309 results about "Rivaroxaban" patented technology

The invention relates to a quickly releasing oral solid medicinal composition containing rivaroxaban and a preparation method thereof. Proper medical auxiliaries are treated by a wet granulation process, and are mixed with active components of rivaroxaban to obtain the medicinal composition with remarkably improved dissolution. The preparation method has the characteristics of simple process and industrial production, and solves the problem of complicated preparation process in the prior art.

The invention discloses a rivaroxaban intermediate, a structural formula of the rivaroxaban intermediate is represented by the following formula (III). The invention further discloses a preparation method for rivaroxaban. The method is characterized by: carrying out a cyclization reaction for 4-(4-isocyanatophenyl)-3-morpholinone and (R)-epichlorohydrin under a catalytic action of magnesium halide to generate (S)-4- morpholinonephenyloxazolidinone, followed by carrying out functional group conversion to obtain 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl] phenyl}-morpholine-3-ketone, then reacting with 5-chlorothiophene-2-formyl chloride to prepare the rivaroxaban. The preparation method provided by the present invention has advantages of mild reaction conditions, simple operation, high reaction yield and the like. In addition, the use of toxic and harmful reagents is avoided during the synthesis process, such that environmental pollution is reduced, and the method is applicable for the industrial production.

The invention discloses a method for preparing a rivaroxaban solid composition. The method comprises the following steps: crushing rivaroxaban by adopting a wet crushing method, and simultaneously preparing a suspension solution; spraying the suspension solution into other auxiliaries to prepare grains with proper sizes; further preparing minimum medical dosage units. The method has the beneficial effects that: the problem that the grain diameter cannot be reduced to 5mu m when rivaroxaban particles are prepared by adopting a conventional crushing method can be solved, and the dissolution speed of the rivaroxaban preparation can be increased.

The invention relates to a method for synthesizing rivaroxaban, in particular to a method for preparing rivaroxaban from 4-(4-aminophenyl)-3-morpholinone. The method is easy to operate for synthesizing the rivaroxaban, does not adopt toxic substances, is high in yield of rivaroxaban and low in cost and is suitable for industrial production.

The invention relates to an analysis and detection method for a rivaroxaban intermediate, which is particularly used for mass control on the rivaroxaban intermediate. A chromatographic column (C18, 4.6mm*150mm, 5 microns) which takes octadecyl silane bonded silica gel as a packing and a perchloric acid solution and methanol as flow phases are adopted for gradient elution, and analysis and detection are performed by a high performance liquid chromatography method under the conditions that the detection wavelength is 240nm-250nm, the column temperature is 30-40 DEG C and the velocity is 0.7-1.1 ml/min. By adopting the analysis and detection method provided by the invention, the rivaroxaban intermediate can be effectively separated from impurities of the rivaroxaban intermediate, and moreover, the method has the advantages of high separation degree and sensitivity, good repeatability and durability, short analysis time, simplicity in operation and stable and reliable result.

The invention relates to a pharmaceutical composition containing rivaroxaban, in particular to a solid pharmaceutical composition containing rivaroxaban and a preparation method of the solid pharmaceutical composition. The solid pharmaceutical composition containing the rivaroxaban can be further prepared into a film-coated tablet by a specific preparation technology to serve as a specific administration mode. The solid pharmaceutical composition containing the rivaroxaban and the preparation method of the solid pharmaceutical composition have the advantages that by application of the specific preparation technology, using surfactants in a preparation is avoided and dissolution rate of the tablet is increased effectively; by means of using sodium stearyl fumarate in the composition, marked increase of degraded impurities I during long-term storage of the tablet is avoided effectively; through stability accelerating research, the film-coated tablet containing the rivaroxaban, prepared by the prescription and technological steps, is stable and controllable in quality.

The invention discloses a method for simultaneously detecting Rivaroxaban tablet relevant substances by high performance liquid chromatography. According to the chromatographic conditions, octadecyl silane is used as a filling agent of a chromatographic column; acetonitrile-buffer salts (containing phosphate and ion-pairing agents) are used as a flowing phase to perform gradient elution; an ultraviolet detector is used as a detector. By using the method provided by the invention, impurities in Rivaroxaban tablets can be effectively detected out; the analysis time is short; the efficiency is high; a simple and reliable method is provided for the Rivaroxaban tablets.

The present invention discloses a preparation method for a rivaroxaban intermediate compound represented by a formula 5, wherein the preparation method comprises the following steps: carrying out a benzyl group removing reaction of a compound 4 in a solvent to prepare a compound 5. The present invention further discloses a rivaroxaban preparation method and intermediate compounds. According to the preparation method, chiral raw materials are easy to obtain, and have cheap price, the process is simple, the post treatment is simple, the intermediate and the final product are easy to purify, the total yield is high, the purity is high, and industrial production is easily achieved.

The invention relates to an oral tablet containing rivaroxaban. The tablet is prepared by adopting a powder direct mixing and tabletting method. an inventor solves partial problems and solves the problems of pitted surface, sticking, loosening tablet and disintegration and dissolution rate and stability problems through addition and replacement of a proper additives and a screening experiment, so as to obtain a novel formula of rivaroxaban tablets and a preparation method of the rivaroxaban tablets by adopting the powder direct mixing and tabletting method. Each rivaroxaban tablet comprises the following components by weight: 5-20mg of rivaroxaban, 60-80mg of lactose, 4-6mg of mannitol, 2-4mg of croscarmellose sodium, 1-3mg of citric acid, 0.5-2mg of lauryl sodium sulfate, 3-5mg of carbomer, 3-5mg of povidone K90, 3-5mg of hydroxyl propyl cellulose, 0.5-2mg of magnesium stearate and 0.5-2mg of silicon dioxide.

The invention belongs to the field of analytical chemistry, and concretely relates to a method for separating and measuring rivaroxaban and its impurities, and an application thereof. A reagent composition for separating and measuring rivaroxaban and its impurities comprises: a diluent which is an aqueous solution of acetonitrile and an acid; a mobile phase A which is a buffer salt solution containing methanol and acetonitrile; and mobile phase B which is a mixture of the buffer salt solution and acetonitrile. The method for separating and measuring rivaroxaban and its impurities by using thereagent composition comprises the following steps: dissolving rivaroxaban in the diluent to obtain a sample solution; preparing the mobile phases; injecting the sample solution into a separation and detection system, and eluting and separating the sample solution with the mobile phases to obtain an eluate; and adding the eluate into a detector, and measuring the eluate. The method has the advantages of realization of complete separation of the rivaroxaban and its impurities, good baseline, high sensitivity, short analysis time, good reappearance, and realization of effective separation and themeasurement of the content of every relevant substance in a rivaroxaban raw medicine and a rivaroxaban preparation.

The invention provides a synthesis method of an important intermediate 4-(4-aminophenyl)-3-morpholone of a new anticoagulant rivaroxaban, belonging to the field of chemical synthesis. The method comprises the following steps: 1) cyclizing nitroaniline and di-halogen aether to obtain 4-(4-nitrophenyl)-morpholine; 2) reacting 4-(4-nitrophenyl)-morpholine and organic hydroperoxide under the action of a catalyst to generate 4-(4-nitrophenyl)-morpholone; and 3) reducing the 4-(4-nitrophenyl)-morpholone into the under the action of a catalyst, wherein the mol yield of the three steps is higher than 49% (on the basis of nitroaniline). The synthesis method provided by the invention has the characteristics of accessible raw materials, low price, simple operation steps, mild reaction environment and the like, and is suitable for industrialized mass production; and the three wastes are easy to process.

The invention relates to a separation determination method of a rivaroxaban optical isomer. According to the invention, proper amounts of a rivaroxaban optical isomer sample requiring detection and a rivaroxaban racemate standard sample with known component contents are fetched, and are respectively dissolved by using acetonitrile, such that acetonitrile solutions of the rivaroxaban optical isomer sample requiring detection and of the rivaroxaban racemate standard sample with known component contents are prepared; a bonded chiral column CHIRALPAKIC column is adopted, and feeding is carried out; a detection wavelength is 210-260nm, a column temperature is 15-35 DEG C, a feeding volume is 5-20mul, and a mobile phase flow rate is controlled at 0.7-1.0ml/min, such that the separation of the rivaroxaban optical isomer requiring separation is finished; and with an area normalization method, the obtained separation spectrum of the rivaroxaban optical isomer sample requiring detection and the separation spectrum of the rivaroxaban racemate standard sample with known component contents are compared, such that S-configuration and R-configuration rivaroxaban contents in the rivaroxaban optical isomer requiring detection are calculated.

The invention belongs to the technical field of drugs and in particular relates to a rivaroxaban tablet. The rivaroxaban tablet contains rivaroxaban, hydroxypropyl cellulose and fumed silica and is prepared by dissolving rivaroxaban and hydroxypropyl cellulose in diethylene glycol monoethyl ether, adding fumed silica for adsorption, then mixing the materials with pharmaceutically acceptable auxiliary materials uniformly and pressing the mixture by adopting a direct tabletting process. Compared with the prior art, the rivaroxaban tablet is high in drug dissolution speed and simple in process and dispenses with addition of surfactants and micronization treatment.

The invention discloses a method for synthesizing a rivaroxaban intermediate 4-(4-aminophenyl)-3-molindone. The method comprises the following steps: reacting paranitroaniline with ethylene oxide to obtain a compound II; performing a cyclization reaction on the compound II and bromoacetyl bromide to obtain a compound III; adding the compound III into iron powder to perform a reduction reaction to obtain the 4-(4-aminophenyl)-3-molindone. According to the method, the raw materials are low in cost and easily obtained, the cost is low, the synthesis operation is simple, industrial nitration is avoided, environmental pollution is greatly reduced, and the method is suitable for industrial production.

The present invention discloses rivaroxaban-containing tablets, which are prepared from a raw material containing micronized rivaroxaban and an auxiliary material containing a water soluble filler, wherein a weight ratio of the rivaroxaban to the water soluble filler is 1:0.5-50, and the water-soluble filler is one or a plurality of materials selected from lactose, mannitol, sorbitol and sucrose. According to the present invention, the hydrophilicity of the rivaroxaban is significantly improved, the rapid dissolution the rivaroxaban in the gastrointestinal tract body fluid is easily achieved, the preparation process is simple, the operation is convenient, and the method is suitable for industrial large-scale production.

The present invention relates to a process for determining the suitability for distribution of a batch of rivaroxaban or of a pharmaceutical composition thereof. In particular, it also relates to two impurities of rivaroxaban, to their use as reference markers to determine the purity of a sample of rivaroxaban or a composition thereof, to analytical methods for determining the purity of a sample of rivaroxaban or a composition thereof and to a process of preparing rivaroxaban or pharmaceutical compositions thereof which are free or substantially free of such impurities.

The present invention belongs to the technical field of medicine, and particularly relates to rivaroxaban tablets and a preparation method thereof. The preparation method comprises: dispersing rivaroxaban in an aqueous solution containing sucrose, adding to a nanometer bead mill to grind, granulating the obtained suspension on a pharmaceutically-acceptable excipient, drying, adding a lubricant, uniformly mixing, and tabletting. According to the present invention, the preparation process is simple, and the raw material does not require the separate micro-powder treatment; any surfactants are not added so as to improve medication safety; the drug dissolution is rapid, wherein the 5 min dissolution achieves more than or equal to 90%; and the preparation process is simple, and the method is suitable for industrial production.

The invention provides a synthesis method of rivaroxaban. The synthesis method comprises the following steps of: (a) reacting a compound shown as a formula (I) with sodium azide to obtain a compound shown as a formula (II), and reacting the compound shown as the formula (II) with acetic anhydride to produce a compound shown as a formula (III); (b) reacting a compound shown as a formula (IV) and a compound shown as a formula (V) to obtain a compound shown as a formula (VI); (c) reacting the compound shown as the formula (VI) with the compound shown as the formula (II) or the compound shown as the formula (III) under the action of an alkali to obtain a compound shown as a formula (VII); (d) reacting the compound shown as the formula (VII) with hydrazine hydrate to obtain a compound shown as a formula (VIII); and (e) reacting the compound shown as the formula (VIII) with a compound shown as a formula (IX) to obtain the compound rivaroxaban shown as a formula (X). The synthesis method has the advantages of fewer reaction steps, mild reaction conditions, simpleness for post-treatment, and suitability for industrial mass production.

The invention provides a rivaroxaban oral microsphere preparation. The rivaroxaban oral microsphere preparation comprises rivaroxaban and a water-soluble polymer carrier, wherein the water-soluble polymer carrier comprises one or a few of hydroxypropyl methyl cellulose, polyethylene glycol, polyvinylpyrrolidone and cellulose polymer, the weight ratio of the rivaroxaban and water-soluble polymer carrier is 1:(1-10), and the average grain diameter of the microsphere is 38-79 m um. According to the microsphere preparation, the solubility and bioavailability of indissolvable medicines are improved, and the preparation of rivaroxaban medicinal preparation is no longer restricted by crystal form.

The invention belongs to the field of analytical chemistry, and discloses a method for separating and determining rivaroxaban related substances and the content thereof through liquid chromatography. The method is characterized in that the content of rivaroxaban and related substances thereof can be quantitatively determined through using a chromatographic column with octadecylsilane chemically bonded silica as a packing material and using a certain ratio of buffer salt solution-organic phase as a mobile phase, so the quality of rivaroxaban can be effectively controlled. The method has the advantages of strong specificity, high accuracy and simple operation.

The invention discloses a preparation method of (S)-N-glycidol phthalimide in a structural formula 1. The method comprises the following steps of: I, phthalimide salt of a structural formula 9 and a compound of a structural formula 10 are subjected to heating reflux for reaction in an alcohols solvent to obtain the compound of a structural formula 11; II, the compound of the structural formula 11 obtained form the step I is reacted with the compound of a structural formula 12 in an aprotic solvent under the action of alkaline to obtain a (S)-N-glycidol phthalimide crude product of the structural formula 1; and III, the (S)-N-glycidol phthalimide crude product of the structural formula 1 obtained from the step II is refined by ethanol to obtain the (S)-N-glycidol phthalimide with the optical purity larger than or equal to 99.0%. The preparation method is simple to operate and good in safety, the optical purity of the obtained product is high (larger than or equal to 99.0%), and the preparation method is suitable for industrial production. The invention also discloses a novel synthetic method of Rivaroxaban.

The invention relates to the field of pharmaceutical chemicals, and in particular relates to a rivaroxaban pharmaceutical composition and a preparation method thereof; the pharmaceutical composition consists of a rivaroxaban active substance, a solubilizer, a binding agent, a lubricant, a filling agent and a disintegrating agent, wherein the rivaroxaban active substance is not subject to hydrophilic treatment; and the solubilizer accounts for about 1.5%-3.5% in the entire composition in percentage by mass. The rivaroxaban pharmaceutical composition is stable and good in dissolution; and the preparation method is simple and convenient and is energy-saving, and the preparation method is applicable to industrial production.

The invention discloses a preparation method of rivaroxaban. With (S)-4-chloro-3-hydroxybutyronitrile (compound 1) as a raw material, the rivaroxaban is obtained through phthalimide potassium salt substitution, cyano hydrolysis, Hofmann rearranging cyclization, Ullmann coupling, hydrazinolysis and amidation. The rivaroxaban is introduced into a chiral center instead of (S)-epoxy chloropropane which is volatile, high in toxicity and unstable; the safety is relatively high; precious catalyst, raw materials and reagent with large environmental pollution are avoided in the total process in the total synthetic route; the overall synthesis process is small in pollution and easy to treat; the yield and the purity of various steps are high; the preparation method is environmentally friendly, low in production cost and suitable for industrial production.

The invention relates to a rivaroxaban-containing pharmaceutical preparation. Specifically, the pharmaceutical preparation is composed of 3-30% of rivaroxaban, 7-50% of a disintegrant, 45-90% of a diluent, 0.1-5% of a wetting agent and 0.1-1% of a lubricant, wherein the sum of the weight percentages of the components is 100%. The conventional content of the disintegrant is broken, the viscous component proportion is increased, the disintegration time is prolonged so as to increase the wetting time of rivaroxaban, the problem of poor dissolvability of the insoluble drug rivaroxaban is solved, and simultaneously, the stability of the preparation is improved.

The invention provides a preparation method of rivaroxaban, which uses 4-(4-iodophenyl)-3-morpholone and (S)-(+)-N-(3-amino-2-hydroxyisopropyl)phthalimide as initial raw materials. The synthesis route is simple, the reaction conditions in each reaction are mild, and the product is easy to separate; and thus, the reaction yield is high, the product purity is high, and the method can be used for industrial production.