title: Evaluation of a crystalline nanosuspension: polymorphism, process induced transformation and in vivo studies.
abstract: The aim of this work was to evaluate a crystalline nanosuspension of an investigational anticancer compound, SN 30191. Solid forms of SN 30191 were prepared and characterized by thermal analysis, infrared spectroscopy, ¹³C CP/MAS SSNMR spectroscopy, SEM and powder XRD. Wet milling was performed using a high pressure homogenizer and process induced transformations were studied as a function of time and pressure using infrared spectroscopy. Dose-toxicity and pharmacokinetics (PK) of the nanocrystal formulation were evaluated in mice after intravenous administration. SN 30191 was found to exist in two polymorphic forms (I and II) and a hydrate with an equilibrium solubility < 0.1 μg/ml (pH 1.3-11.0, 37 °C). Wet milling resulted in solid state transformation as a function of pressure. Form II was found to transform into form I at intermediate pressures. A further increase in pressure resulted in formation of a hydrate. The final nanosuspension consisted of SN 30191 as a hydrate. The dose-toxicity studies revealed higher tolerance (~4 times) for the nanosuspension (10 mg/kg) when compared with a solution formulation (2.5 mg/kg). Compared with solution formulation, the nanosuspension allowed the delivery of a higher dose and rendered possible the performance of PK and tissue distribution studies in animals.
authors.affiliation: School of Pharmacy, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Puneet
authors.initials: P
authors.lastname: Sharma
authors.forename: Zoran D
authors.initials: ZD
authors.lastname: Zujovic
authors.forename: Graham A
authors.initials: GA
authors.lastname: Bowmaker
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Marshall
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.forename: Sanjay
authors.initials: S
authors.lastname: Garg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D004055:Differential Thermal Analysis; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008855:Microscopy, Electron, Scanning; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry*; D044367:Phase Transition; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D012995:Solubility; D013055:Spectrophotometry, Infrared; D013535:Suspensions; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011744:Pyrimidinones; C559992:SN 30191; D013535:Suspensions