Model for the Analysis of Membrane-Type Dissolution Tests for Inhaled Drugs

Abstract

Impactor-type dose deposition is a common prerequisite for dissolution testing of inhaled medicines, and drug release typically takes place through a membrane. The purpose of this work is to develop a mechanistic model for such combined dissolution and release processes, focusing on a drug that initially is present in solid form. Our starting points are the Noyes–Whitney (or Nernst–Brunner) equation and Fick’s law. A detailed mechanistic analysis of the drug release process is provided, and approximate closed-form expressions for the amount of the drug that remains in solid form and the amount of the drug that has been released are derived. Comparisons with numerical data demonstrated the accuracy of the approximate expressions. Comparisons with experimental release data from literature demonstrated that the model can be used to establish rate-controlling release mechanisms. In conclusion, the model constitutes a valuable tool for the analysis of in vitro dissolution data for inhaled drugs.

Optimization of the Transwell® System for Assessing the Dissolution Behavior of Orally Inhaled Drug Products through In Vitro and In Silico Approaches

“…In contrast with May’s model, this further integrates dissolution and diffusion steps. Our model further differs from May’s and a recently published model developed by Frenning et al regarding membrane-based dissolution tests [ 34 ], as it considers the sampling procedures within the model. Using the parameters employed by May et al to describe the dissolution process (diffusion coefficient in the stagnant layer, thickness of the stagnant layer), we were unable to predict the experimental dissolution profiles of DPI formulation C (data not shown).…”

Characterization of Membrane-Type Dissolution Profiles of Clinically Available Orally Inhaled Products Using a Weibull Fit and a Mechanistic Model

“…This definition of is consistent with the one used in our previous work. 15 From eq 2 , it can be seen that , that is, equals the product of the dissolution rate constant k , the initial weight-specific surface area , and the solubility .…”

“…In order to extend the above results to the case when dissolution occurs in a donor compartment and drug subsequently diffuses across a membrane into an acceptor compartment, we use the same nondimensional variables as in our previous work. 15 Hence, we introduce the nondimensional time τ = t / t diss , and the nondimensional “concentrations” of dissolved and solid drug, c = C / S 0 and s = S / S 0 together with the nondimensional solubility c s = C s / S 0 . Here, S 0 is the initial value of S , calculated as the ratio between the initial mass of drug and the volume of the donor compartment, implying that 1/ c s represents the ratio between the initial amount of the drug in the donor compartment and the maximal amount that can be dissolved without efflux, that is, a dose number for the drug in the donor compartment.…”

“… 14 To this end, we have previously developed a mechanistic model that combines drug dissolution in the donor compartment with diffusional permeation through the membrane. 15 For simplicity, a monodisperse powder was assumed. The modeling results exhibited an adequate correspondence with prior experiments and could be used to determine rate-limiting processes.…”

“…The aim of this study was twofold. First, to extend our previously developed mechanistic model for membrane-type dissolution tests for inhaled drugs 15 to polydisperse powders by using a novel methodology that retains the continuous particle-size distribution. Second, to demonstrate how such a mechanistic analysis can be used to minimize the effect of the membrane on dissolution data obtained from Transwell dissolution tests, thus providing improved estimates of important dissolution parameters.…”