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. 2016 Jul 14;21(7):917.
doi: 10.3390/molecules21070917.

In Situ Investigation of a Self-Accelerated Cocrystal Formation by Grinding Pyrazinamide with Oxalic Acid

Hannes Kulla  1   2 , Sebastian Greiser  3 , Sigrid Benemann  4 , Klaus Rademann  5 , Franziska Emmerling  6
Affiliations

In Situ Investigation of a Self-Accelerated Cocrystal Formation by Grinding Pyrazinamide with Oxalic Acid

Hannes Kulla et al. Molecules. .

Abstract

A new cocrystal of pyrazinamide with oxalic acid was prepared mechanochemically and characterized by PXRD, Raman spectroscopy, solid-state NMR spectroscopy, DTA-TG, and SEM. Based on powder X-ray diffraction data the structure was solved. The formation pathway of the reaction was studied in situ using combined synchrotron PXRD and Raman spectroscopy. Using oxalic acid dihydrate the initially neat grinding turned into a rapid self-accelerated liquid-assisted grinding process by the release of crystallization water. Under these conditions, the cocrystal was formed directly within two minutes.

Keywords: cocrystal; hydrate; in situ; mechanochemistry; pyrazinamide.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Powder patterns of the PZA:OA (1:1) cocrystal (center) and the reactants pyrazinamide (bottom) and oxalic acid dihydrate (top).
Figure 2
Figure 2
(a) Hydrogen bond interactions indicated by green dashed lines (b) structure of the PZA:OA (1:1) cocrystal, view along the b-axis.
Figure 3
Figure 3
Solid-state NMR spectra of the PZA:OA (1:1) cocrystal (center) and the reactants pyrazinamide (bottom) and oxalic acid dihydrate (top).
Figure 4
Figure 4
Time resolved investigation of the synthesis process of the PZA:OA (1:1) cocrystal obtained by neat grinding of PZA with oxalic acid dihydrate followed in situ by synchrotron XRD (left) and Raman spectroscopy (right). The Raman spectrum of the empty Perspex jar (gray) indicates which modes of the following synthesis process arise from the sample holder and which from the reaction mixture. Yellow: reactants; orange: reactants and product; red: product.
Figure 5
Figure 5
Time resolved investigation of the synthesis process of the PZA:OA (1:1) cocrystal obtained by neat grinding of PZA with oxalic acid anhydrous followed in situ by synchrotron XRD (left) and Raman spectroscopy (right). The Raman spectrum of the empty Perspex jar (gray) indicates which modes of the following synthesis process arise from the sample holder and which from the reaction mixture. Yellow: reactants; orange: reactants and product; red: product.
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