By Timina Olive Kayaviri U29/3570/2010 Supervisor : Dr. Amugune

1. 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

2. 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.

3. 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

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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%.

12. 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.

13. 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 complyand 006 where one tablet had a % dissolution content above 200 %.

14. 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.

15. 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.