• Kalliomaki, Katriina
• Rantanen, Jukka
• Munk, Tommy
• Tenhu, Heikki
• Rades, Thomas
• Hietala, Sami
• Baldursdottir, Stefania
• Nuopponen, Markus
• Kapp, Sebastian

Abstract

The use of additives in crystallization of pharmaceuticals is known to influence the particulate properties critically affecting down-stream processing and the final product performance.Desired functionality can be build into these materials, e.g. via optimized synthesis of a polymeric additive.One such additive is the thermosensitive polymer, poly(N-isopropyl acrylamide) (PNIPAM).The use of PNIPAM as a crystallization additive provides a possibility to affect viscosity in separation temperatures and nucleation and growth rates in higher temperatures.In this study, novel PNIPAM derivatives consisting of both isotactic-rich and atactic blocks were used as additives in evaporative crystallization of a model compound, nitrofurantoin (NF).Special attention was paid to possible interactions between NF and PNIPAM and the aggregation state of PNIPAM as a function of temperature and solvent composition.Optical light microscopy, Raman and FTIR spectroscopy were used to investigate the structure of the NF crystals and possible interaction with PNIPAM.A drastic change in the growth mechanism of nitrofurantoin crystals as monohydrate form II (NFMH-II) was observed in the presence of PNIPAM; the morphology of crystals changed from needle to dendritic shape.Additionally, the amphiphilic nature of PNIPAM increased the solubility of nitrofurantoin in water.PNIPAMs with varying molecular weights and stereoregularities resulted in similar changes in the crystal habit of the drug regardless of whether the polymer was aggregated or not.However, with increased additive concentration slower nucleation and growth rates of the crystals were observed.Heating of the crystallization medium resulted in phase separation of the PNIPAM.The phase separation had an influence on the achieved crystal morphology resulting in fewer, visually larger and more irregular dendritic crystals.No proof of hydrogen bond formation between PNIPAM and NF was observed, and the suggested mechanism for the observed dendritic morphology is related to the steric hindrance phenomenon.PNIPAM can be used as a crystallization additive with an obvious effect on the growth of NF crystals.The structural design of PNIPAM and related viscosity changes as a function of temperature can be used to optimize nucleation, growth and separation of crystals from the crystallization medium.[on SciFinder (R)]

Topics

• impedance spectroscopy
• morphology
• compound
• polymer
• phase
• viscosity
• Hydrogen
• molecular weight
• crystallization
• microscopy