ABSTRACT
Ziprasidone hydrochloride is a second-generation antipsychotic drug employed for the treatment of schizophrenia and acute mania or mixed episodes associated with bipolar disorder. During the scale-up of ziprasidone hydrochloride, an unknown impurity was observed in the batches ranging from 0.10% to 0.15% by HPLC-UV analysis. The structure of an unknown impurity was proposed as 3,3'-methylenebis(5-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloroindolin-2-one) which is named as methylene ziprasidone dimer (MZD impurity). It was isolated from an enriched sample by preparative HPLC, and its structure was elucidated by comprehensive analysis of HRMS, 1D NMR (1H, 13C), DEPT-135, 2D NMR (COSY, HSQC, HMBC) spectroscopy. A plausible mechanism for the formation of isolated impurity is proposed.
Subject(s)
Drug Contamination , Piperazines , Chromatography, High Pressure Liquid , ThiazolesABSTRACT
Sugar-modified nucleosides have gained considerable attention in the scientific community, either for use as molecular probes or as therapeutic agents. When the methylene group of the ribose ring is replaced with a sulfur atom at the 3'-position, these compounds have proved to be structurally potent nucleoside analogues, and the best example is BCH-189. The majority of methods traditionally involves the chemical modification of nucleoside structures. It requires the creation of artificial sugars, which is accompanied by coupling nucleobases via N-glycosylation. However, over the last three decades, efforts were made for the synthesis of 1,3-oxathiolane nucleosides by selective N-glycosylation of carbohydrate precursors at C-1, and this approach has emerged as a strong alternative that allows simple modification. This review aims to provide a comprehensive overview on the reported methods in the literature to access 1,3-oxathiolane nucleosides. The first focus of this review is the construction of the 1,3-oxathiolane ring from different starting materials. The second focus involves the coupling of the 1,3-oxathiolane ring with different nucleobases in a way that only one isomer is produced in a stereoselective manner via N-glycosylation. An emphasis has been placed on the C-N-glycosidic bond constructed during the formation of the nucleoside analogue. The third focus is on the separation of enantiomers of 1,3-oxathiolane nucleosides via resolution methods. The chemical as well as enzymatic procedures are reviewed and segregated in this review for effective synthesis of 1,3-oxathiolane nucleoside analogues.
ABSTRACT
Tris(hydroxymethyl) aminomethane (tris) salt of API ramipril was synthesized, and characterized by FTIR, TG-DSC and ab initio X-ray powder structure analysis. The compound, ramipril-tris (II), crystallizes in the monoclinic space group P2(1) with a=24.3341(15), b=6.4645(5), c=9.5357(7) Å, ß=96.917(3)° and V=1489.1(3) Å(3). The crystal structure has been determined from laboratory X-ray powder diffraction data using direct space global optimization strategy (simulated annealing) followed by the Rietveld refinement. A network of intermolecular OH O, CH N and CH O hydrogen bonds between the ramipril-ramipril, tris-tris and ramipril-tris components in the compound generates a two-dimensional molecular assembly in (110) plane. A comparative study of solid-state stabilities of ramipril-tris (II) with that of ramipril (I) and ramipril-erbumine (III) indicates that ramipril-tris (II) is the most stable one among the three, and the conversion to impurity D after 72 h at 80 °C is only 1.5%. The solution phase analysis at different pH values also reveals a greater stability of ramipril-tris (II) over ramipril (I).