By Timina Olive Kayaviri Supervisor : Dr. Amugune SIMULTANEOUS ASSAY AND DISSOLUTION PROFILES OF ACECLOFENAC AND PARACETAMOL IN FIXED DOSE COMBINATION TABLETS ON THE KENYAN MARKET By Timina Olive Kayaviri U29/3570/2010 Supervisor : Dr. Amugune

INTRODUCTION Fixed dose combinations (FDCs)are becoming more popular over the years because they Are convenient and easy to handle Confer increased patient compliance. Reduce development of resistance. Are cheaper than the individual drugs given concurrently Have simpler distribution patterns. Decrease incidences of monotherapy in cases where it’s not recommended.

INTRODUCTION….. Pain is the most common reason patients seek medical attention. Analgesic therapy that combines individual agents with different mechanisms of action has potential advantages Example: NSAID- paracetamol combinations such as with aceclofenac. Combined adverse reactions is a major cause for concern. Systemic absorption of an orally administered drug in a solid dosage form is a function of disintegration, dissolution and the transfer across membranes. There is the need for comparative analysis of different brands to assess factors that affect bioavailability

JUSTIFICATION Few post marketing surveillance studies have been done on aceclofenac and paracetamol FDCs Side effects, widespread use and increasing number of generic products in the market Brands may contain equal active pharmaceutical ingredient (API) content but have varying dissolution profiles.

STUDY OBJECTIVES Overall objective To determine the quality of different paracetamol and aceclofenac FDCs on the Kenyan market as per the official monographs. Specific objectives To carry out assay of paracetamol and aceclofenac in FDCs on the Kenyan market. To carry out dissolution test on these FDCs. To determine whether the different brands are pharmaceutically interchangable.

METHODOLOGY Eight samples were obtained from different Pharmacies in Nairobi. Samples contained 100mg aceclofenac and 500mg paracetamol. Uniformity of weight test was carried out according to the United States Pharmacopoeia (USP). Assay of the API was carried out using HPLC. The samples were separated using HPLC system consisting UV – Visible detector at 210nm and a C16 column (15cm x 4.6mm, 5µm), using a mixture of 0.1% v/v triethylamine (pH 3.0) and acetonitrile (50:50) as the mobile phase at a flow rate of 2ml/minute.

Methodology… Dissolution conditions were 900ml dissolution medium (phosphate buffer pH 7.4), medium temperature 37°C Dissolution tests were carried out using the USP dissolution apparatus II set at 75 revolutions per minute for 45 minutes. Amount of API dissolved was determined by HPLC under the same conditions as the assay.

RESULTS AND DISCUSSION - Uniformity of weight Tablets had total weights ranging between 650mg and 900 mg. % relative standard deviation ranged from -4.2 % to 2.6 % compared to the specified range of -5 % to 5 %. This is the case for all the batches except 004, which had a lower limit of -5.8 %. Uniformity of weight can be viewed as a measure of the uniformity of content.

Uniformity of weight Variations in weight can be attributed to factors such as uneven particle sizes and uneven flow of the particles uneven mixing of the excipients insufficient amount of lubricant or glidant the coating film in coated tablets vibrations These can be overcome by evaluating particle size before compression, incorporating enough amount of excipients and reducing vibrations.

RESULTS AND DISCUSSION - Assay Run time for the assay was set at twelve minutes and chromatograms obtained, a typical one being shown below. Peak at 2.58 minutes represents paracetamol while that at 8.134 minutes represents aceclofenac.

Assay The content was calculated by comparing standard and sample peak areas. % label claim was calculated by comparing the content and the manufacturers label claim. Manufacturers label claim was that each tablet contains 100mg aceclofenac and 500mg paracetamol. General USP specifications state that each batch should have API content between 90% and 110% of the label claim. All the brands complied with the specifications for the assay according to the USP, with values ranging from 95% to 105% for paracetamol and 93% to 104% for aceclofenac except for one (brand 007), whose aceclofenac content was 85%.

RESULTS AND DISCUSSION - Dissolution Chromatograms for the amount of sample dissolved after 45 minutes were obtained after running the sample for twelve minutes. A typical one is shown below with peak at 3.178 minutes representing paracetamol and that at 6.661 minutes representing aceclofenac.

Dissolution The amount of sample dissolved was calculated by comparing standard and sample peak areas. USP general chapters 711 indicate that every tablet tested for dissolution should be Q+5, where Q is quantity specified in the specific monograph, in this case is considered to be 70%, the lowest % of content dissolved allowed for immediate release tablets. All the brands tested complied except brand 003 where two tablets complied with the test while four failed to comply and 006 where one tablet had a % dissolution content above 200 %.

CONCLUSION Four Brands (001, 002, 005 and 008) complied with all the tests carried out in this study. 50 % of samples complied with all the tests and may be considered to be interchangeable. The objectives of the study were achieved. Results are useful in guiding the regulator, clinicians and patients on brands that comply with monograph specifications. Results may indicate that nearly half of the drugs in the market are not recommended for use.

RECOMMENDATIONS For future studies, the School should facilitate method development and validation for key FDCs. There is need for more frequent and continuous post marketing surveillance studies on these FDCs.