(M1130-01-02) Impact of Granulation Solvent on Release Performance of Dual Matrix Extended-Release Tablets of Highly Water-Soluble Drugs Formulated Using Compritol^®888ATO and Methocel^® as Release Retarding Agents

Purpose: Compritol^®888ATO (Glyceryl Behenate) a non – ionic solid triglyceride provides a versatile diffusion controlled waxy, hydrophobic extended-release (ER) matrix that functions without altering its physical state and does not require any special environmental conditions to activate its effect. Hydroxypropylmethylcellulose (HPMC) an ER matrix forming polymer functions by diffusion of the dissolved drug through the swollen gel layer and generally shows a burst effect, caused by dissolution and leaching of drug particles present at the tablet surface prior to formation of the release controlling gel thereby posing challenge in controlling initial drug release of highly water-soluble drugs. Thus, a combination of Compritol^®888ATO and HPMC polymers as ER dual matrix forming agents aids in better controlling the drug release of highly water-soluble Active Pharmaceutical Ingredients (APIs). Owing to poor flow properties of HPMC polymers, wet granulation process is highly recommended to avoid problems during tablet manufacturing on high-speed rotary tablet presses. The type of granulation solvent used during wet granulation process not only affects the degree of hydration of HPMC polymers thereby impacting the release of drug from the matrix but also the granule and tablet properties. Thus, this study evaluates the impact of different granulation solvents on the performance of highly water-soluble high dose Metformin Hydrochloride 1000mg dual matrix ER tablets USP/NF and of freely water-soluble low dose Metoprolol Succinate 95mg dual matrix ER tablets USP/NF formulated using combination of Compritol^®888ATO and Methocel^®K100M as ER dual matrix forming agents by wet granulation process.

Methods: Impact of three granulation solvents namely deionized water (DW), isopropyl alcohol (IPA) and DW: IPA (1:1) mixture was studied. Formula for Metformin Hydrochloride 1000mg ER tablets USP/NF and Metoprolol Succinate 95mg ER tablets USP/NF used in the study is provided in Figure 1. Wet granulation process for each API was conducted in rapid mixer granulator of 2 Litres capacity using the above granulation solvents. Tablets were compressed using fully motorized multi-station tablet press using caplet punches of 21 x 11 mm dimension for Metformin Hydrochloride 1000mg ER tablets USP/NF and round standard concave punches of 11 mm diameter for Metoprolol Succinate 95mg ER tablets USP/NF. The impact of granulation solvent on granule and tablet properties was evaluated by studying granule density, particle size distribution, flow properties (Carr's Index, Hausners Ratio, Bulk Density and Tap Density), tablet hardness & tensile strength, extent of tablet swelling and drug release kinetics. The in vitro dissolution study was conducted as per Dissolution Test 4 specified in USP41/NF36 monograph for Metformin Hydrochloride 1000mg ER Tablets USP/NF and Dissolution Test 1 for Metoprolol Succinate 95mg ER tablets USP/NF.

Results: Owing to high dose of Metformin Hydrochloride 1000mg ER dual matrix tablets USP/NF, the API occupied more than 70% of the matrix space while the concentration of both release controlling agents was restricted to about 20%. Amongst the granulation solvents evaluated for Metformin Hydrochloride 1000mg ER tablets USP/NF, better control on particle size distribution was observed with granules formulated using DW as granulating solvent in comparison to IPA & DW: IPA (1:1) owing to better hydration of Methocel^®K100M. Whereas DW: IPA (1:1) as granulating solvent overall proved to be effective in improving flow properties of granules, obtaining higher tablet hardness values and drug release profile complying within USP/NF specifications indicated in Figure 2. Metoprolol Succinate being freely water soluble required considerable amount of release retarding agents to achieve desired release profile wherein the API occupied 15% of the tablet matrix while the dual release retarding agents constituted to 57% of total tablet weight. No impact of the granulation solvents was found on the drug release profile and all three variants formulated using the granulation solvents under study were found to be complying within USP/NF specifications. Good control over granule particle size distribution was observed with DW and IPA: DW (1:1) mixture. Dissolution studies results are indicated in Figure 3.

Conclusion: Impact of granulation solvent was observed and affected the release profile of Metformin Hydrochloride that occupied 70% of the matrix space, while no impact was found on Metoprolol Succinate occupying only 15% of matrix space. Thus, it can be concluded that the choice of granulation solvent impacts release performance of dual matrix extended-release tablets formulated using Compritol^®888ATO and Methocel^® as release retarding agents and is governed by percentage of API occupying the ER matrix.

References: 2. N. G. Raghavendra Rao*, K. Richard Prasanna Raj, B. Sanjeev Nayak. Review on Matrix Tablet as Sustained Release. Int. J. Pharm. Res. & Allied Sciences, Volume 2, Issue 3 (2013),1-17

Acknowledgements:The authors would like to acknowledge Colorcon Inc. (India) for helping with gift samples of various grades of Methocel® polymers.


Figure 1: Formula for Metformin Hydrochloride 1000 mg Dual Matrix ER tablets USP/NF and Metoprolol Succinate 95 mg Dual Matrix ER tablets
USP/NF


Figure 2: Impact of Granulation Solvent on Drug Release Profile of Metformin Hydrochloride 1000 mg Dual Matrix ER tablets USP/NF


Figure 3: Impact of Granulation Solvent on Drug Release Profile of Metoprolol Succinate 95 mg Dual Matrix ER tablets USP/NF