Preformulation study

1. PREFORMULATION
Kiran C Rodge

2. Content
01
02
03
04
05
Definition
Need of Preformulation
Types of Preformulation
studies
Fundamental Properties
Derived Properties

3. To Examine physico chemical properties of drug
and Excipients before formulation of dosage form
Definition

4. Need of Preformulation
Quality of dosage form
Uniformity
Optimization
Preliminary
Evaluation
Kinetics and
Stability
Minimize Cost
Minimize Errors
CMC fulfillment for IND,NDA
& ANDA
Compatibility

5. Types of Properties
Those properties comes along with molecule
Those properties came after different unit
process
Fundamental Properties
Derived Properties

7. Fundamental Properties
Spectroscopy Solubility
Melting Point Assay

8. Spectroscopy
 Simple analytical method
 Generally UV Spectroscopy used and then followed by HPLC
 Ultraviolet range – 190 to 390 nm
 Visible range -- 380 to 740 nm
 Beer –Lambert law
A= eCl

9. Solubility
Aqueous Solubility
Why we check Aqueous
Solubility ?
Kaplan (1972)
1%---1 to 7 pH----37°C
If not found go for salt
formation
Intrinsic Solubility
Applications
1) Solubility
2) Drug absorption in
vivo
3) Partition
chromatography
pKa value
Acid in weak acid & base
in weak base
Solubility Measured
1) At 4°C
2) At 37°C
pKa value is the negative
base at 10 log of the acid dis
sociation constant (Ka) of sol
ution.
pKa = - log10 Ka
The smaller the value of
pKa the stronger the acid.
Henderson – hasselbalch Eq.
Partition Coefficient

10. Melting Point
Capillary
Melting
Thermal
Methods
Hot stage
Microscopy
The Temperature at which solid convert in liquid ,where solid and liquid phase exist in equilibrium.
Differential Thermal Analysis:-
Measured temperature difference between
sample and reference as a function of
temperature or time when heating at the
constant rate.
Differential Scanning Calorimetry:-
Amount of energy required to keep
sample at the same temperature
at the reference.

11. Assay
 Assay Design
 Assay
Development
Property Assay Requirement of sam
ple
•SolubilityaAqueous
•Nonaqueous
UV Chromophore
pKa UV or potentiometric
titration
Acid or basic group
Po, w/log P UVTLCHPLC Chromophore
Hygroscopicity DVSTGA No particular require
ment
•StabilityHydrolysis
•Photolysis
•Oxidation
HPLC, plus suitable
storage conditions
No particular require
ment
aSolubility will depend on physical form.
Derived property Technique
Melting point DSC or melting point apparatus
Enthalpy of fusion (and so ideal
solubility)
DSC
Physical forms (polymorphs, pse
udopolymorphs or amorphous)
DSC, XRPD, microscopy
•Particle shapeSize distribution
•Morphology
•Rugosity
•Habit
MicroscopyParticle sizingBET (
surface area)
•DensityBulk
•Tapped
•True
Tapping densitometer
Flow Angle of repose
Compressibility Carr’s indexHausner ratio
Excipient compatibility HPLC, DSC

13. Derived Properties
Microscopy Flow properties
Drug excipient
compatibility
Drug stability

14. Microscopy
Crystal Morphology---- The study of crystal internally and externally
Crystal System (Internal Study) Crystal habit (External Study)
1. Cubic
2. Hexagonal
3. Tetragonal
4. Trigonal
5. Orthorhombic
6. Monoclinic
7. Ttriclinic
1.Tabular
2.Platy
3.Prismatic
4.Acicular
5.Bladed

15. Microscopy
Particle Size analysis----
Most pharmaceutical powders have crystals in the range 0.5 –300 μm
Determination Method
 Microscopy method
 Sieving Method
 Sedimentation or Anderson Pipette method
 Coulter counter method

16. Flow Properties
Bulk Density= Mass / Volume
Tapped Density = Mass /Tapped Volume
Hausner’s Ratio = Tapped Density / Bulk Density
Carr’s Index = (TD-BD /TD)100
Angle of Repose (tan Φ)=h / r
Sr. No.
Flow Angle of response Carr’s index
1) Excellent < 25 5-15
2) Good 25-30 12-16
3) Fair to passable 30-40 18-21
4) Poor > 40 23-35
5) Very poor - 33-38
6) Extremely poor - < 40

17. Drug excipient compatibility
The potential interactions between drugs and excipients have effects on the chemical, physical,
bioavailability and stability of the dosage form.
 Physical incompatibility
 Chemical incompatibility
 Therapeutic incompatibility

18. Analytical Techniques Used to Detect
Drug-Excipient Compatibility
Spectroscopic techniques
 FT-IR Spectroscopy
 Diffuse Reflectance
Spectroscopy (DRS)
 Powder X-ray diffraction (PXRD)
 Solid state nuclear magnetic
resonance spectroscopy (ss NMR)
Microscopic technique
 Scanning electron microscopy (SEM).
Chromatography
 Self-Interactive Chromatography (SIC)
 Thin Layer Chromatography (TLC)
 High-Performance Liquid Chromatography (HPLC)
.
Thermal methods
 Differential scanning calorimetry (DSC)
 Isothermal microcalorimetry
 Hot stage microscopy (HSM)

19. Drug & Product Stability
Physical
Chemical
MicrobiologicalTherapeutic
Toxicological

20. Physical Stability
 Loss of water
 Absorption of water
 Loss of volatile constituents
 Crystal growth
 Polymorphism
 Color changes

21. Chemical Stability
 Hydrolysis
 Oxidation
 Dimerization
 Polymerization
 Isomeric change
 Photodegradation