posted on 2023-01-04, 21:05authored byDrew Scott, Naomi E. B. Briggs, Anna Formosa, Annessa Burnett, Bimbisar Desai, Greg Hammersmith, Kersten Rapp, Gerard Capellades, Allan S. Myerson, Thomas D. Roper
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.