Absorptive Dissolution Testing of Supersaturating Systems: Impact of Absorptive Sink Conditions on Solution Phase Behavior and Mass Transport

Abstract

One of the most commonly used formulation development tools is dissolution testing. However, for solubility enhancing formulations, a simple closed compartment conventional dissolution apparatus operating under sink conditions often fails to predict oral bioavailability and differentiate between formulations. Hence, increasing attention is being paid to combined dissolution-absorption testing. The currently available mass transport apparatuses, however, have certain limitations, the most important being the small membrane surface area, which results in slow mass transfer. In this study, a novel high surface area, flow-through absorptive dissolution testing apparatus was developed and tested on a weakly basic model drug, nevirapine. Following optimization of the experimental parameters, the mass transfer attained for a nevirapine solution was 30 times higher in 60 min as compared to a side-by-side diffusion cell. To further evaluate the system, nevirapine powder and commercial tablets were first dissolved at an acidic pH, followed by pH increase, creating a supersaturated solution. Detailed information related to the extent of supersaturation achieved in crystallizing and noncrystallizing systems could be obtained from the combined dissolution-mass transport measurements. Differences in donor cell compartment concentration-time profiles were noted for absorptive versus closed compartment conditions. It is anticipated that this approach could be a promising tool to identify solubility enabling formulations that perform optimally in vivo.

Evaluating side-by-side diffusion models for studying drug supersaturation in an absorptive environment: a case example of fenofibrate and felodipine

“…These results contradict previously published results by, for example Bevernage et al ., Hate et al . and Berben et al ., who saw that the inclusion of an absorptive compartment stabilized a supersaturated system and decreased the amount of precipitation . However, as both the model drugs (loveride and nevirapine) and experimental model setup (shaken Caco‐2 Transwells, use of hollow fibres and the AMI system) in the study by Bevernage et al ., Hate et al .…”

“…In their setup, drug absorption was mimicked using a hollow fibre membrane module with a surface area of 115 cm 2 , and a continuous flow of donor (50mL) and acceptor media on either side of a membrane, which allowed a 30 times higher mass transfer of the weak base nevirapine, as compared to using a side‐by‐side diffusion cell . Using the high surface area, flow‐through absorptive dissolution model, Hate et al insured a A/V ratio of 2.3 cm −1 and showed that the presence of an absorptive compartment during dissolution studies can alter the crystallization kinetics of nevirapine formulations. At low levels of supersaturation, drug absorption inhibited drug precipitation; however, at high levels of supersaturations, nevirapine precipitated rapidly independently of absorption .…”

“…Using the high surface area, flow‐through absorptive dissolution model, Hate et al insured a A/V ratio of 2.3 cm −1 and showed that the presence of an absorptive compartment during dissolution studies can alter the crystallization kinetics of nevirapine formulations. At low levels of supersaturation, drug absorption inhibited drug precipitation; however, at high levels of supersaturations, nevirapine precipitated rapidly independently of absorption . The rapid drug precipitation observed by Hate et al .…”

Biopharmaceutic IVIVE—Mechanistic Modeling of Single- and Two-Phase In Vitro Experiments to Obtain Drug-Specific Parameters for Incorporation Into PBPK Models

“…8,9 A number of techniques have been employed to achieve sink or near sink conditions viz. (1) increasing the dissolution media volume (typically up to 900-1000 mL in USP I and II apparatus), (2) addition of solubility enhancers such as surfactants, 10 (3) continuous media change flow through cell (USP IV) apparatus, [11][12][13] (4) integrating sink dialysis bag, or (5) use of an additional (organic) phase into which drug can partition. [14][15][16][17][18] The 2-phase in vitro system contains an aqueous medium within which the drug product undergoes dissolution and an additional (immiscible) organic layer to simulate an absorptive sink.…”

“…The Simcyp In Vitro data Analysis (SIVA) toolkit supports the analysis of complex in vitro data and allows seamless in vitroin vivo extrapolation (IVIV_E), which is a key element in successful prediction of in vivo behavior with physiologically based pharmacokinetic (PBPK) models. 11 The underlying principle of biopharmaceutical IVIV_E and its application in PBPK prediction sciences have already been explained in detail elsewhere. [20][21][22] The SIVA toolkit thus assists with the analysis of complex data generated from biopharmaceutic experiments for solubilitydsimple buffers and simulated intestinal fluidsdand dis-solutiondUSP II, USP IV, transfer models, media change experiments, 2-phase, mDiss etc.…”