Censi Roberta, Rascioni Riccardo, Di Martino Piera
School of Pharmacy, University of Camerino, Italy.
School of Pharmacy, University of Camerino, Italy.
Eur J Pharm Biopharm. 2015 May;92:192-203. doi: 10.1016/j.ejpb.2015.03.014. Epub 2015 Mar 19.
The aim of the present work was to investigate the solid state change of the anhydrous and hydrate solid forms of sodium naproxen under different grinding and environmental conditions. Grinding was carried out manually in a mortar under the following conditions: at room temperature under air atmosphere (Method A), in the presence of liquid nitrogen under air atmosphere (Method B), at room temperature under nitrogen atmosphere (Method C), and in the presence of liquid nitrogen under nitrogen atmosphere (Method D). Among the hydrates, the following forms were used: a dihydrate form (DSN) obtained by exposing the anhydrous form at 55% RH; a dihydrate form (CSN) obtained by crystallizing sodium naproxen from water; the tetrahydrate form (TSN) obtained by exposing the anhydrous form at 75% RH. The metastable monohydrate form (MSN), previously described in the literature, was not used because of its high physical instability. The chemical stability during grinding was firstly assessed and proven by HPLC. Modification of the particle size and shape, and changes in the solid state under different grinding methods were evaluated by scanning electron microscopy, and X-ray powder diffractometry and thermogravimetry, respectively. The study demonstrated the strong influence of starting form, grinding and environmental conditions on particle size, shape and solid state of recovered sodium naproxen forms. In particular, it was demonstrated that in the absence of liquid nitrogen (Methods A and C), either at air or at nitrogen atmosphere, the monohydrate form (MSN) was obtained from any hydrates, meaning that these grinding conditions favored the dehydration of superior hydrates. The grinding process carried out in the presence of liquid nitrogen (Method B) led to further hydration of the starting materials: new hydrate forms were identified as one pentahydrate form and one hexahydrate form. The hydration was caused by the condensation of the atmospheric water on sodium naproxen particles by liquid nitrogen and by the grinding forces that created a close contact between water and drug. The simultaneous disruption of the crystals, occurring during grinding, and their close contact with water molecules promoted the conversion in higher hydrates. Under the Method D, it was possible to highlight a certain tendency to hydration probably due to a rearrangement of water already present into the hydrates, but results were substantially different from Method B. Thus, summarizing, the different SN forms behave differently under different grinding and environmental conditions.
本研究的目的是研究萘普生钠无水和水合物固体形式在不同研磨和环境条件下的固态变化。研磨在研钵中手动进行，条件如下：室温下在空气气氛中（方法A）、在空气气氛中存在液氮的情况下（方法B）、室温下在氮气气氛中（方法C）以及在氮气气氛中存在液氮的情况下（方法D）。在水合物中，使用了以下形式：通过将无水形式暴露在55%相对湿度下获得的二水合物形式（DSN）；通过从水中结晶萘普生钠获得的二水合物形式（CSN）；通过将无水形式暴露在75%相对湿度下获得的四水合物形式（TSN）。文献中先前描述的亚稳单水合物形式（MSN）因其高物理不稳定性而未被使用。研磨过程中的化学稳定性首先通过高效液相色谱法进行评估和验证。通过扫描电子显微镜、X射线粉末衍射法和热重分析法分别评估了不同研磨方法下颗粒尺寸和形状的变化以及固态变化。该研究表明起始形式、研磨和环境条件对回收的萘普生钠形式的颗粒尺寸、形状和固态有强烈影响。特别是，结果表明在没有液氮的情况下（方法A和C），无论是在空气还是氮气气氛中，任何水合物都能得到单水合物形式（MSN），这意味着这些研磨条件有利于高级水合物的脱水。在液氮存在下进行的研磨过程（方法B）导致起始材料进一步水合：新的水合物形式被鉴定为一种五水合物形式和一种六水合物形式。水合是由液氮使大气中的水在萘普生钠颗粒上凝结以及研磨力使水与药物紧密接触引起的。研磨过程中晶体的同时破坏以及它们与水分子的紧密接触促进了向高级水合物的转化。在方法D下，可能由于水合物中已存在的水的重新排列而突出显示出一定的水合趋势，但结果与方法B有很大不同。因此，总的来说，不同的SN形式在不同的研磨和环境条件下表现不同。
