Abstract
Montelukast is a weak acid drug characterized by its low solubility in the range of pH 1.2 to 4.5, which may lead to dissolution-limited absorption. The aim of this paper is to develop an in vivo predictive dissolution method for montelukast and to check its performance by establishing a level-A in vitro-in vivo correlation (IVIVC). During the development of a generic film-coated tablet formulation, two clinical trials were done with three different experimental formulations to achieve a similar formulation to the reference one. A dissolution test procedure with a flow-through cell (USP IV) was used to predict the in vivo absorption behavior. The method proposed is based on a flow rate of 5 mL/min and changes of pH mediums from 1.2 to 4.5 and then to 6.8 with standard pharmacopoeia buffers. In order to improve the dissolution of montelukast, sodium dodecyl sulfate was added to the 4.5 and 6.8 pH mediums. Dissolution profiles in from the new method were used to develop a level-A IVIVC. One-step level-A IVIVC was developed from dissolution profiles and fractions absorbed obtained by the Loo–Riegelman method. Time scaling with Levy’s plot was necessary to achieve a linear IVIVC. One-step differential equation-based IVIVC was also developed with a time-scaling function. The developed method showed similar results to a previously proposed biopredictive method for montelukast, and the added value showed the ability to discriminate among different release rates in vitro, matching the in vivo clinical bioequivalence results.
Highlights
They are of analytical grade
Test tablet formulations were prepared by the Spanish Normon pharmaceutical company, described in this paper as Test 1, Test 2, and Test 3
Dissolution studies in the rotating paddle equipment were conducted at a rotational speed of 50 rpm using 900 mL of various dissolution media at pH 1.2, 4.5, and 6.8
Summary
Due to its pH-dependent solubility (from 0.18 μg/mL at pH 1.2 to 0.24 mg/mL at pH 7.5 [1]), in vitro conventional dissolution tests may be not useful to predict the in vivo behavior of montelukast products, as they do not reflect the physiological pH changes during intestinal transit or the actual luminal fluid volumes. Dynamic dissolution methods, such as a USP IV flow through apparatus, allows the pH changes in the intestinal lumen and the hydrodynamic conditions and 4.0/). Plasma concentrations of montelukast from two different bioequivalence trials were used to develop a level-A
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