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Estimation of Drug–Polymer Miscibility and Solubility in Amorphous Solid Dispersions Using Experimentally Determined Interaction Parameters

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Abstract

Purpose

The amorphous form of a drug may provide enhanced solubility, dissolution rate, and bioavailability but will also potentially crystallize over time. Miscible polymeric additives provide a means to increase physical stability. Understanding the miscibility of drug–polymer systems is of interest to optimize the formulation of such systems. The purpose of this work was to develop experimental models which allow for more quantitative estimates of the thermodynamics of mixing amorphous drugs with glassy polymers.

Materials and Methods

The thermodynamics of mixing several amorphous drugs with amorphous polymers was estimated by coupling solution theory with experimental data. The entropy of mixing was estimated using Flory–Huggins lattice theory. The enthalpy of mixing and any deviations from the entropy as predicted by Flory–Huggins lattice theory were estimated using two separate experimental techniques; (1) melting point depression of the crystalline drug in the presence of the amorphous polymer was measured using differential scanning calorimetry and (2) determination of the solubility of the drug in 1-ethyl-2-pyrrolidone. The estimated activity coefficient was used to calculate the free energy of mixing of the drugs in the polymers and the corresponding solubility.

Results

Mixtures previously reported as miscible showed various degrees of melting point depression while systems reported as immiscible or partially miscible showed little or no melting point depression. The solubility of several compounds in 1-ethyl-2-pyrrolidone predicts that most drugs have a rather low solubility in poly(vinylpyrrolidone).

Conclusions

Miscibility of various drugs with polymers can be explored by coupling solution theories with experimental data. These approximations provide insight into the physical stability of drug–polymer mixtures and the thermodynamic driving force for crystallization.

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Acknowledgements

This work was supported in part by a fellowship from Merck Research Laboratories. AstraZeneca is acknowledged for financial support. Jared Baird is thanked for his help in measuring the solubility of the model compounds in 1-ethyl-2-pyrrolidone. Håkan Wikström is thanked for his help in measuring the solubility of sucrose using HPLC and Sheri Shamblin is thanked for providing heat capacity values for indomethacin and sucrose. Professors George Zografi, Rodolfo Pinal, Ken Morris, and Steve Byrn are acknowledged for their input. The PhRMA Foundation is acknowledged for a pre-doctoral fellowship to PJM. LST thanks AFPE/AACP for a New Investigator Award.

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  1. Materials Characterization and Technology Assessment, Merck & Co., Inc., West Point, Pennsylvania, 19486, USA

    Patrick J. Marsac

  2. College of Pharmacy, University of Kentucky, 501C, 725 Rose Street, Lexington, KY, 40536, USA

    Tonglei Li

  3. Department of Industrial and Physical Pharmacy, School of Pharmacy, Purdue University, West Lafayette, IN, 47907, USA

    Patrick J. Marsac & Lynne S. Taylor

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Marsac, P.J., Li, T. & Taylor, L.S. Estimation of Drug–Polymer Miscibility and Solubility in Amorphous Solid Dispersions Using Experimentally Determined Interaction Parameters. Pharm Res 26, 139–151 (2009). https://doi.org/10.1007/s11095-008-9721-1

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