preformulation Studies

1. PREFORMULATION
STUDIES
Presented by :
Naimat afridi

2. INTRODUCTION
Definition
It is defined as the phase of R&D in which
preformulation studies characterize physical and
chemical properties of a drug molecule in order to
develop safe,effective and stable dosage form.
Goals of preformulation
 Quantization of physical and chemical
properties will assist in developing a;
a. Stable
b. Safe
c. Effective formulation

3. A- Physical description and Bulk Characterization
1. Crystallinity and polymorphism
2. Hygroscopicity
3. Fine particle characterization
4. Powder flow properties
B- Solubility analysis
1. Ionization constant (pKa)
2. Partition coefficient
3. Aquous solubility
4. pH-Solubility Profile
C- Stability analysis
1. Photolytic stability
2. Stability to Oxidation
3. Compatibility studies
Major areas of preformulation
studies

4. A. Physical description and Bulk Characterization:
1- CRYSTALLINITY AND POLYMORPHISM
 Solid drug materials may occur as:
a. Amorphous (higher solubility)
b. Crystalline (higher stability)
 Scientists prefer crystalline form due to stablility.
e.g Crystalline form of penicilline G is more stable
 But sometime it is necessary to use amorphus form as in
the case of Novobiocine

5. Polymorphism
 Different polymorphs exhibits different
solubilities,therapeutic activity and stability.
 Companies prefer to develop the most stable
polymorph
 Pseudopolymorphism
Solvates
Hydrates
Determination method:
 Thermodyanamically-van,t Hoff plot(solubility vs
temperature)
 Directly – by microscopic determination

6. 2- HYGROSCOPICITY
Ability of substance to absorb moisture
from environment.
Changes in moisture level can greatly
influence many parameters such as;
chemical stability , flowability , and
compatibility.
Methods
I. Gravimetric method
II. Karl Fischer titration

7. 3- FINE PARTICLE CHARACTERIZATION
Particle size of drugs may affect
formulation and product efficacy.
Certain physical and chemical
properties of drug substances are
affected by the particle size
distribution including ; drug dissolution
rate , content uniformity , texture ,
stability , flow characteristics , and
sedimentation rates.

8. METHODS TO EVALUATE PARTICLE
SIZE
 1.Sieving or screening
 2.Optical microscopy
 3.Sedimentation
 4.Coulter counter method .

9. 4- POWDER FLOW PROPERTIES
Flow properties are significantly affected
by:
Changes in particle size,
density,
shape,
adsorbed moisture
Methods of determination
 Angle of repose
 Compressability index
 Hausner’s Ratio
which may arise from
processing or formulation.

10. B- Solubility analysis
1. Ionization constant (pKa)
 The dissociation constant (Ka) is a value used to
describe the tendency of compounds or ions to
dissociate.
 Determination of the Pka for a drug capable of
ionization within a pH range of 1to10 is important since
solubility, and consequently absorption, can be altered
by changing pH.
Methods for determination of pKa:
a. Potentiometric method
b. Spectrophotometric method
c. Solubility method
d. Conductometric method

11. 2- Partition coefficient
The concentration ratio of a substance distributed between two
phases (i.e., octanol and water) at equilibrium:
P = Co/Cw
Determined by Shak Flask Method
 Partition Coefficient is usefull bcz
• It measure lipophilicity
• Major role in drug transport
• Analytical separation

12. 3- Aquous solubility
The concentration at which the solution phase is in equilibrium
with
a given solid phase at a stated temperature and pressure.
Determination
Aquous solubility is determined when excess of drug is added to
certain aqueuous media, and agitated until equilibrium is
achieved.
General Method of Increasing the Solubility
 Addition of co-solvent
 pH change method
 Reduction of particle size
 Temperature change method
 Addition of Surfactant
 Complexation

13. 4- 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

14. ..

15. C- Stability analysis
Preformulation stabilitystudies are usually the first
quantitative assessment of chemical stability of a
new drug.
These studies include both solution and solid state
experiments under conditions typical for the handling,
formulation, storage, and administration of a drug
candidate as well as stability in presence of other
excipients.
Factors affecting chemical stability critical in rational
dosage form design include;
 Temperature
 pH
 Dosageformdiluents

16. Stability studies Include
1. Photolytic stability
2. Stability to Oxidation
3. Compatibility studies

17. Compatibility studies
 The knowledge of drug excipients interaction is useful
for the formulation to select appropriate excipients.
 The described preformulation screening of drug
excipients interaction requires only 5mg of drug in a
50% mixture with the excipients to maximize the
likelihood of obscuring an interaction .
 Mixtures should be examined under nitrogen to
ultimate oxidation and paralytic effect at a standard
heating rate on DSC, over a temperature range, which
will encompass any thermal changes due to both the
drug and appearance or disappearance one or more
peaks in themogrames of drug excipient mixtures are
considered of indication of interaction.

18. Thanks