PREFORMULATION

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Seminar on….. Preformulation – General Considerations :

Seminar on….. Preformulation – General Considerations Presented By… Saiesh phaldesai

Contents:

Contents Introduction Objectives Commencement of formal preformulation studies Preformulation consideration areas References

Introduction:

Introduction Definition – Preformulation testing is the first step in the rational development of dosage forms of drug substances. It can be defined as an investigation of physical & chemical properties of drug substances alone & when combined with excipients . Aim Of Preformulation – To maintain stability, efficacy, quality, bioavailability and standard of drug substances.

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Objectives – To establish a necessary physicochemical properties of new drug. To detection of its kinetic rate profile. To establish its physical characteristics. To establish its compatibility with common excipients. The overall objective of preformulation testing is to generate information useful to formulator in developing stable & bioavailable dosage forms which can be mass produced.

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Commencement Of Formal Preformulation Studies – At the point after biological screening, after deciding for further development of the compound in clinical trials. Before starting preformulation studies scientist must consider the following – - Available physicochemical data, chemical structure, different salts available. - Supply situation & development schedule. - Therapeutic class of compound .

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Preformulation Consideration Areas – Organoleptic Properties Purity Bulk Characterisation Solubility Analysis Stability Analysis Compatibility Studies

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Organoleptic Properties Color Odour Taste Non uniformity Odour in batch For consumer of color shows gives stability acceptance poor quality. Problem.

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Purity - The purity tests are generally designed to estimate the levels of all known & significant impurities & contamination in drug substance under the evaluation. - The standards are numerically expressed in max. tolerable limits. - E.g. maximum tolerable limit of diazotizable substance of chlorthiazide is 1%.

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Effect - - Presence of impurity can affect a stability of product & increases toxicity. Techniques to determine presence of impurities - - Melting Point , Differential Thermal Analysis, Differential Scanning Colorimetry, Thin Layer Chromatography, HPLC .

Differential Thermal Analysis:

Differential Thermal Analysis Heat loss and gain resulting from physical & chemical changes occurring in sample is recorded as a function of temperature as the substance is heated at uniform temp. - Based on van’t hoff’s equation- Ts = Tm – RT²I/ ∆Hf F Where, Ts= Sample temp. Tm= M.P. of pure compound I = Mole fraction of impurity ∆ Hf = Heat of fusion F= Fraction melted up to Ts

Crystallinity:

Crystallinity Crystal Habit - Outer appearance of a crystal. Internal Structure- Molecular arrangement within solid. Crystal habit & internal structure of drug can affect bulk & physiochemical properties ranges from flowability to chemical stability . Types - Crystalline - Constitute atoms or molecules in a 3-dimensional array. Amorphous - Having no internal structure.

Polymorphism:

Polymorphism To crystallize as more than one distinct crystalline species with different internal structure. Types – Enantiotropic- Monotropic - Different polymorphic forms differ from each other with respect to- Bioavailability- e.g. Chloramphenicol Palmitate. Chemical Stability – e.g. Methyl Prednisolone Tableting Behaviour – e.g. Aspirin. Physical Stability – e.g. Phenylbutazone .

Particle Size:

Particle Size Fundamental effect on two important concerns in solid dosage formulations – - Dose Uniformity. - Dissolution Rate. New drug particle should be tested during preformulation with smallest particle size as it maximize the drug’s surface area for interaction. Small particle size have more effective surface area hence more is the dissolution rate which increases the rate & extent of bioavailability.

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The bulk flow property, formulation,homogeneity,dissolution rate & dose uniformity are related to size & shape of drug particle. Fine particle has following effect – Dissolution Solubility Flow properties Degradation of drug GI absorption- e.g. sulphadiazine.

Powder Flow Properties:

Powder Flow Properties Powder flow properties can be affected by change in particle size, shape & density. The flow properties depends upon following- Force of friction. Cohesion between one particle to another. Fine particle posses poor flow by filling void spaces between larger particles causing packing & densification of particles.. By using glident we can alter the flow properties. e.g. Starch, Talc.

Determination Of Powder Flow Properties:

Determination Of Powder Flow Properties By determining Angle Of Repose. A greater angle of repose indicate poor flow. It should be less than 30°. & can be determined by following equation. Tan Q = h/r. where, Q= angle of repose. h=height of pile. 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 is compressibility i.e. Ability of powder to decrease in volume under pressure. % compressibility = TBD-LBD/TBD . Χ 100 Interpretation Of Carr’s Index 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 Very Very Poor

Determination Of Particle Size.:

Determination Of Particle Size. Method Useful Range Sieving above 33 μ m Optical Microscopy 0.2-100 μ m Electron Microscopy 0.005-1 μ m Sedimentation 2-50 μ m Gas Permeability 5-100 μ m Gas Adsorption 0.005-20 μ m Coulter Counter 1-100 μ m

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Other methods used to study particle size - Acoustic Spectroscopy. Dynamic Image Analysis. Electrical Sensing Zone. Laser Diffraction. Photon Correlation Spectroscopy. Physical Standards – The International Fine Particle Research Institute (IFPRI) has manufactured a set of standards composed of either Barium Titanate Glass or Glassy Carbon. These standard offer potential to explore the effects of particle optical properties on the performance of particle size instruments. The available standards are MBP 1-10 μ m & MBP 10-100 μ m.

Particle Shape :

Particle Shape Definition – parameters which are used to defining particle shape are as follows- Elongation- Circularity- CE Diameter- Why Measure Particle Shape? for application where samples are very close in size, measurement of subtle variations in shape may be necessary.

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Effect Of Particle Shape- particle shape has direct influence on product performance & its measurement plays important role in product & process performance. Determination Of Particle Shape - Microscopy. Image Analysis Technique . PAT - Designed to improve process control which delivers greater efficiency, less waste & lower production cost. End point is defined which closely relates to product quality e.g. –granule size, morphic form or blend uniformity.

Surface Area:

Surface Area Definition - surface area is the measure of exposed surface of a solid sample on molecular scale. Specific Surface Area- the surface area per unit weight is called as specific surface area. Geometric Surface Area- area calculated from length dimensions of solid assuming that all surfaces are smooth.

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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 . Determination Of Surface Area – Gas Permeability BET Method Scanning Electron Microscopy .

References:

References Bentley's Textbook Of Pharmaceutics By E. A. Rawlins, 8 th Edition, Baillere Tindall, London. Theory And Practice Of Industrial Pharmacy By Leon Lachman, H.A. Liberman, Verghese Publication House, 3 rd Edition, Dader, Bombay. Pharmaceutical Preformulation By James A. Willis, Ellis Harwood Limited, 1998. Physical Pharmacy By Alfred Martin, James Swarbrick. Arthur Cammarata, Verghese Publ. House, Bombay. Www.Google.Com Journal Of Pharmaceutical Science, Vol. 96 Number 6, June 2007.

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