Preformulation studies of ceftriaxone for pediatric non-parenteral administration as an alternative to existing injectable formulations

• Published in: European journal of pharmaceutical sciences Vol. 104; pp. 382 - 392
• Main Authors: Kauss, Tina, Marchivie, Mathieu, Phoeung, Thida, Gaubert, Alexandra, Désiré, Amélie, Tonelli, Giovanni, Boyer, Chantal, Langlois, Marie-Hélène, Cartwright, Anthony, Gomes, Melba, White, Nicholas, Gaudin, Karen
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15-06-2017; Elsevier
• Subjects: Anti-Bacterial Agents - chemistry; Ceftriaxone; Ceftriaxone - chemistry; Chemical Sciences; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Compatibility; Dosage Forms; Drug Stability; Excipients - chemistry; Humidity; Material chemistry; Near infrared (NIR) spectroscopy; Non-parenteral administration; Pharmaceutical process simulation; Powder Diffraction; Rheology; Solubility; Spectroscopy, Near-Infrared; Stability; X-Ray Diffraction; X-ray diffraction (XRD); Near infrared (NIR) spectroscopy; Non-parenteral administration; Stability; Pharmaceutical process simulation; X-ray diffraction (XRD); Ceftriaxone; Compatibility
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2017.04.010

Ceftriaxone, a third generation cephalosporin, has a wide antibacterial spectrum that has good CNS penetration, which makes it potentially suitable for initial treatment of severe neonatal pediatric infections providing suitable formulation. We evaluated its physicochemical and technical characteristics to assess its potential for development as a non-parenteral dosage form. As ceftriaxone is marked only for injectable use, these data are not available. Using HPLC and Karl Fischer titration, sensitivity of ceftriaxone to water, feasibility and impact of pharmaceutical processes and compatibility with common pharmaceutical excipients were assessed. X-ray diffraction studies gave deeper insight into the mechanisms involved in degradation. Chemometrical analysis of near infrared spectra enabled classification of ceftriaxone powder according to exposure conditions or processes applied. The results showed that ceftriaxone was not highly hygroscopic, could be processed in all climatic zones, but should be packaged protected against humidity. Controlling water presence in formulation was shown critical, as ceftriaxone degraded in the presence of water content above 2.4% w/w. To improve flowability, a critical parameter for dry dosage form development, granulation (wet and dry techniques, providing complete drying and moderate force compaction respectively) was shown feasible. Compression with moderate forces was possible, but grinding and high compression forces significantly affected long term ceftriaxone stability and should be avoided. Based on these results, development of ceftriaxone non-parenteral solid or liquid non-aqueous forms appears feasible.
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