Growing single crystals of small molecules by thermal recrystallization, a viable option even for minute amounts of material?

Nievergelt, Philipp P.; Spingler, Bernhard

doi:10.1039/c6ce02222g

Cited by 16 publications

(11 citation statements)

References 35 publications

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“…Subsequent combination of frames/scans yielded new reflections consistent with the presence of CBZ III, improving the agreement of relative peak heights with reference data. Therefore, due to only CBZ III being observed via PXRD and the high percentage of needles observed visually, we conclude that this must be a rare case of CBZ III presenting as needle crystals as was previously reported from cooling crystallization in isopropanol and in the presence of surfactants . Additionally, we rationalize the faster conversion of CBZ II to CBZ III observed in the KRAIC-D compared to batch slurrying techniques by the intensified mixing induced within the segmented flow environment …”

Section: Resultssupporting

confidence: 81%

Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction

et al. 2020

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Understanding the transitions between polymorphs is essential in the development of strategies for manufacturing and maximizing the efficiency of pharmaceuticals. However, this can be extremely challenging: crystallization can be influenced by subtle changes in environment such as temperature and mixing intensity or even imperfections in the crystallizer walls. Here, we highlight the importance of in situ measurements in understanding crystallization mechanisms, where a segmented flow crystallizer was used to study the crystallization of the pharmaceuticals urea:barbituric acid (UBA) and carbamazepine (CBZ). The reactor provides highly reproducible reaction conditions, while in situ synchrotron powder X-ray diffraction (PXRD) enables us to monitor the evolution of this system. UBA has two polymorphs of almost equivalent free-energy and so is typically obtained as a polymorphic mixture. In situ PXRD uncovered a progression of polymorphs from UBA III to the thermodynamic polymorph UBA I, where different positions along the length of the tubular flow crystallizer correspond to different reaction times. Addition of UBA I seed crystals modified this pathway such that only UBA I was observed throughout, while transformation from UBA III into UBA I still occurred in the presence of UBA III seeds. Information regarding the mixing-dependent kinetics of the CBZ form II to III transformation was also uncovered in a series of seeded and unseeded flow crystallization runs, despite atypical habit expression. These results illustrate the importance of coupling controlled reaction environments with in situ XRD to study the phase relationships in polymorphic materials. ASSOCIATED CONTENT Supporting InformationDetailed information regarding the experimental set-up, methodology and supporting experimental results is supplied as a word document, and a video showing the unusual needle habit of CBZ form III is supplied as a mp4 file in the supporting information. This material is available free of charge via the Internet at http://pubs.acs.org

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Section: Resultssupporting

confidence: 81%

Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction

et al. 2020

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“…Recently, several innovations have been described that, with the help of crystallography, allow the structure determination of compounds, which had previously been impossible by applying the methods of traditional crystal growth. 9 , 10 The ‘crystalline sponge’ method was originally introduced in 2013 by Fujita and co-workers 11 and has further been improved over the last few years. 12 , 13 This method opened up new possibilities for determining the crystal structures of apolar compounds that are available only in minute amounts.…”

Section: Introductionmentioning

confidence: 99%

A high throughput screening method for the nano-crystallization of salts of organic cations

et al. 2018

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“…Refer to Figures to for ORTEP diagrams and the labeling scheme used. The X-ray structure of ( 1 ) was first reported in 1981, , with a more recent structure also reported in 1989, 2003, , 2008, 2011, 2013, 2015, 2016, − and 2017 . The X-ray structure obtained in this work was found to be in excellent agreement with data reported for a high resolution structure with mean differences in bond lengths and angles of 0.002 Å and 0.004°, respectively.…”

Section: Results and Discussionmentioning

confidence: 80%

Exploring the Solubility of the Carbamazepine–Saccharin Cocrystal: A Charge Density Study

Stanton

Fakih

et al. 2018

Crystal Growth & Design

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Carbamazepine (CBZ) is used in the treatment of multiple neurological conditions. Although efficacious, its potential has been limited by its poor solubility, which means that patients are required to take very large doses to gain the desired effect. Co-crystals have been proposed as a means of improving the physicochemical properties of pharmaceutical compounds while maintaining their efficacy. CBZ cocrystallized with saccharin (SAC) and nicotinamide (NIC) have previously been studied, with the CBZ-SAC crystal being more soluble than the commercially available product Tegretol, which only contains CBZ, while the nicotinamide cocrystal was found to be less soluble. High-resolution X-ray crystallography has been carried out on the CBZ-SAC cocrystal and its individual constituents to determine which features of the electron density distribution contribute to the differing physical properties. The number of hydrogen bonds found for the CBZ, SAC, and CBZ-SAC systems were 8, 5, and 10, respectively. Homosynthons (interactions between a pair of identical functional groups) are the primary bonding motif in CBZ and SAC, while a heterosynthon is also present in the cocrystal. Molecular electrostatic potential (MEP) maps show that cocrystallization results in changes in distribution around the carboxamide group, thus accommodating heterosynthon formation and leading to subsequent charge redistribution across the CBZ molecule. Additional lattice energy calculations were not able to provide a definitive answer as to which system was most stable. Solid state entropy calculations revealed that the CBZ-SAC cocrystal had a higher entropy, providing explanations for the lower melting point and improved dissolution profile previously described. These investigations at an electronic level help to explain the greater solubility of the CBZ-SAC cocrystal compared to CBZ alone.

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Growing single crystals of small molecules by thermal recrystallization, a viable option even for minute amounts of material?

Cited by 16 publications

References 35 publications

Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction

Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray Diffraction

A high throughput screening method for the nano-crystallization of salts of organic cations

Exploring the Solubility of the Carbamazepine–Saccharin Cocrystal: A Charge Density Study

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