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PHARMACEUTIC

AL
PREFORMULATIO
N

R & D (M.Pharm Pharmaceutics)


What is Preformulation ?
 It can be defined as an investigation of
physical and chemical properties of a
drug substance - alone and when
combined with excipients.
 Preformulation is the first step in the

rational development of dosage forms of


a drug substance.
 The overall objective of preformulation
testing is to generate information
useful to the formulator in developing
stable and bioavailable dosage forms
which can be mass-produced.

Properties associated with
drug
 Bulk properties (Physical
Properties)
 Physicochemical properties

 Stability considerations

 Biopharmaceutical considerations
Bulk / Physical Properties
Bulk / Physical Properties
 Organoleptic
 Particle size, shape, and surface

area
 Crystallinity and polymorphism

 Water adsorption /

Hygroscopicity.

Bulk / Physical Properties
 Bulk density
 Adhesion

 Powder flow

 Compressibility
Organoleptic Properties
 Colour:
 Colourcan be useful when describing different
batches of drug it can sometimes be used as an
indicator of solvent presence or, more
importantly, of degradation. In addition, subtle
differences in colour may be due to variations in
the particle size distribution.
 Usually colour is subjective and is based on
individual perception; however, more
quantitative measurements can be obtained by
using, e.g.,tristimulus colorimetry
 The shelf life of the formulations could be
specified using the Commission Internationale
de’Ecalarage (CIE) system for colour.
 Odour:
 No strong odours should be present.
 Any deviation from the substance’s
characteristic odour is to be considered
and checked for degradations in the
substance.

 Taste:
 Unpalatable  decreasing the solubility
(in case of DPI’s)
  supressedby 
coating
 flavours

excipients
Particle size, shape, and
surface area
 Particle size:
 GeneralTechniques For
Determining Particle Size
 Microscopy
 Sieving (Quantitative particle size
distribution analysis)
 Electronic means
 Blockage of electrical conductivity
path (coulter counter)
 Light scattering
 Laser scattering
Common Techniques for Measuring Fine Particles of
Various Sizes

 Technique Particle size (µ m)


Microscopic 1 - 100
Sieve > 50
Sedimentation >1
Elutriation 1 - 50
Centrifugal < 50
Permeability >1
Light scattering 0.5 - 50


Determination of Surface Area
 Brunauer-Emmett-Teller (BET)
method
 Dynamic method of gas

adsorption

Some facts of surface area
 At relatively large diameters, the specific
surface area is insensitive to an
increase in diameter
 At very small diameters the surface area
is comparatively very sensitive.
 Relatively high surface area most often
reflects a relatively small particle size,
except porous or strongly
agglomerated mass
 Small particles (thus of high surface
area) agglomerate more readily, and
often to render the inner pores and
Particle shape
 Particle shape is of consideration in the
flow properties of the drug.
 The particle shape (crystalline structure)
can be changed to our convenience and
requirements by controlled
recrystallization.
Crystallinity and
polymorphism
 Polymorphism is a solid crystalline phase
of a given compound resulting from the
possibility of at least two different
arrangements of that compound in the
solid state.

Polymorphism study is conducted
to:
 Manufacture the desired forms
consistently
 Understand the effects of pharmaceutical
manipulations , e.g : granulation, milling
and compression
 Evaluate and predict the storage
conditions on dosage forms e.g : crystal
growth in creams, suspensions and
MDI’s.
Polymorphism can be
screened by:
 Crystallization from different solvents at
different speeds and temperatures
 Precipitation
 Concentration or evaporation
 Crystallization from the melt
 Grinding and compression
 Lyophilization
 Spray drying
Crystal habit
 Crystal morphology or habit is important,
since it can influence many properties
of the compound. For example, powder
flow properties, compaction and
stability have all been found to be
dependent on crystal morphology.
Examples of crystal habits
Overcoming crystallinity
problems
 If a particular formulation is unstable or
having problem in formulation due to the
crystal habit of the substance, then it is
recrystallized from different solvents to
obtain the required crystal habit.
 The effect of impurities on the crystal habit
should not be overlooked, as these can act
as crystal poisons or promote growth in a
particular crystallographic direction
 The most accurate way of determining
the symmetry of a crystal is to use an
optical goniometer to measure the
angles between the crystal faces.
Hygroscopicity
 Many compounds and salts are sensitive
to the presence of water vapour or
moisture. When compounds interact
with moisture, they retain the water by
either bulk or surface adsorption,
capillary condensation, chemical
reaction.
 Deliquescence is where a solid dissolves
and saturates a thin film of water on its
Degree of hygroscopicity
 Slightly hygroscopic: Increase in mass is
less than 2 percent m/m and equal to or
greater than 0.2 percent m/m.
 Hygroscopic: Increase in mass is less than
15 percent m/m and equal to or greater
than 0.2 percent m/m.
 Very hygroscopic: Increase in mass is
equal to or greater than 15 percent
m/m.
 Deliquescent: Sufficient water is absorbed
to form a liquid.
Bulk density
 The density of a powder sample is usually
referred to as the bulk density, and the
volume includes both the particulate
volume and the pore volume.
 Minimum bulk density is when the volume
of the powder is at a maximum, caused
by aeration, just prior to complete
breakup of the bulk.
 Poured bulk density is when the volume is
measured after pouring powder into a
cylinder, creating a relatively loose
structure.
 Tapped bulk density is, in theory, the
maximum bulk density that can be
achieved without deformation of the
particles.
Powder flow
 Good flow properties are a prerequisite
for the successful manufacture of both
tablets and powder-filled hard gelatin
capsules.
 It is a property of all powders to resist the
differential movement between
particles when subjected to external
stresses.
 This resistance is due to the cohesive
forces between particles.
Three principal types of interparticle force
have been identified
 forces due to electrostatic charging
 vander Waals forces
 forces due to moisture
Measuring Powder Flow
Properties
 Shear Cell
Method

 Powders with particles below 50 µm will
generally exhibit irregular or no flow
due to vander Waals forces
 Particle shape is also important; for
example, the force between a sphere
and plane surface is about twice that
between two equal sized spheres.

 Changes in Bulk Density:
 The increase in bulk density of a powder is
related to the cohesivity of a powder.
Ratios of the poured to tapped bulk
densities are expressed in two ways to
give indices of flowability.

 The Hausner Ratio varies from about 1.2
for a free-flowing powder to 1.6 for
cohesive powders.
 The Carr Index classifications are
Angle of Repose
 If powder is poured from a funnel onto a
horizontal surface, it will form a cone.
The angle between the sides of the
cone and the horizontal is referred to as
the angle of repose.
 angles less than 30°are usually indicative
of good flow, while powders with angles
greater than 40°are likely to be
problematic.
Physico-chemical
properties
Physico-chemical properties
 Solubility analysis
 Ionization
 Partition coefficients
 Dissolution
Solubility
 Solubility is the extent of drug that goes
into solution form.

Solubility standards
 Many drugs are ionizable organic
compounds, and thus there are a
number of parameters that will
determine the solubility of a compound.
These parameters include, e.g.,
molecular size and substituent groups
on the molecule, degree of ionization,
ionic strength, salt form, temperature,
crystal properties and complexation.
Determination of Solubility
Semiquantitative determination:
Solvent Vigorously Examine
(fixed volume) shaking visually

Adding solute in small Undissolved


incremental amounts solute particles ?

No Yes

Total amount
Estimated solubility added up
Accurately Quantitative determination:
Excess drug powder Shaking at constant
Ampul/vial
150 mg/ml (15 %) temperature
(2-5 ml)
+ solvent (25 or 37 oC)
2 - 8 oC ?
The first few ml’s of the filtrates should be 48 hr
discarded due to possible filter adsorption

Determine the drug Membrane filter


concentration in the 0.45 µ m
filtrate
72 hr
Determine the drug
Same Membrane filter
concentration in the
concentration ? 0.45 µ m
filtrate

Determine the drug ? hr


Solubility concentration in the Membrane filter
filtrate 0.45 µ m
 Highly insoluble drug administered
in small doses may exhibit good
absorption
 Unstable drug in highly acidic
environment of stomach, high
solubility and consequent rapid
dissolution could result in a
decreased bioavailability
 The solubility of every new drug
must be determined as a function
of pH over the physiological pH
Problems in Solubility Determination of Poorly
Soluble Compounds
 Solubilities could be
overestimated due to the
presence of soluble impurities
 Saturation solubility is not

reached in a reasonable length


of time unless the amount of
solid used is greatly in excess of
that needed to saturation
 Many compounds in solution
degrade, thus making an
accurate determination of
solubility difficult
 Difficulty is also encountered in

the determination of solubility


of metastable forms that
transform to more stable forms
pH-Solubility Profile
Stir in beaker Continuous
Excess drug with distilled stirring of
powder water suspension

Filter Measure Stirring


pH of Add
suspension acid/base

SOLUBILITY pH
5

Indomethacin
4 (weak acid)
Log aqueous solubility

3 Chlorpromazine
(weak base)

2
(µ mol)

1
Oxytetracycline
(amphoteric)

2 4 6 8 10 12 14

pH
Enhancing solubility
 Salt forms
 Complexation
 Using mixed solvents
 Use more soluble metastable
polymorph
 Use of complexation (eg.

Ribloflavin-xanthines complex)
 Use of suitable surfactant


Salt forms
 Drugs which are acidic or
basic in nature, if needed are
converted to a stable salt
form.


NSAID’s : alclofenac, diclofenac,
fenbufen, ibuprofen, naproxen
 Weak acid pKa ~ 4, low solubility

Salt forms: sodium, N-(2-hydroxy
ethyl) piperazinium
arginium
 N-methylglucosammonium
 Solubility
 diclofenac (free acid) : 0.8 x 10
-5 M (25 oC)
 diclofenac sodium : 24.5 mg/ml
 Quinolones enoxacin, norfloxacin,
 ciprofloxacin

 Salt forms lactate, acetate, gluconate,


 galacturonate, aspartate,
 glutamate, etc.
 Solubility
 Free base : < 0.1 mg/ml (25 oC)
 Salt forms : > 100 mg/ml (25 oC)
Dissolution
 Dissolution is the dynamic process by
which a material is dissolved in a
solvent and is characterised by a rate
(amount dissolved per time unit)
kd << ka  “dissolution rate-limited”

kd ka ke
D Xg C, Vc
Dissolution Absorption Xc Elimination

Absorption site Central compartment


(gi-tract) (blood circulation)

Diagram showing dissolution and absorption of


solid dosage form into blood circulation
Determination of dissolution
 Dissolution can be determined by
 Rotatingdisk method (Woods apparatus)
 Nelson constant surface method

Rotating-disk method (Wood apparatus)

Stirring shaft

Lower punch

Rubber gasket

Tablet die

Compressed tablet
Dissolution medium
Nelson Constant Surface
method
Dissolution
medium
Rotating
Paddle
Hardened wax
or paraffin Tablet surface
Particulate Dissolution
 Particulate dissolution is used to study
the influence on dissolution of particle
size, surface area, and mixing with
excipients.
 The rate of dissolution normally

increased with a decrease in the


particle size.

 Occasionally, however, an inverse relationship
of particle size to dissolution is encountered.
 This may be explained on the basis of effective
or available, rather than absolute, surface
area; and it is caused by incomplete wetting
of the powder.
 Incorporation of a surfactant in the dissolution
medium may provide the expected
relationship.

Means of enhancing the slow
dissolution:
In absence of more soluble physical or chemical

form of the drug -


 Particle size reduction (most commonly used).
 Enhanced surface area by adsorbing the drug
on an inert excipient with a high surface area,
i.e., fumed silicon dioxide.
 Comelting, coprecipitating, or triturating the
drug with some excipients.
 Incorporation of suitable surfactant.


Partition Coefficient
 Like biological membrane in general, the gi
membranes are largely lipoidal in character.
 The rate and extent of absorption decreased
with the increasing polarity of molecules.
 Partition coefficient (distribution coefficient):
the ratio in which a solute distributes itself
between the two phases of two immiscible
liquids that are in contact with each other
(mostly n-octanol/water).

 Partition coefficient K O/W can be
determined by spectrophoteometric
methods.
Ionization constant
 The unionized species are more lipid-soluble
and hence more readily absorbed.
 The gi absorption of weakly acidic or basic
drugs is related to the fraction of unionized
drug in solution.
 Factors affecting absorption:
 - pH at the site of absorption
 - Ionization constant
 - Lipid solubility of unionized species
Henderson-Hasselbalch equation
For acids:

 pH = pKa + log [ionized form]/


[unionized form]
For bases:

 pH = pKa + log [unionized form]/


[ionized form]

Determination of Ionization Constant
 Potentiometric pH-Titration
 pH-Spectrophotometry Method

 pH-Solubility Analysis
pKa Determinations
 Many potential candidate drugs are weak
acids or bases, therefore, one of the most
important determinations carried out prior
to development is the pKa or ionization
constant. Strong acids, e.g., HCl, are
ionized at all pH values, whereas the
ionization of weak acids is dependent on
pH. It is useful to know the extent to which
the molecule is ionized at a certain pH,
since properties such as solubility, stability,
drug absorption and activity are affected
Methods for the determination of
pKa
 Potentiometric titration
 UV spectotroscopy
 Solubility measurements
 HPLC techniques
 Capillary zone electrophoresis
 Foaming activity

Stability considerations
Stability
 Solid state
 Relative Humidity
 Compatibility
 Solution
 pH
 Buffer
 Solvent
 Temperature

 Compatibility with excipients
 All the drug substances are checked for
their compatibility with the excipients,
and their stability in the dosage form.
Biopharmaceutical
considerations
 Absorption
 Route
 Rate
 Extent
 Mechanism
 Absorption windows
 Food effects
 Metabolism
 First
pass metabolism
 Enzyme induction
 Metabolism in GIT
 Duration of action
 Dosing
 Controlled release
REFERENCES:
 Modern Pharmaceutics – Gilbert.S.Banker
 Theory and Practice of Industrial Pharmacy – Leon
Lachman
 Solid Dosage Forms Vol1 - Lachman & Lieberman
 Liquid Dosage Forms (Parenterals)Vol 1 - Lachman
& Lieberman
 Preformulation in Solid Dosage Form Development
- Moji Christianah Adeyeye, Harry G. Brittain.
 Stability of Drugs and Dosage Forms - Sumie
Yoshioka
 Pharmaceutical Preformulation And Formulation A
Practical Guide From Candidate Drug Selection
THANK YOU