(M1230-08-49) Physical Evaluation of a Late Appearing Polymorph of Ritonavir Form III

Purpose: Ritonavir, a marketed product for the treatment of HIV/AIDS, is a notorious example of disappearing polymorphs and has been shown to exist in different forms (1). In our laboratory, Form III was prepared via faster nucleation and growth conditions from melt/cool crystallization than had been previously reported (2). The current research describes results obtained from evaluation of Ritonavir Form III physical properties with respect to both equilibrium solubility and stability compared to previously known forms.

Methods: Ritonavir Form III was physically characterized using x-ray powder diffraction (XRPD) followed by indexing to confirm a single phase, differential scanning calorimetry (DSC), thermogravimetry (TG), and hot stage optical microscopy (HSOM) to evaluate thermal properties, dynamic vapor sorption (DVS) to monitor hygroscopicity, and for spectroscopic properties using Raman. The physical stability of Form III was evaluated by both XRPD and Raman after subjecting the material to a series of stresses such as elevated temperature and humidity (40 °C/75% RH) for up to three months, 15 min high compression, and long-term stability (over one year) at ambient conditions. The equilibrium solubility of Form III in aqueous media for up to 48 hrs. was measured using UV/VIS spectroscopy, while recovered solids from the experiments were evaluated by XPRD for form change.

Results: Ritonavir Form III displayed a unique crystalline structure compared to known Forms I and II. The material was shown to be composed of a single phase by indexing. Thermal properties indicated a sharp melt with onset at ~ 114 °C and an endothermic maximum at ~118 °C. HSOM confirmed the thermal events. Negligible weight loss was observed by TG up to 180 °C, and Form III was shown to be slightly hygroscopic with weight gain of ~ 0.3% and no hysteresis. Form III was also stable for one month following exposure to 40 °C/75% RH according to XRPD and Raman spectroscopy. Upon exposure to high compression (700 lbs. for 15 min) the form remained unchanged. After one year storage at ambient conditions, Form III is still stable. The equilibrium solubility of Form III in 0.1 N HCl was significantly higher than Form II (12-fold), moderately higher than Form I (4-fold) and on the same order of magnitude as amorphous material. The XRPD of the materials recovered after solubility measurements indicated no form change after 48 hrs.

Conclusion: Ritonavir Form III was physically characterized using XRPD with indexing, DSC, TG, HSOM, DVS and Raman spectroscopy. The results indicated a crystalline material comprised of a single phase that melts at approximately 114 °C, with negligible weight loss and is slightly hygroscopic. Form III was also shown to be physically stable upon exposure to elevated temperature and humidity conditions for one month according to both XRPD and Raman spectroscopy, unlike amorphous material which crystallized to Form I after one month. Form III remained unchanged after being subjected to high compression, and has also remained unchanged after storage at ambient conditions for over a year. In addition, Form III displayed improved solubility in aqueous media compared to both Forms I and Forms II and was similar to that of amorphous material after equilibrium conditions were obtained. Results of this research indicate that Ritonavir Form III has acceptable physical properties and it is advantageous compared to Form II and amorphous material when considering both solubility and stability, respectively.

References: 1. Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Ritonavir: An Extraordinary Example of Conformational Polymorphism. Pharmaceutical Research 2001, 18(6), 859-866. DOI: 10.1023/a:1011052932607.
2. Parent S, Smith P, Purcell D, Smith D, Bogdanowich-Knipp S, Bhavsar A, Chan, L, Croom, J, Bauser, H, McCalip, A, Byrn, S and Radocea, A. Ritonavir Form III: A Coincidental Concurrent Discovery. Crystal Growth & Design 2023 23(1), 320-325. DOI: 10.1021/acs.cgd.2c01017.