In Vivo Predictive Dissolution: Analyzing the impact of Bicarbonate Buffer and Hydrodynamics on Dissolution.

Abstract

When a drug is given orally, one of the major factors that impacts safety and efficacy is dissolution rate. Two important in vivo parameters that impact dissolution that are not well accounted for in current dissolution methods are the physiological buffer species bicarbonate and hydrodynamics. This work explores important aspects of each of these.

Dissolution of pure drug using rotating disk dissolution methodology was used to evaluate the accuracy of several physically realistic simultaneous diffusion and chemical reaction schemes for CO2-bicarbonate buffer. Experimental results for ibuprofen, ketoprofen, indomethacin, 2-napthoic acid, benzoic acid, and haloperidol dissolution confirmed that the CO2 hydration reaction is sufficiently slow that it plays an insignificant role in the hydrodynamic boundary layer. Therefore carbonic acid undergoes an irreversible reaction to form CO2 and H2O. Dissolution experiments were also performed in the USP 2 (paddle) apparatus using suspended ibuprofen particles and tablets to demonstrate that the CO2-bicarbonate transport analysis can be successfully applied to pharmaceutical dosage forms. This transport analysis allows for predictions of phosphate buffers that more closely simulate dissolution in vivo. In the case of weak acid and weak base BCS class 2 drugs phosphate buffer concentrations are typically 1-15mM at pH 6.5.

The role of hydrodynamics on particle dissolution was studied using the USP 4 (flow through) apparatus because it provides relatively well-defined fluid velocity profiles that may simulate in vivo conditions. Experimental results showed that increasing the fluid velocity resulted in increased particle dissolution rates. The impact of fluid velocity can only be accurately predicted with knowledge of particle Reynolds number and the void space of the solid particles suspended in solution. The suspensions studied were consistent with predictions assuming a void fraction of 0.25.

The impact of hydrodynamics was also studied for erodible HPMC tablets using the USP 4 apparatus. In vitro erosion studies using bulk fluid velocities that simulate average intestinal flow rates (~0.1cm/sec) resulted in erosion rates that were 2-4.5 times slower than erosion rates observed for the same formulations in humans. It was concluded that the USP 4 apparatus may not provide hydrodynamics that accurately simulate in vivo tablet erosion.