Pre-formulation and chemical stability studies of penethamate, a benzylpenicillin ester prodrug, in aqueous vehicles.

Abstract

Penethamate (PNT) is a diethylaminoethyl ester prodrug of benzylpenicillin used to treat bovine mastitis via the intramuscular route. Because of its instability, PNT products must be reconstituted before administration and the reconstituted injection has a short shelf life (7 days at 2-8°C). The purpose of this paper was to investigate whether the stability of PNT can be improved in order to achieve a chemically stable ready-to-use aqueous-based PNT formulation or at least to extend the shelf life of the reconstituted suspension. A chemical stability study of PNT in aqueous-based solutions as a function of pH, buffer strength, solvent mixtures and temperature, supported by studies of its solubility in mixed solvents, allowed predictions of the shelf life of PNT solution and suspension formulations. PNT degraded in aqueous solutions by several pathways over the pH range 2.0-9.3 with a V-shaped pH-rate profile and a minimum pH of around 4.5. The stability of PNT solutions in mixed solvents was greater than in aqueous solutions. For example, in propylene glycol:citrate buffer (60:40, v/v, pH 4.5), the half-life of PNT was 4.3 days compared with 1.8 days in aqueous buffer. However, solubility of PNT in the mixed solvent was higher than that in aqueous solution and this had an adverse effect on the stability of suspensions. By judicious choosing of pH and mixed solvent, it is possible to achieve a storage life of a PNT suspension of 5.5 months at 5°C, not sufficient for a ready-to-use product but a dramatic improvement in the storage life of the reconstituted product.

• Authors: Rohit Jain, Zimei Wu, Olaf Bork, Ian G Tucker
• Journal: Drug development and industrial pharmacy (Drug Dev Ind Pharm) Vol. 38 Issue 1 Pg. 55-63 (Jan 2012) ISSN: 1520-5762 [Electronic] England
• PMID: 21696334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Buffers
• Esters
• Excipients
• Prodrugs
• Solutions
• Solvents
• Suspensions
• Water
• penethamate hydroiodide
• Penicillin G

Topics

• Buffers
• Chemistry, Pharmaceutical
• Drug Stability
• Esters (chemistry)
• Excipients (chemistry)
• Half-Life
• Hydrogen-Ion Concentration
• Penicillin G (analogs & derivatives, chemistry)
• Pharmacokinetics
• Prodrugs (chemistry)
• Solubility
• Solutions (chemistry)
• Solvents (chemistry)
• Suspensions (chemistry)
• Temperature
• Water (chemistry)