV b. Effect of Compatible Excipients
(2) IR on Dissolution
c. Kinetic Studies of Solution
Degradation
d. Use of Radio-labeled Drug
 Organoleptic properties

Unfortunately, many drug substances in use

today are unpalatable and dosage forms
containing such drugs (oral preparations( may
require the addition of flavors and/or colors.

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1.1 Color

Unappealing to the eye ==> instrumental methods or

variable from batch to batch

Record of early batches ==> establishing “specs” is

very useful for later production

Undesirable or ==> incorporation of a dye variable

color in the body or coating
 COLOR

• Color is generally a function of a drug’s inherent

chemical structure relating to a certain level of
unsaturation.
• Color intensity relates to the extent of conjugated
unsaturation as well as the presence of
chromophores.
• Some compound may appear to have color
although structurally saturated.
• Stability problems, improve appearance by
including dye in body or coating

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 Odour
• The substance may exhibit an inherent odor
characteristic of major functional groups present.
• Odor greatly affects the flavor of a preparation or
food stuff.
Taste:-
• If taste is considered as unpalatable, consideration is
to be given to the use of a less soluble chemical form
of the drug.

• The odour and taste may be suppressed by using

appropriate flavors and excipients or by coating the
final product.

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 Suggested terminology to describe
organoleptic properties of
pharmaceutical powders
• Colour Odour Taste

• Off-white Pungent acidic

• Cream yellow sulfurous bitter
• Tan fruity bland
• Shiny Aromatic intense
• odourless sweet
• Tasteless
 2. PURITY
• Materials with impurities not necessary to be
rejected
• Another control parameter for comparison with
subsequent batches
• More direct concerns - impurity can affect:
- Stability: metal contamination in ppm
- Appearance: off-color -> recrystallized -> white
- Toxic: aromatic amine (p-amino phenol) -> carcinogenic
• Often remedial action => simple recrystallization
 Purity
• Purity studies are essential for further studies
to be carried out safely.
• Impurities may make a compound toxic or
render it unstable.
• TLC,HPLC,GC and Paper chromatography used.
• HPLC-Impurity Index(II), Homogeneity
index(HI).
• DTA, gravimetric analysis and melting point by
hot stage microscopy are other techniques.
• Impurity index(II):defined as the ratio of all responses (peak
areas) due to components other than the main one to the total
area response.
• Homogeneity index(HI): defined as the ratio of response(peak
area) due to main component to the total response.
• Eg.: main component –retention time: 4.39min
• -area response: 4620
• Impurities – 7 minor peaks ;area response: 251
• - total area response : 251+4620
• Impurity index : = 251/(4620+ 251)
• = .0515
• Homogeneity index : = 1 - .0515
• = .9485
 Other Tools In Assesment Of Impurity
• Differential thermal analysis(DTA)
• Thermogravimetric analysis(TGA)
• Differential scanning calorimetry(DSC)
• Powder X-Ray Diffraction(PXRD)