Quantifying Molecular Mixing and Heterogeneity in Pharmaceutical Dispersions at Sub-100 nm Resolution by Spin Diffusion NMR
Quantifying Molecular Mixing and Heterogeneity in Pharmaceutical Dispersions at Sub-100 nm Resolution by Spin Diffusion NMR
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DOI：
10.1021/acs.molpharmaceut.0c00592
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发表时间：
2020-09-08
影响因子：
4.9
通讯作者：
Schmidt-Rohr, Klaus
中科院分区：
文献类型：
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作者：
Duan, Pu;Lamm, Matthew S.;Schmidt-Rohr, Klaus
非晶态固体分散体(ASD)的分子相容性和均一性是影响其物理化学稳定性、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物质和聚合物组分良好混合的标准，但可能具有误导性，无法在高分辨率下定量分析结构域大小。另一方面，成像技术可以在纳米尺度上表征颗粒表面的相分离，但它们通常需要定制的样品制备和处理。此外，混合系统不一定是同质的。与众多评估ASD中药物物质和聚合物混合的研究相比，相组成的不均质性仍未得到充分研究。为了克服分析挑战，我们开发了一种H-1自旋扩散核磁共振技术来量化低于100 nm分辨率的体相ASD的分子混合。它结合了弛豫滤波(T-2H和T-1 Rho)，使得活性药物成分(API)在自旋扩散开始向聚合物基质时成为H-1磁化的主要来源。硝苯地平-聚(乙烯基吡咯烷酮)喷雾干燥(NIF-PVP)ASD在载药量为5wt%时是一个均匀的参比体系，在大约3ms的短自旋扩散时间内，从API到聚合物的磁化转移是平衡的。虽然在186℃、载药量为40wt%的热熔融挤压(HME)制备的NIF-PVP ASD中也观察到了1 nm尺度上的快速初始磁化转移证明混合，但在>；=30 nm尺度上记录了峰强度的不完全平衡。通过滤光片中NIF磁化强度的部分反转和H-1-C-13异核相关(HETCOR)核磁共振证实了不均匀性，这导致了更明显的偏离平衡。这与观测到的NIF和PVP的H-1自旋晶格差分弛豫以及原子力显微镜(AFM)图像中观察到的20 nm尺度的磁畴结构相一致。在两个不同组成的混合相的模型中一致地再现了不完全平衡和微分松弛，例如，40wt%的ASD具有15wt%的载药量，其余60wt%的ASD具有56wt%的载药量。对于我们研究的样品，热熔融挤压比喷雾干燥产生更多的不均匀样品。据我们所知，这种自旋扩散核磁共振方法提供了目前最高分辨率的不均匀分子混合和药物分散体大样本中的相组成的定量，这些样品是通过与工业药物开发相关的设备、程序和药物负载生产的。
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 H-1 spin diffusion NMR technique to quantify molecular mixing of bulk ASDs at sub-100 nm resolution. It combines relaxation filtering (T-2H and T-1 rho) that leaves the active pharmaceutical ingredient (API) as the main source of H-1 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 similar to 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 degrees 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 H-1-C-13 heteronuclear correlation (HETCOR) NMR. It is consistent with the observed differential H-1 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.