Crystal Habit Modification And Regulation Of Small Molecule Organic Compounds In Solution Crystallization

In the solution crystallization,many small molecule organic compounds are generally assembled into crystals by hydrogen bonding interactions.Regarding on the PBC growth mechanism and the directionality of hydrogen bonding,crystals often grow as needles or flakes with low bulk density and poor flowability,resulting in serious product post-processing problems.In this work,the four small molecule organic compounds,calcium D-pantothenate,thiamine nitrate,pyridoxine hydrochloride,and isoniazid,were studied to reveal the effects of process parameters,additives,and solvents on crystal habit,and attempt to solve the industrial problem that the crystal habits of small molecule organic compounds are difficult to control accurately in solution crystallization.Firstly,aiming at the problem that calcium D-pantothenate,one of the important feed additives,usually presents needle-like crystal habit which is easy to get agglomerated,and resulting in low crystal purity.By controlling the temperature and solvent parameters during the phase transformation process,a route for preparing calcium D-pantothenate tetramethanol monohydrate(D-PC·4Me OH·H₂O)with block-like habit was developed.Then,the solvent-free calcium D-pantothenate with block-like habit was obtained by controlling the thermal transformation of D-PC·4Me OH·H₂O.This study is of great significance for the industrial scale-up of calcium D-pantothenate.Secondly,in the view of insufficient understanding of the additive on modulating crystal growth,which leads to the low efficiency in crystal habit optimization.This work presents a case study of the feed additive,thiamine nitrate(VB1),which generally grows into rod-like with large aspect ratio,resulting in low bulk density and poor flowability.Experiments found that sodium alkyl sulfate and sodium alkylbenzene sulfonate had a significant inhibitory effect on the axial(100)surface growth of VB1crystal,thereby modifying VB1 to be block-like habit;while alkyl sodium sulfonate presented no effect on VB1 crystal habit.The molecular dynamic simulation using Materials Studio software showed that sodium alkyl sulfate and sodium alkylbenzene sulfonate can be selectively adsorbed on(100)crystal surface of VB1 by strong electrostatic and hydrogen-bonding interactions,thus hindering its axial growth.Then,to further enrich the understanding the mechanism of the surfactant in controlling the crystal habit,the crystal growth of pyridoxine hydrochloride(VB6),one kind of the additives,in the presence of ionic and nonionic surfactants was studied.It was found that the ionic surfactants can modulate VB6 crystal habit from block to needle.On the one hand,the ionic surfactants can be adsorbed on VB6 crystal surface by strong electrostatic interactions therby inhibiting VB6 crystal growth;on the other hand,the ionic surfactants can enhance VB6 crystal growth by promoting the Cl^-ions integration to VB6 crystal surfaces.While for the nonionic surfactant,whihc had a slight inhibitory effect on VB6 crystal growth by nonspecific aggregation on VB6crystal surfaces,therby presenting almost no effect on VB6 crystal habit.Finally,to address the problem the traditional molecular dynamic simulation methods generally predict crystal habit based on the the adsorption energy,which is hard to uncover the effect of solvent on crystal growth visually.In this work,the constant chemical potential dynamics simulation method was developed to study the effect of solvent on the crystal growth of isoniazid,which is the first-line anti-tuberculosis drug.The simulation results revealed a rough growth mechanism for the fast growing(110)surface along the axial direction of isoniazid crystal,the bulk transport of the solute was the limiting-step,and the relative growth rate of which surface decreased from methanol,ethanol to isopropanol.On the other hand,the slow growing(002)surface along the radial direction appeared to follow a stepwise growth mechanism,with a surface integration step chiefly controlling the growth,and the relative growth rate of which surface increased from methanol to ethanol and isopropanol.