Preformulations

1. PREFORMULATIONS
Dr. Basavaraj K. NanjwadeM. Pharm., Ph. D
Department of Pharmaceutics
Faculty of Pharmacy
Omer Al-Mukhtar University
Tobruk, Libya.
E-mail: nanjwadebk@gmail.com
2014/06/10 1
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

2. CONTENTS
• Concept of preformulation
• Physical properties (description, particle size)
• Partition coefficient
• Polymorphism,
• Solubility
• Salt formation
• Chemical properties
• Drug stability
• Hydrolytic degradation
• Drug-excipient interaction
• Permeability
• Proteins and peptides
• Formulation ingredients
• References
2014/06/10 2
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

3. Concept of Preformulation
• Prior to the development of tablets, capsules and
injections are major dosage forms, it is essential that
certain fundamental physical and chemical properties
of the drug molecule and other derived properties of
the drug powder are determined.
• This information dictates many of the subsequent
events and approaches in formulation development.
• This first learning phase is known as preformulation.
2014/06/10 3
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

4. Importance of Preformulation
 To form desired quality dosage forms.
 To achieve high degree of uniformity, physiological
availability and therapeutic qualities.
 To develop an optimum dosage form.
 For targeted drug delivery systems.
 For patient compliance.
 To minimize cost of finished product.
 To minimize errors in formulation of dosage form.
2014/06/10 4
Faculty of Pharmacy, Omer Al-Mukhtar
University, Tobruk, Libya.

5. Physical properties
(Description)
• The physical properties of drug molecules can affect the
structure and stability of formulations and may also alter the
bioavailability of the drugs from the dosage forms.
• Hence, physical properties of drugs are important in the
dosage form design.
• The following physical properties influence dosage form
design.
1. Particle size
2. Polymorphism
3. Salt
2014/06/10 5
Faculty of Pharmacy, Omer Al-Mukhtar
University, Tobruk, Libya.

6. Physical properties
(Particle size)
• Small particles are particularly important in low-dose
high-potency drug candidates, as large particle
populations are necessary to ensure adequate blend
homogeneity, and for any drug whose aqueous
solubility is poor, as dissolution rate is directly
proportional to surface area.
• Commercial powders consist of aggregation of small
particles.
• The particles size is usually denoted as coarse
powder, fine powder and very fine powder etc.
2014/06/10 6
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

7. • In aerosols the particle size of 0.5 to 4 microns is
optimal to exhibit its action.
• Particle size is also an important parameter in
determining sedimentation rates in suspensions and
emulsions.
• The simplest method for small quantities is the
microscope.
• The Coulter Counter and laser light scattering are
widely used for routine bulk analysis and research.
Physical properties
(Particle size)
2014/06/10 7
Faculty of Pharmacy, Omer Al-Mukhtar
University, Tobruk, Libya.

8. Partition coefficient
• When a solute is shaken with two immiscible liquids,
solute itself distribute in the liquids in such a way that
the concentration solute in the both the liquids will be
the constant temperature.
• If C1 and C2 are the concentration of the substances in
solvent 1 and 2, the distribution coefficient or
partition coefficient K = C1/C2.
• Partition coefficients of a drug are helpful in the
study of its absorption, distribution, metabolism and
elimination.
2014/06/10 8
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

9. Polymorphism
• It is the ability of the compound to crystallize
as more than one distinct crystalline species
with different internal lattice.
• Different crystalline forms are called
polymorphs.
• Polymorphs are of 2 types
1. Enatiotropic
2. Monotropic
2014/06/10 9
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

10. Parameters of polymorphs
to investigated are
1.No.of polymers that exist
2. Relative degree of stability
3. Presence of glassy state
4. Stabilization of metastable forms
5. Solubility
6. Temperature stability range
2014/06/10 10
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

11. Solubility
• The amount of substance that passes into solution in order to
establish equilibrium at constant temperature and pressure to
produce a saturated solution.
 If solubility is < 1 mg/ml indicates need for salt formation to
improve solubility.
 If solubility is < 1 mg/ml in pH= 1 to 7, preformulation study
should be initiated.
 Solubility should ideally be measured at two temperatures:
4°C and 37°C.
 4 °C to ensure Physical stability.
 37 °C to support Biopharmaceutical evaluation.
2014/06/10 11
Faculty of Pharmacy, Omer Al-Mukhtar
University, Tobruk, Libya.

12. Descriptive Solubility
2014/06/10
Faculty of Pharmacy, Omer Al-Mukhtar
University, Tobruk, Libya.
12
Description Parts of solvent required for
one part of solute
Very soluble < 1
Freely soluble 1 - 10
Soluble 10 - 30
Sparingly soluble 30 - 100
Slightly soluble 100 - 1000
Very slightly soluble 1000 - 10,000
Insoluble > 10,000

13. Solubility Analysis
 Preformulation solubility studies focus on drug solvent
system that could occur during the delivery of drug
candidate.
 For e.g. A drug for oral administration should be
examined for solubility in media having isotonic chloride
ion concentration and acidic pH.
 Analytic method that are particularly useful for solubility
measurement include HPLC, UV spectroscopy,
Fluorescence spectroscopy and Gas chromatography.
 Reverse phase HPLC offer accurate and efficient mean
of collecting solubility data of drug.
2014/06/10
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.
13

14. Salt formation
• Salts prepared from strong acids or bases are freely
soluble but very hygroscopic.
• It is often better to use a weaker acid or base to form
the salt, provided any solubility requirements are met.
• A less soluble salt will generally be less hygroscopic
and form less acidic or basic solutions.
• The dissolution rate of a particular salt is usually
much greater than that of the parent drug.
• Sodium and potassium salts of weak acids dissolve
much rapidly than do the parent acids.
2014/06/10 14
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

15. Chemical properties
• Cyclodextrine molecule have cylindrical shape with
central axial cavity and resembles with shape of
truncated cone.
• The interior cavity is hydrophobic and the outside of
the molecule is hydrophilic.
2014/06/10 15
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

16. Drug stability
• The potency should not fall below 95% under the
recommended storage conditions and the product
should still look and perform as it did when first
manufactured.
• Drug degradation occurs by four main processes;
1. Hydrolysis
2. Oxidation
3. Photolysis
4. Trace metal catalysis
2014/06/10 16
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

17. Hydrolytic degradation
• The most likely cause of drug instability is
hydrolysis.
• Water plays a dominant role and in many cases it is
implicated passively as a solvent vector between two
reacting species in solution.
• The solution is often saturated, so that studies in
dilute solution can be completely misleading.
• Hydrolytic reactions involve nucleophilic attack of
labile bonds
• When this attack is by a solvent other than water it is
known as solvolysis
2014/06/10 17
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

18. • Some interactions between the drug molecules and
the additives are given below,
1. Carboxymethyl cellulose forms complex with
quinine, procaine etc.
2. Carrageenan forms complex with chlorpromazine,
antihistamine etc.
3. Sodium alginate forms complex with Ca ++
ions.
4. PVP and polyethyleneglycol interact with phenolic
groups of resorcinol, tannic acid leading to
precipitation.
Drug-excipient interaction
2014/06/10 18
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

19. Permeability
• Measuring the rate of permeation across membranes
that are used to gain an assessment of oral absorption
in humans.
• These range from computational predictions and both
physicochemical and biological methods.
• The biological methods can be further subdivided
into in vitro, in situ and in vivo methods.
• In general, the more complex the technique the more
accurate is the assessment of oral absorption in
humans.
2014/06/10 19
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

20. Proteins and peptides
• Nowadays most proteins and peptides used in therapy or
under development are produced by recombinant DNA or
hybridoma technology (known as biotechnology or
biotech products).
• It is clear that pharmaceutical proteins and peptides offer
special challenges to the pharmaceutical formulator.
• Proteins and peptides structure, being stabilized by
relatively weak physical bonds, is readily and irreversibly
changed.
• Examples are human insulin, erythropoietin, monoclonal
antibodies, cytokines and interferons
2014/06/10 20
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

21. Formulation ingredients
Components Quantity
Phenobarbital 65.0 mg
Lactose (fine powder) 40.0 mg
Starch 10.0 mg
Starch paste q. s.
Talc 10.0 mg
Mineral oils 4.0 mg
2014/06/10 21
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.

22. THANK YOUe-mail: nanjwadebk@gmail.com
2014/06/10 22
Faculty of Pharmacy, Omer Al-Mukhtar University,
Tobruk, Libya.