A Theoretical-Empirical Analysis on the Initial Dissolution Rate of Drugs from Polydispersed Particles

Abstract

The number of poorly water-soluble drug candidates in drug discovery has recently increased.1) Their limited solubility often causes not only poor but also variable oral absorption because the dissolution rate is insufficient to completely dissolve the drug in the gastrointestinal (GI) tract. Thus, control of the dissolution rate of drug is significant in obtaining sufficient oral absorption. One of the important factors in determining the dissolution rate of an active pharmaceutical ingredient (API) is particle size. Thus, understanding the dissolution of an API will benefit from clarification of the relationship between particle size and dissolution.The dissolution rate can be calculated from particle diameter under the assumption that the particles are spheres of relatively the same size because the dissolution rate of a drug is proportional to the solid surface area, as expressed by the Noyes-Whitney Equation.2) APIs normally include various or polydispersed particle sizes and, to specify the particle diameter for these polydispersed particles, representative diameters such as mean particle diameter or a statistical descriptor of cumulative undersize particles, such as D 50 or D 90 to designate diameters below which 50% or 90% of the drug is contained, are used. However, knowledge of the relationship between representative particle diameters and the dissolution rate is insufficient, and there is no validated method for determining the appropriate particle diameter in order to calculate the dissolution rate. In the present study, we attempt to identify the mean particle diameter of a drug with polydispersed particles that would best determine the dissolution rate of the drug. Our approach includes an investigation into the theory of the relationship between mean particle diameters and dissolution under sink conditions, simulation profiles of the dissolution of different particle sizes of a hypothetically generated drug, experimental dissolution profiles of different particle sizes of aprepitant as the model of a poorly water-soluble drug, the use of the dissolution profiles to predict dissolution in the human GI tracts, and lastly, discussion of particle size requirements for APIs. THEORETICAL BACKGROUNDDissolution Rate Equations for Mono-Dispersed Particles The Noyes-Whitney equation was used to determine the dissolution of a single particle.2) The Noyes-Whitney model of dissolution is based on the assumption that the particles have the same diameter a(t) and the ratio of D/h, where D is the diffusion coefficient and h is the diffusion layer thickness, is constant during the dissolution process. The dissolution rate is given by the following equation: (1) where X s (t) is the mass of undissolved drug at time t, C s is the saturated solubility of drug, C is the dissolved drug concentration at time t and a(t) is a function of t.Solving with the volume of the particle and density, r, results in:Equating Eq. 1 with Eq. 3 gives: (4) To simplify, dissolution under sink conditions is assumed to clarify the relation...

Correlation between microstructure and bioequivalence in Anti-HIV Drug Efavirenz

“…In our case, the mean particle size does not correlate, either with the (in vitro) dissolution profiles or with the (in vivo) bioequivalence results. Takano et al propose d [3,2] should correlate with dissolution [36]. However, they assume particles are spherical in their model, which is a strong simplification.…”