A Study of Fasoracetam's Solid State Forms: a Potential Anti-Alzheimer Pharmaceutical
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Accepted Manuscript A study of Fasoracetam's solid state forms: A potential anti-Alzheimer pharmaceutical Bram Harmsen, Koen Robeyns, Johan Wouters, Tom Leyssens PII: S0022-3549(17)30019-9 DOI: 10.1016/j.xphs.2017.01.016 Reference: XPHS 624 To appear in: Journal of Pharmaceutical Sciences Received Date: 21 September 2016 Revised Date: 21 December 2016 Accepted Date: 11 January 2017 Please cite this article as: Harmsen B, Robeyns K, Wouters J, Leyssens T, A study of Fasoracetam's solid state forms: A potential anti-Alzheimer pharmaceutical, Journal of Pharmaceutical Sciences (2017), doi: 10.1016/j.xphs.2017.01.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT 1 A study of Fasoracetam's solid state forms: A potential anti-Alzheimer 2 pharmaceutical 3 Bram Harmsen†, Koen Robeyns†, Johan Wouters‡ ,Tom Leyssens†* 4 †: Institute of Condensed Matter and Nanosciences, Université Catholique de Louvain, Louvain-la-Neuve, Belgium 5 ‡: Namur Institute for Life Sciences (Narilis), UNamur, Namur, Belgium 6 7 Abstract 8 9 Different solid state forms of the research chemical fasoracetam, which counters the effects of 10 Alzheimer’s disease, have been subjected to a thermal and structural analysis. Single crystals 11 were obtained from solution evaporation and from the melt. Single crystal x-ray analyses of the 12 crystals show the existence of two hydrated and one non-hydrated crystalline form of 13 fasoracetam. Under ambient conditions, the hydrate form I is found to be the most stable form, 14 showing a melting point of 57°C. This low melting p oint, combined with possible water losses 15 could cause problems when formulating the hydrated form and impact the storage conditions of 16 the compound. 17 18 Keywords: Polymorphism, Crystal structure, Thermogravimetric analysis, Calorimetry (DSC), Solvent 19 evaporation, Hydrate, Alzheimer's disease 20 21 1. Introduction 22 23 Fasoracetam (NS-105, 5-oxo-D-prolinepiperidinamide) is part of the racetam family, a drug of 24 the pyrrolidone class and currently considered a research chemical 1. The class is characterized 25 by its nootropic (e.g. piracetam and fasoracetam), stimulating (e.g. oxiracetam) and 26 anticonvulsant (e.g levetiracetam) properties 2–6. Studies have shown promising results in its 27 ability to counter and reverse the effect of AlzheiMANUSCRIPTmer’s disease 7–9. It is a known fact that the 28 nature of a solid state form directly impacts bioavailability 10,11 , solubility 12,13 and other 29 pharmacokinetic parameters, which need to be controlled for maximum dosage effect and 30 consistency. It is therefore important to exercise control over the solid phase form 14,15 . 31 Screening for different solid phases of novel drugs has now become an integral part of the drug 32 development process 16,17 . Additionally, legal instances still consider alternative solid forms as 33 novel, hence a formulation with such a novel form would not infringe an existing patent18 . 34 Besides identifying different solid forms, an understanding of the thermodynamic relationships 35 between these forms is also recommended, to avoid future issues related to phase 36 transformations, as illustrated by the Ritonavir and Rotigotine cases, where a market withdrawal 37 of the drug occurred due to phase transformations of the API 19,20 . 38 39 Scheme 1: Chemical structure of Fasoracetam 40 Fasoracetam (scheme 1) is a promising research chemical and at ambient conditions available 41 in solid form. However, no crystal structure was yet reported in literature, nor any solid screen 42 performed for thisACCEPTED compound. The chemical structure of Fasoracetam shows two amide 43 functions which commonly take part in hydrogen bonding patterns, as the carbonyl can serve as 44 a hydrogen acceptor, whereas the amide can act as a hydrogen donor. Having multiple 45 hydrogen bonding sites available, this could possibly lead to different packing arrangements. 46 Furthermore, other racetam compounds have already shown a propensity towards the formation 47 of multiple solid state forms 21 . 48 In this contribution, we therefore set out to identify different solid state forms of fasoracetam and 49 describe these from a structural as well as a thermodynamical point of view. We identified a Download English Version: https://daneshyari.com/en/article/8514277 Download Persian Version: https://daneshyari.com/article/8514277 Daneshyari.com.