(M0930-06-39) Developing Multiple Strengths of Controlled Release Tablet Formulations

Purpose: Hydrophilic matrix formulations are frequently used in developing controlled release tablets due to the numerous benefits they offer to both patients and manufacturers. One significant advantage of these formulations is the flexibility to make multiple drug strengths using mainly the same ingredients and manufacturing process. A simple method to achieve a higher dose utilizing a lower dose formulation involves preparing a common blend and compressing it into tablets of varying sizes and weights. This method simplifies development and optimizes a single formulation, but it has some drawbacks. Higher doses can result in larger tablet sizes, requiring more excipients, different packaging sizes, and increased costs. Most importantly, large tablets can lead to decreased patient acceptance and medication adherence. This study aimed to develop a controlled release matrix tablet formulation for phenylephrine hydrochloride (HCl), a model drug, in two dose strengths (120 mg and 240 mg) with a similar release profile and minimal changes in formulation comprised of commonly used excipients such as microcrystalline cellulose (MCC), a filler, and hydroxypropyl methylcellulose, (HPMC, hypromellose), a release rate controlling polymer. The goal was to achieve a 24-hour drug release duration, with approximately 50%-55% of the drug released within the first 4 hours.

Methods: Matrix tablet formulations consisted of 30% and 40% w/w phenylephrine HCl as the model drug, 30%-60% w/w hypromellose (METHOCEL™ K100M DC2) as the release rate-controlling polymer, 8.5%-38.5% w/w microcrystalline cellulose, low nitrite (LN) (Avicel^® PH-102 LN) as the filler, 0.5% w/w colloidal silica (SiO2, Cab-O-Sil^®) as the anti-adherent, and 1% w/w magnesium stearate as the lubricant. The low-strength formulation blend was compressed into 400 mg tablets whereas the high-strength blend into 600 mg tablets, using a compaction simulator with standard round concave punch tooling. The resulting matrix tablets were evaluated for physical properties and drug release. Tensile strength (TS) of the tablets was calculated, and tablets with TS of approximately 1.5 MPa - 2 MPa were selected for further studies. Biorelevant dissolution testing was carried out on the tablets using USP apparatus 2 at 50 rpm in simulated intestinal fluid (SIF), pH 6.8.

Results: Formulation Properties: Tabletability of 120 mg and 240 mg phenylephrine formulation blends are shown in Figure 1a and 1b, respectively. As the compression force increased, the TS of tablet increased. In 120 mg formulations (Fig. 1a) HPMC level varied from 30% to 60% and MCC from 38.5% to 8.5%. MCC has excellent compactibility and as its level in the formulation increased, the TS increased. The 240 mg formulation has a similar composition to the 120 mg formulation, containing 50% HPMC but with higher API concentration (40% vs 30%) and lower MCC level (8.5% vs 18.5%), resulting in lower tabletability as compared to the 120 mg formulation. Drug release: Figure 2 shows comparative release profiles of phenylephrine from the 120 mg and 240 mg dose tablets. Fig. 2a indicates the highest concentration of HPMC (60%) provided the slowest release profile for the 120 mg tablets, matching the target release profile. In this formulation, the API level was 30% and tablet weight was 400 mg. Fig. 2b shows a similar release from the 240 mg tablets, where the API level increased by 10% and the tablet weight by 50% (600 mg) to accommodate the dose. A slight modification in the low-dose formulation resulted in developing a higher dose tablet with slight increase in tablet size and excipients volume. Two controlled release matrix tablet formulations for phenylephrine hydrochloride (HCl), a model drug, were developed in 120 mg and 240 mg strengths with similar release profiles. The higher dose strength tablets (240 mg) were developed by making slight modifications to the low-dose formulation, resulting in a 50% increase in tablet size. A particle engineered grade of hypromellose (METHOCEL™ K100M DC2) and a low nitrite grade of MCC (Avicel^® PH-102 LN) with inherently good flow properties were successfully employed in manufacturing the tablets via a simple direct compression method. Both formulations demonstrated great blend properties, high tablet tensile strength, and low tablet friability. It was shown that multiple strengths formulations can be successfully developed for matrix tablet manufacturing. This may be beneficial for both patients in terms of medication adherence and manufacturers in terms of cost and productivity.


Figure 1. Tabletability of 120 mg phenylephrine HCl formulations at varying level of HPMC and MCC


Figure 2. Comparative release profiles of 120 mg phenylephrine HCl formulations


Figure 2. Comparative release profiles of phenylephrine HCl formulations