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. 2023 Aug 29;28(17):6320.
doi: 10.3390/molecules28176320.

Crystallization Selectivity of Ribavirin Solution and Amorphous Phase

Fuying Li  1   2 , Shiying Chen  1 , Haoxin Hu  3 , Chengfeng Liang  1 , Shiyu Sun  1 , Can Jin  4 , Fenghua Chen  1
Affiliations

Crystallization Selectivity of Ribavirin Solution and Amorphous Phase

Fuying Li et al. Molecules. .

Abstract

Crystallization selectivity is an important principle in polymorph control. Ribavirin Form I, Form II, DMSO solvate, and amorphous ribavirin are prepared, and the short-range order similarities between these solid forms and ribavirin aqueous solution and DMSO solution are compared via mid-frequency Raman difference spectra (MFRDS). The crystallization process from amorphous ribavirin to Form I and from solution to amorphous phase is explained. Reasons for the difficulty in preparing the DMSO solvate are proposed. The rationale provided for the crystallization selectivity provides a foundation for the synthesis of metastable phases with a robust and convenient method.

Keywords: amorphous phase; crystallization selectivity; mid-frequency Raman difference spectra; ribavirin; solution; solvate.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular structure of ribavirin.
Figure 2
Figure 2
Molecular crystal structures of ribavirin Form II and Form I (public data from the Cambridge Crystallographic Data Centre, CCDC, www.ccdc.cam.ac.uk, accessed on 25 April 2023).
Figure 3
Figure 3
PXRD patterns of ribavirin (a) Form II; (b) amorphous phase; (c) Form I with Form II impurity; and (d) DMSO solvate with Form II impurity.
Figure 4
Figure 4
LFRS of ribavirin (a) Form II, amorphous phase, Form I and (b) DMSO solvate.
Figure 5
Figure 5
MFRS (300–1800 cm−1) of amorphous ribavirin, Form I, and Form II normalized by the intensities at 1514, 1505, and 1503 cm−1, separately. The strongest MFRS band is normalized.
Figure 6
Figure 6
MFRDS between (a) amorphous ribavirin and Form I; (b) amorphous ribavirin and Form II; and (c) Form I and Form II. Each MFRDS contains 3 × 3 lines.
Figure 7
Figure 7
MFRS of ribavirin aqueous solution normalized by intensity at 1519 cm−1.
Figure 8
Figure 8
MFRDS between (a) ribavirin aqueous solution and amorphous ribavirin; (b) aqueous solution and Form I; and (c) aqueous solution and Form II. Each MFRDS contains 3 × 3 lines.
Figure 9
Figure 9
PXRD patterns of (a) evaporation product of 100 μL ribavirin–saturated aqueous solution at room temperature on an aluminum substrate; (b) spray–drying product of ribavirin aqueous solution (conditions are described in the Section 4); and evaporation products of 100 μL ribavirin–saturated (c) acetone; and (d) methanol solutions at 60 °C.
Figure 10
Figure 10
A schematic crystallization process of ribavirin aqueous solution. The process was divided into a kinetic process (Ostwald’s step rule) and a thermodynamic process. The kinetic process provides a metastable phase, while the thermodynamic process provides the most stable phase under given conditions.
Figure 11
Figure 11
MFRS of DMSO normalized by intensity of the band at 669 cm−1, ribavirin DMSO solution normalized by intensity at 670 cm−1, and ribavirin solute in DMSO solution normalized by intensity at 1508 cm−1.
Figure 12
Figure 12
MFRS of (a) DMSO solvate with signals of DMSO solvent; and (b) DMSO solvate subtracting DMSO (ribavirin solvate).
Figure 13
Figure 13
MFRDS of ribavirin solute in DMSO solution and (a) amorphous ribavirin; (b) solvate-ribavirin; (c) Form I; and (d) Form II.
See this image and copyright information in PMC

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