Preformulation

 Preformulation is a stage of development during whichPreformulation is a stage of development during which
the physicochemical properties of drug substance arethe physicochemical properties of drug substance are
characterized.characterized.
 Prior to the development of any dosage form new drug , itPrior to the development of any dosage form new drug , it
is essential that certain fundamental physical & chemicalis essential that certain fundamental physical & chemical
properties of drug powder are determined .properties of drug powder are determined .
 This information may dictate many of subsequent event &This information may dictate many of subsequent event &
approaches in formulation development.approaches in formulation development.
PreformulationPreformulation
2

DEFINITIONDEFINITION
Investigation of physico-chemical propertiesInvestigation of physico-chemical properties
of the new drug compound that could affectof the new drug compound that could affect
drug performance and development of andrug performance and development of an
effective dosage form”.effective dosage form”.
Preformulation commences when a newlyPreformulation commences when a newly
synthesized drug shows a sufficientsynthesized drug shows a sufficient
pharmacologic promise in animal model topharmacologic promise in animal model to
warrant evaluation in man.warrant evaluation in man.
3

 The preformulation is the first step in the rationalThe preformulation is the first step in the rational
development of a dosage form of a drug substancedevelopment of a dosage form of a drug substance
alone and when combined with excipients.alone and when combined with excipients.
 Objective :Objective :
To generate useful information to the formulatorTo generate useful information to the formulator
to design an optimum drug delivery system.to design an optimum drug delivery system.
4

 To establish the necessary physicochemicalTo establish the necessary physicochemical
parameters of new drug substances.parameters of new drug substances.
 To determine kinetic rate profile.To determine kinetic rate profile.
 To establish physical characteristics.To establish physical characteristics.
 To establish compatibility with commonTo establish compatibility with common
excipientsexcipients..
GOALS OF PREFORMULATIONGOALS OF PREFORMULATION
5

 It is important to understand the physicalIt is important to understand the physical
description of a drug substance (whetherdescription of a drug substance (whether
it is solid, semisolid or liquid) prior toit is solid, semisolid or liquid) prior to
dosage form development.dosage form development.
 Most drugs in use today are solidMost drugs in use today are solid
materials and less number are liquid inmaterials and less number are liquid in
nature.nature.
Physical DescriptionPhysical Description
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 Liquid drugs have two problems in the design ofLiquid drugs have two problems in the design of
a dosage form which are:a dosage form which are:
 1.1. The volatility: they must be physically sealedThe volatility: they must be physically sealed
from the atmosphere to prevent evaporation.from the atmosphere to prevent evaporation.
 2.2. They cannot generally be formulated into tabletThey cannot generally be formulated into tablet
(the most popular form of oral medication).(the most popular form of oral medication).
Physical DescriptionPhysical Description
7

 To solve these problems, two easy methodsTo solve these problems, two easy methods
are used to formulate liquid drugs intoare used to formulate liquid drugs into
solid dosage forms.solid dosage forms.
 First, by soft gelatin capsule, e.g.,vitamin A.First, by soft gelatin capsule, e.g.,vitamin A.
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The second method involves theThe second method involves the
conversion of the liquid drug intoconversion of the liquid drug into
solid derivatives such as salt or ester.solid derivatives such as salt or ester.
For instance,For instance, scopolaminescopolamine is liquid butis liquid but
itsits hydrobromide salthydrobromide salt is solid.is solid.
9

 Each a pure substance has a definite meltingEach a pure substance has a definite melting
point. If not pure, the substance will exhibit apoint. If not pure, the substance will exhibit a
change in melting point. The pure substanceschange in melting point. The pure substances
have always higher melting points than theirhave always higher melting points than their
impure mixtures. This phenomenon is calledimpure mixtures. This phenomenon is called
melting point depression and commonlymelting point depression and commonly
used to determine the purity of a drugused to determine the purity of a drug
substance.substance.
Melting PointMelting Point
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Unfortunately, many drug substances inUnfortunately, many drug substances in
use today are unpalatable and dosageuse today are unpalatable and dosage
forms containing such drugs (oralforms containing such drugs (oral
preparationspreparations(( may require the addition ofmay require the addition of
flavors and/or colors.flavors and/or colors.
Organoleptic propertiesOrganoleptic properties
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 Color is generally a function of a drug’s inherent chemical structureColor is generally a function of a drug’s inherent chemical structure
relating to a certain level of unsaturation.relating to a certain level of unsaturation.
 Color intensity relates to the extent of conjugated unsaturation as wellColor intensity relates to the extent of conjugated unsaturation as well
as the presence of chromophores.as the presence of chromophores.
 Some compound may appear to have color although structurallySome compound may appear to have color although structurally
saturated.saturated.
COLORCOLOR
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 The substance may exhibit an inherent odor characteristicThe substance may exhibit an inherent odor characteristic
of major functional groups present.of major functional groups present.
 Odor greatly affects the flavor of a preparation or foodOdor greatly affects the flavor of a preparation or food
stuff.stuff.
TasteTaste
 If taste is considered as unpalatable, consideration is to beIf taste is considered as unpalatable, consideration is to be
given to the use of a less soluble chemical form of the drug.given to the use of a less soluble chemical form of the drug.
 The odour and taste may be suppressed by usingThe odour and taste may be suppressed by using
appropriate flavors and excipients or by coating the finalappropriate flavors and excipients or by coating the final
product.product.
OdourOdour
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 Particle size can influence variety ofParticle size can influence variety of
important factors :important factors :
- Dissolution rate- Dissolution rate
- Suspendability- Suspendability
- Uniform distribution- Uniform distribution
- Penetrability- Penetrability
- Lack of grittiness- Lack of grittiness
PARTICLE SIZEPARTICLE SIZE
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SievingSieving
MicroscopyMicroscopy
Sedimentation rate methodSedimentation rate method
Light energy diffractionLight energy diffraction
Laser holographyLaser holography
Cascade impactionCascade impaction
Methods to Determine Particle SizeMethods to Determine Particle Size
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1.1. Sieving method :Sieving method :
 Range : 50 – 150 µmRange : 50 – 150 µm
 Simple, inexpensiveSimple, inexpensive
 If powder is not dry, the apertures get clogged.If powder is not dry, the apertures get clogged.
2.2. Microscopy :Microscopy :
 Range : 0.2 – 100 µmRange : 0.2 – 100 µm
 Particle size can be determined by the use ofParticle size can be determined by the use of
calibrated grid background.calibrated grid background.
 Most direct method.Most direct method.
 Slow & tedious method.Slow & tedious method.
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3.3. Sedimentation method :Sedimentation method :
 Range : 1 - 200 µmRange : 1 - 200 µm
 Andreasen pipette is used.Andreasen pipette is used.
4. Cascade impaction :4. Cascade impaction :
 The principle that a particle driven by an airstream will hit a surfaceThe principle that a particle driven by an airstream will hit a surface
in its path, provide that its inertia is sufficient to overcome the drugin its path, provide that its inertia is sufficient to overcome the drug
force that tends to keep in it in airstreamforce that tends to keep in it in airstream..
17

5. Light energy diffraction :5. Light energy diffraction :
 Range : 0.5 – 500 µmRange : 0.5 – 500 µm
 Particle size is determined by the reduction in lightParticle size is determined by the reduction in light
reaching the sensor as the particle, dispersed in a liquidreaching the sensor as the particle, dispersed in a liquid
or gas, passes through the sensing zone.or gas, passes through the sensing zone.
 Quick & fast.Quick & fast.
6. Laser holography :6. Laser holography :
 Range : 1.4 – 100 µmRange : 1.4 – 100 µm
 A pulsed laser is fired through an aerosolized particleA pulsed laser is fired through an aerosolized particle
spray & photographed in three dimensional withspray & photographed in three dimensional with
holographic camera, allowing the particles to beholographic camera, allowing the particles to be
individually imaged & sized.individually imaged & sized.
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 Particle size is characterized using these terms :Particle size is characterized using these terms :
i.i. Very coarse (#8)Very coarse (#8)
ii.ii. Coarse (#20)Coarse (#20)
iii.iii. Moderately coarse (#40)Moderately coarse (#40)
iv.iv. Fine (#60)Fine (#60)
v.v. Very fine (#80)Very fine (#80)
PARTICLE SIZEPARTICLE SIZE
19

 Powder flow properties can be affected by change in particlePowder flow properties can be affected by change in particle
size, shape & density.size, shape & density.
 The flow properties depends upon following-The flow properties depends upon following-
1.1. Force of friction.Force of friction.
2.2. Cohesion between one particle to another.Cohesion between one particle to another.
 Fine particle posses poor flow by filling void spaces betweenFine particle posses poor flow by filling void spaces between
larger particles causing packing & densification of particles..larger particles causing packing & densification of particles..
 By using glident we can alter the flow properties.By using glident we can alter the flow properties.
e.g. Starch, Talc.e.g. Starch, Talc.
POWDER FLOW PROPERTIESPOWDER FLOW PROPERTIES
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Determination Of Powder Flow PropertiesDetermination Of Powder Flow Properties
 By determiningBy determining Angle OfAngle Of
Repose.Repose.
 A greater angle of reposeA greater angle of repose
indicate poor flow.indicate poor flow.
 It should be less than 30°.It should be less than 30°.
& can be determined by& can be determined by
following equation.following equation.
tan θ = h/r.tan θ = h/r.
where, θ = angle of repose.where, θ = angle of repose.
h=height of pile.h=height of pile.
r= radius.r= radius.
Angle Of
Repose
( In degree)
Type Of Flow
<25 Excellent
25-30 Good
30-40 Passable
>40 Very poor
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 Measurement of free flowing powder byMeasurement of free flowing powder by compressibility.compressibility.
 Also known asAlso known as Carr's index.Carr's index.
CARR’S INDEX(%) =(CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY)TAPPED DENSITY – POURED DENSITY) XX 100100
TAPPED DENSITYTAPPED DENSITY
 It is simple, fast & popular method of predicting powderIt is simple, fast & popular method of predicting powder
flow characteristics.flow characteristics.
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Carr’s Index Type of flow
5-15 Excellent
12-16 Good
18-21 Fair To Passable
23-35 Poor
33-38 Very Poor
>40 Extremely Poor
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 Particle shape will influence the surfaceParticle shape will influence the surface
area, flow of particles, packing &area, flow of particles, packing &
compaction properties of the particles.compaction properties of the particles.
 A sphere has minimum surface area per unitA sphere has minimum surface area per unit
volume.volume.
 Therefore, these properties can be comparedTherefore, these properties can be compared
for spheres & asymmetric particles, in orderfor spheres & asymmetric particles, in order
to decide the shape.to decide the shape.
PARTICLE SHAPEPARTICLE SHAPE
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Cont…

 Particle size & surface area are inversely related to each other.Particle size & surface area are inversely related to each other.
 Smaller the drug particle, greater the surface area.Smaller the drug particle, greater the surface area.
 Specific surfaceSpecific surface is defined as the surface area per unit weight (Sw) oris defined as the surface area per unit weight (Sw) or
unit volume (Sv) of the material.unit volume (Sv) of the material.
SURFACE AREASURFACE AREA
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 WHEN DRUG IS UNSTABLE.WHEN DRUG IS UNSTABLE.
 DEGRADE IN SOLUTION FORM.DEGRADE IN SOLUTION FORM.
 PRODUCE UNDESIRABLE EFFECTS.PRODUCE UNDESIRABLE EFFECTS.
 WHEN SUSTAINED EFFECT IS DESIRED.WHEN SUSTAINED EFFECT IS DESIRED.
HOWEVER SIZE REDUCTIONHOWEVER SIZE REDUCTION
IS NOT REQUIRED IN FOLLOWING CASESIS NOT REQUIRED IN FOLLOWING CASES
26

 Preformulation solubility studies focus on drug
solvent system that could occur during the delivery of
drug candidate.
 For e.g. A drug for oral administration should be
examined for solubility in media having isotonic
chloride ion concentration and acidic pH.
27

 Analytic method that are particularly useful
for solubility measurement include HPLC, UV
spectroscopy, Fluorescence spectroscopy and
Gas chromatography.
 Reverse phase HPLC offer accurate and
efficient mean of collecting solubility data of
drug.
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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
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 Ionization constant (pKa)
Can be calculated by Henderson Hasselbach
equation-
For acidic drugs….pH= pKa+ log [ionized drug]
[unionized drug]
For basic drugs….pH= pKa+ log[unionized drug]
[ionized drug]
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 Partition Coefficient
 It is the ratio of unionized drug distributed
between organic and aqueous phase at equilibrium.
P o/w = ( C oil / C water )equilibrium
31

Determination of solubility
 The following points should be considered
 The solvent & solute must be pure.
 A saturated solution must be obtained before any
solution is removed for analysis.
 The method of separating a sample of saturated
solution from undissolved solute must be
satisfactory.
 The method of analyzing solution must be reliable
 Temperature must be adequately controlled .
32

 Addition of co-solvent
 pH change method
 Reduction of particle size
 Temperature change method
 Addition of Surfactant
 Complexation
33
General Method of Increasing
the Solubility

Applications of solubilization
 Drugs with limited aqueous solubility can be
solubilized. These include oil-soluble
vitamins, steroid hormones and
antimicrobial agents etc.
 Both oil-soluble and water-soluble
compounds can be combined in a single
phase system as in case of multivitamin
preparations.34

 Solubilization may lead to enhanced
absorption and increased biological
activity.
 Drug absorption from ointment bases
and suppositories also increased.
35

 Aqueous concentrates of volatile oils can be
prepared by solubilization.
 Example: soaps used for solubilising
phenolic compounds for use as
disinfectants- Lysol, Roxenol etc.
 Barbiturates, anticoagulant, alkloidal drugs
are dissolved with polysorbate by
solubilization.36

37
Formulation Challenges with Poorly Soluble
Compounds
Poor dissolution rate
Low and variable bioavailability
More potential for food effect
Inability to deliver high doses for
toxicity studies
Difficulty in developing parenteral
formulations

Stability is the extent to which a product
retains (throughout its period of storage
and use, i.e., its shelf life) the same
properties that it possessed at the time of
its manufacture.
One of the principles of dosage form
design is to ensure that the chemical
integrity of drug substances is maintained
during the usable life of the product.38
Stability

Three types of stability concern the
pharmacists:
l. Chemical: Each active ingredient retains
its chemical integrity within the specified
limits.
2. Physical: The original physical
properties (including appearance, taste,
color and odor) are retained.
3. Biological: Sterility is retained (No
microbial growth).
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Preformulation

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Preformulation