Nucleation Study Of Pharmaceutical Metastable Solid State In Nano Scale Confinement

The development of metastable solid state（amorphous and metastable crystal form）of active pharmaceutical ingredients is an effective method to improve the bioavailability of poorly soluble drugs.While their thermodynamic instability property poses a huge challenge for its preparation and storage.Confined crystallization is an effective method to prepare a pure metastable solid state with enhanced physical stability.While the mechanism of amorphous and polymorphic nucleation in confined spaces remains to be studied.In this work,biocompatible materials were used to construct confined spaces.Effects of confined space parameters on the nucleation of the metastable solid form were explored.The details are as follows:Firstly,effects of silica pore size and drug loading on the nucleation rate of confined amorphous vortioxetine（VXT）were investigated.Three mesoporous silica particles（MSP）with different pore sizes were selected:2.80 nm,9.50 nm,and 25.30nm.Results showed that pore sizes of MSP had a huge influence on physical stability of confined VXT.Samples in MSP with 9.50 nm pores had the lowest nucleation rate.In addition,with VXT loading decreasing,the nucleation rate of amorphous VXT decreased.Nitrogen adsorption and desorption measurements and ¹H-¹³C CPMAS NMR experiments were executed.Results showed that in MSP with 9.50 nm pores,VXT molecules were in a dispersed absorpation state,and the VXT-VXT interaction was weak.This could delay the nucleation of the confined amorphous VXT and was conductive to its physical stability.Then,a suitable range of space size and drug loading were proposed for stabilizing the amorphous drug,according to the average size of drug molecule and the pore size and pore volume of porous material.Secondly,effect of MSP surface chemistry on the nucleation rate of amorphous VXT was investigated.The surface of MSP was modified with different functional groups,according to the bonding ability of VXT.Fourier transform infrared spectroscopy and nitrogen adsorption and desorption measurements were executed to analyze the VXT-MSP interactions and the adsorption state of confined VXT molecules.Results showed that the strong VXT-MSP interaction was conductive to the dispersive adsorption of VXT in MSP pores.It could weaken the VXT-VXT intermolecular interaction,inhibit the nucleation of amorphous VXT and enhance its physical stability.Subsequently,starting from the crystallization of amorphous vortioxetine hydrobromide（VH）in silica nanopores,the solvent effect on polymorphic nucleation in nanoscale space was investigated.Interplay between solvent properties and silica pore sizes on the nucleation of VH polymorphs was found.In small pores（≤50 nm）,the nucleation of VH metastable formαwas affected by the molecular volume of solvent.While in large pores（>50 nm）,it was influenced by the hydrogen bond donor capacity of solvent.The pore size-dependently solvent effect on polymorphic formation was explained,by analyzing the structures of preferred crystal surfaces of VH as well as the size confinement effect of confined space.Besides,compared to the bulk formα,confined formαin silica pores had better physical stability.In addition,confined formαalso behaved faster dissolution rate and inhibited polymorphic conversion during dissolution process.Finally,metastable crystal form II of carbamazepine（CBZ）with controlled dissolution properties was prepared by confinement crystallization in hydrogel@emulsion system.The O/W emulsion with CBZ enriched in oil phase was prepared by water-anisole-Tween80/Spam80 system.By adjusting the initial size of emulsion droplet,the supersaturation rate of CBZ in droplets during evaporative crystallization process could be changed.Then the metastable form II of CBZ was prepared.Subsequently,the O/W emulsion of CBZ was encapsulated by alginate gel（ALG）to obtain CBA-ALG composite.The dissolution rate of CBZ form II loaded in ALG gel could be adjusted by changing the size of gel beads.