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PubMed1999

Dissolution specifications based on release rates.

A procedure based on release rates is proposed for the establishment of dissolution specifications that ensure the bioequivalence of a test and a reference product. This procedure, which confines Cmax (the maximum concentration of the drug in vivo) and AUCinfinity (the area under the time-concentration curve, extrapolated to infinity) values within any desired range (relative to a reference product), can be used as an alternative to the methods presented in the FDA guidance1 or the USP.2 The method is appropriate for zero-order or first-order release products with linear Level A in vitro/in vivo correlations (IVIVC). Based on the result that the relative difference in Cmax must always be smaller than the relative difference in the absorption rate constants (for any test and reference products of a given drug), the "minimum range" specifications are set. These specifications, which are identical for both zero-order and first-order release products, are of general validity. They depend only on the relative extents of release, but are otherwise drug or formulation independent. For certain extended release products demonstrating a constant release rate that is unaffected by dissolution conditions (thus allowing the assumption of Level A IVIVC), the "minimum range" dissolution limits are applicable even when in vivo data is not available. If the reference product in vivo data is available, wider limits (which are product specific) may be set. If the drug disposition is monoexponential, the specifications generated are the widest possible. They are termed the "ideal" specifications. In the case of a multiexponential disposition, the limits set by the procedure will (generally) not be the widest possible. Although the method is based on one-compartment models, it is essentially model independent in the sense that microscopic modeling is redundant for its application.

Algorithms↗

PubMed1997

On the variability of dissolution data.

PURPOSE: To investigate dissolution data variability and its origins. METHODS: The Weibull function with four parameters t0 (dissolution lag-time), K (the rate parameter), beta (the shape parameter) and D (the fraction dissolved as t-->infinity), is used to describe the dissolution curve. The variance of the dissolution data is expressed in terms of these parameters and their individual variances sigma t02, sigma K2, sigma beta 2, and sigma D2. These four variances originate from variable physical properties of the dosage units and from a variable dissolution environment. Therefore, dissolution data variability depends on both, the functional form of the curve and on the variance of the physical conditions. The use of this method enables the elucidation of the sources of dissolution data variability. RESULTS: In the case of a sigmoidal dissolution curve (beta > 1), data variance is zero as dissolution begins (following dissolution lag-time). This initial variance diverges when the dissolution curve is non-sigmoidal (with beta < 1) but assumes a finite value, proportional to the dissolution lag-time variance (sigma t02) when the data fits a regular first order rate curve (beta = 1). Following a long dissolution time, data variance attains a constant value equal to the dissolution extent variance, sigma D2. When the dissolution curve is sigmoidal and the variability related to the dissolution extent is sufficiently small (sigma D/D < < 1), a maximum in the variance is expected at some intermediate time point (corresponding to the curve inflection point, when the main source of variability is dissolution lag-time t0, or around t = 1/K + t0, when the main sources of variability are the rate parameter K or the shape parameter beta). When the curve is sigmoidal (beta > 1) and the main source of variability relates to the dissolution extent, the overall variance grows with time all the way to the plateau of the dissolution curve. With a non-sigmoidal dissolution curve (beta < or = 1), data variability decreases with time soon after dissolution begins. In that case, if the main source of variability is the dissolution lag-time (t0), the variance decreases all the way to the plateau of the dissolution curve. If the dissolution extent, D, is the main source of variability, a minimum in the variance is expected at some intermediate time point. The dissolution relative variance, on the other hand, diverges as dissolution begins and decreases with time at least until 63% of the drug is released, irrespective to the Weibull parameter values. Later, it may decrease or increase, attaining a fixed value (sigma D2/D2) at the plateau of the dissolution curve. CONCLUSIONS: The particular time dependence of dissolution data variance is well defined in terms of the Weibull shape parameters and their individual variances. Dissolution data variability may decrease or increase with time long the curve. It may attain a maximum or a minimum value at some intermediate time point. It may converge or diverge as dissolution begins. When the dissolution data is well fitted to the Weibull function, the sources of data variability (in terms of the Weibull parameters) may be elucidated. The variability of dissolution data originates from physical sources but is also dependent on the functional form of the curve.

Analysis of Variance↗