Ultrasound-assisted and solution-mediated crystallization of valsartan: Controlling phase transformation and crystal morphology

Valsartan (VAL) is a famous drug which is widely used in the treatment of hypertension. It is quite difficult to separate the crystalline VAL with good crystal morphology from solution. In this work, the solution-mediated phase transformation of VAL is studied for efficiently preparing stable crystals. The effects of temperature, solute concentration, seeds and agitation rate on the transition behavior of VAL were investigated. Interestingly, two different amorphous forms and one crystalline form are discovered coexisting in the phase transformation stage. A stable crystalline VAL has been obtained by controlling the phase transformation process. Meanwhile, it is found that fibrous solids appear and then gradually converts into plate-like crystals or spherical particles. In order to regulate the crystal shape and size of VAL, the ultrasound-assisted crystallization with or without additive was studied. The results indicate that ultrasound has significantly accelerated the phase transformation process. The aggregation of particles was suppressed by ultrasound and the average crystal size could become even smaller than 5 mu m. Furthermore, we discovered that some additives including small molecules and polymers exerted influence on particle size distribution. Molecular dynamics simulations were carried out to explore the role of solvent and additive on molecular assembly of VAL, helping understand the mechanism of the above crystallization process. This work highlights new possibilities to facilitate phase transformation and give new insights on the role of ultrasound and additive in regulating the solid form, crystal shape and size.