Use of Extrusion–Spheronization to Develop Controlled-Release Dosage Forms for Diltiazem Hydrochloride

*To whom all correspondence should be addressed. uring the past few decades, various types of oral controlled-release (CR) formulations have been developed to improve the clinical efficacy of drugs having short half lives as well as to increase patient compliance (1, 2). These formulations are designed to deliver drugs at a predetermined rate over a wide range of conditions and durations of therapeutic treatments. Matrix-based systems, in which the drug is dispersed as a fine powder from a matrix of polymericand non-polymeric release modifying agents, are preferred CR drug delivery systems because they are easy to manufacture (3). The process of extrusion–spheronization (ES), introduced by Reynolds (4) and Conine and Hadley (5), has become the method of choice for developing multiunit, pellet-based dosage forms. ES offers the technological advantage of providing multiparticulates with a spherical shape, good flow properties, low friabilities, and uniform packing characteristics. In addition to high drug load, the pellet offers the advantage of achieving modified drug release by incorporating release modifying agents such as ethylcellulose, acrylic polymers, chitosan, and glyceryl monostearate in the formulation (6–9). However, the number of formulation aids and release modifying excipients available for ES is very limited because of the properties needed for their wet mass. Pellets can be compressed to yield a single unit dosage form or can be coated to deliver a drug at a desired rate at the same site or various sites within the gastrointestinal tract. The application of ES for the development of CR formulations for highly water-soluble drugs without involving a coating step in the manufacturing operation is an area of interest because the methodology combines the advantages of a CR matrix system with an ES technology. Hence, the objective of the present study was to use ES to develop a matrix-based CR formulation for diltiazem hydrochloride (DLT), a highly watersoluble Class I drug that releases the drug at a predetermined rate on the basis of pharmacokinetic principles. The drug has a saturation solubility of 590 mg/mL in phosphate buffer pH 7.4 (10). Various approaches involving the modification of the formulation composition or process were adopted to achieve the target drug-release profile. To test the effectiveness of using various excipients for successful ES, batch yields were determined and pellets were evaluated for physical characteristics such as particle size and distribution, crushing strength, and density. D