(M1330-07-46) Development and In Vitro Evaluation of Modified Release Bupropion Hydrochloride Tablets for Enhanced Drug Delivery

Purpose: Bupropion, [(±)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one], is a norepinephrine and dopamine reuptake inhibitor classified as an atypical antidepressant [1]. In addition to its primary use in the treatment of major depressive disorder, bupropion is also prescribed as a pharmacological aid for smoking cessation [2]. Furthermore, it has shown effectiveness as monotherapy in the management of obesity and in the regulation of food intake, highlighting its therapeutic versatility. The present study focuses on the development and evaluation of modified release tablet formulations of bupropion hydrochloride (BUP·HCl) using a matrix-based design. The primary objective was to optimize the drug release profile in a controlled manner, aiming at achieving BUP·HCl quantitative release within eight hours. The in vitro release behavior of the newly formulated tablets was compared to that of the reference listed drug, Wellbutrin^® XR (150 mg and 300 mg). The dissolution experiment was carried out under biorelevant conditions to simulate gastrointestinal transit. Initially, the release studies were conducted in an acidic medium (pH 1.2) to mimic the gastric environment, and subsequently in a pH 6.8 buffer solution to simulate the intestinal conditions. These experimental conditions enabled the assessment of release kinetics and the potential bioavailability of the developed formulations under physiologically relevant pH transitions.

Methods: For the preparation of the modified-release tablets, a variety of excipients and polymers commonly used extended-release drug delivery systems were employed. These included the polymethacrylate polymer Eudragit® L 100-55, starch-based excipients (Starlac® and Startab®), glyceryl behenate (Compritol® 888 ATO), lactose monohydrate (both pure and as part of Starlac®), hydroxypropyl methylcellulose (HPMC K15M), hydroxypropyl cellulose (HPC Celny VH FP) and crospovidone (Polyplasdone^® XL-10). Magnesium stearate was used as a lubricant. Table 1 shows the composition of the developed formulations. The BUP·HCl tablets were prepared by direct compression. All excipients, excluding magnesium stearate, were accurately weighed and blended in a powder mixer at 32 rpm for 10 minutes. Magnesium stearate was then added and the resulting mixture was blended for an additional 5 minutes under the same conditions. For each tablet, 225 mg of the final blend was weighed and compressed in a 10 mm die using a hydraulic press. Compression force was adjusted based on prior hardness testing to ensure uniform tablet strength. For dry-coated tablets, a two-step compression process was followed. Core tablets were first compressed in a 10 mm die, and then transferred to a 13 mm die, where the coating blend was added.

Results: The test results are depicted as diagrams of % BUP HCL release vs. time in Figures 1 and 2. It was found that the use of HPMC, HPC, Eudragit and glyceryl behenate contributed to a relatively slow and gradual release of the active substance, particularly at 0≤t≤120 minutes. Conversely, the presence of lactose, starch, and crospovidone in the matrix tablets appeared to enhance the drug release rate during the same initial period. Specifically, formulations containing HPMC and HPC Celny promoted gel formation upon contact with the dissolution medium, reinforcing the mucoadhesive properties of the tablet. Both excipients swell and form gels when hydrated, thus significantly reducing the release rate of the active ingredient. Moreover, the addition of Compritol 888, a hydrophobic lipid excipient, contributed to the formation of a lipidic matrix, further delaying the dissolution and extending the release of the active ingredient. The use of Eudragit L100-55 polymer in the dry coating, assisted in forming pores in the matrix at the intestinal pH, promoting a higher drug release in the neutral environment, while controlling the release under acidic conditions. Lactose monohydrate, being a highly water-soluble and inert excipient, facilitated the drug’s dissolution. Starch, serving as a diluent, also played a role in accelerating the release rate. Additionally, the use of crospovidone, an excipient with disintegrant and dissolving properties, significantly increased the dissolution rate of BUP·HCl by promoting rapid disintegration of the matrix.

Conclusion: In conclusion, the appropriate selection and use of the aforementioned excipients in the formulations of extended-release BUP·HCl tablets can contribute to minimizing abrupt drug concentration spikes, while maintaining steady therapeutic levels over a prolonged period. This may lead to a reduction in the occurrence of adverse side effects and an improvement in the overall therapeutic efficacy of the formulation.

References: 1. Foley KF, DeSanty KP, Kast RE. Bupropion: Pharmacology and therapeutic applications. Expert Rev Neurother. 2006;6:1249–65.
2. Damaj MI, Grabus SD, Navarro HA, Vann RE, Warner JA, King LS, et al. Effects of hydroxymetabolites of bupropion on nicotine dependence behavior in mice. Journal of Pharmacology and Experimental Therapeutics. 2010;334:1087–95.

Acknowledgements: The research work was supported by the Hellenic Foundation for Research and Innovation (HFRI) under the 5th Call for HFRI PhD Fellowships grant to C.P. (Fellowship Number: 20610).


Composition of the developed formulations


Dissolution profiles of BUP⋅HCl from tablet formaulations F1-4 and the commercially available Wellbutrin XR 150 and 300 mg tablets, at pH 1.2 (0–120 min) and at pH 6.8 (120–480 min). Results represent the mean value (n = 3, SD < 2).


Dissolution profiles of BUP⋅HCl from coated tablets and the commercially available Wellbutrin XR 150 and 300 mg tablets, at pH 1.2 (0–120 min) and at pH 6.8 (120–480 min). Results represent the mean value (n = 3, SD < 2).