This document discusses pre-formulation, which involves investigating the physical and chemical properties of a drug substance alone or combined with excipients. The goal is to develop a stable, effective dosage form. Key tests described include identifying purity, density, compressibility, hygroscopicity, particle size, solid state properties, and compatibility with excipients. Properties like solubility, partition coefficient, and stability are also important to determine for pre-formulation.

1. Pre-Formulation
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2. Content
1- Introduction
2- Definition
3- Objective
4-Preformulation tests
5- References
ANAND PHARMACY COLLEGE, ANAND 2

3. Introduction
Mostly all drugs are marketed as tablets, capsules
or other dosage form . . Before the development of any
dosage form to form new drug for major dosage
forms .
we must be know fundamental physical &
chemical properties of drug powder.
This is known as preformulation
Preformulation testing is the first step in
development of dosage forms. 3

4. Definition
It is defined as " an investigation of physical
and chemical properties of a drug substance – alone
or when combined with excipients.
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5. Goal of preformulation.
1- To formulate an elegant, safe, efficacy , stable dosage
form with good bioavailability.
2- To determine kinetic rate profile.
3- To establish compatibility with common excipients.
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6. Preformulation testing
1-organo-leptic properties of drug
2- purity
3- identification
4- density
5- Compressibility
6- Hygroscopicity
7- Powder flow properties
8-Particle size analysis
9-solid-state properties
10- Excipient compatibility
11- Solubility
12- Stability
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7. Preformulation testing
The prior step in preformulation testing includes
determination of organo-leptic properties
These -- includes description of drug substances by
determination of colour, odour and recording of
specified terminology.
Colour Taste Odour
white Acidic Pungent
Cream yellow Bitter Fruity
Shiny Sweet Aromatic
Tasteless Odourless
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8. Purity:
The investigators ▬►must be sure that the
early samples used for preformulating studies
should be:
1- Pure
2- Presence of impurities must be determined,
Because may affect measured properties.
The tools in assessment of purity include:
►1- For qualitative information →IR and M.P.
►2- For quantitative information→ UV,fluorescens
►3- Other techniques such as TLC, HPLC employed.
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9. Identification / assay of any substance.
1- Spectroscopy
i- IR
ii- NMR
2- MELTING POINT
3-UV
4-HPLC
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10. DENSITY
The ratio of mass to volume is known as density.
Density = Mass (gms.)/ Volume (ml.)
Types of Density :
i- Bulk density
ii- Tapped density
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11. Bulk Density (g/cm3)
Bulk drug powder is sieved through 40 mesh
screen. Weight is taken and poured into a
graduated cylinder via a large funnel. The
volume is called bulk volume.
Apperant Bulk Density = Wieght of powder
Bulk volume
Tapped density (g/cm3)
Bulk powder is sieved through 40 mesh
screen. Weight is taken and poured into a
graduated cylinder. The cylinder is tapped a
mechanical tapper apparatus. The volume
reached a minimum – called tapped volume.
Tapped Density= Wieght of powder
Tapped volume
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12. Compressibility :
Compressibility is the ability of powder to
decrease in volume under pressure.
% Compressibility = Tapped density – bulk density * 100
Tapped density
Empirical guide for flowability is given by the
Carr's compressibility index.
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13. Relationship between powder flowability and %
compressibility
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% Compressibility Range Flow Description
5-15 Excellent (free flowing granules)
12-16 Good ( free flowing powder granules)
18-21 Fair to passable
23-28 Poor
28-35 Poor
35-38 Very poor
>40 Extremely poor ( cohesive powder)

14. . Hygroscopicity
It is the tendency of material to absorb moisture from
atmosphere
Wholly Or partially liquefied forming solution..
Examples:
- Ephedrine
- Hyoscymine
- Phenobarbital
- Pilocarpine
- Glycerinated gelatin & PEG base of
suppository are hygroscopic in nature.
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15. Powder Flow Properties
Flow properties of powder affected by change in
particle size, shape & density.
Flow properties depends upon following-
i- Force of friction.
ii- Cohesion between one particle to another.
Fine particle posses poor flow by filling
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16. Determination Of Powder Flow Properties
Powder flow properties:
Includes ----
a) Angle of Repose
b) Bulk Density
Greater angle of repose→poor flow.
It should be less than 30°.
Angle of repose is measured by the equation:
tanθ = h /r
h = height of conical heap
r = radius of horizontal plane of
powder glidant is to be added
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Angle of
repose
Type of flow Type of
powder
<25 Excellent Non cohesive
25-30 Good Non cohesive
30-40 Passable Cohesive
>40 Very poor Very
Cohesive

17. Measurement of free flowing powder by
compressibility Bulk Density
Also known as Carr's index.
Simple, fast & popular method of predicting powder
flow characteristics.
CARR’S INDEX(%) =(Tapped Density – Poured Density) X 100
Tapped Density
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Determination of Powder Flow Properties

18. Carr’s Index Type of flow
5-15 Excellent
12-16 Good
18-21 Fair To Passable
23-35 Poor
33-38 Very Poor
>40 Extremely Poor
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Determination of Powder Flow Properties

19. Particle Size.
Terms of particle size characterized :
1. Very coarse (#8)
2. Coarse (#20)
3. Moderately coarse (#40)
4. Fine (#60)
5. Very fine (#80)
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20. Important factors influence by particle size:
1- Dissolution rate
2- Suspendability
3- Penetrability
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Particle Size

21. Methods to Determine Particle Size
- Sieving
- Microscopy
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22. 1- Sieving method :
1. Range : 50 – 150 µm
2. Simple, inexpensive
3. If powder is not dry, the apertures get clogged.
2- Microscopy :
1. Range : 0.2 – 100 µm
2. Most direct method.
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Methods to Determine Particle Size

23. Solid-State Properties:
Crystal habit & internal structure of drug can
affect:
Bulk & physicochemical property of molecule.
*Crystal habit " Outer appearance of crystal"
*Internal structure"Mol. arrangement of solid."
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24. Habit is the description of the outer appearance
of a crystal
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25. 04/05/2012 KLE College of Pharmacy, Nipani. 25
Different shapes internal structure of crystals

26. Depending on internal structure compounds is classified as:
1. Crystalline
2. Amorphous
Crystalline state
Atoms / molecules arranged in highly ordered form
Amorphous forms
Atoms / molecules are randomly placed.
Solids do not have any fixed internal structure.
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Different shapes of crystals

27. - Solubility & dissolution rate are greater for amorphous
form then crystalline, as amorphous form has higher
thermodynamic energy.
- Crystalline form has lesser solubility than its amorphous form
- Amorphous forms have greater solubility than its crystalline
forms
Eg. Novobiocin amorphous form well absorbed whereas
Novobiocin crystalline form poorlly absorded.
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Different shapes of crystals

28. Polymorphism
Polymorphs: Where substance exists in more than
one crystalline form.
Such a stable polymorph represents:
- The lowest energy state,
- Highest melting point
- Least solubility
Example
1) Chloromphenicol exist in A,B & C forms,
- B form is more stable & most preferable.
2) Riboflavin has I, II & III forms,
- III form shows 20 times more water
solubility than form I.
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29. Polymorph differ from each other with by their
physical property such as:
- Solubility
- Melting point
- Density
- Hardness
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Polymorphism

30. Techniques for studies of crystals
Microscopy
Crystalline structures are visible (Refract the polarized light).
Amorphous are invisible
X-ray diffraction
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31. DRUG – EXCIPIENT COMPATIBILITY:-
■ The successful formulation of a stable and effective solid dosage form depends on
the careful selection of the excipients which are added to facilitate administration,
promote the consistent release and bioavailability of drug and protect it from
degradation.
Drug No interaction
50% of mixture of Excipient
drug & Excipient DSC recommended
Excipient Interaction
H.P.L.C.
or T.L.C.
Alternative excipient YES Drug No
suggested Breakdown

32. THERMAL ANALYTICAL PROFILE :
Differential Scanning Calorimetry (DSC) and
Differential Thermal Analysis (DTA) measure the
heat loss or gain resulting from physical or chemical
changes within a sample as a function of temperature .
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33. acyclovir
Ethylcellulose film
DSC thermograms of
pure acyclovir and pure
ethylcellulose films
DSC thermograms of
ethylcellulose film
containing acyclovir with
propylene glycol
and Tween
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34. SOLUBILITY
The solubility of drug is an important physicochemical
property because it affects the bioavailability of the
drug, the rate of drug release into dissolution medium
and
SOLUBILITY
The amount of substance that passes into solution in
order to establish equilibrium at constant
temperature and pressure to produce a saturated
solution.
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35. DESCRIPTIVE SOLUBILITIES (I.P.)
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
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36. If solubility is <1mg/ml indicates need for salt formation
to improve solubility.
If solubility is <1mg/ml in pH= 1 to 7, preformulation
study should be initiated.
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SOLUBILITY

37. Solvent
(fixed volume)
Adding solute in small
incremental amounts
Vigorously
shaking
Undissolved
solute particles ?
Examine
visually
Yes
No
Total amount
added up
Estimated solubility
Semiquantitative determination:
Determination of Solubility…
37

38. 3. PARTITION COEFFICIENT
Partition coefficient influence permeation of a drug across
biological membrane.
Partition coefficient. Is a ratio of equilibrium concentration of
drug in oil phase to equilibrium concentration of drug in aqueous
phase .
K = Co / Cw
Co- Organic phase concentrate
Cw- Aqueous phase concentration
Means;
- Drug with extremely high partition co-efficient (i.e. very oil-
soluble ) readily penetrate the membranes.
- Drugs with excessive aqueous solubility i.e. low oil/water partition
co-efficient cannot penetrate the membrane
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K=Co/Cw

39. 1. Addition of co-solvent
2. pH change method
3. Reduction of particle size
4. Temperature change method
5. Salt formation
6. Prodrug
7. Complexation
39
Method of Increasing Solubility

40. Stability testing….
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41. Why Stability?
Stability provide a evidence on how the quality
of a drug substance or drug product varies with
time under the influence of a variety of
environmental factors such as…..
Temperature,
Humidity and
Light
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42. Study Storage condition
Minimum time period
covered by data at
submission
Long term 25°C ± 2°C / 60% ± 5% 12 months
Intermediate 30°C ± 2°C / 65% ± 5% . 6 months
Accelerated 40°C ± 2°C / 75% ± 5% 6 months
Drug substances - General case
Drug substances - intended for storage in a Refrigerator
Study Storage condition Minimum time period
covered by data at
submission
Long term 5°C ± 3°C 12 months
Accelerated 25°C ± 2°C / 60% ± 5% 6 months
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43. Testing scope for Solid dosage
■ Physical-chemical properties
– Appearance
– Moisture
– Hardness
– Disintegration
– Dissolution
■ Chemical properties
– identification
– Assay
■
Tablet & Capsule
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44. Testing scope for Oral liquid form
1- Physical-chemical properties
– pH
– Color & clarity of solution
– Viscosity
– Particle size distribution (suspensions)
2- Chemical properties
– Assay
– identification
3- Microbial properties
■
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45. Testing scope for
LIQUID FORMS for inj. and PARENTRAL
1- Physical-chemical properties
– pH
– Loss on weight
– Color & clarity of solution
– isotonic solution
2- Chemical properties
– Assay
– identification
3- Microbial properties
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46. Testing scope for SEMI LIQUID FORMS
1- Physical-chemical properties
– Appearance, odor, homogenesity, consistency
– Loss on weight, Viscosity
– Content uniformity (within the container)
2- Chemical properties
– Assay
– identification
3- Microbial properties
■
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