511The quantitative prediction of drug dissolution profiles is critically important for elucidating the pharmacokinetic behavior of drugs. The determination of drug dissolution in vitro is one of the key elements in the pharmaceutical development process and is sometimes used as a surrogate for the assessment of bioequivalence. Therefore, many mathematical models for predicting drug dissolution, which can be roughly categorized into mechanistic and empirical methods, have been proposed.The basic mechanistic models for solid dissolution were developed by Noyes-Whitney 1) and later Nernst 2) and Brunner.3) These familiar models are known as "diffusion-controlled models" today. Furthermore, based on these models, the "cube-root law" devised by Hixson and Crowell 4) and other equations 5,6) were developed. One of the significant advantages of these mechanistic models is that they allow easy prediction of a drug dissolution profile without requiring a dissolution test because physical parameters such as solubility, density, diffusivity etc., which are components of the equations, can be determined by more convenient experiments. In addition, since the crucial parameters that influence drug dissolution patterns have been clarified, the models may be useful for controlling drug dissolution patterns. Although, to the best of our knowledge, perfect sink conditions, in which the bulk concentration of a drug is considerably less than its solubility, have been universally assumed in these models, discrepancies between the theoretical and experimental data have been found for water-insoluble drugs, suggesting that the development of new mechanistic models for predicting almost all kinds of drug dissolution is desired.On the other hand, empirical and semiempirical models, not mechanistic models, have also been developed by numerous researchers.7,10,11) A general empirical equation called the Weibull model has been applied to the drug dissolution process by Langenbucher,7) and this model can be adapted to almost all kinds of drug dissolution (Goldsmith et al.,8) Vudathala and Rogers
9)). Korsmeyer et al. 10,11) also developed a semiempirical model called the Korsmeyer-Peppas model. This Korsmeyer-Peppas model is surprisingly simple, but is capable of predicting many kinds of drug dissolution profiles. Although both the Weibull and Korsmeyer-Peppas models are able to describe drug dissolution profiles even if the drug is water-soluble or not, a dissolution test is required to determine the parameters of the equations because these models are not mechanistic. Therefore, empirical and semiempirical models are difficult to apply to the control of drug dissolution patterns as desired.It has been estimated that more than 40% of the new chemical entities developed through a high throughput drug discovery program have poor water solubility.12,13) In order to effectively develop pharmaceutical products, the establishment of a new mechanistic model that is independent of drug solubility is desired. The purpose of the present study is to...
