Development of a Novel Bicarbonate Buffer System: Dissolution from Enteric Coated Microparticles

Introduction
Compendial dissolution media for dissolution testing results in poor in vitro–in vivo correlations due to significant differences in ionic composition compared with the fluids of the small intestine. Dissolution media based on bicarbonate buffers closely mimics the environment of intestinal fluids; however they are unstable due to a loss of CO2 causing a rise in pH. Purging CO2 gas into the medium stabilises the buffer; however, this changes the hydrodynamics in the dissolution vessel and is not compatible with bio-relevant media e.g. FeSSIF.
The aims of this project were to develop a novel system to stabilise bicarbonate buffer without purging gas into the solution and develop a single vessel method for convenience in media transfer during dissolution testing of enteric coated microparticles.
Methods
A single vessel method was developed where an enteric coated product was tested in 0.1M HCl and subsequently a modified salt solution based on Hanks buffer was added to increase the pH to 6.2. A novel gas supply system was applied to stabilise the bicarbonate buffer and provide a pH change using N2 and CO2 gas by suppling the gases through a partially sealed bespoke lid. The pH was controlled using in-line pH meters (NICO 2000) connected to a feedback system (Fig 1). Prednisolone was layered onto microcrystalline cellulose cores, Cellets 100®, using a fluid-bed coater (Mini-Glatt, Glatt GmbH) followed by polymer coating using Eudragit L30 D-55 to produce enteric coated microparticles. Drug release was determined from gastro-resistant prednisolone tablets (Actavis, Barnstaple, UK) and enteric coated microparticles using USP II apparatus with paddle speed of 100 rpm in 0.1M HCl for 2 hours followed by pH 6.8 phosphate buffer or pH 6.2-6.8 bicarbonate buffer.
Results
A reproducible method was successfully developed to increase pH of 0.1M HCl to pH 6.2 (6.19±0.09, n=15) after the addition of the modified Hanks salt solution. The use of the gas supply system was able to increase pH from 6.2 to 6.8 with N2 in 30-60 minutes without any significant disruption to the surface of the dissolution medium and stabilise its pH at pH 6.8 for 2 hours (Fig 2). Less than 10% drug release was achieved for enteric coated prednisolone tablets and microparticles after 2 hours in 0.1M HCl. Drug release was almost immediate in the compendial pH 6.8 phosphate buffer for both formulations. A substantial lag time (55 min) in drug release was observed in bicarbonate buffer for the enteric coated prednisolone tablets (Fig 3). Drug release from microparticles was significantly faster in bicarbonate buffer than tablets with a shorter lag time (15min) due to larger surface area.
Conclusions
The novel dissolution system offers a one vessel method for media transfer for testing enteric coated products using bicarbonate buffers. It is compatible with bio-relevant media and meeting compendial requirements, and thus offer a means for applying bicarbonate buffers for Quality Control testing with improved in vitro-in vivo correlation.
Enteric coated microparticles show faster drug release in bicarbonate buffers than tablets making them advantageous for drugs with a narrow absorption window.