Evaluation of a crystalline nanosuspension: Polymorphism, process induced transformation and in vivo studies

• Published in: International journal of pharmaceutics Vol. 408; no. 1-2; pp. 138 - 151
• Main Authors: Sharma, Puneet, Zujovic, Zoran D., Bowmaker, Graham A., Denny, William A., Garg, Sanjay
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 15.04.2011; Elsevier
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - toxicity; Biological and medical sciences; Chemistry, Pharmaceutical; Crystallization; Differential Thermal Analysis; Dose-Response Relationship, Drug; Drug Carriers - chemistry; Drug Stability; General pharmacology; High pressure homogenization; in vivo studies; infrared spectroscopy; Injections, Intravenous; intravenous injection; Male; Medical sciences; Mice; Mice, Inbred C57BL; Microscopy, Electron, Scanning; Molecular Structure; nanocrystals; Nanoparticles - chemistry; Nanosuspension; Pharmaceutical technology. Pharmaceutical industry; pharmacokinetics; Pharmacology. Drug treatments; Phase Transition; Polymorph; Process induced transformation; Pyrimidinones - administration & dosage; Pyrimidinones - chemistry; Pyrimidinones - pharmacokinetics; Pyrimidinones - toxicity; scanning electron microscopy; Solid state; Solubility; Spectrophotometry, Infrared; Suspensions; thermal analysis; Tissue Distribution; Wet milling; X-ray diffraction; Polymorph; High pressure homogenization; Solid state; Nanosuspension; Wet milling; Process induced transformation; Evaluation; Pharmaceutical technology; Grinding(comminution); Homogenization; Process; High pressure; In vivo; Nanotechnology; Polymorphism
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2011.01.032

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<0.1μg/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 (10mg/kg) when compared with a solution formulation (2.5mg/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.