PRESENTED BY,MANGIRISH.R.TENDULKAR

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Preformulation study is the foundation of developing robust formulation.

It can be defined as a phase of research & development process for an investigation of physical and chemical properties of new drug substance alone or in combination with other excepients in order to development of safe and effective dosage

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The overall objective of preformulation testing is to generate information useful to the formulator:

To formulate stable and effective dosage form To increased drug stability To improve drug bioavailability Reduce drug excipient incompatibility

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Preformulation studies begins or shall be updated: immediately after the synthesis and initial toxicity

screening of a new drug. when a newly synthesized drug shows

pharmacological evidence that requires further evaluation in man

when formulation and dosage form changes are required

when solid form changes of DS are required

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1. NATURE 2. COLOUR3. ODOUR4. TASTE5. MELTING POINT6. FLOW PROPERTIES7. PURITY

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Organoleptic properties

Particle size and shape

Purity Surface area

Hygroscopicity

Bulk density

1. Nature of the drugs can either be : Crystalline Amorphous.

CRYSTALLINE: Solids that have a definite geometrical shape are known as crystalline Solids.

Amorphous: Solids that don’t have a definite geometrical shape are known as Amorphous Solids

2. Nature of the drugs plays an important role in the formulation.

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Crystalline solids have the following fundamentals properties.

1. They have characteristic geometrical shape. 2. They have highly ordered three-dimensional arrangements of

particles. 3. They are bounded by PLANES or FACES 4. Planes of a crystal intersect at particular angles. 5. They have sharp melting and boiling points.Eg:

Amorphous solids have the following properties:   1. In these solids particles are randomly arranged in three

dimension. 2. They don’t have sharp melting points. 3. Amorphous solids are formed due to sudden cooling of

liquid. 4. Amorphous solids melt over a wide range of temperature

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It is the inherent chemical structure relating to the certain level of unsaturation.

Intensity relates to the extent of unsaturation as well as the presence of the chromophores.

Some compounds may appear to have colour although it is structurally saturated

Eg: 1) off white: 2) cream yellow:

3) shiny: boric acid

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One should also take into account of the compatibility of the drugs with the excipients.

EG: amino acids containing drugs cant be used when lactose is used as the diluent.

Also take into consideration the colour of the drug with colouring agents to be added to avoid mottling at the final stages of the formlation

Eg: chinese paracetamol is yellowish in colour . It should be properly mixed with the excipients so that there is no mottling problem.

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The drug may exhibit an inherit odour charactertics of the major functional group present

It greatly affects the flavor of the preparation or the foodstuff.

Types of odour:1. Pungent2. Sulfurous3. fruity4. Aromatic5. odourless

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It is the most important parameter of the drug . Consider with respect to the patient compliance.

If the taste is considered as unpalatable or bitter in taste it should be suppressed by the addition of the appropriate flavors and excipients & by sugar coating.

EG: SWEET SOUR BITTER SALTY TASTELESS.

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Purity studies are essential for further studies to be carried out safely.

Impurities may make a compound toxic or render it unstable.

TLC,HPLC,GC and Paper chromatography used. HPLC-Impurity Index(II), Homogeneity index(HI). DTA, gravimetric analysis and melting point by

hot stage microscopy are other techniques.

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Impurity index(II):defined as the ratio of all responses (peak areas) due to components other than the main one to the total area response.

Homogeneity index(HI): defined as the ratio of response(peak area) due to main component to the total response.

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Differential thermal analysis(DTA) Thermogravimetric analysis(TGA) Differential scanning calorimetry(DSC) Powder X-Ray Differaction(PXRD)

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Differential Scanning Colorimetry (DSC) and Differential Thermal Analysis (DTH) measures the heat loss or heat gain - resulting from physical or chemical changes.

Two types of processes 1) Endothermic : like fusion, boiling,

sublimation, vaporization, desolvation 2)Exothermic : like crystallization ,degradation Quantitative measurement of these process have

many application in preformulation study including Purity, Polymorphism, solvation, degradation

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Crystalline materials gives characteristics pattern – by peaks in certain position & varying intensities

different Polymorphs – different x-ray diffraction pattern due to crystal lattice.

Single crystal x-ray analysis provides precise identification & description of a crystalline substances.

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All substances are transparent examined under microscope – are either isotropic or anisotropic

Isotropic substances do not transmit the light – appears black – and have single refractive index. E.g. Sodium Chloride

Anisotropic substances – more than one refractive index – appear bright and brilliant color – uniaxial and biaxial

Color depends upon – thickness of crystal and diff. in refractive indices.

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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 Shape Electrostatic Charge Adsorbed Moisture

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Free flowing drug may become cohesive and necessitates an entirely new formulation strategy

A melting point can be used to identify a substance and to get an indication of its purity.

The melting point (or freezing point) of a solid is the temperature at which the solid exists in equilibrium with its liquid state under an external pressure of one atmosphere. Both the melting point range (the interval between the beginning of liquefaction and complete liquefaction) and the temperature of complete liquefaction are valuable indicators of the purity of the solid compound.

A pure crystalline organic compound usually possesses a sharp melting point and it melts completely over a narrow temperature range of not more than 0.5-1.0oC, provided good technique is followed. The presence of even small amounts of impurities usually produces a depression of the temperature at which melting is complete and usually produces a marked increase in the width of the melting point range.

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Fill a melting point capillary tube with the sample of interest by thrusting the open end into the powder several times

In order to work the plug of solid material down to the sealed end of the capillary, tap the sealed end on the table, or lightly draw a file (or the jagged end of a tweezers) across the tube held loosely in the hand.

Repeat the procedure until the tube contains a 3 mm column of densely packed powder in the bottom.

Place the thermometer in the apparatus so that the mercury container is in level with the mouth of the circulator tube.

Place the capillary in the melting point apparatus through one of the side tubes so that the sealed end of the capillary is touching the front of the mercury reservoir and begin to heat the apparatus with a micro burner.

Place the burner under the back end of the oil bath of the apparatus to ensure the circulation of the silicone oil. Great care should be taken about the rate of heating because the small amount of crystals in the capillary can follow the temperature of the oil bath much faster than the thermometer, so the temperature read a the time of melting is several degrees below the true melting point. 22

Place the burner under the back end of the oil bath of the apparatus to ensure the circulation of the silicone oil. Great care should be taken about the rate of heating because the small amount of crystals in the capillary can follow the temperature of the oil bath much faster than the thermometer, so the temperature read a the time of melting is several degrees below the true melting point.

Place the burner under the back end of the oil bath of the apparatus to ensure the circulation of the silicone oil. Great care should be taken about the rate of heating because the small amount of crystals in the capillary can follow the temperature of the oil bath much faster than the thermometer, so the temperature read a the time of melting is several degrees below the true melting point.

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Maker :Labindia model no.:MR-VIS

It is used to measure the melting point of the final formulation or the API. 

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Preformulation studies have a significant part to play in anticipating formulation problems and identifying logical path in both liquid and solid dosage form technology. 

By comparing the physicochemical properties of each drug candidate with in a therapeutic group, the preformulation scientist can assist:◦ the synthetic chemist to identify the optimum molecule, ◦ provide the biologist with suitable vehicles to elicit

pharmacological response and◦ advise the bulk chemist about the selection and production of

the best salt with appropriate particle size and morphology for subsequent processing.               

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LACHMAN L.,LIBERMAN H.,KAING J.;”The theory and practice of industrial pharmacy”; 3 edition,p.n.-171-196,

Introduction to pharmaceutics by atmaram pawar carrier publications 2008

www.authorstream.com

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