The effect of low concentrations of molecularly dispersed poly(vinylpyrrolidone) on indomethacin crystallization from the amorphous state.

PURPOSE: To investigate the effect of low concentrations of molecularly dispersed poly(vinylpyrrolidone) (PVP) on indomethacin (IMC) crystallization from the amorphous state using particle size effects to identify possible mechanisms of crystallization inhibition. METHODS: Different particle sizes of amorphous IMC and 1, 2, and 5% PVP were stored dry at 30 degrees C for 84 days. PXRD was used to calculate the rate and extent of crystallization and the polymorph formed. RESULTS: Crystallization from amorphous IMC and IMC/PVP molecular dispersions yielded the gamma polymorph of IMC. Crystallization rates were reduced at larger particle size and in the presence of 1, 2, and 5%PVP. Crystallization did not reach completion in some IMC/PVP samples, with the quantity of uncrystallized amorphous phase proportional to particle size. CONCLUSIONS: Low concentrations of molecularly dispersed PVP affected IMC crystallization from the amorphous state. Formation of gamma-IMC at rates dependent on particle size indicated that surface nucleation predominated in both the absence and presence of PVP. Excellent correlation was seen between the extent of crystallization and simulated depths of crystal penetration, supporting the hypothesis that increasing local PVP concentration inhibits crystal growth from surface nuclei into the amorphous particle.

Water vapor absorption into amorphous hydrophobic drug/poly(vinylpyrrolidone) dispersions.

Water vapor absorption isotherms were measured for three amorphous hydrophobic drug/poly(vinylpyrrolidone) (PVP) dispersions in the concentration range 10-90% w/w PVP. Experimental isotherms were compared to predicted isotherms calculated using each individual component isotherm multiplied by its weight fraction. Indomethacin (IMC)/PVP, ursodeoxycholic acid (UDCA)/PVP and indapamide (IDP)/PVP amorphous dispersions all exhibited experimental isotherms reduced relative to predicted isotherms indicating that dispersion formation altered the water vapor absorption properties of the individual components. For all three drug/PVP systems, deviation from predicted water uptake was greatest close to the 1:1 drug:PVP monomer composition, indicating that intermolecular interaction in amorphous dispersions affects the water uptake properties of the individual components. Using dry glass transition temperature (T(g)) data, the extent of drug/PVP interaction was shown to be greatest in the IDP/PVP system, which could explain why the largest reduction in water vapor absorption was found in this system. The plasticizing effect of absorbed water varied according to dry dispersion PVP content in all systems and the resulting nonideal changes in free volume, calculated using the Vrentas model, were greatest close to the 1:1 drug:PVP monomer composition. A three-component Flory-Huggins model successfully predicted isotherms for IMC/PVP compositions from 60 to 90% w/w PVP and identified an IMC-PVP interaction parameter chi in the range 1.27-1.49, values that suggest poor homogeneity of mixing in the dry system. These data indicate that amorphous dispersion formation causes both chemical and physical changes in the individual amorphous components that can have a significant effect on their water vapor absorption properties.

Cryogenic grinding of indomethacin polymorphs and solvates: assessment of amorphous phase formation and amorphous phase physical stability.

The effect of cryogenic grinding on five crystal forms of indomethacin (IMC) was investigated with particular interest in the formation of amorphous phase. Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) demonstrated that amorphous phase formation took place for all three polymorphs (gamma, alpha, and delta) and one solvate (IMC methanolate). In the latter case, a postgrinding drying stage was needed to remove desolvated methanol from the ground amorphous product because methanol destabilized amorphous IMC presumably via a plasticizing effect. The crystal structure of another solvate, IMC t-butanolate, was unaffected by grinding, indicating that amorphous phase formation on grinding does not occur in all cases. Ground amorphous materials possessed similar glass transition temperatures but significant differences in physical stability as assessed by both isothermal and nonisothermal crystallization. It is argued that physical factors, namely residual crystal phase and specific surface area, determine the isothermal and nonisothermal crystallization behavior of ground amorphous samples as opposed to intrinsic differences in the structure of the amorphous phase.