CN105461569A - Novel citric acid alverine crystal form and preparation method thereof - Google Patents
Novel citric acid alverine crystal form and preparation method thereof Download PDFInfo
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- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
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- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
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Abstract
The invention relates to a novel citric acid alverine crystal form, a preparation method thereof and a medicine composition using the crystal form as an active ingredient. The preparation method comprises the steps that phenylpropanol which is cheap and easy to obtain and serves as a start and is subjected to sulfoacid esterification and bromination to obtain 3-phenyl bromo propane; adding ethylamine hydrochloride in batches into excessive feed of the 3-phenyl bromo propane under the condition that organic base triethylamine and phase transfer catalyst exist to generate alverine free base in a 'one pot' mode; an organic layer is purified to be reacted with citric acid to produce crude citric acid alverine; the crude citric acid alverine is recrystallized through N-methyl pyrrolidone-water-DMF mixed solvent to obtain the novel crystal form B. Characteristic diffraction peaks are achieved at the positions of 4.18, 15.21, 20.53 and other positions of the value of 2 theta. The synthetic process route of the crystal form has the advantages that raw materials are easy to obtain, few reaction steps are needed, the condition is mild, operation is simple, and yield is high, and is environmentally friendly and easy to industrialize.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of new crystal of alverine citrate, i.e. crystal form B and preparation method thereof, also relate to the pharmaceutical composition comprising this new crystal and removing the pharmaceutical use in smooth muscle spasm.
Background technology
Alverine citrate, chemistry N-ethyl-N-(3-hydrocinnamyl) amphetamine Citrate trianion by name is a kind of Papaverine derivative of synthetic, is a kind of agents of calcium ion channel modulators with highly selective researched and developed by Norgine company of Britain.Alverine citrate went on the market in Britain first in 1996.It directly acts on unstriated muscle, optionally acts on the unstriated muscle of gi tract, uterus and Genito-urinary organ, has spasmolysis.Clinical pain, the biliary spasm being used for the treatment of irritable bowel syndrome, enterospasm, stomachache and being caused by diverticulosis, and the spasmic pain etc. of urinary tract stone or infection initiation.
Structural formula is as follows
。
At present, two import kinds are only had at the alverine preparation of China's listing, be the compound alverine citrate soft capsule (the happy strong element of trade(brand)name) in the excellent pharmaceutical factory made in Germany of alverine citrate capsule (trade(brand)name Spasmonal) and France of Norgine company of Britain respectively, domestic medicine still belongs to blank.
About the synthesis route of alverine, mainly contain following four kinds of methods.
Article 1, route French Patent FR20040004639 reports, with phenylpropyl alcohol acyl chlorides for raw material, reduces after ethamine amidation, with phenylpropionic acid dehydrating condensation under DCC effect, then obtains end product through lithium aluminium hydride reduction.This route cost of material is more expensive, need through twice reduction, and reaction conditions is harsher, and total recovery is not good.
Article 2 route is that the people such as Mao Xiantong report in " Hubei Chemical, 2000,4:23-24 ", with methyl phenyl ketone and ethylamine hydrochloride for raw material, through Mannich reaction, huang-Minlon reaction and obtain finished product with Citric Acid salify, total recovery is 46%, and the hydrazine toxicity used in this route is larger.This operational path method used is classical reaction, but reaction conditions is difficult to reach and larger to the harm of environment when scale operation, reaction needed as reducing carbonyl in huang-Minlon reaction is carried out under the condition of high temperature, and hydrazine reagent used has certain harm and toxicity to environment and people.
Article 3 route is " ChemBer, 1939,72:2161-2167 " is with the chloro-3-phenyl-propane of 1-for raw material, with ethamine under sodium hydroxide effect in pyroreaction, then through hydrochloric acid salify, add the steps such as alkali deacidification and obtain target product; This route cost of material is more expensive, and reaction is not thorough, also needs two-step purifying; Ethamine at high temperature volatility is comparatively large, and total recovery is not high.
Article 4 route is reference " Chinese Journal of Pharmaceuticals, 2012,43(3): 164-166 " and Chinese patent CN101838205A, and they disclose a kind of preparation method of new alverine citrate.The method take phenylpropyl alcohol as starting raw material, phenylpropyl alcohol is obtained 3-phenyl-bromide propane through bromo-reaction, obtained N-ethylamphetamine is reacted again with ethylamine solution, N-ethylamphetamine more in the basic conditions with 3-phenyl bromopropane reaction, and obtain diphenylpropyl ethamine through molecular distillation, and last and Citric Acid effect obtains final product--alverine citrate.The method step is long, needs first to prepare N-ethylamphetamine, then prepares diphenylpropyl ethamine; Need the ethylamine solution using larger danger in addition, this solution boiling point is very low, is about 16.6 DEG C, uses and stores equal inconvenience; Also will carry out molecular distillation operation, industrial being also difficult to realizes simultaneously.
Prior art report about alverine and Citric Acid salification process, and last recrystallizing and refining operation is all that use dehydrated alcohol is as solvent.Mensuration and the name of the crystal formation of alverine citrate is not specifically related in all documents.Also namely: alverine citrate of the prior art, the crystal type product of anhydrous ethanol solvent is almost all come from.In this alcohol crystal thing water, solubleness is poor, causes its solid preparation dissolution efficiency in vivo not high, and its major defect also has the poor stability in high humidity environment, is unfavorable for the prolonged storage of medicine.
Chemical compound lot can the form of different crystal forms or polymorphic form exist, and the crystal formation of same compound may be better more water-soluble than other crystal formations, and mobility is better, is easier to compressing tablet shaping etc.For pharmaceutical preparation, some solid form may be easier to bioavailable, simultaneously more stable under preparation, storage and biotic condition.
For the production process of raw material medicine, look for stability by force, be beneficial to prolonged storage or keep the stable crystal formation of physical chemistry to have great importance at certain environment.In order to improve its solubleness in water or dissolution rate, or the stability of long-term storage, research and development one is easy to useful in preparing drug formulations, and being easy to again realize industrialized new crystal is the focus paid close attention to.Crystal formation in view of compound is related to stability and solubleness, and then has an immense impact on to drug effect performance.Therefore, the improvement of suitable crystal formation to the some drugs character of alverine citrate is found significant.
Summary of the invention
Technical problem to be solved by this invention overcomes above-mentioned deficiency, and research and design one has good stability or solvability, is suitable for the alverine citrate new crystal of suitability for industrialized production, and preparation method thereof with the application in pharmaceutical industries.
First object of the present invention is to provide new crystal of a kind of alverine citrate monohydrate and preparation method thereof.Present invention also offers containing the pharmaceutical composition of this crystal form B as activeconstituents, and it removes the application in the medicine in smooth muscle spasm in preparation treatment.
The present inventor, in the process of research alverine citrate new crystal, goes through lot of experiments, unexpectedly obtains a kind of stability and all ideal new crystal of dissolution rate, called after alverine citrate crystal form B.
The invention provides a kind of crystal B of alverine citrate, this crystal formation is alverine citrate monohydrate, and structure is as follows; In X-ray powder diffraction figure, source of radiation is Cu-K α
1, be that 4.19,15.21,20.53 places have main significant diffractive features peak in 2 θ values, wherein 2 θ value limit of error are ± 0.2.
More characteristically, in the X-ray powder diffraction figure of this crystal form B, be that 4.19,7.82,10.23,12.09,13.11,15.21,17.46,19.09,20.53,26.51 places have diffraction peak in 2 θ values, wherein 2 θ value limit of error are ± 0.2; Its DSC collection of illustrative plates is at 84.6 ± 2.0 DEG C, and 103.4 ± 2.0 DEG C have dehydration endotherm peak and melting endotherm(ic)peak respectively.
More specifically, above-mentioned alverine citrate crystal form B, use Cu-K α radiation, as shown in Figure 1, DSC collection of illustrative plates refers to accompanying drawing 2, TG collection of illustrative plates as shown in Figure 3 to the collection of illustrative plates of its X-ray powder diffraction.
For crystal form B of the present invention, adopt Ka Erfeixiushi aquametry to confirm the existence of stoichiometric monohydrate, water content is between 3.3 ~ 4.0%.
TG collection of illustrative plates shows, between temperature 80 ~ 100 DEG C, because heated sample is slowly dewatered, the mass loss in its TG figure is equivalent to a crystal water, continues heating subsequently, and the fusion and decomposition obtaining sample is weightless.Equally, 84.6 ± 2.0 DEG C in DSC collection of illustrative plates, 103.4 ± 2.0 DEG C have dehydration endotherm peak and melting endotherm(ic)peak respectively, and this result is mutually corresponding with the weightless result of TG.
Those skilled in the art are to be understood that, various crystal formation data listed by the present invention, owing to being subject to the impact of the various factors such as test set and condition, X-ray powder diffraction pattern measured by same crystal formation go out that peak position or intensity can there is some difference, therefore, the experimental error of the diffraction peak Angle value in the X-ray powder diffraction pattern of crystal formation of the present invention is ± 0.2.
Another object of the present invention is to provide a kind of preparation method of alverine citrate crystal form B, and the method comprises following steps:
(1) between temperature 45 ~ 50 DEG C, Citric Acid is added thermosol in the mixed solvent of ethyl acetate and Virahol clear, drip the ethyl acetate solution of alverine free alkali, drip and finish, under continuing reflux state, stir 0.5 ~ 1h, Temperature fall to 20 ~ 30 DEG C, a large amount of white solid is separated out, suction filtration, washing, obtain alverine citrate, HPLC purity % more than 98.5 of wherein said " alverine free alkali ";
(2) by the alverine citrate of step 1 gained at temperature 45 ~ 50 DEG C, stirring and dissolving, in the mixed solvent of N-Methyl pyrrolidone and water, adds appropriate DMF, be cooled to-5 ~ 0 DEG C, leave standstill crystallization 4 ~ 5h, filter crystallize out, 35 ~ 40 DEG C of drying under reduced pressure, to obtain final product;
Or, by the alverine citrate of step 1 gained, at temperature 45 ~ 50 DEG C, stirring and dissolving, in the mixed solvent of N-Methyl pyrrolidone and water, is cooled to 10 ~ 15 DEG C, adds the crystal seed of gained alverine citrate crystal form B of the present invention, leave standstill crystallization 1.5 ~ 2h, filter crystallize out, 35 ~ 40 DEG C of drying under reduced pressure, to obtain final product.
Further, crystal form B of the present invention should be specifically noted that control temperature and humidity in drying process.The compound crystal separated can under room temperature or comparatively high temps (being less than 60 DEG C) drying under reduced pressure.In order to avoid generating anhydrous crystal forms, preferred drying temperature is 35 ~ 40 DEG C, and preferred relative humidity controls 20 ~ 40%.Also namely: in the process of dry alverine citrate crystal form B, for preventing excessive dehydration, humidity time dry should control the relative humidity 20 ~ 40%.
Further preferably, in step 1, ethyl acetate: the volume ratio of Virahol is 2 ~ 3:1, and ethyl acetate/isopropyl alcohol mixed solvent volume is 4 ~ 6 times of alverine free base weight, and unit is mL/g.
Further preferably, in step 2, N-Methyl pyrrolidone: the volume ratio of water is 1:1 ~ 1.5, and N-Methyl pyrrolidone/water mixed solvent volume is 4 ~ 5 times of the alverine citrate weight of step 1 gained, and unit is mL/g; DMF volume is 0.1 ~ 0.2 times of N-Methyl pyrrolidone and water mixed solvent cumulative volume; The amount of added crystal seed is 1 ~ 2% of the alverine citrate weight of step 1 gained.
The present invention is preparing in alverine citrate process, and the HPLC purity of the alverine free alkali of use is more than 98.5%, otherwise brings disadvantageous effect by the salt-forming reaction of follow-up alverine and the refining of monohydrate; Particularly, its preparation method comprises following steps:
A formula 2 compound phenylpropyl alcohol is dissolved in the dichloromethane solvent containing triethylamine by (), be cooled to 0 ~ 5 DEG C, slowly drip methylsulfonyl chloride, drip and finish, slowly rise to 25 ~ 30 DEG C, stirring reaction 2 ~ 4h, TLC monitoring reaction is complete, is concentrated into by reaction solution dry, obtain formula 3 compound, without separation, add appropriate DMF and dissolve, add Sodium Bromide, stirring reaction 6 ~ 8h at 25 ~ 30 DEG C, TLC monitoring reaction is complete, filters, adds water and ethyl acetate in filtrate, extraction separatory, after organic layer is washed, dry, concentrate and obtain formula 4 compound;
B formula 4 compound is dissolved in volume ratio DMF by (): in water=1:1 mixed solvent, add triethylamine and phase-transfer catalyst,
Temperature control is between 10 ~ 15 DEG C, add ethylamine hydrochloride in batches, finish, slowly be warming up to 35 ~ 40 DEG C, rapid stirring reaction 4 ~ 6h, TLC monitoring reaction is complete, filter, water and ethyl acetate is added in filtrate, extraction separatory, organic layer is concentrated into dry, in the crude product of gained alverine free alkali, add normal hexane stir and wash 0.5h, suction filtration, filter cake n-hexane, 3mol/LHCl is added in the filtrate of normal hexane, regulate pH2 ~ 3, stir, leave standstill separatory, aqueous phase n-hexane, collect aqueous phase, water layer shifts with methylene dichloride and extracts alverine hydrochloride, dichloromethane layer is used 5% solution of potassium carbonate successively, water, and saturated common salt water washing, anhydrous sodium sulfate drying, be concentrated into dry, obtain yellow oil formula 5 compound, HPLC purity is more than 98.5%, wherein, phase-transfer catalyst is selected from tetrabutylammonium chloride, Tetrabutyl amonium bromide, the one in benzyltriethylammoinium chloride.
Preferably, in step a, phenylpropyl alcohol: methylsulfonyl chloride: the mol ratio of Sodium Bromide is 1:1.5 ~ 2:2.5 ~ 3.
Preferably, in step b, phase-transfer catalyst is preferably benzyltriethylammoinium chloride; Formula 4 compound: the mol ratio of ethylamine hydrochloride is 2.2 ~ 2.5:1.
Present invention also offers a kind of pharmaceutical composition, comprise formula 1 compound crystal form B provided by the invention as activeconstituents, and pharmaceutically acceptable auxiliary material.The preparation of pharmaceutical composition is oral preparations, comprises tablet, granule, capsule, microcapsule, pill, dry suspensoid, pulvis.Preferably, preparation of the present invention, is preferably capsule.Specifically, in above-mentioned oral dosage form, crystal formation of the present invention contained by every agent (calculating with alverine) is for 30 ~ 100mg, is preferably 60mg.Medicinal compositions of the present invention obtains by conventional pharmaceutical adjuvants well known in the art and method.
This medicinal compositions may be used for treating the pharmaceutical use removing smooth muscle spasm aspect.
For oral solid preparation, conventional pharmaceutical excipient comprises weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent comprises starch, lactose, N.F,USP MANNITOL, Microcrystalline Cellulose; Tackiness agent comprises starch, lactose, N.F,USP MANNITOL, Microcrystalline Cellulose; Disintegrating agent comprises cross-linked cellulose sodium, polyvinylpolypyrrolidone, the HPMC of low replacement; Lubricant comprises Magnesium Stearate, talcum powder, polyoxyethylene glycol, Stepanol MG, micropowder silica gel, talcum powder etc.Pharmaceutical excipient as required, also can add tinting material and sweeting agent etc.
Preferably, alverine citrate dosage form of the present invention is preferably capsule, specifically can be divided into hard capsule and soft capsule.The hard capsule of alverine citrate includes crystal form B disclosed by the invention, starch, Magnesium Stearate, purified water, through wet granulation method, adopts 3# gelatin hollow capsule shell to carry out filling and forms.
The soft capsule of alverine citrate includes crystal form B disclosed by the invention and Simethicone, and both are mainly stirred the filling of rear injection soft gelatin capsule and form by preparation technology.
Technical solution of the present invention achieves following useful technique effect:
(1) the present invention reports a kind of alverine citrate crystal form B of novelty, and this crystal form B is chemically belonging to monohydrate, and crystal formation shelf stability is good, the water-soluble anhydrous crystal forms being better than having reported; The bulk drug of this crystal formation is very stable at memory period, and under hot and humid condition, particularly high humidity environment, crystal formation does not change; Purity and stable content good, single assorted little.
(2) preparation method of the present invention is more simple and convenient, and circulation ratio is strong; Pollution-free, cost is low, and the new crystal yield obtained is high, and purity is high, is applicable to scale operation; Both achieved easy and simple to handle, process stabilizing and yield advantages of higher, eliminate tedious steps of the prior art, effectively can also remove impurity, improves product purity.
(3) the alverine free alkali of HPLC purity of the present invention more than 98.5% is that the novel synthetic route of employing one and simple and easy to do technique are prepared from.The use of this route, solves the defects such as alverine free alkali synthesis purity in prior art not high (lower than 97%, always assorted content overproof) admirably.The present inventor probes into through deep technique, also special in the bromo-derivative impurity in alverine synthesis, the i.e. easy excessive problem of content of formula 4 compound, establish the mode of " first form alverine hydrochloride, rear alkalization dissociates ", adopt the washing system of normal hexane-water-dichloro hexane to remove, eliminate the impurity (bromo-derivative of the extremely difficult purifying of re-crystallization stage, i.e. formula 4 compound), greatly improve the purity of free alkali, also for good basis has been laid in follow-up salify and crystal formation preparation.
(4) the present inventor is for the large quantity research of crystallization condition and carefully exploration, be surprised to find on the basis of the mixed solvent of N-Methyl pyrrolidone and water, suitably add DMF, leave standstill crystallization through low temperature (-5 ~ 0 DEG C), obtain highly purified monohydrate crystal form with less solvent system and high yield.Using this monohydrate crystal form as crystal seed, by the interpolation of monohydrate crystal seed, without the need to long-time suspendible, leave standstill, recrystallization temperature low especially, or crystallization technique complicated especially, just can with speed (usual 1.5 ~ 2h) faster in higher temperature (10 ~ 15 DEG C), higher yield, is easy to industrialized method, obtained required hydrate novel crystal form.
(5) stability test result shows, alverine citrate new crystal B of the present invention, and in the intense environment such as hot and humid, crystal formation does not change, purity and stable content good, single assorted and total assorted content is low.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of alverine citrate crystal form B.
Fig. 2 is the DSC figure of alverine citrate crystal form B.
Fig. 3 is the TG figure of alverine citrate crystal form B.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is further described.
The preparation of embodiment 1 alverine free alkali
By formula 2 compound phenylpropyl alcohol (137g; 1mol) be dissolved in the dichloromethane solvent 900mL containing triethylamine (205g, 2mol), be cooled to 0-5 DEG C; slow dropping methylsulfonyl chloride (172g; 1.5mol), drip and finish, slowly rise to 25 ~ 30 DEG C; stirring reaction 2 ~ 4h; TLC monitoring reaction is complete, is concentrated into by reaction solution dry, obtains formula 3 compound; Without separation, add appropriate DMF and dissolve, add Sodium Bromide (255g, 2.5mol), at 25 ~ 30 DEG C, stirring reaction 6 ~ 8h, TLC monitoring reaction is complete, filters, water 800mL and ethyl acetate 1000mL is added in filtrate, extraction separatory, after organic layer is washed, dry, concentrated obtain formula 4 compound and be about 160g, yield 80%.
By above-mentioned formula 4 compound (160g, 0.79mol) be about dissolved in volume ratio DMF: in water=1:1 mixed solvent 1000mL, add triethylamine (100g, 1mol) with benzyltriethylammoinium chloride (12g, 0.05mol), temperature control is between 10 ~ 15 DEG C, add ethylamine hydrochloride (29.5g in batches, 0.36mol), finish, slowly be warming up to 35 ~ 40 DEG C, rapid stirring 4 ~ 6h, TLC monitoring reaction is complete, filter, water 800mL and ethyl acetate 800mL is added in filtrate, extraction separatory, organic layer is concentrated into dry, normal hexane 1500mL agitator treating 0.5h is added in the crude product of gained alverine free alkali, suction filtration, filter cake 300mL n-hexane, 3mol/LHCl is added in the filtrate of normal hexane, regulate pH2-3, stir, leave standstill separatory, aqueous phase normal hexane 300mL washs, collect aqueous phase, water layer is extracted with methylene dichloride 1000mL again and shifts alverine hydrochloride, dichloromethane layer is used 5% solution of potassium carbonate successively, water, and saturated common salt water washing, anhydrous sodium sulfate drying, be concentrated into dry, obtain yellow oil formula 5 compound and be about 175g, yield 82%, HPLC purity about 98.6%.
The preparation of embodiment 2 alverine free alkali
By formula 2 compound phenylpropyl alcohol (137g, 1mol) be dissolved in the dichloromethane solvent 1000mL containing triethylamine (208g, 2mol), be cooled to 0 ~ 5 DEG C, slow dropping methylsulfonyl chloride (228g, 2mol), drip and finish, slowly rise to 25 ~ 30 DEG C, stirring reaction 2 ~ 4h, TLC monitoring reaction is complete, is concentrated into by reaction solution dry, obtains formula 3 compound; Without separation, add appropriate DMF and dissolve, add Sodium Bromide (306g, 3mol), at 25 ~ 30 DEG C, stirring reaction 6 ~ 8h, TLC monitoring reaction is complete, filters, water 800mL and ethyl acetate 1000mL is added in filtrate, extraction separatory, after organic layer is washed, dry, concentrated obtain formula 4 compound and be about 165g, yield 80%.
By above-mentioned formula 4 compound (165g, 0.80mol) be about dissolved in volume ratio DMF: in water=1:1 mixed solvent 1200mL, add triethylamine (110g, 1mol) with benzyltriethylammoinium chloride (12g, 0.05mol), temperature control is between 10 ~ 15 DEG C, add ethylamine hydrochloride (26.2g in batches, 0.32mol), finish, slowly be warming up to 35 ~ 40 DEG C, rapid stirring 4 ~ 6h, TLC monitoring reaction is complete, filter, water 800mL and ethyl acetate 800mL is added in filtrate, extraction separatory, organic layer is concentrated into dry, normal hexane 1500mL agitator treating 0.5h is added in the crude product of gained alverine free alkali, suction filtration, filter cake 300mL n-hexane, 3NHCl is added in the filtrate of normal hexane, regulate pH2 ~ 3, stir, leave standstill separatory, aqueous phase normal hexane 300mL washs, collect aqueous phase, water layer is extracted with methylene dichloride 1000mL again and shifts alverine hydrochloride, dichloromethane layer is used 5% solution of potassium carbonate successively, water, and saturated common salt water washing, anhydrous sodium sulfate drying, be concentrated into dry, obtain yellow oil formula 5 compound 170g, yield about 80%, HPLC purity about 98.5%.
The preparation of embodiment 3 alverine citrate crystal form B
Embodiment 1 method is first adopted to obtain the alverine free alkali of HPLC purity 98.6%, then salify and refining by the following method.
Between temperature 45-50 DEG C, by Citric Acid (57.5g, 0.3mol) thermosol clarification in the mixed solvent of ethyl acetate 240mL and Virahol 120mL, drip above-mentioned gained alverine free alkali (85g, ethyl acetate 100mL solution 0.3mol), drip and finish, under continuing reflux state, stir 0.5 ~ 1h, Temperature fall to 20 ~ 30 DEG C, a large amount of white solid is separated out, suction filtration, washing, obtains alverine citrate and is about 128g.
The alverine citrate of above-mentioned gained is about 128g, and at temperature 45 ~ 50 DEG C, stirring and dissolving is in the mixed solvent of N-Methyl pyrrolidone 260mL and water 260mL, add appropriate DMF and be about 55mL, be cooled to-5 ~ 0 DEG C, leave standstill crystallization 4-5h, filter crystallize out, filter crystallize out, 35 ~ 40 DEG C of drying under reduced pressure, humid control, in the relative humidity of 20 ~ 40%, obtains off-white color solid 122g, yield about 92%, HPLC purity is 99.7%.
The preparation of embodiment 4 FCE-26743A Mesylate Form B
Embodiment 1 method is first adopted to obtain the alverine free alkali of HPLC purity 98.6%, then salify and refining by the following method.
Between temperature 45 ~ 50 DEG C, by Citric Acid (58.3g, 0.3mol) thermosol clarification in the mixed solvent of ethyl acetate 375mL and Virahol 125mL, drip appeal gained alverine free alkali (86g, ethyl acetate 150mL solution 0.3mol), drip and finish, under continuing reflux state, stir 0.5 ~ 1h, Temperature fall to 20 ~ 30 DEG C, a large amount of white solid is separated out, suction filtration, washing, obtains alverine citrate and is about 126g.
The alverine citrate of above-mentioned gained is about 126g, and at temperature 45 ~ 50 DEG C, stirring and dissolving is in the mixed solvent of N-Methyl pyrrolidone 500mL and water 125mL, be cooled to 10 ~ 15 DEG C, the crystal seed adding gained alverine citrate crystal form B of the present invention is about 1.2g, leaves standstill crystallization 1.5-2h, filters crystallize out, 35 ~ 40 DEG C of drying under reduced pressure, humid control, in the relative humidity of 20 ~ 40%, obtains off-white color solid 119g, yield about 91%, HPLC purity is 99.6%.
Embodiment 5 contrasts the preparation of crystal form A
Alverine citrate of the prior art almost all from ethyl alcohol recrystallization, temporarily referred to as crystal form A.Experimental technique in the present inventor's reference " Chinese Journal of Pharmaceuticals; 2012,43:164-166 " and Chinese patent CN200910103386, adopts same alverine free alkali, gas phase purity is greater than 98.5%, carries out the salify in alcohol solvent and recrystallization process.
By alverine free alkali (10g, 35.6mmol), Citric Acid (6.9g, 36.0mmol) with dehydrated alcohol 150mL, reflux 20min, is cooled to 0 DEG C of standing 0.5h, filters, filter cake dehydrated alcohol recrystallization, obtain white solid, namely contrast crystal form A and be about 14.5g, yield 96%, purity 99.5%.
The sign of embodiment 6 alverine citrate crystal form B
Above-described embodiment 2 or the obtained alverine citrate crystal form B of embodiment 3 be placed on powder diffractometer (ThermoX ' TRA type X-ray diffractometer) by X-ray method (x-ray powder diffraction in Chinese Pharmacopoeia annex), with Cu-K α 40kV ~ 40mAX-x radiation x, scan at 3 ~ 50 degree of 2 θ with the sweep velocity of 8 degree/point.By differential thermal analysis DSC method, on NETZSCHDSC204 type differential thermal analyzer, with 10 DEG C/min temperature rise rate, 30-300 DEG C of temperature range interscan.TG thermogravimetric analysis is also carry out according to pharmacopoeial requirements.
For crystal form B of the present invention, adopt Ka Erfeixiushi aquametry to confirm the existence of stoichiometric monohydrate, water content is 3.65 ~ 3.78%.
Results of elemental analyses shows below, theoretical value C:63.53%, H:7.59%, N:2.85%, measured value C:63.59%, H:7.61%, N:2.88%
More specifically, as shown in Figure 1, DSC collection of illustrative plates refers to accompanying drawing 2, TG collection of illustrative plates as shown in Figure 3 to the collection of illustrative plates of its X-ray powder diffraction.
In the X-ray powder diffraction figure of the crystal B of alverine citrate, be that 4.19,15.21,20.53 places have the strongest characteristic diffraction peak in 2 θ values, wherein 2 θ value limit of error are ± 0.2.More characteristically, in the X-ray powder diffraction figure of this crystal form B, be that 4.19,7.82,10.23,12.09,13.11,15.21,17.46,19.09,20.53,26.51 places have the strongest and secondary strong characteristic diffraction peak in 2 θ values, wherein 2 θ value limit of error are ± 0.2; Its DSC collection of illustrative plates is at 84.6 ± 2.0 DEG C, and 103.4 ± 2.0 DEG C have dehydration endotherm peak and melting endotherm(ic)peak respectively.
TG collection of illustrative plates shows, between temperature 80 ~ 100 DEG C, because heated sample is slowly dewatered, the mass loss in its TG figure is equivalent to a crystal water, continues heating subsequently, and the fusion and decomposition obtaining sample is weightless.Equally, 84.6 ± 2.0 DEG C in DSC collection of illustrative plates, 103.4 ± 2.0 DEG C have dehydration endotherm peak and melting endotherm(ic)peak respectively, and this result also result weightless with TG is mutually corresponding.
The estimation of stability of embodiment 7 alverine citrate crystal form B
By the alcohol crystal thing crystal form A of alverine citrate crystal form B of the present invention and bibliographical information, carry out influence factor test, accelerated stability test, test method is see the bulk drug in Chinese Pharmacopoeia annex and pharmaceutical preparation stability test governing principle.
(1), influence factor test:
1, high temperature test: get alverine citrate crystal form A and crystal form B, at 60 DEG C of temperature place 10 days, in the 5th day and the 10th day sampling, mensuration indices and 0 time sample compare, test-results sees the following form.
2, high wet test: get alverine citrate crystal form A and crystal form B, places 10 days under RH75%, and in the 5th day and sampling in the 10th day, mensuration indices and 0 day sample compared, and test-results sees the following form.
3, strong illumination test: get alverine citrate crystal form A and crystal form B, be place 10 days under the condition of (4500 ± 500) LX in illumination, samples in the 5th day and the 10th day, and the sample of mensuration indices and 0 day compares, and test-results sees the following form.
(2) accelerated stability test
By alverine citrate crystal form A and crystal form B, in climatic chamber, carry out the accelerated stability test of 6 months.Test conditions is: 40 DEG C/75% relative humidity (RH), respectively at sampling in 0,1,2,3,6 month, carries out purity and foreign impurity matters test (high performance liquid chromatography) and PXRD and characterizes, the results are shown in following table.
From upper table result, the stability of alverine citrate crystal form B is better than of the prior art.In hot and humid condition, particularly in high humidity environment, crystal formation does not change, purity and stable content good, single assorted and total assorted less.Thus, the alverine citrate crystal form B of gained of the present invention, has fairly obvious lifting in stability, with the obvious advantage.
The hard capsule of embodiment 8 alverine citrate crystal form B and preparation technology
Alverine citrate crystal form B 60g (with alverine weighing scale)
Starch 85g
Magnesium Stearate 1g
Purified Water q. s
Prepare 1000 hard capsules altogether
Preparation technology: the alverine raw material of recipe quantity and starch mixing are also crossed 80 mesh sieves repeatedly, stirs in stirrer; Stir while add appropriate purified water, stir 3 ~ 5min in stirrer discontinuous formula, pour out particle, reach the state of " hold agglomerating, namely light pressure falls apart "; Above-mentioned wet granular is crossed 24 mesh sieves to wet whole grain, dry 2 hours in 60 DEG C of baking ovens, control moisture about 4%; The particle of oven dry is crossed the whole grain of 24 mesh sieve; The particle that above-mentioned dry whole grain completes is weighed and added Magnesium Stearate in proportion, mixes by equal increments method, obtain alverine citrate intermediate; Alverine citrate intermediate 3# capsule-filling plate is carried out filling, finally aluminum-plastic packaged, to obtain final product.
The soft capsule of embodiment 9 alverine citrate crystal form B and preparation technology
Alverine citrate crystal form B 60g (with alverine weighing scale)
Simethicone 300g
Prepare 1000 soft capsules altogether
Preparation technology: add the Simethicone of 50% in the mixing container, stir with the speed of 10 ~ 15 revs/min, to guarantee that Simethicone can not by violent stirring, this stirring contributes to the mobility forming and keep Simethicone, thus obtains the optimum dispersion of alverine citrate.Divide 3 batches to add alverine citrate again, carry out vigorous stirring, control stirring velocity at 1500 ~ 1700 revs/min, guarantee to disperse and dispersate even, finally add the remainder of Simethicone, continue stirring 30 ~ 60min, inject soft gelatin capsule immediately, encapsulating is shaped, and to obtain final product.
The preparation dissolution rate of embodiment 10 alverine citrate crystal form B is evaluated
Dissolving-out method: Chinese Pharmacopoeia 2015 editions
Paddle method rotating speed: 50 turns
Medium temperature: 37 ± 0.5 DEG C
Measuring method: ultraviolet visible spectrophotometry
Method of calculation: external standard method
Contrast solution compound method: get the reference substance being dried to constant weight appropriate, accurately weighed, be diluted to the solution of about 5 μ g in every 1ml with dissolution medium.
Take the contrast crystal form A of same quality and the obtained alverine citrate crystal form B of embodiment 2 respectively, adopt identical technique to obtain hard capsule preparation, often criticize 6, using water as dissolution medium, test according to above-mentioned stripping and measuring method.The appropriate also fluid infusion of solution is got respectively at 5min, 10min, 15min, 30min, 45min, 60min, filter, it is appropriate that precision measures filtrate, adds the solution that stripping WATER AS FLOW MEDIUM is diluted to about 5 μ g in every 1ml, calculate dissolution rate according to high-efficient liquid phase technique, result is as shown in the table.
Be not difficult to find out by upper table result, make identical capsule under similarity condition after, in same time (first 15 minutes), after crystal formation of the present invention makes preparation, its dissolution rate is faster, and result of extraction is better.The dissolution rate of alverine citrate crystal form B hard capsule is greater than contrast crystal form A and is correlated with the dissolution rate of capsule.The capsule that the present invention adopts alverine citrate crystal form B to make dissolution rate and aspect of performance outstanding.
The stability test of embodiment 11 alverine citrate crystal form B hard capsule is investigated
According to the investigation project in " the medicine stability test governing principle " of Chinese Pharmacopoeia 2015 editions listed by stability test, factors influencing is carried out to alverine citrate crystal form B hard capsule of the present invention.
Prepare alverine citrate crystal form B hard capsule according to the method for the embodiment of the present invention, pack according to commercially available situation, be placed in intensity of illumination 4500Lx ± 500Lx, high temperature 60 DEG C and high humidity RH92.5 ± 5% time, place 10 days, detect respectively at the 5th day and sampling in the 10th day, the results are shown in following table.
Conclusion: this product after factors influencing, content, related substance, content color, and 15min dissolution rate is with comparing there was no significant difference in 0 day, be salable product, further demonstrate that the present invention's crystal form B used is that preparation prepared by raw material possesses higher stability.
Should be noted that; the foregoing is only preferred embodiment of the present invention; be not limited to scope of the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (10)
1. an alverine citrate crystal form B, is characterized in that, this crystal form B is the new crystal of alverine citrate monohydrate, has as shown in the formula the structure shown in 1,
；
And using Cu-K α radiation, in its X-ray powder diffraction pattern, be that 4.19,15.21,20.53 places have significant diffractive features peak in 2 θ values, wherein 2 θ value limit of error are ± 0.2.
2. alverine citrate crystal form B according to claim 1, it is characterized in that, use Cu-K α radiation, its X-ray powder diffraction pattern, be that 4.19,7.82,10.23,12.09,13.11,15.21,17.46,19.09,20.53,26.51 places have diffraction peak in 2 θ values, wherein 2 θ value limit of error are ± 0.2; Further, its DSC collection of illustrative plates is at 84.6 ± 2.0 DEG C, and 103.4 ± 2.0 DEG C have dehydration endotherm peak and melting endotherm(ic)peak respectively.
3. alverine citrate crystal form B according to claim 2, is characterized in that, as shown in Figure 1, as shown in Figure 2, its TG collection of illustrative plates as shown in Figure 3 for its DSC collection of illustrative plates for its PXRD collection of illustrative plates; And adopting Ka Erfeixiushi aquametry to confirm the existence of stoichiometric monohydrate, the water content of this crystal form B is between 3.3 ~ 4.0%.
4. prepare a method for alverine citrate crystal form B as claimed any one in claims 1 to 3, it is characterized in that, comprise following steps:
(1) between temperature 45 ~ 50 DEG C, Citric Acid is added thermosol in the mixed solvent of ethyl acetate and Virahol clear, drip the ethyl acetate solution of alverine free alkali, drip and finish, under continuing reflux state, stir 0.5 ~ 1h, Temperature fall to 20 ~ 30 DEG C, a large amount of white solid is separated out, suction filtration, washing, obtain alverine citrate, the HPLC purity of wherein said " alverine free alkali " is more than 98.5%;
(2) by the alverine citrate of step 1 gained, at temperature 45 ~ 50 DEG C, stirring and dissolving is in the mixed solvent of N-Methyl pyrrolidone and water, add appropriate DMF, be cooled to-5 ~ 0 DEG C, leave standstill crystallization 4 ~ 5h, filter crystallize out, 35 ~ 40 DEG C of drying under reduced pressure, to obtain final product;
Or, by the alverine citrate of step 1 gained, at temperature 45 ~ 50 DEG C, stirring and dissolving, in the mixed solvent of N-Methyl pyrrolidone and water, is cooled to 10 ~ 15 DEG C, adds the crystal seed of the alverine citrate crystal form B of gained of the present invention, leave standstill crystallization 1.5 ~ 2h, filter crystallize out, 35 ~ 40 DEG C of drying under reduced pressure, to obtain final product.
5. preparation method according to claim 4, is characterized in that, in the process of drying under reduced pressure finished product alverine citrate crystal form B, for preventing excessive dehydration, humidity time dry should control the relative humidity 20 ~ 40%.
6. preparation method according to claim 4, is characterized in that, in step 1, and ethyl acetate: the volume ratio of Virahol is 2 ~ 3:1, and ethyl acetate/isopropyl alcohol mixed solvent volume is 4 ~ 6 times of alverine free base weight, and unit is mL/g; In step 2, N-Methyl pyrrolidone: the volume ratio of water is 1:1 ~ 1.5, and N-Methyl pyrrolidone/water mixed solvent volume is 4 ~ 5 times of the alverine citrate weight of step 1 gained, and unit is mL/g; DMF volume is 0.1 ~ 0.2 times of N-Methyl pyrrolidone and water mixed solvent cumulative volume; The amount of added crystal seed is 1 ~ 2% of the alverine citrate weight of step 1 gained.
7. preparation method according to claim 6, is characterized in that, the alverine free alkali of described HPLC purity more than 98.5% adopts following synthetic route and technique to be prepared from, and specifically comprises following steps:
A formula 2 compound phenylpropyl alcohol is dissolved in the dichloromethane solvent containing triethylamine by (), be cooled to 0 ~ 5 DEG C, slowly drip methylsulfonyl chloride, drip and finish, slowly rise to 25 ~ 30 DEG C, stirring reaction 2 ~ 4h, TLC monitoring reaction is complete, is concentrated into by reaction solution dry, obtain formula 3 compound, without separation, add appropriate DMF and dissolve, add Sodium Bromide, stirring reaction 6 ~ 8h at 25 ~ 30 DEG C, TLC monitoring reaction is complete, filters, adds water and ethyl acetate in filtrate, extraction separatory, after organic layer is washed, dry, concentrate and obtain formula 4 compound;
B formula 4 compound is dissolved in volume ratio DMF by (): in water=1:1 mixed solvent, add triethylamine and phase-transfer catalyst, temperature control is between 10 ~ 15 DEG C, add ethylamine hydrochloride in batches, finish, slowly be warming up to 35 ~ 40 DEG C, rapid stirring reaction 4 ~ 6h, TLC monitoring reaction is complete, filter, water and ethyl acetate is added in filtrate, extraction separatory, organic layer is concentrated into dry, in the crude product of gained alverine free alkali, add normal hexane stir and wash 0.5h, suction filtration, filter cake n-hexane, 3mol/LHCl is added in the filtrate of normal hexane, regulate pH2 ~ 3, stir, leave standstill separatory, aqueous phase n-hexane, collect aqueous phase, water layer shifts with methylene dichloride and extracts alverine hydrochloride, dichloromethane layer is used 5% solution of potassium carbonate successively, water, and saturated common salt water washing, anhydrous sodium sulfate drying, be concentrated into dry, obtain yellow oil formula 5 compound, HPLC purity is more than 98.5%, wherein, phase-transfer catalyst is selected from the one in tetrabutylammonium chloride, Tetrabutyl amonium bromide, benzyltriethylammoinium chloride.
8. preparation method according to claim 7, is characterized in that, in step a, and phenylpropyl alcohol: methylsulfonyl chloride: the mol ratio of Sodium Bromide is 1:1.5 ~ 2:2.5 ~ 3; In step b, phase-transfer catalyst is preferably benzyltriethylammoinium chloride; Formula 4 compound: the mol ratio of ethylamine hydrochloride is 2.2 ~ 2.5:1.
9. a pharmaceutical composition, is characterized in that, comprises alverine citrate crystal form B as claimed any one in claims 1 to 3 as activeconstituents, and pharmaceutically acceptable auxiliary material; Further, the dosage form of pharmaceutical composition is capsule.
10. pharmaceutical composition according to claim 9, is characterized in that, said preparation form is hard capsule, and prescription contains alverine citrate crystal form B as claimed any one in claims 1 to 3, starch, Magnesium Stearate, purified water; Through wet granulation method, adopt 3# gelatin hollow capsule shell to carry out filling and form; Or the dosage form of this pharmaceutical composition is soft capsule, be that alverine citrate crystal form B as claimed any one in claims 1 to 3 and Simethicone are stirred, inject soft gelatin capsule filling and form.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20060223891A1 (en) * | 2003-06-13 | 2006-10-05 | Cerep | Use of alverine, alone or in combination with a tricyclic antidepressant or an antidepressant which is a specific inhibitor of serotonin reuptake for treatment of depression |
| CN101838205A (en) * | 2009-03-16 | 2010-09-22 | 重庆北碚现代应用药物研究所 | New method for preparing alverine citrate |
| CN103508898A (en) * | 2012-06-26 | 2014-01-15 | 河北凯盛医药科技有限公司 | Novel preparation method of alverine citrate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20060223891A1 (en) * | 2003-06-13 | 2006-10-05 | Cerep | Use of alverine, alone or in combination with a tricyclic antidepressant or an antidepressant which is a specific inhibitor of serotonin reuptake for treatment of depression |
| CN101838205A (en) * | 2009-03-16 | 2010-09-22 | 重庆北碚现代应用药物研究所 | New method for preparing alverine citrate |
| CN103508898A (en) * | 2012-06-26 | 2014-01-15 | 河北凯盛医药科技有限公司 | Novel preparation method of alverine citrate |
Non-Patent Citations (1)
| Title |
|---|
| 杨丹等: "枸橼酸阿尔维林的合成", 《中国医药工业杂志》 * |
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|---|---|---|---|---|
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