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Dehydration of nitrofurantoin monohydrate during melt extrusion Dhara Raijada, Lærke Arnfast, Andrew D. Bond, Johanna Aho, Johan Bøtker, Niklas Sandler, and Jukka Rantanen Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 30 May 2017 Downloaded from http://pubs.acs.org on May 31, 2017
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Dehydration of nitrofurantoin monohydrate during melt extrusion Dhara Raijada#,†,‡, Lærke Arnfast#,‡ , Andrew D. Bond¤, Johanna Aho#, Johan Bøtker#, Niklas Sandler§, Jukka Rantanen#,*:
[email protected] # Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2100, Denmark § Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Abo Akademi University, FI-20520 Turku, Finland ¤ Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK ‡These authors contributed equally
ABSTRACT. Hot melt extrusion is important for the development of advanced pharmaceutical dosage forms. In this study, the dehydration of nitrofurantoin monohydrate during melt extrusion below the expected dehydration temperature has been investigated. The influence of process time, temperature and drug-polymer ratio on the solid form of the drug compound were studied on drug-polymer physical mixtures with thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), rheometry, and hot-stage microscopy and compared with data generated from the extruded products. Extensive dehydration of
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nitrofurantoin monohydrate was surprisingly observed at extrusion temperatures as low as 70 °C in contrast with TGA and DSC analysis of the pure drug indicating dehydration onset at around 90 °C. This was related to shear induced solution-mediated transformation, where nitrofurantoin dissolved into the molten polymer and rapidly recrystallized as nitrofurantoin anhydrate, as well as simultaneous solid-solid transformation. In conclusion, these types of complex interactions may cause unexpected solid form transformations of the drug in a melt-based drug product and therefore need to be considered during the drug development process.
INTRODUCTION Hot melt extrusion is an increasingly important technique in the production of advanced dosage forms1, partly owing to its superior potential for integration into a continuous manufacturing line with limited powder handling steps2, partly to the diversity in downstream processing options enabling the production of granules, pellets, tablets, films, implantable rods– in essence, by cutting, molding or calendaring the melt3-5. Hot melt extrusion involves the mixing of active compound and excipients (mainly thermoplastic polymers) under thermal and mechanical stress followed by extrusion through a die, often with the aim of melting or dispersing the drug in the polymeric excipient to obtain a product in which the active compound is in an amorphous state6, 7, although other solid form transformations, intended or unintended, may occur during hot melt processing
8-10
. Hot melt extrusion is also importantly linked to the
manufacturing of innovative pharmaceutical products, since several additive manufacturingbased solutions involve melt extrusion, followed by, e.g., Fused Deposition Modeling (FDM) 3D printing11, 12. The solid form behaviour in this challenging processing environment is not yet fully understood and the combination of molten polymer and thermal/mechanical stress can cause some unwanted surprises during the drug development process13-16.
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More than one third of the pharmaceutical compounds are known to exist as hydrates17. It is well known that hydrate forms can exhibit different physicochemical properties as compared to the corresponding anhydrate forms. Hydrates can be generated unintentionally during any stage of a product life cycle. In some cases, a hydrate form may be the only stable form under ambient conditions18-20 and therefore, it is often the preferred option as a starting material for formulation development. Nitrofurantoin monohydrate is a special compound with a feature of having at least two different monohydrate structures (polymorphic hydrate, NF monohydrate forms I and II), and one of these monohydrate forms (form II) has an unconventionally high dehydration temperature, 120 °C21, 22. These two forms can be isolated by controlling the water activity and evaporation rate during evaporative crystallization23-25. A hydrate form of a given active compound may behave differently in the presence of a molten polymer under hot melt extrusion process conditions, compared to the corresponding anhydrate form. Additionally, the commonly accepted rules utilized during traditional downstream processing of pharmaceuticals are not readily applicable in the melt extrusion environment. Mechanistic description of solutionmediated transformations (SMTs) occurring during aqueous processing, e.g., hydrate formation during wet granulation, has been well-reported in the literature26,
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. The reverse phase
transformation, namely dehydration of a given hydrate compound using gas-liquid-solid operations (viz. fluid bed drying) involves fundamentally different heat transfer mechanisms when compared to a situation where the compound of interest is exposed to hot molten polymer. This behaviour might prove to be either beneficial or detrimental to the hot melt processed formulation. Therefore, it is important to investigate the behaviour of hydrates during the hot melt extrusion process and to provide mechanistic insight into potential phase changes affecting the performance of the final medicinal product.
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When a hydrate of a given compound is selected as starting material for hot melt extrusion, various scenarios can be assumed; they might undergo dehydration leading to liberation of water molecules which might act as a plasticizer of the polymer, and/or they might create entrapped bubbles in the extruded product leading to a less stable product with varying dissolution profiles. When the solid form of a drug has a different interaction potential with different polymers the drug release might get affected based on their interaction potential with the polymers, e.g. phase transformations in carbamazepine solid forms are known to be affected by the interaction potential with different polymers/excipients (or even with the different components in the dissolution media)28-30. Additionally, the amount of drug load in polymers is known to affect the quality of the extruded product31. In the end, the maximum amount of drug load for generation of good quality extruded product might be dependent on the properties of the initial solid form. Also, the solid form of the extruded product can be affected by the amount of drug load (whether below or above the saturation solubility of the drug in polymer). In the present study, nitrofurantoin monohydrate and polyethylene oxide (PEO 100,000) were used as a model drug-polymer system in investigation of hydrate behaviour during hot melt extrusion process. PEO 100,000 was chosen because this polymer can be extruded at low temperatures (
