The development of efavirenz and praziquantel amorphous solid dispersions

Abstract

Many active pharmaceutical ingredients (API) that are highly permeable, have low aqueous solubility. Such APIs are classified as Biopharmaceutics classification system (BCS) class II drugs. Efavirenz and praziquantel both belong to this class. Efavirenz (EFA) is a non-nucleoside, reverse transcriptase inhibitor that is used in combination for the treatment of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), whereas praziquantel (PZQ) is an anti-helminthic agent, used in the treatment of schistosomiasis (bilharzia). To increase the solubility of these drugs, amorphous forms can be created. The problem with amorphous forms is that they are unstable, whilst crystallisation is almost always a given. To increase the stability of these APIs, amorphous solid dispersions (ASD) are created by using polymers that increase the physical stability of the API and counter crystallisation. Efavirenz ASDs were prepared by using polyvinylpyrrolidone (PVP) 25, PVP 30 and the PVP VA 64 copolymer. 1.5% of sodium laurel sulphate (SLS) was added as surfactant. The binary mixtures increased the physical stability of the API, whereas the amorphous form of efavirenz crystallised with agitation. The ASD containing [EFA/PVP 25 (3:1) + 1.5% SLS] was physically stable, since no crystallisation had occurred over the 3 months of accelerated stability testing at 40°C and 75% RH. It was, however, chemically unstable, as a total degradation of 66.7% had occurred. The dissolution of this ASD showed an increase in solubility with a total of 5.97% of the API having dissolved after 3 hours. The ASD containing [EFA/PVP 30 (3:1) + 1.5% SLS] was also physically stable, as no crystallisation took place over the 3 months of testing, but degradation of 79.4% was measured. The dissolution rate of this ASD after 3 hours was the best at 6.44%. The ASD containing [EFA/PVP VA 64 (3:1) + 1.5% SLS] was physically stable, as no crystallisation had occurred over the 3 months of testing, with degradation measured at 78.6%. Dissolution of the API from this ASD was 4.42% after 3 hours. It is also noteworthy that these ASDs remained amorphous after dissolution. The preparation of praziquantel proved difficult and only one ASD was created that was rubbery and elastic, which made further testing difficult. This ASD contained praziquantel and HPMCAS in the ratio of 1:3. Because of the HPMCAS, which is used in modified release preparations, initial dissolution in water delivered unsatisfactory results. As a result of this, the dissolution studies were carried out in a buffered solution at pH 6.8 over 24 hours, resulting in 99.39% of the API having dissolved after 24 hours.