A new soluble and bioactive polymorph of praziquantel

作者：Zanolla Debora; Perissutti Beatrice^*; Passerini Nadia; Chierotti Michele R; Hasa Dritan; Voinovich Dario; Gigli Lara; Demitri Nicola; Geremia Silvano; Keiser Jennifer; Cerreia Vioglio Paolo; Albertini Beatrice

来源：European Journal of Pharmaceutics and Biopharmaceutics, 2018, 127: 19-28.

DOI：10.1016/j.ejpb.2018.01.018

• Praziquantel
• Mechanochemistry
• Solid-state reactions
• Polymorphism
• Solubility
• Bioactivity
• Crystal structure solution
• DFT-D calculations
• Neglected tropical diseases

Praziquantel is the only available drug to treat Schistosomiasis. However, its utilization is limited by many drawbacks, including the high therapeutic dose needed, resulting in large tablets and capsules difficult to be swallowed, especially from pediatric patients. In this study, an alternative option to overcome these disadvantages is proposed: to switch to a novel crystalline polymorph of racemic compound praziquantel. The preparation of the crystalline polymorph was realized via a neat grinding process in a vibrational mill. The new phase (Form B) was chemically identical to the starting material (as proved by HPLC, H-1 NMR, and polarimetry), but showed different physical properties (as evaluated by SEM, differential scanning calorimetry, thermogravimetry, ATR-FTIR spectroscopy, X-ray powder diffraction, and solid-state NMR). Furthermore, the crystal structure of the new phase was solved from the powder synchrotron X-ray diffraction pattern, resulting in a monoclinic C2/c cell and validated by DFT-D calculation. Moreover the simulated solid-state NMR C-13 chemical shifts were in excellent agreement with the experimental data. The conversion of original praziquantel into Form B showed to affect positively the water solubility and the intrinsic dissolution rate of praziquantel. Both the in vitro and in vivo activity against Schistosoma mansoni were maintained. Our findings suggest that the new phase, that proved to be physically stable for at least one year, is a promising product for designing a new praziquantel formulation.

• 出版日期2018-6