title: Inhibition of the spontaneous polymorphic transition of pyrazinamide γ form at room temperature by co-spray drying with 1,3-dimethylurea.
abstract: The present study focuses on the ability of excipients to induce the crystallization of a specific polymorphic form of pyrazinamide (PZA) and more interestingly, to block the irreversible solid-solid transition of the metastable forms of the PZA to the stable form at room temperature. We outline an experimental protocol for the production of a structurally pure γ form of PZA by means of spray drying. Without any particular treatment, phase transition to δ form was detected after 14 days of storage under ambient conditions. In order to prevent this irreversible phase transition, different excipients were co-spray dried with PZA. By co-spray drying 5% in mass of 1,3-dimethylurea (DMU) with PZA, we noticed its ability in preventing phase transitions and thus to maintain PZA under its γ form up to 12 months of storage at room temperature. Raman spectroscopy evidenced how DMU crystals surround particles of γ PZA which suggest that DMU might interact with the surface of PZA particles, thus blocking the phase transition. On the other hand, the co-spray drying of PZA with the polymerpolyvinylpyrrolidone (PVP) resulted in the crystallization of δ form of PZA. The physical mixture was intact over 12 months of storage at room temperature.
authors.affiliation: SMS Laboratory, Crystallogenesis Unit, EA 3233, University of ROUEN, rue Lucien Tesnière - F-76821 Mont Saint-Aignan Cedex, France. Electronic address: grace.baaklini1@univ-rouen.fr.
authors.forename: G
authors.initials: G
authors.lastname: Baaklini
authors.affiliation: SMS Laboratory, Crystallogenesis Unit, EA 3233, University of ROUEN, rue Lucien Tesnière - F-76821 Mont Saint-Aignan Cedex, France.
authors.forename: V
authors.initials: V
authors.lastname: Dupray
authors.affiliation: SMS Laboratory, Crystallogenesis Unit, EA 3233, University of ROUEN, rue Lucien Tesnière - F-76821 Mont Saint-Aignan Cedex, France.
authors.forename: G
authors.initials: G
authors.lastname: Coquerel
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning; D003460:Crystallization; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry*; D008782:Methylurea Compounds / Q000737:chemistry*; D008855:Microscopy, Electron, Scanning; D011205:Povidone / Q000737:chemistry*; D033362:Powder Diffraction; D011718:Pyrazinamide / Q000737:chemistry*; D013059:Spectrum Analysis, Raman; D013696:Temperature; D014961:X-Ray Diffraction
chemical_list: D000995:Antitubercular Agents; D005079:Excipients; D008782:Methylurea Compounds; D011718:Pyrazinamide; D011205:Povidone; C018276:1,3-dimethylurea
keywords: 1,1-Diethylurea (PubChem CID:12472); 1,3-Dimethylurea; 1,3-Dimethylurea (PubchemCID : 7293); Citric acid (PubChem CID: 311); Co-spray drying; Glycine (PubChem CID: 750); Physical stability; Polymorphic transition; Polyvinylpyrrolidone (PubChemCID: 11989721); Pyrazinamide; Pyrazinamide (PubChemCID: 1046); Sodium chloride (PubChem CID: 5234); Urea (PubChemCID: 1176); d-Mannitol (PubChem CID: 6251); l-Arginine (PubChemCID: 6322)