Formulation and Monitoring the Stability of Artesunate in Artesunate - Amodiaquine Combination Tablets

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Dispensing of antimalarial poses a challenge to the formulating pharmacist while presenting the combination of the two drugs in a single dosage form. The objective of formulating a single dosage form of artesunate and amodiaquine is to improve patient compliance and adherence to the drug resulting in decreased possibility of recurrence or developing resistance to malaria. Based on a WHO response to antimalarial drug resistance which calls for a period of change when treatment failure exceeds 25%, Ghana adopted a new antimalarial drug policy with artesunate – amodiaquine being chosen as the most cost-effective compared to all other alternatives. But with the new policy, for a 70kg+ patient to be adequately treated using the 50mg Artesunate and 150mg Amodiaquine formulation, he/she requires a total of 24 tablets in a three day treatment regimen programme. With such a treatment programme, many were those who expressed apprehension about the efficacy with respect to drug compliance and adherence. Amodiaquine is a 4 – aminoquinoline and artesunate is a water soluble hemi – succinate derivative of artemisinin. Amodiaquine acts by accumulating in the lysosomes of the parasites bringing about loss of its function, and also binds to their nucleoproteins inhibiting the DNA and RNA polymerase, which end up generating free radicals. Artesunate acts by heme – mediated decomposition of its endoperoxide bond to produce carbon – free radicals. This work aims to formulate combination tablets of artesunate and amodiaquine and to develop a simple and precise HPLC method to monitor the stability of the single dosage form using accelerated stability studies. In this work, a single dosage form of artesunate and amodiaquine was formulated. Each dosage form contains 100mg of artesunate and 300mg of amodiaquine constituting two tablets daily and a total of six tablets for three days for the full dose of adults in the treatment of malaria. A simple, accurate and precise isocratic reverse phase HPLC method with a mobile phase comprising 0.3% v/v of glacial acetic acid, acetonitrile and triethylamine in the ratio of 55%: 45%: 0.3% was developed using a C8 column. The final pH was always in the range of 4.5±0.1. A flow rate of 2.0ml/min with UV detection set at 254nm was employed at room temperature. Artesunate had a retention time of 4.13 minutes and amodiaquine had a retention time of 5.93 minutes. A linear calibration curve was obtained with r2 value of 0.998. RSD obtained was less than 1% indicating a high precision of the method. The method proved to be robust with variations in the mobile phase and stationary phase compositions. The limit of detection of artesunate and amodiaquine are 1.29*10-4 %w/v and 3.3*10-5 %w/v respectively. The limit of quantification of artesunate and amodiaquine are 6.45*10-4 %w/v 1.65*10-4 %w/v respectively. The shelf – life of the artesunate in the artesunate – amodiaquine combination tablets is 0.41 years or 4.1 months at 28oC and 0.1 years or 1.2 months at 40oC. Artesunate – amodiaquine combination tablets were found to have a short stability period. Artesunate and amodiaquine are incompatible, and there is severe degradation of the drugs in presence of each other.
A thesis submitted to the Department of Pharmaceutical Chemistry, Kwame Nkrumah University of Science and Technology in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE,July, 2009