3. INTRODUCTION
• Prior to the development of any dosage form of new
drug, it is essential that certain fundamental physical &
chemical properties of drug powder are determined .
• “Investigation of physico-chemical properties of the new
drug compound that could affect drug performance &
development of an effective dosage form”.
• The preformulation is the first step in the rational
development of a dosage form of a drug substance alone
and when combined with excipients.
4. OBJETIVES
• To develop the elegant, stable, effective and safe dosage
form by establishing kinetic rate profile, compatibility
with the other ingredients .
• To establish Physico-chemical parameter of new drug
substances.
• To generate useful information to the formulator to
design an optimum drug delivery system.
5. PHYSICOCHEMICAL
PARAMETERS
Organoleptic properties:
Color, Odor & Taste
Bulk characterization:
a) Crystallinity & Polymorphism
b) Hygroscopicity
c) Fine particle characterization
d) Bulk density
e) Powder flow properties
Solubility analysis:
a) pKa determination
b) Partition coefficient
c) Dissolution studies
Stability analysis:
a) Chemical
b) Physical
c) Biological
Compatability
6. ORGANOLEPTIC PROPERTIES
Color:
Color may be off-white, cream yellow, shiny. Should be appealing
to the eyes. Can be checked by instrumental or visible methods.
Coating is done if found undisirable.
Odor & Taste:
Odor may be pungent, sulphurus, fruity, aromatic, & odourless.
Unpalatable drugs need flavors, coating or excipeints.
Taste may be acidic, bitter, bland, intense, sweet and tasteless
Drugs irritating to skin should be handle with precaution.
Flavors, colors, dyes used may affects the stability.
7. BULK CHARACTERIZATION
Crystallinity & Polymorphism:
The internal structure of solid compound - Crystallinity.
Absent in liquid & vapour states.
The crystal habit - outer appearance and internal structure
arrangement.
Change in chemical form alters both. (e.g. Salt)
8. BULK CHARACTERIZATION
Crystallinity & Polymorphism:
Polymorphism is the ability of the compound to crystallize as
more than one distinct crystalline species with different internal
structure.
Formation of different polymorphs depends on solvents,
temperature, pressure, rate of cooling, etc.
Polymorphic transitions can also occur during milling,
granulating, drying and compressing operations
Different polymorphs vary in physical properties such as
dissolution, solid-state stability, compatibility, etc
e.g. Chloramphenicol - A,B,C form, B form is more stable.
Riboflavin - I, II & III form, III shows 20 times more
solubility than I
9. BULK CHARACTERIZATION
Hygroscopicity:
Tendency to absorb moisture - Hygroscopicity.
Depends on relative humidity of the surroundings.
Deliquescent material – absorb sufficient moisture –
dissolve. e.g. NaCl
Efflorescent material - loses water to form a lower
hydrate – e.g. Gypsum (CaSO42H2O – CaSO4)
Thus this affects stability, flow ability &
compatability.
Controlled Temp & Humidity conditions are
required during production.
Methods - Karl Fischer, TGA, GC
10. BULK CHARACTERIZATION
Fine Particle Characterization:
Study of particle size give an information about solubility,
dissolution rate, absorption, bioavailability, content uniformity,
taste, texture, color, flow characteristics, sedimentation rates &
stability.
Particle size and surface area of a solid drug are inversely
related to each other. Smaller particle size greater the surface
area. e.g.: Griseofulvin
The flow properties of a powder will determine the nature and
quantity of excipients needed to prepare a compressed or a
powder dosage form.
Particle size is characterized using terms :
Very coarse (#8), Coarse (#20), Moderately coarse (#40), Fine
(#60), Very fine (#80)
Methods- SEM, Light Microscope with calibrated grid
11. BULK CHARACTERIZATION
Bulk Density:
Amount per unit size or weight per volume. (Bulk &
Tap density)
Varies with method of crystallization, milling
formulation.
Important to know for the selection of high dose
capsule . Low density – Big size
Homogeneity of low dose formulation, where there
are large differences in drug & excipient densities.
Affect the flow properties. Can be corrected by
milling, slugging.
12. BULK CHARACTERIZATION
Powder Flow Properties:
The flow properties depends upon Force of friction
& Cohesion between one particle to another.
Critical for efficient tablet operation such as
compression.
Affected by changes in particle size, density, shape
& adsorbed moisture.
Fine particle posses poor flow by filling void spaces
between larger particles causing packing &
densification of particles
Studied by Angle of Repose.
Altered by using glident/lubricant. e.g. Starch, Talc.
13. SOLUBILITY ANALYSIS
For therapeutic efficacy drug must enter systemic circulation.
To enter systemic circulation is must be in solution form.
Orally administered drug must dissolve in the aqueous fluid of the GIT prior
to absorption.
Insoluble compounds exhibits incomplete absorption (<1%, 10mg/ml).
One Important goal of the preformulation effort is to devise a method for
making solutions of the drug.
Physicochemical properties, pressure, acidity & basicity, physical agitation
etc. affects the solubility.
So, there is a need to perform Solubility analysis to provide a basis for later
formulation work & drug performance.
pH, Temp, Ionic Strength & Buffer Conc. mainly affects solubility of Drug.
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14. 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 14
15. SOLUBILITY ANALYSIS
pKa Determination:
pKa is the dissociation constant of a drug .
The pH at which drug is 50% ionized & 50 % unionized.
Majority of the drug are basic (75%), acids (20%) &
neutral (5%).
• Absorption is governed to a large extent by their degree of
ionization as they are presented to the membrane barrier.
• The unionized substances are lipid soluble where as, the
ionized substances are a lipid insoluble.
• The concept of pKa is derived from the Henderson‐
Hasselbalch equation:
• For acidic compounds pH= pKa + log (ionized drug/
unionized drug)
• For basic compounds pH= Pkw pKb + log (unionized‐
drug/ionized drug)
16. SOLUBILITY ANALYSIS
Partition Coefficient:
Ratio of the unionized drug distributed between organic & aqueous
phase at equilibrium.
K = Co / Cw (At equilibrium)
Where, Co-organic phase concentration
Cw-aqueous phase concentration
Partition coefficient influence permeation of a drug across biological
membrane.
Measurement of a drug’s lipophilicity & an indication of its ability to
cross cell membrane.
Following administration, the drug must travel through a variety of
membranes to gain access to the target area.
Drug with extremely high partition co-efficient (i.e. very oil-soluble )
readily penetrate the membranes.
While drugs with excessive aqueous solubility i.e. low oil/water
partition co-efficient cannot penetrate the membrane.
17. SOLUBILITY ANALYSIS
Dissolution Studies:
Speed or rate at which drug substance dissolves in a medium.
If solubility of drug exceeded 1mg/ml at pH 7, no
bioavailability problem, but below 1mg / ml, quite possible.
To know the gastrointestinal absorption & other
physicochemical properties.
Helpful in developing new drug formulation.
The dissolution rate is described by Noyes-Whiteny
equation.
This equation reveals that the dissolution rate of a drug may
be increased by increasing surface area (reducing particle
size).
18. 18
Poor dissolution rate
Low and variable bioavailability
More potential for food effect
Inability to deliver high doses for toxicity studies
Difficulty in developing parenteral formulations
Solubility can be improved by
Addition of co-solvent,
pH change method,
Reduction of particle size,
Complexation.
Salt formation
FORMULATION CHALLENGES
FOR POORLY SOLUBLE DRUG SUBSTANCES
19. Three types of stability concern the pharmacists:
l. Chemical: Each active ingredient retains its chemical
integrity within the specified limits.
2. Physical: The original physical properties (including
appearance, taste, color and odor) are retained.
3. Biological: Sterility is retained (No microbial growth).
STABILITY
20. Stability is the extent to which a product retains (throughout
its period of storage and use, i.e., its shelf life) the same
properties that it possessed at the time of its manufacture.
One of the principles of dosage form design is to ensure that
the chemical integrity of drug substances is maintained
during the usable life of the product.
In this study includes both solutions and solid-state
experiments under various conditions for handling,
formulation, storage, and in vivo administration.
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STABILITY
21. Solution phase stability: The effect of pH on stability is
important in the development of both oral and Parenteral
dosage forms
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…
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STABILITY
22. Compatibility test play a very important role in the
preformulation studies of oral dosage forms.
Problems arise because of the interaction with other drug
substances and with preservatives, stabilizers, dyes, and
flavors.
It is important for the formulator of a new drug substance to
know with which excipients he can work and which he
cannot.
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COMPATABILITY
23. Preformulation studies have a significant part to play in anticipating
formulation problems and identifying logical path in both liquid and
solid dosage form technology.
Helps in selection of drug candidate itself, suitable dosage form,
excipients, manufacturing process, container closure system etc.
Thorough Preformulation work is the foundation of developing
efficacious and economical formulations.
The most appropriate salt development and Stability studies in
solution will indicate the feasibility of parental or other liquid
dosage form and can identify methods of stabilization.
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CONCLUSION
24. 1. Lachman L, Lieberman H A and Joseph L K: The Theory and Practice of
Industrial Pharmacy.
2. Brahmankar DM and Jaiswal SB: Absorption of drugs in:. Biopharmaceutics
and Pharmacokinetics A treatise.
3. ‘A REVIEW ON PHARMACEUTICAL PREFORMULATION STUDIES IN
FORMULATION AND DEVELOPMENT OF NEW DRUG MOLECULES’
by Gita Chaurasia, Department of Pharmaceutics, Siddhant College of
pharmacy, Sudumbare, Pune, Maharashtra, India.
4. ‘Pharmaceutical Preformulation Studies in Formulation & Development of
New Dosage Form : A Review’ by Garima Verma & Manoj Kumar Mishra,
Int. J of Pharma Research & Review, Oct 2016;5 (10):12-20.
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REFERENCES