Controlling the Release of Highly Dosed and Highly Soluble Drugs

The authors formulated bupropion hydrochloride tablets with various grades of methacrylic copolymers and analyzed the properties of the resulting dosage forms. This article is part of PharmTech's supplement "Solid Dosage and Excipients 2010."
Apr 30, 2010

This article is part of PharmTech's supplement "Solid Dosage and Excipients 2010."


Figure 1 (ALL FIGURES ARE COUTESY OF THE AUTHORS)
The aim of controlled drug-delivery systems is to achieve and maintain the desired drug concentration promptly at the proper site in the body. Sustained-release matrix formulations are a popular choice for modified-release tablets. The processes to obtain matrix tablets includes direct compression, dry or wet granulation, and melt extrusion (1). The selection of the active ingredient and of the retarding polymer, along with the other excipients, affects the mechanism and rate of release.


Figure 2
Modern controlled-release dosage forms require reliable excipients to ensure that the drug release rate is reproducible within a narrow range. In single-unit controlled-release tablets, water-swellable polymers traditionally have been popular as release retardants that form hydrocolloid matrices. However, forming inert matrices using methacrylic copolymers (Eudragit polymers, Evonik Röhm, Darmstadt, Germany) offers attractive, innovative options for specific drug-release targets because of the polymers' functionalities. They provide controlled release through diffusion and pore diffusion in a manner that can be pH-dependent or -independent, depending upon the polymer (2).


Figure 3
Eudragit polymers are synthetic neutral, cationic, and anionic polymethacrylates composed of different methacrylic acids, amines, and ester derivatives in various ratios (3). They provide targeted delivery and have been used for more than 50 years in the pharmaceutical industry for various applications, traditionally with a focus on functional film coatings. Eudragit polymers are available as dry solids, in dispersions, and as organic solutions. For the manufacture of matrix tablets, the polymers can be processed in all common granulation techniques, as well as in direct compression. Their binding properties produce tablets with advantageous hardness compared with hydrogel matrix formers (see Figure 1) Good hardness indicates good compressibility.


Table I: US Pharmacopeia dissolution specification for extended-release bupropion hydrochloride tablets.
For the study described in this article, the authors selected bupropion hydrochloride as the model drug. Bupropion hydrochloride, a white crystalline material, is a Class I drug with high water solubility (312 mg/mL) and high alcohol solubility (193 mg/mL) (4). An antidepressant of the aminoketone class, bupropion hydrochloride is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin. Its action is mediated by noradrenergic or dopaminergic mechanisms (5). It is available in 100-mg, 150-mg, and 200-mg strengths as sustained-release tablets and is manufactured and marketed globally by GlaxoSmithKline (London) under the brand Wellbutrin SR. Wellbutrin SR 150-mg tablets are circular, biconvex, film-coated, purple pills that weigh 420 mg. The US Pharmacopeia's (USP) monograph for extended-release bupropion hydrochloride tablets provides the in vitro release requirements, which are listed in Table I.

This article describes the development of bupropion hydrochloride matrix tablets that match the USP specifications (6). To evaluate the effectiveness of Eudragit polymers in retarding the drug release and in resisting ethanol influence, the authors developed a 150-mg sustained-release bupropion hydrochloride matrix tablet with anionic, cationic, and neutral Eudragit polymers. The development involved formulating a low-weight tablet and comparing in vitro release with the USP monograph. This study created matrix technology using top-spray granulation in a fluid-bed processor.


Table II: Batch of 1500 matrix tablets with methacrylic copolymers (Eudragit NM 30 D).
The US Food and Drug Administration recommends that the ethanol-resistance test for extended-release bupropion hydrochloride tablets be conducted in 0.1 N HCl compared with 0.1 N HCl with varying ethanol concentrations ranging from 5% v/v to 40% v/v (7).