PREFORMULATION
Physical and dissolution
characteristics
Learning objective
At the end of this session students should able to
• Understand the bulk characteristics and
solubility studies in preformulation studies.
• Explain the effects of bulk characteristics like
particle size, shape, crystalinity, flow
characteristic and dissolution characteristics.
• Describe the methods used to identify the
characteristics of drugs
Outline Of Principal Areas Of
Preformulation Research
Principal areas
Stability analysis
Physico-chemical
properties Solution stability
Bulk
Solubility analysis Solid state
Organoleptic characterization
Crystallinity and stability
properties Ionization constant pka
polymorphism Bulk stability
Purity PH solubility profile
Hygroscopicity Compatibility
Particle size Common ion effect
and shape Particle size
characterization Thermal effects
Surface
Bulk density Partition co-efficient
area
solubilization
Powder flow
Dissolution
properties
PARICLE SIZE
• Particle size is a determinant of surface area
• Particle size can influence variety of important factors
Dissolution rate, Suspendability, Uniform distribution,
Penetrability, Lack of grittiness
• Small particle size have more effective surface area
hence more is the dissolution rate which increases the
rate & extent of bioavailability.
Techniques particle size (µm)
• Methods to Determine Microscopic 1-1000
Particle Size Sieve >50
Sedimentation. >1
coulter counter
Elutriation 1-50
Laser holography Centrifugal <50
Cascade impaction Permeability >1
Light scattering 0.5-50
SURFACE AREA DETERMINATION
o Particle size & surface area are inversely related to
each other.
o Smaller the drug particle, greater the surface area.
Specific surface is defined as the surface area
per unit weight (Sw) or unit volume (Sv) of the
material.
Effect of Surface Area
Larger is the surface area, rapid is the dissolution.
Greater is the surface area of powder, greater is
the resistance to flow.
Measurement of surface area
• It is determined based on Brunaver-Emette-
Teller (BET)theory of adsorption. Most
substances adsorb mono molecular layer of
gas (Nitrogen) at temperature.
• Air adsorption and permeability methods
• SEM (scanning electron microscopy)
PARTICLE SHAPE
particle shape has direct influence on process &
product performance
light microscope with calibrated grid (few
restrictions) or Image Analysis Technique used to
measure the shape
Surface morphology can be observed by scanning
electron microscopy.
n(N)=-nIn(g)+q
Where N=no.of squares.
g=length of grid size.
n&q are constants.
BULK CHARACTERIZATION
CRYSTALINITY
• Crystal habit & internal structure
of drug can affect bulk &
physicochemical property
of molecule.
• Crystal habit is description of
outer appearance of crystal.
• Internal structure is molecular
arrangement within the solid.
• Change with internal structure
usually alters crystal habit.
Eg. Conversion of sodium salt to its
free acid form produce
both change in internal
structure & crystal habit.
Amorphous CRYSTALINE
High Thermodynamic Energy Lesser than amorphous
Atoms and molecules randomly place in a Atoms and molecules arranged in three
liquid melt dimensional array
Prepared by rapid precipitation, Some amount of crystallization solvent
lyophilization or rapid cooling of liquid melts present inside the crystal
High solubility and dissolution rates Less solubility and dissolution rates
Upon storage becomes solid form Crystal takes water and produces hydrates
Anhydrous forms having high solubility rates Eg. Amorphous form of Novobiocin is well
absorbed whereas crystalline form results in
poor absorption.
The crystal habit can also influence the ease of
compression of a tablet and the flow properties of
the drug in the solid state.
Crystal habit and internal structure of a drug can
affect bulk and physicochemical properties, which
ranges from flowability to chemical stability.
Upon storage, the amorphous forms tend to convert
to more stable crystalline forms.
Methods used to study solid forms
POLYMORPHISM
• It is the ability of the compound to crystallize as
more than one distinct crystalline species with
different internal lattice. Different crystalline forms
are called polymorphs.
• Polymorphs are of 2 types
1. Enatiotropic E.g. Sulfur.
2. Monotropic E.g. Glyceryl stearate.
• Polymorph differ from each other with respect to
their physical property such as
Solubility, Melting point, Density, Hardness,
Compression characteristics optical properties and
vapour pressure.
During preformulation it is important to identify the
polymorph that is stable at room temp.
Widely used techniques to study crystals & polymorphs:
• X-Ray diffraction,
• Infra red spectroscopy,
• Differential scanning calorimetry (DSC)
• differential thermal analysis (DTA) and
• Hot stage microscope.
HYGROSCOPICITY
Many substances, particularly water soluble salt
form have a tendency to absorb atmospheric
moisture. So these hygroscopic compounds
should be stored in a well closed container.
Change in moisture level can influence chemical
stability , flowability, and compatibility.
It can be monitored by Karl Fischer titration,
TGA, gravimetric, gas chromatography.
Effect of hygrocopicity
And also during production of dosage from using these
compounds the humidity should be maintained at a
controlled manner. E.g. During capsule filling 30-50%
relative humidity is maintained.
During preformulation the moisture content range
should be specified. If the granules have more moisture
content it lead to poor flow and excess hardness of the
tablet.
If the granules contain less moisture, the compressed
tablet may face problem of less hardness, and more
friability.
In such cases good packing like Eg. Strip or Blister
packing is essential. It is better to add silica gel packs in
the bulk container of tablet or capsules.
BULK DENSITY
• Differs due to method of crystallization, milling or formulation
• Corrected by milling, slugging and formulation.
• Its important in high dose capsule, homogeneity of low dose
formulation and also in tablet punching will be problematic when
large difference in densities of drug & excipients.
• Determine the size of the capsule by using graph.
• Determination of true density
Suspend the powder to insoluble solvent with small amount of
surfactant mixture. Agitate it vigorously , the samples are
centrifuged briefly and then left to stand undisturbed
until settling has reached equilibrium. The sample
that remains suspended corresponds to the true
density of the material. Checked with Calibrated
Pycnometer.
POWDER FLOW
The pharmaceutical powders are classified as ---
• FREE FLOWING
• COHESIVE OR NON FREE FLOWING
The powder flow are affected by the changes in –
Density
Particle Size Free flowing drug may become
Shape cohesive and necessitates
Electrostatic Charge an entirely new
Adsorbed Moisture formulation strategy
The powders, which flow poorly, cannot be transformed uniformly in to
capsules or die cavity during tablet compression. It leads to un-uniformity
of dosage units.
By using glidant we can alter the flow properties. e.g. Starch, Talc,
magnesium stearate.
Determination of Powder Flow Properties: By determining Angle
of Repose and compressibility.
Angle Of Repose.
By determining Angle Of Angle Of Type Of Flow
Repose. Repose
( In degree)
A greater angle of repose
indicate poor flow.
<25 Excellent
It should be less than 30°.
& can be determined by
following equation. 25-30 Good
tan θ = h/r.
where, θ = angle of repose. 30-40 Passable
h=height of pile.
>40 Very poor
r= radius.
Compression properties:
• Plastic materials: when the ductile material deform by changing shape.
During compression, more intimate mix of the lubricant (Mg stearate)
leads to poor bonding.
• Fragmenting materials: it is the materials that lubricant mixing time nor
dwell time do not affect the bonding strength.
Usually these materials showed low crushing strength and high friability.
• Elastic materials: they are materials that showed very little permanent
change upon compression e.g. paracetamol. The material rebound
(elastically recover) when the compression load released.
These materials usually showed capping and lamination after
compression
• Punch filming (sticking): the adherence of the powder to the surfaces of
the punches and the die. Generally, the lubricant is very effective
antiadherent.
Efficient mixing of the lubricant should prevent sticking.
Carr’s index
Carr’s index (Consolidation index)
=
Measures of free flowing powders is COMPRESSIBILITY.
%compressibility=(ρ1-ρ0)/ρ1 X100
Hausner ratio
Ratios less than 1.25 indicate good flow
Ratios greater than 1.5 indicates poor flow.
Ratios between 1.25 and 1.5, added glidant
normally improves flow.
Determination of Solubility
Solvent Vigorously Examine
(fixed volume) shaking visually
Adding solute in small
incremental amounts
Undissolved
solute particles ?
No Yes
Total amount
Estimated solubility
added up
SOLUBILITY
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
Effect Of Solubility
For the absorption of the drug from the dosage form in to the
systemic circulation, it has to cross lipid membrane, so it should
possess lipid solubility. Also it should have aqueous solubility for
the absorption at the site. Therefore, this is importance of the
solubility for its therapeutic activity.
Temperature Effect:
Most solution process is endothermic and thus increasing the
solution temperature, there by increasing solubility.
If a solution process is exothermic, increase in temperature
will decrease the solubility of materials.
Solubilization: It is the process by which the apparent solubility of
poorly or sparingly soluble substance is increased by the
presence of surfactant micelles, in which a thermodynamically
stable solution is formed
General Method of Increasing the Solubility
Addition of co-solvent
pH change method
Reduction of particle size
Temperature change method
Hydrotrophy
Addition of Surfactant
Dielectrical Constant
Complexation
Partition Coefficient
It is the ratio of unionized drug distributed between
organic and aqueous phase at equilibrium.
P o/w = C oil / C water
• Its ratio of unionised drug in organic & aq.Phase
• It measure lipophilicity
• Major role in drug transport
• Analytical separation
Partition co efficient of the drugs are useful in the study of its
absorption, distribution, metabolism and elimination.
If the lipid solubility of the drug is more it is having more
penetration power through the biological membrane.
Aqueous solubility is essential for the absorption at the site.
During preformulation study, the partition co-efficient of the all
the excipients likely to be added in to the formulation should
considered.
Ionization Constant
• The unionized species are 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
“pH-partition theory”
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
1. Potentiometric pH-Titration
2. pH-Spectrophotometry Method
3. pH-Solubility Analysis
DISSOLUTION CHARACTERISTICS
It is the process of conversion or change of drug form into solution form,
so that body can absorb the drug. This process is called as dissolution.
The absorption of solid dosage form administered through orally can be
represented by following chart.
Where Kd is dissolution rate constant and Ka is absorption constant.
Dissolution of a drug particle is controlled by several physico chemical
properties like crystal habit, particle size, solubility, surface area and
wetting properties. Dissolution test can be used to identify potential
problematic areas.
Intrinsic Dissolution
Film Theory
The dissolution of a solid in its own solution is
adequately described by Noyes-Nernst’s “Film Theory”
-dW = DAK (Cs - C)
dt h
where
dW/dt = dissolution rate
A = surface area of the dissolving solid
D = diffusion coefficient
K = partition coefficient
h = aqueous diffusion layer
Cs = solubility of solute
C = solute concentration in the bulk medium
The dissolution rate may be affected by chemical form, crystal form, particle
size and surface properties of the drug.
Chemical form: The acid, base and different salt forms may give
significant difference in dissolution rate, Eg. the dissolution rate of the
sodium salt of sulphathiazole in O.1 N Hcl is 5500 times faster than the
free base.
Crystal form: Metastable polymorphs such as sulfathiazole II have a
greater dissolution rate compared to the stable sulfathiazole I.
Particle size: Reduction of particles size produces a greater surface area
available for liquid contact. E.g., griseofulvin
Surface properties of the drug: The high surface energy of a micronized
powder may result in poor wettability and agglomerates in the dissolution
media. Under these circumstances, the dissolution rate decreases,
because the total surface area is unavailable to the fluid.
Reference
• Lachman, L, Leiberman, HA and Kanig, JL, 1999. The
Theory and Practice of Industrial Pharmacy, Lea and
Febiger, Philadelphia.
• Aulton, ME, 2001. Pharmaceutics: The Science of
Dosage form Design, 2nd, Churchill Livingstone,
Edinburgh.
• Pharmaceutical dosage forms and drug delivery system
by Ansel.
Thank you
