pharmaceutical preformulation in briefly.pictorial representation of preformulation

1. M R SUMON SARKAR
Department of pharmacy

3. Contents:
Introduction
Salt formation
Prodrug
Physiochemical characterization
 Conclusion
 References
 Bulk characterization
 Solubility analysis
 Stability analysis

4.  Preformulation is defined as the phase of research and development in which
preformulation studies characterize physical and chemical properties of drug
molecule in order to develop safe , effective and stable dosage form.
INTRODUCTION
a) Compound identity.
b) Formula and molecular weight.
c) Structure.
d) Therapeutic indications:
- Probable human dose.
- Desired dosage form(s)
- Bioavailability model
- Competitive products
Essential information helpful in design the preformulation evaluation of a new
drug:

5. e) Potential hazards
f) Initial bulk lots:
- Lot number
- Crystallization solvent(s)
- Particle size range
- Melting point
- % volatiles
g) Analytical methods:
- HPLC assay
- TLC assay
- UV/ Visible spectroscopy
h) Key dates
- Bulk scale up
- Toxicology start date
- Clinical supplies preparation
- IND filling
- Phase 1 testing
i)Critical development issues
Essential information helpful in design the preformulation evaluation of a new
drug:

6. SALT FORMATION
 Formed by the addition or removal of a proton to form and ionized drug
molecule, which is then neutralized with a counter ion.
Ephedrine Hydrochloride
Advantages:
 Salts are more water soluble than the corresponding un-ionized molecule.
 Improving bioavailability.

7. PRODRUG
 Synthetic derivatives(e.g. ester and amides) of drug molecules that may have intrinsic
pharmacologic activity but usually must undergo some transformation in vivo to liberate the active
drug molecule.
 Objectives:
 To improve biologic or pharmaceutical properties of a compound.
water
soluble
Rapidly
hydrolyzed in
gastric acid
Water
insoluble
Don’t
hydrolyzed in
gastric acid.
Protonated erythromycin Erythromycin estolate

8. Bulkcharacterization
Polymorphism
Crystallinity
Hygroscopicity
Fine particle
characterization
Bulk densities
Powder flow
properties

9. Polymorphism refers to the arrangement of a drug substance in various crystal forms or
polymorphs.Polymorphs have the same chemical structure but different physical properties. Such as-
solubility, density, hardness and compression and characteristics.
Polymorphism can be classified as one of the two types:
Enantiotrophic: one polymorph can be reversibly changed into another by varing temperature and
pressure.Eg. Sulfur
Monotropic: One polymorph which is unstable at all temp. & pressure is called as Monotropic
polymorph. Eg. Glyceryl stearate
Polymorphism:
Sulfur

10. Crystallinity:
 All of the available forms of a drugs is essential both in terms of optimizing drug
product performance but also ensuring market exclusively .
 Bulk and physicochemical properties (e.g. ranging from flow ability to chemical
stability) are affected by crystal habit and internal structure.
Example: The shelf life of etoposide-
As a non aqueous concentrate in
a sealed vial.
More than 2 years 24 hour
The shelf life
reduces
Diluted for intravenous injection
with saline at 15-25⁰C.

11. Six basic habits described in the USP:
ColumnarTabular
Equant
Plate
Blade
Acicular

12. HYGROSCOPICITY
Hygroscopicity is the capacity of a product to react to the moisture content of the air
by absorbing or releasing water vapor.
It can be graded in terms of water uptake as a function of humidity.
Deliquescent
Very Hygroscopic
Moderately hygroscopic
Slightly hygroscopic
Nonhygroscopic
Moisturecontent(%w/w)
RH(%)Efflorscent
Figure: Definition of hygroscopicity profiles.

13. FINE PARTICLE CHARACTERIZATION:
 The particle size distribution of active ingredients and excipients is an important
physical characteristic of the materials used to create pharmaceutical products. The
size distribution product performance, processability, stability and appearance of the
end product.
API Excipien
t
Product (Proper matching)
Proper matching of active pharmaceutical ingredient and excipient particle size is
important for several process steps.

14. Techniques Parameters measured
Laser diffraction Particle size
Dynamic light scattering Particle size, Zeta potential, molecular
weight
Automated imaging/image analysis Particle size , Particle shape ,Particle count ,
Particle location
Electron stream sensing zone Particle size, particle charge
X ray sedimentation Particle size
Scanning electron microscopy Surface morphology
Various fine particle characterization techniques are-

15. Bulk density :
 It is the ratio of total mass of the powder to the bulk volume of the powder. It is expressed in gm/ml and
is given by-
Where ,M is the total mass of the powder and V˳ is the bulk volume of the powder.
Db = M/V˳
 Bulk density is determined by pouring presieved(40 mesh) bulk into a graduated cylinder via a large
funnel and measuring the volume as is.
 Tapped density is determined by placing a
graduated cyclinder containing a known
mass of drug or formulation on a
mechanical tapper machine, which is
operate for a fixed number of taps(-1000)
until the powder bed volume has reached
a minimum.

16. POWDER FLOW PROPERTIES:
The flow properties depend upon following-
1. Force of friction.
2. Cohesion between one particle to another.
Fine particle posses poor flow by filling void spaces between larger particles causing
packing & densification of particles.
By using glident we can alter the flow properties. e.g. Talc

17. Angle Of
Repose
( In degree)
Type Of Flow
<25 Excellent
25-30 Good
30-40 Passable
>40 Very poor
DeterminationOf Powder Flow Properties:
 By determining Angle Of
Repose.
 A greater angle of repose
indicate poor flow.
 It should be less than 30°.
& can be determined by
following equation.
tan θ = h/r.
where, θ = angle of repose.
h=height.
r= radius.

18.  Measurement of free flowing powder by
compressibility.
 Also known as Carr's index.
CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) X 100
TAPPED DENSITY
 It is simple, fast & popular method of predicting powder
flow characteristics.
Determination Of PowderFlow Properties:

19. Carr’s Index Type of flow
<10 Excellent
11-15 Good
16-25 Fair To Passable
26-31 Poor
32-39 Very Poor
>40 Extremely Poor
Determination Of Powder Flow Properties

20. SOLUBILITY ANALYSIS
 One important goal of the pre formulation effort is to device a method for making solution of the drug
.
 A drug must process some aqueous solubillity for therapeutic efficacy . In order for a drug to enter
the systemic circulation to exert therapeutic effects, it must first be in solution.
 Relatively insoluble compounds often exhibit
incomplete absorption.
 It focuses on drug solvent interaction that could
occur during the delivery of a drug candidate .

21. Ionization
constant-pka
pH solubility
profile
Common ion
effect-ksp
Thermal
effects
Solubilization
Dissolution
Partition
coefficient
Preformulation solubility studies include-

22. Methods for improving drug solubility-
 Chemical modification of the drug into salt or ester form.
 Solubilization by complexation.
 Use of co-solvents.
 Ionization.
 Using surfectants.
 Use of various techniques. Such as- micronization or solid dispersion.
 Adjustment of the pH of the solvent in which the drug is to be dissolved.

23.  In this study includes both solutions and solid-state experiments under various conditions for handling,
formulation, storage, and in vivo administration.
 solution phase stability: The effect of pH on stability is important in the development of both oral and
Parenteral dosage forms
Stability analysis
DRUG STABILITY
 Acid sensitive drugs protected from highly acidic
environment of the stomach by coating it with
suitable polymers.
 Solid phase stability depends on several factors
like temperature, pH, humidity, hydrolysis,
oxidation, etc

24. Compatibility test play a very important role in the preformulation studies of oral dosage
forms.
An incompatibility in the dosage form can result in any of the following changes:
Changes in organoleptic properties.
Changes in dissolution performance.
Physical form conversion.
An decrease in potency.
Drug- excipient compatibility:

25.  Preformulation studies on a new drug molecule provide useful
information for subsequent formulation of a physiochemically stable and
biopharmaceutically suitable dosage form.
 Preformulation work is the foundation of developing efficacious and
economical formulations.
CONCLUSION

26. Leon Lachman, Liberman. The theory and practice of
Industrial pharmacy, Edn 4. CBS publishing house, New
Delhi.2013 p:217-307.
Banker GS, Rhodes CT. Modern pharmaceutics, Edn 4.
Marcel Dekker, NewYork. 2002 p:167-184.
Loyd V . Allen, Nicholas G.popovich, Howard C. Ansel.
Ansel’s pharmaceutical Dosage forms & Drug delivery
systems, Edn 8. B.I.Publication pvt. Ltd, p:187-193,42 &
43,126-133.
Brahmankar D.M, Jaiswal BS. Biopharmaceutics and
pharmacokinetics a Treatise, Edn 2. Vallabh Prakashan,
Nagpur. 2009; p: 37-45
REFERENCE