The Effects of Solid Dispersion on a Pyrimidinone
A compound developed as a new drug by the Upjohn Company, 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone (ABPP), shows antiviral activity against a broad spectrum of animal viruses, as well as inducing production of interferon. However, possible pharmaceutical uses of ABPP are inhibited by its poor aqueous solubility and slow, irregular dissolution. ABPP has a highly crystalline structure, and is highly hydrophobic due to its crystalline bonds. Theoretically, if GI absorption of ABPP is limited b9 its dissolution, then enhancement of dissolution should increase drug absorption, and hence bioavailability. Solid dispersions of ABPP were prepared by co-melting with: polyethylene glycol (PEG), or by co-precipitation with polyvinylpyrrolidone (PVP). The solid dispersions gave dissolution rates 15-20 times faster than pure ABPP, and samples formulated with PUP showed a corresponding increase in drug bioavailability in studies with beagle dogs. Apparent solubilities of ABPP in aqueous solution showed a 10-fold increase in the PVP-formulated coprecipitate. X~ray analysis indicates that the coprecipitate has transformed the drug into an amorphous, high-energy state. Infrared analysis indicates stabilization of ABPP in the -enol form when coprecipitated with PVP. Hydrogen bonding between ABPP and PVP is proposed as a mechanism for stabilization of the drug in -enol form over the keto- form present in the crystalline bulk drug. PVP is proposed to aid in the dissolution and dispersion of ABPP into aqueous solution. DSC studies indicate a chemical reaction between ABPP and PVP at elevated temperatures, leading to the de-bromination of ABPP. However, no chemical reactions were observed at the temperature necessary for solid dispersion formulation.