The document discusses preformulation, which involves determining the physicochemical properties of a new drug substance to aid in developing a stable dosage form. Key goals are to formulate a safe, effective dosage form with good bioavailability. The document outlines areas studied in preformulation including solubility, polymorphism, hygroscopicity, and particle characterization. Understanding these properties helps ensure the drug will perform as intended.

2. Preformulation
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.

3. DEFINITION:-
Investigation of physico-chemical properties of the
new drug compound that could affect drug
performance and development of an efficacious
dosage form.
Characterization of physical, chemical andCharacterization of physical, chemical and
mechanical properties of new drug molecule inmechanical properties of new drug molecule in
order to develop safe, effective , and stable dosageorder to develop safe, effective , and stable dosage
form.form.

4. GOALS OF PREFORMULATION
To formulate an elegant, safe, efficacious
dosage form with good bioavailability.
To formulate new dosage form of already
existing drug.
Determination of all the properties of drug
and the best suitable dosage form for the
drug molecule.

6. Outline of principal areas of
preformulation research
Principal areas
Physico-chemical
properties Bulk
characterisation
Stability analysis
Solubility
analysisOrganoleptic
properties
Particle size
and shape
Purity
Surface
area
Crystallinity and
polimorphism
Hygroscopicity
Particle size
characterization
Bulk density
Powder flow
properties
Ionization constant pka
PH solubility profile
Common ion
effect
Thermal
effects
solubilization
Partition co-efficient
Dissolution
Solution stability
Solid state
stability
Bulk
stability
Compatibility

7. PHYSICOCHEMICAL PROPERTIES
BULK PROPERTIES
Bulk properties of the solid form such as crystallinity,
polymorphism, particle size, powder flow property, and
surface characteristics are likely to change during process
development.
CRYSTALINITY
The crystal habit describes the outer appearance of crystals
( platy, equant, needle, bladed, etc.) and internal structure
arrangement. Compounds have several different habits,
depending on the environment for growing crystals.

8. Polymorphism
polymorphism is the ability of the compound to crystallize as
more than one distinct crystalline species with different
internal structure.
Formation of different polymorphs depends on solvents,
temperature, pressure, rate of cooling, etc.
Polymorphic transitions can also occur during milling,
granulating, drying and compressing operations
Different polymorphs vary in physical properties such as
dissolution, solid-state stability, compatibility, etc

9. Polymorphs
Enatiotrophic :sulphur
Monotrophic : Glyceryl stearate
Transition temparature :identical free energy
Stable polymorph in room temperature with stability
profile

10. HYGROSCOPICITY
The tendency of a solid to take up water from the
atmosphere, as it is subjected to a controlled RH
program under isothermal condition i.e.
hygroscopicity.
Classified based on the amount of rate of water
uptake when a solid is exposed to controlled RH
value at a specified temperature.
Deliquesent material : NaCl

11. Particle Characterization
Powder Flow
 The pharmaceutical powders are classified as ---
 FREE FLOWING
 COHESIVE OR NON FREE FLOWING
 The powder flow are affected by the changes in –
 Density
 Particle Size
 Shape Free flowing drug may become cohesive and
 Electrostatic Charge necessitates an entirely new formulation strategy
 Adsorbed Moisture

12. Particle size
Study of particle size give an information about solubility,
dissolution rate, absorption, etc.
particle size and surface area of a solid drug are inversely related
to each other.
eg: Griseofulvin
Powder flow property
The flow properties of a powder will determine the nature and
quantity of excipients needed to prepare a compressed or a
powder dosage form.
This refers mainly to factors such as the ability to process the
powder through machines.

13.  Several rates of flow (g/sec) determinations at each of variety of orifice
sizes (1/8 to ½ inches) should be made.
 Greater the standard deviation between multiple flow rate measurements
greater is the weight variation in products produced from the powder.
 It was found that the dependence of flow rate (w) on the true particle
density(ρ),gravity(g), orifice diameter(D) by
 D= A (4w/60πρ√g)^1/n
 A and n are constants dependent upon material and particle size
 Other measures of free flowing powders is
 COMPRESSIBILITY.
 %compressibility=(ρ1-ρ0)/ρ1
 Angle of repose is not much useful as lack of precision

14. Solubility analysis
The solubility of every new drug must be determined as a
function of pH over the physiological pH range of 1 - 8
Preformulation solubility studies include
pKa determination
pH solubility profile
Temperature dependence
Solubility products
Solubilization mechanisms
Rate of dissolution

15. Determination of Solubility
 Semiquantitative determination:
Solvent
(fixed volume)
Adding solute in small
incremental amounts
Vigorously
shaking
Undissolved
solute particles ?
Examine
visually
YesNo
Total amount
added up
Estimated solubility

16. Accurately Quantitative determination:
Excess drug powder
150 mg/ml (15 %)
+ solvent
Ampul/vial
(2-5 ml)
Shaking at constant
temperature
(25 or 37 o
C)
2 - 8 o
C ?
Membrane filter
0.45 µm
Determine the drug
concentration in the
filtrate
Determine the drug
concentration in the
filtrate
Determine the drug
concentration in the
filtrate
Membrane filter
0.45 µm
Membrane filter
0.45 µm
Same
concentration ?
The first few ml’s of the filtrates should be
discarded due to possible filter adsorption
Solubility
48 hr
72 hr
? hr

17. Drug pKa / Ionization at physiological pH
pKa is the dissociation constant of a drug.
The nonionized substances is lipid soluble thus
dissolve in lipid material of the membrane and
transported by passive diffusion.
Where as, the ionized substances is a lipid
insoluble therefore permeation is slow.

18. The percentage of ionization can be calculated as …
For Acidic compounds:
For Basic compounds:
Degree of ionization depends up on the pH.
 for acidic drugs pKa ranges from 3-7.5.
 for basic drugs pKa ranges from 7-11.
% ionized = 100/ 1+ antilog (pKa – pH)
% ionized = 100/ 1+ antilog (pH – pKa)

19. pH-Solubility Profile
Excess drug
powder
Stir in beaker
with distilled
water
Continuous
stirring of
suspension
Add
acid/base
Measure
pH of
suspension
Determine the
concentration
of drug in
the filtrate
SOLUBILITY pH

20. Common Ion Effect

22. Effect of Temperature
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.

23. Applications:
Pharmaceutical solutions must be administered at or near
room temperature. So, it is more important factor for
product storage than the formulation.
To increase the solubility of sparingly soluble solute.
To increase the stability by reducing the moisture content.