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A Novel Method for Determining the Solubility of Small Molecules in Aqueous Media and Polymer Solvent Systems Using Solution Calorimetry

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ABSTRACT

Purpose

To explore the application of solution calorimetry for measuring drug solubility in experimentally challenging situations while providing additional information on the physical properties of the solute material.

Methods

A semi-adiabatic solution calorimeter was used to measure the heat of dissolution of prednisolone and chlorpropamide in aqueous solvents and of griseofulvin and ritonavir in viscous solutions containing polyvinylpyrrolidone and N-ethylpyrrolidone.

Results

Dissolution end point was clearly ascertained when heat generation stopped. The heat of solution was a linear function of dissolved mass for all drugs (<10% RSD, except for chlorpropamide). Heats of solution of 9.8 ± 0.8, 28.8 ± 0.6, 45.7 ± 1.6 and 159.8 ± 20.1 J/g were obtained for griseofulvin, ritonavir, prednisolone and chlorpropamide, respectively. Saturation was identifiable by a plateau in the heat signal and the crossing of the two linear segments corresponds to the solubility limit. The solubilities of prednisolone and chlopropamide in water by the calorimetric method were 0.23 and 0.158 mg/mL, respectively, in agreement with the shake-flask/HPLC-UV determined values of 0.212 ± 0.013 and 0.169 ± 0.015 mg/mL, respectively. For the higher solubility and high viscosity systems of griseofulvin and ritonavir in NEP/PVP mixtures, respectively, solubility values of 65 and 594 mg/g, respectively, were obtained.

Conclusion

Solution calorimetry offers a reliable method for measuring drug solubility in organic and aqueous solvents. The approach is complementary to the traditional shake-flask method, providing information on the solid properties of the solute. For highly viscous solutions, the calorimetric approach is advantageous.

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors thank Drs. Aziz Bakri and Nawel Khalef from Joseph Fourier University in Grenoble, France, and Dr. Nathan Hesse from TA Instruments for their help and support with the solution calorimeter. The Dane O. Kildsig Center for Pharmaceutical Processing Research (CPPR).

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Authors and Affiliations

  1. Department of Industrial & Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA

    Hala M. Fadda, Xin Chen & Rodolfo Pinal

  2. Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, Butler University, Indianapolis, Indiana, USA

    Hala M. Fadda

  3. Pharmaceutical Sciences Research & Development, Eli Lilly & Company, Indianapolis, Indiana, USA

    Aktham Aburub & Dinesh Mishra

Authors
  1. Hala M. Fadda
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  2. Xin Chen
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  3. Aktham Aburub
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  4. Dinesh Mishra
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  5. Rodolfo Pinal
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Correspondence to Rodolfo Pinal.

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Fadda, H.M., Chen, X., Aburub, A. et al. A Novel Method for Determining the Solubility of Small Molecules in Aqueous Media and Polymer Solvent Systems Using Solution Calorimetry. Pharm Res 31, 1735–1743 (2014). https://doi.org/10.1007/s11095-013-1278-y

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  • DOI: https://doi.org/10.1007/s11095-013-1278-y

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