CN103012385A - Crystal form of luliconazole and preparation method thereof - Google Patents
Crystal form of luliconazole and preparation method thereof Download PDFInfo
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- CN103012385A CN103012385A CN2012100358347A CN201210035834A CN103012385A CN 103012385 A CN103012385 A CN 103012385A CN 2012100358347 A CN2012100358347 A CN 2012100358347A CN 201210035834 A CN201210035834 A CN 201210035834A CN 103012385 A CN103012385 A CN 103012385A
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- luliconazole
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- ethyl acetate
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- 239000013078 crystal Substances 0.000 title claims abstract description 97
- 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 69
- 229960000570 luliconazole Drugs 0.000 title claims abstract description 69
- 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
- 238000010992 reflux Methods 0.000 claims description 19
- 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
- 238000001816 cooling Methods 0.000 claims description 4
- 238000001914 filtration Methods 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
- 238000001035 drying 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 17
- 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
- 238000011160 research Methods 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
- 238000004519 manufacturing process Methods 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
- 241000220317 Rosa Species 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
- 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
- 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
- 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
- 239000011159 matrix material Substances 0.000 description 1
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- 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 the general formula (I)
14H
9C
12N
3S
2), (-)-(E)-(4R)-4-(2,4 dichloro benzene base)-1, the inferior replacement of 3-dithiolane-2-(1H-imidazoles-1-replaces) acetonitrile,
Be the imidazoles antifungal drug of Nihon Nihyaku Co., Ltd's exploitation, early namely begin I clinical trial phase, the II clinical trial phase fs of nonclinical test and emulsifiable paste, thereafter owing to strategic reason has stopped development process.The nineties Nihon Nihyaku Co., Ltd and the Pola Chemical Co., Ltd joint development that subscribes to the agreement, Pola Chemical Co., Ltd is in II clinical trial phase subordinate phase and the III clinical trial phase of 2001 beginning emulsifiable pastes, and carried out lotion the I clinical trial phase and with the simultaneous test of emulsifiable paste.Final this medicine got the Green Light in June, 2005, rose on July 20th, 2005 with trade(brand)name Le リ コ Application (Lulicon) listing, and emulsifiable paste and lotion specification are 1%, are used for following fungi infestation: tinea is sick--the ringworm of the foot, ringworm of the body, jock itch; Monilial infection-rotten to the corn disease, intertrigo between referring to; Purplish or white patches on the skin wind.Have that skin stores that rate is high, medication cycle short (for half of general medicine), good effect and be difficult for the competitive edge of recurrence.
The existing patent of WO97/02821 provides the preparation method and application of luliconazole, but does not disclose the crystalline structure of luliconazole.Crystal is to arrange the solid matter that consists of on space periodic ground by atom (or ion, molecule), and the crystallization of organic drug all belongs to molecular lattice basically, produces different crystal formations along with the difference of processing condition.Single compound can produce various polymorphics (or crystalline structure), and wherein each form can have different or special physicals.The different crystal forms of same medicine often causes medicine in significant differences such as the physico-chemical properties such as outward appearance, solubleness, fusing point, density and drug dissolution, biological effectivenesses, thereby affects the performance of the curative effects such as medicine stability, bioavailability.Molecule is different in sterie configuration, conformation and arrangement in the structure cell of different crystal forms, makes its solvability different with dissolution rate, directly affects preparation absorption, distribution, drainage and metabolism in vivo, the final differences that cause clinical drug effect because of the bioavailability difference.
The polymorphous research of medicine become new drug development and examine, the production of medicine and quality control and new drug formulation determine before the indispensable important component part of designing institute.Research and grasp medicine polymorphic and character thereof will help to guarantee the physical and chemical stability of pharmaceutical preparation in production and storage process, improve the bioavailability of medicine, reduce toxicity, promote result for the treatment of.On the other hand, the technological process of some preparations can change polymorphous molecular structure, dot matrix is arranged, and the crystal formation of medicine is changed, thereby affect medicine stripping and absorption in vivo, and then affect the treatment.By understanding and analyzing in each solid preparation course of processing various factors and can control medicine crystal growth and crystal formation to the impact of polymorph medicine, reduce to greatest extent the generation of poor efficiency, invalid crystal formation, guarantee security and validity that medicine uses.Simultaneously, can be by certain brilliant means that turn, seek the new crystal formation of medicine, new curative effect.
Summary of the invention
The technical problem to be solved in the present invention provides crystal formation of a kind of luliconazole and preparation method thereof.This luliconazole crystal formation has good stability, is convenient to produce, transports and stores, and can satisfy the advantages such as all requirements as preparation raw material.
For solving the problems of the technologies described above, first aspect of the present invention, the crystal formation I of luliconazole is provided, characterize by the X-ray diffraction pattern that comprises two above absorption peaks, wherein, described two above absorption peaks, being selected from 2 θ values is 8.20,9.91,10.98,12.22,13.49,13.64,14.75,16.38,18.33,20.05,20.71,21.34,21.84,22.25,22.66,22.86,23.36,23.90,24.03,24.52,24.73,25.08,25.73,26.89,27.08,27.42,27.99,28.63,29.72,29.92,30.24,31.35,32.22,32.35,32.77,33.03,33.16,33.46,33.70,34.02,34.61,35.03,35.26,35.77,37.09,37.36,37.58,38.76 and the peak at 38.93 ± 0.2 ° of θ places.
Second aspect provides to have basically such as Fig. 1,3,5,7 or the crystal formation I of the luliconazole of XRD (X-ray diffraction analysis) spectrogram shown in Figure 9.
Aspect the 3rd of the present invention, the crystal formation I of luliconazole is provided, by DSC (differential scanning calorimetry, dsc) trace characterizes, described DSC trace is included in the endotherm(ic)peak that 145.35～155.44 ℃ [i.e. 147.35～153.44 (equal ± 2 ℃)] are located, preferably 150.36 ± 2 ℃ of endotherm(ic)peaks of locating.
Aspect the 4th, the crystal formation I of luliconazole is provided, characterize by the DSC trace, described DSC trace comprises that-68.33 ,-69.17 ,-69.95 ,-71.59 ,-76.24 ,-78.55 ,-78.97 reach the enthalpy of phase change at-76.47 ± 2J/g place.
Aspect the 5th, provide to have basically such as Fig. 2,4,6,8,10,11,12 or the luliconazole crystal formation I of DSC trace shown in Figure 13.
The 6th aspect of the present invention provides a kind of method for the preparation of luliconazole crystal formation I, may further comprise the steps:
(a) luliconazole is dissolved in the hydrocarbon of 5-8 carbon atom, 4 carbon atoms with interior halohydrocarbon, 5 carbon atoms with interior ketone, 7 carbon atoms with interior ester, 8 carbon atoms with interior ether, 4 carbon atoms with in interior alcohol, 9 carbon atoms one or more organic solvents with interior benzene homologues;
(b) precipitate in the solution that crystalline solid is obtained from step (a);
(c) separate the crystalline solid that from step (b), obtains.
Wherein, in the step (a), the hydrocarbon of 5-8 carbon atom comprises: normal hexane, hexanaphthene, normal heptane;
4 carbon atoms comprise with interior halohydrocarbon: methylene dichloride, chloroform;
5 carbon atoms comprise with interior ketone: acetone, butanone;
7 carbon atoms comprise with interior ester: ethyl acetate, Iso Butyl Acetate, butylacetate;
8 carbon atoms comprise with interior ether: ether, tetrahydrofuran (THF), isopropyl ether, methyl tertiary butyl ether;
4 carbon atoms comprise with interior alcohol: methyl alcohol, ethanol, Virahol;
9 carbon atoms comprise with interior benzene homologues: toluene, dimethylbenzene.
In the described step (a), heated solvent is to refluxing.
In the described step (b), come the precipitated crystal solid by cooling solution.
In the described step (c), by filtering the crystalline solid of precipitation separation.
Above method for the preparation of luliconazole crystal formation I also can comprise: under vacuum, the crystalline solid of separating in the drying step (c) is until reach constant weight.
The 7th aspect provides the method for a kind of crystal formation I for the preparation of luliconazole, may further comprise the steps:
(a) heating is dissolved in the extremely backflow of luliconazole in the 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 of Iso Butyl Acetate, isopropyl ether and methyl tertiary butyl ether: 1: 1.
(b) cooling from the solution of step (a) until throw out form; And
(c) filtration obtains solid from the suspension of step (b) and 30～60 ℃ of vacuum-dryings, until reach constant weight.
In addition, the present invention selects at the solvent that is used for the dissolving luliconazole, and also research is found:
1) the 0.50g luliconazole is dissolved in the 3mL methylene dichloride, is heated to the dissolving that refluxes, drip rapidly the 3mL sherwood oil, can separate out oily matter;
2) the 0.50g luliconazole is dissolved in 5mL ethyl acetate or the acetone, is heated to the dissolving that refluxes, drip rapidly the 10mL sherwood oil, can separate out oily matter;
3) the 0.50g luliconazole is dissolved in 5mL ethanol, methyl alcohol or the Virahol, is heated to the dissolving that refluxes, drip rapidly the 10mL deionized water, can separate out oily matter.
Therefore, the present invention is preferred above-mentioned organic solvent.
The crystal formation I of luliconazole of the present invention has favourable performance, for example, good solvability, bioavailability, stability, tractability, security, compressibility or usefulness etc., thereby, can be used for preparing in the medicine for the treatment of or prevent 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.
Description of drawings
The present invention is further detailed explanation below in conjunction with accompanying drawing and embodiment:
Fig. 1 is the XRD spectra of the crystal formation I of the embodiment of the invention 1 luliconazole;
Fig. 2 is the DSC trace of the crystal formation I of the embodiment of the invention 1 luliconazole;
Fig. 3 is the XRD spectra of the crystal formation I of the embodiment of the invention 2 luliconazoles;
Fig. 4 is the DSC trace of the crystal formation I of the embodiment of the invention 2 luliconazoles;
Fig. 5 is the XRD spectra of the crystal formation I of the embodiment of the invention 3 luliconazoles;
Fig. 6 is the DSC trace of the crystal formation I of the embodiment of the invention 3 luliconazoles;
Fig. 7 is the XRD spectra of the crystal formation I of the embodiment of the invention 4 luliconazoles;
Fig. 8 is the DSC trace of the crystal formation I of the embodiment of the invention 4 luliconazoles;
Fig. 9 is the XRD spectra of the crystal formation I of the embodiment of the invention 5 luliconazoles;
Figure 10 is the DSC trace of the crystal formation I of the embodiment of the invention 5 luliconazoles;
Figure 11 is the DSC trace of the crystal formation I of the embodiment of the invention 6 luliconazoles;
Figure 12 is the DSC trace of the crystal formation I of the embodiment of the invention 7 luliconazoles;
Figure 13 is the DSC trace of the crystal formation I of the embodiment of the invention 8 luliconazoles.
Embodiment
Luliconazole in following examples is according to the gained that is prepared of describing among EP0218736A1 and the US4636519.
In addition, the testing conditions of the XRD that relates in following examples, DSC and HPLC 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: Switzerland Mei Tele company (Mettler), instrument title: differential scanning calorimeter (DSC), instrument model: DSC1; 25 ℃～200 ℃ of testing method, 5 ℃/min or 25 ℃～180 ℃, 5 ℃/min;
3、HPLC：
Instrument: U.S. Dionex UltiMate3000 analytical system, DAD detector;
Chromatographic column: Venusil XBP-184.6 * 250mm particle diameter 5 μ m apertures
Column temperature: 25 ℃;
Moving phase: acetonitrile: water=55: 45;
Flow velocity: 1.5 ml/min;
Detect wavelength: 298nm UV;
Retention time: cis-isomeride: 9.35 minutes; Luliconazole: 9.94 minutes;
Wherein, chirality HPLC condition is as follows:
Instrument: U.S. Dionex UltiMate3000 analytical system, DAD detector;
Chromatographic column: CHIRALCEL OD-H 4.6 * 250mm particle diameter 5 μ m;
Column temperature: 25 ℃;
Moving phase: normal hexane: dehydrated alcohol=70: 30;
Flow velocity: 1.0 ml/min;
Detect wavelength: 298nm UV;
Retention time: cis R isomer: 18.20 minutes; Luliconazole: 21.42 minutes; Luliconazole S isomer: 40.06 minutes.
The 0.50g luliconazole is dissolved in the 5mL methylene dichloride, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 30 ℃ of vacuum-dryings get crystalline powder (the crystal formation I of luliconazole) 0.45g to constant weight.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 tabulation of the crystal formation I of table 1 embodiment 1 luliconazole
It is 8.20 in 2 θ values that table 1 provides the crystal formation I of the present embodiment 1 luliconazole, 9.88,12.20,13.46,13.63,16.36,18.31,20.02,20.70,21.32,21.82,22.22,22.63,23.34,24.50,24.70,25.71,27.05,27.41,27.97,28.59,29.73,29.91,30.23,31.33,32.19,33.04,34.02,34.59,35.25,37.10,37.34,37.59 and there is corresponding absorption peak the position at 38.76 ° of θ places.
The DSC trace that Fig. 2 provides the crystal formation I of the present embodiment 1 luliconazole to comprise 149.00～152.94 ℃ of endotherm(ic)peaks of locating, and Fig. 2 crystal formation I that the present embodiment 1 luliconazole also is provided is at the DSC trace of the enthalpy of phase change at-68.33J/g place.
The 0.50g luliconazole is dissolved in the 5mL acetone, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 40 ℃ of vacuum-dryings get crystalline powder 0.47g to constant weight.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 tabulation of the crystal formation I of table 2 embodiment 2 luliconazoles
It is 9.90 in 2 θ values that table 2 provides the crystal formation I of the present embodiment 2 luliconazoles, 12.21,13.64,16.38,18.32,20.03,20.68,21.34,21.84,22.24,22.66,23.36,23.99,24.51,24.73,25.06,25.73,26.87,27.07,27.42,27.99,28.64,29.64,29.90,30.23,31.36,32.21,32.77,33.01,34.02,34.59,35.26,35.74,37.05,37.34,37.56,38.75 and there is corresponding absorption peak the position at 38.92 ° of θ places.
The DSC trace that Fig. 4 provides the crystal formation I of the present embodiment 2 luliconazoles to comprise 149.06～152.59 ℃ of endotherm(ic)peaks of locating, and Fig. 4 crystal formation I that the present embodiment 2 luliconazoles also are provided is at the DSC trace of the enthalpy of phase change at-71.59J/g place.
Embodiment 3
The 0.50g luliconazole is dissolved in the 5mL ethyl acetate, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 50 ℃ of vacuum-dryings get crystalline powder 0.41g to constant weight.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 tabulation of the crystal formation I of table 3 embodiment 3 luliconazoles
It is 9.93 in 2 θ values that table 3 provides the crystal formation I of the present embodiment 3 luliconazoles, 10.98,12.26,13.54,13.67,14.79,16.43,18.34,20.08,20.75,21.36,21.88,22.29,22.68,23.38,23.81,24.06,24.56,24.75,25.75,26.92,27.11,28.01,28.66,29.72,29.95,30.27,31.38,32.25,32.78,33.13,33.49,34.02,34.65,35.03,35.30,35.76,37.16,37.38 and there is corresponding absorption peak the position at 38.77 ° of θ places.
The DSC trace that Fig. 6 provides the crystal formation I of the present embodiment 3 luliconazoles to comprise 149.61～153.44 ℃ of endotherm(ic)peaks of locating, and Fig. 6 crystal formation I that the present embodiment 3 luliconazoles also are provided is at the DSC trace of the enthalpy of phase change at-78.97J/g place.
Embodiment 4
The 0.50g luliconazole is dissolved in the 5mL tetrahydrofuran (THF), is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 60 ℃ of vacuum-dryings get crystalline powder 0.50g to constant weight.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 tabulation of the crystal formation I of table 4 embodiment 4 luliconazoles
It is 9.90 in 2 θ values that table 4 provides the crystal formation I of the present embodiment 4 luliconazoles, 12.21,13.49,13.62,14.74,16.38,18.33,20.06,20.70,21.34,21.84,22.24,22.66,22.85,23.35,24.02,24.52,24.73,25.73,26.87,27.07,27.42,28.01,29.73,29.91,30.23,31.34,32.20,32.35,32.76,33.02,33.16,33.46,33.70,34.04,34.60,35.26,35.80,37.10,37.38,37.59 and there is corresponding absorption peak the position at 38.75 ° of θ places.
The DSC trace that Fig. 8 provides the crystal formation I of the present embodiment 4 luliconazoles to comprise 149.33～153.13 ℃ of endotherm(ic)peaks of locating, and Fig. 8 crystal formation I that the present embodiment 4 luliconazoles also are provided is at the DSC trace of the enthalpy of phase change at-76.47J/g place.
Embodiment 5
The 0.50g luliconazole is dissolved in the 5mL methyl alcohol, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 35 ℃ of vacuum-dryings get crystalline powder 0.49g to constant weight.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 tabulation of the crystal formation I of table 5 embodiment 5 luliconazoles
It is 9.92 in 2 θ values that table 5 provides the crystal formation I of the present embodiment 5 luliconazoles, 12.22,13.65,14.71,16.38,18.33,20.04,21.35,21.84,22.25,22.67,22.87,23.36,24.02,24.52,24.75,25.10,25.73,26.88,27.08,27.43,27.99,29.76,29.93,30.25,31.34,32.23,32.77,33.04,33.18,33.44,34.04,34.62,35.27,35.77,37.05,37.38,37.56,38.78 and the peak at 38.95 ° of θ places.
The DSC trace that Figure 10 provides the crystal formation I of the present embodiment 5 luliconazoles to comprise 149.30～152.88 ℃ of endotherm(ic)peaks of locating, and Figure 10 crystal formation I that the present embodiment 5 luliconazoles also are provided is at the DSC trace of the enthalpy of phase change at-69.95J/g place.
Embodiment 6
The 0.50g luliconazole is dissolved in the mixed solvent of 2mL toluene and 4mL butanone, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 45 ℃ of vacuum-dryings get crystalline powder 0.48g to constant weight.Yield is 96%, HPLC 〉=99.9%, ee value 〉=99%.Measure its DSC trace, the results are shown in Figure 11.
The DSC trace that Figure 11 provides the crystal formation I of the present embodiment 6 luliconazoles to comprise 148.00～151.50 ℃ of endotherm(ic)peaks of locating, and Figure 11 crystal formation I that the present embodiment 6 luliconazoles also are provided is at the DSC trace of the enthalpy of phase change at-69.17J/g place.
Embodiment 7
The 0.50g luliconazole is dissolved in the mixed solvent of 4.5mL chloroform and 1.5mL normal hexane, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 55 ℃ of vacuum-dryings get crystalline powder 0.49g to constant weight.Yield is 98%, HPLC 〉=99.9%, ee value 〉=99%.Measure its DSC trace, the results are shown in Figure 12.
The DSC trace that Figure 12 provides the crystal formation I of the present embodiment 7 luliconazoles to comprise 149.42～153.15 ℃ of endotherm(ic)peaks of locating, and Figure 12 crystal formation I that the present embodiment 7 luliconazoles also are provided is at the DSC trace of the enthalpy of phase change at-78.55J/g place.
Embodiment 8
The 0.50g luliconazole is dissolved in the mixed solvent of 4mL Iso Butyl Acetate, 1mL isopropyl ether and 1mL methyl tertiary butyl ether, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 42 ℃ of vacuum-dryings get crystalline powder 0.43g to constant weight.Yield is 86%, HPLC 〉=99.9%, ee value 〉=99%.Measure its DSC trace, the results are shown in Figure 13.
The DSC trace that Figure 13 provides the crystal formation I of the present embodiment 8 luliconazoles to comprise 147.35～151.09 ℃ of endotherm(ic)peaks of locating, and Figure 13 also provides the present embodiment 8 luliconazole crystal formation I DSC trace at the enthalpy of phase change at-76.24J/g place.
Embodiment 9
The 0.50g luliconazole is dissolved in 3mL methylene dichloride and the 3mL ethyl acetate, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 32 ℃ of vacuum-dryings get crystalline powder (the crystal formation I of luliconazole) 0.44g to constant weight.Yield is 88%, HPLC 〉=99.9%, ee value 〉=99%.
The 0.50g luliconazole is dissolved in 3mL methyl alcohol and the 3mL acetone, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 36 ℃ of vacuum-dryings get crystalline powder (the crystal formation I of luliconazole) 0.46g to constant weight.Yield is 92%, HPLC 〉=99.9%, ee value 〉=99%.
Embodiment 11
The 0.50g luliconazole is dissolved in 3mL ethyl acetate and the 3mL dehydrated alcohol, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 38 ℃ of vacuum-dryings get crystalline powder (the crystal formation I of luliconazole) 0.45g to constant weight.Yield is 90%, HPLC 〉=99.9%, ee value 〉=99%.
Embodiment 12
The 0.50g luliconazole is dissolved in 3mL ethyl acetate and the 3mL acetone, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 46 ℃ of vacuum-dryings get crystalline powder (the crystal formation I of luliconazole) 0.43g to constant weight.Yield is 86%, HPLC 〉=99.9%, ee value 〉=99%.
Embodiment 13
The 0.50g luliconazole is dissolved in 4mL ethyl acetate and the 2mL normal hexane, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 48 ℃ of vacuum-dryings get crystalline powder (the crystal formation I of luliconazole) 0.45g to constant weight.Yield is 90%, HPLC 〉=99.9%, ee value 〉=99%.
Embodiment 14
The 0.50g luliconazole is dissolved in 2mL ethyl acetate, 2mL methyl alcohol and the 2mL acetone, is heated to the dissolving that refluxes, be cooled to crystal and separate out fully, filter, 52 ℃ of vacuum-dryings get crystalline powder (the crystal formation I of luliconazole) 0.44g to constant weight.Yield is 88%, HPLC 〉=99.9%, ee value 〉=99%.
Claims (14)
1. the crystal formation I of a luliconazole, it is characterized in that: characterize by the X-ray diffraction pattern that comprises two above absorption peaks, wherein, described two above absorption peaks, being selected from 2 θ values is 8.20,9.91,10.98,12.22,13.49,13.64,14.75,16.38,18.33,20.05,20.71,21.34,21.84,22.25,22.66,22.86,23.36,23.90,24.03,24.52,24.73,25.08,25.73,26.89,27.08,27.42,27.99,28.63,29.72,29.92,30.24,31.35,32.22,32.35,32.77,33.03,33.16,33.46,33.70,34.02,34.61,35.03,35.26,35.77,37.09,37.36,37.58,38.76 and the peak at 38.93 ± 0.2 ° of θ places.
2. the crystal formation I of a luliconazole is characterized in that: have basically such as Fig. 1,3,5,7 or XRD spectra shown in Figure 9.
3. the crystal formation I of a luliconazole, it is characterized in that: characterize by the DSC trace, described DSC trace is included in 145.35～155.44 ℃ of endotherm(ic)peaks of locating.
4. the crystal formation I of luliconazole as claimed in claim 3, it is characterized in that: described DSC trace is included in 150.36 ± 2 ℃ of endotherm(ic)peaks of locating.
5. the crystal formation I of a luliconazole is characterized in that: characterize by the DSC trace, described DSC trace comprises-68.33 ,-69.17 ,-69.95 ,-71.59 ,-76.24 ,-78.55 ,-78.97 and the enthalpy of phase change at-76.47 ± 2J/g place.
6. the crystal formation I of a luliconazole is characterized in that: have basically such as Fig. 2,4,6,8,10,11,12 or DSC trace shown in Figure 13.
7. such as the method for each described crystal formation I for the preparation of luliconazole of claim 1-6, it is characterized in that, may further comprise the steps:
(a) luliconazole is dissolved in the hydrocarbon of 5-8 carbon atom, 4 carbon atoms with interior halohydrocarbon, 5 carbon atoms with interior ketone, 7 carbon atoms with interior ester, 8 carbon atoms with interior ether, 4 carbon atoms with in interior alcohol, 9 carbon atoms one or more organic solvents with interior benzene homologues;
(b) precipitate in the solution that crystalline solid is obtained from step (a);
(c) separate the crystalline solid that from step (b), obtains.
8. method as claimed in claim 7, it is characterized in that: in the described step (a), the hydrocarbon of 5-8 carbon atom comprises: normal hexane, hexanaphthene, normal heptane;
4 carbon atoms comprise with interior halohydrocarbon: methylene dichloride, chloroform;
5 carbon atoms comprise with interior ketone: acetone, butanone;
7 carbon atoms comprise with interior ester: ethyl acetate, Iso Butyl Acetate, butylacetate;
8 carbon atoms comprise with interior ether: ether, tetrahydrofuran (THF), isopropyl ether, methyl tertiary butyl ether;
4 carbon atoms comprise with interior alcohol: methyl alcohol, ethanol, Virahol;
9 carbon atoms comprise with interior benzene homologues: toluene, dimethylbenzene.
9. method as claimed in claim 7 is characterized in that: in the described step (a), heated solvent is to refluxing.
10. method as claimed in claim 7 is characterized in that: in the described step (b), come the precipitated crystal solid by cooling solution.
11. method as claimed in claim 7 is characterized in that: in the described step (c), by filtering the crystalline solid of precipitation separation.
12. method as claimed in claim 7 is characterized in that: also comprise: the crystalline solid of separating in the drying step under vacuum (c), until reach constant weight.
13. the method for the crystal formation I for the preparation of luliconazole as claimed in claim 7 is characterized in that, may further comprise the steps:
(a) heating is dissolved in the extremely backflow of luliconazole in the 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) cooling from the solution of step (a) until throw out form; And
(c) filtration obtains solid from the suspension of step (b) and 30～60 ℃ of vacuum-dryings, until reach constant weight.
14. method 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 of Iso Butyl Acetate, isopropyl ether and methyl tertiary butyl ether: 1: 1.
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| WO2014042231A1 (en) * | 2012-09-14 | 2014-03-20 | Pola Pharma Inc. | Crystal and pharmaceutical preparation containing the same crystal |
| WO2014041846A1 (en) * | 2012-09-14 | 2014-03-20 | Pola Pharma Inc. | Use of surface free energy for differential evaluation of crystal, crystal evaluated on basis of surface free energy as index, and phrmaceutical composition prepared by containing the crystal |
| JP2014218511A (en) * | 2013-04-30 | 2014-11-20 | 株式会社ポーラファルマ | Crystal evaluated using surface free energy thereof as index and pharmaceutical composition containing crystal |
| JP2015027984A (en) * | 2013-06-24 | 2015-02-12 | 株式会社ポーラファルマ | Crystal and pharmaceutical preparation containing the crystal |
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| CN104619704A (en) * | 2012-09-14 | 2015-05-13 | 宝丽制药股份有限公司 | Use of surface free energy for differential evaluation of crystal, crystal evaluated on basis of surface free energy as index, and phrmaceutical composition prepared by containing the crystal |
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Application publication date: 20130403 Assignee: HUBEI BIO-PHARMACEUTICAL INDUSTRIAL TECHNOLOGICAL INSTITUTE Inc. Assignor: VIWIT PHARMACEUTICAL Co.,Ltd. Contract record no.: 2017990000463 Denomination of invention: Crystal form of luliconazole and preparation method thereof Granted publication date: 20150708 License type: Exclusive License Record date: 20171127 |
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