The development of sulfadoxine and nevirapine pharmaceutical amorphous solid dispersions
Solid oral dosage forms are the most convenient and prevalent dosage form in the pharmaceutical industry although an estimated 90% of drugs currently in development can be classified as poorly soluble. These drugs will subsequently present with poor dissolution which can lead to inadequate bioavailability. Sulfadoxine (SULF) and nevirapine (NEV) both present with poor dissolution and solubility properties. Sulfadoxine is a long-acting sulfonamide with antibacterial and antimalarial properties. Regardless of the dissolution problem, artemisin-based combination therapies, such as artesunate in combination with sulfadoxine-pyrimethamine are still the recommended treatment for uncomplicated Plasmodium falciparum malaria. Nevirapine, an NNRTI is used to reduce morbidity and mortality caused by HIV-1 and AIDS. Nevirapine is especially used as prophylaxis against mother-to-child HIV transmission. Limited information regarding improvement in dissolution for sulfadoxine has been reported. Nevirapine has undergone various studies, but with no outstanding success rate regarding the improvement of its limited solubility. The aim of this study was to improve the aqueous solubility, and dissolution rate, of the chosen drugs (sulfadoxine and nevirapine) by creating stable pharmaceutical amorphous solid dispersions (PhASDs) using a modified screening of polymers for amorphous drug stabilisation (SPADS) process. The use of dispersions, especially with polymers, enhances drug solubility and inhibits recrystallisation; this leads to an increase in stability and an extended shelf-life. The amorphous form presents with a higher thermodynamic activity, is more reactive and has a greater dissolution and solubility rate than its crystalline equivalent. Various polymers were initially screened in order to find the combination and ratio, API:polymer, which was miscible and deemed to be successful. After thorough screening the optimal combination API:polymer was found (both APIs delivered most successful results with PVP 25 as polymer) and further experiments were concluded. Manufacturing methods such as hot-melt and solvent-evaporation were experimented with in order to find the most successful method for the development of the PhASD. Hot-melt was an unsuccessful method for both the APIs, though solvent evaporation (by means of spray drying and rotary evaporator) delivered promising results. The SULF:PVP 25 1:2 mixture prepared through rotary evaporation was the only SULF mixture which proved to be mainly amorphous. The NEV spray dried product (NEV:PVP 25 1:4) was a pharmaceutical amorphous solid dispersion (PhASD) and completely amorphous. The product (NEV:PVP 25 1:4) obtained through rotary evaporation was a nanocrystalline solid dispersion (NCSD). Though amorphous forms are susceptible to reconvert to the crystalline form over time, accelerated stability studies were performed on the resulting PhASDs and NCSD under extreme conditions of 45˚C / 75% RH in order to determine whether recrystallisation occurred or degradation took place. The PhASD SULF:PVP 25 1:2 indicated that the exposure to humidity had a plasticising effect as minimal crystal growth occurred. The NEV:PVP 25 1:4 NCSD did not deliver pronounced crystal growth as was found with the sulfadoxine PhASD (SULF:PVP 1:2). HPLC analyses revealed little to no chemical degradation of either sulfadoxine or nevirapine occurred after three month stability testing. The PhASD, SULF:PVP 25 1:2 delivered a dissolution value of 214.39 μg/ml which is an improvement of 66.95 μg/ml within the first five minutes of dissolution testing when comparing to the SULF raw material (147.44 μg/ml). The nevirapine NCSD prepared through rotary evaporation yielded a five-fold improvement and the PhASD prepared by spray drying, yielded a six-fold improvement in dissolution within the first five minutes of the study. The PhASDs and nanocrystalline solid dispersion maintained the solubility advantage throughout the remainder of the three hour dissolution study. The solubility of both APIs remains challenging, as a drastic improvement in dissolution was not achieved for SULFA especially. The improvement of the solubility of NEV in the NEV dispersions, both NCSD and PhASD proved to be more significant.
- Health Sciences