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Impact of Intermolecular Interactions, Dimeric Structures on the Glass Forming Ability of Naproxen, and a Series of Its Derivatives
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-08-29 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00725
Aldona Minecka 1 , Ewa Kaminska 1 , Magdalena Tarnacka 2, 3 , Iwona Grudzka-Flak 2, 3 , Mariola Bartoszek 4 , Kamila Wolnica 2, 3 , Mateusz Dulski 2, 5 , Kamil Kaminski 2, 3 , Marian Paluch 2, 3
Affiliation  

In this article, thermal properties, molecular dynamics, crystallization kinetics, and intermolecular interactions in pure naproxen (NAP), its amide (NH2–NAP), and four esters (methyl, Met-NAP; isopropyl, Iso-NAP; hexyl, Hex-NAP; and benzyl, Ben-NAP) have been investigated using differential scanning calorimetry as well as broadband dielectric and Fourier transform infrared spectroscopies. We found that the modification of the NAP molecule by substituting a hydrogen atom from the hydroxyl group strongly inhibits the crystallization tendency of this active pharmaceutical ingredient (API) and simultaneously increases its glass forming ability (GFA). In this context, it is worthwhile to stress that pure naproxen and its amide crystallized very quickly, regardless of the cooling rate. Therefore, these compounds cannot be classified as good glass-formers. On the other hand, ester derivatives of API can be easily vitrified. Moreover, dielectric measurements revealed that with an increasing molecular weight of the substituent, the rate of crystallization process slows down significantly. Consequently, Ben-NAP was characterized by the highest GFA among all investigated API esters. Comprehensive FTIR studies clearly indicated that the strong tendency to create dimeric structures in the nonmodified NAP and NH2–NAP is responsible for their enhanced crystallization. At the first sight, our results stay in contrast to most literature data, showing that H-bonds favor the glass formation ability. However, this effect is usually observed for the materials, which form extensive multidirectional hydrogen bonds and associates. In NAP and NH2–NAP, the situation is much different, since both compounds exist mainly as dimers. Therefore, one can postulate that specific intermolecular interactions are an important parameter determining the GFA of different materials, including APIs.

中文翻译:

分子间相互作用,二聚体结构对萘普生及其一系列衍生物的玻璃形成能力的影响

本文探讨了纯萘普生(NAP)及其酰胺(NH 2-NAP)和四种酯(甲基,Met-NAP;异丙基,Iso-NAP;己基,Hex-NAP;苄基,Ben-NAP)已使用差示扫描量热法以及宽带电介质和傅里叶变换红外光谱法进行了研究。 。我们发现通过从羟基取代氢原子对NAP分子进行的修饰强烈抑制了该活性药物成分(API)的结晶趋势,同时提高了其玻璃形成能力(GFA)。在这种情况下,值得强调的是,不管冷却速率如何,纯萘普生及其酰胺都非常快地结晶。因此,这些化合物不能归类为良好的玻璃形成剂。另一方面,API的酯衍生物可以容易地玻璃化。而且,介电测量表明,随着取代基分子量的增加,结晶过程的速度大大降低。因此,Ben-NAP的特征是在所有研究的API酯中GFA最高。全面的FTIR研究清楚表明,在未修饰的NAP和NH中形成二聚体结构的强烈趋势2 –NAP负责增强结晶。乍一看,我们的结果与大多数文献数据相反,表明氢键有利于玻璃的形成能力。然而,通常对于形成广泛的多方向氢键和缔合体的材料观察到这种效果。在NAP和NH 2 -NAP中,情况大不相同,因为这两种化合物主要以二聚体形式存在。因此,可以假定特定的分子间相互作用是确定包括API在内的不同材料的GFA的重要参数。
更新日期:2018-08-29
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