Impact of Polymers on the Melt Crystal Growth Rate of Indomethacin Polymorphs

Abstract

Crystal growth from amorphous drugs is of interest in the context of solubility enhancing formulations. Herein, the impact of polymers on the crystal growth of different polymorphs from the undercooled liquid was investigated using indomethacin (IDM) as a model compound and hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone (PVP) as polymeric inhibitors. Samples sandwiched between two coverslips were prepared by melt quenching, and polymorphs were identified using Raman spectroscopy, hot stage microscopy, and X-ray diffraction. Crystal growth rates of δ, α, and γ polymorphs were measured in the absence and presence of polymers. Polymorphs grown from pure IDM melt showed different crystal growth rates at a given temperature, that persisted when differences in the extent of undercooling were accounted for. The crystal growth rates of IDM crystals were reduced by the three polymers. At lower temperatures, the effectiveness of the polymers in inhibiting crystal growth decreased in the order of PVP > HPMC > HPMCAS. Interestingly, it was found that the same polymer had different inhibitory effects on the crystal growth of different polymorphs, with polymers being least effective in inhibiting the growth of the γ polymorph. Clearly the impact of polymers on crystal growth from undercooled melts is highly complex, depending not only on the properties of the liquid phase, but also on the growing crystal polymorph.