| The nucleation and growth of crystals are affected by many factors,and the nucleation and growth of crystals regulated by templates has attracted much attention in the field of crystallization.In this paper,aiming at problems such as difficult to control crystal nucleation and unsatisfactory crystal habit of crystal products,the effects of templates such as functionalized nanosilica,organic small molecule crystals and polymers on crystal nucleation and growth were investigated by experiments and molecular simulation,and the mechanisms of templates in promoting crystal nucleation,inducing the selective nucleation of metastable crystal form and regulating crystal habit were discussed.Firstly,the effect of functionalized nanosilica on crystal nucleation was investigated.Malonamide was selected as the model,and functionalized nanosilica decorated with-NH2,-OH and-（CH2）7-CH3 functional groups were prepared as templates.The induction time of malonamide in pure methanol and with template was measured and the nucleation parameters were calculated.The results showed that all three templates shortened the induction time and lowered the nucleation energy barrier.The order of the promotion effect of the template decorated with different functional groups on nucleation is-OH>-（CH2）7-CH3>-NH2.The molecular simulation results show that the interaction between the-OH modified template and the malonamide molecule is stronger than that of the-NH2 modified template.The aggregation of malonamide molecules on the template surface and the formation of intermolecular hydrogen bonds are the key steps to reduce the nucleation energy barrier and increase the nucleation rate.Secondly,the regulating effect of organic small molecule crystal template on the nucleation of polymorphs was investigated.Experiments showed that malonamide can induce the selective nucleation of metastable crystal form of pimelic acid.The single crystal induced experiment showed that the（1 1 1）and（0 1 1）crystal faces of the template has a stronger induction effect.The amide groups at both ends of the malonamide molecules on the（1 1 1）and（0 1 1）crystal faces of the template are exposed on the faces,which makes it easier for the crystal faces to adsorb pimelic acid molecules.Molecular simulation results showed that the interaction between the（1 1 1）/（0 1 1）faces and pimelic acid molecules is stronger,which is beneficial to induce the selective nucleation of pimelic acid on the corresponding crystal faces.Subsequently,the model system was extended to cocrystal with polymorphs,and the effect of polymer templates on the theophylline-benzamide cocrystal was studied.In suspension and mechanical ball milling experiments,the effect of solvent and polymer on the crystal form of the product was determined.In isopropyl acetate suspensions,polymers such as PVP-K17 can induce the selective nucleation of cocrystal form I.The crystal face of the cocrystal form I exposed more carbonyl and amide groups,and the adsorption of PVP-K17 molecules was stronger.Finally,combined with the results of molecular simulation,the mechanism of the selective nucleation of cocrystal form I induced by polymer was analyzed.Finally,the regulating effect of polymers on crystal growth was investigated.The cooling crystallization experiment of p-aminobenzoic acid（PABA）showed that PVP-K17 could regulate the PABA crystals from long rod to bulk,and the regulating effect of PVP weakened with the increase of chain length.The single crystal growth experiments showed that the polymer significantly inhibited the axial and radial growth of PABA crystals,but the inhibitory effect weakened with the increase of PVP chain length.Molecular simulation results showed that the interaction energy and adsorption energy between PVP-K17 and（1 1 0）/（0 1 1）face of PABA crystal were stronger,and PVP-K17 can be selectively adsorbed on these crystal faces.Finally,the regulation mechanism of PVP-K17 on the crystal habit of PABA was proposed. |
