Determining the suitability of mass spectrometry for understanding the dissolution processes involved with pharmaceutical tablets.

Claire Lewis,Tony Bristow,Andrew Ray,Stephen Wren

doi:10.1002/rcm.7203

Abstract

A current challenge for analytical chemists is the development of the measurement systems and approaches required to understand dynamic processes such as tablet dissolution. The design and development of oral tablets could be improved by the availability of detailed information about the rates of release of the individual tablet components. Small footprint mass spectrometry (MS) systems are gaining use for on-line reaction monitoring because of their ability to rapidly determine multiple reactant, intermediate, and product species. We have therefore assessed the utility of such MS systems to the study of dissolution processes. Aqueous dissolution media containing phosphate and other non-volatile buffer salts were pumped from a standard USPII dissolution vessel through an active splitter and back. The splitter sampled the dissolution stream and diluted it into a make-up flow which was pumped to a small single quadrupole mass spectrometer. Single ion monitoring was used to quantify the ions of interest. Three different bio-relevant dissolution media were studied to gauge the effect of the sample matrix. Individual dissolution profiles were obtained from a tablet containing three drugs, and lactose as the soluble filler. This was successfully demonstrated with three different bio-relevant media designed to reflect the pH of the different sections of the human gastro-intestinal tract. Component concentrations as low as 0.06 µg/mL (representing 1% dissolution) were detected. The MS dissolution profiles correlated with the visual observation of tablet dissolution. MS gave linear responses with concentration for the individual components, although analysis of the tablet solution indicated that ion suppression is an area for further investigation. An on-line MS system was used to determine the individual dissolution profiles of three drugs and lactose as they were released from the same tablet. The level of each of these components in solution was determined every 10 seconds, and each had a similar release profile. The dissolution profiles were determined using inorganic buffer solutions at three different bio-relevant pHs.

Highlights

Pharmaceuticals are typically administered as solid oral tablets but for the drug to be available for absorption in the Gastro Intestinal Tract (GIT) it must be in solution
The same procedure was performed by dissolving the Active Pharmaceutical Ingredients (APIs) and the lactose standards in blank FaSSiF buffer, a commonly used dissolution medium, representative of fluid from the intestine in its fasted state
This allowed the effect of fasted state simulated intestinal fluid (FaSSIF) on ionisation to be understood and allowed a more direct comparison with conditions to be used in the dissolution test itself

Summary

Introduction

Pharmaceuticals are typically administered as solid oral tablets but for the drug to be available for absorption in the Gastro Intestinal Tract (GIT) it must be in solution. In recent years the dissolution test has been used as a tool to improve understanding of dissolution mechanisms, and so aid in the design and development of new formulations. The expectation of regulatory authorities is that the conditions used in the registered dissolution test will be related to those which exist in the GIT. This has led to increasing emphasis on the use of dissolution media with pHs and other characteristics which are relevant to those of the GIT. [4] There is a need for improved analytical methods to improve our understanding of tablet dissolution processes HCl/NaCl buffers at pH 1.2 simulate the fasted state of the stomach, acetate buffers at pH 4.5 the fed state of the stomach, and phosphate buffers at neutral pHs the conditions in the small intestine. [3] Recent reviews have emphasised the need for better in vitro tools that are predictive of in vivo behavior. [4] There is a need for improved analytical methods to improve our understanding of tablet dissolution processes

Methods

Results

Conclusion