Monitoring ibuprofen–nicotinamide cocrystal formation during solvent free continuous cocrystallization (SFCC) using near infrared spectroscopy as a PAT tool

• Published in: International journal of pharmaceutics Vol. 426; no. 1-2; pp. 15 - 20
• Main Authors: Kelly, A.L., Gough, T., Dhumal, R.S., Halsey, S.A., Paradkar, A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.04.2012
• Subjects: Chemistry, Pharmaceutical; Cocrystals; Crystallization; Crystallography, X-Ray; Drug Compounding; extrusion; Hot melt extrusion; Ibuprofen; Ibuprofen - chemistry; least squares; Least-Squares Analysis; mixing; near-infrared spectroscopy; Niacinamide - chemistry; Nicotinamide; NIR spectroscopy; PAT; Powder Diffraction; Process analytics; process monitoring; QbD; solvents; Solvents - chemistry; Spectroscopy, Near-Infrared; Technology, Pharmaceutical - methods; Temperature; Time Factors; Twin screw extrusion; X-ray diffraction; PAT; QbD; Process analytics; Ibuprofen; Hot melt extrusion; Twin screw extrusion; Nicotinamide; Cocrystals; NIR spectroscopy
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2011.12.033

The purpose of this work was to explore NIR spectroscopy as a PAT tool to monitor the formation of ibuprofen and nicotinamide cocrystals during extrusion based solvent free continuous cocrystallization (SFCC). Drug and co-former were gravimetrically fed into a heated co-rotating twin screw extruder to form cocrystals. Real-time process monitoring was performed using a high temperature NIR probe in the extruder die to assess cocrystal content and subsequently compared to off-line powder X-ray diffraction measurements. The effect of processing variables, such as temperature and mixing intensity, on the extent of cocrystal formation was investigated. NIR spectroscopy was sensitive to cocrystal formation with the appearance of new peaks and peak shifts, particularly in the 4800–5200cm−1 wave-number region. PXRD confirmed an increased conversion of the mixture into cocrystal with increase in barrel temperature and screw mixing intensity. A decrease in screw rotation speed also provided improved cocrystal yield due to the material experiencing longer residence times within the process. A partial least squares analysis in this region of NIR spectrum correlated well with PXRD data, providing a best fit with cocrystal conversion when a limited range of process conditions were considered, for example a single set temperature. The study suggests that NIR spectroscopy could be used to monitor cocrystal purity on an industrial scale using this continuous, solvent-free process.