Crystal habit and crystal form are critical elements in determining product properties and functions. In this work, we developed a microfluidic antisolvent crystallization technique to rapidly screen and accurately co...Crystal habit and crystal form are critical elements in determining product properties and functions. In this work, we developed a microfluidic antisolvent crystallization technique to rapidly screen and accurately control the solid form and crystal habit of triphenylmethanol(Ph_(3)COH). This advanced technique separates the primary mixing of solutions from crystal formation(nucleation and growth) by introducing the microfluidic device, avoiding clogging in microchannels to obtain high-quality crystals. The results show that we can achieve controllable preparation of pure 2Ph_(3)COH·DMSO(DMSO solvate), pure Ph_(3)COH(form β), and mixed crystals with different mass ratios. Moreover, the microscale can prompt the DMSO solvate to grow into hexagonal sheet-like and bulk crystals. We can regulate the aspect ratio of hexagonal sheet-like crystals in binary solvents and control the crystal habit of the form β to transition between long needle-like shapes and short hexagonal prisms in DMF-H_(2)O. Meanwhile, we revealed that the solvent ratio, the antisolvent flow rate, and the initial concentration of Ph_(3)COH are the main factors affecting the solid form selectivity and morphology transition. Such a novel method would be considered as a promising technique to be extended to screen and control key crystallization parameters of other substances.展开更多
Drug particles with spherical morphology possess amazing advantages in terms of particle flowability,mechanical properties,drug solubility,and bioavailability.The growth mechanism of drug spherulite is of great import...Drug particles with spherical morphology possess amazing advantages in terms of particle flowability,mechanical properties,drug solubility,and bioavailability.The growth mechanism of drug spherulite is of great importance for the preparation and regulation of spherulites.Herein,ceftriaxone sodium spherulites were fabricated by the antisolvent crystallization method using dropwise addition of ceftriaxone sodium solution to acetone.Online observation of the whole crystallization process combined with electron microscopy technique revealed the spherical growth process from amorphous form to spherulites.As the supersaturation of the crystallization system was adjusted,the ceftriaxone sodium crystals transformed from amorphous form to spherulites.In the process of antisolvent crystallization with acetone as antisolvent,when the theoretical supersaturation degree S was higher than 2.62,the crystallization system tended to appear amorphous form;when S was between 2.57 and 2.62,the amorphous form transformed into clustered spherulites;when S was less than 2.57,the surface of spherulites will be covered with flaky crystal,which transformed into urchin-like type.With the understanding of the spherical growth mechanism,the ceftriaxone sodium spherulites prepared in this research with modified supersaturation control had a low residue of antisolvent acetone,and the flowability was significantly improved.展开更多
The nucleation and growth kinetics of benzoic acid were determined in a population balance model,describing the seeded batch antisolvent crystallization process.The process analytical technologies(PATs)were utilized t...The nucleation and growth kinetics of benzoic acid were determined in a population balance model,describing the seeded batch antisolvent crystallization process.The process analytical technologies(PATs)were utilized to record the evolution of chord length distributions(CLDs)in solid phase together with the concentration decay in liquid phase,which provided essential experimental information for parameter estimation.The model was solved using standard method of moments based on the moments calculated from CLDs and solute concentration.A developed model,incorporating the nucleation and crystal growth as functions of both supersaturation and solvent composition,has been constructed by fitting the zeroth moment of particles and concentration trends.The determined kinetic parameters were consequently validated against a new experiment with a different flow rate,indicating that the developed model predicted crystallization process reasonably well.This work illustrates the strategy in construct a population balance model for further simulation,model-based optimization and control studies of benzoic acid in antisolvent crystallization.展开更多
基金supported by the National Natural Science Foundation of China (No.22278128)。
文摘Crystal habit and crystal form are critical elements in determining product properties and functions. In this work, we developed a microfluidic antisolvent crystallization technique to rapidly screen and accurately control the solid form and crystal habit of triphenylmethanol(Ph_(3)COH). This advanced technique separates the primary mixing of solutions from crystal formation(nucleation and growth) by introducing the microfluidic device, avoiding clogging in microchannels to obtain high-quality crystals. The results show that we can achieve controllable preparation of pure 2Ph_(3)COH·DMSO(DMSO solvate), pure Ph_(3)COH(form β), and mixed crystals with different mass ratios. Moreover, the microscale can prompt the DMSO solvate to grow into hexagonal sheet-like and bulk crystals. We can regulate the aspect ratio of hexagonal sheet-like crystals in binary solvents and control the crystal habit of the form β to transition between long needle-like shapes and short hexagonal prisms in DMF-H_(2)O. Meanwhile, we revealed that the solvent ratio, the antisolvent flow rate, and the initial concentration of Ph_(3)COH are the main factors affecting the solid form selectivity and morphology transition. Such a novel method would be considered as a promising technique to be extended to screen and control key crystallization parameters of other substances.
基金the financial contribution from Central Guidance on Local Science and Technology Development Fund of Liaoning Province(grant No.2023JH6/100100004)National Key Research and Development Program of China(grant No.2021YFC2901300)+3 种基金National Natural Science Foundation of China(grant No.22021005,22378041)Fundamental Research Funds for the Central Universities(grant No.DUT22YG208,DUT22LAB603)Key Research and Development Projects in Shandong Province(grant No.2022CXGC010303)acknowledge the assistance of Dalian University of Technology Instrumental Analysis Center.
文摘Drug particles with spherical morphology possess amazing advantages in terms of particle flowability,mechanical properties,drug solubility,and bioavailability.The growth mechanism of drug spherulite is of great importance for the preparation and regulation of spherulites.Herein,ceftriaxone sodium spherulites were fabricated by the antisolvent crystallization method using dropwise addition of ceftriaxone sodium solution to acetone.Online observation of the whole crystallization process combined with electron microscopy technique revealed the spherical growth process from amorphous form to spherulites.As the supersaturation of the crystallization system was adjusted,the ceftriaxone sodium crystals transformed from amorphous form to spherulites.In the process of antisolvent crystallization with acetone as antisolvent,when the theoretical supersaturation degree S was higher than 2.62,the crystallization system tended to appear amorphous form;when S was between 2.57 and 2.62,the amorphous form transformed into clustered spherulites;when S was less than 2.57,the surface of spherulites will be covered with flaky crystal,which transformed into urchin-like type.With the understanding of the spherical growth mechanism,the ceftriaxone sodium spherulites prepared in this research with modified supersaturation control had a low residue of antisolvent acetone,and the flowability was significantly improved.
基金supported by National Natural Science Foundation of China (grant Nos.22108061,22178054,and 22068002)Natural Science Foundation of Hebei Province (grant No.B2022407009)Academic and Technical Leader Training Program for Major Disciplinessin Jiangxi Province (grant No.20212BCJ23001).
文摘The nucleation and growth kinetics of benzoic acid were determined in a population balance model,describing the seeded batch antisolvent crystallization process.The process analytical technologies(PATs)were utilized to record the evolution of chord length distributions(CLDs)in solid phase together with the concentration decay in liquid phase,which provided essential experimental information for parameter estimation.The model was solved using standard method of moments based on the moments calculated from CLDs and solute concentration.A developed model,incorporating the nucleation and crystal growth as functions of both supersaturation and solvent composition,has been constructed by fitting the zeroth moment of particles and concentration trends.The determined kinetic parameters were consequently validated against a new experiment with a different flow rate,indicating that the developed model predicted crystallization process reasonably well.This work illustrates the strategy in construct a population balance model for further simulation,model-based optimization and control studies of benzoic acid in antisolvent crystallization.