SOLID-STATE PROPERTIES IN PREFORMULATION

C E N T R E F O R P H A R M A C E UT I C A L S C I E N C E S
JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY
KUKATPALLY, HYDERABAD-500085.
(2010-2012).
The solid-state properties estimated in preformulation are:

 Particle size

 Particle surface area

 Flow properties

 Crystallinity & Polymorphism

 Hygroscopicity

 Moisture content

 Melting point

 Purity
PARTICLE SIZE:

Study of particle size gives an information about solubility, dissolution rate

and absorption.

 Particle size and surface area of the solid drug are inversely related to each
other.
ex: Griseofulvin

 Particle size should be uniform for both API and excipients. This is to
ensure uniform distribution of dose and to prevent any interactions due to
uneven sizes of the particles.
METHODS OF DETERMINATION OF PARTICLE SIZE:

SIEVING METHOD:

Particle size range between 50 and 1500 µm are estimated by sieving method.

This method directly gives weight distribution.

Percent of coarse particle as quickly estimated

Sieve shaker
 Designations and dimension of I.P specification sieve

Sieve Aperture Sieve Aperture

number size number size
micrometer micrometer
10 1700 44 325

12 1400 60 250

16 1000 85 35

22 710 100 36

25 600 120 34

30 500 150 36

36 425 170 35
SEDIMENTATION METHOD:

This method may be used over a size range of 1 to 200µm.

In this method, sedimentation of particles are evaluated by different techniques-

Andreasen pipette method.

Balance method.

Hydrometer method.
Andreasen pipette
procedure
Andreasen pipette consist of 550ml of vessel containing 10ml pipette
sealed into a ground glass stopper.
The pipette is placed in cylinder, it’s lower tip is 20cm below the surface of
the suspension.

Prepare 1 or 2% suspension of powder in suitable medium. A

deflocculating agent will helping uniform distribution.

Transfer the suspension into the andreasen vessel.

Place the stopper and shake the vessel to distribute the suspension
uniformly.

At various time intervals 10ml samples are withdrawn and discharge by
means of two-ways stopcock.

The samples are evaporated and weighed.

Coulter counter method (or) conductivity method:

The particle size ranging from 0.5 to 500 micrometer is measured by this
method.
This method gives number distribution. In this particle is measured and
converted into particle diameter.
Optical Microscopy method:

particle size ranging from 0.2 to 100 micrometer.

Microscopic method is used in the particle size determination of

suspension, emulsion and aerosols.
This is the tedious but more accurate method for small quantities.

In this method, the particle size is estimated using an eye-piece

micrometer, previously calibrated using a stage micrometer.

This method directly gives number distribution, which can further

be converted to weight distribution.

 The disadvantage of this method is estimation of the depth of the

particle can not be determine.

Large sample is required.

 Particle surface area:

The particle surface area is a function of drug solubility or dissolution rate

and hence forms an important basis in preformulation study.

Dissolution rate of a substance is directly proportional to its surface area

METHODS FOR DETERMINATION OF SURFACE AREA:

 Adsorption Method.

 Air permeability method.

 Bet technique.
Adsorption method

Particles with a large specific surface area are good adsorbents for the
adsorption of gases and solutes from solution.

The adsorbed layer is monomolecular at low temaperature and become

multimolecular at high temperature.

This principal is used to estimate specific surface area.

Air pemeability method:

The prinicpal resistance to the flow of fluid such air through a plug of
compacted powder is the surface of the powder.

The greater is the surface area, the greater is the resistance to flow.

this method powder is packed in the sample holder as a compact plug.

In this packing, surface surface contacts between particles appear as a

series of capillaries

The surface area of these capillaries is function of the surface area of

the powder.
The air, which is allowed to pass, travel through these capillaries and
thus the method is related to surface area of powder.

When the air is allowed to pass through the powder bed at a constant
pressure, the bed resist the flow of air. This results in the pressure drop.

The permeability of air for a given pressure drop is inversely

proportional to specific surface.
Fisher subsieve sizer:

Commercially used for surface area measurement.

Bet technique:

Proposed by scientists, Braunauer, Emmette, and Teller.

This method represents the multi molecular adsorption of gases over the
solid drug particles.

In this method the preferred gases are inert gases like nitrogen and
krypton. The volume of gas filled in the container is first measured.

Nitrogen is used for samples exhibiting larger surface areas, while smaller
surface area materials are measured using krypton.

The low vapor pressure of krypton causes large amount of gas to be

absorbed on the solid, and hence gives more accurate results.
Flow properties

Irregular flow of the powders from hopper producess tablets with

nonuniform weights.

Flow property depends upon the particle size and shape, porosity and
density of the bulk powder.
particle size:

If the particle size is small, the powder flow is restricted owing to
cohesion of particles.

As the particle size increases the flow of powder increases

Nature of the particle:

Smooth surface of the particle improves the flow.

Surface roughness leads to poor flow due to friction, cohesiveness

Moisture content:

The higher the moisture content the greater the risk of cohesion and
adhesion
Angle of repose:

The angle repose is defined as the maximum angle possible between the surface
of the pile of powder and the horizontal plane

SNO Angle of Type of flow

response
1 <25 Excellent

2 25-30 Good

3 30-40 Passable

4 >40 Very poor

Carr’s index = (Tapped density – Poured density) * 100 / Tapped density.

SNO CARR’S INDEX TYPE OF FLOW

(%)
1 5-15 Excellent flow

2 12-16 Good flow

3 18-21 Fair to Passable

flow
4 23-35 Poor flow

5 33-38 Very poor flow

6 >40 Extremely poor

flow
Hygroscopicity
 Hygroscopicity is the ability of a substance to attract water
molecules from the surrounding environment by absorption or
adsorption .
These phenomena of either absorption or desorption of moisture
occurs as a function of relative humidity (RH) of atmosphere.
Samples of bulk drug are placed in a open containers with a thin
powder bed to assure maximum atmospheric exposure . Samples
are then exposed to a controlled relative humidity environments
prepared with saturated aqueous salt solution .
The moisture uptake should be monitored at time points
representative of handling (0 to 24 hours) and storage (0 to 12
weeks)
METHODS OF DETERMINATION OF HYGROSCOPICITY:

DYNAMIC VAPOR SORPTION:

Measurement of hygroscopicity can be carried out using a DVS sorption

Analyzer

The RH is generated by bubbling nitrogen through a water reservoir

where it is saturated with moisture. By the use of a mixing chamber, the
moist nitrogen is mixed with dry nitrogen in a fixed ratio, thus producing
the required RH.

The moist nitrogen is then passed over the sample and the instrument is
programmed such that the increase in weight due to moisture is monitored
with time using an ultra- sensitive microbalance.
The compound takes up moisture and reaches equilibrium, at which point,
the next humidity stage starts.

The absorption and desorption of moisture as well as effect of temperature

can be studied in this method.

Also this method is of major application in preformulation as a small

quantity of even 1 mg can be assessed.
ISOTHERMAL MICROCALORIMETRY:

This technique is used to measure the hygroscopicity of small quantity of

drug substance.

The instrument utilizes a perfusion attachment with a precision flow

stitching valve.

The moist gas is pumped into a reaction ampoule through two inlets, one
that delivers dry nitrogen at 0% RH and the other that delivers the nitrogen
that has been saturated by passing it through two humidifier chambers
maintained at 100% RH.

Another technique of microcalorimetry is the internal hygrostat method,

i.e. static mode. In this method, the compound is sealed into a vial with a
sealed pipette tip containing the saturated solution to give the required RH
 CRYSTALLINITY & POLYMORPHISM

Habit is the outer appearance of crystal

Internal
structure

• Repeated spacing of atoms •Randomly placed molecules

• Have less energy •Have more energy
• Need lot of energy to break •Need less energy to break crystalline form
crystalline form •So solubility is high
• So Solubility is low
 POLYMORPHISM

Ability of compound to crystallize as more than 1 distinct crystalline

species with different internal lattices

eg : sulphur eg : glyceryl stearates

DIFFERENTIAL SCANNING CALORIMETRY (DSC):

It is a thermal analytical method of characterization of polymorphs.

There are two types of DSC:

Heat flux type:

Here, the sample and reference cells are heated at a constant rate and
thermocouples are used to detect the extent of the differential heat transfer
between the two pans.

Power compensation type:

In this type of calorimeter, if an exothermic or endothermic reaction occurs
when the sample is heated, the power added or subtracted to one or both of
the furnaces to compensate for the energy change occurring in the sample is
measured.
In both instruments, a few mg of sample are weighed into an aluminum
pan that can be open, hermetically sealed, or pierced to allow the escape of
water, solvent or decomposition products form pyrolysis reactions
HOT STAGE MICROSCOPY(HSM):
X-RAY POWDER DIFFRACTION:
SOLUTION CALORIMETRY

Solution calorimetry involves the measurement of heat flow when a

compound dissolves into a solvent.

There are two types of solution calorimeters, i.e.

Isoperibol
Isothermal

In the Isoperibol technique, the heat change caused by the dissolution of the
solute gives rise to a change in the temperature of the solution.

This results in a time-temperature plot from which the heat of solution is

calculated.

In the Isothermal technique, any heat change is compensated by an equal, but
opposite, energy change, which is the heat of solution.
It is also used to evaluate amorphous and crystalline content in a binary
mixture, since the enthalpy of solution of amorphous compound is an exothermic
event whereas that of crystalline form is an endothermic event
REFRACTOMETRY:

Different polymorphs have different internal structures and they will

belong to Different crystal systems;

Therefore, polymorphs can be distinguished using polarized light and a

microscope.

The crystals can be either isotropic or anisotropic. In isotropic crystals, the

velocity of light is same in all directions, whereas anisotropic crystals have
two or three different light velocities or refractive indices.
MOISTURE CONTENT

Moisture content in a drug substance may be a characteristic (as in case

of hydrates) but mostly is a function of impurity of the substance.

It leads to degradation, polymorphism and also causes incompatibility

with other excipients.
In case of solid dosage forms it also causes poor compaction.

METHODS OF DETERMINATION OF MOISTURE CONTENT:

Karl fischer titration method:

Loss on drying:
KARL FISCHER TITRATION METHOD:

Two methods of titration depending on whether the end point is detected

visually or electrometrically are specified.

The visual method is only applicable to colorless solutions but can be used
when no electrometric apparatus is available.

The electrometric method, whether by direct titration or back-titration, is

the more accurate one and for this reason recommended.

The principle of the test consists in reaction of any water present in a test
portion with a solution of iodine and sulphur dioxide in a pyridine/methanol
mixture (Karl Fischer reagent), previously standardized by titration with an
exactly known mass of water.
LOSS ON DRYING:

In this method, a weighed quantity of substance is taken and placed in

a drier for a considerable period of time and the weight after drying is
estimated.

The difference of both the weights gives the moisture content of the
substance.
MELTING POINT

The melting point of a pure crystalline solid is defined as the

temperature at which the pure solid and liquid exist in equilibrium.

DETERMINATION OF MELTING POINT:

 CAPILLARY MELTING:

 HOT STAGE MICROSCOPY (HSM):

 PURITY

DETERMINATION OF PURITY:

 Melting Point Depression Method

The melting point of a pure crystalline solid is defined as

the temperature at which the pure solid and liquid exist in
equilibrium.

 Differential Scanning Calorimetry

 HPLC Method
REFERENCES:

 Lachman L, Liberman HA, Kanig JL. The Theory and Practice of

Industrial Pharmacy.

 Subrahmanyam CVS. Textbook of Physical Pharmaceutics.

Wikipedia..com.

Martin’s Physical pharmacy and pharmaceutical sciences