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Investigating Cocrystallization of Carbamazepine with Structurally Compatible Coformers: New Cocrystal and Eutectic Phases with Enhanced Dissolution

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A Correction to this article was published on 03 February 2021

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Abstract

In this work, carbamazepine (CBZ), an anticonvulsant drug was cocrystallized with several structurally complement coformers (coformers with amide, acid and hydrazide functional groups) to enhance its dissolution. CBZ formed a cocrystal phase with acetamide (ACE) when mixtures of CBZ and ACE (containing CBZ mole fractions, XCBZ of 0.25, 0.33, 0.5, and 0.67) were subjected to solid-state grinding (SSG), evaporative crystallization (EC), slurry conversion (SC), and slow cooling crystallization (SLC). Upon heating, the CBZ-ACE cocrystal phase formed from CBZ-ACE mixtures containing XCBZ of 0.25, 0.33 and 0.67 underwent solid-state phase transition to CBZ form I and CBZ cocrytsal phase obtained from the CBZ-ACE mixture containing XCBZ of 0.5 converted to CBZ form III. Interestingly, slow cooling cocrystallization experiments resulted in crystallization of a cocrystal as well as the CBZ dihydrate forms. The powder dissolution studies demonstrated that among the different CBZ-ACE-SSG cocrystal phases, CBZ-ACE-SSG-XCBZ-0.33 cocrystal exhibited 7.47 times improved dissolution whereas the CBZ eutectic phase with nicotinic acid hydrazide (NAH) exhibited 4.93 times increased dissolution when compared to raw CBZ.

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  • 03 February 2021

    The original article can be found online at <ExternalRef><RefSource>https://doi.org/10.1208/s12249-021-01930-1</RefSource><RefTarget Address="10.1208/s12249-021-01930-1" TargetType="DOI"/></ExternalRef>

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Acknowledgments

The authors acknowledge the Central Instrumentation Facility (CIF) of Indian Institute of Technology Gandhinagar (IITGN) for providing access to various instruments, namely PXRD, FE-SEM, DSC, and FIST-SCXRD, respectively. The authors are very grateful to Prof. Celine Besnard, Senior Scientist, University of Geneva for her valuable suggestions in collection of SCXRD data and usage of CryAlis Pro software in data analysis.

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  1. Biological Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat, 382355, India

    Indumathi Sathisaran

  2. Chemical Engineering, Indian Institute of Technology Gandhinagar, Palaj, Gujarat, 382355, India

    Sameer Vishvanath Dalvi

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Correspondence to Sameer Vishvanath Dalvi.

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The original online version of this article was revised: In the original article, only two supplemental figures (S1 and S30) in the ESM were published, whereas 37 figures (S2-S29 and S31-S39), a table S1 and a reference were not.

Supplementary Information

The chemical structures of CBZ, ACE, PMA, SBA, AZA, SEA, ISN, NAH and MAH, the PXRD patterns of fresh unheated and heated CBZ-ACE-SSG mixtures containing CBZ mole fractions of 0.25, 0.33, 0.5 and 0.67 are provided in the supplementary information. The PXRD patterns of raw ACE, raw CBZ and CBZ-ACE cocrystals prepared by EC, SC and SLC, the Raman spectra of raw ACE, raw CBZ and CBZ-ACE cocrystals prepared by EC, SC and SLC, and SEM micrographs of CBZ-ACE cocrystals prepared by EC are shown in the supplementary material. A snapshot of the lattice of CBZ-ACE cocrystal prepared by EC of CBZ-ACE-SSG-XCBZ-0.25 mixture in acetone-toluene (1:1 volume ratio) visualized using CryAlisPro software, the PXRD patterns and Raman spectra of CBZ dihydrates prepared by SLC of CBZ-ACE-XCBZ-0.5 and 0.67 in acetone and toluene, a schematic representation of the proposed non-covalent intermolecular interaction (hydrogen bonding) between CBZ and ACE in CBZ-ACE cocrystal, the PXRD patterns of raw CBZ, CBZ-ACE-XCBZ-0.25, 0.33, 0.5, 0.67 cocrystal phases. The DSC thermograms of SSG mixtures of CBZ-PMA, CBZ-SBA, CBZ-AZA, CBZ-SEA, CBZ-ISN, CBZ-NAH and CBZ-MAH pairs containing various CBZ mole fractions ranging from 0 to 1, the binary phase diagrams of CBZ-PMA, CBZ-AZA, CBZ-SEA and CBZ-NAH systems, PXRD patterns of CBZ-PMA, CBZ-AZA, CBZ-SEA and CBZ-NAH eutectic compositions, the PXRD patterns of the CBZ-ACE cocrystal prepared with XCBZ of 0.33, 0.5 and 0.67, CBZ-PMA-XCBZ-0.25 eutectic, CBZ-SBA-XCBZ-0.5 eutectic, CBZ-AZA-XCBZ-0.33 eutectic, CBZ-SEA-XCBZ-0.5 eutectic, CBZ-ISN-XCBZ-0.5 eutectic and CBZ-NAH-XCBZ-0.33 eutectic phases recorded before and after the powder dissolution experiments and a table presenting the Raman band assignments to the molecular vibrations for Raw CBZ, CBZ-ACE cocrystal and CBZ dihydrate prepared by SLC of CBZ-ACE-XCBZ-0.25 and CBZ-ACE-XCBZ-0.5 in acetone are provided in the supplementary material.

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Sathisaran, I., Dalvi, S.V. Investigating Cocrystallization of Carbamazepine with Structurally Compatible Coformers: New Cocrystal and Eutectic Phases with Enhanced Dissolution. AAPS PharmSciTech 22, 29 (2021). https://doi.org/10.1208/s12249-020-01888-6

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