Design and Evaluation of a New Fixed-Dose Immediate Release Capsule of Atenolol, Enalapril Maleate and Hydrochlorothiazide
Nickania A. Pryce
Department of Pharmaceutics, School of Pharmacy, College of Health Sciences, University of Technology, Jamaica, 237 Old Hope Road, Kingston 6, Jamaica.
Amusa S. Adebayo *
Department of Biopharmaceutical Sciences, School of Pharmacy, Roosevelt University, Chicago, Illinois, USA.
Deon A. Bennett
Department of Chemistry, Faculty of Science and Sports, University of Technology, Jamaica, 237 Old Hope Road, Kingston 6, Jamaica.
Eugenie Brown-Myrie
Department of Pharmaceutics, School of Pharmacy, College of Health Sciences, University of Technology, Jamaica, 237 Old Hope Road, Kingston 6, Jamaica.
*Author to whom correspondence should be addressed.
Abstract
Aim and Objectives: To design, formulate and perform in vitro studies of a fixed dose combination (FDC) immediate release solid dosage form of the antihypertensive drugs atenolol, enalapril and hydrochlorothiazide. The objectives of the study were to perform pre-formulation studies, design an immediate-release FDC capsule dosage form, and evaluate the prepared dosage form.
Methods: Differential Scanning Calorimetric (DSC) analysis of physical mixtures of drugs and drug-excipient combinations was used to assess compatibility. Binary mixtures of atenolol and enalapril form a eutectic mixture indicating that a tablet dosage form, in which the drugs would be highly compressed together, may not be stable. Hard gelatin shell encapsulation was therefore employed. Atenolol and enalapril were separately dry-granulated with hydrochlorothiazide and excipients and mixed together at appropriate therapeutic proportions and encapsulated in size 1 hard gelatin capsules (HGC). Preliminary screening produced five formulations each with similar proportions of the 3-drug FDC but with 5 different levels of disintegrant. Capsule weight variation, disintegration time and dissolution rate were determined as output variables, following USP procedures. For the dissolution studies, a reverse phase high-pressure liquid chromatographic (RP-HPLC) method was developed for simultaneous analysis of the three drugs.
Results: Granules possessed good fluidity (compressibility index 8.53 to 11.63 and tapped bulk density 1.09 to 1.132). Capsule disintegration time was generally £ 2 minutes while 80% of each drug dissolved within 20 minutes. Capsules showed no sign of physical instability or adverse effect during a period of 1 year shelf storage at room temperature (average temperature 25°C).
Conclusions: Granules possess adequate fluidity and compressibility for filling into HGC. Results generally indicated that an immediate release FDC capsule of atenolol, enalapril and hydrochlorothiazide was stable for more than 1 year of observation. Capsule disintegration time and dissolution rate were generally within the USP specification.
Keywords: Atenolol, enalapril, hydrochlorothiazide, fixed-dose combination, eutectic mixture.