RESUMO
A gradient elution preparative chromatography method was developed for the recovery of the antibiotic ertapenem from crystallization mother-liquor streams. The preparative HPLC method that was developed on the lab-scale employs an analytical size column of conventional dimensions (25 cm x 0.46 cm) packed with Kromasil C8 stationary phase. Gradient elution was used with aqueous acetic acid and acetonitrile as mobile phases. A target of processing approximately 30 mg of ertapenem per half an hour at a flow rate of 1.5 mL/min with high yield and adequate rejection of all major impurities was achieved. This corresponds to a productivity of approximately 0.6 kg ertapenem as free acid per kilogram of stationary phase per day (kkd). The scalability of the method was demonstrated by using a 5 cm i.d. column configuration to generate 10 g of purified ertapenem. This work complements a previous study improving on the productivity and throughput of the method by employing gradient elution and the use of crystallization to remove some key impurities that are chromatographically difficult to resolve [A. Vailaya, P. Sajonz, O. Sudah, V. Capodanno, R. Helmy, F.D. Antia, J. Chromatogr. A 1079 (2005) 80].
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , beta-Lactamas/isolamento & purificação , Cristalização , Indústria Farmacêutica , ErtapenemRESUMO
6-(Nitrooxy)hexyl-(2z)-4-(acetyloxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoate (enoate 1) was investigated as a novel therapy for pain relief. In a recent manufacturing run at the pilot plant scale, the enoate drug substance was found to have a yellowish color not observed previously. An unknown impurity at trace level was detected by high-performance liquid chromatographic (HPLC) analysis and found to be the primary cause for the color of the drug substance. The colored impurity was enriched by preparative HPLC and structurally elucidated by liquid chromatography/tandem mass spectrometry (LC/MS/MS). It was found that the colored impurity was derived from the product of oxidative dimerization of rofecoxib, an impurity present in the enoic acid intermediate. It was further revealed by the photodiode array and LC/MS/MS data that the colored impurity exists in the drug substance as a pair of double-bond isomers with one isomer at majority. These findings were also confirmed by synthesizing the colored impurity through the proposed pathway.
Assuntos
Butiratos/química , Cromatografia Líquida/métodos , Contaminação de Medicamentos , Espectrometria de Massas/métodos , Nitrocompostos/química , Cor , Lactonas/química , Estrutura Molecular , Oxirredução , Sulfonas/químicaRESUMO
Preparative chromatography was successfully employed to recover ertapenem from mother liquor streams. The recovery process involved concentration of mother liquor stream by evaporation, purification by reversed-phase preparative high-performance liquid chromatography (HPLC), and removal of chromatographic solvents in the recovered fractions by evaporation. HPLC feed was prepared by stripping off the organic solvents from the mother liquor using a wiped-film evaporator. Purification was first carried out on a 25 cm x 0.46 cm analytical column packed with 10-microm Kromasil C8 particles and then scaled up to a 25 cm x 5 cm preparative column. Gram-level recovery of ertapenem with high purity was achieved by exploiting a novel approach based on pH mismatch between the feed and the eluent. Purified ertapenem streams from preparative HPLC runs were combined, evaporated and recycled into the crystallizer for ertapenem isolation.
Assuntos
Antibacterianos/isolamento & purificação , Cromatografia Líquida de Alta Pressão/métodos , Lactamas/isolamento & purificação , Estabilidade de Medicamentos , Ertapenem , Concentração de Íons de Hidrogênio , Dinâmica não Linear , beta-LactamasRESUMO
In this study, we report the use of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FT-IR) for the identification and quantitation of two polymorphs of Aprepitant, a substance P antagonist for chemotherapy-induced emesis. Mixtures of the polymorph pair were prepared by weight and ATR-FT-IR spectra of the powdered samples were obtained over the wavelength range of 700-1500 cm(-1). Significant spectral differences between the two polymorphs at 1140 cm(-1) show that ATR-FT-IR can provide definitive identification of the polymorphs. To investigate the feasibility of ATR-FT-IR for quantitation of polymorphic forms of Aprepitant, a calibration plot was constructed with known mixtures of the two polymorphs by plotting the peak ratio of the second derivative of absorbance spectra against the weight percent of form II in the polymorphic mixture. Using this novel approach, 3 wt % of one crystal form could be detected in mixtures of the two polymorphs. The accuracy of ATR-FT-IR in determining polymorph purity of the drug substance was tested by comparing the results with those obtained by X-ray powder diffractometry (XRPD). Indeed, polymorphic purity results obtained by ATR-FT-IR were found to be in good agreement with the predictions made by XRPD and compared favorably with actual values in the known mixtures. The present study clearly demonstrates the potential of ATR-FT-IR as a quick, easy, and inexpensive alternative to XRPD for the determination of polymorphic identity and purity of solid drug substances. The technique is ideally suited for polymorph analysis, because it is precise, accurate, and requires minimal sample preparation.