Elucidation of the Controlled-Release Behavior of Metoprolol Succinate from Directly Compressed Xanthan Gum/Chitosan Polymers: Computational and Experimental Studies

Abstract

The development and evaluation of a controlled-release (CR) pharmaceutical solid dosage form comprising xanthan gum (XG), low molecular weight chitosan (LCS) and metoprolol succinate (MS) is reported. The research is, partly, based upon the utilization of computational tools; in this case molecular dynamics simulations (MDs) and response surface method (RSM), in order to underpin the design/prediction and to minimize the experimental work required to achieve the desired pharmaceutical outcomes. The capability of the system to control the release of MS was studied as a function of LCS (% w/w) and total polymer (LCS and XG) to drug ratio (P:D) at different tablet tensile strengths. MDs trajectories, obtained by using different ratios of XG:LCS as well as XG and high molecular weight CS (HCS), showed that the driving force for the interaction between XG and LCS is electrostatic in nature, the most favourable complex is formed when LCS is used at 15 % (w/w) and, importantly, that the interaction between XG and LCS is more favourable than that between XG and HCS. RSM outputs revealed that the release of the drug from the LCS/XG matrix is highly dependent on both the % LCS and the P:D ratio and that the required CR effect can be achieved when using weight fractions of LCS ≤ 20% and P:D ratios ≥ 2.6:1. Results obtained from in-vitro drug release and swelling studies on the prepared tablets showed that using LCS at the weight fractions suggested by MDs and RSM data plays a major role in overcoming the high sensitivity of the controlled drug release effect of XG on ionic strength and pH changes of the dissolution media. In addition, it was found that polymer relaxation is the major contributor to the release of MS from LCS-XG tablets. Using Raman spectroscopy, MS was shown to be localized more in the core of the tablets at the initial stages of dissolution due to film formation between LCS and XG on the tablet surface which prevents excess water penetration into the matrix. In the later stages of the dissolution process, the film starts to dissolve/erode allowing full tablet hydration and a uniform drug distribution in the swollen tablet.

A Direct Compression Matrix Made from Xanthan Gum and Low Molecular Weight Chitosan Designed to Improve Compressibility in Controlled Release Tablets

“…Moreover, the use of LCS at an optimum fractional content of 15% ( w / w ) supports a previous finding on optimum LCS content for interaction between XG and LCS using molecular dynamics simulations. The later study confirms that the most favourable complex is formed at an LCS content of 15% w / w [32]. On the other hand, the use of LCS at low concentrations within the XG/LCS mixture is advantageous when compared to reported work on high molecular weight chitosan and XG mixtures [27,28].…”

“…The matrix:drug ratio was fixed at a previously reported value of 2.61:1. The foregoing represents the recommended ratio which provides optimum drug release performance [32]. Therefore, in order to attain optimum tabletability, the RSM data were used to determine the range of compression pressures and/or the LCS content that can overcome the low matrix compactibility.…”

“…Hence, a new range spreads out in space to span new concentration and pressure limits which become 12%–85% LCS ( w / w ) and 40.6–173.3 MPa, respectively for this work (Table 1). The new range is wide enough to specifically include the previously reported LCS content of 15% which provided the most favourable interaction with XG [32]. Although 50% w / w was the highest chitosan concentration used in previous work for controlled release preparations [28,30], the new range extends to an extreme LCS content of 85% w / w (α).…”

“…In fact, the %LCS content was found to be a major process attribute in order to attain the desired drug release profile. In this context, an LCS content of 15% w / w provided the most suitable ratio for interaction with XG [32]. However, there is a lack of information as to why LCS content is crucial for enhancing mechanical strength of compacts compared to compression pressure.…”

Xanthan gum in drug release

“…There are several reports of the use of hydrogels based on xanthan gum alone and crosslinked with other polymers such as karaya gum, guar gum, hydroxypropyl methylcellulose, and polyvinylpyrrolidone (50,(69)(70)(71). Xanthan gum hydrogels have been applied as drug carriers and controlled drug release systems, allowing the controlled delivery of different drugs, including caffeine, azithromycin, ibuprofen, and propranolol HCl (39,(72)(73)(74)(75).…”