Guner Gulenay, Amjad Ayesha, Berrios Matthew, Kannan Manisha, Bilgili Ecevit
Otto H. York Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA.
Pharmaceutics. 2023 Jan 30;15(2):450. doi: 10.3390/pharmaceutics15020450.
The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on the solution-mediated precipitation from griseofulvin ASDs. Nanoparticle crystals (nanoseeds) were used as a more realistic surrogate for residual crystals compared with conventional micron-sized seeds. ASDs of griseofulvin with Soluplus (Sol), Kollidon VA64 (VA64), and hydroxypropyl methyl cellulose (HPMC) were prepared by spray-drying. Nanoseeds produced by wet media milling were used in the dissolution and desupersaturation experiments. DLS, SEM, XRPD, and DSC were used for characterization. The results from the solvent-shift tests suggest that the drug nanoseeds led to a faster and higher extent of desupersaturation than the as-received micron-sized crystals and that the higher seed loading facilitated desupersaturation. Sol was the only effective nucleation inhibitor; the overall precipitation inhibition capability was ranked: Sol > HPMC > VA64. In the dissolution tests, only the Sol-based ASDs generated significant supersaturation, which decreased upon an increase in the nanoseed loading. This study has demonstrated the importance of using drug nanocrystals in lieu of conventional coarse crystals in desupersaturation and dissolution tests in ASD development.
在溶剂转移（去饱和）和溶解试验中，使用微米级晶种研究了无定形固体分散体（ASD）生产和储存过程中形成的残留药物晶体的影响。本研究考察了晶种大小负载量对灰黄霉素ASD溶液介导沉淀的影响。与传统的微米级晶种相比，纳米颗粒晶体（纳米晶种）被用作残留晶体更现实的替代物。通过喷雾干燥制备了含Solupuls（Sol）、共聚维酮VA64（VA64）和羟丙基甲基纤维素（HPMC）的灰黄霉素ASD。通过湿法介质研磨制备的纳米晶种用于溶解和去饱和实验。使用动态光散射（DLS）、扫描电子显微镜（SEM）、X射线粉末衍射（XRPD）和差示扫描量热法（DSC）进行表征。溶剂转移试验结果表明，药物纳米晶种比原样的微米级晶体导致更快、更高程度的去饱和，并且更高的晶种负载量促进了去饱和。Sol是唯一有效的成核抑制剂；总体沉淀抑制能力排序为：Sol＞HPMC＞VA64。在溶解试验中，只有基于Sol的ASD产生显著的过饱和度，过饱和度随着纳米晶种负载量的增加而降低。本研究证明了在ASD开发的去饱和和溶解试验中，使用药物纳米晶体代替传统粗晶体的重要性。
