PREFORMULATION

OF
SOLID DOSAGE FORMS
PRESENTED BY
ASHWANI GOYAL
Ist SEMESTER
M.PHARMACY
CHITKARA UNIVERSITY
HIMUDA EDUCATIONAL HUB
BAROTIWALA

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WHAT IS PREFORMULATION?

 Preformulation is usually defined as the science of the

physicochemical characterization of candidate drugs prior to
compounding process. However, any studies carried out to
define conditions under which the candidate drug would be
formulated can also be termed as preformulation.

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Commencement of preformulation
 Preformulation commences when a newly synthesized drug
shows a sufficient pharmacological response in animal models
to warrant evaluation in humans.


 Preformulation studies provides

1. Rationale for molecular modeling
2. Rationale for formulation design.

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Goal of preformulation studies
The goal of the preformulation studies are


1. To establish the physicochemical parameters of the new drug.

2. To establish kinetic rate profile.
3. To establish its physical characteristics.
4. To establish its compatibility with the common excipients.
5. Provide scientific data to support the dosage form design and
evaluation of product efficacy, stability and bioavailability.


 In short the goal is to develop stable, safe and efficacious

formulation with

 MAXIMUM BIOAVALABILITY .

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Preformulation of solid dosage forms
It include the study of the following properties:


1. Particle size distribution

2. Surface area measurement
3. True density
4. Flow properties
5. Crystallinity and polymorphism
6. Hygroscopicity
7. Bulk density.
8. Hygroscopicity.
9. Melting point.
10.Compression properties
11.Solubility
12.
13. 5
 

 Particle size Distribution


 Particle size distribution is expressed as the
number or weight of particles lying within
certain size range.

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Particle size distribution measurement
Methods
 There are various methods available for the particle size
determination the most widely used method are:
1. Sieving method
2. Sedimentation method
3. Optical microscopy
4. Coulter counter
5. Electron microscopy
6. Laser light diffraction method

Special methods for the micronized particle
1. Scanning electron microscopy
2. Laser light diffraction e.g. Malvern zetasizer and aerosizer

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Particle size distribution


 For submicron materials following methods are used for the

particle size determination:
1. Quasi elastic light scattering technique
2. Photo correlation spectroscopy (PCS)
3. Single particle optical sizing.


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Sieving method
1. Particle size range between 50 and 1500µm .
2. Size is expressed as d ,which describes the diameter of a sphere that
sieve

passes through a sieve aperture as the asymmetric particles.

3. The sieve method finds application in dosage form development of
the tablets and capsules.
4. Normally 15 percent of fine powder should be present in granulated
material to get proper flow of material and achieve good
compaction.
Advantages

Inexpensive, simple, rapid and reproducible.

Disadvantages

a) Lower limit is 50µm

b) If powder is not dry, aperture becomes clogged with particles leading
to improper sieving.
c) During attrition size reduction may occur.
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Condutimetry method or coulter
counter method
1. Particle size ranging from 0.5 to 500µm is measured
2. Particle volume is measured and converted into the particle
diameter.
3. Size is expressed as volume diameter ,dv, it describes the
diameter of the sphere having the same volume as that of
asymmetric particle.
4. It is expensive method
5. Used in the study of particle growth in suspension and solutions.

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Optical microscopy
1. Particle size range of 0.2-1.00µm can be measured by this
method.
2. The size is expressed as projected diameter, which describes
the diameter of a sphere having the same area as the
asymmetric particle when observed under a microscope .
3. This method is used in the particle size determination of
suspension, emulsion and aerosols.

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Optical method

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Sedimentation method
1. Sedimentation method may be used over a size range of 1 to
200µm.
2. In this method size is expressed as stokes's diameter dst ,which
describes the diameter of an equivalent sphere having the
same rate of sedimentation as that of asymmetric particle.
3. Sedimentation of particles is evaluated by different methods e.g.
anderasen pipette method, balance method and hydrometer
method.

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 Laser light diffraction method
1. In laser diffraction particle size analysis, a representative cloud of
particles passes through a broadened beam of laser light.
2. laser light scatters the incident light onto a Fourier lens.
3. This lens focuses the scattered light onto a detector array and,
using an inversion algorithm, a particle size distribution is
inferred from the collected diffracted light data.
4. Sizing particles using this technique depends upon accurate,
reproducible, high resolution light scatter measurements to
ensure full characterisation of the sample.
5. Modern laser diffraction instruments use Mie
Theory as the basis of their size calculations.
6.

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Laser light diffaraction

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 Scanning electron microscopy
1. The first SEM image was obtained by Max Knoll, who in 1935
obtained an image of silicon steel showing electron
channelling contrast
2. The scanning electron microscope (SEM) is a type of
electron microscope that images the sample surface by
scanning it with a high-energy beam of electrons
3. The signals result from interactions of the electron beam with
atoms at or near the surface of the sample.
4. A wide range of magnifications is possible, from about 10 times
(about equivalent to that of a powerful hand-lens) to more
than 500,000 times, about 250 times the magnification limit
of the best light microscopes

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Scanning electron microscope

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 S URFACE AREA MEASUREMENT

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Surface area measurement methods
Importance of surface area measurement
1. Dissolution is a parameter of the surface area ( which is given by
noye’s whiteny equation)
2. Surface area can also be quoted if the particle size is difficult to
measure.
3.
Methods

1. Adsorption methods e.g. determination by gas adsorption

2. Air permeability methods

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Adsorption method
1. Particles having large specific surface area are good adsorbents
of gases and solutes from solutions.
2. Amount of gas adsorbed on the surface is function of the surface
area of the powder.
3. This method is also used to measure the surface diameter.

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Air permeability method

1. This is the official method is I.P

2. Specific surface area is required for the proper absorption of the
drugs e.g. griseofulvin, an antifungal antibiotic, should have
surface area of not less than 13000 to 17000 cm2/g.

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 Principle
1. In this method powder is packed in the sample holder as a
compact plug.
2. In this packing, surface surface contacts between particles appear
as a series of capillaries.
3. The surface area of these capillaries is function of the surface
area of the powder.
4. The air, which is allowed to pass, travel through these capillaries
and thus the method is related to surface area of powder.
5. When the air is allowed to pass through the powder bed at a
constant pressure, the bed resist the flow of air. This results in
the pressure drop.
6. The greater the surface area per gram of the powder, Sw, the
greater the resistance to the flow. The permeability of air for
a given pressure drop is inversely proportional to specific
surface.
 22
Apparatus used: t
 Fisher subsieve sizer is commercially used for
surface area measurement

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 Density
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 True density
 It is the density of the material itself. It is defined as
 True density = weight of powder/true volume of powder
1.
 The density is dependent upon the type of atoms in a molecule,
arrangement of molecules in the sample


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 Methods of measurement
 The most common methods used for the measurement of true
density are:


1. Gas displacement method (Helium or Nitrogen)

2.
3. Liquid displacement.
4.
5. Floatation in liquid.


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 Helium displacement method
q Helium penetrates the small pores and cervices therefore this
method gives a value closer to true density
q
q Helium pycnometer is used for this method.

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 Bulk density
 Mathematically it is defined as :
 bulk density = mass of powder(w)/ Bulk volume (Vb)
Importance

1. The size of the capsules is determined by bulk volume for a given

dose of material.
2. Bulk density is used to check the uniformity of the bulk
chemicals
3. It helps in selecting the proper size a container, packing material,
mixing apparatus in the production of tablets and capsules.

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 Flow Properties

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 Flow properties
1. Irregular flow of the powders from the hopper produces tablets
with non uniform weights.
2. Loss of content uniformity and dose precision
3. Flow properties depends upon particle size shape, porosity and
density of the bulk powder.

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 Flow properties
Particle size
1. Particle size is very small flow is restricted owing to cohesion of
particles.
2. As the particle size increases to optimum (400-800µm the flow
increases
Nature of Particles

1. Smooth surface of the powder improves flow

2. Surface roughness leads to poor flow due to friction and
cohesiveness.
Moisture content

1. Higher moisture greater risk of cohesion and adhesion

2.

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 Flow properties
Angle of repose
Frictional forces leads to improper flow the forces are quantified by

the angle of repose.



Definition:
Angle of repose is defined as the maximum angle possible between

the surface of a pile of the powder on the horizontal surface.

 tanƟ = h/r

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 Angle of repose
1. Lower the angle of repose, the better the flow property.
2. Decrease in particle size leads to a high angel of repose.
3. Lubricants at low concentration decreases the angle of repose, at
high concentration enhance angle of repose


 RELATIONSHIP B/W ANGLE OF REPOSE AND

POWDER FLOW


Angle of repose in Flow

1.
degrees
<25 Excellent
25-30 Good
30-40 Passable
>40 Very poor
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 Carr’s index
 Carr’s compressibility index :
Carr’s index (%) = Tapped
density–bulk density x100/
 Tapped density
 Decreasing the voids, decreasing the tapped
density (w/v),decreasing the index, so good
flow properties
Carr’s index Flow properties
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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 Hausner’s index
 Hausner ratio: has been defined by Hausner:


 Hausner ratio = Tapped density/Poured or bulk density x 100



**Value less than 1.25 indicates good flow (= 20%Carr),

**Value greater than 1.5 indicates poor flow (=33% Carr).

**Between 1.25 and 1.5, added glidant normally improves flow.

> 1.5 added glidant doesn’t improve flow

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Compression properties

 Compression force is very important for the formulation.



 Hence compression force is measured.



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 

 H ygroscopicity

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 Hygroscocity
1. Many compounds absorb water vapor or moisture.
2. Hygroscopicity affects the stability, dissolution, compaction and
lubricity of the compounds.
3. Generally hygroscopic substances are rejected.
4.
Hygroscopicity is classified into the four classes:

1. Slightly hygroscopic
2. Hygroscopic
3. Very hygroscopic
4. Deliquescent


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 Measurement of
Hygroscopicity
1. Dynamic vapour sorption method.
2.
3. Isothermal microcalorimetry.
4.
5. Analytical methods i.e. gravimetric, karl Fischer's titrations, gas
chromatography
6.

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 

 Crystallinity and Polymorphism

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Crystallinity and polymorphism
Solid drug materials may occur as:


1. Amorphous (higher solubility)

2. Crystalline drugs (higher stability)


 The amorphous or crystalline characters of drugs of great

importance to
1. Its ease of formulation and handling.
2. Its chemical stability.
3. Its biological activity.

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 Amorphous form
Amorphous drugs have atoms or molecules randomly placed as
in a liquid. (particles without definite structure)
1. Randomly arranged atoms or molecules
2. Amorphous forms are typically prepared by: rapid
precipitation, lyophilisation, or rapid cooling of liquid
metals.
Advantage:

1. Amorphous forms are of higher thermodynamic energy than

corresponding crystalline forms
2. Greater solubilities as well as dissolution rates.

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 Amorphous form
Disadvantage for developing an amorphous form:
• Upon storage, amorphous solids tend to revert to more stable
forms. This thermodynamic
• instability can occur during bulk processing or within dosage
forms.
Amorphous forms of drugs may be used:

E.g. Novobiocin It is inactive when administered in crystalline

form, but when they are administered in the amorphous

form, absorption from the gastrointestinal tract proceeds
rapidly with good therapeutic response

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 Crystalline forms
q Crystals are characterized by repetitious spacing of
constituent atoms or molecules in a three dimensional
array (substances of definite identifiable shape, fixed
molecular order).
q Crystalline forms of drugs may be used because of greater
stability than the corresponding amorphous form.
q
q For example: the crystalline forms of penicillin G as K or
Na salt is considerably more stable and result in excellent
therapeutic response than amorphous forms.

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 Polymorphism
• Polymorphism is the ability of a compound to crystallize as
more than one distinct crystalline species with different
internal lattices or crystal packing arrangement even they
are chemically identical
Depending upon:

 (1)the conditions (2) Temperature(3) solvent (4) time

 Under which crystallization is induced.
Significance of polymorphism:

 different polymorphs exhibits different solubilities,

therapeutic activity and stability Chemical stability and
solubility changes due to polymorphism can have an impact
on a drug’s bioavailability.

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 Methods of measurement

 The most widely used methods are



q Differential scanning calorimetry (DSC)

q
q Thermogravimetric analysis (TGA)
q
q X-RAY diffraction (only for crystalline drugs)

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 Differential scanning calorimetry
 In this the difference in temperature between the sample and
thermally inert reference material is measured as a function of
temperature.

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 Thermogravimetric analysis
 It provides a quantitative measurement of any weight changes
associated with thermally induced transitions.

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 Melting Point

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 Melting point
 Melting point of compound is important for its purity,
manufacturing and storage.


 Methods for determination:

q Hot stage microscopy (HSM).
q Capillary Melting
q Differential Scanning Calorimetry thermal analysis.
q


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 METHODS
Capillary Melting:


• The observation of melting in a capillary tube in contact with heated

metal block occurs.
• In this it is difficult to assign accurate melting point.


Hot stage Microscopy:



• Visual observation under a microscope equipped with heated and

lagged sample stage.
• It is more precise.


Differential scanning Calorimetry



• The sample size required is very small i.e. 2-5 mg

• It measure the temperature difference between the sample and
reference as a function of temperature and time.
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 Solubility
q The solubility of drug is an important physicochemical property
because it effects the bioavailability of the drug, the rate of
drug release into dissolution medium and consequently, the
therapeutic efficiency of the pharmaceutical product.
q The solubility of the molecules in various solvents is determined
as a first step. This information is valuable is developing a
formulation. Solubility is usually determined in variety of
commonly used solvents and some oils if the molecules is
lipophillic.
q The solubility of material is usually determined by the
equilibrium solubility method, which employs a saturated
solution of the material, obtained by stirring an excess of
material in the solvent for a prolonged until equilibrium
achieved.
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 Solvents used for solubility
determination
Common solvents used for solubility determination are :-


q Water, Glycerine
q Sorbitol
q Ethyl Alcohol
q Methanol ,Benzyl Alcohol ,Isopropyl Alcohol ,Tweens
,Polysorbates, Polyethylene Glycols ,Propylene Glycol
•

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Compatibility with excipients

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 REFERENCES

• Subrahmanyam C.V.S. “Textbook of Physical Pharmaceutics” ;

Vallabh Prakashan ; pp.180-234.


• Ali javed; Khar R.K. “Dosage form Design”; Vallabh Prakashan;

pp. 1-31.
•

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