Effect of pepsin on maintaining the supersaturation of the HCl salt of a weakly basic drug: a case study

• Published in: Pharmaceutical development and technology Vol. 21; no. 3; pp. 311 - 320
• Main Authors: Pinnamaneni, Swathi, Rinaldi, Frank A., Jayawickrama, Dimuthu A., Li, Jinjiang, Dali, Mandar V.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02-04-2016
• Subjects: Chemistry, Pharmaceutical - methods; Hydrochloric Acid - chemistry; Hydrogen-Ion Concentration; Pepsin A - chemistry; Pharmaceutical Solutions - chemistry; Precipitation inhibitor; simulated gastric fluid; Solubility; supersaturation; Precipitation inhibitor; supersaturation; simulated gastric fluid
• ISSN: 1083-7450; 1097-9867
• DOI: 10.3109/10837450.2014.1003653

The impact of pepsin on the maintenance of supersaturated solution of the HCl salt of a weakly basic drug was evaluated in simulated gastric fluid by monitoring the drug solubility in the absence and presence of pepsin. In the presence of pepsin, the HCl salt maintained its apparent solubility through 24 h, whereas, no such solubility advantage was seen in the absence of pepsin. Consequently, a minimum inhibitory concentration of pepsin is required for maintenance of supersaturation. In addition, NMR study seems to indicate a molecular level interaction between pepsin and HCl salt leading to a weak binding between the two. Therefore, for the HCl salts of weak bases having disproportionation potential, it is preferred that preformulation solubility studies are conducted in the presence of pepsin to reflect their in vivo behavior in maintaining supersaturation solubility.