Controlling the Release of Highly Dosed and Highly Soluble Drugs

This article is part of PharmTech's "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).

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.

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.

Table I: US Pharmacopeia dissolution specification for extended-release bupropion hydrochloride tablets.

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.

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).

Table II: Batch of 1500 matrix tablets with methacrylic copolymers (Eudragit NM 30 D).

Materials and methods

Materials. Bupropion hydrochloride was purchased from Divi's Laboratories (Hyderabad, India). The excipients used for matrix granulation included L-cysteine hydrochloride (Merck Group, Darmstadt, Germany), microcrystalline cellulose (Avicel PH 101, FMC Biopolymers, Philadelphia), povidone K 90 (BASF, Ludwigshafen, Germany), talc (Luzenac, Toulouse, France), calcium stearate (Ferro, Cleveland), and glyceryl behenate (Gattefossé, Saint-Priest France). The study involved Eudragit NM 30 D, Eudragit RS PO, and Eudragit FS 30 D (Evonik Röhm).

Method of manufacturing. Granulation was carried out in a GPCG 1.1 granulator (Glatt, Binzen, Germany). The blending was carried out in a double-cone blender (CTC GMP, M/s Wintech, Mumbai), and the lubricated granules were compressed on a 16-station rotary-compression machine equipped with 10.3-mm circular punches with corresponding dies (CPM D3-16, M/s CLIT, Ahmedabad, India).

Bupropion matrix with neutral polymer. Eudragit NM 30 D is the aqueous dispersion of a neutral copolymer composed of ethyl acrylate and methyl methacrylate (3). The authors used it to develop a matrix polymer.

Requisite quantities of bupropion hydrochloride, diluents, and L-cysteine hydrochloride, a stabilizer that maintains acidic pH in the formulation, were weighed and mixed. Eudragit NM 30 D was sprayed at a programmed rate to obtain a mass of suitable consistency that was dried to achieve loss on drying of 1.5–2.0% w/w. The presifted lubricants were weighed and blended with dried granules and compressed. The targeted tablet weight was 400 mg.

Bupropion matrix tablet with anionic polymer. Eudragit FS 30 D is the aqueous dispersion of an anionic copolymer made of methyl-acrylate, methyl methacrylate, and methacrylic acid. It has an acidic pH (3).

Requisite quantities of bupropion hydrochloride, diluents, and L-cysteine hydrochloride were premixed. Eudragit FS 30 D was sprayed on the above blend at a predetermined rate, and the mass was dried to a moisture content of 1.5–2.0% w/w. The presifted lubricants were weighed and blended with dried granules and compressed into a tablet (8).

Bupropion matrix with cationic polymer. Eudragit RS PO is the powder grade of a copolymer of acrylic and methacrylic acid esters and approximately 5% ammonio methacrylate units (3). Requisite quantities of bupropion hydrochloride, diluents, and L-cysteine hydrochloride were weighed and mixed.

Eudragit RS PO was dissolved in a 9:1 ethanol–water mixture and sprayed at specified rate to obtain a mass of suitable consistency. The mass was dried to achieve a moisture content of 1.5–2.0% w/w. The presifted lubricants were weighed and blended with dried granules and compressed.

The in vitro release of bupropion hydrochloride from all tablets was studied in USP Type II (Paddle) device set at 50 rpm in 900 mL of purified water maintained at 37 ± 0.5 °C. Samples were taken periodically for 8 h and analyzed at 298 nm. The same analytical procedure was employed to determine the release in 0.1 N HCl and 40% ethanolic 0.1 N HCl.

The tablets were packed in sealed high-density polyethylene containers and charged on stability as per the International Conference on Harmonization's guidelines. The assay and dissolution were carried out in accordance with the USP monograph for extended-release bupropion hydrochloride tablets (6).

Results and discussion

Table III: Batch of 1500 matrix tablets with methacrylic copolymers (Eudragit FS 30 D).

Eudragit polymers enabled the authors to produce tablets with excellent hardness. The crushing strength of the tablets and their friability are summarized in Table V.

The release profiles of bupropion hydrochloride from the tablets prepared using different ionic grades of Eudragit at initial conditions and under three months' accelerated stability conditions are shown in Figures 2–4.

Figure 4

The matrix tablets formed with Eudragit polymers were sufficiently integrated and uniform to control the release of the highly soluble drug over 8 h, thus complying with USP specifications. Because it is a neutral polymer, Eudragit NM 30 D is compatible with most active ingredients. During the development of bupropion tablets with Eudragit NM 30 D, the authors added Eudragit RS PO, another strong retardant, to the solid form. This addition led to even stronger retardation without increasing water quantity during the process.

Figure 5

Similar dissolution results were observed when the neutral polymer was replaced with anionic polymer Eudragit FS 30 D. At a 15% concentration, the USP matching profile was attained at initial and accelerated stability conditions.

When the authors dispersed the cationic powder grade Eudragit RS PO into a hydroalcoholic medium, the tablet achieved the USP matching profile with 40% polymer concentration at the initial and the accelerated stability conditions.

Table IV: Batch of 1500 matrix tablets with methacrylic copolymers (Eudragit RS PO).

Assay of bupropion hydrochloride. Bupropion hydrochloride content in the tablets manufactured with different ionic grades of Eudragit was analyzed at the initial and at the end of three months' accelerated stability conditions. The results of the content are given in Table VI.

The assay results confirmed the quality of all matrix tablets tested. The drug stayed stable in the polymer matrix without any degradation over time.

Figure 6

Ethanol resistance test. Five years ago, FDA became vigilant following an incident of ethanol consumption associated with a marketed analgesic preparation. Modified-release formulations of this analgesic with a reasonably narrow therapeutic index have been coming under scrutiny. FDA's Guidance for Industry: Individual Product Bioequivalence Recommendations contains a list of controlled-release formulations for which in vitro dissolution testing in hydroalcoholic media is required (7). The list includes extended-release bupropion hydrochloride tablets. In fact, if the reference listed product is rugged and no labeling cautions are warranted, it would be highly desirable for any generic product to be similarly robust, even if its modified-release mechanism were different from that of the innovator product (9).

Figure 7

The comparative release profiles of matrix tablets with Eudragit polymers in 0.1 N HCl and 40% ethanolic 0.1 N HCl are shown in Figures 5–7.

Table V: Hardness and friability data of trials with different grades of methacrylic copolymers (Eudragit).

No investigated matrix formulations showed a significant difference between the medium without and with 40% alcohol content. The marketed product shares this characteristic. The similarity factor F2, which denotes the closeness between the dissolution values of the in-house formulation and the marketed product, was more than 60. Hence, all tested Eudragit matrix formulations fulfilled the FDA recommendation for robust formulations that prevent alcohol dose dumping.

Conclusion

Table VI: Assay of bupropion hydrochloride under initial and three months accelerated storage stability conditions.

The current study, which was designed to control the release of bupropion hydrochloride with various ionic and nonionic Eudragit grades in matrix technology, yielded attractive results. The tablets prepared showed matching USP release profiles in the beginning and under accelerated stability conditions, thus demonstrating stable formulations. All three Eudragit polymers tested showed strong retardant properties. Among the polymers, the aqueous dispersions were more effective than the powder grade. Dissolution profiles within specifications were achieved at low polymer levels of 15%. Thus, excellent formulation options are available for highly soluble actives, particularly for highly dosed actives that result in low tablet weights. The strength of these formulations is evidenced by the growing number that is available on the international market. Furthermore, regulators require extended-release bupropion hydrochloride tablets to demonstrate 40% ethanol resistance, which was proven for all tested Eudragit formulations.

Table VII: Dissolution conditions for bupropion hydrochloride ethanol resistance as per FDA.

Eudragit polymers are well estabilshed in pharmaceutical coating applications. The current study showed that Eudragit polymers also can be used for matrix applications for controlling the drug release. Eudragit polymers enable the realization of small dosage forms with high drug content. The current study showed that Eudragit polymers can be used to formulate matrix systems with unique dissolution characteristics and superior tablet properties.

Shripad Gadhinglajkar is head of research and development projects in the formulation and development group, Gopeshkumar Singh is an assistant manager for formulation development, Smitha Shetty is an assistant manager in the analytical department, and Brigitte Skalsky* is a global marketing manager of pharmaceutical services, all at Evonik Röhm, Kirschenallee, 64293 Darmstadt, Germany, tel. +49 6151 18-4389, fax +49 6151 18-844389, brigitte.skalsky@evonik.com<.

*To whom all correspondence should be addressed.

References:

1. D. Gallardo and M. Assmus, Pharma Polymers News Bull. (12), 1–2 (2005).

2. B. Skalsky, Pharma Polymers News Bull. (16/01), 2–3 (2009).

3. Eudragit Application Guidelines, (Evonik Röhm Pharma Polymers, Darmstadt, Germany, 11th ed., 2009).

4. The Merck Index, M.J. O'Neil, Ed. (Merck Research Laboratories, Whitehouse Station, NJ, 14th ed., 2006), p. 246

5. Physician's Desk Reference, J. Reed, Ed. (PDR Network, Montvale, NJ, 63rd ed., 2009), p. 1653

6. USP 32–NF 27 (US Pharmacopeial Convention, Rockville, MD, 2009), p. 1723

7. FDA, Individual Product Bioequivalence Recommendations, Bupropion Hydrochloride Extended Release Tablets (Rockville, MD, April 2008).

8. S. Bodinge et al., poster, AAPS (Los Angeles, 2009).

9. R. Meyer and A. Hussain, presentation, FDA's ACPS Meeting, (Rockville, MD, 2005).

10. D. Gallardo, M. Assmus, and B. Skalsky, presentation, CRS Annual Meeting (Miami, FL, 2005).