(M1230-01-05) Comparison of Commonly Used Hydrophilic Polymers for Matrix Tablet Formulation and Evaluation of Drug Release in Hydro-Alcoholic Media

Purpose: Purpose of work was to study effect of hydro-alcoholic dissolution media on drug release from extended-release matrix tablets. Hydrophilic matrices are a popular and extensively used strategy for oral extended-release drug delivery. Rapid polymer hydration and uniform gel formation are critical to the performance of hydrophilic matrix systems^[1]. Hypromellose (hydroxypropyl methylcellulose, HPMC), Polyethylene oxide (PEO) and Carbomer (Carbopol) are the polymer of choice as the rate-controlling carrier when matrix approach uses to retard drug release from tablets. According to Centers for Disease Control and Prevention (CDC), more than half of adults in the U.S. report drinking alcohol. The potential effect of alcoholic drinks in significantly accelerating drug release from ER oral formulations has been of some concern^[2]. ER formulations, which are intended for once or twice daily administration, are designed with a higher unit dose of the drug than conventional formulations. Therefore, it is imperative that retardation properties are tightly controlled to ensure that a rapid release of the drug, or dose dumping, cannot occur. Alcohol breaks down the ER formulation, and, as a result, increases peak plasma concentration causing potentially lethal dose dumping^[3]. Several publications have outlined the influence of hydro-alcoholic media on the performance of solid oral ER systems in the years since the FDA alert.

Methods: In the present study, Theophylline was chosen as the model drug due to its short half-life, making it an ideal candidate for extended-release formulations. Three commonly used rate-controlling polymers—HPMC, PEO, and Carbomer—were utilized to prepare matrix tablets. These tablets were evaluated for their integrity in preventing dose dumping in dissolution media containing varying concentrations of alcohol (5 & 40% w/v) and their drug release profiles were measured over 2 hours as recommended by FDA . The matrix tablet formulations comprised 20% w/w Theophylline as the model drug, microcrystalline cellulose (Avicel® PH-112) as the filler, 2.5-10% w/w Carbopol 71G, 20-40% w/w Hypromellose K100M premium CR, and 20-40% w/w Polyox WSR 301 (PEO) as the rate-controlling matrix polymers, 0.5% w/w colloidal silicon dioxide (Cab-O-Sil®) as the anti-adherent, and 1% w/w magnesium stearate as the lubricant. Each formulation was compressed into 500 mg tablets using a standard round 10.0 mm concave punch tooling. The resulting matrix tablets were evaluated for physical properties and drug release. Dissolution testing was performed on six tablets using USP apparatus 2 at 50 rpm in a pH 6.8 phosphate buffer for 12 hours and in 0.1 N HCl with 5% v/v and 40% v/v ethanol for 2 hours (FDA product specific guidance for ER product testing in alcohol).

Results: Formulations containing Polyox WSR 301 exhibited better compressibility as compared to formulations containing Carbopol 71G and Hypromellose K100M premium CR because PEO exhibited plastic deformation properties which contributed to tablet hardness. Figure 1 illustrates the comparative release profiles of formulations containing 0.25-10% w/w of Carbopol  71 G, 20-40% Hypromellose K100 M premium CR, and 20-40% Polyox WSR 301 as rate-controlling matrix polymers. It was observed that 10% and 15% Carbopol 71G resulted in faster drug release, while 20% Carbopol 71G showed slower drug release. In the case of Hypromellose K100M CR, 20% exhibited faster drug release, whereas 30% and 40% showed slower drug release compared to the brand product. For Polyox WSR 301, 20% demonstrated faster drug release, whereas 40% had slower drug release compared to the brand. The 30% Polyox WSR 301 formulation showed a satisfactory in-vitro drug release profile, closely matching the brand product (f2 = 89). Therefore, the batch containing 30% Polyox WSR 301 was tested in dissolution media containing 5% ethanol and 40% ethanol, and the same was done for the brand product. Figures 2 and Figure 3 show the dissolution comparison of the brand in media (0.1 N HCL) with different ethanol concentrations and the 30% Polyox WSR in media with varying ethanol concentrations respectively.

Conclusion: The release of highly soluble theophylline (100 mg) was prolonged using 30% Polyox WSR 301 in the formulation, aligning with the release profile of the brand product. Extended-release tablets formulated with Polyox WSR 301 maintained their structural integrity in media containing 5% and 40% w/v ethanol. This study confirms that PEO matrices provide consistent drug release in physiological media (pH 6.8 Phosphate buffer) as well hydro-alcoholic media, with no evidence of potential dose dumping.

References: 1. Levina M, Vuong H, Rajabi-Siahboomi AR. The influence of hydro-alcoholic media on hypromellose matrix systems. Drug Dev Ind Pharm. 2007;33(10):1125-34.
2. Roth W, Setnik B, Zietsch M, Burst A, Breitenbach J, Sellers E, et al. Ethanol effects on drug release from Verapamil Meltrex, an innovative melt extruded formulation. Int J Pharm. 2009;368(1-2):72-5.
3. Cvijić S, Aleksić I, Ibrić S, Parojčić J. Assessing the risk of alcohol-induced dose dumping from sustained-release oral dosage forms: in vitro–in silico approach. Pharmaceutical Development and Technology. 2018;23(9):921-32.