Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
AL
PREFORMULATIO
N
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
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
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
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
kd ka ke
D Xg C, Vc
Dissolution Absorption Xc Elimination
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
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-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