Study On Preparation Of Drug Enantiomers And Its Application

Chirality is one of the essential attributes in nature. Chiral technique is a front subject in chemical industry and pharmaceutical industry. Although chiral compounds have many similar physical and chemical properties between their different enantiomers, some cases have already proved that the action and biological effects produced by a pair of enantiomers are not quite the same after they entered into animal and human body. When chiral drugs entered into a life body, there is a process of recognition-accommodation-interaction between the chiral biological systems and chiral drugs, they can arouse different pharmacokinetics in absorption, translocation, metabolism and different drug binding target such as receptors, enzymes, ion channels between the different enantiomers of chiral drugs. Finally they can generate different efficacies, side effects and toxic reactions. In the thesis, preparation and separation of drug enantiomers were studied by using modern chiral techniques with the methods of HPLC, liquid-liquid extraction and crystallization. Influence of pH value, concentratrations of chiral and organic solvent on the separation behaviors of enantiomers. Mathematical models were established for chiral separations. Preparation and separation of entiomers of sertraline and finasteride were studied. The main research and results can be summarized as following.The enantiomeric resolution and determination of finasteride, dihydrofinasteride, racemic-sertraline hydrochloride and cis-sertraline hydrochloride was studied by HPLC. The method was applied to determination of amount of the enantiomers with good linear relationship and selection. The effects of various factors and temperature on enantioselectivity have been investigated, and the chiral recognition mechanisms have also been discussed further according to the relative thermodynamic parameters. The enantiomeric resolution of them with CPs was mainly determained by interactionΔH。A HPLC method for simultaneous quantification and dissolution of tramadol hydrochloride and paracetamol in compound tramadol hydro- chloride tablets had been established. The two components could be assayed by Diamonsil C₁₈ column and an eluant of methyl alcohol -0.02mol/L potassium phosphate monobasic(45:55) as mobile phase with the flow rate of 1.0 ml.min^-1, the wavelength of detection was at 220 nm. The separation and determination of two constituents could be accomplished simultaneously. The calibration curves were linear within the ranges of 10.8-37.8μg.ml^-1 for tramadol hydrochloride and 91- 318.5μg.ml^-1 for paracetamol. The average recoveries of tramadol hydro- chloride and paracetamol were 100.3%(RSD=0.48%) and 99.7% (RSD = 0.40 %), respectively. The method is simple, rapid, and accurate, and can be used for simultaneous quantitative analysis of the two components and its dissolution in compound tramadol hydrochloride tablets.Distribution behavior of cis-enantiomer sertraline hydrochloride was examined in the aqueous and organic solvent of a two-phase systems containing D-mandelic ester as chiral selector. The influence of pH, organic solvents and the concentrations of chiral selector on K, a and-Δ(ΔG) for cis-enantiomer sertraline was investigated with D- mande -lic acid derivatives as chiral selectors. The extraction performance and chiral recognition mechanism were studied with different length of alkyl chain of D-mandelic acid. The results showed that the D- mandelic esters formed more stable diastereomeric complexes with sertraline hydrochloride (1S,4S) than with (1R,4R). The partition coefficients(K) and separation factors(α) increased with increasing length of alkyl chain of D-mandelic esters. Along with the pH value aggrandizement, the K larger, but the a lower. Different organic solvent and concentration of phosphate salt also have a large influence on K andα.Based on mass balance law and chemical equilibrium theory, the basic law of chemical equilibrium for chiral drugs was put forward. It is pointed that it may represent the relation of drug enantiomers as the solution of the drug enantiome is saturated as follows: K= Cs/C_R. Only the equilibrium constant is more or less than 1, the separation of enantiomers can be achieved by crystallization.Based on mass balance law, the basic law for racemate crystallization was studied. It is pointed that it can represent the interrelationship of isomers in racemic crystallization system as follows: C_R+βC_R0 = C_R0, C_S+βC_S0 = C_S0. The balance relationship exists in solution as follows: K_R= C_R /C_R0, K_S = C_S /C_SO. K_R and K_S are partition constant. Enantiomeric excess can show as follows:The influence of organic solvents (ethyl acetate, propyl acetate, toluene, acetone, methyl alcohol and tetrahydrofuran) and temperature etc on equilibrium constant(K) and enantiomeric excess(e.e) of racemic sertraline hydrochloride was studied .The resolution process of racemic sertraline hydrochloride is studied. An efficient and practical method to directly resolve racemic sertraline hydrochloride into optically pure sertraline hydrochloride has benn developed by modification of a racemic sertraline hydrochloride. Enantiomers(S) of chiral enantiomer can be easily obtained with method and the e.e value is more than 99%. And the effects of the reaction time and the quantity of solvent on the yield of the enantiomer were examined via orthogonal experiment. Under the optimal conditions, the yield of S- is 36.6 %.The synthesis of finasteride was studied. Finasteride was synthesized from 3-oxo-4-androstene-17β-carboxylic acid by ammoniumation, cleavage ofΔ-4-double bond, ring closure with ammonia, then hydrogenation with Pd/C and dehydro- genation of 1,2-position with DDQ/BSTFA. The structure of finasteride was verified by IR, DSC, X-ray, ¹H-NMR and MS. The synthetic route was successful without using those expensive reagents such as PtO₂, (COCl)₂ and poisonous reagents such as (PhSeO)₂O and dioxane. The over yield was 30.6%, and it is suitable for the needs of industrial production. A cleaner, simpler, and more efficient synthesis route of sertr- aline has been developed and is presented in this paper. Sertraline was synthesized from orthodichlorobenzene, andα-naphonalol by Friedel-Crafts reaction, ammoniumation with methylimine, then hydrogenation with KBH₄, resolution with D-(-)mandelic acid. The structure of sertraline was verified by HPLC, IR, DSC, X-ray, ¹H-NMR and MS.Novel polymeric microspheres for controlled release of finesteride had been prepared. The novel polycarbonate, poly (propylene carbonate maleate) (PPCMA) was used as drug carrier. The PPCMA microspheres loaded with finasteride were elaborated by a simple oil-in-water (O/W) emulsion-solvent evaporation method. The results showed that the mean diameter of microspheres was 1-3μm, and had both smooth and spherical surfaces, the encapsulation efficiency was up to 85.76%. In vitro drug release of these microcapsules was performed in a pH value 7.4 phosphate-buffered solution. A prolonged in vitro drug release profile was observed, a continuous drug release was observed for up to 5-6 weeks. The release profiles of finasteride from PPCMA microcapsules were found to be biphasic with a burst release followed by a gradual release phase, and followed the Higuchi matrix model.