Spherical Crystal Design: Preparation Strategy And Prediction Of Anti-caking Performance

Spherical crystals are special crystalline products with enhanced performance,unique functions and extra values.It has become a hot spot in the high-tech fields of pharmaceutical,food,daily chemical,fertilizer,and military industries.However,it is still challenging for preparing the given crystals into spheres with the desired performance.To solve this issue,three universal strategies were developed for designing spherical crystallization processes,i.e.spherical agglomeration,spherulitic growth and multi-crystal cluster crystallization.A quantitative prediction method for the anti-caking performance of spherical crystals was proposed.In this way,the quantitative relationship among the key process parameters of crystallization,the morphology of spheres,and the anti-caking performance can be confirmed,which achieves the rational design and preparation of spherical crystals.Strategies for selecting ternary solvent systems and process control of spherical agglomeration were developed.The strategy for selecting solvent systems emphasizes wettability as the key parameter which is quantitatively estimated by the Lifshitz-van der Waals acid-base approach.Valid systems therefore are selected in the first place while invalid ones are removed effectively according to the wettability difference.With the aid of the strategy,4 valid solvent systems for cefotaxime sodium from 720 solvent combinations and 24 valid ones for benzoic acid from 2184 solvent combinations were selected successfully without missing the reported systems.The strategy for process control is designed with the independent size space and shape space so that the quantitative relationship between process parameters and morphology of spheres can be established.This strategy successfully tuned the spherical agglomerate size of benzoic acid from 1000 ?m to 5000 ?m avoiding wide size distribution and fragments by the conventional strategy.A strategy for designing a spherulitic growth process was developed.It predicts the critical supersaturation of spherulitic growth with the rough growth model.Based on the strategy,spherulites of clopidogrel hydrogen sulfate(Form I)and fructose were successfully prepared.In the case study of clopidogrel hydrogen sulfate,it indicated the theoretical drawbacks of the single solvent system designed by the trial-and-error method in literature,and the mixture system designed by the strategy achieved the targets of spherical shape,no crystal form transformation,and no jelly-like phase.A novel spherical crystallization method was developed.According to crystal clusters nucleation and growth on crystal surfaces and attrition effect of agitation,it prepares spherical crystals in a single solvent(water)system under a common condition of supersaturation.Its strategy was developed with a multi-crystal cluster model and agglomerate size model.Spherical crystals of potassium chloride,sodium chloride and cesium iodide were prepared successfully by the strategy.A quantitative prediction method for the anti-caking performance of crystals was developed.It considers crystal size and shape by developing a modified model for predicting single bridge growth and the multiple spheres method.The nonhomogeneous bridge networks are then constructed based on the discrete element method simulation.The outputs include the time and location dependent mechanical,morphological and statistical indices.The spherical crystal of potassium chloride with good anti-caking performance was designed by this method and prepared by the multicrystal cluster strategy.