Measuring the solubility of a quickly transforming metastable polymorph of carbamazepine

Marcus A. O'Mahony; Denise M. Croker; Åke C. Rasmuson; Stéphane Veesler; Benjamin K. Hodnett

doi:10.1021/op300228g

Measuring the solubility of a quickly transforming metastable polymorph of carbamazepine

Marcus A. O'Mahony, Denise M. Croker, Åke C. Rasmuson, Stéphane Veesler, Benjamin K. Hodnett

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Abstract

The solubility of the stable FIII polymorph of the pharmaceutical compound carbamazepine was measured by determining its solubility gravimetrically in ethanol and methanol. Where the metastable FI polymorph was suspended in a solution of ethanol, the stable FIII polymorph nucleated immediately, initiating a solution-mediated transformation from FI to FIII. This meant that the FI polymorph was not in thermodynamic equilibrium with the solution as FI was continually dissolving while FIII was growing. We show that the solubility of FI can be accurately measured by in situ microscopy using an adaption of the bracketing method, and the results show that the solubility is close to but higher than the maximum solution concentration reached during the solution-mediated transformation from FI to FIII carbamazepine in both solvents. The technique demonstrates a relatively simple and robust method for determining the solubility of a metastable crystalline phase which transforms quickly in solution.

Original language	English
Pages (from-to)	512-518
Number of pages	7
Journal	Organic Process Research and Development
Volume	17
Issue number	3
DOIs	https://doi.org/10.1021/op300228g
Publication status	Published - 15 Mar 2013

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title = "Measuring the solubility of a quickly transforming metastable polymorph of carbamazepine",

abstract = "The solubility of the stable FIII polymorph of the pharmaceutical compound carbamazepine was measured by determining its solubility gravimetrically in ethanol and methanol. Where the metastable FI polymorph was suspended in a solution of ethanol, the stable FIII polymorph nucleated immediately, initiating a solution-mediated transformation from FI to FIII. This meant that the FI polymorph was not in thermodynamic equilibrium with the solution as FI was continually dissolving while FIII was growing. We show that the solubility of FI can be accurately measured by in situ microscopy using an adaption of the bracketing method, and the results show that the solubility is close to but higher than the maximum solution concentration reached during the solution-mediated transformation from FI to FIII carbamazepine in both solvents. The technique demonstrates a relatively simple and robust method for determining the solubility of a metastable crystalline phase which transforms quickly in solution.",

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T1 - Measuring the solubility of a quickly transforming metastable polymorph of carbamazepine

AU - O'Mahony, Marcus A.

AU - Croker, Denise M.

AU - Rasmuson, Åke C.

AU - Veesler, Stéphane

AU - Hodnett, Benjamin K.

PY - 2013/3/15

Y1 - 2013/3/15

N2 - The solubility of the stable FIII polymorph of the pharmaceutical compound carbamazepine was measured by determining its solubility gravimetrically in ethanol and methanol. Where the metastable FI polymorph was suspended in a solution of ethanol, the stable FIII polymorph nucleated immediately, initiating a solution-mediated transformation from FI to FIII. This meant that the FI polymorph was not in thermodynamic equilibrium with the solution as FI was continually dissolving while FIII was growing. We show that the solubility of FI can be accurately measured by in situ microscopy using an adaption of the bracketing method, and the results show that the solubility is close to but higher than the maximum solution concentration reached during the solution-mediated transformation from FI to FIII carbamazepine in both solvents. The technique demonstrates a relatively simple and robust method for determining the solubility of a metastable crystalline phase which transforms quickly in solution.

AB - The solubility of the stable FIII polymorph of the pharmaceutical compound carbamazepine was measured by determining its solubility gravimetrically in ethanol and methanol. Where the metastable FI polymorph was suspended in a solution of ethanol, the stable FIII polymorph nucleated immediately, initiating a solution-mediated transformation from FI to FIII. This meant that the FI polymorph was not in thermodynamic equilibrium with the solution as FI was continually dissolving while FIII was growing. We show that the solubility of FI can be accurately measured by in situ microscopy using an adaption of the bracketing method, and the results show that the solubility is close to but higher than the maximum solution concentration reached during the solution-mediated transformation from FI to FIII carbamazepine in both solvents. The technique demonstrates a relatively simple and robust method for determining the solubility of a metastable crystalline phase which transforms quickly in solution.

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Measuring the solubility of a quickly transforming metastable polymorph of carbamazepine

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