CN105218626A - A kind of argatroban new crystal and preparation method thereof - Google Patents
A kind of argatroban new crystal and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of argatroban new crystal and preparation method thereof, represent there is characteristic peak 4.0 ± 0.1,6.9 ± 0.1,7.9 ± 0.1,9.6 ± 0.1,10.1 ± 0.1,13.6 ± 0.1,15.0 ± 0.1,17.1 ± 0.1,19.8 ± 0.1,21.1 ± 0.1,23.6 ± 0.1,29.9 ± 0.1 with X-ray powder diffraction 2 θ.Argatroban crude product is dissolved in solvent Virahol, strength of solution 0.09 ~ 0.3g/mL, be heated to 30 ~ 50 DEG C, stirring and dissolving is clarified, in solution, drip anti-solvent water, then cool to 5 ~ 15 DEG C, constant temperature keeps 2 ~ 4h, magma after filtration, washing, dry, obtain described argatroban new crystal crystal.The ratio of products obtained therefrom R and S, in 57 ~ 67:43 ~ 33 scope that Chinese Pharmacopoeia specifies, has pharmacologically active.Yield is 91 ~ 94%, HPLC detection purity is 99.9%, and product stability is good.Crystal is bar-shaped, any surface finish and regular edges, and product is without coalescent.
Description
Technical field
The invention belongs to medical crystallization technique field, a kind of new crystal being specifically related to argatroban and preparation method thereof.
Technical background
Argatroban is the antithrombotic being developed synthesis by Mitsubishi (Mitsubishi) chemistry institute the earliest, first clinical treatment peripheral arterial occlusive disease is applied to, then be used for the treatment of acute cerebral thrombosis to be formed, and the assisting therapy of myocardial infarction thrombolysis, and lack the anti-freezing process of patient when carrying out hemodialysis for antithrombin.It can direct reversible and thrombin action, has better anti-freezing and anti thrombotic action, has therapeutic efficiency high, the advantages such as rate of side effects is low than heparin.
FDA Food and Drug Administration (FDA) have approved Smithkline Beecham (SmithKlineBeecham) and Texas biotech company (TexasBiotechnology) injection antithrombotic small-molecule drug argatroban in 2000 is applied to the treatment to needing to carry out percutaneous coronary intervention (PIC) patient.The multicenter phase ii clinical trial result that the international apoplexy conference of apoplexy association of U.S. Di28Jie on March 5th, 2003 is announced shows, evident in efficacy in acute ischemic stroke treatment of argatroban, security is high.
Argatroban (Argatroban), chemical name is (2R, 4R)-4-methyl isophthalic acid-[N-((R; S)-3-methyl isophthalic acid, 2,3; 4-tetrahydrochysene-8-quinoline alkylsulfonyl)-L-arginyl]-2 piperidine carboxylic acid, molecular formula C
23h
36n
6o
5s, molecular weight is 508.63, and chemical structural formula is:
Current argatroban is starting raw material mainly with nitro-L-arginine, carries out condensation reaction obtain with piperidine carboxylic acid ester or quinoline sulphonic acid chlorine.Because final stage experienced by asymmetric catalytic hydrogenation, what this route directly obtained (easily absorbs water for unbodied argatroban, poor stability), the argatroban monohydrate that further crystallization processes just can obtain stable in properties need be carried out, i.e. commercially available argatroban.But, in the process that whole crystallization processes improves, in strict accordance with Legal Norms such as state food pharmaceuticals administration standard YBH11142005, the Pharmacopoeia of the People's Republic of China 2010 editions, GSPs (2010 revision), need ensure that the ratio of R and S on argatroban No. 21 positions needs to control in the scope of 57 ~ 67:43 ~ 33.
Patent CN101560244 proposes and obtains argatroban crystal using ethanol and water mixture as solvent recrystallization, and its yield is 63%.Patent CN101914133A reports a kind of crystal formation obtaining argatroban in methyl alcohol and water mixed solvent, and its yield is 70%, and its x-ray diffraction pattern characteristic peak is 7.56,9.28,10.32,11.04,11.96,14.42,15.18,15.88,16.76,17.82,18.66 (2 θ) etc.Patent CN1951936A reports and obtain a kind of argatroban crystal formation in the mixed solvent of methyl alcohol, ethanol, Virahol and water, the volume ratio of methyl alcohol, ethanol, Virahol and water is 1:1 ~ 6, the ratio of argatroban and solvent is 1:15 ~ 30, through 5-7 recrystallization, obtain the argatroban crystal that purity is 98%.Patent CN101362746A reports a kind of crystal formation obtaining argatroban from methyl alcohol, ethanol and Virahol, and its x-ray diffraction pattern characteristic peak is 7.0,8.2, and 9.3,9.9,10.4,11.1,12.0,16.7,18.7,21.5,26.0 (2 θ).
In sum, in above argatroban crystal preparation technique, some has used the methyl alcohol of injury HUMAN HEALTH, and water consumption is large, and be unfavorable for environment protection and HUMAN HEALTH, resource is not utilized effectively and saves; The number of times of some technique recrystallizations is more, and the yield of its product fails effectively to improve, and is unfavorable for that industrial production is applied.
Summary of the invention
In order to overcome argatroban crystal complex process prepared by art methods, solvent poison and solvent usage quantity greatly, recrystallization often, the not high defect of yield; The invention provides new crystal of a kind of argatroban and preparation method thereof.
The crystal of a kind of argatroban new crystal provided by the invention, its X-ray powder diffraction is shown in accompanying drawing 1, represents there is characteristic peak at 4.0 ± 0.1,6.9 ± 0.1,7.9 ± 0.1,9.6 ± 0.1,10.1 ± 0.1,13.6 ± 0.1,15.0 ± 0.1,17.1 ± 0.1,19.8 ± 0.1,21.1 ± 0.1,23.6 ± 0.1,29.9 ± 0.1 degree of places with diffraction angle 2 θ.
The ratio of R and S of argatroban new crystal of the present invention, in 57 ~ 67:43 ~ 33 scope that Chinese Pharmacopoeia specifies, has pharmacologically active.
The differential scanning calorimetric DSC figure of argatroban new crystal of the present invention, seeing accompanying drawing 2, have feature endotherm(ic)peak at 172 ± 3 DEG C, is the fusing point of crystal.
The preparation method of argatroban crystal formation of the present invention, comprises following method, but is not limited only to following methods:
Argatroban crude product is dissolved in solvent Virahol, strength of solution 0.09 ~ 0.3g/mL, be heated to 30 ~ 50 DEG C, stirring and dissolving is clarified, in solution, drip anti-solvent water, then cool to 5 ~ 15 DEG C, constant temperature keeps 2 ~ 4h, magma after filtration, washing, dry, obtain described argatroban new crystal crystal.
The consumption of described anti-solvent water is 0.5 ~ 2 times of solvent Virahol volume.
Described anti-solvent water add 1 ~ 5%/min that speed is anti-solvent volume.
Described rate of temperature fall is 0.1 ~ 0.5 DEG C/min.
Described drying conditions is temperature 60 ~ 90 DEG C of vacuum-dryings, and time of drying is 6 ~ 8h.
The present invention be by argatroban dissolving crude product in good solvent, then lysate is dropped in anti-solvent, by the interphase interaction of good solvent and anti-solvent, good solvent and solute and anti-solvent and solute, then solution is cooled, solution is reached capacity, crystallize out.Product nucleating growth is formed jointly by dissolved and cooling, and Neither of the two can be dispensed for dissolved process and process of cooling.The impellent of crystallization nucleation, growth is degree of supersaturation (Δ c=c-c
*=concentration-equilibrium concentration or solubleness), it produces by lowering the temperature or adding dissolved agent.Too fast rate of temperature fall or dissolved agent add, and degree of supersaturation is increased faster, easily break out nucleation, product is in small, broken bits, impurity inclusion, crystal purity is poor.The present invention is according to its solubility curve Changing Pattern, rate of temperature fall (0.1 ~ 0.5 DEG C/min), make degree of supersaturation be in homogeneous level all the time, create the physical chemistry Stationary Random Environments being conducive to crystallization nucleation, growth, to ensure high process yield and satisfactory stability.
The inventive method is compared to other concise in technology, and mild condition, reproducible, solvent usage quantity is few, and yield is high, is convenient to carry out suitability for industrialized production.Crystallisation process yield is 91 ~ 94%, and product HPLC detects purity 99.9%.Crystal is bar-shaped, any surface finish and regular edges, product without coalescent, as shown in Figure 4.
The stability of described argatroban new crystal is investigated, described argatroban crystal formation product is evenly split in uncovered culture dish, thickness of sample is less than 5mm, sealing is placed in moisture eliminator, control temperature, at 20 ~ 100 DEG C, carries out XRD detection respectively at sampling in 50 days, 100 days, and contrasts with the result of the 0th day, as shown in Figure 3, the new crystal of result display argatroban changes concrete collection of illustrative plates.
The stability of described argatroban new crystal is investigated, affiliated argatroban crystal formation product is placed in 25 DEG C, RH75% respectively; 40 DEG C, RH75% and 60 DEG C, RH75% condition under carry out accelerated test, respectively at 1,2,3, sampling in 6 months, investigates the change of the aspects such as its appearance luster, product purity and transformation of crystal.See the following form.
From the accelerated test in table, under acceleration conditions, its appearance luster and crystal formation are all unchanged for argatroban crystal prepared by the present invention, and its change of purity growth is in time extremely small.Fig. 3 and upper table all show the good stability of product of the present invention.
Accompanying drawing explanation
The x-ray diffraction pattern of Fig. 1 argatroban new crystal of the present invention.
The differential scanning calorimetric DSC figure of Fig. 2 argatroban new crystal of the present invention.
The stability test trace analysis of Fig. 3 argatroban crystal formation of the present invention is wherein 0 day crystalline product from top to bottom according to this, the XRD spectra of 50 days and 100 days.
Fig. 4 argatroban crystal formation of the present invention microphotograph.
Embodiment
Be below the embodiment example of described argatroban crystal formation, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Precise 10.0g argatroban in 100ml crystallizer, add 30ml Virahol be heated to 30 DEG C clearly molten; 30ml water is added, 0.1 DEG C/min slow cooling to 5 DEG C, constant temperature growing the grain 2h with the drop rate of 0.3ml/min; After crystallization is complete, filtration washing, 90 DEG C vacuumize dry 8h, obtain 9.1g product; Yield is that 91%, HPLC detects purity 99.9%.The powder x-ray diffraction collection of illustrative plates of product is consistent with Fig. 1, and as shown in Figure 2, and the ratio of R/S (R/S=63.5/36.4) meets medical requirement to DSC collection of illustrative plates.
Embodiment 2
Precise 10.0g argatroban in 200ml crystallizer, add 100ml Virahol be heated to 35 DEG C clearly molten; 50.0ml water is added, 0.2 DEG C/min slow cooling to 10 DEG C, constant temperature growing the grain 3h with the drop rate of 0.5ml/min; After crystallization is complete, filtration washing, 80 DEG C vacuumize dry 8h, obtain 9.23g solid; Yield is 92.3%, it is 99.9% that HPLC detects purity, the powder x-ray diffraction collection of illustrative plates of product has characteristic peak at 4.01,6.90,7.89,9.59,10.10,13.61,15.01,17.11,19.79,21.11,23.60,29.89 degree of places, it is 173 DEG C that DSC shows its fusing point, and the ratio of R/S (R/S=63.9/36.1) meets medical requirement.
Embodiment 3
Precise 14.5g argatroban in 250ml crystallizer, add 160ml Virahol be heated to 45 DEG C clearly molten; 240ml water is added, 0.3 DEG C/min slow cooling to 15 DEG C, constant temperature growing the grain 4h with the drop rate of 12ml/min; After crystallization is complete, filtration washing, 60 DEG C vacuumize dry 8h, obtain 13.46 products; Yield is 92.8%, HPLC detection purity is 99.9%.The powder x-ray diffraction collection of illustrative plates of product has characteristic peak at 4.06,6.91,7.90,9.63,10.12,13.60,15.01,17.10,19.85,21.15,23.58,29.87 degree of places, it is 174 DEG C that DSC shows its fusing point, and the ratio of R/S (R/S=63.6/36.3) meets medical requirement.
Embodiment 4
Precise 14.0g argatroban is in 150ml crystallizer, and it is clearly molten to add 60ml Virahol 40 DEG C; 120ml water is added, 0.5 DEG C/min slow cooling to 10 DEG C, constant temperature growing the grain 2h with the drop rate of 3.6ml/min; After crystallization is complete, filtration washing, 70 DEG C vacuumize dry 8h, obtain 12.8g solid; Yield is 91.4%, it is 99.9% that HPLC detects purity, the powder x-ray diffraction collection of illustrative plates of product has characteristic peak at 4.09,6.96,7.83,9.61,10.91,13.66,15.08,17.00,19.75,21.16,23.52,29.91 degree, it is 175 DEG C that DSC shows its fusing point, and the ratio of R/S (R/S=63.2/36.8) meets medical requirement.
Embodiment 5
Precise 30.0g argatroban, in 400ml crystallizer, adds the Virahol of 260ml, and 50 DEG C clearly molten; 130ml water is added, 0.4 DEG C/min slow cooling to 10 DEG C, constant temperature growing the grain 3h with the drop rate of 5.2ml/min; After crystallization is complete, filtration washing, 80 DEG C vacuumize dry 8h, obtain 28.2g solid; Yield is 94%, it is 99.9% that HPLC detects purity, the powder x-ray diffraction collection of illustrative plates of product has characteristic peak at 3.98,6.92,7.93,9.51,10.03,13.61,15.44,17.18,19.83,21.10,23.61,29.88 degree of places, it is 169 DEG C that DSC shows its fusing point, and the ratio of R/S (R/S=64.2/35.8) meets medical requirement.
Embodiment 6
Precise 30.0g argatroban is in 250ml crystallizer, and the Virahol 40 DEG C adding 120ml is clearly molten; 120ml water is added, 0.5 DEG C/min slow cooling to 5 DEG C, constant temperature growing the grain 4h with the drop rate of 2.4ml/min; After crystallization is complete, filtration washing, 90 DEG C vacuumize dry 8h, obtain 28.1g solid; Yield is 93.7%, it is 99.9% that HPLC detects purity, there is characteristic peak at powder x-ray diffraction collection of illustrative plates 3.93,6.52,7.90,9.66,10.05,13.57,15.04,17.94,19.80,21.09,23.64,29.87 degree of places of product, it is 171 DEG C that DSC shows its fusing point, and the ratio of R/S (R/S=64.6/35.4) meets medical requirement.
Claims (6)
1. a crystal for argatroban, is characterized in that the X-ray powder diffraction represented with 2 θ has characteristic peak at 4.0 ± 0.1,6.9 ± 0.1,7.9 ± 0.1,9.6 ± 0.1,10.1 ± 0.1,13.6 ± 0.1,15.0 ± 0.1,17.1 ± 0.1,19.8 ± 0.1,21.1 ± 0.1,23.6 ± 0.1,29.9 ± 0.1 degree of places; Its DSC collection of illustrative plates has feature endotherm(ic)peak at 172 ± 3 DEG C.
2. the preparation method of argatroban crystal formation as claimed in claim 1, argatroban crude product is it is characterized in that to be dissolved in solvent Virahol, strength of solution 0.09 ~ 0.3g/mL, be heated to 30 ~ 50 DEG C, stirring and dissolving is clarified, and drips anti-solvent water in solution, then 5 ~ 15 DEG C are cooled to, constant temperature keeps 2 ~ 4h, magma after filtration, washing, dry, obtain described argatroban new crystal crystal.
3. method as claimed in claim 2, is characterized in that the consumption of described anti-solvent water is 0.5 ~ 2 times of solvent Virahol volume.
4. method as claimed in claim 2, what it is characterized in that described anti-solvent water adds 1 ~ 5%/min that speed is anti-solvent volume.
5. method as claimed in claim 2, is characterized in that rate of temperature fall is 0.1 ~ 0.5 DEG C/min.
6. method as claimed in claim 2, it is characterized in that described drying conditions is temperature 60 ~ 90 DEG C of vacuum-dryings, time of drying is 6 ~ 8h.
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| CN110452285A (en) * | 2019-09-12 | 2019-11-15 | 北京悦康科创医药科技股份有限公司 | A kind of argatroban monocrystalline and its cultural method and application |
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| CN102382169A (en) * | 2007-08-06 | 2012-03-21 | 博瑞生物医药技术(苏州)有限公司 | Argatroban single stereoisomer separation method and polymorph |
| CN103772486A (en) * | 2014-01-06 | 2014-05-07 | 天津大学 | Novel crystal form of argatroban and preparation method thereof |
| CN103923168A (en) * | 2013-01-14 | 2014-07-16 | 山东新时代药业有限公司 | Preparation method of argatroban monohydrate |
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| CN101362746A (en) * | 2007-08-06 | 2009-02-11 | 袁建栋 | Separation method of argatroban single stereoisomers and polymorph |
| CN102382169A (en) * | 2007-08-06 | 2012-03-21 | 博瑞生物医药技术(苏州)有限公司 | Argatroban single stereoisomer separation method and polymorph |
| CN103923168A (en) * | 2013-01-14 | 2014-07-16 | 山东新时代药业有限公司 | Preparation method of argatroban monohydrate |
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| CN110452285A (en) * | 2019-09-12 | 2019-11-15 | 北京悦康科创医药科技股份有限公司 | A kind of argatroban monocrystalline and its cultural method and application |
| CN110452285B (en) * | 2019-09-12 | 2021-05-25 | 北京悦康科创医药科技股份有限公司 | Argatroban single crystal and culture method and application thereof |
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