Yu, S, Zhang, Y and Wang, XZ (2019) Improved Understanding of Cefixime Trihydrate Reactive Crystallization and Process Scale-up with the Aid of PAT. Organic Process Research and Development, 23 (2). pp. 177-188. ISSN 1083-6160
Abstract
Reactive crystallization to make cefixime trihydrate crystals via cefixime disodium reacting with hydrogen chloride was investigated using ATR FTIR and an online imaging instrument with the aim of developing an improved understanding of the operation and condition optimization and scale-up. The operation involves times of continuing introduction of aqueous HCl solution into a cefixime disodium solution in water and also periods at which HCl was stopped for breeding of crystals. The concentration profile of the reactant cefixime disodium monitored by ATR FTIR being almost constant in the first 30–40 min since the start of introduction of HCl suggests that cefixime disodium (cefixime2–) reacts with HCl to form cefixime sodium (cefixime1–) first, prior to the formation of solids. Online imaging, off-line SEM image analysis, and XRD analysis revealed that spherical amorphous solids were formed first; the solids were then aggregated, followed by phase transition on the surface of aggregates to well-shaped crystals. The causal relationship between the process conditions and the size, impurity content, crystallinity, and whiteness of the cefixime trihydrate crystals was also investigated. It was found that the solution pH value at the time at which introduction of the first portion of HCl solution was stopped to begin breeding crystals has a major impact on both the size and the whiteness of the crystals. High pH value favors smaller crystals with a sharp white appearance. The length of the crystal breeding time was found to be critical to the crystallinity. Explanation of the observed phenomena and an operational envelope were defined. The size distribution, whiteness, impurity content, and crystallinity of cefixime trihydrate crystals were satisfactory as long as the operation was kept within the defined envelope. The experiments were conducted on a 2 L reactor, then successfully scaled-up to 50 and 4000 L in industry after having considered the scale-up factor in stirrer rotation speed.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2019, American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic Process Research and Development © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.oprd.8b00190. |
Keywords: | reactive crystallization; cefixime trihydrate; process analytical technology; particle size distribution; crystallinity |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemical & Process Engineering (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 12 Aug 2019 09:42 |
Last Modified: | 10 Jan 2020 01:39 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.oprd.8b00190 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:149568 |