A rotated Doehlert matrix was utilized to explore the experimental design space around the milling parameters of Praziquantel (PZQ) polymorph B formation in terms of frequency and milling time. Three experimental responses were evaluated on the resulting ground samples: two quantitative responses, i.e. median particle size by Laser Light scattering (LLS) and drug recovery by HPLC, and one qualitative dependent variable, i.e. the obtained PZQ crystalline form, characterized through X-Ray Powder Diffraction (XRPD) and confirmed by Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). Temperature inside the jars was kept under constant control during the milling process by using temperature sensor equipped jars (thermojars), thus allowing evaluation of the obtained solid states at each experimental point, considering the specific temperature of the process. This explorative analysis led to the finding of a novel PZQ polymorph, named “Form C”, produced without degradation, then fully characterized, including by means of Synchrotron XRPD, Polarimetric, FT-IR, SS-NMR, ESEM and saturation solubility. Crystal structure was solved from XRPD data and its geometry was optimized by DFT calculations (CASTEP). Finally, Form C and Form A activity against adult schistosoma mansoni were compared through in vitro testing, and Form C's physical stability checked. The new polymorph, crystallizing in space group I2/c, physically stable for approximately 2 months, showed a m.p. of 106.84 °C and displayed excellent biopharmaceutical properties (water solubility of 382.69±9.26 mg/l), while preserving excellent activity levels against adult schistosoma mansoni.

Exploring mechanochemical parameters using a DoE approach: Crystal structure solution from synchrotron XRPD and characterization of a new praziquantel polymorph

Zanolla D.;Perissutti B.
;
Demitri N.;Passerini N.;Franceschinis E.;Voinovich D.
2019-01-01

Abstract

A rotated Doehlert matrix was utilized to explore the experimental design space around the milling parameters of Praziquantel (PZQ) polymorph B formation in terms of frequency and milling time. Three experimental responses were evaluated on the resulting ground samples: two quantitative responses, i.e. median particle size by Laser Light scattering (LLS) and drug recovery by HPLC, and one qualitative dependent variable, i.e. the obtained PZQ crystalline form, characterized through X-Ray Powder Diffraction (XRPD) and confirmed by Differential Scanning Calorimetry (DSC) and Thermogravimetric analysis (TGA). Temperature inside the jars was kept under constant control during the milling process by using temperature sensor equipped jars (thermojars), thus allowing evaluation of the obtained solid states at each experimental point, considering the specific temperature of the process. This explorative analysis led to the finding of a novel PZQ polymorph, named “Form C”, produced without degradation, then fully characterized, including by means of Synchrotron XRPD, Polarimetric, FT-IR, SS-NMR, ESEM and saturation solubility. Crystal structure was solved from XRPD data and its geometry was optimized by DFT calculations (CASTEP). Finally, Form C and Form A activity against adult schistosoma mansoni were compared through in vitro testing, and Form C's physical stability checked. The new polymorph, crystallizing in space group I2/c, physically stable for approximately 2 months, showed a m.p. of 106.84 °C and displayed excellent biopharmaceutical properties (water solubility of 382.69±9.26 mg/l), while preserving excellent activity levels against adult schistosoma mansoni.
2019
Pubblicato
https://www.sciencedirect.com/science/article/pii/S0928098719303574?via=ihub
File in questo prodotto:
File Dimensione Formato  
alide.pdf

Accesso chiuso

Descrizione: pdf versione editoriale
Tipologia: Documento in Versione Editoriale
Licenza: Copyright Editore
Dimensione 5.4 MB
Formato Adobe PDF
5.4 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Supplementary information Perissutti et al. 2019.docx

Accesso chiuso

Descrizione: supplementary info
Tipologia: Bozza finale post-referaggio (post-print)
Licenza: Copyright Editore
Dimensione 634.62 kB
Formato Microsoft Word XML
634.62 kB Microsoft Word XML   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2952535
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 20
  • ???jsp.display-item.citation.isi??? 20
social impact