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Quantifying Molecular Mixing and Heterogeneity in Pharmaceutical Dispersions at Sub-100 nm Resolution by Spin Diffusion NMR.
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2020-07-31 , DOI: 10.1021/acs.molpharmaceut.0c00592
Pu Duan 1 , Matthew S Lamm 2 , Fengyuan Yang 2 , Wei Xu 2 , Daniel Skomski 2 , Yongchao Su 2, 3, 4 , Klaus Schmidt-Rohr 1
Affiliation  

Molecular miscibility and homogeneity of amorphous solid dispersions (ASDs) are critical attributes that impact physicochemical stability, bioavailability, and processability. Observation of a single glass transition is utilized as a criterion for good mixing of drug substance and polymeric components but can be misleading and cannot quantitatively analyze the domain size at high resolution. While imaging techniques, on the other hand, can characterize phase separation on the particle surface at the nanometer scale, they often require customized sample preparation and handling. Moreover, a mixed system is not necessarily homogeneous. Compared to the numerous studies that have evaluated the mixing of drug substance and polymer in ASDs, inhomogeneity in the phase compositions has remained significantly underexplored. To overcome the analytical challenge, we have developed a 1H spin diffusion NMR technique to quantify molecular mixing of bulk ASDs at sub-100 nm resolution. It combines relaxation filtering (T2H and T) that leaves the active pharmaceutical ingredient (API) as the main source of 1H magnetization at the start of spin diffusion to the polymer matrix. A spray-dried nifedipine–poly(vinylpyrrolidone) (Nif–PVP) ASD at a 5 wt % drug loading was a homogeneous reference system that exhibited equilibration of magnetization transfer from API to polymer within a short spin diffusion time of ∼3 ms. While fast initial magnetization transfer proving mixing on the 1 nm scale was also observed in Nif–PVP ASDs prepared by hot-melt extrusion (HME) at 186 °C at a 40 wt % drug loading, incomplete equilibration of peak intensities documented inhomogeneity on the ≥30 nm scale. The nonuniformity was confirmed by the partial inversion of the Nif magnetization in the filter that resulted in an even more pronounced deviation from equilibration and by 1H–13C heteronuclear correlation (HETCOR) NMR. It is consistent with the observed differential 1H spin–lattice relaxation of Nif and PVP as well as a domain structure on the 20 nm scale observed in atomic force microscopy (AFM) images. The incomplete equilibration and differential relaxation were consistently reproduced in a model of two mixed phases of different compositions, e.g., 40 wt % of the ASD with a 15 wt % drug loading and the remaining 60 wt % with a 56 wt % drug loading. Hot-melt extrusion produced more inhomogeneous samples than spray drying for the samples examined in our study. To the best of our knowledge, this spin diffusion NMR method provides currently the highest-resolution quantification of inhomogeneous molecular mixing and phase composition in bulk samples of pharmaceutical dispersions produced with equipment, procedures, and drug loadings that are relevant to industrial drug development.

中文翻译:

通过自旋扩散NMR定量分析低于100 nm分辨率的药物分散体中的分子混合和非均质性。

非晶态固体分散体(ASD)的分子可混溶性和均质性是影响理化稳定性,生物利用度和可加工性的关键属性。单一玻璃化转变的观察被用作药物和聚合物成分良好混合的标准,但可能会产生误导,并且无法以高分辨率定量分析畴尺寸。另一方面,成像技术可以表征纳米级颗粒表面的相分离,但它们通常需要定制的样品制备和处理方法。而且,混合系统不一定是均匀的。与评估ASD中原料药和聚合物混合的众多研究相比,相组成的不均匀性仍未得到充分研究。1 H自旋扩散NMR技术可量化低于100 nm分辨率的大量ASD的分子混合。它结合松弛滤波(Ť 2HŤ ),该叶片将活性药物成分(API),其的主要来源1自旋扩散开始到聚合物基体的H磁化。载药量为5 wt%的喷雾干燥硝苯地平-聚(乙烯基吡咯烷酮)(Nif-PVP)ASD是一种均相参比系统,在约3 ms的短时间自旋扩散时间内,显示出从API到聚合物的磁化转移达到平衡。尽管通过热熔挤出(HME)在186°C和40 wt%的药物负载下制备的Nif-PVP ASD也观察到了快速的初始磁化传递证明混合,但在1纳米尺度上混合时,峰强度的不平衡证明了不均匀性。 ≥30nm标度。过滤器中Nif磁化强度的部分反转证实了这种不均匀性,这导致了更加明显的平衡偏差和1 H– 13C异核相关(HETCOR)NMR。与观察到的差异1一致Nif和PVP的H自旋晶格弛豫以及在原子力显微镜(AFM)图像中观察到的20 nm尺度的畴结构。在具有不同组成的两个混合相的模型中一致地再现了不完全的平衡和差异松弛,例如,40wt%的ASD具有15wt%的药物负载,其余的60wt%具有56wt%的药物负载。对于我们研究中的样品,热熔挤出比喷雾干燥产生的样品更加不均匀。据我们所知,这种自旋扩散NMR方法目前提供了最高分辨率的定量方法,用于定量分析与工业药物开发相关的设备,程序和载药量而制得的药物分散体样品中的不均匀分子混合和相组成。
更新日期:2020-09-09
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