Kinetics of degradation and solubilisation of selected anti viral drugs

Abstract

Combination antiretroviral therapy is essential for the treatment of HIV/AIDS. At least three active drugs, usually from two different classes, are required to effectively suppress the virus to allow recovery of the immune system and reduce the emergence of HIV resistance. Nevirapine (NVP), lamivudine (3TC) and zidovudine (AZT) form part of the first-line regimen for the treatment of HIV/AIDS as stipulated by the World Health Organization (WHO). Current anti-retroviral therapy is extremely complicated, requiring between 2 and 20 dosage units a day from different dosage forms. Furthermore, the drugs themselves are very expensive. It is clear that there is a great need for more powerful drugs and easier regimens to be developed and become available to more people in the near future. Combining the above mentioned drugs into one dosage form will not only be more cost-effective but will also increase patient adherence. Both 3TC and AZT are readily soluble in an aqueous environment with solubilities of 70 mg/ml and 20.1 mg/ml respectively. NVP is practically insoluble in water (± 0.1 mg/ml) and its solubility decreases even further with an increase in pH, thus, making it difficult to formulate a liquid dosage form at physiological pH. Furthermore, there is very little literature available about the stability and degradation kinetics of NVP. The goal of the study was to gather information about the stability and degradation kinetics of NVP including pH-stability and measurement of the rate of degradation. Chapter 1 gives a literature overview of stability and degradation kinetics. Chapter 2 gives information about the three drugs used in the study, namely: NVP, 3TC and AZT. Chapter 3 gives a literature overview of solubility and techniques for solubilising drugs. Chapter 4 gives information about the various solubilising and complexing agents used in the study. Chapter 5 describes the methods used in the stability tests, pH-solubility tests, phase-solubility tests and solubility tests using different co-solvents. Chapter 6 and 7 finally deals with the results obtained and the conclusions that were made. Stability tests were done on the three drugs separately, as well as in combination, to ascertain the effect that combining the drugs have on their stability. The tests show NVP to be very stable with a t90 (pH 7) of -3000 days. 3TC is less stable with increased degradation at pH <4 but still has a long t90 of -2500 days at pH 7. AZT is the most stable of the three drugs as very little degradation occurred. Also, AZT is the most stable in the combination with 3TC and NVP. However, all of the drugs showed increased degradation in combination. NVP is approximately 10 times less stable in combination at pH 7. The shelf life of NVP decreased from -3000 days to -300 days in combination with 3TC and AZT. Therefore, it would be possible to formulate an aqueous solution with NVP as a single drug but a combination formulation with 3TC and AZT is not recommended as the shelf life decreases to substandard levels for both NVP and 3TC. Solubility studies and phase-solubility studies were conducted with NVP in various co-solvents and complexing agents. In conclusion it can be said that none of the solubilising techniques investigated were of any practical value in increasing NVP's solubility.