Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Eur J Pharm Biopharm. 2013 Nov;85(3 Pt B):942-51. doi: 10.1016/j.ejpb.2013.09.002. Epub 2013 Sep 27.
Amorphous forms of furosemide sodium salt and furosemide free acid were prepared by spray drying. For the preparation of the amorphous free acid, methanol was utilised as the solvent, whereas the amorphous sodium salt was formed from a sodium hydroxide-containing aqueous solvent in equimolar amounts of NaOH and furosemide. Information about the structural differences between the two amorphous forms was obtained by Fourier Transform Infrared Spectroscopy (FTIR), and glass transition temperature (Tg) was determined using Differential Scanning Calorimetry (DSC). The stability and devitrification tendency of the two amorphous forms were investigated by X-ray Powder Diffraction (XRPD). The apparent solubility of the two amorphous forms and the crystalline free acid form of furosemide in various gastric and intestinal stimulated media was determined. Moreover, the dissolution characteristics of the two amorphous forms and of crystalline free acid were investigated. FTIR confirmed molecular differences between the amorphous free acid and salt. The amorphous salt showed a Tg of 101.2 °C, whereas the Tg for the amorphous free acid was found to be 61.8 °C. The amorphous free acid was physically stable for 4 days at 22 °C and 33% relative humidity (RH), while the amorphous salt exhibited physical stability for 291 days at the same storage conditions. When storing the amorphous forms at 40 °C and 75% RH both forms converted to crystalline forms after 2 days. The apparent solubility of the amorphous salt form was higher than that of both amorphous and crystalline free acid in all media studied. All three forms of furosemide exhibited a greater solubility in the presence of biorelevant media as compared to buffer, however, an overall trend for a further increase in solubility in relation to an increase in media surfactant concentration was not seen. The amorphous salt demonstrated an 8- and 20-fold higher intrinsic dissolution rate (IDR) when compared to amorphous and crystalline free acid, respectively. The promising properties of the amorphous salt in vitro were further evaluated in an in vivo study, where solid dosage forms of the amorphous salt, amorphous and crystalline free acid and a solution of furosemide were administered orally to rats. The amorphous salt exhibited a significantly faster Tmax compared to the solution and amorphous and crystalline free acid. Cmax for the solution was significantly higher compared to the three furosemide forms. No significant difference was found in AUC and absolute bioavailability for the solution, crystalline free acid and the two amorphous forms of furosemide. It can be concluded that the higher IDR and higher apparent solubility of the amorphous salt resulted in a faster Tmax compared to the amorphous and crystalline free acid.
通过喷雾干燥法制备了呋塞米钠盐和游离酸的无定形形式。为了制备无定形游离酸，甲醇被用作溶剂，而无定形的氢氧化钠盐则是由含有氢氧化钠的水溶液以等摩尔量的氢氧化钠和呋塞米形成的。通过傅里叶变换红外光谱（FTIR）获得了两种无定形形式之间结构差异的信息，并通过差示扫描量热法（DSC）确定了玻璃化转变温度（Tg）。通过 X 射线粉末衍射（XRPD）研究了两种无定形形式的稳定性和析晶趋势。测定了两种无定形形式和呋塞米游离酸的结晶形式在各种胃和肠刺激介质中的表观溶解度。此外，还研究了两种无定形形式和结晶游离酸的溶解特性。FTIR 证实了无定形游离酸和盐之间的分子差异。无定形盐的 Tg 为 101.2°C，而无定形游离酸的 Tg 为 61.8°C。无定形游离酸在 22°C 和 33%相对湿度（RH）下稳定 4 天，而无定形盐在相同的储存条件下稳定 291 天。当在 40°C 和 75%RH 下储存两种无定形形式时，两种形式在 2 天后均转化为结晶形式。无定形盐的表观溶解度高于所有研究介质中的无定形和结晶游离酸。与缓冲液相比，所有三种呋塞米形式在存在生物相关介质时都表现出更高的溶解度，然而，并没有看到随着介质表面活性剂浓度的增加而溶解度进一步增加的总体趋势。与无定形游离酸相比，无定形盐的固有溶出速率（IDR）分别提高了 8 倍和 20 倍。无定形盐在体外的良好性质在体内研究中进一步得到了评估，其中无定形盐、无定形和结晶游离酸的固体剂型以及呋塞米溶液被给予大鼠口服。无定形盐与溶液和无定形及结晶游离酸相比，Tmax 明显更快。溶液的 Cmax 明显高于三种呋塞米形式。溶液、结晶游离酸和两种无定形呋塞米形式的 AUC 和绝对生物利用度没有显著差异。可以得出结论，无定形盐的更高 IDR 和更高表观溶解度导致 Tmax 比无定形和结晶游离酸更快。
