The development of paracetamol and dapsone amorphous solid dispersions

MSc (Pharmaceutics), North-West University, Potchefstroom CampusThe development of APIs was focused on the crystalline form over the years, but as the poor solubility of new drugs increased, the focus turned to developing the amorphous form of the drug. Dapsone (DAP) is no exception, as this drug has poor aqueous solubility and dissolution rate profile. Paracetamol (PCA) is hydrophobic and can present with problematic equilibrium solubility. DAP is a bacteriostatic sulfone with activity primarily against Mycobacterium leprae. Interestingly, DAP has a double function of antimicrobial/antiprotozoal and anti-inflammatory. Therefore, more diseases such as malaria, tuberculosis and dermatitis can be treated with DAP. PCA also known as acetaminophen in some countries, is an analgesic and antipyretic agent with no significant anti-inflammatory effects. It is readily available over the counter to treat various types of pain. DAP and PCA are both used in this study as model drugs for screening of polymers for amorphous drug stabilisation (SPADS) to be used in the production and study of pharmaceutical amorphous solid dispersions (PhASDs). The development of the new product is done to improve the dissolution profile of the active ingredient (API) by combining it with a polymer. The polymer stabilises the amorphous form of the API and thus preventing any recrystallisation and improving shelf life. The amorphous form of the API was used because of the solubility advantages, but a suitable polymer has to be used to overcome the disadvantages such as the poor thermodynamical stability. The process starts with a large number of polymer candidates and ratios of which unsuitable combinations will be eliminated as fast as possible. The API:polymer ratios are screened for further eliminations and accepted when deemed miscible. For paracetamol (PCA) the PhASDs, PCA:PVP 25 1:1, PCA: PVP 90 1:1 and PCA:PVP VA 64 1:3 were selected as suitable candidates that underwent further testing. All three PhASDs showed promising results (miscibility and amorphous structure) in the pre-screening before dissolution tests were done. It was clear after the dissolution tests were conducted that only PCA:PVP 25 1:1 showed an increase in solubility, and the rest showed no improvement over the raw material. PCA:PVP 25 1:1 improved the solubility of the PCA raw material slightly from 2.11 mg/ml to 2.37 mg/ml. For dapsone (DAP) the PhASDs DAP:PVP 25 1:1 and DAP:PVP 90 1:2 were selected and tested. The results showed that these PhASDs are miscible and amorphous. Since DAP is also used as a hardening agent, the dapsone manufacturing process was a challenge. It was in certain cases impossible to remove the PhASD successfully from the petri dishes. After dissolution testing was conducted, it became clear that there was no improvement in the solubility of the raw material. The peak concentration of DAP raw material was 6.44 μg/ml and the values obtained for the two tested PhASDs were 3.54 μg/ml (DAP:PVP 25 1:1) and 3.62 μg/ml (DAP:PVP 90 1:2) respectively. The PhASDs are placed under extreme stability testing conditions of 45°C and 75% RH for 6 months in order to determine the physical stability. DAP:PVP 25 1:1 showed a change in the XRPD only after 6 months suggesting that the product recrystallised, but DAP:PVP 90 1:2 showed no change and thus remained in its amorphous form. PCA:PVP 25 1:1 showed some visible recrystallisation after 4 months. Although negative results were obtained overall with regard to the dissolution testing for both actives, it is noteworthy that the release of paracetamol was delayed and maybe a matter to consider in future studies where delayed release dosage forms are required.Master