Hansen Jerome, Kleinebudde Peter
Institute of Pharmaceutics and Biopharmaceutics, Heinrich Heine Universitaet Duesseldorf, Universitaetsstrasse 1, 40225, Duesseldorf, Germany.
Pharm Res. 2022 Dec;39(12):3123-3136. doi: 10.1007/s11095-022-03212-2. Epub 2022 Mar 9.
Quasi-emulsion solvent-diffusion crystallization (QESD) is a type of spherical crystallization which can be used as a particle design method to improve the flowability and micromeritic properties of drugs or excipients. Spherical particles are generated by dispersing a solvent phase in an antisolvent so that a transient emulsion is formed. Within the droplets the material can crystallize and agglomerate into spherical, hollow particles. Surfactants, such as surface-active polymers like hypromellose, are often required to stabilize the quasi-emulsion. To gain further understanding for the role of the stabilizer, a new screening-method was developed which compared different surface active polymers in solution at similar dynamic viscosities rather than at a set concentration. The dynamic viscosities of a low-viscosity grade hypromellose solution used in the previous publications describing the QESD crystallization of metformin hydrochloride by the authors was used as a target value. QESD crystallizations of metformin hydrochloride (MF) and celecoxib showed that the type of stabilizer and whether it is dissolved in the solvent or antisolvent has an effect on the agglomerates. For MF, the type of hypromellose used can have a significant influence on the properties of the agglomerates. More polymers could be used to stabilize the transient emulsion of celecoxib than previously found in literature. Furthermore, QESD crystallizations seem to be more robust when the stabilizer is dissolved in the antisolvent, however this can lead to a reduced drug load of the agglomerates.
准乳液溶剂扩散结晶法（QESD）是一种球形结晶方法，可作为一种颗粒设计方法来改善药物或辅料的流动性和粉体学性质。通过将溶剂相分散在反溶剂中形成瞬时乳液，从而生成球形颗粒。在液滴内部，物质可以结晶并聚集成球形空心颗粒。通常需要表面活性剂，如羟丙甲纤维素等表面活性聚合物来稳定准乳液。为了进一步了解稳定剂的作用，开发了一种新的筛选方法，该方法比较了具有相似动态粘度而非设定浓度的溶液中的不同表面活性聚合物。作者在之前描述盐酸二甲双胍QESD结晶的出版物中使用的低粘度级羟丙甲纤维素溶液的动态粘度被用作目标值。盐酸二甲双胍（MF）和塞来昔布的QESD结晶表明，稳定剂的类型以及它是溶解在溶剂中还是反溶剂中会对聚集体产生影响。对于MF，所用羟丙甲纤维素的类型会对聚集体的性质产生显著影响。可用于稳定塞来昔布瞬时乳液的聚合物比文献中先前发现的更多。此外，当稳定剂溶解在反溶剂中时，QESD结晶似乎更稳定，然而这可能会导致聚集体的载药量降低。
