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. 2018 Oct;107(10):2731-2734.
doi: 10.1016/j.xphs.2018.06.020. Epub 2018 Jun 28.

Solid-State Insight Into the Action of a Pharmaceutical Solvate: Structural, Thermal, and Dissolution Analysis of Indinavir Sulfate Ethanolate

Chengcheng Zhang  1 , Kortney M Kersten  1 , Jeff W Kampf  1 , Adam J Matzger  2
Affiliations

Solid-State Insight Into the Action of a Pharmaceutical Solvate: Structural, Thermal, and Dissolution Analysis of Indinavir Sulfate Ethanolate

Chengcheng Zhang et al. J Pharm Sci. 2018 Oct.

Abstract

The crystal structure of indinavir sulfate, a pharmaceutical administered as an ethanol solvate, is presented, revealing a unique channel/ionic solvate structure to be characteristic of the compound. The properties of the material with regard to thermal treatment and water adsorption follow closely from the structure. The in situ amorphization of the pharmaceutical upon contacting liquid water is observed and highlights the unique dissolution enhancement of marketing the crystalline solvate dosage. Through survey of published crystal structures, an ambiguous sulfate/bisulfate ionization state is also observed in the crystal, which challenges the general understanding of the pharmaceutical. This study provides a solid-state insight into the function of a special multicomponent crystalline pharmaceutical form.

Keywords: amorphism; crystal structure; desolvation; salts; solvates.

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Figures

Figure 1.
Figure 1.
a) Chemical structure of indinavir sulfate ethanolate (Crixivan). b) Illustration of hydrogen bonding interactions in the crystal structure of indinavir sulfate/bisulfate ethanolate revolving around the sulfate/bisulfate ion; only fragments of indinavir molecules are shown White = hydrogen, grey = carbon, blue = nitrogen, red = oxygen, yellow = sulfur.
Figure 2.
Figure 2.
Statistical analysis of C-N-C bond angles in structures containing pyridine/pyridinium (a) and OS bond distances (b) in structures containing sulfate/bisulfate collected from the CSD.
Figure 3.
Figure 3.
Crystal structure overview of indinavir sulfate/bisulfate ethanolate. a) The helical chains intercalated by sulfate/bisulfate ions along b-axis. Both ethanol molecules are presented as whole occupancy with the disordered parts omitted for clarity. Blue = indinavir molecule, white = hydrogen, black = carbon, red = oxygen, yellow = sulfur. b) Illustration of the solvent channel along b-axis, ethanol molecules are shown in space-filling style. c) View of the void space in the channels with indinavir sulfate/bisulfate shown in space-filling style with ethanol omitted.
Figure 4.
Figure 4.
Temperature-dependent PXRD patterns of indinavir sulfate/bisulfate ethanolate.
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