Study On The Preparation Idebenone With High Purity By Crystallization

Idebenone (IDBN) is a short-chain quinine analogue acts as a protent free-radicalscavenger and a novel kind of specific medicine for the treatment of Alzheimer’s disease andmental symptoms, it could improve brain function, have a mild antihypertensive effect.Besides it could be used in clinical treatment which is a kind of intelligent promote medicine.Now more and more is widely used in the cosmetics because it’s strong antioxidant andanti-aging effect. But there are some problems in pharmaceutical production, such as lowerpurity and bad morphology. Therefore systematically studying on how to improve the purityof pharmaceutical ingredient is necessary. This paper established a new type of purificationmethods of cooling and drowning-out crystallization to improve the purity of idebenone.The presence of solvents is essential in all steps of pharmaceutical processes, such ascrystallization process. This paper had screened out several appropriate crystallizationsolvents according to the material polarity and the "similar miscibility" principle, finallyn-hexane-methylene chloride were selected as crystallization solvents on the basis of thesolubility and the purify effects of idebenone. The yield was decided by the crystallizationthermodynamics law, the solubility of idebenone in n-hexane-methylene chloride wasmeasured by static method, the calculate formulas of solubility of idebenone was obtainedthrough Van’t-Hoff equation, used the experience equation to model-fitting, experimentresults show that the solubility of IDBN in different solvent ratios was increasing with thetemperature increasing.Oiling out, an undesirable effect of the crystallization of organic molecules from solution,usually disturbs the crystallization process and deteriorates the product properties. In thiswork the purification of raw idebenone that oils out was firstly attempted by use of bothcooling crystallization and drowning out from n-hexane/methylene chloride mixtures.Experimental results had shown that, oiling out can greatly affect the outcome ofcrystallization: at low initial concentrations, oiling out did not take place and crystallizationproceeded normally to harvest the product with high purity; while at high initialconcentrations, oiling out frequently occurred and crystallization was hindered or evenstopped. This paper made in-depth research on the oiling-out direct at some pharmaceuticalmolecule crystal process, the phase diagram for IDBN was constructed and that providesvaluable information about the conditions of temperature and concentration for liquid-liquidand solid-liquid phase separation.In order to obtain high yields and purity production, based on the crystallizationthemodynamic and oiling-out crystallization process of idebenone, studied the operatingconditions of cooling crystallization and drowning-out crastallization on the purity ofproduction. Determining the operating conditions for the cooling crysallizaton: initial concentration is3.37g/(100g solvent), the ratio of n-hexane and methylene chloride is7:1,the cooling rate is0.1°C min-1, adding1-3%seed in the metastable zone, medium speed;Determining the operating conditions for the drowning-out crystallization: crystallizationtemperature is0°C, the addition rate of antisolvent is shown in Figure6-3, without thecrystal grownth time. Comparing the merits of two crystallization methods, the results showthat drowning-out crystallization is superior cooling crystallization.These above basis researches could provide some useful evidences for the industrializedproduction process of idebenone, there is no similar report published in literature about theresearch up to data, especially about the research of oiling-out in pharmaceutical moleculecrystal process, there is no report about the new oiling-out crystallization process in ourcountry or foreign country.