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PREFORMULATIONOF

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

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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

7. Scanning electron microscopy

8. 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 method1. Particle size range between 50 and 1500µm .

2. Size is expressed as dsieve ,which describes the diameter of a sphere that 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.

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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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SURFACE 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.

Methods

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

4. 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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Principle1. 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.

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tApparatus used:

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

The density is dependent upon the type of atoms in a molecule, arrangement of molecules in the sample

Methods of measurement

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

1. Gas displacement method (Helium or Nitrogen)

2. Liquid displacement.

3. Floatation in liquid.

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Helium displacement method

Helium penetrates the small pores and cervices therefore this method gives a value closer to true density

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

3. Smooth surface of the powder improves flow

4. Surface roughness leads to poor flow due to friction and cohesiveness.

Moisture content

5. Higher moisture greater risk of cohesion and adhesion

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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 degrees Flow

<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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Hygroscopicity

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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.

Hygroscopicity is classified into the four classes:

4. Slightly hygroscopic

5. Hygroscopic

6. Very hygroscopic

7. Deliquescent

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Measurement of Hygroscopicity

1. Dynamic vapour sorption method.

2. Isothermal microcalorimetry.

3. Analytical methods i.e. gravimetric, karl Fischer's titrations, gas chromatography

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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

3. Its ease of formulation and handling.

4. Its chemical stability.

5. 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:

3. Amorphous forms are of higher thermodynamic energy than corresponding crystalline forms

4. 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

Crystals are characterized by repetitious spacing of constituent atoms or molecules in a three dimensional array (substances of definite identifiable shape, fixed molecular order).

Crystalline forms of drugs may be used because of greater stability than the corresponding amorphous form.

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

Differential scanning calorimetry (DSC)

Thermogravimetric analysis (TGA)

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

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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

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.

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.  

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 :- Water, Glycerine Sorbitol Ethyl Alcohol 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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