Science and Technology Production
Memoria de resúmenes Congreso de Química 2022 - V Reunión de la Asociación Latinoamericana de Cristalografía - Diffractometric, spectrophotometric, and thermal characterization of the hydrochloride salt hemihydrate of tioconazole
Congress
Authorship:
MORONI, ALDANA BEATRIZ ; Pérez Mayoral, Elena ; Lionello, Diego F. ; Vega, Daniel R. ; Kaufman, Teodoro S. ; Calvo, Natalia L.Date:
2023Publishing House and Editing Place:
Universidad de Costa RicaSummary *
Tioconazole (TCZ) is an imidazole antifungal agent with broad-spectrum activity and low aqueous solubility, which limits its bioavailability and antifungal activity (1). A more soluble form with improved solubility properties would be desired. Solid-state characterization is of paramount importance because it provides key information related to the physicochemical and functional properties of the active pharmaceutical ingredients. To obtain a suitable new solid phase of TCZ in the form of crystals for single crystal X-ray diffraction (SCXRD) measurements from aqueous hydrochloric acid, enabling solution and refinement of their crystal structure, and to characterize them further by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and solid state nuclear magnetic resonance (ssNMR). Single crystals of TCZ hydrochloride hemihidrate were obtained from slow evaporation at room temperature of a supersaturated solution of TCZ in 1M HCl. A suitable single crystal was selected and used as material for the SCXRD analysis at three different temperatures (302 K, 333 K, and 283 K after the heating stage). All structures were resolved and refined into a triclinic space group (Figure 1). The structure at 302 K resulted in a hemihydrate salt containing in the asymmetric unit two crystallographically independent TCZ+- Cl− ion pairs and a water molecule (located in channels) with the following lattice parameters: a = 10.3995(5) A, b = 11.0516(6) A, c = 18.6950(9) A, α = 78.245(2) °; β = 84.851(2) °, and γ = 84.851(2)°. At 333 K, the asymmetric unit presented only one ion pair with a remaining 10% H2O, which resulted in a unit cell of half its volume with different dimensions compared to that observedat 302 K. In each ion pair, the TCZ+ cation and the Cl− anion are linked by N+−H···Cl− interactions. By lowering the temperature to 283 K, the recovery of the unit cell volume and the percentage ofwater (as verified by TGA) were observed. The powder X-ray diffraction pattern of the new solidphase was different from that of TCZ, confirming their structural differences. The DSC profile ofTCZHCl•H2O presented a first endothermic event from room temperature to 90 ºC associated witha mass loss of 2.10% (determined by TGA), which is consistent with the theoretical value expectedfor the loss of H2O from TCZ hydrochloride hemihydrate (~2.08%). This dehydration event resulted in an anhydrous phase that evidences two additional superimposed endothermic events, with peaks centered at 148.0 and 158.1ºC, which occur without mass loss (according to TGA). This suggests a phase transformation process at 148 °C to the final solid form, which melts at 158.1 °C without decomposition. The CPMAS 13C ssNMR spectra of TCZ and TCZHCl•H2O contain less resonances than those expected in the aromatic region, which are observed as wide peaks with multiple and overlapped signals consistent with the presence of more than one molecule in the corresponding crystallographic asymmetric units. Tentative signal assignments were made by comparison with the 13C NMR data of the compounds dissolved in DMSO-d6 and with the guide of the corresponding NQS (NonQuaternary Supression) sub-spectra. The CP-MAS 15N ssNMR spectrum of TCZ (Figure 2C) showed a peak at δ = -205 ppm that was attributed to Na, whereas the signal at δ = -118 ppm was assigned to Nb, with the aid of solution 15N HMBC spectra taken in DMSOd6. For the analysis of the spectrum of TCZHCl•H2O (Figure 2A), a new experiment with a contact time of 500 μs was carried out, revealing that Nb displayed a more shielded signal as a resonance at δ = -197 ppm (Δδ = 81.6 ppm), and that Na was found at δ = -195 ppm (Δδ = -8.6 ppm) slightly deshielded with regards to TCZ. Taken together, these results confirm that Nb supports protonation, and suggest that the positive charge is delocalized across the imidazole ring. SCXRD measurements revealed that the new solid phase is a channel hydrate protonated at the distal nitrogen atom of the imidazole ring. Information provided by the agent in SIGEVAKey Words
SOLID STATE NUCLEAR MAGNETIC RESONANCESINGLE CRYSTAL X-RAY DIFFRACTIONTIOCONAZOLE