Research On Batch Crystallization Process Of Glycolide And Polymorph Selection In Continuous Crystallization

Since crystalline solids have different polymorphs,their physico-chemical properties can vary substantially.On this occount the design of controlled processes that ensure the consistent production of a desired polymorph is an important goal in the manufacturing of crystalline products.Glycolide is an important molecule as it is the precursor to polyglycolid acid(PGA)and one of the monomers involved in poly(lactic-co-glycolic)acid(PLGA),both of which belongs to the biodegradable materials.Glycolide crystallizes in two known structure polymorphs,form 1 and form 2,which can easily appear concomitantly from solution crystallization.In this work,polymorphism in glycolide was investigated systematically through the study of thermodynamic stabilities,crystal structures,morphologies and polymorphic nucleation selection in order to develop the crystallization process of glycolide form 1.The polymorph selection in a single-stage MSMPRC process combined with wet milling was investigated on the basis of a population balance equation model.Wet milling turned out to be an attractive tool for process intensification in a continuous crystallization process.A two-stage MSMPRC was further considered to illustrate the dissolution behaviour leading to polymorph transformation at steady state.Polymorphs(form 1 and form 2)of glycolide were confirmed to be enantiotropically related through the characterization of PXRD and thermal analysis(TG and DSC).The solubilities of these two forms were experimentally measured in five pure solvents under different temperature ranges by using the isothermal gravimetrical method.The transition temperature of glycolide polymorphs was estimated through solubility extrapolation method and(35)H_tr method,which was further confirmed as308.35±0.5 K via the isothermal transformation method in situ monitored by Raman spectroscopy.On the basis of the thermodynamic properties and equations,the free Gibbs energies of form 1,form 2and liquid state of glycolide were calculated and the stability ranges for them were verified.It was found that the phase transformation process between form 1 and form 2 of glycolide had to overcome a high energy barrier,the magnitude of which was estimated using the Starink's isoconversional method.The differences of molecule conformer and packing in two glycolide polymorphs'structures were elucidated.Crystal morphologies predicted from BFDH model and AE model were in good agreement with the experimental results.The polymorph nucleation selection for glycolide was investigated in different solvents at varied temperatures and supersaturations.Combined the polymorph nucleation results from literature,the Ostwald rule under high supersaturations was validated.A population balance model for continuous crystallization processes involving wet milling for polymorphic substances was developed.The population balance model was transformed into a dimensionless one.This led to a surprisingly small number of parameter groups(combinations of operating conditions and kinetic parameters)that control the polymorphic outcome of the process.Specifically,when wet milling is introduced to the process,the polymorph that breaks more readily can be obtained in a wider range of operating conditions(feed concentration,residence time).The operating region where the stable polymorph is obtained can be enlarged when two polymorphs break equally.Furthermore,the dependence of the mean size of the particles obtained,the fraction of solute recovered,and the productivity of such a process on the dimensionless varibles was rationalized.The analysis approach introduced here can be used to identify operating spaces for single-stage continuous crystallization processes where the right polymorph is reliably obtained and where size,solute recovery,and productivity are guaranteed to desired levels.The analytical solution of number density in a two-stage MSMPRC process was solved and proved for the case of crystallization and dissolution,respectively.This provided a useful insight toward the polymorph selection in a two-stage MSMPRC process where phase transformation may occur.Given these comprehensive study,a well controlled batch crystallization process leading to the production of desired form 1 of glycolide was developed successfully.