This study reports the appearance and characterization of multiple new polymorphic forms of indomethacin. Considering the interest in amorphous suspensions for toxicology studies of poorly water-soluble drugs, we sought to investigate the crystallization behavior of amorphous indomethacin in aqueous suspension. Specifically, the effect of pH and temperature on crystallization behavior was studied. Quench cooled amorphous powder was added to buffered media at different pH values (1.2, 4.5, and 6.8) at 5 and 25 °C. Both the solid and the solution were analyzed at different time points up to 24 h. Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy (with principal component analysis) was used to study solid-phase transformations and ultraviolet (UV) spectroscopy used to probe solution concentration. The crystallization onset time decreased and rate of crystallization increased with increasing pH and temperature. Diverse polymorphic forms were observed, with three new forms being identified; these were named ε, ζ, and η. At 25 °C, the amorphous form recrystallized directly to the α form, except at pH 6.8, where it initially converted briefly into the ε form. At 5 °C, all three new polymorphic forms were observed sequentially in the order ε, ζ, and then η, with the number of these forms observed increasing sequentially with decreasing pH. The three new forms exhibited distinct X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC), and FTIR and Raman spectroscopy profiles. The solution concentration profiles suggest that the relative physical stabilities of the polymorphs at 5 °C from lowest to highest is ε < ζ < η < α. The appearance of new polymorphs in this study suggests that amorphous suspensions are worth considering when performing polymorphic screening studies.

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Co-milling of various carbamazepine (CBZ) polymorphic forms (form I, III and dihydate) with nicotinamide (NIC) was performed in this study to investigate the formation kinetics of carbamazepine−nicotinamide cocrystals (CBZ−NIC) and to evaluate their physical stability. Milling was carried out at room temperature using an oscillatory ball mill at a 1:1 molar ratio of CBZ and NIC for various times up to 60 min. A freshly prepared sample was used for each milling. In the stability study, the milled samples (4, 10, 15, and 30 min) were stored under four conditions (20 and 40 °C; 33 and 75%RH) for up to four weeks. Samples were analyzed by X-ray powder diffraction (XRPD) and differential scanning calorimetry. XRPD showed that all CBZ forms used in this study formed cocrystals when co-milled with NIC (characteristic XRPD peaks at 6.6, 8.9, 10.1, 20.4, and 26.5 °2θ). Cocrystal formation was qualitatively found to be fastest for CBZ dihydrate (CBZ DH, ∼1 min), followed by CBZ form I (∼6 min), and CBZ form III (∼15 min). Upon storage, cocrystals formed from CBZ DH were found to be physically stable under all conditions studied, regardless of a small amount of impurity. For the two anhydrous forms (CBZ I and III), the physical stability of the co-milled CBZ−NIC samples was dependent on the duration of milling, the relative humidity, and temperature of the storage conditions. Under “mild” storage conditions (i.e., 20 °C/33%RH), either partially or fully formed CBZ−NIC cocrystals were found to revert back to pure CBZ and NIC. Under “moderate” storage conditions (i.e., 20 °C/75%RH and 40 °C/33%RH), CBZ−NIC cocrystals reverting to pure CBZ and NIC would occur initially, followed by cocrystal formation with increasing storage time. On the other hand, “stress” storage conditions (i.e., 40 °C/75%RH) were found to be ideal for cocrystal formation and stability. Moisture has been found to favor cocrystallization. Water molecules appear to have a significant effect on the formation (water molecules from CBZ DH) and the stability (high humidity) of the CBZ−NIC cocrystal. The “purity” of the cocrystal samples (i.e., presence of CBZ and/or NIC seeds) can affect the physical stability of CBZ−NIC cocrystals prepared by mechanical activation.

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