CN105693699A - Topiroxostat novel crystal form and preparation method thereof - Google Patents
Topiroxostat novel crystal form and preparation method thereof Download PDFInfo
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Abstract
The invention relates to topiroxostat (5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole) novel crystal form and a preparation method thereof. The novel crystal form provided by the invention can be used for treating uarthritis and hyperuricemia. The novel crystal form provided by the invention has the advantages that the stability is high; the industrial purification effect is obvious; the solubility and the hygroscopicity conform to medicinal requirements. The crystal form A provided by the invention has the adverse performance beneficial to industrial production, and important values are realized on future medicine optimization and development. The structure formula is shown as the accompanying drawing.
Description
Technical field
The present invention relates to chemical medicine, particularly relate to crystal form A of 5-(2-cyano group-4-pyridine radicals)-3-(4-pyridine radicals)-1,2,4-triazole and preparation method thereof。
Background technology
Holder pyrrole department he, chemical name is 5-(2-cyano group-4-pyridine radicals)-3-(4-pyridine radicals)-1,2,4-triazole, is by a kind of xanthine oxidoreductase enzyme (XOR) inhibitor of Japanese fuji medicine Co., Ltd. research and development。He listed in Japan's approval on June 28th, 2013 to hold in the palm pyrrole department, was used for treating gout and hyperuricemia。The chemical constitution of this medicine is such as shown in formula I:
Polymorph in pharmaceuticals (drugpolymorphism) refers to that medicine has two or more different crystal forms state of matter。Polymorphism is widely present in medicine。The different crystal forms of same medicine has significant difference in dissolubility, fusing point, density, stability etc., thus affecting the stability of medicine, homogeneity, bioavailability, efficacy and saferry to some extent。Therefore, medicament research and development carries out comprehensive and systematic screening polymorph, select to be best suitable for the crystal formation of exploitation, be one of very important important research content。
It was found that hold in the palm pyrrole department, he equally exists polymorphism。Yuan Yan company protects his three crystal formations of holder pyrrole department in patent WO2014017515A1; crystal formation I, crystal form II, hydrate crystal forms; but patent is not directed to the hygroscopicity of three kinds of crystal formations; the physico-chemical properties such as stability; only refer only to crystal formation I water solublity good; and medicament research and development carries out comprehensive and systematic screening polymorph, select to be best suitable for the crystal formation of exploitation, be one of very important important research content。Based on this, it is necessary to carry out the screening polymorph of formula (1) compound further, developing the anhydrous crystal forms of good stability, low in hygroscopicity, applicable industrialized production, the subsequent development for medicine provides more better selections。
The present inventor is found that a kind of novel crystal forms of formula (1) compound in research process, and this stability of crystal form is good, dissolubility, draws and moist meets medicinal requirements。
Summary of the invention
It is an object of the present invention to provide a kind of novel crystal forms of formula I compound, called after crystal form A。
Crystal form A provided by the invention, it is characterised in that its X-ray powder diffraction figure is that 10.2 ° ± 0.2 °, 17.0 ° ± 0.2 °, 27.3 ° ± 0.2 ° place has characteristic peak in 2theta value。
Further, crystal form A provided by the invention, it is further characterized in that, its X-ray powder diffraction figure is that the place in 15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 ° or two places or three places have characteristic peak in 2theta value。
Further, crystal form A provided by the invention, it is further characterized in that, its X-ray powder diffraction figure is that 15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 ° place has characteristic peak in 2theta value。
Further, crystal form A provided by the invention, it is further characterized in that, its X-ray powder diffraction figure is the place in 15.5 ° ± 0.2 °, 20.6 ° ± 0.2 ° or two places have characteristic peak in 2theta value。
Further, crystal form A provided by the invention, it is further characterized in that, its X-ray powder diffraction figure is that 15.5 ° ± 0.2 °, 20.6 ° ± 0.2 ° place has characteristic peak in 2theta value。
Preferably, the crystal form A of confession of the present invention, it is that 10.2 ° ± 0.2 °, 17.0 ° ± 0.2 °, 27.3 ° ± 0.2 °, 15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 °, 15.5 ° ± 0.2 °, 20.6 ° ± 0.2 ° place has characteristic peak that its X-ray powder diffraction figure includes in 2theta value。
Further, crystal form A provided by the invention, it is further characterized in that, its X-ray powder diffraction figure is substantially as shown in Figure 1。
Further, crystal form A provided by the invention, it is characterised in that when carrying out differential scanning calorimetric analysis, heating starts endothermic peak occur near 326 DEG C, and its differential scanning calorimetric thermogram is substantially as shown in Figure 2。
The preparation method that it is a further object to provide crystal form A, it is characterized in that, being dissolved in the mixed solvent system of one or more solvents by the powder of formula I compound, by suspendible stirring, decrease temperature crystalline, volatilization crystallization, anti-solvent is added or the method for crystallising of reversely anti-solvent interpolation obtains。
Further, the mixed solvent system of the preferred ketones solvent of described dicyandiamide solution or ketones solvent and alkyl nitrile。
Further, described ketones solvent more preferably 1-methyl pyrrolidone;Described alkyl nitrile more preferably acetonitrile。
It is a further object to provide the Pharmaceutical composition of the crystal form A of a kind of formula I compound comprising effective therapeutic dose and pharmaceutic adjuvant。Be usually the mixing of the crystal form A of the formula I compound of therapeutically effective amount and one or more pharmaceutic adjuvants or contact and make Pharmaceutical composition or preparation, this Pharmaceutical composition or preparation be know in pharmaceutical field in the way of be prepared。
Aforementioned pharmaceutical compositions can be made into certain dosage form, by applicable administration。The approach such as such as oral, parenteral (including subcutaneous, muscle, vein or Intradermal), rectum, transdermal, per nasal, vagina。The dosage form being suitable for oral administration includes tablet, capsule, granule, powder, pill, powder, lozenge, solution, syrup or suspensoid, as required, may be adapted to the quickly release of active constituents of medicine, postpones release or regulate release;The dosage form being suitable for parenteral includes aqueous or nonaqueous aseptic injectable solution, emulsion or suspension;The dosage form being suitable for rectally includes suppository or enema;The dosage form being suitable for transdermal administration includes ointment, cream, patch;The dosage form being suitable for nose administration includes aerosol, spray, nasal drop;The dosage form being suitable for vagina administration includes suppository, suppository, gel, paste or spray。Preferably due to the crystal formation of the present invention has beat all agent of low hygroscopicity and the stability in water or in ethanol water, therefore, be especially suitable for preparing into tablet, suspensoid, capsule, disintegrating tablet, namely release, slow release and controlled release tablet;More preferably tablet, suspensoid and capsule。
Acceptable excipient on aforementioned pharmaceutical compositions Chinese materia medica, when solid oral dosage form, include but not limited to: diluent, for instance starch, pregelatinized Starch, lactose, Powderd cellulose, microcrystalline Cellulose, calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar etc.;Binding agent, for instance arabic gum, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, Polyethylene Glycol etc.;Disintegrating agent, for instance starch, sodium starch glycollate, pregelatinized Starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, silica sol etc.;Lubricant, for instance stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate etc.;Fluidizer, for instance silica sol etc.;Complex forming agents, for instance the cyclodextrin of various ranks and resin;Rate of release controlling agent, for instance hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methylcellulose, methyl methacrylate, wax etc.。Other available pharmaceutically acceptable excipient include but not limited to film former, plasticizer, coloring agent, flavoring agent, viscosity modifier, preservative, antioxidant etc.。Optionally, tablet is coated with coatings, Lac isolation coat, sugar-coat or polymer coating are such as provided, polymer in coatings is hydroxypropyl methyl cellulose, polyvinyl alcohol, ethyl cellulose, methacrylic polymer, hydroxypropyl cellulose or starch such as, antitack agent such as silicon dioxide, Pulvis Talci can also be included, opacifiers is titanium dioxide such as, and coloring agent is iron oxides coloring agent such as。When liquid oral dosage form, suitable excipient includes water, oils, alcohols, glycols, flavoring agent, preservative, stabilizer, coloring agent etc.;The sterile suspensions of water or non-water can contain suspending agent and thickening agent;Excipient suitable in aqueous suspension includes rubber polymer or natural gums such as Radix Acaciae senegalis, Herba Xanthii natural gum, alginate, glucosan, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin。When parenteral dosage forms, the excipient of the aseptic injectable solution of water or non-water is generally sterilized water, normal saline or D/W, it is possible to containing buffer agent, antioxidant, antibacterial with the isotonic solute of this pharmaceutical composition and blood can be made。Each excipient must be acceptable, can be compatible and harmless for patient with other compositions in formula。
Described pharmaceutical composition can use in prior art and well known to a person skilled in the art prepared by method。When preparing pharmaceutical composition, pharmaceutically acceptable to crystal form A of the present invention and one or more excipient is mixed mutually, optionally mix mutually with one or more other active constituents of medicine。Such as, tablet, capsule, granule can be prepared by techniques such as mixing, granulation, tabletting or filling capsules;Powder is prepared by the finely ground active constituents of medicine to suitable size and excipient being mixed;Solution and syrup can be prepared by being dissolved in suitably seasoned water or aqueous solution by active constituents of medicine;Suspensoid can be prepared by being scattered in pharmaceutically acceptable carrier by active constituents of medicine。
It is especially mentioned that the wet granulation technology of solid preparation, wet granulation for tablet, preparation technology is: the dry solids such as mixed active composition, filler, binding agent, with wetting agent such as water or alcohol moistening, the solid of this moistening is made condensation product or granule, continuing wet granulation, until obtaining required uniform grading, being subsequently dried this granular product。Then the dry granule obtained is mixed with disintegrating agent, lubricant, antitack agent etc., tabletting in pelleter;Alternatively, coating is carried out with suitable coating powder。
Formula provided by the invention (I) compound crystal form A can serve as xanthine oxidase inhibitor, and the crystal formation of the present invention can regulate the activity of xanthine oxidase by dosage。Crystal form A can be used for that the xanthine oxidase for the treatment of individual (such as patient) is diseases related or disease, and it is undertaken by the compound crystal form of therapeutically effective amount or the present invention of therapeutically effective dosage or its pharmaceutical composition are delivered medicine to the individuality needing this treatment。Formula provided by the invention (I) compound crystal form A can be also used for treatment hyperuricemia and the gout that causes of hyperuricemia。
The invention have the benefit that
Crystal form A provided by the invention has good stability, and low in hygroscopicity, medicine can be avoided well to store and occur in development process to turn crystalline substance, thus avoiding the change of bioavailability and drug effect。
Crystal form A provided by the invention has higher dissolubility, meets bioavailability and drug effect requirement。
In the preparation method of the crystal form A of the present invention: described " patent crystal formation " refers to the crystal formation in prior art WO2014017515。
Term as used herein " effective therapeutic dose " or " therapeutically effective amount " refer to the amount of reactive compound or the medicament causing biological respinse or the drug reaction sought in tissue, system, animal, individuality or people by research worker, veterinary, doctor or other clinicists。
Term as used herein " treatment " refers to one of the following or multiple: (1) prevention disease;Such as may tend to disease, disease or obstacle, preventing this disease, disease or obstacle but without suffering or show in the pathological changes of this disease or the individuality of symptom;(2) this disease is suppressed;Such as in just suffering or show the pathological changes of this disease, disease or obstacle or the individuality of symptom, suppress this disease, disease or obstacle;And (3) improve this disease;Such as, in suffering or show the pathological changes of this disease, disease or obstacle or the individuality of symptom, this disease, disease or obstacle (namely reversing pathological changes and/or symptom) are improved, for instance lower the severity of disease。
Term as used herein " polymorphic " refers to the different crystal forms of same compound and includes but not limited to comprise the hydrate of same compound and other solid state molecular forms of solvate。Same drug molecule forms the phenomenon of multiple crystal formation and is called that polymorph in pharmaceuticals, polymorph in pharmaceuticals are ubiquitous phenomenons in solid drugs。Known have such polymorphous medical compounds, owing to its physicochemical properties are different, pharmacologically active, dissolubility, bioavailability and stability etc. brought impact。Therefore, exist in polymorphous situation at the compound useful as medicine, it is desirable to from these polymorphics, manufacture the crystal-form compound that serviceability is high。
Term as used herein " X-ray powder diffraction figure " refer to experimental observation to diffraction pattern or be derived from its parameter。X-ray powder diffraction figure is characterized by peak position and peak intensity。
Term used in the present invention " crystal " or " crystal formation " refer to be characterized by shown X-ray diffractogram and confirm。It will be appreciated by those skilled in the art that the discussed physicochemical property of the present invention can be characterized, experimental error therein depends on the purity of the condition of instrument, the preparation of sample and sample。Particularly, as well known to those skilled in the art, X-ray diffractogram would generally change along with the condition of instrument。Special needs to be pointed out is, the relative intensity of X-ray diffractogram is likely to and changes along with the change of experiment condition, so the order of peak intensity cannot function as unique or deciding factor。It addition, the experimental error of peak angle degree is generally 5% or less, the error of these angles also should be considered into, allows generally for ± the error of 0.2 °。Further, since the impact of the empirical factors such as height of specimen, the overall offset of peak angle degree can be caused, allow generally for certain skew。Thus, it will be appreciated by persons skilled in the art that in the present invention, the x-ray diffraction pattern of a crystal formation need not be completely the same with the X-ray diffractogram in example referred herein。Any crystal formation having with the same or analogous figure of the characteristic peak in these collection of illustrative plates belongs within scope of the invention。The collection of illustrative plates of the collection of illustrative plates listed by the present invention and a unknown crystal formation can be compared by those skilled in the art, is identical or different crystal formation with what confirm this two groups of collection of illustrative plates reflection。
Accompanying drawing explanation
Fig. 1 is the XRPD figure of crystal form A
Fig. 2 is the DSC figure of crystal form A
Fig. 3 is crystal form A1H-NMR schemes
Fig. 4 is the DVS figure of crystal form A
Fig. 5 is XRPD comparison diagram before and after the DVS of crystal form A
Fig. 6 is crystal form A and be placed on 5 DEG C, 25 DEG C/60%RH, the folded figure of the XRPD of 15 days (being followed successively by initial crystal form A from top to bottom, 5 DEG C, 25 DEG C/60%RH, place the XRPD figure of 15 days when 40 DEG C/75%RH) when 40 DEG C/75%RH
Fig. 7 is crystal form A and be placed on 5 DEG C, 25 DEG C/60%RH, the folded figure of the XRPD of 30 days (being followed successively by initial crystal form A from top to bottom, 5 DEG C, 25 DEG C/60%RH, place the XRPD figure of 15 days when 40 DEG C/75%RH) when 40 DEG C/75%RH
Fig. 8 is crystal form A and be placed on 5 DEG C, 25 DEG C/60%RH, the folded figure of the XRPD of 90 days (being followed successively by initial crystal form A from top to bottom, 5 DEG C, 25 DEG C/60%RH, place the XRPD figure of 15 days when 40 DEG C/75%RH) when 40 DEG C/75%RH
Fig. 9 is the XRPD figure (be followed successively by initial crystal form A from top to bottom, 5 DEG C, 25 DEG C, 50 DEG C of balances XRPD figure after 1 hour) that crystal form A balances gained solid after 1 hour
Figure 10 is the patent crystal formation I XRPD figure (be followed successively by initial crystal formation I from top to bottom, 5 DEG C, 25 DEG C, 50 DEG C of balances XRPD figure after 1 hour) balancing gained solid after 1 hour
Figure 11 is the transformation graph of a relation of patent crystal formation I and crystal form A
Detailed description of the invention
Hereinafter the present invention will be expanded on further by specific embodiment, but be not limited to protection scope of the present invention。Preparation method and use instrument can be made improvements by those skilled in the art in right, and these improvement also should be regarded as protection scope of the present invention。Therefore, the protection domain of patent of the present invention should be as the criterion with claims。
Being explained as follows of abbreviation used in the present invention:
XRPD:X ray powder diffraction
DSC: differential scanning calorimetric analysis
1HNMR: proton nmr spectra
X-ray powder diffraction figure of the present invention gathers on PanalyticalEmpyreanX ray powder diffractometer。The method parameter of X-ray powder diffraction of the present invention is as follows:
X ray reflection parameter: Cu, K α
1.540598;1.544426
K α 2/K α 1 intensity: 0.50
Voltage: 45 KVs (kV)
Electric current: 40 milliamperes (mA)
Sweep limits: spend from 3.0 to 40.0
Differential scanning calorimetric analysis of the present invention (DSC) figure gathers on TAQ2000。The method parameter of differential scanning calorimetric analysis of the present invention (DSC) is as follows:
Sweep speed: 10 DEG C/min
Protective gas: nitrogen
Embodiment 1
The preparation method of formula I compound crystal form A:
7.4mg formula I compound as its free base is dissolved in the 1-methyl pyrrolidone of 0.18mL, agitating solution, and the acetonitrile of 2.0mL is added drop-wise in above-mentioned solution, and under room temperature condition, continuing stirring 1 hour, filter, gained solid is detected as crystal form A。
The X-ray powder diffraction data of the crystal formation that the present embodiment obtains are as shown in table 1。Its XRPD schemes such as Fig. 1。The X-ray powder diffraction data of the crystal formation that the present embodiment obtains include but not limited to table 1 data。Its DSC figure such as Fig. 2, its1HNMR schemes as shown in Figure 3。
The X-ray powder diffraction data of table 1 crystal form A
Embodiment 2
The preparation method of formula I compound crystal form A:
Being dissolved in the 1-methyl pyrrolidone of 0.18mL by 7.4mg formula I compound as its free base, dropped to by this solution in the acetonitrile of 2.0mL under stirring condition, under room temperature condition, continue stirring 1 hour, filter, gained solid is detected as crystal form A。
The ray powder diffraction data of the crystal form A that the present embodiment obtains is as shown in table 2。
The X-ray powder diffraction data of table 2 crystal form A
2theta | D interval | Intensity % |
10.26 | 8.63 | 100.00 |
13.32 | 6.65 | 3.75 |
15.47 | 5.73 | 37.53 |
15.65 | 5.66 | 26.03 |
17.03 | 5.21 | 56.34 |
19.14 | 4.64 | 1.04 |
20.63 | 4.30 | 52.42 |
21.58 | 4.12 | 14.49 |
22.28 | 3.99 | 1.85 |
23.50 | 3.79 | 3.57 |
24.53 | 3.63 | 21.85 |
25.17 | 3.54 | 3.86 |
27.27 | 3.27 | 25.98 |
28.08 | 3.18 | 6.88 |
31.24 | 2.86 | 3.03 |
34.74 | 2.58 | 2.05 |
37.63 | 2.39 | 1.59 |
Embodiment 3
Formula I compound crystal form A draws moist experiment:
Under 25 DEG C of conditions, take crystal form A of the present invention and be about 10mg and carry out dynamic water absorption (DVS) and test it and draw moist。Experimental result is as shown in table 3, and the DVS of crystal form A schemes as shown in Figure 4, XRPD comparison diagram before and after DVS as it is shown in figure 5, wherein upper figure be before DVS, figure below is after DVS。
Table 3
About draw moist feature description with draw moist weightening finish define (Chinese Pharmacopoeia version annex XIXJ medicine in 2010 draws moist test direction principle, experiment condition: 25 DEG C ± 1 DEG C, 80% relative humidity):
Deliquescence: absorb the fractal one-tenth liquid of enough water
Great draw moist: draw wet weightening finish and be not less than 15%
Have draw moist: drawing wet weightening finish and less than 15% but being not less than 2%
Slightly draw moist: draw wet weightening finish and less than 2% but be not less than 0.2%
Nothing or moist almost without drawing: drawing wet weightening finish less than 0.2%
It is shown that the crystal form A of the present invention balance under 80% humidity after weightening finish 1.00%, belong to slightly draw moist。This character shows that this crystal formation is susceptible to humidity impact or deliquescence, facilitates its long storage periods to place。On the other hand, owing to this crystal formation draws moist relatively low, without special drying condition in preparation process, simplify preparation and aftertreatment technology to a certain extent, it is easy to industrialization。Owing to this crystal formation divides content to be held essentially constant at different humidity Water Under, condition of storage is required not harsh, greatly reduces material storing and the cost of quality control aspect, there is very strong economic worth。
Embodiment 4
Formula I compound crystal form A and patent crystal form II dissolubility comparative study:
The crystal form A prepared in embodiment 1 is used respectively with patent crystal form II sample SGF (simulated gastric fluid), pH5.0FeSSIF (under simulation fed conditions intestinal juice), it is configured to saturated solution under pH6.5FaSSIF (under simulation fasted conditions intestinal juice) and pure water room temperature, at 1 hour, 4 hours and measure the content of sample in saturated solution by high performance liquid chromatography (HPLC) method after 24 hours。Experimental result is as shown in table 4。
Table 4 crystal form A and patent crystal formation dissolubility comparative study
Be can be seen that by above-mentioned comparing result, at SGF, after FaSSIF and FeSSIF places 1 hour, after 4 hours with the novel crystal forms A of the present invention after 24 hours compared with patent crystal form II, dissolubility is higher, when SGF (simulated gastric fluid) and pH5.0FeSSIF (under simulation fed conditions intestinal juice), the dissolubility of crystal form A is about about 1.3 times of patent crystal form II, and when pH6.5FaSSIF (under simulation fasted conditions intestinal juice), the dissolubility of crystal form A is about about 3 times of patent crystal form II, dissolubility significantly improves, and then contribute to the raising of bioavailability。
Embodiment 5
The stability of formula I compound crystal form A and purity research
The new crystal form A present invention prepared is positioned over 5 DEG C, 25 DEG C/RH60%, when 40 DEG C/RH is 75% 90 days, respectively at 15 days, within 30 days and 90 days, respectively sample once, detect the crystal form X RPD change of sample respectively, and record its chemical purity by HPLC, result of the test display crystal form A has good physical stability and higher chemical purity, purity data result is as shown in table 5, Fig. 6, 7, 8 represent that crystal form A is positioned over 5 DEG C respectively, 25 DEG C/RH60%, when 40 DEG C/RH is 75% 15 days, XRPD result (Fig. 6: be followed successively by initial crystal form A from top to bottom of 30 days and 90 days, 5 DEG C, 25 DEG C/60%RH, the XRPD figure of 15 days is placed when 40 DEG C/75%RH;Fig. 7: be followed successively by initial crystal form A from top to bottom, 25 DEG C/60%RH, places the XRPD figure of 30 days by 5 DEG C when 40 DEG C/75%RH;Fig. 8: be followed successively by initial crystal form A from top to bottom, 25 DEG C/60%RH, places the XRPD figure of 90 days by 5 DEG C when 40 DEG C/75%RH)。
The stability (purity %) of table 5 crystal form A
5 DEG C/(%) | 25 DEG C/60%RH (%) | 40 DEG C/75%RH (%) | |
Initial | 99.83 | 99.83 | 99.83 |
15 days | 99.92 | 99.90 | 99.88 |
30 days | 99.91 | 99.88 | 99.87 |
90 days | 99.91 | 99.86 | 99.82 |
It is shown that formula (I) compound crystal form A is at 5 DEG C, under (25 DEG C/60%RH) steady in a long-term and acceleration for stabilization (40 DEG C/75%RH) condition, in placement process, sample is stable, and purity is almost constant。Above-mentioned result of the test shows, the crystal form A of formula provided by the invention (I) compound has good stability and higher purity。
Embodiment 6
Take appropriate formula I compound crystal form A and the patent crystal formation I appropriate methyl iso-butyl ketone (MIBK) of addition (MIBK) and be made into suspension, it is respectively placed in 5 DEG C, 25 DEG C, balance 1 hour at 50 DEG C, centrifugal, liquid high performance liquid chromatography surveys concentration, and solid XRPD tests, and result is as shown in table 6。Fig. 9,10 respectively crystal form A and crystal formation I balance 1 hour after XRPD figure (Fig. 9: be followed successively by the XRPD figure of crystal form A before balance from top to bottom, 5 DEG C, 25 DEG C, balance the XRPD figure of 1 hour at 50 DEG C of gained solid;Figure 10: before being followed successively by balance from top to bottom, the XRPD of crystal formation I schemes, 5 DEG C, 25 DEG C, balances the XRPD figure of 1 hour at 50 DEG C)。
The equilbrium solubility data of table 6 crystal form A and patent crystal formation I
Initial crystal formation | Solvent | Temperature/DEG C | Concentration/mg/mL | Final crystal formation |
Crystal form A | MIBK | 5 | 0.17 | Crystal form A |
Crystal form A | MIBK | 25 | 0.22 | Crystal form A |
Crystal form A | MIBK | 50 | 0.39 | Crystal form A |
Patent crystal formation I | MIBK | 5 | 0.17 | Patent crystal formation I |
Patent crystal formation I | MIBK | 25 | 0.25 | Patent crystal formation I |
Patent crystal formation I | MIBK | 50 | 0.42 | Patent crystal formation I |
Based on the data of the dissolubility of upper table crystal formation I and crystal form A and temperature, the crystal formation I drawn according to model Hough equation and the transforming relationship figure of crystal form A, such as Figure 11。Inverted relation research, crystal form A is always more stable than crystal formation I when more than 5 DEG C。
Claims (11)
1. a crystal form A for formula (I) compound,
It is characterized in that, its X-ray powder diffraction figure is that 10.2 ° ± 0.2 °, 17.0 ° ± 0.2 °, 27.3 ° ± 0.2 ° place has characteristic peak in 2theta value。
2. crystal form A according to claim 1, is further characterized in that, its X-ray powder diffraction figure is that the place in 15.7 ° ± 0.2 °, 21.6 ° ± 0.2 °, 24.5 ° ± 0.2 ° or two places or three places have characteristic peak in 2theta value。
3. the crystal form A according to any one of claim 1 or 2, is further characterized in that, its X-ray powder diffraction figure is the place in 15.5 ° ± 0.2 °, 20.6 ° ± 0.2 ° or two places have characteristic peak in 2theta value。
4. the crystal form A according to any one of claim 1-3, it is characterised in that its X-ray powder diffraction figure is substantially consistent with Fig. 1。
5. the preparation method of formula (I) the compound crystal form A as described in any one of claim 1-4, it is characterized in that, being dissolved in the dicyandiamide solution of one or more solvents by the powder of formula (I) compound, by suspendible stirring, decrease temperature crystalline, volatilization crystallization, anti-solvent is added or the method for crystallising of reversely anti-solvent interpolation obtains。
6. preparation method according to claim 5, described dicyandiamide solution is ketones solvent or the mixed solvent system of ketones solvent and alkyl nitrile。
7. preparation method according to claim 6, described ketones solvent is 1-methyl pyrrolidone。
8. preparation method according to claim 6, described alkyl nitrile is acetonitrile。
9. a pharmaceutical composition, described Pharmaceutical composition comprises the crystal form A described in any one of claim 1-4 of effective dose and pharmaceutically acceptable pharmaceutic adjuvant。
10. pharmaceutical composition according to claim 9, it is characterised in that described crystal form A can be used for preparation treatment gout and hyperuricemia pharmaceutical preparation。
11. the crystal form A according to any one of claim 1-4 is in the purposes for the treatment of gout and hyperuricemia。
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1561340A (en) * | 2002-01-28 | 2005-01-05 | 株式会社富士药品 | Novel 1,2,4-triazole compound |
JP2005041802A (en) * | 2003-07-25 | 2005-02-17 | Fujiyakuhin Co Ltd | Method for producing 1,2,4-triazole compound |
CN1826335A (en) * | 2003-07-24 | 2006-08-30 | 株式会社富士药品 | Process for producing 1,2,4-triazole compound and intermediate therefor |
CN103724329A (en) * | 2013-12-23 | 2014-04-16 | 济南百诺医药科技开发有限公司 | Preparation method of 4-[5-(pyridyl-4-yl)-1H-[1,2,4]triazolyl-3-yl]pyridyl-2-formonitrile |
CN104151297A (en) * | 2014-08-27 | 2014-11-19 | 庄妍 | Preparation of 4-[5-(pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-2-formonitrile |
CN104230891A (en) * | 2014-08-27 | 2014-12-24 | 庄妍 | Preparation method of topiroxostat |
CN104411686A (en) * | 2012-07-25 | 2015-03-11 | 株式会社富士药品 | Method of producing 4-[5-(pyridin-4-yl)-1h-1,2,4-triazole-3-yl]pyridin-2-carbonitrile, and intermediary thereof |
CN104411700A (en) * | 2012-07-25 | 2015-03-11 | 株式会社富士药品 | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ519984A (en) * | 2000-01-07 | 2004-03-26 | Transform Pharmaceuticals Inc | High-throughput formation, identification, and analysis of diverse solid-forms |
CN104961730B (en) * | 2015-06-18 | 2017-05-17 | 山东金城医药化工股份有限公司 | Novel topiroxostat crystal form and method for preparing same |
-
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1561340A (en) * | 2002-01-28 | 2005-01-05 | 株式会社富士药品 | Novel 1,2,4-triazole compound |
CN1826335A (en) * | 2003-07-24 | 2006-08-30 | 株式会社富士药品 | Process for producing 1,2,4-triazole compound and intermediate therefor |
JP2005041802A (en) * | 2003-07-25 | 2005-02-17 | Fujiyakuhin Co Ltd | Method for producing 1,2,4-triazole compound |
CN104411686A (en) * | 2012-07-25 | 2015-03-11 | 株式会社富士药品 | Method of producing 4-[5-(pyridin-4-yl)-1h-1,2,4-triazole-3-yl]pyridin-2-carbonitrile, and intermediary thereof |
CN104411700A (en) * | 2012-07-25 | 2015-03-11 | 株式会社富士药品 | 4-[5-(pyridine-4-yl)-1h-1,2,4-triazole-3-yl]pyridine-2-carbonitrile crystalline polymorph and production method therefor |
CN103724329A (en) * | 2013-12-23 | 2014-04-16 | 济南百诺医药科技开发有限公司 | Preparation method of 4-[5-(pyridyl-4-yl)-1H-[1,2,4]triazolyl-3-yl]pyridyl-2-formonitrile |
CN104151297A (en) * | 2014-08-27 | 2014-11-19 | 庄妍 | Preparation of 4-[5-(pyridine-4-yl)-1H-[1,2,4]triazole-3-yl]pyridine-2-formonitrile |
CN104230891A (en) * | 2014-08-27 | 2014-12-24 | 庄妍 | Preparation method of topiroxostat |
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JP2018510173A (en) | 2018-04-12 |
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