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DOI: 10.1007/s11095-008-9784-zPages: 855-864

Solubility of Small-Molecule Crystals in Polymers: d-Mannitol in PVP, Indomethacin in PVP/VA, and Nifedipine in PVP/VA

1. University of Wisconsin, Madison, School of Pharmacy and Department of Chemistry

2. Global Pharmaceutical R & D, Abbott Laboratories, Solid State Sciences

Correspondence to:
Lian Yu
Tel: +1-608-2632263




Amorphous pharmaceuticals, a viable approach to enhancing bioavailability, must be stable against crystallization. An amorphous drug can be stabilized by dispersing it in a polymer matrix. To implement this approach, it is desirable to know the drug’s solubility in the chosen polymer, which defines the maximal drug loading without risk of crystallization. Measuring the solubility of a crystalline drug in a polymer is difficult because the high viscosity of polymers makes achieving solubility equilibrium difficult.


Differential Scanning Calorimetry (DSC) was used to detect dissolution endpoints of solute/polymer mixtures prepared by cryomilling. This method was validated against other solubility-indicating methods.


The solubilities of several small-molecule crystals in polymers were measured for the first time near the glass transition temperature, including d-mannitol (β polymorph) in PVP, indomethacin (γ polymorph) in PVP/VA, and nifedipine (α polymorph) in PVP/VA.


A DSC method was developed for measuring the solubility of crystalline drugs in polymers. Cryomilling the components prior to DSC analysis improved the uniformity of the mixtures and facilitated the determination of dissolution endpoints. This method has the potential of providing useful data for designing physically stable formulations of amorphous drugs.

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  • Accepted: Nov 4, 2008
  • Online: Dec 4, 2008

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