DEFINITION:
Characterization of physical, chemical and mechanical
properties of new drug molecule in order to develop safe,
effective,and stable dosage form.
GOAL OF PREFORMULATION:
To formulate an elegant, safe, efficacious dosage form
with good bioavailability.
To formulate new dosage form of already existing drug.
Determination of all the properties of drug and the best
suitable dosage form for the drug molecule.
Pharmaceutical factor mainly include those parameters of drug
which affect the final dosage form manufacturing process like…..
Flow property
Density
Compressibility
Hygroscopicity
Electrostatic charge
Osmolarity
Rheology
Wettability
Syringabilty
1)FLOW PROPERTY
(A) Introduction



Flow property is an important factor that determines the fate of
drug molecule.
Sufficient flow is required for uniformity of dosage form. So it
is necessary to judge the flow of material in preformulation
stage of the dosage form.
However extreme increase in flow may improve weight
uniformity but may reduce content uniformity through
increased segregation.
(B) Method of determination
 By Angle of repose
 By hopper flow rate
 By bulk density
 By angle of spatula
 By vibrational capillary method
LATEST TECHNOLOGY TO DETERMINE FLOW PROPERTY

REPOSOGRAPH:

It is a stable instrument which at best can only indicate
comparative flow properties.
The formation of sharp cone would mean poor flow
property while a good spread would indicate a superior
flow property.

FT (FREEMAN TECHNOLOGY) RHEOMETER:
• An instrument for measuring flow property.
• It can discriminate between the samples that differ
by 1% Moisture.
• Important for optimizing granulation because
moisture variation have significant impact on final
product quality.

NEW MEASUREMENT SYSTEM TO EVALUATE
POWDER FLOWABILITY BASED ON
VIBRATIONAL CAPILLARY METHOD:
 Evaluates flowability of micrometer sizes particles
under actual flow condition.
 The amplitude and frequency of vibration is
controlled by computer and mass of powder
discharged from vibrating capillary tube is
measured by digital balance.
 The mass flow rate is measured by digital
processing.
[Chemical Abstract ,Jan. 2007, 146:9806]
Angle of Repose
 Indirect method of quantifying powder flowability,because

of their relationship with interparticle cohesion.
It is a maximum angle between the surface of a pile of
powder & horizontal plane.

Angle of repose is measured by the equation:
tanθ=h /r
here, h=height of conical heap &
r=radius of horizontal plane of powder
DETERMINATION OF
ANGLE OF REPOSE
Static angle of repose
Fixed height cone,
Fixed base cone,
Tilting table
Dynamic angle of repose
Rotating cylinder
Rotating Drum
Drained angle of repose
Ledge type,
Crater type
RELATION BETWEEN ANGLE OF REPOSE & TYPE
OF FLOW & TYPE OF POWDER
Angle of
repose
<25
Type of flow
Excellent
Type of
powder
Non cohesive
25-30
Good
Non cohesive
30-40
Passable
Cohesive
>40
Very poor
Very Cohesive
HAUSNER’S RATIO

This is a simplex index that can be determined on
small quantities of powder.
Hausner-ratio= Tapped densityβ max)
poured density(Pβ min)
Hausner ratio
Type of Flow
<1.25
1.25-1.5
>1.5
Good flow
Moderate
Poor flow
(C) FACTOR AFFECTING FLOW
PROPERTY

Particle size and Particle size distribution

Particle shape and Surface roughness

Density and Porosity

Hygroscopicity

Electrostatic charge
(D) IMPROVEMENT OF
FLOWABILITY








By addition of glidant
By addition of fine or by size reduction
By wet granulation
By removing static charge
By densification with the help of slugging
Using auger feed equipment
By addition of flow activator. Eg. MgO
By use silicon treated powder for Hygroscopic &
moist powder. e.g. silicon coated talc or Nabicarbonate
 By altering process condition like vibration assisted
hopper or forced feeder
 By use of spray drying : Advantose 100 maltose
powder has improved flow property than MCC by
using this process.
2. DENSITY
(A) INTRODUCTION :
The ratio of mass to volume is known as
density.
Density = Mass (gms.)/ Volume (ml.)

TYPES OF DENSITY :
(a) Bulk density
(b)Tapped density
(c)True density
(d)Granule density :- may affect
compressibility, tablet porosity,
disintegration, dissolution
(B) Method of Determination
Parameter
Method
1. Bulk density
Measuring cylinder
2. Tapped Density
Mechanical Device
Mercury Displacement
3. True Density
Helium densitometer
(Helium Pycnometer)
Mercury Instrution
Porosimetry
Bulk density measurement :

It is determined by pouring
presieved (40-mesh) bulk drug into a
graduate cylinder via-a large funnel
and measuring the volume and
weight.
Tapped density measurement:

It is determined by placing a
graduated cylinder containing an
known mass of drug or formulation
on a mechanical tapper apparatus,
which is operated for a fixed
numbers of taps(about-1000)untill
the powder bed volume has reached
a minimum.
Measurement of True Density:
True density can be determined using
three methods:
 displacement of a liquid,
 displacement of a gas (pycnometry), or
 floatation in a liquid.
 The liquid displacement is tedious and
tends to underestimate the true density.
 Displacement of a gas is more
accurate, but needs relatively
expensive instrumentation. Gas
pycnometers rely on the measurement
of pressure changes, as a reference
volume of gas, typically helium, added
to, or deleted from, the test cell.
 As an alternative, the floatation method
is simple to use and inexpensive.

An improved method for fast online
measuring of density of solid
substances:
A densitometer for measuring of bulk density of solid
& liquid consists of one vibrator means, to support
pre-weighed samples to be tested in container with
predefined shapes on this vibrator & atleast one
ultrasonic sensor operatively connected to control
unit such that sensor is adapted to transmit and
receive reflected ultrasonic pulses to ascertain
density of samples utilizing the said values of the fill
levels of samples in containers.
(chemical abstract ,October 2007)
(C) CORRELATION WITH FLOWABILITY
Carr’s index = Tapped density- Bulk density/ Tapped density
Hausner ratio = Tapped density / Bulk density
(D) IMPORTANCE

In case of combination therapy or physical mixture ,if both
drug or drug & excipients have different density then creates
problem of segregation (demixing).
 Important in decide size & type of processing equipment.
E.g. decide size of capsule formulation, Suppositories.
 Devereux et.al. compared GI transit time of multiple unit
formulation of densities 2.8g/cm3 & 1.5g/cm3 & found
significantly delayed gastric emptying of heavier pdt.
(Review article, IJPS, sept-oct,2008)
3. COMPRESSIBILITY
(A)
INTRODUCTION

Compressibility is the ability of powder to decrease in
volume under pressure.
%compressibility =
Tapped density – bulk density * 100
Tapped density

Neumann and Carr developed a simple test to evaluate
flowability of a powder by comparing the poured (fluff) density
(Pβmin)and tapped density (Pβmax) of a powder and the rate at
which it packed down.

Useful empirical guide is given by the Carr's compressibility
index. here compressibility is misnomer since compression is not
involved.
Relationship between powder flowability and
% compressibility
SR. NO
% COMPRESSIBILTY RANGE
FLOW DESCRIPTIONS
1
5-15
Excellent (free flowing granules)
2
12-16
Good ( free flowing powder
granules)
3
18-21
Fair to passable ( powder
granules
4
23-28
Poor ( very fluid powder)
5
28-35
Poor ( fluid cohesive powder)
6
35-38
Very poor ( fluid cohesive
powder)
7
>40
Extremely poor ( cohesive
powder)
(B) The characteristics Of material may be :1. PLASTICITY
Plastic material are capable of permanent
deformation, also exhibit a degree of brittleness
(fragmentability)
 But plastic material will get bonding after
Viscoelastic deformation.

2. FRAGMENTABILITY

If material is fragmentable, neither lubricant
mixing time nor dwell time affecting the tablet
strength.
3. ELASTICITY
E.g. paracetamol, acetyl salicylic acid
 If material is elastic, it rebound when
compression force is released.
 Elastic material may lead to capping &
lamination
 They require wet massing to induce plasticity
or plastic tableting material.
4. PUNCH FILMING [STICKING]:
 This may lead to chipping of tablet.
(C) METHOD OF IMPROVEMENT

If plastic material
add fragmentable excipient
e.g.. Lactose .

If Elastic material
By plastic tableting material
Wet granulation ,
Pre compression.

If sticky material
By change in salt form,
By using high excipient ratio,
By wet massing,
By addition of Mg-stearate.
NPTAB Technology:
Innovative technology combining pellet coating
with direct compression.
 Active drug is sprayed on carrier containing sugar
sphere & these layered spheres are directly
compressed.

“ Multifunctional co-processesed excepients with
improved compression properties are used for
improved tabletting performance.”
(CHEMICAL ABSTRACT, July 20,2009,151,
No.3: 63288g)
4. HYGROSCOPICITY
(A) INTRODUCTION
 Hygroscopicity: - It is the tendency of
material to absorb moisture from
atmosphere & be dynamic equilibrium with
water in the atmosphere.
 Deliquescent: - It is the hygroscopic
substance which absorb moisture from air
and they can be liquefied by partially or
wholly forming solution.
 Efflorescent: - a substance which loses
water to form a lower hydrate or become
anhydrous is term as efflorescent.
List of examples:
Hygroscopic & Deliquescent
 Ephedrine
 Hyoscymine
 Phenobarbital
 Pilocarpine
 Physostigmine
Efflorescent
atropine
cocaine
codeine
scopolamine
caffeine
Glycerinated gelatin & PEG base of suppository
are hygroscopic in nature.
(B) METHOD OF DETERMINATION

To carry out study, sample of compound are accurately
weighed into container and placed at various humid
condition for period of upto 2 weeks.
If Weight gain – Deliquescent or Hygroscopic
If Weight loss – Efflorescent

Also determined by TGA, GC, & KF titration



Versaperm has deviced a WVTR meter that can measure
the permeability of package to moisture in as little as
30 min.so that humidity can be accurately controlled.
(C) IMPORTANCE:
It affects the flow property.
 It affects compression characteristic ,
granulation & hardness of final tablet.
 It also affects compaction.
 Important in aerosol.
 Affects chemical stability of hydrolysable
drug.

(E) METHODS OF IMPROVEMENT
 For granulation of hygroscopic material use nonaqueous solvent.
 For efflorescent material , use anhydrous salt.
 Add finely powdered adsorbents like MgO or Mg
carbonate.
 Perform the entire tableting operation under
controlled humidity condition.
 Store in desiccant, foil, blister, glass bottle.
 Use of Ion-exchange resins.
Eg. Complexation of Ranitidine with Indion234.
( Journal of Pharmaceutical Research, vol.8.No.2,
Apr 2009:112-115)
Examples:
 Starch is hygroscopic ,but on pregelatinization it exhibits

lower propensity for moisture, thus providing excellent
stabilization for moisture sensitive active drugs.
A new multifunctional excipient, Galen IQ.
Problem associated with Hygroscopic material:
Stick- slip mechanism of powder flow:
It is pulsatile flow of granular material. It causes
problem in die filling for tableting.
“ The length of stick slip event increases with
moisture content, increasing load, etc .”
(Chemical Abstract vol.146:9803)
5. ELECTROSTATIC CHARGE
INTRODUCTION:
A)
Electrostatic charges are the consequence of
classic attraction & repulsion effect between the
charges.
Electrostatic charge is produced:





By separation of positive & negative charge
By mechanical impact
By friction between two surface
By rupturing of particle
By separation of solid & liquid surface
Pharmaceutical processing procedure such as
mixing,micronizing, milling, sieving, rubbing,
compressing, spray drying & congealing, pan
coating & packaging can induce static charge.
(B) METHOD OF DETERMINATION:

INOSTAT, measures negative charge on the
surface in volts/cm, when material is flowing from
hopper.

ELPI(13-stage Electrical Low Pressure Impactor),
gives detailed charge profile of MDI aerosol
particles. This has practical application on lung
deposition of MDI aerosol.

Electrostatic testers which consists of electrostatic
voltage sensing probes.
C) FACTORS AFFECTING STATIC CHARGE

Effect of particle shape. e.g.- PCM
Fine crystalline form >Crystalline form > Granules
with EC > Granules with starch.

Effect of tablet excipient. e.g.- Acetaminophen with
mannitol(+++) > SDL(++) > Mg stearate(+)

Effect of Particle size.

Effect of moisture.
(D) IMPORTANCE
In preformulation of suspension .
 Affects flow property of powder.
 Affects mixing process.
 For thermal stability of emulsions.
 It may damage tablet machine.
 It may affect compression coating.

E) METHOD OF REMOVAL OF STATIC
CHARGE






Addition of diluents or lubricant.
Surface coating of particle with
amphiphilic substance of o/w type. Eg
Aerosol.
Use crystallization method using more
polar solvent.
By granulation.
Store under influence of air with
sufficient humidity.
Super critical fluid technology.
Example: Poloxamer reduce
electrostatic charge on the surface of
polystyrene.
6. OSMOLARITY
A) INTRODUCTION

It is a colligative property
DEFINITIONS:
Osmoles : No. of osmotically active particles in
solution.
 Osmolarity : osmoles or milliosmoles per liter of
solution.
 Osmolality :osmoles or milliosmoles per kg of
solvent.
 Isoosmotic: when two different solutions are
separated by semipermiable membrane have same
osmotic pressure so called as isoosmotic.
 Isotonic: when two different solutions are separated
by biological membrane have same osmotic pressure
so called as isotonic.

(B) Method of Determination
Osmolality should be measured carefully
with a vapour pressure or freezing point
osmometer or cryoscopic osmometer.
 Vapour pressure osmometer: Measures
concentration of osmotically active particles
that reduce V.P of solution.
 Membrane osmometer: This invention is
directed to a membrane osmometer for
direct measurement of osmotic pressures.

( United States Patent 4455864 )

Clifton nanolitre osmometer
(C) IMPORTANCE
Normal serum osmolality to be
285
mosmol/kg.
 Maintain osmolarity by 1%variation.
 It should be proper maintained in


Oral nutrition fluid
 Peripheral infusion
 Parenteral product
 Ophthalmic preparation

Administration of Paratonic solution can
lead to crenulation or lysis of RBC.
7. RHEOLOGY
(A) DEFINITION
It describes flow of liquid and/or
deformation of solid under stress.
(B) TYPE OF FLOW:
 Newtonian flow
 Non Newtonian flow

NEWTONIAN FLOW
It is a flow in which a direct proportionality exists
between shear stress and shear rate. E.g. water, simple
organic liquid & dilute suspension , Glycerin.

NON NEWTONIAN FLOW
Where there no direct relation between shear stress and shear rate.

There are three type
(1) PLASTIC FLOW
It is the Newtonian system at shear stress above yield
value. Eg. Flocculated suspension.
(2) PSEUDOPLASTIC FLOW
Here yield value not associated .As applies shear stress
increasing, viscosity decreases and disarranged
molecules begin to align their long axes inline of
molecules.
Eg. Aq. Dispersion of tragacanth, Na-CMC, PVP.
(3) DILATANT FLOW
Opposite to pseudoplastic flow
Increase in the shear rate, increasing in resistance to
flow as viscosity increases.
E.g. deflocculated suspension of Mg magma
RHEOGRAM
(C) DETERMINATION OF VISCOSITY
 Capillary viscometer
 Falling sphere viscometer
 Cup and bob viscometer
 Cone and plate viscometer
 Brook field viscometer
 Ultrasonic Shear Rheometer :- For analysing
protein solution rheology.
 Instron Capillary Rheometer :- Measures
viscosity as a function of rate of shear &
temp at a high rate of shear.
D)IMPORTANCE
[1] FLUID
 For mixing
 For particle size reduction of disperse system
 Passing though orifice, pouring, packaging in bottle,
passing though hypodermic needle.
 Flow though pipe
 Physical stability of disperse system
[2] QUASISOLIDS
 Spreading and adherence to skin
 Removal from jar
 Capacity of solids to mix with liquid
 Release of drug from base
[3] SOLID
Flow of powder from hopper and into a die cavity in
tableting or in encapsulation
 Packagability of powder or granules solids.
[4] PROCESSING
 Production capacity of the equipment
 Processing efficiency

THIXOTROPHY:
In thixotropy apply shear stress convert gel – sol &
remove shear stress convert sol – gel, means gel to
sol to gel.
 Application :- for stability of suspension
 e.g. conc. Parental suspension containing 40-70% w/v
of procaine penicillin G

8. WETTABILITY
(A) INTRODUCTION
 Wettability of a solid is an important
property with regards to formulation of
solid dosage form.
 Adsorption at solid surface is involved
in wetting & detergency.
 It may influence granulation of solid,
penetration of dissolution fluid into
tablet and granules & adhesion of
coating material to tablet.
(B) METHOD OF DETERMINATION :


By contact angle:
The contact angle is the angle between a liquid
droplet and the surface over which it spreads.
Contact angle – 00 – complete wetting.
Contact angle – 1800 – No wetting .
By Draves test:
(C) IMPORTANCE:


Crystal structure can influence the contact angle.
Problems associated with Wettability of powder are
poor dissolution rate & low adhesion of film coating.
(C) IMPROVEMENT

Mixing with hydrophilic excipient like Na
CMC (water soluble) and bentonite, Al Mg
silicate & colloidal silica (water insoluble).

Use of wetting agent (HLB value 6-9) which
acts by lowering contact angle. It displaces
air & replace it with liquid phase.

Wetting of powder by non aqueous solvent
can be enhanced by certain lanolin
derivative.
9. SYRINGABILTY






It is more mechanical property rather than
pharmaceutical property.
This phenomenon happens when a liquid
dosage form passes through a syringe.
The flow of material is dependant on size &
shape of crystals of material.
Plates can easily move one over another .so,
no friction observed & can easily pass through
the syringe.
While in case of needles or cubes or prisms ,
they can’t pass through the syringe easily.
So, we can arrange the degree of syringabilty
in following way:
Plates > Needles > Cubes > Prisms
REFERENCES
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

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Alfred Martin, physical Pharmacy, 4thedition, 1999, B.I. Waverly, New Delhi.
Leon Lachman ,H.A. Lieberman , J.L.Kanig , the theory and practice of
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Leon Lachman, H, A. Lieberman, Pharmaceutical dosage form –tablet volume
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Leon Lachman, H, A. Lieberman, Pharmaceutical dosage form-parental
Dosage form volume 1
Michael E. Aulton, Pharmaceutics: The science of dosage form design ELBS
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