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. 2021 Aug 25;13(9):1328.
doi: 10.3390/pharmaceutics13091328.

Exploring Taxifolin Polymorphs: Insights on Hydrate and Anhydrous Forms

Fernanda Cristina Stenger Moura  1 , Nicola Pinna  2 , Riccardo Vivani  2 , Gisele Elias Nunes  3 , Aurélie Schoubben  2 , Tania Mari Bellé Bresolin  1 , Ivan Helmuth Bechold  3 , Maurizio Ricci  2
Affiliations

Exploring Taxifolin Polymorphs: Insights on Hydrate and Anhydrous Forms

Fernanda Cristina Stenger Moura et al. Pharmaceutics. .

Abstract

Taxifolin, also known as dihydroquercetin, possesses several interesting biological properties. The purpose of the study was to identify polymorphs of taxifolin prepared using crystallization in different solvents. Data from X-ray powder diffraction, differential scanning calorimetry, and thermogravimetry enabled us to detect six different crystalline phases for taxifolin. Besides the already known fully hydrated phase, one partially hydrated phase, one monohydrated phase, two anhydrous polymorphs, and one probably solvated phase were obtained. The unit cell parameters were defined for three of them, while one anhydrous polymorph was fully structurally characterized by X-ray powder diffraction data. Scanning electron microscopy and hot stage microscopy were also employed to characterize the crystallized taxifolin powders. The hydrate and anhydrous forms showed remarkable stability in drastic storage conditions, and their solubility was deeply evaluated. The anhydrous form converted into the hydrate form during the equilibrium solubility study and taxifolin equilibrium solubility was about 1.2 mg/mL. The hydrate taxifolin intrinsic dissolution rate was 56.4 μg cm-2 min-1. Using Wood's apparatus, it was not possible to determine the intrinsic dissolution rate of anhydrous taxifolin that is expected to solubilize more rapidly than the hydrate form. In view of its high stability, its use can be hypothesized.

Keywords: X-ray powder diffraction; differential scanning calorimetry; equilibrium solubility; intrinsic solubility; polymorphism; taxifolin; thermogravimetry.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Scheme 1
Scheme 1
Molecular structure of Tax.
Figure 1
Figure 1
XRPD patterns of Tax-ET (a); Tax-ME (b); Tax-EA (c); Tax-AC (d); Tax-CH-ME (e); Tax-DM-ET (f); Tax-ACN (g); Tax-AET (h); Tax-AACN (i); Pristine-Tax (j). The pattern of Phase 1 calculated from single crystal structure [34] is also reported for comparison (red line, s.c.).
Figure 2
Figure 2
TG, DTG, and DSC curves of Tax-ET (a); Tax-EA (b); Tax-ACN (c); Tax-AET (d); Tax-AACN (e); Pristine-Tax (f).
Figure 3
Figure 3
Scheme of the structure of Phase 1 (a); and Phase 3 (b). Carbon atoms are black, oxygen atoms are red, while hydrogen bonds are represented as dashed lines. Water molecules are labeled as in [34].
Figure 4
Figure 4
XRPD patterns of Tax-ET at 25 °C, Phase 1 (a); at 70 °C, Phase 2 (b); and at 120 °C, Phase 3 (c).
Figure 5
Figure 5
SEM images of Pristine-Tax (a); Tax-ET (b); Tax-ME (c); Tax-CH-ME (d); Tax-ACN (e); Tax-EA (f); Tax-AET (g); Tax-AACN (h); Tax-AC (i); Tax-DM-ET (j).
Figure 6
Figure 6
ATR-FTIR spectra of Pristine-Tax (a); Tax-ACN (b); Tax-ET (c); Tax-EA (d); Tax-AET (e); Tax-AACN (f).
Figure 7
Figure 7
Hot stage microscopy images of Pristine-Tax (a); Tax-ET (b); Tax-AET (c); Tax-EA (d); Tax-ACN (e); Tax- AACN (f). The scale bar in the pictures corresponds to 10 μm.
Figure 8
Figure 8
Equilibrium solubility at 37 °C of Tax-ET in pH 1.2 (■) and pH 4.5 (▲) solutions and Tax-EA in pH 1.2 (☐) and pH 4.5 (△) solutions. The scale bars correspond to the standard deviation values; experiments were performed in triplicate.
Figure 9
Figure 9
Tax-ET (a) and Tax-EA (b) dissolution profile at 37 °C in pH 4.5 solution and 100 rpm agitation. The scale bars correspond to the standard deviation values; experiments were performed in triplicate.
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