Physicochemical properties of drug

1. Need for dosage form;
Pre-formulation Studies
DR MEHREEN RAHMAN
LECTURER, UNIVERSITY OF PESHAWAR

2. Need of Dosage forms
• To provide mechanism for the safe & convenient delivery of accurate dose.
• To protect from environment i.e. destructive effect of oxygen or humidity.
• To protect from the destructive effect of gastric acid after oral
administration Ex. Enteric coated tablet.
• To conceal the bitter, salty, nauseous odor of drug substance. Ex. Capsule,
Coated tablet.
• To provide liquid preparation which are unstable or insoluble in vehicle. Ex.
Suspension
• To provide clear dosage forms of substance. Ex. Syrups , Solutions
• To provide rate controlled drug action. Ex. Sustained Release & Controlled
release Tablets
• To provide optimal drug action from topical administration. Ex. Ointments,
Creams, Patches

3. New Drug
Development Process
from Discovery to
post marketing

4. Isolation/ Chemical Synthesis
Pharmacological Screening
Toxicology
Preformulation Study /
Characterization
Formulation
Phase-I Clinical Study
Phase-II / III Studies
Submission to regulatory authority
Testing

7. Pre-formulation
It is the first step in the rational development of dosage forms of a
drug substance.
It is defined as phase of research and development in which physical and
chemical properties of a drug molecule is investigated, in order to develop safe,
effective and stable dosage form

8. Objectives
1. To establish the physico-chemical parameters of new drug substance.
2. To determine its kinetic rate profile and stability .
3. To establish the compatibility with the common excipient.
4. It provides insights into how drug products should be processed and store to ensure their
quality

9. The formal preformulation study should start at the point after
biological screening, when a decision is made for further
development of the compound in clinical trials.
Before embarking upon a formal program, the preformulation
scientist must consider the following:
1. The available physicochemical data (including chemical
structure, different salts available)
2. The therapeutic class of the compound and anticipated dose
3. The supply situation and the development schedule (i.e., the
time available)
4. The availability of a stability-indicating assay
5. The nature of the information the formulator should have or
would like to have

10. Characterization and its impact
Determination Impacts on
Melting Point or boiling point Purity determination, dosage form design, stability tests
UV absorption spectrum Assay development
IR absorption spectrum Quantitative & qualitative tests
Assay development All qualitative & quantitative tests
Solubility Assay development, dosage form design, stability, bioavailability
pKa (if an acid or base) and pH
solubility profiling
Salt selection, dosage form design, stability, bioavailability
Partition coefficient Dosage form design, stability, bioavailability
Polymorphism Processing, stability, solubility, bioavailability
Microscopic appearance, Particle
Size, Shape & Surface area
Dissolution rate, stability tests
Interaction with excipients Processing, dosage form design, stability, bioavailability
Chemical Stability Profile Pharmacological activity and toxicology
Flowability Formulation Development
Hygroscopicity Stability

11. 1. Stability (2) pH-Solubility Profile
a. Solid State (3) Salt Forms
(1) Temperature (4) Co-solvents
(2) Light (5) Complexation
(3) Humidity (6) Prodrug
b. Solution j. Effect of pH on UV Spectra
(1) Solvent k. Ionization Constant
(2) pH l. Volatility
(3) Light m. Optical Activity
2. Solid State Compatibility n. Polymorphism Potential
a. TLC Analysis o. Solvate Formation
b. DRS Analysis (Dielectric Relaxation Spectroscopy) 4. Physico-mechanical Properties
3. Physico-chemical Properties a. Bulk and Tapped Density
a. Molecular Structure and Weight b. Compressibility
b. Color c. Photomicrograph
c. Odor 5. In Vitro Availability Properties
d. Particle size, Shape, and Crystallinity a. Dissolution of Drug Crystal
e. Melting Point b. Dissolution of Pure Drug Pellet
f. Thermal Analysis Profile c. Dissolution Analysis of Pure Drug
g. Hygroscopicity Potential d. Rat Everted Gut Technique
h. Absorbance Spectra 6. Other Studies
(1) UV a. Plasma Protein Binding
(2) IR b. Effect of Compatible Excipients on Dissolution
i. Solubility c. Kinetic Studies of Solution Degradation
(1) Water and Other Solvents d. Use of Radio-labeled Drug

12. MAJOR AREA OF PREFORMULATION
RESEARCH
A. PHYSICAL CHARACTERISTICS
Organoleptic properties
Bulk characterization:
1. Crystallinity & polymorphism,
2. Hygroscopicity,
3. Fine particle characterization,
4. Powder flow properties.

13. Solubility analysis:
1. Ionization constant –PKa
2. pH solubility profile
3. 3. Common ion effect-Ksp
4. Solubilization
5. Dissolution
6. Partition co-efficient
Stability analysis:
1. Solution stability
2. pH rate profile
3. Solid state stability
4. Bulk stability
5. Stability in toxicology formulation

14. B. CHEMICAL CHARACTERISTICS
Hydrolysis
Oxidation
Photostability
Racemization
Polymerization
Isomerization

15. Organoleptic Properties
Colour, odour, taste and texture of the new drug must be recorded

16. ORGANOLEPTIC PROPERTIES
Color
Unappealing to the eye or
variable from batch to
batch
Instrumental methods
Record of early batches
is very useful for later
production
establishing “specs”
Undesirable or variable
color
incorporation of a dye
in the body or coating

17. Odor and Taste
Unpalatable use of less soluble chemical
form (bioavailability not
compromised!)
suppressed by:
-Flavors
-Excipients
-Coating
Drug substances irritating to skin
or
Sternutatory (sneezing)
handling precautions
Flavors, dyes, excipients used Stability / bioavailability

18. Bulk characterization
Crystallinity
Crystal habit & internal structure of drug can affect
physico-chemical properties which range from flow
ability to chemical stability.
Crystal habit means the description of outer
appearance of a crystal.
Internal structure describes the molecular
arrangement within the solid, changes in internal
structure usually alter crystal habit.
A single internal structure for a compound can have several different habits, depending on
the environment for growing crystals.
Changes with internal structure usually alter the crystal habit while such chemical changes
as conversion of a sodium salt to its free acid form produce both a change in internal structure
and crystal habit.

19. The internal structure of a solid can be classified as:
(i) crystalline (ii) amorphous
Crystals: are characterized by repetitious spacing of constituent atoms or molecules
in a 3D array.
Amorphous forms: have atoms or molecules randomly placed as in a liquid.
Note: amorphous forms are usually of higher thermodynamic energy than
crystalline forms
solubilities as well as dissolution rates are greater.
Eg; Amorphous form of Novobiocin is well absorbed whereas crystalline
form has poor absorption
Disadv. of amorphous : Upon storage, amorphous solids tend to revert to
more stable forms thermodynamic instability, which occur during bulk processing
or within dosage forms.

20. A crystalline compound contain either: stoichiometric or
nonstoichiometric amount of crystallization
solvent.
1. Nonstoichiometric adducts (inclusions or
clathrates) involve entrapped solvent molecules
within the crystal lattice.
Disadv: undesirable, owing to its lack of reproducibility, and
should be avoided for development.
2. Stoichiometric adduct (solvate) crystallizing
solvent molecules incorporated into specific sites
within the crystal lattice.
Note: When the incorporated solvent is water, the complex is
called a hydrate, and the terms hemihydrate, monohydrate, and
dihydrate describes hydrated forms while if a compound is not
containing any water within its crystal structure is termed
anhydrous.

21. Hydrate compounds have
aqueous solubilities less than their
anhydrous forms.
Conversion of an anhydrous
compound to a hydrate within the
dosage form
reduce the dissolution rate and
extent of drug absorption.

22. Polymorphism
It is the ability of a compound or element to crystalize as more than one distinct crystalline species with
different internal lattices.
Different crystalline forms are called polymorphs
Change in chemical stability and solubility
impact a drug's bioavailability and its development program.
Polymorphs are of 2 types
The polymorph which can be changes from to another by varying temperature or pressure is called
enantiotropic polymorphs.
Eg: Sulphur
One polymorph which is unstable at all temperature and pressure is called as monotropic polymorphs.
Eg: glyceryl sterate

23. Polymorphs differ from each other with respect to their physical
properties
1. Solubility
2. Melting point
3. Density
4. Hardness
5. Compression
Chloramphenicol palmitate exists in three crystalline polymorphic
forms (A, B, and C) and an amorphous form.
The relative absorption of polymorphic forms A and B from oral
suspensions; represent an increase in a "peak" serum levels as a the
percentage of form B polymorph increase (more soluble& stable
polymorph.

24. Analytical methods for characterization of solid form
1. Microscopy
2. Hot stage microscopy
3. Thermal Analysis
4. X ray Diffraction
5. Infrared (IR) spectroscopy
6. Proton magnetic resonance (PMR)
7. Nuclear magnetic resonance (NMR)
8. Scanning electron microscopy (SEM)

25. During the pre-formulation phase, the following should be investigated:
1. How many polymorphs exist?
2. What is the stability of each form?
3. What is the solubility of each form?
4. Decide which polymorphic form of the drug will be best suited to processing
into the desirable dosage form.
5. Prevent transitions to the unwanted polymorph(s).
Polymorphic transitions can have a profound effect on granule processing,
possibly influencing tablet hardness & dissolution rates. Examples include:
1) The transitions between different polymorphic forms of carbamezepine cause
a reduction in granule yield, in turn affecting tablet hardness & tablet
dissolution.
2) Different etoposide polymorphs exhibit differing dissolution rates.
3) Different polymorphic forms of chloramphenicol hydrate show different
bioavailabilities.

26. Conduct polymorphism
screening on drug
substance
Can different
polymorph
formed?
Characterize the
form e.g. X-Ray,
microscopy
spectroscopy
Do they have
different
properties
solubility,
stability, m.p. etc
Drug safety
performance or
efficacy effected
Set acceptance criteria for
polymorph content in the drug
substance
Does the drug product performance testing
provide adequate control of the polymorph
ratio changes? (e.g. dissolution)
Monitor polymorph
forms during stability
of drug product
Does change occur
which could affect
safety
Establish acceptance
criteria which are
consistent with safety &
efficacy
No
further
action
NO
YES
YES
YES
NO
YES
Establish acceptance
criteria for the relevant
performance
No need to set
acceptance
criteria for
polymorph
change in drug
product
N
O
N
O
YES
YES

28. Hygroscopicity is tested by
Samples are exposed to moisture
Exposed to control relative humidity environment
Moisture uptake is monitored at different time points
Analytical methods used
1. Gravimetry
2. Karl Fisher titration
3. Gas chromatography

29. PARTICLE SIZE, SHAPE, AND SURFACE AREA
Effects of particle size distribution and shape on:
Chemical and physical properties of drug substances.
Bioavailability of drug substances (griseofulvin,
chlorpropamide).
Flow and mixing efficiency of powders and granules in
making tablets.
Fine materials tend to require more amount of
granulating liquid (cimetidine).
Stability, fine materials relatively more open to attack
from atmospheric O2, heat, light, humidity, and
interacting excipients than coarse materials.

30. PARTICLE SIZE, SHAPE, AND SURFACE AREA
Effects of particle size distribution and shape on:
Chemical and physical properties of drug substances.
Bioavailability of drug substances (griseofulvin,
chlorpropamide).
Flow and mixing efficiency of powders and granules in
making tablets.
Fine materials tend to require more amount of
granulating liquid (cimetidine).
Stability, fine materials relatively more open to attack
from atmospheric O2, heat, light, humidity, and
interacting excipients than coarse materials.

31. Table 2. Influence of Particle Size on Reaction of Sulfacetamide
with Phthalic anhydride in 1:2 Molar Compacts after 3 hr at 95
°C
Particle size of % Conversion
sulfacetamide + SD
(mm)
128 21.54 + 2.74
164 19.43 + 3.25
214 17.25 + 2.88
302 15.69 + 7.90
387 9.34 + 4.41
Weng and Parrott

32. Very fine materials are difficult to handle, overcome by creating solid solution
in a carrier (water-soluble polymer).
Important to decide, maintain, and control a desired size range.
Safest - grind most new drugs with particle diameter > 100 mm (~ 140 mesh)
down to ~ 10 - 40 mm (~ 325 mesh).
Particles with diameter < 30 mm (~ 400 mesh), grinding is unnecessary except
needle-like => improve flow.
Drawbacks to grinding:
- material losses
- static charge build-up
- aggregation => increase hydrophobicity
=> lowering dissolution rate
- polymorphic or chemical transformations

34. General Techniques For Determining Particle Size
Microscopy
Most rapid technique.
But for quantitative size determination requires
counting large number of particles.
For size ~ 1 mm upward (magnification x400).
Suspending material in non-dissolving fluid (water or
mineral oil)
Polarizing lens to observe birefringence => change in
amorphous state after grinding?

35. Sieving
Quantitative particle size distribution analysis.
- For size > 50 mm upward.
- Shape has strong influence on results.

36. Electronic means
 To encompass most pharmaceutical powders
ranging in size 1 - 120 mm:
 Blockage of electrical conductivity path
(Coulter)
- Light blockage (HIAC) [adopted by USP]
- Light scattering (Royco)
- Laser scattering (Malvern)

37. Other techniques
Centrifugation
Air suspension
Sedimentation (Adreasen pipet, recording balance)
Disfavor now because of their tedious nature.

38. Common Techniques for Measuring Fine Particles of Various
Sizes
Technique Particle size (mm)
Microscopic 1 - 100
Sieve > 50
Sedimentation > 1
Elutriation 1 - 50
Centrifugal < 50
Permeability > 1
Light scattering 0.5 - 50
(Parrott)

39. Determination of Surface Area
Surface areas of powders
=> increasing attention in recent years: reflect the particle size
Grinding operation:
particle size => surface area.
Brunauer-Emmett-Teller (BET) theory of adsorption
Most substances will adsorb a monomolecular layer of a gas under
certain conditions of partial pressure (of the gas) and temperature.
Knowing the monolayer capacity of an adsorbent (i.e., the quantity of
adsorbate that can be accommodated as a monolayer on the surface of a solid,
the adsorbent) and the area of the adsorbate molecule, the surface area can, in
principle be calculated.

40. Today’s writing Boot Camp!!!