New Case of Pharmaceutical Solid-State Forms: Several Novel Solvates/Polymorphs of Nilotinib and Their Phase Transformation Controls

Abstract

Nilotinib as a type of anticancer drug was designed for the treatment of chronic myeloid leukemia that is resistant to imatinib. Presently, very few studies of nilotinib polymorphs have been reported because of the sparing solubility of the free base compared with its salt forms. Besides, there are also hardly reports for its solvates. Notably, in this study, eight different nilotinib solid-state forms, including six new solvates (form H1, form H2a, form H2b, form H2c, form H3, and form H4) and two desolvated polymorphs (form C and form D) were initially obtained. The crystallography data of form H2a, form H2b, and form H2c were obtained using single-crystal X-ray diffraction. We found that form H2a, form H2b, and form H2c were isolated site solvates. Besides, form H1 and form H3 are suspected to be isolated site solvates based on their thermal characterizations. Furthermore, we performed antisolvent experiments and used the diffusion theory to explain the mechanism successfully. In addition, we performed a series of solventmediated phase transformation experiments of the solid-state forms specifically and studied the transformation between nilotinib solvates. To the best of our knowledge, this is the first study to report the eight new crystal forms of nilotinib. Therefore, the present study fulfills the research blank in the crystallography field of nilotinib.

Investigation of the Influence of Anti-Solvent Precipitation Parameters on the Physical Stability of Amorphous Solids

“…As illustrated in Figure 1 a, the PXRD patterns of the dried samples obtained at feeding rates of 0.1 and 0.5 mL/min exhibited distinct peaks at 9.07°, 13.08°, 13.82°, 16.68°, 17.85°, 18.26°, 20.84°, 21.39°, 24.11°, and 25.22°, which corresponded to the crystalline Form A of nilotinib free base. These findings align precisely with the characteristic peaks of nilotinib free base Form A documented in the previous literature [ 25 , 26 ]. Nevertheless, when the feeding rates were set at 5, 35, and 70 mL/min, the dried samples solely exhibited the existence of a halo peak that corresponds to the amorphous state of a nilotinib free base.…”

“…The DSC analysis was performed to further validate the previously mentioned findings obtained from PXRD analysis. As illustrated in Figure 2 a, the samples produced at varying feeding rates displayed a solitary endothermic peak, corresponding to the melting temperatures (T m ) of nilotinib free base crystalline Form A (T mA , 235 °C) [ 25 , 26 ]. In addition, the T mA of the samples precipitated at feeding rates of 0.1 and 0.5 mL/min was observed to be slightly lower than the T mA of the samples precipitated at feeding rates exceeding 5 mL/min.…”

Polymorph Screening of the Antitumor Drug Ripretinib─Selective Preference of Dimer Synthons

“…Investigating phase transformation between several solid forms of a drug is very important during research and development, as the most stable solid form is selected to commercialize . It is not desirable that the marketed solid form transforms to a more stable phase at storage conditions .…”

“…Investigating phase transformation between several solid forms of a drug is very important during research and development, as the most stable solid form is selected to commercialize. 31 It is not desirable that the marketed solid form transforms to a more stable phase at storage conditions. 32 Phase transformation results change physicochemical properties, and the altered form may not qualify the bioequivalence profile of an innovator drug.…”

Synthetic Strategies toward Higher Cocrystals of Some Resorcinols

“…The study of cocrystals, or more accurately multicomponent molecular crystals, continues to be an active area of research in crystal engineering after 3 decades of investigation and research. − This is so because this subject has been found to be of considerable commercial interest and useful in practical applications in the pharmaceutical industry. , Key to these applications is the fact that cocrystal formation of active pharmaceutical ingredients (APIs) is often accompanied by changes in the solubility and permeability of the drug under consideration. , Since many computationally designed drugs suffer from shortcomings with respect to both these abovementioned properties, cocrystal formation might result in a more bioavailable product. − This is clearly a desired outcome and so there is a continued interest in identifying new cocrystals of APIs. − …”