Chemometric approach for the optimization of controlled release tablets with respect to reference product

An active drug is usually not used for a patient alone. A formulation is generated to reduce the side effects, to improve bioavailability, to control active drug release and to provide patient compliance with the use of excipients. Controlled release (CR) systems are of great interest for the delivery of active drugs because they provide directly delivery of maximum concentration level of it at controlled rate with causing less harm. Developing and optimizing the formulation of such tablets is a complex procedure since it includes the optimization of many factors. In this thesis, production of CR tablets was aimed. After optimizing each component's amount except active ingredient, the produced tablets were compared with a reference product. For this purpose, Niacin, a potent lipid modifying agent, was chosen as the drug substance where different CR tablet formulation trials were performed. In order to obtain a similar formulation to the reference product, Niascor 500 mg ER Tablet, dry granulation and wet granulation techniques were applied in the production step. Three experimental parameters (amount of HPMC E15, HPMC K 100M and Avicel PH 102 for the first design of experiments; amount of HPMC K 100M CR, Lactose Monohydrate and Avicel PH 102 for the second one) were optimized by using the Fractional Factorial Design Methodology. In all 16 formulations trials (Batch no: 01N14 - 16N14), the active pharmaceutical ingredient (Niacin) and stearic acid amounts were constant. Firstly, physical tests, like water content, dimensions (thickness, diameter), average weight, hardness and friability of the produced tablets, were applied and obtained results were compared with the test results of reference product. As a consequence, all results were found to be within the limits. The assay analyses of formulated products were conducted with the same HPLC method and all obtained results (as mg niacin/tablet and as % niacin/tablet) varied within acceptable limits. Afterwards, dissolution tests, a primary quality control test for new drug products, were performed for all the formulations using a UV Spectrophotometric method at a wavelength of 262 nm in the suitable dissolution medium and the percentage drug release of six tablets for each formulation were calculated. In addition, the similarity factor (f2) and the difference factor (f1) values were calculated and compared with those of the reference product. In conclusion, Niacin 500 mg ER Tablet-Capsule drug product, produced within the scope of this thesis, showed similar dissolution profiles in different pH media (0.1 N HCl, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and distilled water) with the corresponding reference drug product Niascor 500 mg ER Tablet. Similarity calculation was performed according to 'Guidance for Industry, Extended Release Oral Dosage Forms' and after all comparisons, unit formula of the 16N14 numbered wet granulated formulation, consists of 500.0 mg of Niacin, 140.0 mg of HPMC K 100M CR, 35.0 mg of Lactose Monohydrate, 13.0 mg of Avicel PH 102 and 5.0 mg of Stearic acid, was revealed as the final formulation for this study.