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.

Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

“…If solubility of a metastable form is to be investigated, there are additional challenges to be addressed, such as preventing form transitions within the time necessary for measurement. 47,50,51 3. As crystallisation is predominantly used as a purification technique, the solubility of likely impurities from synthesis would be useful to know to allow for solvent selection based on impurity rejection.…”

Solubility correlation and thermodynamic analysis of two forms of Metaxalone in different pure solvents

“…Polymorphs are solid phases of the same compound but with different crystal structures. These different crystal structures exist due to the different molecular arrangements of the molecules giving rise to differences in free energy and thus solubility [4]. Hence, it is necessary to study the solubility properties of polymorph for the purpose of separation and purification through crystallization process.…”

On the solubility advantage of a pharmaceutical’s glassy state over the crystal state, and of its crystal polymorphs

“…Lastly, we consider the data from O'Mahony et al [69] recent study of solubility of two polymorphs of carbamezapine: (i) the triclinic polymorph (FI), and (ii) the P-monoclinic polymorph (FIII) [69]. (i) In both methanol and ethanol as solvents, the measured solubility of FI, s FI , is higher than that of FIII, s FIII , (ii) in the 278-308 K range, s FIII is 3.1-3.6-times more in methanol than in ethanol (Table I, [69]), and (iii) f meas (=s FI /s FIII ) as determined from the data in their Table 2 [69] is 1.49 at 283 K, 1.36 at 295 K, and 1.31 at 303 K, and (iv) attempted measurement of s FI in ethanol at 283, 293 and 303 K shows increase in s FI to a plateau-like concentration and then a decrease in s FI as FI transforms to FIII (Fig.…”