Theoretical Analysis of Drug Dissolution: I. Solubility and Intrinsic Dissolution Rate.

The first-principles approach presented in this work combines surface kinetics and convective diffusion modeling applied to compounds with pH-dependent solubility and in different dissolution media. This analysis is based on experimental data available for approximately 100 compounds of pharmaceutical interest. Overall, there is a linear relationship between the drug solubility and intrinsic dissolution rate expressed through the total kinetic coefficient of dissolution and dimensionless numbers defining the mass transfer regime. The contribution of surface kinetics appears to be significant constituting on average ∼20% resistance to the dissolution flux in the compendial rotating disk apparatus at 100 rpm. The surface kinetics contribution becomes more dominant under conditions of fast laminar or turbulent flows or in cases when the surface kinetic coefficient may decrease as a function of solution composition or pH. Limitations of the well-known convective diffusion equation for rotating disk by Levich are examined using direct computational modeling with simultaneous dissociation and acid-base reactions in which intrinsic dissolution rate is strongly dependent on pH profile and solution ionic strength. It is shown that concept of diffusion boundary layer does not strictly apply for reacting/interacting species and that thin-film diffusion models cannot be used quantitatively in general case.

Understanding the degradation pathway of a poorly water-soluble drug formulated in PEG-400.

VX-497 is a poorly water-soluble compound. It is formulated in PEG-400 and encapsulated in softgel capsules. Although the drug product is stable at refrigerated conditions, many degradation peaks have been observed at accelerated storage conditions. An investigation utilizing high performance liquid chromatography-mass spectrometry (HPLC-MS) was conducted to understand the degradation mechanism of the active pharmaceutical ingredient (VX-497) in PEG-400 formulation. Results revealed that the degradation was mainly caused by the reaction between VX-497 with moisture (hydrolysis) and PEG-400 (PEGylation). The numerous degradation peaks observed in the samples stored at accelerated conditions were PEG adducts covalently attached to portions of the VX-497 molecule, which were confirmed by comparison with synthetic markers. Investigation also found that an impurity, which was present in the VX-497 drug substance, reacted with PEG-400 following the same reaction mechanism, and generated additional impurities in the VX-497 drug product. By changing the process for drug substance synthesis, pure batches of VX-497 were obtained. Furthermore, it was found that the reaction between VX-497 and PEG-400 was temperature and time dependent. When the drug product was manufactured at 45 degrees C and the processing time was controlled, the PEG degradants and by-products were reduced to non-detectable levels, resulting in greatly improved drug product quality. This paper presents an integrated effort among analytical, process, and formulation scientists on how to develop a better drug product by understanding the fundamental issues of the drug product, namely the degradation mechanism.

Investigation of critical factors for the resolution of SR695, a key impurity, from efavirenz in the reversed-phase assay of efavirenz dosage forms.

An investigation of the critical factors effecting the resolution of SR695 from efavirenz in the assay of efavirenz by reversed-phase HPLC was performed. This study was implemented to address the inability of a subset of the Zorbax SB-CN columns used in this method to adequately perform this separation, which were otherwise indistinguishable from columns of this type that could. In this study, column temperature, detector time-constant, pre-gradient isocratic hold-time, pre-column mixing volume, column, and HPLC type were considered. Experimental Design methods were employed to find the relative importance of these factors and to find parameters that would optimize the resolution of SR695 and efavirenz on any HPLC, with any column of this type, for both efavirenz oral liquid and capsule samples. It was also desired that this method change be minimal, so that extensive revalidation would not be required. The most important factors were the column temperature, with lower temperatures giving better resolution, and pre-column mixing volume of sample with mobile phase, with higher mixing volumes giving better resolution up to an asymptote reached at around 150 microl. Added pre-gradient isocratic hold time was found to result in a small improvement in resolution, but was insignificant compared with the other factors mentioned above. A possible explanation is given for the mechanism by which temperature and pre-column mixing have this effect on the resolution obtained in this assay.