Baloxavir Marboxil Polymorphs: Investigating the Influence of Molecule Packing on the Dissolution Behavior

Abstract

Baloxavir marboxil (BXM) is a new blockbuster FDA-approved anti-influenza virus agent. However, its poor solubility has limited its oral bioavailability. In this study, BXM was crystallized from several organic solvents, obtaining three polymorphs, and their dissolution behaviors were studied. Detailed crystallographic examination revealed that Form I is monoclinic, space group P21, with unit cell parameters a = 7.1159 (3) Å, b = 20.1967 (8) Å, c = 9.4878 (4) Å, β = 109.033 (1)°, V = 1289.02 (9) Å3, and Z = 2, and Form II is monoclinic, space group P21, with unit cell parameters a = 7.1002 (14) Å, b = 39.310 (7) Å, c = 9.7808 (18) Å, β = 110.966 (5)°, V = 2549.2 (8) Å3, and Z = 4. Form I has a rectangular three-dimensional energy frameworks net, while Form II has a two-dimensional net. On the other hand, Form II has a much larger percentage of its surface area of exposed hydrogen bond acceptors than Form I. These crystallographic features offered increased solubility and dissolution rate to Form II. The results of stability and solubility experiments suggest that Form II may be preferred in the solid form used for the industrial preparation of BXM medicinal products.

Solvates and Polymorphs of Baloxavir Marboxil: Crystal Structure and Phase Transformation Study

“…Figure shows the PXRD patterns of the seven solid forms, and all of the solid forms give unique PXRD patterns. The diffraction peak positions of forms I, II, and III are consistent with the reported forms in the literature . S MA and S 2‑THF are identified as methyl acetate solvates and 2-methyltetrahydrofuran solvates by SCXRD, respectively.…”

“…Forms I, form II, and form III heated to 180 °C showed no exothermic and endothermic peaks and no weight loss, which were consistent with the literature (Figure S10). 35 As shown in Figure 8, the TGA curves of solvates showed weight loss stages, and the DSC curves showed endothermic peaks at the same position corresponding to the escape of the solvent molecules. The desolvation of the four solvates upon heating seems to be a one-step process with a characteristic desolvation endothermic peak associated with the weight loss.…”

“…Further, the experimental PXRD pattern peak positions (deg) and relative intensities (%) of form III, S DIOX , and S THF are provided in Table S2 for comparison. The preparation of form III has been described in the literature; in our study, form III could only be obtained by the phase transition of S MA after grinding and the PXRD pattern of S MA was obtained without grinding S MA . Although the PXRD patterns of form II and form III are similar, a detailed comparison of PXRD patterns indicates that they are different forms (Figure S3).…”

“…The diffraction peak positions of forms I, II, and III are consistent with the reported forms in the literature. 35 S MA and S 2-THF are identified as methyl acetate solvates and 2-methyltetrahydro-furan solvates by SCXRD, respectively. The experimental PXRD patterns of form I, form II, S MA , and S 2-THF closely match the simulated ones (Figure S1), confirming the formation of pure phases.…”

“…Solvates seem to be formed easily for BXM, but solvates cannot be accurately identified due to the lack of crystal structure information. So far, only two single-crystal structures of BXM (form I and form II) have been solved, 35 and the single-crystal structures of solvates have not been reported. Moreover, the detailed transformation relationships between the different solid forms of BXM are unclear.…”