CN103012385B - Crystal form of luliconazole and preparation method thereof - Google Patents
Crystal form of luliconazole and preparation method thereof Download PDFInfo
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- CN103012385B CN103012385B CN201210035834.7A CN201210035834A CN103012385B CN 103012385 B CN103012385 B CN 103012385B CN 201210035834 A CN201210035834 A CN 201210035834A CN 103012385 B CN103012385 B CN 103012385B
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- luliconazole
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- YTAOBBFIOAEMLL-REQDGWNSSA-N Luliconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@H](CS\1)SC/1=C(\C#N)N1C=NC=C1 YTAOBBFIOAEMLL-REQDGWNSSA-N 0.000 title claims abstract description 101
- 229960000570 luliconazole Drugs 0.000 title claims abstract description 101
- 239000013078 crystal Substances 0.000 title claims abstract description 97
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 35
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000007787 solid Substances 0.000 claims abstract description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 5
- 150000002148 esters Chemical class 0.000 claims abstract description 5
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 5
- 150000002576 ketones Chemical class 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 93
- 230000015572 biosynthetic process Effects 0.000 claims description 73
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000001291 vacuum drying Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 238000010521 absorption reaction Methods 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 7
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 7
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002244 precipitate Substances 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 238000000113 differential scanning calorimetry Methods 0.000 abstract description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 abstract 1
- 150000001555 benzenes Chemical class 0.000 abstract 1
- 150000008282 halocarbons Chemical class 0.000 abstract 1
- 230000001376 precipitating effect Effects 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 description 65
- 239000003814 drug Substances 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 239000000843 powder Substances 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 208000002474 Tinea Diseases 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- HNSDLXPSAYFUHK-UHFFFAOYSA-N 1,4-bis(2-ethylhexyl) sulfosuccinate Chemical compound CCCCC(CC)COC(=O)CC(S(O)(=O)=O)C(=O)OCC(CC)CCCC HNSDLXPSAYFUHK-UHFFFAOYSA-N 0.000 description 2
- 206010007134 Candida infections Diseases 0.000 description 2
- 241000130764 Tinea Species 0.000 description 2
- 241000893966 Trichophyton verrucosum Species 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- 206010061217 Infestation Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 201000010618 Tinea cruris Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 208000005005 intertrigo Diseases 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a crystal form of luliconazole and a preparation method thereof. The crystal form can be represented by an XRD (X-ray diffraction) spectrogram, an XRD peak and a DSC (differential scanning calorimetry) trace. The preparation method comprises the following steps of: a) dissolving luliconazole in one or more organic solvents of hydrocarbon with 5-8 carbon atoms, halogenated hydrocarbon with fewer than 4 carbon atoms, ketone with fewer than 5 carbon atoms, ester with fewer than 7 carbon atoms, ether with fewer than 8 carbon atoms, alcohol with fewer than 4 carbon atoms and benzene series with fewer than 9 carbon atoms; b) precipitating the crystalline solid from the solution obtained by the step a); and c) separating the crystalline solid obtained by the step b). The crystal form of luliconazole, disclosed by the invention, has the characteristics of good solubility, bioavailability, stability, tractability, safety, compressibility, efficiency and the like.
Description
Technical field
The present invention relates to a kind of crystal formation and preparation method thereof, particularly relate to crystal formation of a kind of luliconazole and preparation method thereof.
Background technology
Luliconazole (C shown in general formula (I)
14h
9c
12n
3s
2), (-)-(E)-(4R)-4-(2,4 dichloro benzene base)-1,3-dithiolane-2-Asia replaces (1H-imidazoles-1-replaces) acetonitrile,
Be the imidazoles antifungal drug of Nihon Nihyaku Co., Ltd's exploitation, comparatively early namely start I clinical trial phase, the II clinical trial phase first stage of nonclinical test and emulsifiable paste, thereafter because strategic reasons stopped development process.The nineties Nihon Nihyaku Co., Ltd and Pola Chemical Co., Ltd to subscribe to the agreement joint development, Pola Chemical Co., Ltd starts II clinical trial phase subordinate phase and the III clinical trial phase of emulsifiable paste in 2001, and has carried out the I clinical trial phase of lotion and the simultaneous test with emulsifiable paste.This medicine final got the Green Light in June, 2005, and rise on July 20th, 2005 with trade(brand)name Le リ コ Application (Lulicon) listing, emulsifiable paste and lotion specification are 1%, for following fungi infestation: tinea is sick--the ringworm of the foot, ringworm of the body, jock itch; Rotten to the corn disease, intertrigo between monilial infection-refer to; Purplish or white patches on the skin wind.Have that skin stores that rate is high, the medication cycle short (half for general medicine), good effect and the competitive edge not easily recurred.
The existing patent of WO97/02821 provides the preparation method and application of luliconazole, but does not disclose the crystalline structure of luliconazole.Crystal arranges at space periodic the solid matter formed by atom (or ion, molecule), and the crystallization of organic drug all belongs to molecular lattice substantially, produces different crystal formations along with the difference of processing condition.Single compound can produce various polymorphic (or crystalline structure), and wherein each form can have different or special physicals.The different crystal forms of same medicine often causes medicine in physico-chemical property and the significant differences such as drug dissolution, biological effectiveness such as outward appearance, solubleness, fusing point, density, thus affects the performance of the curative effect such as medicine stability, bioavailability.In the structure cell of different crystal forms, molecule is different from arrangement in sterie configuration, conformation, makes its solvability different with dissolution rate, directly affects preparation absorption in vivo, distribution, excretion and metabolism, finally causes the difference of clinical drug effect because bioavailability is different.
The research of polymorph in pharmaceuticals become new drug development and examination & approval, the production of medicine and quality control and new drug formulation determine before the indispensable important component part of design.Study and grasp polymorph in pharmaceuticals and character thereof, will contribute to ensureing that pharmaceutical preparation is at the physical and chemical stability produced and in storage process, improves the bioavailability of medicine, minimizing toxicity, promotes result for the treatment of.On the other hand, the technological process of some preparations can change polymorphous molecular structure, lattice arrangement, and the crystal formation of medicine is changed, thus affects medicine stripping in vivo and absorption, and then affects the treatment.On the impact of polymorph medicine by understanding and analyzing various factors in each solid preparation course of processing, medicine crystal growth and crystal formation can be controlled, reduce the generation of poor efficiency, invalid crystal formation to greatest extent, guarantee the security that medicine uses and validity.Meanwhile, brilliant means can be turned by certain, seek the new crystal formation of medicine, new curative effect.
Summary of the invention
The technical problem to be solved in the present invention is to provide crystal formation of a kind of luliconazole and preparation method thereof.This luliconazole crystal formation has good stability, is convenient to produce, transport and storing, and can meet the advantage such as all requirements as preparation raw material.
For solving the problems of the technologies described above, first aspect of the present invention, provide the crystal formation I of luliconazole, characterized by the X-ray diffraction pattern comprising two or more absorption peak, wherein, described two or more absorption peak, being selected from 2 θ values is 8.20, 9.91, 10.98, 12.22, 13.49, 13.64, 14.75, 16.38, 18.33, 20.05, 20.71, 21.34, 21.84, 22.25, 22.66, 22.86, 23.36, 23.90, 24.03, 24.52, 24.73, 25.08, 25.73, 26.89, 27.08, 27.42, 27.99, 28.63, 29.72, 29.92, 30.24, 31.35, 32.22, 32.35, 32.77, 33.03, 33.16, 33.46, 33.70, 34.02, 34.61, 35.03, 35.26, 35.77, 37.09, 37.36, 37.58, the peak at 38.76 and 38.93 ± 0.2 ° of θ places.
Second aspect, provide have substantially as Fig. 1,3,5,7 or Fig. 9 shown in the crystal formation I of luliconazole of XRD (X-ray diffraction analysis) spectrogram.
In 3rd of the present invention, provide the crystal formation I of luliconazole, by DSC (differential scanningcalorimetry, dsc) trace characterizes, described DSC trace is included in the endotherm(ic)peak at 145.35 ~ 155.44 DEG C of [i.e. 147.35 ~ 153.44 (equal ± 2 DEG C)] places, preferably in the endotherm(ic)peak at 150.36 ± 2 DEG C of places.
In the 4th, provide the crystal formation I of luliconazole, characterized by DSC trace, described DSC trace comprises the enthalpy of phase change at-68.33 ,-69.17 ,-69.95 ,-71.59 ,-76.24 ,-78.55 ,-78.97 and-76.47 ± 2J/g place.
In the 5th, provide have substantially as Fig. 2,4,6,8,10,11,12 or Figure 13 shown in the luliconazole crystal formation I of DSC trace.
6th aspect of the present invention, provides a kind of method for the preparation of luliconazole crystal formation I, comprises the following steps:
A luliconazole is dissolved in one or more organic solvents of ether within halohydrocarbon within the hydrocarbon of 5-8 carbon atom, 4 carbon atoms, the ketone within 5 carbon atoms, the ester within 7 carbon atoms, 8 carbon atoms, the alcohol within 4 carbon atoms, the benzene homologues within 9 carbon atoms by ();
Precipitate in b solution that () makes crystalline solid obtain from step (a);
C () is separated the crystalline solid obtained from step (b).
Wherein, in step (a), the hydrocarbon of 5-8 carbon atom, comprising: normal hexane, hexanaphthene, normal heptane;
Halohydrocarbon within 4 carbon atoms, comprising: methylene dichloride, chloroform;
Ketone within 5 carbon atoms, comprising: acetone, butanone;
Ester within 7 carbon atoms, comprising: ethyl acetate, Iso Butyl Acetate, butylacetate;
Ether within 8 carbon atoms, comprising: ether, tetrahydrofuran (THF), isopropyl ether, methyl tertiary butyl ether;
Alcohol within 4 carbon atoms, comprising: methyl alcohol, ethanol, Virahol;
Benzene homologues within 9 carbon atoms, comprising: toluene, dimethylbenzene.
In described step (a), heated solvent is to backflow.
In described step (b), carry out precipitated crystal solid by cooling solution.
In described step (c), by filtering the crystalline solid of precipitation separation.
Above for the preparation of the method for luliconazole crystal formation I, also can comprise: under vacuo, the crystalline solid be separated in drying step (c), until reach constant weight.
7th aspect, provides a kind of method of crystal formation I for the preparation of luliconazole, comprises the following steps:
A () heating is dissolved in the luliconazole extremely backflow in organic solvent;
Wherein, this organic solvent is selected from:
1) methylene dichloride;
2) acetone;
3) ethyl acetate, the mixture of ethyl acetate and methylene dichloride, the mixture of ethyl acetate and ethanol, the mixture of ethyl acetate and acetone, the mixture of ethyl acetate and normal hexane, or the mixture of ethyl acetate, methyl alcohol and acetone;
4) tetrahydrofuran (THF);
5) methyl alcohol, or the mixture of methyl alcohol and acetone;
6) mixture of toluene and butanone;
7) mixture of chloroform and normal hexane;
Or 8) mixture of Iso Butyl Acetate, isopropyl ether and methyl tertiary butyl ether;
Preferably, described 3) in, the volumetric mixture ratio of ethyl acetate and methylene dichloride is 1 ~ 4: 1; The volumetric mixture ratio of ethyl acetate and ethanol is 1 ~ 4: 1; The volumetric mixture ratio of ethyl acetate and acetone is 1 ~ 4: 1; The volumetric mixture ratio of ethyl acetate and normal hexane is 1 ~ 4: 1; The volumetric mixture ratio of ethyl acetate, methyl alcohol and acetone is 1 ~ 4: 1: 1;
Described 5), in, the volumetric mixture ratio of methyl alcohol and acetone is 1 ~ 4: 1;
Described 6), in, the volumetric mixture ratio of toluene and butanone is 1: 1 ~ 4;
Described 7) in, chloroform and normal hexane volumetric mixture ratio be 1 ~ 4: 1;
Described 8) in, the mixture 1 ~ 4: 1: 1 of Iso Butyl Acetate, isopropyl ether and methyl tertiary butyl ether.
B () cools the solution from step (a) until throw out is formed; And
C () is filtered the suspension from step (b) and is obtained solid, until reach constant weight 30 ~ 60 DEG C of vacuum-dryings.
In addition, the present invention, in the solvent for dissolving luliconazole is selected, also studies discovery:
1) 0.50g luliconazole is dissolved in 3mL methylene dichloride, is heated to backflow and dissolves, drip 3mL sherwood oil rapidly, can oily matter be separated out;
2) 0.50g luliconazole is dissolved in 5mL ethyl acetate or acetone, is heated to backflow and dissolves, drip 10mL sherwood oil rapidly, can oily matter be separated out;
3) 0.50g luliconazole is dissolved in 5mL ethanol, methyl alcohol or Virahol, is heated to backflow and dissolves, drip 10mL deionized water rapidly, can oily matter be separated out.
Therefore, the present invention is preferred above-mentioned organic solvent.
The crystal formation I of luliconazole of the present invention has favourable performance, such as, good solvability, bioavailability, stability, tractability, security, compressibility or usefulness etc., thus, can be used for preparing in treatment or the medicine that prevents fungal infections, wherein, this medicine can comprise: the medicine for the treatment of or prevention tinea disease, monilial infection and purplish or white patches on the skin wind.
Accompanying drawing explanation
Below in conjunction with accompanying drawing and embodiment, the present invention is further detailed explanation:
Fig. 1 is the XRD spectra of the crystal formation I of the embodiment of the present invention 1 luliconazole;
Fig. 2 is the DSC trace of the crystal formation I of the embodiment of the present invention 1 luliconazole;
Fig. 3 is the XRD spectra of the crystal formation I of the embodiment of the present invention 2 luliconazole;
Fig. 4 is the DSC trace of the crystal formation I of the embodiment of the present invention 2 luliconazole;
Fig. 5 is the XRD spectra of the crystal formation I of the embodiment of the present invention 3 luliconazole;
Fig. 6 is the DSC trace of the crystal formation I of the embodiment of the present invention 3 luliconazole;
Fig. 7 is the XRD spectra of the crystal formation I of the embodiment of the present invention 4 luliconazole;
Fig. 8 is the DSC trace of the crystal formation I of the embodiment of the present invention 4 luliconazole;
Fig. 9 is the XRD spectra of the crystal formation I of the embodiment of the present invention 5 luliconazole;
Figure 10 is the DSC trace of the crystal formation I of the embodiment of the present invention 5 luliconazole;
Figure 11 is the DSC trace of the crystal formation I of the embodiment of the present invention 6 luliconazole;
Figure 12 is the DSC trace of the crystal formation I of the embodiment of the present invention 7 luliconazole;
Figure 13 is the DSC trace of the crystal formation I of the embodiment of the present invention 8 luliconazole.
Embodiment
Luliconazole in following examples, is prepared gained according to what describe in EP0218736A1 and US4636519.
In addition, the testing conditions of XRD, DSC and HPLC of relating in following examples can carry out according to as follows:
1.XRD：
Instrument Bruker D8Advance XRD;
Method 1) scanning angle: 3 °-40 °;
2) scanning step: 0.02 °;
3) sweep velocity: 0.2 second/step;
2、DSC：
Instrument company: Mei Tele company of Switzerland (Mettler), instrument title: differential scanning calorimeter (DSC), INSTRUMENT MODEL: DSC1; Testing method 25 DEG C ~ 200 DEG C, 5 DEG C/min or 25 DEG C ~ 180 DEG C, 5 DEG C/min;
3、HPLC：
Instrument: U.S. Dionex UltiMate3000 analytical system, DAD detector;
Chromatographic column: Venusil XBP-184.6 × 250mm particle diameter 5 μm of apertures
Column temperature: 25 DEG C;
Moving phase: acetonitrile: water=55: 45;
Flow velocity: 1.5 ml/min;
Determined wavelength: 298nm UV;
Retention time: cis-isomeride: 9.35 minutes; Luliconazole: 9.94 minutes;
Wherein, Chiral HPLC conditions is as follows:
Instrument: U.S. Dionex UltiMate3000 analytical system, DAD detector;
Chromatographic column: CHIRALCEL OD-H 4.6 × 250mm particle diameter 5 μm;
Column temperature: 25 DEG C;
Moving phase: normal hexane: dehydrated alcohol=70: 30;
Flow velocity: 1.0 ml/min;
Determined wavelength: 298nm UV;
Retention time: cis R isomer: 18.20 minutes; Luliconazole: 21.42 minutes; Luliconazole S isomer: 40.06 minutes.
Embodiment 1
Be dissolved in 5mL methylene dichloride by 0.50g luliconazole, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 30 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder (the crystal formation I of luliconazole) 0.45g.Yield is 90%, HPLC >=99.9%, ee value (enantiomeric excess, enantiomeric excess) >=99%.Measure its XRD spectra and DSC trace, the results are shown in Figure 1, Fig. 2 and table 1.
The XRD diffraction peak list of the crystal formation I of table 1 embodiment 1 luliconazole
The crystal formation I that table 1 provides the present embodiment 1 luliconazole is 8.20 in 2 θ values, 9.88, 12.20, 13.46, 13.63, 16.36, 18.31, 20.02, 20.70, 21.32, 21.82, 22.22, 22.63, 23.34, 24.50, 24.70, 25.71, 27.05, 27.41, 27.97, 28.59, 29.73, 29.91, 30.23, 31.33, 32.19, 33.04, 34.02, 34.59, 35.25, 37.10, 37.34, there is corresponding absorption peak the position at 37.59 and 38.76 ° of θ places.
The crystal formation I that Fig. 2 provides the present embodiment 1 luliconazole comprises the DSC trace of the endotherm(ic)peak at 149.00 ~ 152.94 DEG C of places, and the DSC trace of enthalpy of phase change that Fig. 2 crystal formation I of additionally providing the present embodiment 1 luliconazole locates at-68.33J/g.
Embodiment 2
Be dissolved in 5mL acetone by 0.50g luliconazole, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 40 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder 0.47g.Yield is 94%, HPLC >=99.9%, ee value >=99%.Measure its XRD spectra and DSC trace, the results are shown in Figure 3, Fig. 4 and table 2.
The XRD diffraction peak list of the crystal formation I of table 2 embodiment 2 luliconazole
The crystal formation I that table 2 provides the present embodiment 2 luliconazole is 9.90 in 2 θ values, 12.21, 13.64, 16.38, 18.32, 20.03, 20.68, 21.34, 21.84, 22.24, 22.66, 23.36, 23.99, 24.51, 24.73, 25.06, 25.73, 26.87, 27.07, 27.42, 27.99, 28.64, 29.64, 29.90, 30.23, 31.36, 32.21, 32.77, 33.01, 34.02, 34.59, 35.26, 35.74, 37.05, 37.34, 37.56, there is corresponding absorption peak the position at 38.75 and 38.92 ° of θ places.
The crystal formation I that Fig. 4 provides the present embodiment 2 luliconazole comprises the DSC trace of the endotherm(ic)peak at 149.06 ~ 152.59 DEG C of places, and the DSC trace of enthalpy of phase change that Fig. 4 crystal formation I of additionally providing the present embodiment 2 luliconazole locates at-71.59J/g.
Embodiment 3
Be dissolved in 5mL ethyl acetate by 0.50g luliconazole, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 50 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder 0.41g.Yield is 82%, HPLC >=99.9%, ee value >=99%.Measure its XRD spectra and DSC trace, the results are shown in Figure 5, Fig. 6 and table 3.
The XRD diffraction peak list of the crystal formation I of table 3 embodiment 3 luliconazole
The crystal formation I that table 3 provides the present embodiment 3 luliconazole is 9.93 in 2 θ values, 10.98, 12.26, 13.54, 13.67, 14.79, 16.43, 18.34, 20.08, 20.75, 21.36, 21.88, 22.29, 22.68, 23.38, 23.81, 24.06, 24.56, 24.75, 25.75, 26.92, 27.11, 28.01, 28.66, 29.72, 29.95, 30.27, 31.38, 32.25, 32.78, 33.13, 33.49, 34.02, 34.65, 35.03, 35.30, 35.76, 37.16, there is corresponding absorption peak the position at 37.38 and 38.77 ° of θ places.
The crystal formation I that Fig. 6 provides the present embodiment 3 luliconazole comprises the DSC trace of the endotherm(ic)peak at 149.61 ~ 153.44 DEG C of places, and the DSC trace of enthalpy of phase change that Fig. 6 crystal formation I of additionally providing the present embodiment 3 luliconazole locates at-78.97J/g.
Embodiment 4
Be dissolved in 5mL tetrahydrofuran (THF) by 0.50g luliconazole, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 60 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder 0.50g.Yield is 100%, HPLC >=99.9%, ee value >=99%.Measure its XRD spectra and DSC trace, the results are shown in Figure 7, Fig. 8 and table 4.
The XRD diffraction peak list of the crystal formation I of table 4 embodiment 4 luliconazole
The crystal formation I that table 4 provides the present embodiment 4 luliconazole is 9.90 in 2 θ values, 12.21, 13.49, 13.62, 14.74, 16.38, 18.33, 20.06, 20.70, 21.34, 21.84, 22.24, 22.66, 22.85, 23.35, 24.02, 24.52, 24.73, 25.73, 26.87, 27.07, 27.42, 28.01, 29.73, 29.91, 30.23, 31.34, 32.20, 32.35, 32.76, 33.02, 33.16, 33.46, 33.70, 34.04, 34.60, 35.26, 35.80, 37.10, 37.38, there is corresponding absorption peak the position at 37.59 and 38.75 ° of θ places.
The crystal formation I that Fig. 8 provides the present embodiment 4 luliconazole comprises the DSC trace of the endotherm(ic)peak at 149.33 ~ 153.13 DEG C of places, and the DSC trace of enthalpy of phase change that Fig. 8 crystal formation I of additionally providing the present embodiment 4 luliconazole locates at-76.47J/g.
Embodiment 5
Be dissolved in 5mL methyl alcohol by 0.50g luliconazole, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 35 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder 0.49g.Yield is 98%, HPLC >=99.9%, ee value >=99%.Measure its XRD spectra and DSC trace, the results are shown in Figure 9, Figure 10 and table 5.
The XRD diffraction peak list of the crystal formation I of table 5 embodiment 5 luliconazole
The crystal formation I that table 5 provides the present embodiment 5 luliconazole is 9.92 in 2 θ values, 12.22, 13.65, 14.71, 16.38, 18.33, 20.04, 21.35, 21.84, 22.25, 22.67, 22.87, 23.36, 24.02, 24.52, 24.75, 25.10, 25.73, 26.88, 27.08, 27.43, 27.99, 29.76, 29.93, 30.25, 31.34, 32.23, 32.77, 33.04, 33.18, 33.44, 34.04, 34.62, 35.27, 35.77, 37.05, 37.38, 37.56, the peak at 38.78 and 38.95 ° of θ places.
The crystal formation I that Figure 10 provides the present embodiment 5 luliconazole comprises the DSC trace of the endotherm(ic)peak at 149.30 ~ 152.88 DEG C of places, and the DSC trace of enthalpy of phase change that Figure 10 crystal formation I of additionally providing the present embodiment 5 luliconazole locates at-69.95J/g.
Embodiment 6
Be dissolved in by 0.50g luliconazole in the mixed solvent of 2mL toluene and 4mL butanone, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 45 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder 0.48g.Yield is 96%, HPLC >=99.9%, ee value >=99%.Measure its DSC trace, the results are shown in Figure 11.
The crystal formation I that Figure 11 provides the present embodiment 6 luliconazole comprises the DSC trace of the endotherm(ic)peak at 148.00 ~ 151.50 DEG C of places, and the DSC trace of enthalpy of phase change that Figure 11 crystal formation I of additionally providing the present embodiment 6 luliconazole locates at-69.17J/g.
Embodiment 7
Be dissolved in by 0.50g luliconazole in the mixed solvent of 4.5mL chloroform and 1.5mL normal hexane, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 55 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder 0.49g.Yield is 98%, HPLC >=99.9%, ee value >=99%.Measure its DSC trace, the results are shown in Figure 12.
The crystal formation I that Figure 12 provides the present embodiment 7 luliconazole comprises the DSC trace of the endotherm(ic)peak at 149.42 ~ 153.15 DEG C of places, and the DSC trace of enthalpy of phase change that Figure 12 crystal formation I of additionally providing the present embodiment 7 luliconazole locates at-78.55J/g.
Embodiment 8
Be dissolved in by 0.50g luliconazole in the mixed solvent of 4mL Iso Butyl Acetate, 1mL isopropyl ether and 1mL methyl tertiary butyl ether, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 42 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder 0.43g.Yield is 86%, HPLC >=99.9%, ee value >=99%.Measure its DSC trace, the results are shown in Figure 13.
The crystal formation I that Figure 13 provides the present embodiment 8 luliconazole comprises the DSC trace of the endotherm(ic)peak at 147.35 ~ 151.09 DEG C of places, and Figure 13 additionally provides the DSC trace of the enthalpy of phase change that the present embodiment 8 luliconazole crystal formation I locates at-76.24J/g.
Embodiment 9
Be dissolved in by 0.50g luliconazole in 3mL methylene dichloride and 3mL ethyl acetate, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 32 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder (the crystal formation I of luliconazole) 0.44g.Yield is 88%, HPLC >=99.9%, ee value >=99%.
Embodiment 10
Be dissolved in by 0.50g luliconazole in 3mL methyl alcohol and 3mL acetone, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 36 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder (the crystal formation I of luliconazole) 0.46g.Yield is 92%, HPLC >=99.9%, ee value >=99%.
Embodiment 11
Be dissolved in by 0.50g luliconazole in 3mL ethyl acetate and 3mL dehydrated alcohol, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 38 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder (the crystal formation I of luliconazole) 0.45g.Yield is 90%, HPLC >=99.9%, ee value >=99%.
Embodiment 12
Be dissolved in by 0.50g luliconazole in 3mL ethyl acetate and 3mL acetone, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 46 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder (the crystal formation I of luliconazole) 0.43g.Yield is 86%, HPLC >=99.9%, ee value >=99%.
Embodiment 13
Be dissolved in by 0.50g luliconazole in 4mL ethyl acetate and 2mL normal hexane, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 48 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder (the crystal formation I of luliconazole) 0.45g.Yield is 90%, HPLC >=99.9%, ee value >=99%.
Embodiment 14
Be dissolved in by 0.50g luliconazole in 2mL ethyl acetate, 2mL methyl alcohol and 2mL acetone, be heated to backflow and dissolve, be cooled to crystal and separate out completely, filter, 52 DEG C of vacuum-dryings, to constant weight, obtain crystalline powder (the crystal formation I of luliconazole) 0.44g.Yield is 88%, HPLC >=99.9%, ee value >=99%.
Claims (14)
1. the crystal formation I of a luliconazole, it is characterized in that: characterized by the X-ray diffraction pattern comprising two or more absorption peak, wherein, described two or more absorption peak, being selected from 2 θ values is 8.20, 9.91, 10.98, 12.22, 13.49, 13.64, 14.75, 16.38, 18.33, 20.05, 20.71, 21.34, 21.84, 22.25, 22.66, 22.86, 23.36, 23.90, 24.03, 24.52, 24.73, 25.08, 25.73, 26.89, 27.08, 27.42, 27.99, 28.63, 29.72, 29.92, 30.24, 31.35, 32.22, 32.35, 32.77, 33.03, 33.16, 33.46, 33.70, 34.02, 34.61, 35.03, 35.26, 35.77, 37.09, 37.36, 37.58, the peak at 38.76 and 38.93 ± 0.2 ° of θ places.
2. a crystal formation I for luliconazole, is characterized in that: have substantially as Fig. 1,3,5,7 or Fig. 9 shown in XRD spectra.
3. a crystal formation I for luliconazole, be is characterized in that: characterized by DSC trace, and described DSC trace is included in the endotherm(ic)peak at 145.35 ~ 155.44 DEG C of places.
4. the crystal formation I of luliconazole as claimed in claim 3, is characterized in that: described DSC trace is included in the endotherm(ic)peak at 150.36 ± 2 DEG C of places.
5. a crystal formation I for luliconazole, it is characterized in that: characterized by DSC trace, described DSC trace comprises the enthalpy of phase change at-68.33 ,-69.17 ,-69.95 ,-71.59 ,-76.24 ,-78.55 ,-78.97 and-76.47 ± 2J/g place.
6. a crystal formation I for luliconazole, is characterized in that: have substantially as Fig. 2,4,6,8,10,11,12 or Figure 13 shown in DSC trace.
7., for the preparation of a method of the crystal formation I of the luliconazole as described in any one of claim 1-6, it is characterized in that, comprise the following steps:
A luliconazole is dissolved in one or more organic solvents of ether within halohydrocarbon within the hydrocarbon of 5-8 carbon atom, 4 carbon atoms, the ketone within 5 carbon atoms, the ester within 7 carbon atoms, 8 carbon atoms, the alcohol within 4 carbon atoms, the benzene homologues within 9 carbon atoms by ();
Precipitate in b solution that () makes crystalline solid obtain from step (a);
C () is separated the crystalline solid obtained from step (b).
8. method as claimed in claim 7, it is characterized in that: in described step (a), the hydrocarbon of 5-8 carbon atom, comprising: normal hexane, hexanaphthene, normal heptane;
Halohydrocarbon within 4 carbon atoms, comprising: methylene dichloride, chloroform;
Ketone within 5 carbon atoms, comprising: acetone, butanone;
Ester within 7 carbon atoms, comprising: ethyl acetate, Iso Butyl Acetate, butylacetate;
Ether within 8 carbon atoms, comprising: ether, tetrahydrofuran (THF), isopropyl ether, methyl tertiary butyl ether;
Alcohol within 4 carbon atoms, comprising: methyl alcohol, ethanol, Virahol;
Benzene homologues within 9 carbon atoms, comprising: toluene, dimethylbenzene.
9. method as claimed in claim 7, is characterized in that: in described step (a), and heated solvent is to backflow.
10. method as claimed in claim 7, is characterized in that: in described step (b), carrys out precipitated crystal solid by cooling solution.
11. methods as claimed in claim 7, is characterized in that: in described step (c), by filtering the crystalline solid of precipitation separation.
12. methods as claimed in claim 7, is characterized in that: also comprise: the crystalline solid be separated in drying step (c) under vacuo, until reach constant weight.
13., as claimed in claim 7 for the preparation of the method for the crystal formation I of luliconazole, is characterized in that, comprise the following steps:
A () heating is dissolved in the luliconazole extremely backflow in organic solvent;
Wherein, this organic solvent is selected from:
1) methylene dichloride;
2) acetone;
3) ethyl acetate, the mixture of ethyl acetate and methylene dichloride, the mixture of ethyl acetate and ethanol, the mixture of ethyl acetate and acetone, the mixture of ethyl acetate and normal hexane, or the mixture of ethyl acetate, methyl alcohol and acetone;
4) tetrahydrofuran (THF);
5) methyl alcohol, or the mixture of methyl alcohol and acetone;
6) mixture of toluene and butanone;
7) mixture of chloroform and normal hexane;
Or 8) mixture of Iso Butyl Acetate, isopropyl ether and methyl tertiary butyl ether;
B () cools the solution from step (a) until throw out is formed; And
C () is filtered the suspension from step (b) and is obtained solid, until reach constant weight 30 ~ 60 DEG C of vacuum-dryings.
14. methods as claimed in claim 13, is characterized in that, described 3) in, the volumetric mixture ratio of ethyl acetate and methylene dichloride is 1 ~ 4:1; The volumetric mixture ratio of ethyl acetate and ethanol is 1 ~ 4:1; The volumetric mixture ratio of ethyl acetate and acetone is 1 ~ 4:1; The volumetric mixture ratio of ethyl acetate and normal hexane is 1 ~ 4:1; The volumetric mixture ratio of ethyl acetate, methyl alcohol and acetone is 1 ~ 4:1:1;
Described 5), in, the volumetric mixture ratio of methyl alcohol and acetone is 1 ~ 4:1;
Described 6), in, the volumetric mixture ratio of toluene and butanone is 1:1 ~ 4;
Described 7) in, chloroform and normal hexane volumetric mixture ratio be 1 ~ 4:1;
Described 8) in, the mixture 1 ~ 4:1:1 of Iso Butyl Acetate, isopropyl ether and methyl tertiary butyl ether.
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| CN104619704B (en) * | 2012-09-14 | 2017-12-05 | 宝丽制药股份有限公司 | Surface free energy is used for the purposes for breaking up evaluation crystal, the crystal based on surface free energy as metrics evaluation, and the pharmaceutical composition by being prepared comprising the crystal |
| CN104619703A (en) * | 2012-09-14 | 2015-05-13 | 宝丽制药股份有限公司 | Crystal having crystal habits and pharmaceutical composition obtained by processing the crystal |
| WO2014042231A1 (en) * | 2012-09-14 | 2014-03-20 | Pola Pharma Inc. | Crystal and pharmaceutical preparation containing the same crystal |
| JP5589110B1 (en) * | 2013-03-08 | 2014-09-10 | 株式会社ポーラファルマ | Crystal having crystal habit and pharmaceutical composition containing the crystal as an active ingredient |
| JP6268060B2 (en) * | 2013-04-30 | 2018-01-24 | 株式会社ポーラファルマ | Crystals evaluated using surface free energy of crystals as an index, and pharmaceutical compositions containing the crystals |
| JP5699234B2 (en) * | 2013-06-24 | 2015-04-08 | 株式会社ポーラファルマ | Crystal and pharmaceutical preparation containing the crystal |
| JP5680161B1 (en) | 2013-09-06 | 2015-03-04 | 株式会社ポーラファルマ | Crystal having crystal habit and pharmaceutical composition containing the crystal as an active ingredient |
| WO2016092478A1 (en) | 2014-12-12 | 2016-06-16 | Glenmark Pharmaceuticals Limited | Process for preparation of luliconazole |
| JP5795693B2 (en) * | 2015-01-06 | 2015-10-14 | 株式会社ポーラファルマ | Crystal having crystal habit and pharmaceutical composition containing the crystal as an active ingredient |
| JP5951864B1 (en) * | 2015-06-05 | 2016-07-13 | 株式会社ポーラファルマ | Anti-giardia drugs |
| JP2017101009A (en) | 2015-12-04 | 2017-06-08 | 株式会社ポーラファルマ | Anti-acanthamoeba agent and method for producing the same |
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| CN1194582A (en) * | 1995-07-08 | 1998-09-30 | 日本农药株式会社 | Anti fungal agent, compound therefor, process for producing the same |
| WO2010117091A2 (en) * | 2009-04-09 | 2010-10-14 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| WO2010117089A2 (en) * | 2009-04-09 | 2010-10-14 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
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| CN1194582A (en) * | 1995-07-08 | 1998-09-30 | 日本农药株式会社 | Anti fungal agent, compound therefor, process for producing the same |
| WO2010117091A2 (en) * | 2009-04-09 | 2010-10-14 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| WO2010117089A2 (en) * | 2009-04-09 | 2010-10-14 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
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