Tang, XH, Li, Y, Liu, JJ et al. (2 more authors) (2017) Process Analytical Technology (PAT) Aided Identification of Operational Spaces Leading to Tailored Crystal Size Distributions in Azithromycin Crystallization via Coordinated Cooling and Solution Mediated Phase Transition. Organic Process Research and Development, 21 (12). pp. 1963-1971. ISSN 1083-6160
Abstract
Online imaging and ATR-FTIR were applied to azithromycin crystallization in a mixture of acetone and water to identify the operational spaces that consistently led to tailored crystal size distribution (CSD) in the size ranges of < 180 μm (D 50 = 78.3 μm), 180-425 μm (D 50 = 155 μm), and 425-850 μm (D 50 = 433 μm), under the constraints of no change of solvent or addition of crystal growth modifiers, in the meantime satisfying all other specifications including drug stability, purity, impurity content, and avoidance of monohydrates in the dihydrate crystals. Azithromycin crystallization in an acetone and water mixture is both interesting and challenging, as it achieves crystallization via coordinated manipulation of two variables: introduction of water as an antisolvent and temperature reduction via cooling. While the target product crystals are azithromycin dihydrates, it can only first produce monohydrates which are then transformed to dihydrates through solution mediated phase transition (SMPT). The phenomenon of SMPT from monohydrates to dihydrates was visually observed in real-time using an online imaging probe, and the factors affecting the transition were identified and quantified using the ATR-FTIR. Furthermore, it was found that the way water was introduced could affect the hydrate transition and the crystal size distribution of the product. Based on the understanding of the causal relationships between the multiple variables and crystal growth behavior, the operational spaces leading to the three desired CSDs were defined. The results were first obtained in a 1 L crystallizer and then validated in a 25 L crystallizer.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2017, 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, copyright (c) 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.7b00238 |
Keywords: | azithromycin crystallization; process analytical technology; tailored crystal size distributions; solvent mediated phase transition; polymorphism; scale-up |
Dates: |
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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: | 06 Feb 2018 15:56 |
Last Modified: | 22 Nov 2018 01:39 |
Status: | Published |
Publisher: | American Chemical Society |
Identification Number: | 10.1021/acs.oprd.7b00238 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:127033 |