The development of ritonavir and pyrimethamine amorphous solid dispersions

Abstract

Poorly soluble drugs are a major problem in the pharmaceutical industry. Not only does it lead to formulation difficulties, but it also leads to poor absorption and poor bioavailability of drugs. Ritonavir (RTV) is a protease inhibitor (PI) used against Human Immunodeficiency Virus (HIV) and is well known for having poor bioavailability. RTV was previously classified as a BCS Class 4 drug, but more recently as a BCS Class 2 drug. Pyrimethamine (PYR) is used in combination with sulphadoxine as an anti-malarial drug combination in treatment against protozoan parasites such as Plasmodium falciparum and Toxoplasma gondii. RTV and PYR, both having poor aqueous solubility in the crystalline form and instability in the amorphous form. These two drugs were the two model drugs used in the testing of a screening of polymers for amorphous drug stabilisation (SPADS) method to produce and study pharmaceutical amorphous solid dispersions (PhASDs). Six different PhASDs were successfully produced with RTV through rapid solvent evaporation (RSE). The polymers used in each PhASD were: PVP 25, PVP 30, PVP 90, PVP-VA 64, HPMC and HPMCAS. All the PhASDs produced with RTV was in a 1:1 ratio. Each combination underwent dissolution testing and the PhASD produced with RTV and HPMCAS resulted in the biggest improvement in solubility. The solubility of RTV was improved by 4.88 times. Stability testing was also done in order to investigate the physical stability of the amorphous dispersion and the samples seem to have been relatively stable for a period of five months. PYR showed difficulty producing real amorphous PhASDs and only one combination resulted in a true amorphous PhASD. This combination was with PYR and HPMCAS in a 1:3 ratio and was also produced using the RSE method. The PhASD improved the end concentration, i.e. solubility of PYR after dissolution testing with 3.32 times. The PhASD started to show some signs of possible recrystallisation during the three months of stability testing, indicating that the PhASD was not stable under extreme humidity and temperature, and was going to fully re-crystallise very soon.