Conjugated eicosapentanoic acid (cEPA) inhibits L. donovani topoisomerase I and has an antiproliferative activity against L. donovani promastigotes

Conjugated eicosapentaenoic acid inhibits the relaxation activity of purified L. donovani topoisomerase I, with an efficiency higher than that displayed by the corresponding human enzyme. Docking of the acid compound over the 3D structure of the enzyme shows that the complex is stabilized by a large network of interaction between the compound and many residues located in proximity of the active site, including the catalytic tyrosine 222, providing an explanation for its efficient inhibitory effect. The acid has also a strong antiprotozoal activity against L. donovani promastigotes ( EC= 75 µM) whilst it has no effect against murine macrophages (IC ~ 2 mM). Taken together the results indicate that L. donovani topoisomerase I can be considered an interesting molecular target and that conjugated eicosapentaenoic acid can be taken in consideration as a possible lead compound against leishmaniasis

Impurity Purging through Systematic Process Development of a Continuous Two-Stage Crystallization

A methodical development approach was deployed in a novel portable manufacturing (Pharmacy on Demand) unit to purify ciprofloxacin hydrochloride hydrate within assay, water content, and impurity specifications described by the United States Pharmacopeia (USP) monograph and ICH Q3A(R2) guidelines for new impurities in drug substances. A series of design-of-experiment (DOE) and one-factor at a time (OFAT) experiments led to the optimization and control of a continuous two-stage crystallization that increased both the purity and yield of ciprofloxacin hydrochloride hydrate. Additionally, a statistically significant linear model was derived in batch within a 20 °C range that tracked the level of a difficult-to-purge impurity in stage 1 of the purification. This model was tested in continuous flow and predicted the impurity removal within 5% accuracy. With parametric control of process parameters, determined by optimization and modeling work, continuous flow isolations produced an active pharmaceutical ingredient (API) which had no individual impurities above 0.07%, with an isolated yield of 74%. In addition, acceptance criteria for assay (between 98 and 102%) and water content (between 4.7 and 6.7%) were met per the USP monograph for ciprofloxacin hydrochloride hydrate for the first time in the novel POD system