Application of a Biphasic Test for Characterization of In Vitro Drug Release of Immediate Release Formulations of Celecoxib and Its Relevance to In Vivo Absorption

Abstract

A biphasic in vitro test method was used to examine release profiles of a poorly soluble model drug, celecoxib (CEB), from its immediate release formulations. Three formulations of CEB were investigated in this study, including a commercial Celebrex capsule, a solution formulation (containing cosolvent and surfactant) and a supersaturatable self-emulsifying drug delivery system (S-SEDDS). The biphasic test system consisted of an aqueous buffer and a water-immiscible organic solvent (e.g., octanol) with the use of both USP II and IV apparatuses. The aqueous phase provided a nonsink dissolution medium for CEB, while the octanol phase acted as a sink for CEB partitioning. For comparison, CEB concentration-time profiles of these formulations in the aqueous medium under either a sink condition or a nonsink condition were also explored. CEB release profiles of these formulations observed in the aqueous medium from either the sink condition test, the nonsink condition test, or the biphasic test have little relevance to the pharmacokinetic observations (e.g., AUC, C(max)) in human subjects. In contrast, a rank order correlation among the three CEB formulations is obtained between the in vitro AUC values of CEB from the octanol phase up to t = 2 h and the in vivo mean AUC (or C(max)) values. As the biphasic test permits a rapid removal of drug from the aqueous phase by partitioning into the organic phase, the amount of drug in the organic phase represents the amount of drug accumulated in systemic circulation in vivo. This hypothesis provides the scientific rationale for the rank order relationship among these CEB formulations between their CEB concentrations in the organic phase and the relative AUC or C(max). In addition, the biphasic test method permits differentiation and discrimination of key attributes among the three different CEB formulations. This work demonstrates that the biphasic in vitro test method appears to be useful as a tool in evaluating performance of formulations of poorly water-soluble drugs and to provide potential for establishing an in vitro-in vivo relationship.

Evolution of a mini-scale biphasic dissolution model: Impact of model parameters on partitioning of dissolved API and modelling of in vivo-relevant kinetics

“…Paddle speeds less than 60 rpm, however, generated insufficient hydrodynamics [13]. Therefore, in agreement with our results, the optimal rotation speed of 75 rpm for establishing IVIVC with human models was reported by Shi et al [24].…”

“…Various groups used biphasic dissolution models to test dissolution performance of different APIs and formulations. The applied paddle speed in these experiments varied from 50 to 100 rpm [2,15,23,24]. Mudie et al [11] illustrated that rotation speeds higher than 75 rpm should be avoided causing a vortex in the dissolution vessel.…”

Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges

“…Among the multiple advantages of emulsions and microemulsions, two of them should be noted in particular: (1) the potential to avoid precipitation upon dilution, and (2) the combined approaches with other formulation strategies. In addition to traditional emulsions and microemulsions, Gao et al (30)(31)(32) have developed supersaturated self-emulsifying drug delivery system (S-SEDDS) and have significantly improved oral absorption as compared to the conventional SEDDS formulation. S-SEDDS represents a new stable formulation approach which contains reduced amount of a surfactant and effective polymeric crystallization inhibitor (like hydroxypropyl methycellulose [HPMC] and polyvinylpyrrolidone [PVP]) to generate and maintain an in vivo supersaturated drug solution for drugs with poor water solubility.…”

Spray-Drying Technology

“…The can be accomplished by fi ltration or centrifugation of aliquots of the dissolution media; however, these methods are not always effective at eliminating particulates. Alternative methods for measuring free drug include passive diffusion systems employing a semi-permeable membrane and biphasic dissolution systems containing an octanol layer into which the drug partitions (Heigoldt et al 2010 ;Shi et al 2010 ) .…”