in vitro-in vivo correlation

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A M I S T U N I V E R S I T Y MALAYSIA K.JAYA RAJ KUMAR welcome

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in vitro-in vivo correlation According to me , this’s my report According to me , this’s my report Poorly correlated

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Correlation of in vitro rate of dissolution with in vivo absorption is a topic of significant interest to the pharmaceutical industry because it is a means of assuring the bioavailability of active ingredient(s) from a dosage form. Once such a correlation has been established, quantitative predictions regarding the absorption of drug from new formulations may be made without in vivo bioavailability studies . Introduction

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Many studies have been carried out since the late 1980s in attempts to correlate in vitro dissolution with in vivo performance. Some studies have found a significant correlation whereas others have been unsuccessful. This limited success in establishing a quantitative correlation is attributed to the fact that absorption is a complicated process. Physiological factors such as gastric emptying time, metabolism of drug by gut wall enzymes or intestinal microflora , and the hepatic first-pass effect can affect the absorption process.

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Whether such a correlation is established or not, the greatest value of in vitro dissolution lies in the following areas: (1) helping to identify formulations that may present potential bioequivalence problems and (2) ensuring batch to- batch bioequivalence once a formulation has been shown to be bioavailable . Types of correlation There are two basic types of correlations: Rank-order correlation Quantitative correlation.

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Rank order correlation A rank-order correlation is one in which: The y variable increases as x increases (implying that the y variable decreases as x decreases) The y variable increases as x decreases (implying that the y variable decreases as x increases). Variables that are definable by an interval scale or ratio scale may be transformed to rank order forms, which are then treated statistically.

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Quantitative correlation A quantitative correlation is one where the in vivo variable y is related to the in vitro variable x by one of the following equations: (b can be negative). These correlations are of a more informative type. However, such a relationship should probably be derived only when there is a theoretical reason for relating variables as indicated by the equation derived. In such correlations, the terms r (often called the correlation coefficient)

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Properties of the drug Solubility, pKa , particle size, salt, ester, polymorphic and solvate form Some interacting variables which influence the sensitivity and degree of in vivo correlation of in vitro methods for measuring drug release and dissolution.

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Variables of experimental method Hydrodynamic characteristics of the apparatus: Types of agitation Intensity of agitation Dispersion of particles Dissolution fluid pH Buffer capacity Ionic strength Additives Surfactants Complexing agents Absorbents Mucin , bile, enzymes Operating conditions: Agitation intensity Volume of solvent Exchange of solvent

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In vivo absorption variables Relative rates of permeation and transit Site of absorption Effect of GI fluids on Dissolution, absorption and degradation pH Enzymes Bile Mucin Rates and capacity of metabolism by intestinal and hepatic enzymes Condition Of Subject Disease Bed Rest volume of fluid given Fasting

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Dosage form variables Types of dosage form: Tablet Capsule Suspension Enteric Coated Sustained Release Release Characteristics: Diffusion-controlled Dissolution-controlled Presence of reactive substances: Buffering Agents Complexing agents Presence Of Inert Substances Surfactants Hydrophobic Substances Disintegrants

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Correlated variables Variables derived from in vivo data that have been correlated withvariables from in vitro data 1. Peak plasma concentration, (Cp)max 2. Area under the plasma concentration from t= 0 to t=t or t= α 3. Amount of drug excreted in the urine Xu at time t or at t=7t1/2 4. Urinary excretion rate at a given time t 5. Percentage absorbed plot (Wagner–Nelson method) from plasma or urinary data 6. Pharmacological response, e.g. blood sugar lowering or blood pressure.

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Variables derived from in vitro data that have been correlated with variables from in vivo data 1. Disintegration time 2. Time for a certain percentage of drug to dissolve (i.e. t20%, t50%, etc.) 3. Concentration of drug in dissolution fluid at a given time 4. Rate of dissolution 5. Percentage remaining to be dissolved 6. Intrinsic rates of dissolution.

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Thank you