Preparation of valnemulin hydrogen fumarate and its enhanced stability compared with valnemulin hydrochloride.

CONTEXT: It is necessary to develop a new salt of valnemulin to replace the veterinary antibiotic, e.g. valnemulin hydrochloride, in order to overcome its instability during storage and preparation. OBJECTIVE: The objective of this study was to prepare a novel organic acid salt, valnemulin hydrogen fumarate, and to investigate its stability compared with valnemulin hydrochloride. MATERIALS AND METHODS: The crystal of valnemulin hydrogen fumarate was prepared by modified crystallization method; the enhanced stabilities of valnemulin hydrogen fumarate were conducted under irradiation and humid conditions, and the experimental results were simulated at AM1 level of calculations. RESULTS: Valnemulin hydrogen fumarate was more stable than valnemulin hydrochloride. After irradiation for 180 days, the content of valnemulin hydrogen fumarate decreased slightly 2.7%, whereas the content of valnemulin hydrochloride had an obvious decrease of 32.8%. Meanwhile, valnemulin hydrogen fumarate showed better anti-RH (relative humidity) ability than valnemulin hydrochloride. Under conditions of 65% and 85% RH, the absorption values of valnemulin hydrogen fumarate towards water were 0.75% and 1.20% at 48 h, whereas those of valnemulin hydrochloride were 4.50% and 9.71%, respectively. CONCLUSION: The enhanced stability of valnemulin hydrogen fumarate could be attributed to its good crystallinity in comparison with the amorphous valnemulin hydrochloride.

Characterization and In vivo Evaluation of Polymorphic Valnemulin Hydrogen Fumarate.

AIMS: In the present study, a valnemulin hydrogen fumarate prodrug was characterized, its stability was compared with valnemulin hydrochloride, and the efficacy was evaluated in Actinobacillus pleuropneumoniae-induced pneumonia in mice. METHOD: Optical microscopy, X-ray powder diffraction, infrared spectroscopy, and hydrogen nuclear magnetic resonance spectroscopy were used to study the physical and chemical properties of the prodrug. The thermal stability was investigated in comparison with valnemulin hydrochloride to improve the preparation process of valnemulin hydrogen fumarate soluble powder and maximize its drug effect. Additionally, the efficacy of valnemulin hydrogen fumarate was evaluated in a challenge-treatment trial in mice using an in vitro antimicrobial susceptibility test. RESULTS: The valnemulin hydrogen fumarate had high crystallinity. After light irradiation for 20 days, valnemulin hydrogen fumarate did not degrade, whereas valnemulin hydrochloride did. These results showed that the valnemulin hydrogen fumarate was stable. At the same dose in drinking water, the valnemulin hydrogen fumarate was more effective than the reference drug (tiamulin fumarate) in an Actinobacillus pleuropneumoniae challenge-treatment trial. CONCLUSION: Valnemulin hydrogen fumarate shows excellent potential for application as a veterinary drug.