| With the rapid development of global pharmaceutical industry,the world market for chiral drugs is developing at an unprecedented rate.Since different stereo configurations of chiral drugs exhibit distinct biological activities,pharmacological effects,and toxicological effects,obtaining high-purity single enantiomer of chiral drugs and reducing the dosage of drugs are the frontiers and trends of chiral drug research.Chiral resolution is one of important ways to obtain single enantiomer of chiral drugs.At present,chiral resolution by the formation of diastereomeric salt is the most widely used chiral resolution technology in the industry.In addition,drug cocrystal is multicomponent crystal formed between pharmaceutically active components and cocrystal coformers by non-covalent bonds,which has been increasingly applied in the drug research field,especially for the separation of chiral compounds that cannot form salts or are difficult to form salts.In this paper,ofloxacin as the third-generation quinolone antibacterial agent was used as the research object.The efficient chiral resolution of ofloxacin by drug cocrystal technology was systematically studied.Firstly,the green and efficient resolution of chiral ofloxacin in aqueous solution was carried out by using chiral liquid-solid cocrystal with cheap and readily available tartaric acid derivatives as cocrystal coformers.The effects of types of cocrystal coformers,operating time and temperature,the amounts of ofloxacin and cocrystal coformers on the resolution performance were investigated.The experimental results showed that D-(+)-dibenzoyltartaric acid(D-DBTA)used as resolving agent selectively cocrystallized with R-ofloxacin.When the concentration of ofloxacin was 1.6 g/L,the obtained maximum separation factor and enantiomer excess value(ee)were 10.49 and 81.8%,respectively.However,L-(-)-dibenzoyltartaric acid(L-DBTA)used as resolving agent selectively cocrystallized with S-ofloxacin and the obtained maximum separation factor and ee value were 10.78 and 82.3%,respectively.Reaction crystallization method was used for preparing cocrystals.Various characterization and calculation methods have been used to determine the formation of diastereomeric cocrystal pairs,such as the materials balance calculation before and after crystallization,powder X-ray diffraction(PXRD),Fourier transform infrared spectroscopy(FT-IR),differential scanning calorimetry(DSC),thermogravimetric analysis(TGA),and density functional theory(DFT)calculation.The results showed that 1:1 cocrystal was obtained by forming hydrogen bond between the carboxy groups on the molecules of ofloxacin and the carboxyl groups on the resolving agent,and the crystal structure data of the cocrystals was obtained by the Reflex module of the software Materials Studio.Secondly,the solvent environment has a great influence on the solubility of cocrystals in the diastereomeric cocrystallization resolution process.The interaction between cocrystal molecule and solvent will be influenced by solvent polarity,resulting in solubility difference between the diastereomeric cocrystal pairs,which determines the separation efficiency of the resolution process.In this paper,the solvent effect on the chiral resolution process by cocrystallization was investigated by adding 16 kinds of organic solvents with different polarities into the chiral liquid-solid system.The results showed that when a strong polar solvent like acetonitrile was added into the chiral liquid-solid system,it would be miscible with water to form one liquid phase and chiral ofloxacin could not be separated.When a medium-strong polar solvent like n-octanol was added,a liquid-liquid two-phase system was formed and the separation efficiency was very low.However,when a non-polar solvent like n-hexane was added,a diastereomeric cocrystal pair was formed and chiral liquid-liquid-solid high resolution process was realized.Moreover,the Blends module of Materials Studio software was used to calculate the mixing energy between cocrystal and n-hexane or n-octanol.The obtained mixing energy followed the sequence n-octanol>n-hexane.The higher the mixing energy is,the larger the solubility of the cocrystal in the solvent is.Thus,the solubility of cocrystal in n-hexane is relatively small and it is easy to form diastereomeric cocrystals,leading to the formation of a chiral liquid-liquid-solid resolution process by cocrystallization.The n-hexane was determined as the best adding solvent.When the ofloxacin concentration was 1.0 g/L and D-DBTA was used as the resolution agent,the obtained maximum separation factor and ee value was 5.57 and 66.06%,respectively.Compared with the chiral liquid-solid separation process(the maximum separation factor and ee value was 4.76 and 62.77%under the same conditions),the separation efficiency was improved.Chiral selectivity is an important factor in the chiral separation process,and the study of the process mechanism is of great significance for the control and optimization of the separation process.In this research,the chiral selectivity of chiral resolution of ofloxacin by cocrystallization was systematically investigated by combining cocrystal coformers.The effects of operation conditions on chiral selectivity of the separation process were investigated,such as the different combinations of resolving agents,operating time and the dosage of resolving agents.The cocrystals were characterized by PXRD,FT-IR and TGA.The experimental results showed that when D-DBTA and L-(-)-di-p-methylbenzoyltartaric acid(L-DTTA)were used as the combined resolving agent,the chiral selectivity changed and the D-DBTA+L-DTTA preferentially cocrystallized with S-ofloxacin.The separation factor and ee value after chiral selectivity transition were 2.455 and 41.15%,respectively.When L-DBTA and D-(+)-di-p-methylbenzoyltartaric acid(D-DTTA)were used as the combined resolving agent,the chiral selectivity also changed and L-DBTA+D-DTTA preferentially cocrystallized with R-ofloxacin.The separation factor and ee value after chiral selectivity transition were 1.786 and 27.10%,respectively.Compared with a single resolving agent,chiral selectivity transition could be achieved with the combination of two specific tartaric acid derivatives participated in the chiral ofloxacin separation process,due to the spatial effects between the different molecules.This has great guiding significance for the control and optimization of the chiral separation process.In order to explore the industrial application prospects of the drug cocrystal resolution technology and further to improve the purity and yield of the chiral resolution process,multi-stage cross-flow cocrystalization and multi-stage countercurrent cocrystalization were used to concentrate the target enantiomer in the solid phase.In this research,a four-stage cross-flow and four-stage countercurrent cocrystalization separation and enrichment processes were established,respectively.Firstly,the solid-liquid equilibrium data of the ofloxacin-tartaric acid derivative cocrystal(L-RS cocrystal)was determined and the type of solid solution was determined by thermodynamic basic theory.The determined solid-liquid equilibrium composition was fitted by a polynomial equation.Based on the material balance equation and fitting equation of solid-liquid equilibrium relationship of the four-stage operation process,the theoretical predicted values of operational variables of the each-stage operation process could be obtained by linear programming solution of material dosage and composition by flow simulations.Finally,four-stage cross-flow and counter-current experiments were carried out according to the prediction results,and the purities of the target products obtained by the cross-flow operation and the countercurrent operation were 94.3%and 95.5%,respectively. |
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