Pre-Formulation

1
Content

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

It is defined as " an investigation of physical

and chemical properties of a drug substance – alone
or when combined with excipients.

4
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.

5
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

6
 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
7
 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.

8
Identification / assay of any substance.

1- Spectroscopy
i- IR
ii- NMR
2- MELTING POINT
3-UV
4-HPLC

9
 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

10
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 11

Tapped volume
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.

12
 Relationship between
% Compressibility Range powder
Flowflowability and %
Description
compressibility
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) 13

. 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.
14
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

15
Determination Of Powder Flow Properties

Powder flow properties: Angle of Type of flow Type of

Includes ---- repose powder
a) Angle of Repose
b) Bulk Density <25 Excellent Non cohesive

Greater angle of repose→poor flow. 25-30 Good Non cohesive

It should be less than 30°.
Angle of repose is measured by the equation: 30-40 Passable Cohesive
tanθ = h /r
h = height of conical heap
r = radius of horizontal plane of >40 Very poor Very
powder glidant is to be added Cohesive

16
Determination of Powder Flow Properties

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

17
Determination of Powder Flow Properties

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

18
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)

19
 Particle Size

Important factors influence by particle size:

1- Dissolution rate
2- Suspendability
3- Penetrability

20
Methods to Determine Particle Size

- Sieving
- Microscopy

21
 Methods to Determine Particle Size

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.

22
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."

23
Habit is the description of the outer appearance
of a crystal

24
 Different shapes internal structure of crystals

04/05/2012 KLE College of Pharmacy, Nipani. 25

 Different shapes of crystals

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.

26
 Different shapes of crystals

- 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.

27
 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.
28
 Polymorphism

Polymorph differ from each other with by their

physical property such as:
- Solubility
- Melting point
- Density
- Hardness

29
 Techniques for studies of crystals

Microscopy

Crystalline structures are visible (Refract the polarized light).

Amorphous are invisible

X-ray diffraction

30
 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
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 .

32
 DSC thermograms of
pure acyclovir and pure
ethylcellulose films
acyclovir

Ethylcellulose film

DSC thermograms of
ethylcellulose film
containing acyclovir with
propylene glycol
and Tween

33
 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.

34
 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

35
 SOLUBILITY

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.

36
 Determination of Solubility…

Semiquantitative determination:

Solvent Vigorously Examine

(fixed volume) shaking visually

Adding solute in small

incremental amounts
Undissolved
solute particles ?

No Yes

Total amount
Estimated solubility 37
added up
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
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
38
 Method of Increasing Solubility

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
Stability testing….

40
 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

41
 Drug substances - General case
Minimum time period
Storage condition covered by data at
Study 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 - 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
42
 Testing scope for Solid dosage
Tablet & Capsule
■ Physical-chemical properties
– Appearance
– Moisture
– Hardness
– Disintegration
– Dissolution
■ Chemical properties
– identification
– Assay
■

43
 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

■
44
 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

45
 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

46