CN105461569B - A kind of alverine citrate novel crystal forms and preparation method thereof - Google Patents
A kind of alverine citrate novel crystal forms and preparation method thereof Download PDFInfo
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Abstract
Novel crystal forms B the present invention relates to a kind of alverine citrate and preparation method thereof, and the application crystal formation is used as the pharmaceutical composition of active component.It is initial with phenylpropanol cheap and easy to get that preparation method of the present invention is, 3 phenyl-bromides are obtained for propane through sulfonic acid esterification and bromination；And under organic bases triethylamine and phase transfer catalyst existence condition, be dividedly in some parts ethylamine hydrochloride for the Excess quantities of propane in 3 phenyl-bromides again, " treating different things alike " generate alverine free alkali；After by organic layer purification process, alverine citrate crude product is obtained with citric acid effect.Alverine citrate crude product is recrystallized through the mixed solvent of N methyl pyrrolidone water DMF, obtains novel crystal forms B.In X-ray powder diffraction figure, there is characteristic diffraction peak in 2 θ values 4.18,15.21,20.53 etc..There is synthesis route of the present invention raw material to be easy to get, and reactions steps are few, and mild condition is simple to operate, be an environment-friendly and easy industrialized synthetic route the features such as high income.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of novel crystal forms of alverine citrate, i.e. crystal formation B and its
Preparation method, further relates to medicinal usage of the pharmaceutical composition comprising the novel crystal forms in terms of smooth muscle spasm is released.
Background technology
Alverine citrate, chemical entitled N- ethyls-N- (3- phenylpropyls) amphetamine citrate is a kind of artificial conjunction
Into opium poppy alkali derivant, be by Norgine companies of Britain research and develop a kind of agents of calcium ion channel modulators with high selectivity.
Alverine citrate was listed in Britain first in 1996.It directly acts on smooth muscle, optionally acts on stomach and intestine
The smooth muscle in road, uterus and Genito-urinary organ, with spasmolysis.Be clinically used for treatment irritable bowel syndrome, enterospasm,
Stomachache and the pain, the biliary spasm that are caused by diverticulosis, and urinary stone or the spasmic pain of infection initiation etc..
Structural formula is as follows
At present, the alverine preparation in China's listing only has two import kinds, is respectively Norgine companies of Britain
The compound alverine citrate soft capsule (business in the excellent pharmaceutical factory made in Germany of alverine citrate capsule (trade name Spasmonal) and France
The strong element of name of an article pleasure), domestic medicine still belongs to blank.
About the synthesis route of alverine, mainly there is following four method.
First route French Patent (FRP) FR20040004639 report, with phenylpropyl alcohol acyl chlorides as raw material, after ethamine amidatioon
Reduction, with benzenpropanoic acid DCC effect under dehydrating condensation, then hydrogenated aluminium lithium reduction obtain end-product.The route raw material price compared with
It is expensive, need to be through reducing twice, reaction condition is harsher, and total recovery is not good.
Article 2 route is Mao Xiantong et al. in " Hubei Chemical, 2000,4：Report in 23-24 ", with acetophenone and second
Amine hydrochlorate is raw material, and finished product is obtained into salt through Mannich reactions, huang-Minlon reaction and with citric acid, and total recovery is 46%,
The hydrazine toxicity used in the route is larger.Method used by the process route is classical reaction, but in large-scale production
Reaction condition is extremely difficult to and larger to the harm of environment, and such as the reaction of reducing carbonyl needs the bar in high temperature in huang-Minlon reaction
Carried out under part, hydrazine reagent used has certain harm and toxicity to environment and people.
Article 3 route is " Chem Ber, 1939,72:2161-2167 " be with the chloro- 3- phenyl-propanes of 1- as raw material, with
Ethamine NaOH effect under in pyroreaction, then through hydrochloric acid into salt, plus alkali deacidification etc. step obtain target product；The route
Cost of material is more expensive, and reaction thoroughly, two-step purifying is not needed also；Volatility is larger at high temperature for ethamine, and total recovery is not high.
Article 4 route is bibliography " Chinese Journal of Pharmaceuticals, 2012,43 (3)：164-166 " and Chinese patent
CN101838205A, they disclose a kind of preparation method of new alverine citrate.The method is initial with phenylpropanol
Raw material, is obtained 3- phenyl N-Propyl Bromides, then N-ethylamphetamine, ethylo benzene is obtained with ethylamine solution reaction by phenylpropanol through bromo-reaction
Propylamine again in the basic conditions with 3- phenyl bromopropane reactions, and diphenylpropyl ethamine is obtained by high vacuum distillation, finally with
Citric acid effect is obtained final product -- alverine citrate.The method step is long, it is necessary to first prepare N-ethylamphetamine, then makes
Standby diphenylpropyl ethamine；The ethylamine solution of larger danger is additionally needed to use, the solution boiling point is very low, about 16.6
DEG C, use and store inconvenience；High vacuum distillation operation is also carried out simultaneously, is industrially also difficult to.
What prior art was reported operates on alverine and citric acid salification process, and last recrystallizing and refining,
It is to use absolute ethyl alcohol as solvent.There is no the measure and life of the specifically related to crystal formation of alverine citrate in all documents
Name.Namely：Alverine citrate of the prior art, almost all comes from the crystal type product of anhydrous ethanol solvent.The second
Solubility is poor in alcohol crystal water, causes its solid pharmaceutical preparation dissolution efficiency in vivo not high, and its major defect also has
Stability in high humidity environment is poor, is unfavorable for the longer-term storage of medicine.
Many compounds can exist in the form of different crystal forms or polymorph, and the crystal formation of same compound may be than other
Crystal formation is water-soluble more preferably, and mobility is more preferable, it is easier to compressing tablet shaping etc..For pharmaceutical preparation, some solid forms may
It is easier to be bioavailable, while more stablizing under preparation, storage and biotic factor.
For the production process of raw material medicine, stability is looked for by force, kept beneficial to longer-term storage or in certain environment
The crystal formation of physical chemistry stabilization has great importance.In order to improve its solubility or dissolution rate in water, or for a long time
The stability of storage, researchs and develops a kind of easily prepared pharmaceutical preparation, and Jiao that industrialized novel crystal forms are concerns is easily achieved again
Point.In view of the crystal formation of compound is related to stability and solubility, and then drug effect performance is had an immense impact on.Therefore, find
Suitable improvement of the crystal formation to some drugses property of alverine citrate is significant.
The content of the invention
The technical problems to be solved by the invention are to overcome above-mentioned deficiency, and research and design is a kind of to have good stability or molten
Xie Xing, is suitable to the alverine citrate novel crystal forms of industrialized production, and preparation method thereof with the application in pharmaceutical industries.
The purpose of the present invention is to provide a kind of novel crystal forms of alverine citrate monohydrate and preparation method thereof first.
Present invention also offers containing crystal formation B as active component pharmaceutical composition, and its prepare treatment release smooth muscle
The application in medicine in terms of spasm.
The present inventor, after lot of experiments, unexpectedly obtains during alverine citrate novel crystal forms are studied
The all ideal novel crystal forms of a kind of stability and dissolution rate, are named as alverine citrate crystal formation B.
The invention provides a kind of crystal B of alverine citrate, the crystal formation is alverine citrate monohydrate,
Structure is as follows；In X-ray powder diffraction figure, radiation source is Cu-K α1, it is have master at 4.19,15.21,20.53 in 2 θ values
Significant diffractive features peak is wanted, wherein 2 θ values error ranges are ± 0.2.
More characteristically, in the X-ray powder diffraction figure of crystal formation B, 2 θ values be 4.19,7.82,10.23,12.09,
13.11st, there is diffraction maximum at 15.21,17.46,19.09,20.53,26.51, wherein 2 θ values error ranges are ± 0.2；Its DSC schemes
At 84.6 ± 2.0 DEG C, 103.4 ± 2.0 DEG C have dehydration endotherm peaks and melting endothermic peak to spectrum respectively.
More specifically, above-mentioned alverine citrate crystal formation B, is radiated, the figure of its X-ray powder diffraction using Cu-K α
As shown in Figure 1, DSC collection of illustrative plates refers to accompanying drawing 2 to spectrum, and TG collection of illustrative plates is as shown in Figure 3.
For crystal formation B of the present invention, confirm that the monohydrate of stoichiometry is deposited using Ka Erfeixiushi aquametries
Water content is between 3.3~4.0%.
TG collection of illustrative plates shows, between 80~100 DEG C of temperature, because heating sample is slowly dehydrated, the quality in its TG figure is damaged
Lose equivalent to a crystallization water, continue thereafter with heating, the fusion and decomposition for obtaining sample is weightless.Equally, 84.6 in DSC collection of illustrative plates
± 2.0 DEG C, 103.4 ± 2.0 DEG C have dehydration endotherm peaks and melting endothermic peak respectively, and the result is mutually corresponding with TG weightlessness results.
It should be understood by those skilled in the art that, the various crystal formation data listed by the present invention, due to by testing equipment and
The influence of the various factors such as condition, X-ray powder diffraction pattern measured by same crystal formation goes out peak position or intensity meeting
There is some difference, therefore, the experimental error of the diffraction maximum Angle values in the X-ray powder diffraction pattern of crystal formation of the present invention can
Meaning ± 0.2.
It is a further object to provide a kind of preparation method of alverine citrate crystal formation B, the method is included
Following steps：
(1) between 45~50 DEG C of temperature, citric acid is heated molten clear, drop in the mixed solvent of ethyl acetate and isopropanol
Plus the ethyl acetate solution of alverine free alkali, drop finishes, continues to stir 0.5~1h under reflux state, it is naturally cooling to 20~
30 DEG C, a large amount of white solids are separated out, suction filtration, and washing obtains alverine citrate, wherein " the alverine free alkali "
HPLC purity % more than 98.5；
(2) by the alverine citrate of step 1 gained at 45~50 DEG C of temperature, stirring and dissolving is in N- crassitudes
In the mixed solvent of ketone and water, appropriate DMF is added, be cooled to -5~0 DEG C, stand 4~5h of crystallization, filtered and separate out crystal, 35~
40 DEG C of drying under reduced pressure, obtain final product；
Or, by the alverine citrate of step 1 gained, at 45~50 DEG C of temperature, stirring and dissolving is in N- methyl pyrroles
In the mixed solvent of pyrrolidone and water, 10~15 DEG C are cooled to, add the crystalline substance of present invention gained alverine citrate crystal formation B
Kind, 1.5~2h of crystallization is stood, filtering separates out crystal, and 35~40 DEG C of drying under reduced pressure are obtained final product.
Further, crystal formation B of the present invention should be specifically noted that control temperature and humidity in drying process.The change separated
Solvate crystal can under room temperature or higher temperature (being less than 60 DEG C) drying under reduced pressure.In order to avoid generating anhydrous crystal forms, preferably
Drying temperature is 35~40 DEG C, and preferred relative humidity control is 20~40%.Namely：Drying alverine citrate crystal formation
During B, to prevent excessive dehydration, humidity when drying should control the relative humidity 20~40%.
It is further preferred that in step 1, ethyl acetate：The volume ratio of isopropanol is 2~3：1, ethyl acetate/isopropanol
Mixed solvent volume is 4~6 times of alverine free base weight, and unit is mL/g.
It is further preferred that in step 2,1-METHYLPYRROLIDONE：The volume ratio of water is 1：1~1.5, N- crassitude
Ketone/water mixed solvent volume is 4~5 times of the alverine citrate weight of step 1 gained, and unit is mL/g；DMF volumes are
0.1~0.2 times of 1-METHYLPYRROLIDONE and water mixed solvent cumulative volume；The amount of added crystal seed is the citric acid of step 1 gained
The 1~2% of alverine weight.
During alverine citrate is prepared, the HPLC purity of the alverine free alkali for using is the present invention
More than 98.5%, will otherwise adverse effect be brought to the salt-forming reaction of follow-up alverine and the refined of monohydrate；Specifically,
Its preparation method is comprised the following steps：
A be dissolved in the compound phenylpropanol of formula 2 in the dichloromethane solvent containing triethylamine by (), be cooled to 0~5 DEG C, slowly
Mesyl chloride is added dropwise, drop finishes, is slowly increased to 25~30 DEG C, stirring reaction 2~4h, TLC monitoring reaction is finished, and reaction solution is concentrated
To dry, the compound of formula 3 is obtained, without isolation, add appropriate DMF dissolvings, add sodium bromide, stirring reaction 6 at 25~30 DEG C~
8h, TLC monitoring reaction are finished, and are filtered, and add water and ethyl acetate, extraction point liquid after organic layer is washed, to dry in filtrate,
It is concentrated to give the compound of formula 4；
B the compound of formula 4 is dissolved in volume ratio DMF by ()：Water=1:In 1 mixed solvent, triethylamine and phase transfer catalysis (PTC) are added
Agent, temperature control is dividedly in some parts ethylamine hydrochloride between 10~15 DEG C, finishes, and is to slowly warm up to 35~40 DEG C, quick stirring reaction 4
~6h, TLC monitoring reaction are finished, and are filtered, and add water and ethyl acetate, extraction point liquid to be concentrated to dryness organic layer in filtrate, to
Add n-hexane to stir in the crude product of gained alverine free alkali and wash 0.5h, suction filtration, filter cake is washed with n-hexane, to n-hexane
3mol/L HCl are added in filtrate, pH2~3 are adjusted, stirring stands a point liquid, and water is washed with n-hexane, collects water phase, water layer
Alverine hydrochloride is shifted and extracts with dichloromethane again, by dichloromethane layer successively with 5% solution of potassium carbonate, water, and
Saturated common salt water washing, anhydrous sodium sulfate drying is concentrated to dryness, and obtains the compound of yellow oil formula 5, and HPLC purity is 98.5%
More than；Wherein, phase transfer catalyst is selected from tetrabutylammonium chloride, TBAB, the one kind in benzyltriethylammoinium chloride.
Preferably, in step a, phenylpropanol：Mesyl 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；The compound of formula 4：Ethamine hydrochloric acid
The mol ratio of salt is 2.2~2.5:1.
Present invention also offers a kind of pharmaceutical composition, the compound crystal form B of formula 1 provided comprising the present invention as activity into
Point, and pharmaceutically acceptable auxiliary material.The preparation of pharmaceutical composition is oral formulations, including tablet, granule, capsule,
Microcapsules, pill, dry suspensoid agent, pulvis.Preferably, preparation of the invention, preferably capsule.Specifically, it is above-mentioned oral
Crystal formation (being calculated with alverine) of the present invention is 30~100mg, preferably 60mg contained by every dose in formulation.Pharmaceutical compositions of the present invention
Thing can be obtained by conventional pharmaceutical adjuvants well known in the art and method.
The Pharmaceutical composition can be used for the medicinal usage in terms for the treatment of releases smooth muscle spasm.
For oral solid pharmaceutical preparation, conventional pharmaceutic adjuvant includes filler, adhesive, disintegrant, lubricant
Deng.Filler includes starch, lactose, mannitol, microcrystalline cellulose；Adhesive includes starch, lactose, mannitol, microcrystalline cellulose
Element；Disintegrant includes cross-linked cellulose sodium, PVPP, low substituted HPMC；Lubricant includes stearic acid
Magnesium, talcum powder, polyethylene glycol, Stepanol MG, superfine silica gel powder, talcum powder etc..Pharmaceutic adjuvant as needed, can also be added
Colouring agent and sweetener etc..
Preferably, alverine citrate dosage form of the invention is preferably capsule, particularly may be divided into hard shell capsules and
Soft capsule.The hard shell capsules of alverine citrate include crystal formation B disclosed by the invention, starch, magnesium stearate, purified water, warp
Wet granulation method is crossed, is filled using 3# gelatin hollow capsule shells and formed.
The soft capsule of alverine citrate includes crystal formation B disclosed by the invention and Simethicone, and preparation technology is main
It is to inject to be filled in Perle after both are stirred to form.
Technical solution of the present invention achieves following beneficial technique effect：
(1) present invention reports a kind of alverine citrate crystal formation B of novelty, and crystal formation B belongs to a water in chemistry
Compound, crystal formation shelf stability is good, and water solubility is better than the anhydrous crystal forms reported；The bulk drug of the crystal formation is in memory period ten
Divide stabilization, under hot and humid condition, particularly high humidity environment, crystal formation does not change；Purity and stable content are good, single miscellaneous
It is small.
(2) the simpler convenience of preparation method of the invention, reappearance is strong；Pollution-free, low cost, the novel crystal forms for obtaining are received
Rate is high, and purity is high, is adapted to large-scale production；Both realized easy to operate, the advantages of process stabilizing and high income, eliminated existing
Tedious steps in technology, moreover it is possible to effectively go the removal of impurity, improve product purity.
(3) alverine free alkali of the HPLC purity of the present invention more than 98.5% is using a novelty
What synthetic route and simple and easy to do technique were prepared from.The use of the route, admirably solves A Erwei in the prior art
The defects such as woods free alkali synthesis purity (being less than 97%, total miscellaneous content overproof) not high.The present inventor probes into by deep technique,
Bromo-derivative impurity in also synthesizing particular for alverine, the i.e. easy excessive problem of content of the compound of formula 4, establish " first
Form alverine hydrochloride, alkalize afterwards free " mode, carried out clearly using the washing system of n-hexane-water-dichloro hexane
Remove, eliminate the impurity (bromo-derivative, the i.e. compound of formula 4) of the extremely difficult purifying of re-crystallization stage, greatly improve the purity of free alkali,
Also for follow-up preparation into salt and crystal formation has laid good basis.
(4) numerous studies of the present inventor for crystallization condition and carefully exploration, are surprised to find in N- crassitudes
On the basis of the mixed solvent of ketone and water, DMF is suitably added, by (- 5~0 DEG C) standing crystallization of low temperature, with less solvent body
System and the in high yield monohydrate crystal form of acquisition high-purity.Using this monohydrate crystal form as crystal seed, by monohydrate crystal seed
Addition, be suspended without long-time, stand, especially low recrystallization temperature, or especially complex crystallization technique, in temperature higher
(10~15 DEG C) just can be with speed faster (usual 1.5~2h), yield higher, it is easy to industrialized method, needed for being obtained
Hydrate novel crystal form.
(5) stability test result shows that alverine citrate novel crystal forms B of the invention is violent in hot and humid grade
In environment, crystal formation does not change, and purity and stable content are good, and single miscellaneous and total miscellaneous content is low.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of alverine citrate crystal formation B.
Fig. 2 schemes for the DSC of alverine citrate crystal formation B.
Fig. 3 schemes for the TG of alverine citrate crystal formation B.
Specific embodiment
Technical scheme is further described with reference to specific embodiment.
The preparation of the alverine free alkali of embodiment 1
The compound phenylpropanol (137g, 1mol) of formula 2 is dissolved in the dichloromethane solvent containing triethylamine (205g, 2mol)
In 900mL, 0-5 DEG C is cooled to, is slowly added dropwise mesyl chloride (172g, 1.5mol), drop finishes, be slowly increased to 25~30 DEG C, stirring
Reaction 2~4h, TLC monitoring reaction is finished, and reaction solution is concentrated to dryness, and obtains the compound of formula 3；Without isolation, appropriate DMF is added
Dissolving, adds sodium bromide (255g, 2.5mol), and 6~8h of stirring reaction at 25~30 DEG C, TLC monitoring reaction are finished, filtered, filter
Add water 800mL and ethyl acetate 1000mL, extraction point liquid after organic layer is washed, to dry in liquid, be concentrated to give the chemical combination of formula 4
Thing about 160g, yield 80%.
The compound of above-mentioned formula 4 (160g, 0.79mol) is about dissolved in volume ratio DMF：Water=1:In 1 mixed solvent 1000mL,
Add triethylamine (100g, 1mol) and benzyltriethylammoinium chloride (12g, 0.05mol), temperature control adds between 10~15 DEG C in batches
Enter ethylamine hydrochloride (29.5g, 0.36mol), finish, be to slowly warm up to 35~40 DEG C, quickly stir 4~6h, TLC monitoring reactions
Finish, filter, add water 800mL and ethyl acetate 800mL, extraction point liquid to be concentrated to dryness organic layer, gained A Er in filtrate
Addition n-hexane 1500mL agitator treating 0.5h in the crude product of woods free alkali are tieed up, suction filtration, filter cake is washed with 300mL n-hexanes, to
3mol/L HCl are added in the filtrate of n-hexane, pH2-3 is adjusted, stirring stands a point liquid, and water is mutually washed with n-hexane 300mL, is received
Catchment phase, water layer is extracted with dichloromethane 1000mL again and alverine hydrochloride is shifted, by dichloromethane layer successively with 5%
Solution of potassium carbonate, water, and saturated common salt water washing, anhydrous sodium sulfate drying, are concentrated to dryness, and obtain the chemical combination of yellow oil formula 5
Thing about 175g, yield 82%, HPLC purity about 98.6%.
The preparation of the alverine free alkali of embodiment 2
The compound phenylpropanol (137g, 1mol) of formula 2 is dissolved in the dichloromethane solvent containing triethylamine (208g, 2mol)
In 1000mL, 0~5 DEG C is cooled to, is slowly added dropwise mesyl chloride (228g, 2mol), drop finishes, be slowly increased to 25~30 DEG C, stirring
Reaction 2~4h, TLC monitoring reaction is finished, and reaction solution is concentrated to dryness, and obtains the compound of formula 3；Without isolation, appropriate DMF is added
Dissolving, adds sodium bromide (306g, 3mol), and 6~8h of stirring reaction at 25~30 DEG C, TLC monitoring reaction are finished, filtered, filtrate
Middle addition water 800mL and ethyl acetate 1000mL, extraction point liquid after organic layer is washed, is dried, and is concentrated to give the compound of formula 4
About 165g, yield 80%.
The compound of above-mentioned formula 4 (165g, 0.80mol) is about dissolved in volume ratio DMF：Water=1:In 1 mixed solvent 1200mL,
Add triethylamine (110g, 1mol) and benzyltriethylammoinium chloride (12g, 0.05mol), temperature control adds between 10~15 DEG C in batches
Enter ethylamine hydrochloride (26.2g, 0.32mol), finish, be to slowly warm up to 35~40 DEG C, quickly stir 4~6h, TLC monitoring reactions
Finish, filter, add water 800mL and ethyl acetate 800mL, extraction point liquid to be concentrated to dryness organic layer, gained A Er in filtrate
Addition n-hexane 1500mL agitator treating 0.5h in the crude product of woods free alkali are tieed up, suction filtration, filter cake is washed with 300mL n-hexanes, to
3N HCl are added in the filtrate of n-hexane, pH2~3 are adjusted, stirring stands a point liquid, and water is mutually washed with n-hexane 300mL, is collected
Water phase, water layer is extracted with dichloromethane 1000mL again and alverine hydrochloride is shifted, and dichloromethane layer is used 5% carbon successively
Sour potassium solution, water, and saturated common salt water washing, anhydrous sodium sulfate drying, are concentrated to dryness, and obtain the compound of yellow oil formula 5
170g, yield about 80%, HPLC purity about 98.5%.
The preparation of the alverine citrate crystal formation B of embodiment 3
The alverine free alkali of HPLC purity 98.6% is first obtained using the method for embodiment 1, then by the following method into salt and essence
System.
Between 45-50 DEG C of temperature, by citric acid (57.5g, 0.3mol) ethyl acetate 240mL's and isopropanol 120mL
Thermosol clarification in mixed solvent, is added dropwise the ethyl acetate 100mL solution of above-mentioned gained alverine free alkali (85g, 0.3mol),
Drop finishes, and continues to stir 0.5~1h under reflux state, is naturally cooling to 20~30 DEG C, and a large amount of white solids are separated out, suction filtration, washing,
Obtain alverine citrate about 128g.
By the alverine citrate of above-mentioned gained about 128g, at 45~50 DEG C of temperature, stirring and dissolving is in N- methyl pyrroles
In the mixed solvent of pyrrolidone 260mL and water 260mL, appropriate DMF about 55mL are added, be cooled to -5~0 DEG C, stand crystallization 4-
5h, filtering separates out crystal, filters and separates out crystal, 35~40 DEG C of drying under reduced pressure, relative humidity of the humid control 20~40%, i.e.,
Off-white powder 122g is obtained, yield about 92%, HPLC purity is 99.7%.
The preparation of the alverine citrate crystal formation B of embodiment 4
The alverine free alkali of HPLC purity 98.6% is first obtained using the method for embodiment 1, then by the following method into salt and essence
System.
Between 45~50 DEG C of temperature, by citric acid (58.3g, 0.3mol) ethyl acetate 375mL's and isopropanol 125mL
Thermosol clarification in mixed solvent, is added dropwise the ethyl acetate 150mL solution of appeal gained alverine free alkali (86g, 0.3mol),
Drop finishes, and continues to stir 0.5~1h under reflux state, is naturally cooling to 20~30 DEG C, and a large amount of white solids are separated out, suction filtration, washing,
Obtain alverine citrate about 126g.
By the alverine citrate of above-mentioned gained about 126g, at 45~50 DEG C of temperature, stirring and dissolving is in N- methyl pyrroles
In the mixed solvent of pyrrolidone 500mL and water 125mL, 10~15 DEG C are cooled to, add present invention gained alverine citrate
The crystal seed of crystal formation B about 1.2g, stands crystallization 1.5-2h, and filtering separates out crystal, 35~40 DEG C of drying under reduced pressure, humid control is 20
~40% relative humidity, obtains final product off-white powder 119g, and yield about 91%, HPLC purity is 99.6%.
The preparation of the contrast crystal formation of embodiment 5 A
Alverine citrate of the prior art is temporarily referred to as crystal formation A almost entirely from ethyl alcohol recrystallization.This hair
Person of good sense's bibliography " Chinese Journal of Pharmaceuticals, 2012,43：Reality in 164-166 " and Chinese patent CN200910103386
Proved recipe method, using same alverine free alkali, gas phase purity is more than 98.5%, carries out tying into salt and again in alcohol solvent
Brilliant process.
By alverine free alkali (10g, 35.6mmol), citric acid (6.9g, 36.0mmol) and absolute ethyl alcohol 150mL,
20min is heated to reflux, 0 DEG C of standing 0.5h is cooled to, filtering, filter cake is recrystallized with absolute ethyl alcohol, obtains white solid, that is, contrast brilliant
Type A about 14.5g, yield 96%, purity 99.5%.
The sign of the alverine citrate crystal formation B of embodiment 6
By X-ray method (x-ray powder diffraction in Chinese Pharmacopoeia annex) by above-described embodiment 2 or embodiment 3
Obtained alverine citrate crystal formation B is placed on powder diffractometer (Thermo X ' TRA types X-ray diffractometer), uses Cu-K α
40kV~40mA x-ray radiations, are scanned with the sweep speed of 8 degree mins in 3~50 degree of 2 θ.By differential thermal analysis DSC
Method, on the type differential thermal analyzers of NETZSCH DSC 204, with 10 DEG C/min heating rates, sweeps in 30-300 DEG C of temperature range
Retouch.TG thermogravimetric analysis is also to be carried out according to pharmacopoeial requirements.
For crystal formation B of the present invention, confirm that the monohydrate of stoichiometry is deposited using Ka Erfeixiushi aquametries
It is 3.65~3.78% in, water content.
Elementary analysis result shows as follows, theoretical value C：63.53%, H：7.59%, N：2.85%, measured value C：
63.59%, H：7.61%, N：2.88%
More specifically, the collection of illustrative plates of its X-ray powder diffraction is as shown in Figure 1, DSC collection of illustrative plates refers to accompanying drawing 2, and TG collection of illustrative plates is for example attached
Shown in Fig. 3.
It is have at 4.19,15.21,20.53 in 2 θ values in the X-ray powder diffraction figure of the crystal B of alverine citrate
Most strong characteristic diffraction peak, wherein 2 θ values error ranges are ± 0.2.More characteristically, the X-ray powder diffraction figure of crystal formation B
In, it is have most strong at 4.19,7.82,10.23,12.09,13.11,15.21,17.46,19.09,20.53,26.51 in 2 θ values
With secondary strong characteristic diffraction peak, wherein 2 θ values error ranges be ± 0.2；Its DSC collection of illustrative plates is in 84.6 ± 2.0 DEG C, 103.4 ± 2.0
DEG C there are dehydration endotherm peaks and melting endothermic peak respectively.
TG collection of illustrative plates shows, between 80~100 DEG C of temperature, because heating sample is slowly dehydrated, the quality in its TG figure is damaged
Lose equivalent to a crystallization water, continue thereafter with heating, the fusion and decomposition for obtaining sample is weightless.Equally, 84.6 in DSC collection of illustrative plates
± 2.0 DEG C, 103.4 ± 2.0 DEG C have dehydration endotherm peaks and melting endothermic peak respectively, and the result is also mutually right with TG weightlessness results
Should.
The estimation of stability of the alverine citrate crystal formation B of embodiment 7
By the alverine citrate crystal formation B of the invention and alcohol crystal thing crystal formation A of document report, carry out influence factor
Experiment, accelerated stability test, test method refer to referring to the bulk drug in Chinese Pharmacopoeia annex with pharmaceutical preparation stability test
Lead principle.
(1), influence factor experiment：
1st, hot test：Alverine citrate crystal formation A and crystal formation B is taken, is placed 10 days at a temperature of 60 DEG C, in the 5th day
Sampled with the 10th day, determine indices and be compared with sample when 0, result of the test see the table below.
2nd, wet test high：Take alverine citrate crystal formation A and crystal formation B, in being placed 10 days under RH75%, in the 5th day and
Sample within 10th day, determine indices and be compared with 0 day sample, result of the test see the table below.
3rd, strong illumination experiment：Alverine citrate crystal formation A and crystal formation B is taken, in the bar that illumination is (4500 ± 500) LX
Placed 10 days under part, sampled in the 5th day and the 10th day, determined sample of the indices with 0 day and be compared, result of the test sees below
Table.
(2) accelerated stability test
By alverine citrate crystal formation A and crystal formation B, the accelerated stability test of 6 months is carried out in climatic chamber.
Experimental condition is：40 DEG C/75% relative humidity (RH), sampled respectively at 0,1,2,3,6 months, carried out purity and foreign impurity matters test
(high performance liquid chromatography) and PXRD are characterized, and as a result be see the table below.
From upper table result, the stability of alverine citrate crystal formation B is better than of the prior art.Hot and humid
Condition, particularly in high humidity environment, crystal formation does not change, and purity and stable content are good, single miscellaneous and total miscellaneous smaller.By
This, the alverine citrate crystal formation B obtained by the present invention has fairly obvious lifting in terms of stability, with the obvious advantage.
The hard capsule and preparation technology of the alverine citrate crystal formation B of embodiment 8
Preparation technology：The alverine raw material and starch of recipe quantity are mixed and 80 mesh sieves are crossed repeatedly, stirred in mixer
Mix uniform；Appropriate purified water is added when stirring, 3~5min of batch type in mixer pours out particle, reaches and " holds into
Group, light pressure dissipates " state；Above-mentioned wet granular is crossed into the wet whole grain of 24 mesh sieves, is dried 2 hours in 60 DEG C of baking ovens, control moisture exists
4% or so；The particle of drying is crossed into 24 mesh sieve whole grains；The particle that above-mentioned dry whole grain is completed is weighed and stearic acid is proportionally added into
Magnesium, it is well mixed by equal increments method, obtain final product alverine citrate intermediate；By alverine citrate intermediate 3# glue
Capsule filling plate is filled, last aluminum-plastic packaged, is obtained final product.
The soft capsule and preparation technology of the alverine citrate crystal formation B of embodiment 9
Alverine citrate crystal formation B 60g (in terms of alverine weight)
Simethicone 300g
1000 soft capsules are prepared altogether
Preparation technology：50% Simethicone is added in the mixing container, is stirred with 10~15 revs/min of speed,
To ensure that Simethicone will not be by violent stirring, the stirring contributes to the mobility to form and keep Simethicone, so as to obtain
Obtain the optimum dispersion of alverine citrate.Divide 3 batches of addition alverine citrates again, be stirred vigorously, control is stirred
Speed is mixed at 1500~1700 revs/min, it is ensured that dispersion and dispersate it is uniform, be eventually adding the remainder of Simethicone,
Continue to stir 30~60min, inject in soft gelatin capsule immediately, encapsulating shaping is obtained final product.
The preparation dissolution rate of the alverine citrate crystal formation B of embodiment 10 is evaluated
Dissolving-out method：Chinese Pharmacopoeia 2015 editions
Paddle method rotating speed：50 turns
Medium temperature：37±0.5℃
Assay method：UV-VIS spectrophotometry
Computational methods：External standard method
Contrast solution compound method：Take the dry reference substance to constant weight appropriate, it is accurately weighed, it is diluted to often with dissolution medium
The solution of about 5 μ g in 1ml.
The contrast crystal formation A and alverine citrate crystal formation B obtained in embodiment 2 of same quality are weighed respectively, using complete
Exactly the same technique is obtained hard capsule preparation, 6 every batch, using water as dissolution medium, enters according to above-mentioned dissolution and assay method
Row experiment.The appropriate simultaneously fluid infusion of solution is taken respectively at 5min, 10min, 15min, 30min, 45min, 60min, filtration, precision is measured
Appropriate filtrate, solubilization goes out the solution that WATER AS FLOW MEDIUM is diluted to about 5 μ g in every 1ml, dissolution rate is calculated according to high-efficient liquid phase technique, as a result
It is as shown in the table.
It is not difficult to find out by upper table result, after identical capsule is made under similarity condition, in same time (first 15 minutes), this
After invention crystal formation is made preparation, faster, result of extraction is more preferably for its dissolution rate.Alverine citrate crystal formation B hard capsules
Dissolution rate is greater than the dissolution rate of contrast crystal formation A correlation capsules.The present invention is made of alverine citrate crystal formation B
Capsule is outstanding in dissolution rate and aspect of performance.
The stability test of the alverine citrate crystal formation B hard capsules of embodiment 11 is investigated
Investigation according to listed by stability test in " the medicine stability test guideline " of Chinese Pharmacopoeia 2015 editions
Mesh, factors influencing is carried out to alverine citrate crystal formation B hard capsules of the invention.
Method according to embodiments of the present invention prepares alverine citrate crystal formation B hard capsules, enters according to commercially available situation
Row packaging, is placed in intensity of illumination 4500Lx ± 500Lx, under 60 DEG C of high temperature and high humidity RH92.5 ± 5%, places 10 days, respectively at
Sampling detection in 5th day and the 10th day, as a result see the table below.
Conclusion：This product by after factors influencing, content, relevant material, content color, and 15min dissolution rates
With 0 day compared to there was no significant difference, certified products are, further demonstrate the system that the crystal formation B used by the present invention is prepared for raw material
Agent possesses stability higher.
It should be noted that the foregoing is only presently preferred embodiments of the present invention, it is not intended to limit the invention
Scope, all any modifications done within the spirit and principles in the present invention, equivalent replacement and improvement etc., should be included in
Within protection scope of the present invention.
Claims (7)
1. a kind of alverine citrate crystal formation B, it is characterised in that crystal formation B is the new of alverine citrate monohydrate
Crystal formation, with the structure as shown in following formula 1,
And radiated using Cu-K α, in its X-ray powder diffraction pattern, 2 θ values be 4.19,7.82,10.23,12.09,
13.11st, there is diffraction maximum at 15.21,17.46,19.09,20.53,26.51, wherein 2 θ values error ranges are ± 0.2, its PXRD
Collection of illustrative plates is as shown in Figure 1；
Also, at 84.6 ± 2.0 DEG C, 103.4 ± 2.0 DEG C have dehydration endotherm peaks and melting endothermic peak to its DSC collection of illustrative plates respectively, its
DSC collection of illustrative plates is as shown in Figure 2；
Also, its TG collection of illustrative plates is as shown in Figure 3；
Also, the presence of the monohydrate of stoichiometry is confirmed using Ka Erfeixiushi aquametries, crystal formation B's is aqueous
Amount is between 3.3~4.0%.
2. a kind of method for preparing alverine citrate crystal formation B as claimed in claim 1, it is characterised in that comprising as follows
Step：
(1) between 45~50 DEG C of temperature, citric acid is heated in the mixed solvent of ethyl acetate and isopropanol it is molten clear, be added dropwise Ah
The ethyl acetate solution of Er Weilin free alkalis, drop finishes, and continues to stir 0.5~1h under reflux state, is naturally cooling to 20~30 DEG C,
A large amount of white solids are separated out, suction filtration, and washing obtains alverine citrate, wherein the HPLC of " the alverine free alkali "
Purity is more than 98.5%；
(2) by the alverine citrate of step 1 gained, at 45~50 DEG C of temperature, stirring and dissolving is in 1-METHYLPYRROLIDONE
In the mixed solvent of water, appropriate DMF is added, be cooled to -5~0 DEG C, stand 4~5h of crystallization, filtering separates out crystal, 35~40
DEG C drying under reduced pressure；During drying under reduced pressure alverine citrate crystal formation B, to prevent excessive dehydration, humidity when drying
The relative humidity 20~40% should be controlled, alverine citrate crystal formation B is obtained final product；
Or, by the alverine citrate of step 1 gained, at 45~50 DEG C of temperature, stirring and dissolving is in N- crassitudes
In the mixed solvent of ketone and water, be cooled to 10~15 DEG C, add the crystal seed of alverine citrate crystal formation B, stand crystallization 1.5~
2h, filtering separates out crystal, 35~40 DEG C of drying under reduced pressure；During drying under reduced pressure alverine citrate crystal formation B, to prevent
Excessive dehydration, humidity when drying should control the relative humidity 20~40%, obtain final product alverine citrate crystal formation B.
3. preparation method according to claim 2, it is characterised in that in step 1, ethyl acetate：The volume ratio of isopropanol
It is 2~3:1, ethyl acetate/isopropyl alcohol mixed solvent volume is 4~6 times of alverine free base weight, and unit is mL/g；
In step 2,1-METHYLPYRROLIDONE：The volume ratio of water is 1:1~1.5,1-METHYLPYRROLIDONE/water mixed solvent volume is step
4~5 times of the alverine citrate weight of rapid 1 gained, unit is mL/g；DMF volumes are that 1-METHYLPYRROLIDONE and water are mixed
0.1~0.2 times of bonding solvent cumulative volume；The amount of added crystal seed is the 1~2% of the alverine citrate weight of step 1 gained.
4. preparation method according to claim 3, it is characterised in that A Er of the described HPLC purity more than 98.5%
Dimension woods free alkali is prepared from using following synthetic route and technique, is specifically comprised the following steps：
A be dissolved in the compound phenylpropanol of formula 2 in the dichloromethane solvent containing triethylamine by (), be cooled to 0~5 DEG C, is slowly added dropwise
Mesyl chloride, drop finishes, and is slowly increased to 25~30 DEG C, and stirring reaction 2~4h, TLC monitoring reaction is finished, and reaction solution is concentrated into
It is dry, the compound phenylpropanol methanesulfonates of formula 3 is obtained, without isolation, appropriate DMF dissolvings are added, sodium bromide is added, at 25~30 DEG C
Stirring reaction 6~8h, TLC monitoring reaction is finished, and is filtered, and adds water and ethyl acetate, extraction point liquid to wash organic layer in filtrate
After washing, dry, be concentrated to give the bromo- 3- phenyl-propanes of compound 1- of formula 4；
B the bromo- 3- phenyl-propanes of compound 1- of formula 4 are dissolved in volume ratio DMF by ()：Water=1:In 1 mixed solvent, add triethylamine and
Phase transfer catalyst, temperature control is dividedly in some parts ethylamine hydrochloride between 10~15 DEG C, finishes, and is to slowly warm up to 35~40 DEG C, quickly
Stirring reaction 4~6h, TLC monitoring reaction is finished, and is filtered, and water and ethyl acetate are added in filtrate, and extraction point liquid is dense by organic layer
It is reduced to dry, to adding n-hexane to stir and wash 0.5h in the crude product of gained alverine free alkali, suction filtration, filter cake is washed with n-hexane,
To 3mol/L HCl are added in the filtrate of n-hexane, pH2~3 are adjusted, stirring stands a point liquid, and water is washed with n-hexane, is collected
Water phase, water layer is shifted with dichloromethane and extracts alverine hydrochloride again, and dichloromethane layer is molten with 5% potassium carbonate successively
Liquid, water, and saturated common salt water washing, anhydrous sodium sulfate drying, are concentrated to dryness, and obtain the compound of yellow oil formula 5, and HPLC is pure
Degree is more than 98.5%；Wherein, phase transfer catalyst is selected from tetrabutylammonium chloride, TBAB, benzyl triethyl ammonium chlorination
One kind in ammonium.
5. preparation method according to claim 4, it is characterised in that in step a, phenylpropanol：Mesyl chloride：Sodium bromide
Mol ratio is 1:1.5~2:2.5~3；In step b, phase transfer catalyst is benzyltriethylammoinium chloride；Compound 1- is bromo- for formula 4
3- phenyl-propanes：The mol ratio of ethylamine hydrochloride is 2.2~2.5:1.
6. a kind of pharmaceutical composition, it is characterised in that comprising alverine citrate crystal formation B conducts as claimed in claim 1
Active component, and pharmaceutically acceptable auxiliary material；Also, the dosage form of pharmaceutical composition is capsule.
7. pharmaceutical composition according to claim 6, it is characterised in that said preparation form is hard capsule, prescription contains
Alverine citrate crystal formation B as claimed in claim 1, starch, magnesium stearate, purified water；By wet granulation method, adopt
It is filled with 3# gelatin hollow capsule shells and is formed；Or, the dosage form of the pharmaceutical composition is soft capsule, is such as to weigh
Profit requires that alverine citrate crystal formation B and Simethicone described in 1 stir, injection soft gelatin capsule in filling and
Into.
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