Stepwise dissolution and composition determination of samples of multiple crystals using a dissolution medium containing aqueous alcohol and fluorocarbon phases

Moynihan, Humphrey A.; Armstrong, Declan

doi:10.1039/c9ra02781e

Cited by 4 publications

(7 citation statements)

References 45 publications

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“…Where the impurity is distributed uniformly throughout the bulk crystal, it is likely that incorporation has occurred during the crystal growth ( Figure 4 , lattice substitution). 47 This would give a positive outcome to Decision 4, and the user proceeds to Decision 5.…”

Section: Impurities In Crystallizationmentioning

confidence: 99%

“…By creating a distribution map of the impurity throughout the bulk crystal, it will confirm whether the impurity has been incorporated throughout the growth of the crystals. In an experimental method modified from recent literature, − portions of pure solvent are added to a suspension of crystal product in saturated API solution, to slowly dissolve the contaminated crystals. The concentration change of impurity in the liquid phase upon dissolution gives information on the distribution of impurity throughout the crystal bulk, which is then considered in Decision 4.…”

Section: Impurities In Crystallizationmentioning

confidence: 99%

“…In the case of growth induced inclusions, growth kinetics can have a significant negative impact on crystal purity. , The suggested mitigation strategy is to modify the process conditions to give a different growth regime, for example changing the supersaturation at which nucleation occurs. Where the impurity is distributed uniformly throughout the bulk crystal, it is likely that incorporation has occurred during the crystal growth (Figure , lattice substitution) . This would give a positive outcome to Decision 4, and the user proceeds to Decision 5.…”

Section: Impurities In Crystallizationmentioning

confidence: 99%

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A Structured Approach To Cope with Impurities during Industrial Crystallization Development

Urwin

Levilain

Marziano

et al. 2020

Org. Process Res. Dev.

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The perfect separation with optimal productivity, yield, and purity is very difficult to achieve. Despite its high selectivity, in crystallization unwanted impurities routinely contaminate a crystallization product. Awareness of the mechanism by which the impurity incorporates is key to understanding how to achieve crystals of higher purity. Here, we present a general workflow which can rapidly identify the mechanism of impurity incorporation responsible for poor impurity rejection during a crystallization. A series of four general experiments using standard laboratory instrumentation is required for successful discrimination between incorporation mechanisms. The workflow is demonstrated using four examples of active pharmaceutical ingredients contaminated with structurally related organic impurities. Application of this workflow allows a targeted problem-solving approach to the management of impurities during industrial crystallization development, while also decreasing resources expended on process development.

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Section: Impurities In Crystallizationmentioning

confidence: 99%

Section: Impurities In Crystallizationmentioning

confidence: 99%

Section: Impurities In Crystallizationmentioning

confidence: 99%

See 1 more Smart Citation

A Structured Approach To Cope with Impurities during Industrial Crystallization Development

Urwin

Levilain

Marziano

et al. 2020

Org. Process Res. Dev.

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“…The percentage of impurity dissolved can be plotted as a function of the percentage of the API dissolved. Detailed explanation of these plots is shown elsewhere. ,− …”

Section: Theorymentioning

confidence: 99%

“…For such experiments, it is critical to use material that is representative of the actual process. In this work, we slightly modified the procedure described in the literature ,− to dissolve weighed amounts of representative crystal material. We plot only the percent product dissolved per addition of solvent as opposed to calculating the percent solid (which is the product plus impurities) dissolved in solution, which may be different for conglomerate systems with low solubility impurities.…”

Section: Theorymentioning

confidence: 99%

Case Studies in the Application of a Workflow-Based Crystallization Design for Optimized Impurity Rejection in Pharmaceutical Development

Agrawal

Rawal

Reddy

et al. 2023

Org. Process Res. Dev.

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Crystallization is an important unit operation in pharmaceutical drug substance manufacturing for the isolation of organic products. Impurity control is a recurring critical quality attribute in most commercial pharmaceutical crystallization processes. A systematic workflow that can reveal the incorporation mechanism of various impurities during crystallization and guide us to understand impurity rejection is useful for crystallization process design. Such a workflow was recently published by Urwin et al. Herein, we present three case studies implementing this workflow, covering surface deposition, conglomerate formation, and agglomeration as principal routes for impurity incorporation during crystallization of a drug substance's active pharmaceutical ingredient and its intermediates. We demonstrate the experimental steps to identify various impurity incorporation mechanisms and discuss the strategy for impurity rejection in each case. We built upon the previous approach to demonstrate a material sparing approach through our case studies. We highlight the value of stepwise dissolution and show the importance of doing it early in the impurity incorporation identification stage. At this stage, we introduce a missing incorporation mechanism in prior work, namely, conglomerate systems. We show how to identify and resolve this mode of incorporation mechanism through stepwise dissolution and solubility-limited rejection maps.

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Development of an impurity and hydrate form controlling continuous crystallization to telescope a two-step batch recrystallization in the GDC-4379 drug substance process

Morris¹,

Keogh²,

Farid³

et al. 2022

Chemical Engineering Research and Design

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Stepwise dissolution and composition determination of samples of multiple crystals using a dissolution medium containing aqueous alcohol and fluorocarbon phases

Abstract: A biphasic medium gave controlled partial dissolution of crystals in multi-particle samples allowing the distribution of impurities to be determined.

Cited by 4 publications

References 45 publications

A Structured Approach To Cope with Impurities during Industrial Crystallization Development

A Structured Approach To Cope with Impurities during Industrial Crystallization Development

Case Studies in the Application of a Workflow-Based Crystallization Design for Optimized Impurity Rejection in Pharmaceutical Development

Development of an impurity and hydrate form controlling continuous crystallization to telescope a two-step batch recrystallization in the GDC-4379 drug substance process

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