Design of Spherical Crystallization for Drugs Based on Thermal-Induced Liquid–Liquid Phase Separation: Case Studies of Water-Insoluble Drugs

Abstract

Spherical crystallization of water-insoluble drugs was investigated based on thermal-induced liquid–liquid phase separation (TILLPS) without the use of organic solvent. The phase diagram of the drug in water was constructed first, consisting of solid–liquid and liquid–liquid equilibrium regions. Within the liquid–liquid phase region, droplets of the solute-rich phase were formed and dispersed under appropriate agitation in the solvent-rich phase. After being stabilized by a surfactant, the solute-rich droplets can be converted to monodisperse spherical particles by performing quench cooling crystallization where the drug is crystallized within the confinement of the droplets. Furthermore, the influences of the oil droplets on the size of the resulting crystals were investigated, demonstrating that a decrease of the oil droplet size, controlled by agitation speed, would result in the decline of the product size. l-Menthol and ibuprofen products with a spherical shape and a yield of more than 95% were prepared successfully using the above method, revealing the application prospect of TILLPS in the drug spherical crystallization and it gives important guidance for the preparation of spherical particles of water-insoluble drugs.

The role of ionic vs. non-ionic excipients in APIs-based eutectic systems

“…It is not then expected to observe strong interactions in the binary mixtures, which are very close to those present in the pure compounds as the structural features and functional groups in both are quite similar. This has been also observed before for mixtures of menthol and monocarboxylic acids (Abranches et al, 2020;Alhadid et al, 2020;Martins et al, 2018;Verma and Banerjee, 2018), lidocaine (Corvis et al, 2010;Kang et al, 2000), ibuprofen (Kang et al, 2004;Stott et al, 1998), alcohols and hydrocarbons (Okuniewski et al, 2017(Okuniewski et al, , 2016, or ubiquinone (Sun et al, 2019). Regarding the COSMO-RS predictions, this tool was able to successfully describe the SLE of the mixtures of coumarin + APIs with an average absolute deviation between experimental and predicted temperatures by COSMO-RS of 4.3 ± 2.9 K.…”

Oiling‐Out Crystallization of Beta‐Alanine on Solid Surfaces Controlled by Solvent Exchange

“…Droplet formation from oiling‐out may be used for obtaining different crystal shapes, [ 18–20 ] producing spherical crystals, [ 21,22 ] or separation of fatty acids from the organic phase. [ 23 ] The oiling‐out crystallization can induce different morphologies of crystals, including spherical particles [ 21,24,25 ] and porous particles. [ 26 ] On the other hand, oiling‐out crystallization is often viewed as undesirable because droplets may degrade the quality crystals from higher impurities and reduce the yield of the products due to the loss of the desired compounds to the droplets.…”

Design of Spherical Crystallization of Active Pharmaceutical Ingredients via a Highly Efficient Strategy: From Screening to Preparation

“…This discovery was consistent with many LLPS cases. For instance, the groups of Mazzotti and Gong found that another water-insoluble API, ibuprofen, could also induce LLPS in water. , Li et al studied the LLPS of erythromycin ethylsuccinate (EES) in tetrahydrofuran (THF)–water, where the solubility of EES in THF was much higher than that in water . It was possible to observe the LLPS of butylparaben in the binary solvents of a good solvent (ethanol) and a poor solvent (water) .…”

“…Exploration for cheaper and cleaner production technologies with safer and more efficient solutions is a significant and urgent challenge in the pharmaceutical industry. , Recently, we discovered that spherical particles can be prepared in pure water based on LLPS . Under agitation, one of the two liquid phases acts as the dispersed oil droplets, providing a medium for spherical agglomeration.…”