Instituto de Investigaciones en Tecnología Química (INTEQUI, UNSL-CONICET), Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis (UNSL), Almirante Brown 1455, D5700HGC, San Luis, Argentina.
São Carlos Institute of Physics, Avenida Trabalhador São-carlense 400, Parque Arnold Schimidt, CEP 13566-590, São Carlos, São Paulo, Brazil.
Int J Pharm. 2023 Jul 25;642:123053. doi: 10.1016/j.ijpharm.2023.123053. Epub 2023 May 23.
Famotidine (FMT) is an orally administered histamine H2-receptor blocker with limited bioavailability since it exhibits low solubility and low permeability. In addition, the recent withdrawal of ranitidine from the market, makes famotidine an interesting candidate to obtain solid forms with improved pharmacokinetic performance. In this work, crystal engineering concepts and the co-amorphous formation strategy were applied to obtain two novel solids. Crystalline famotidine malate (FMT-MT) and a vitreous phase (FMT-MTa) were prepared by solvent evaporation and mechanochemical synthesis, respectively. FMT-MT (monoclinic, S.G. P2/n) crystallizes with one FMT and one co-former molecules in the asymmetric unit forming a (R228) structural motif. FMT-MT resulted in a salt by proton transfer from one malic carboxylic group to the guanidine moiety of FMT. The three-dimensional packing is described as undulating layers of alternated FMT and MT running along the a direction. FMT-MTa shows the inherent features of amorphous phases according to powder X-ray diffraction and DSC analysis. The higher physical stability was found for amorphous samples maintained at 4 °C up to 60 days. The solubility assays in water, indicate that FMT-MT and FMT-MTa are 2.02 and 2.68-fold more soluble than the marketed polymorph, whereas similar values were obtained in simulated gastric fluid.
法莫替丁（FMT）是一种口服组胺 H2 受体阻滞剂，由于其溶解度低和渗透性低，生物利用度有限。此外，雷尼替丁最近从市场上撤出，使得法莫替丁成为获得具有改善药代动力学性能的固体形式的有趣候选物。在这项工作中，应用晶体工程概念和共无定形形成策略获得了两种新型固体。通过溶剂蒸发和机械化学合成分别制备了结晶法莫替丁马来酸盐（FMT-MT）和玻璃相（FMT-MTa）。FMT-MT（单斜晶系，S.G. P2/n）在不对称单元中结晶有一个 FMT 和一个共晶分子，形成（R228）结构基序。FMT-MT 通过从一个马来酸的羧酸基团向 FMT 的胍部分转移质子而形成盐。三维堆积被描述为交替的 FMT 和 MT 层沿着 a 方向波动。FMT-MTa 根据粉末 X 射线衍射和 DSC 分析显示出无定形相的固有特征。在 4°C 下保持 60 天的无定形样品具有更高的物理稳定性。在水中的溶解度测定表明，FMT-MT 和 FMT-MTa 的溶解度比市售多晶型物分别提高了 2.02 倍和 2.68 倍，而在模拟胃液中得到了相似的值。
