Introduction to preformulation studies,

1. PREFORMULATION
PRESENTED BY:
DHIRAJ SHRESTHA
M.Pharm
Pharmaceutics

2. • Introduction :
• Organoleptic Properties :
• Purity :
• Particle size, shape and
surface area:

3. INTRODUCTION
• Preformulation testing is the first step in
rational development of dosage forms of a
new drug substance.
• It can be defined as an investigation of
physical and chemical properties of a drug
substances alone and when combined with
excipients.

5. Objective:
• The overall objective of preformulation
testing is to generate information useful to
the formulator in developing stable and bio-
available dosage forms that can be mass
produced .
• Obviously , the type of information needed
will depend on the dosage form to be
developed.

6. PERFORMANCE OF PREFORMULATION
STUDIES:
• The formal preformulation studies should
start at the point after biological screening,
when a decision is made for further
development of compound in the clinical
trials.
• Before the formal program , the
preformulation scientist must consider the
following :
• 1.:Available physicochemical data ( including
chemical structure , different salts available).
• 2: Anticipated Dose.

7. • SELECTIVITY is very critical to success of
preformulation program . Not all the
preformulation parameter are determined for
every new compound .
Data , as they generated , must be reviewed to
decide what additional studies must be
undertaken.
For Eg ,
• A detailed investigation of dissolution is not
necessary for Very soluble compound .
• On the other hand , particle size , surface area,

8. ORGANOLEPTIC PROPERTIES
•A typical preformulation program should begin
with the description of drug substance .
•The color , odor, taste of the new drug must be
recorded using descriptive terminology. It is
important to establish a standard terminology
to describe these properties in order to avoid
confusion among scientists using different
terms to describe the same property.
•During manufacturing of different batches of
new drug, the colour of early batches must be
recorded by using descriptive terminology. A
record of the colour of early batches will be
useful for preparing the appropriate
specification

9. Suggested terminology for organoleptic properties of
pharmaceutical powders are
COLOR ODOUR TASTE
Off white Pungent Acidic
Cream yellow Sulfurous Bitter
Tan Fruity Bland
Shiny Aromatic
odorless
Intense
Sweet
Tasteless

10. • The odour and taste may be suppressed by
using appropriate flavors and excipients or by
coating the final product.
• The flavors , dyes and other excipients
selected to overcome problems variable color
and unpleasant odor and taste must be
screened for their influence on the stability
and bioavailability of active drug.
• Many drug substances are irritating to skin .
Such information may already be available or
developed during the course of
preformulation studies.

11. PURITY studies are must often performed in
an analytical research and development
group. But preformulation scientists must
have some perception or some early
knowledge of purity of drug substance . Early
knowledge is necessary so that preformulation
and clinical trial performance can not be
compromise and it can improve the validity .It

12. • Occasionally an impurity can affect stability .
• Eg.Metal contamination will affect certain
classes of compound
• Presence of impurity makes a compound toxic.
• Eg: Presence of aromatic amines suspected to
be carcinogenic.
• For this some discussion must be initiated
with the chemist preparing the material. so

13. • TLC.
• HPLC.
• Paper chromatography.
• Gas chromatography
Excellent tools for finding out the chemical
homogeneity along with estimation of purity is
given below---

14. TLC CHAMBER

15. HPLC

16. GC

17. PAPER CHR.

18. •It measures Impurity index(II) and homogeneity
index (HI) specially from HPLC chromatography.
All responses due to
other component
•Impurity index(II):----------------------------------------
---
Total response
The responses are obtained as area measurement
in the
chromatographic procedure.

19. • The USP has proposed a related procedure
called ordinary impurities test that estimates
using TLC.
The USP is proposing a general limit of 2% impurity for qualitative
estimation of purity has been done by Gravimetric thermal analyses.
• For quantitative estimation of purity has been done by Differential
scanning calorimetry or by phase-rule solubility analysis.
• ICH guidelines for impurity is given below

21. PARTICLE SIZE, SHAPE AND SURFACE AREA
• Various chemical and physical properties of drug substances are
affected by their particle size distribution and shape. The effect is not only
on the physical properties of the solid drugs but also on their
biopharmaceutical behavior
E.g. bioavailability of griseofulvin and Phenacetin is directly related to
the particle size. distribution .Poorly soluble drugs shows greater
bioavailability in the finely subdivided state then as a coarse-material
• Size also plays a role in the homogeneity of the final tablet. When
large difference in the size exist between the active components and
excipients. So to control non homogeneity of diluents and API sieving can
be done. Not only size but shape also influence the flow and mixing
efficiency of powders and granules.
• Size can also play a factor in stability, fine particles are relatively
more prone to attack by oxygen, heat, light, humidity and interacting
excipients than coarse materials.

22. • Eg:Weng and Parrol investigated influence of particle size of
Sulfacetamide on its reaction with Phthalic anhydrous in 1:2 molar
compacts after 3 hr at 95OC ,which clearly says that the reactivity
occurs due to decreasing of particle size of Sulfacetamide. So
particle size should be maintain and control it.
• The particle size of a new drugs having size above 100µm in
diameter is probably safe to grind . If material consists of particle
size 30µm or less than that are unnecessary for grinding.
• Grinding should reduce coarse materials to ,preferably the 10 to 40
µm ranges.
The particle size has an effect on dissolution rate and solubility .
It is shown Noyes-whitney equation---
dc/dt =KS (Cs-Ct)

23. METHODES FOR DETERMINING PARTICLE
SIZE
• Many method are available for particle size
determining few method is given below----
• 1. Optical microscopy : According to this
method, an emulsion or suspension diluted
or undiluted, is mounted on a slide or ruled
cell and placed on a mechanical stage, where
with the help of micrometer the size of the
particle may be estimated. The photograph
can be taken from which a slide is prepared
and projected onto screen for measurement
.
• Disadvantage:

25. 2.Sieving
This method utilizes a series of standard sieves calibrated by the
National Bureau of standard. Sieve produced by photoetching and
electroforming techniques now available with apertures from 90 µm
down to as low 5 µm

26. Approximate
sieve
number*
Approximate
% sieving
area
Nominal
mesh
aperture
size mm
Tolerance
average
aperture
size +
mm
4 55 4.0 0.136
8 48 2.0 0.07
10 46 1.7 0.06
12 44 1.4 0.05
16 41 1.0 0.03
um + um
22 37 710 25
25 36 60 21
30 38 500 18
36 36 425 15
44 38 355 13
60 37 250 13 (9.9)**
85 35 180 11 (7.6)
100 36 150 9.4 (6.6)
120 34 125 8.1 (5.8)
150 36 106 7.4 (5.2)
170 35 90 6.6 (4.6)
200 36 75 6.1 (4.1)
240 34 63 5.3 (3.7)
300 35 53 4.8 (3.4)

27. •3.sedimentatin rate :
Sedimentation rate ,in which particle size is
measured by the terminal settling velocity of
particles through a liquid medium in a
gravitational or centrifugal environment (range
0.8-300µm)
Sedimentation rate may be calculated
from stokes’ law dx/dt = d²(ρ₁ - ρe)g/18η
Here d – diameter of particle
ρ₁ , ρe - density of particle , medium
G – gravitational constant
η – viscosity of medium
•4.light scattering (0.2-500µm).

29. METHODES FOR DETERMINING SURFACE AREA
The surface area of a powder can be
determined from the knowledge of particle
size distribution . Two methods are available
that permits direct calculation of the surface
area.
• Amount of a gas or liquid solute that is
adsorbed on the sample of powder to form
monolayer.

30. • Adsorption method:
• Particle with a large specific surface are good
adsorbents for the gases and of solutes from
solution .In determining the surface of the
adsorbent ,the volume in cubic centimeters of
gas adsorbed per gm of adsorbent may
plotted against the pressure of the gas at
constant temperature to give type II isotherm
(line in a map).
• The adsorbed layer is monomolecular at low
pressures and becomes multimolecular at

31. • Air permeability method:
The principle resistance to flow of a fluid, such as
air, through a plug of compacted powder is the
surface area of the powder. The greater the surface
area per gram of powder, the greater the resistance
to flow. Hence permeability, for a given pressure
drop across the plug, is inversely proportional to
specific surface.

32. • References:
• Pharmaceutical dosage forms :Tablets Volume1
----By,Leon Lachman.
• Pharmaceutical dosage forms and drug delivery systems
--- By Howard C.Ansel.
• Aultons Pharmaceutics—Third edition
---By Michael E.Aulton.
• Physical pharmacy
---By Alfred Martin
• Indian Pharmacopoeia 1997.
• ICH Guidelines.