A Novel Approach to Evaluate Amorphous-to-Crystalline Transformation of Active Pharmaceutical Ingredients in Solid Dispersion Using Time-Domain NMR
A Novel Approach to Evaluate Amorphous-to-Crystalline Transformation of Active Pharmaceutical Ingredients in Solid Dispersion Using Time-Domain NMR
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DOI：
10.1248/cpb.c18-00887
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发表时间：
2019-03-01
影响因子：
1.7
通讯作者：
Onuki, Yoshinori
中科院分区：
文献类型：
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作者：
Okada, Kotaro;Hirai, Daijiro;Onuki, Yoshinori
本研究的目的是证明时域核磁共振(TD-核磁共振)方法在表征含有固体分散体的活性药物成分(API)的结晶状态方面的有效性。本研究以吲哚美辛(IMC)作为难溶原料药的模型。以不同重量比的聚乙烯吡咯烷酮(PVP)为原料制备了IMC固体分散体。首先，我们测量了固体分散体的T-1弛豫行为。结果表明，T-1弛豫时间(T-1)随API含量的增加而变化，非晶态IMC的T-1值比PVP的T-1值长，因此T-1随API含量的增加而增大。接下来，我们尝试在热应力测试过程中监测IMC在固体分散体中的非晶态向晶态的转变。在固体分散体含有90%IMC的情况下，在热应力测试中可以观察到明显的T-1延长。从粉末X射线衍射谱来看，T-1弛豫行为的变化一定是IMC从非晶态向晶态转变的结果。根据这些发现，我们成功地通过T-1弛豫行为的变化来监测IMC从非晶态到晶态的转变。我们的发现使我们得出结论，TD-核磁共振是一种新的方法来评估原料药在固体分散体中的结晶状态。
The aim of this study was to demonstrate the usefulness of the time-domain NMR (TD-NMR) method to characterize the crystalline state of active pharmaceutical ingredients (APIs) containing a solid dispersion. In this study, indomethacin (IMC) was used as a model for poorly water-soluble API. Solid dispersions of IMC were prepared with polyvinylpyrrolidone (PVP) at different weight ratios. First, we measured the T-1 relaxation behavior of solid dispersions. From the result, the T-1 relaxation time (T-1) changed according to the API content; the T-1 tended to increase with increasing API content because the T-1 value of amorphous IMC was longer than that of PVP. Next, we tried to monitor the amorphous-to-crystalline transformation of IMC in the solid dispersion during the thermal stress test. In the case of solid dispersion containing 90% IMC, a clear prolongation of the T-1 could be observed during the thermal stress test. From the powder X-ray diffraction patterns, the change in T-1 relaxation behavior must be caused by the IMC transformation from amorphous to crystalline. From these findings, we were successful in monitoring the IMC amorphous-to crystalline transformation by the changes in T-1 relaxation behavior. Our findings led us to conclude that TD-NMR is a novel approach for the evaluation of crystalline state of APIs in solid dispersions.