CN110483551B - Crystals of Laratinib free base - Google Patents

Crystals of Laratinib free base Download PDF

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CN110483551B
CN110483551B CN201910812912.1A CN201910812912A CN110483551B CN 110483551 B CN110483551 B CN 110483551B CN 201910812912 A CN201910812912 A CN 201910812912A CN 110483551 B CN110483551 B CN 110483551B
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pyrazolo
tetrahydro
trimethyl
oxo
fluoro
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CN110483551A (en
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赵紫岭
王守亮
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Beijing Saisiyuan Biomedical Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

The invention discloses (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H][2,5,11]Crystals of benzoxadiazepitetradecyl ring-3-carbonitrile (Lauratinib) as a free base, which crystals comprise at least the following characteristic peaks in the X-ray powder diffraction pattern, measured with Cu-Ka radiation: angle of diffraction 2θThe values are 7.85 + -0.2 °, 12.21 + -0.2 °, 17.16 + -0.2 °, 17.92 + -0.2 °, 20.59 + -0.2 ° and 23.44 + -0.2 °; the obtained crystal has good stability and is suitable for industrial production. In addition, the invention also provides a preparation method and a pharmaceutical composition of the crystal.

Description

Crystals of Laratinib free base
Technical Field
The invention relates to crystals of a pharmaceutical compound, in particular to crystals of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine ring-3-carbonitrile, a process for their preparation and pharmaceutical compositions.
Background
U.S. Pat. No. 5,231,178 describes a chemical substance that inhibits abnormal cell growth, in particular (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadiazatetra-c-3-carbonitrile solvate. On day 11/2 of 2018, (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadiazepitetradecyl-3-carbonitrile (loratinib, trade name: Lorbrena), belonging to the third generation Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitor (TKI), for the treatment of patients with progression of disease after treatment with crizotinib and at least one other ALK inhibitor, or ALK-positive metastatic non-small cell lung cancer (NSCLC) who were treated with exenatib (aletinib) or Ceritinib (ceinib) as the first ALK inhibitor but with progression of disease.
U.S. Pat. No. 6,868,0111 describes a method of inhibiting ALK-driven cancer cell proliferation, particularly the use of the compound (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecyl-3-carbonitrile, for better effectiveness in treating ALK-positive metastatic non-small cell lung cancer patients.
Crystalline forms of the free base of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecane-3-carbonitrile (loratidine) and methods of preparation are described in chinese patent application CN107849060A (publication) by Pfizer, U.S. sponish corporation (Pfizer), and further describes pharmaceutical compositions and methods of using the compositions to treat abnormal cell growth such as cancer.
(10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadiazacyclo-3-carbonitrile has certain lipid solubility but is difficult to dissolve in water, and the solubility of different crystal forms is different, so that the dissolution and release of the pharmaceutical composition in vitro are influenced, and the bioavailability of the drug in vivo is further influenced. Therefore, there is considerable promise for the study and preparation of different forms of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile.
Disclosure of Invention
The invention mainly aims to provide a (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecyl-3-carbonitrile crystal which has the advantages of good lipid solubility, good stability, convenience for industrial production and the like.
Another object of the present invention is to provide a process for preparing the crystals of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecyl-3-carbonitrile, which process is low in cost, high in yield and controllable in impurities.
It is still another object of the present invention to provide a pharmaceutical composition comprising the above crystal.
The invention provides (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathidiazacyclo-3-carbonitrile crystals which have diffraction peaks at 7.85 + -0.2 °, 12.21 + -0.2 °, 14.75 + -0.2 °, 17.16 + -0.2 °, 17.92 + -0.2 °, 20.59 + -0.2 °, 23.44 + -0.2 °, 24.45 + -0.2 ° and 24.98 + -0.2 ° in terms of 2 θ, using Cu-Ka radiation and an X-ray diffraction diagram thereof. In particular, there are also one or more (in any combination, including more than two, or all) diffraction peaks at 7.85 ± 0.2 °, 12.21 ± 0.2 °, 17.16 ± 0.2 °, 17.92 ± 0.2 °, 20.59 ± 0.2 °, and 23.44 ± 0.2 °; the X-ray diffraction pattern of the crystal is shown in FIG. 1.
Furthermore, (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] of the present invention][2,5,11]The crystals of benzoxadiazepitetradecyl-3-carbonitrile have an infrared absorption spectrum measured using KBr pellets and characterized by a wavelength of about 3469cm-1，3332cm-1，2998cm-1，2944cm-1，2229cm-1，1627cm-1，1492cm-1，1419cm-1，1369cm-1，1253cm-1，1199cm-1，1166cm-1，1070cm-1，1049cm-1，948cm-1，887cm-1，835cm-1，636cm-1，570cm-1，441cm-1An absorption peak is formed at the equal position; see fig. 2.
In a specific embodiment, the present invention provides (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H][2,5,11]A benzoxadiaza-tetradecachene-3-carbonitrile crystal having19F solid state nuclear magnetic spectrum, said19The F solid state nuclear magnetic spectrum comprises resonance values selected from: -59.4, -82.5, -86.5, -104.9, -127.0 and-168.0 ppm ± 0.2 ppm; as shown in fig. 3.
The invention also provides a method for preparing (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine slow-3-carbonitrile crystals, which comprises the steps of: firstly, (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxaazatetradecane-3-carbonitrile is dissolved in 5-10 times ((v/v)) dioxane under stirring, then 12-16 times (v/v) water is added, and the mixture is placed at room temperature until crystals are slowly separated out; collecting the resulting solid; and filtering and drying the obtained solid to obtain the (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine ring-3-carbonitrile crystal.
The fat solubility of the crystal is good, the use amount of the organic solvent is increased, the product quality is improved limitedly, the yield is reduced greatly, and the overall production cost is increased.
In the invention, the X-powder diffraction test instrument and the test conditions are as follows: rigaku D/max-rA type X-ray diffractometer (Japan science); cu target, graphite curved crystal monochromator, tube voltage of 40kv, tube current of 100mA, wavelength
Figure GDA0003229113620000021
The scanning range is 3-70 degrees.
The related substance high performance liquid chromatography detection conditions and the method comprise the following steps: octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability; the mobile phase was 0.1% formic acid aqueous solution and methanol, and isocratic elution was performed (0.1% formic acid solution: methanol 63: 37; run time: 30 min; flow rate: 1 ml/min); the detection wavelength is 254 nm; the theoretical plate number is not less than 8000 calculated from the peak of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecane-3-carbonitrile. The separation of the (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile peak from the adjacent impurity peaks is satisfactory.
Dissolution rate measurement conditions and methods: measured according to the second method of 0931 of the four general rules of the pharmacopoeia 2015 year edition.
Taking tablet prepared from the product, determining by dissolution method, using acetic acid buffer (pH adjusted to 4.5)900ml as dissolution medium, rotating at 100 rpm, collecting appropriate amount of solution after 60 min, filtering, discarding primary filtrate, and diluting filtrate to obtain sample solution. An appropriate amount of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadiazepin-3-carbonitrile as a control was weighed accurately, and a solution containing about 10. mu.g of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadiazepin-3-carbonitrile per 1ml was prepared with water, as a control solution. Taking the two solutions, measuring absorbance at wavelength of 225nm by ultraviolet-visible spectrophotometry (second method of 0931, the general rule of four parts of the pharmacopoeia 2015 edition in China), and calculating the dissolution amount of each granule (or tablet) according to absorbance by external standard method.
(10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecane-3-carbonitrile crystal characterization.
One, stability
Test samples: crystalline (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile prepared as in example 1.
1. Water or solvent Effect test
Mixing (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadiazatetra-cene nucleus-3-carbonitrile crystals with appropriate excipients and subjecting the mixture to wet granulation, and determining the X-ray diffraction pattern of the obtained sample, comparing the X-ray diffraction pattern of the (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathi-idine nucleus-3-carbonitrile crystals before granulation, no effect or change was found. The results are shown in FIG. 4 with reference to the X-ray diffraction pattern.
2. Crushing test
A proper amount of samples are taken, a high-speed pulverizer is used for pulverization, samples are taken and measured after pulverization, indexes are tested, and results are compared with those before pulverization, and the results are shown in table 1.
TABLE 1 crush test
Figure GDA0003229113620000031
Figure GDA0003229113620000041
3. Mixing experiment with auxiliary materials
Weighing a quantitative (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methylene bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadiazepin tetradecyl-3-carbonitrile and a proper amount of auxiliary materials, wherein the auxiliary materials are selected from lactose, sucrose, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch and the like as fillers, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium and the like as disintegrants, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, povidone and the like as adhesives, stearic acid, magnesium stearate, calcium stearate and the like as lubricants, talcum powder, sodium carboxymethyl cellulose, croscarmellose sodium starch, and the like, Polyethylene glycol, polyvinyl alcohol, titanium dioxide, ferric oxide and the like as coating materials and other pharmaceutically acceptable auxiliary materials. And then sieving the mixture by a 80-mesh sieve for three times and mixing the mixture to prepare a sample of mixed crystals and auxiliary materials. The obtained sample and the mixed auxiliary materials used in the invention are subjected to X-ray diffraction detection, and the detection result is shown in FIG. 6.
4. Illumination test (5000lxs)
A proper amount of samples were taken and placed under the condition of relative illumination intensity of 5000lxs for 30 days, samples were taken on the 10 th day and the 30 th day respectively for determination, and the results were compared with the results on the 0 th day, and the results are shown in Table 2.
TABLE 2 light test
Figure GDA0003229113620000042
5. Accelerated test (40 ℃ C.)
Taking a proper amount of samples, placing the samples at the temperature of 40 ℃ for 30 days, sampling and measuring the samples on the 10 th day and the 30 th day respectively, sampling and measuring the crystal powder data, comparing the appearance, testing indexes and comparing the result with the 0 th day, wherein the result is shown in the table 3.
TABLE 3 accelerated test (40 ℃ C.)
Figure GDA0003229113620000043
Figure GDA0003229113620000051
6. High humidity test
The (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methylene bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadiazepin tetradecyl-3-carbonitrile crystal raw material is uniformly distributed into an open petri dish with the thickness of less than or equal to 5mm, placed in a constant-temperature and constant-humidity incubator with the room temperature (about 25 ℃) and the relative humidity of 90 +/-5 percent, sampled for determination on the 10 th day and the 30 th day respectively, and compared with the results of the 0 th day, and the results are shown in Table 4.
TABLE 4 high humidity test (room temperature, relative humidity: 90. + -. 5%)
Figure GDA0003229113620000052
Solubility
The test is carried out according to the general examples of the Chinese pharmacopoeia 2015 year edition. The method comprises the following steps: an appropriate amount of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecanamine-3-carbonitrile crystals was weighed out precisely, a certain amount of solvent was slowly added thereto, shaking vigorously every 5 minutes for 30 seconds, and the dissolution in 30 minutes was observed, and the results are shown in Table 5.
TABLE 5(10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecane-3-carbonitrile Crystal solubility test
Solvent(s) Amount of sample (g) Adding solvent (ml) Dissolution behavior Conclusion
DMA 1.00215 Less than 10ml Dissolution Is easy to dissolve
DMF 1.00108 Less than 10ml Dissolution Is easy to dissolve
Dioxane (dioxane) 1.01043 Less than 10ml Dissolution Is easy to dissolve
THF 1.00057 Less than 10ml Dissolution Is easy to dissolve
Ethanol 1.00806 Less than 10ml Dissolution Is easy to dissolve
Methanol 1.02143 Less than 30ml Dissolution Dissolution
Water (W) 1.01872 Greater than 10000ml Not dissolving Is almost insoluble
0.1M Hcl 1.00209 Less than 30ml Dissolution Dissolution
0.1M NaOH 1.00075 Greater than 10000ml Not dissolving Is almost insoluble
A series of tests verify that the stability under the conditions of high temperature, illumination, pressure, mechanical shearing force, action with auxiliary materials and the like is researched. It can be seen that the crystals of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile of the present invention are suitable for preparation into formulations.
Drawings
FIG. 1 is an X-ray diffraction pattern of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile crystals of the present invention.
FIG. 2 is an IR spectrum of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine crystals of the present invention.
FIG. 3 is a drawing showing (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] according to the present invention][2,5,11]Crystalline benzoxadiaza-tetradecyl-3-carbonitrile19And F, solid-state nuclear magnetic spectrum.
FIG. 4 is an X-ray diffraction pattern of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile crystals of the present invention after granulation.
FIG. 5 is an X-ray diffraction pattern of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile crystals of the present invention after pulverization.
FIG. 6 is an X-ray diffraction pattern of crystals of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathidiazacyclo-3-carbonitrile of the present invention in combination with an excipient.
FIG. 7 is an X-ray diffraction pattern of crystals of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathidiazacyclo-3-carbonitrile of the invention after 10 days of irradiation.
FIG. 8 is a crystal X-ray diffraction pattern of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathidiazacyclo-3-carbonitrile of the invention after 30 days of irradiation.
FIG. 9 is a crystalline 10-day accelerated X-ray diffraction pattern of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile of the present invention.
FIG. 10 is a crystalline 30-day accelerated test X-ray diffraction pattern of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile of the present invention.
FIG. 11 is a high humidity 10 day test X-ray diffraction pattern of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile crystals of the invention.
FIG. 12 is a high humidity 30 day test X-ray diffraction pattern of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizazepine-3-carbonitrile crystals of the invention.
Detailed Description
The following examples and drawings are intended to describe the present invention more specifically, but the present invention is not limited to the contents of the following examples.
Example 1
Taking 10g of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxatetradecyl oxazazepine-3-carbonitrile, dissolving in 5 times ((v/v)) dioxane under stirring, adding 12 times (v/v) water, and standing at room temperature until crystals slowly precipitate; the resulting solid was filtered and dried, and the X-ray diffraction pattern of the resulting product was shown in FIG. 1.
Example 2
Taking 30g of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxatetradecyl oxazazepine-3-carbonitrile, dissolving in 10 times ((v/v)) dioxane under stirring, adding 12 times (v/v) water, and standing at room temperature until crystals slowly precipitate; the resulting solid was filtered and dried, and the X-ray diffraction pattern of the obtained product was substantially in accordance with that of example 1.
Taking 50g of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecane-3-carbonitrile, dissolving in 10 times ((v/v)) dioxane under stirring, adding 16 times (v/v) water, and standing at room temperature until crystals slowly precipitate; the resulting solid was filtered and dried, and the X-ray diffraction pattern of the obtained product was substantially in accordance with that of example 1.
Example 3 formulation and preparation of tablets:
the above-mentioned (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecyl-3-carbonitrile crystals were formulated into tablets containing 25mg per tablet using several excipients in the following manner, and the results are shown in Table 6.
TABLE 6 prescription conditions
Figure GDA0003229113620000071
The preparation process comprises the following steps: a tablet containing (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxazatetradecylne-3-carbonitrile is produced by mixing the above-mentioned excipient (except magnesium stearate) with (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxazatetradecylne-3-carbonitrile crystals in a mixer, and (3) performing dry granulation, namely adding magnesium stearate into the dry granules, uniformly mixing and tabletting. The reference crystals were mixed, granulated and tabletted in the same way. The results of the dissolution test of the tablet formulation are shown in Table 7.
TABLE 7 comparison of dissolution test results for tablet formulations
Time (min) Reference crystal Novel crystal
30 80.6％ 81.9％
45 86.2％ 88.1％
60 101.3％ 101.8％
The invention is not limited to the content of the above-described embodiments. Any insubstantial improvement made by adopting the technical scheme and the method conception of the invention or the technical scheme and the invention conception which are directly applied to other occasions without improvement belong to the protection scope of the invention.

Claims (6)

1. (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H][2,5,11]Crystals of benzoxadiazepitetradecylring-3-carbonitrile using Cu-Ka radiation, an X-ray diffraction pattern thereof having diffraction peaks, in terms of 2 θ, at 7.85. + -. 0.2 °, 12.21. + -. 0.2 °, 14.75. + -. 0.2 °, 17.16. + -. 0.2 °, 17.92. + -. 0.2 °, 20.59. + -. 0.2 °, 23.44. + -. 0.2 °, 24.45. + -. 0.2 ° and 24.98. + -. 0.2 °, of said crystals, which crystals have19The F solid state nuclear magnetic spectrum comprises resonance values selected from: -59.4 ppm. + -. 0.2ppm, -104.9 ppm. + -. 0.2ppm and-168.0 ppm. + -. 0.2ppm, the infrared absorption spectrum of the crystal as measured by KBr pellet, the infrared absorption spectrum being 3469cm-1，3332cm-1，2998cm-1，2944cm-1，2229cm-1，1627cm-1，1492cm-1，1419cm-1，1369cm-1，1253cm-1，1199cm-1，1070cm-1，948cm-1，887cm-1，835cm-1，570cm-1，441cm-1Has an absorption peak.
2. The crystal of claim 1, which has a crystal data that does not change after mixing with an excipient.
3. The method for producing a crystal according to claim 1 or 2, characterized in that: dissolving the (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecane-3-carbonitrile in dioxane under stirring, adding an appropriate amount of water, and standing at room temperature until crystals slowly precipitate; the solid obtained is collected and the solid obtained is,
the dosage ratio of the (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadiazatetetradecyl-3-carbonitrile to dioxane is 1: 5-1: 10(v/v), the dosage ratio of the (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxathizatetradecane-3-carbonitrile to water is 1: 12-1: 16 (v/v).
4. The process according to claim 3, wherein the ratio of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadizaotetradecahyric-3-carbonitrile to dioxane is 1:7(v/v), and the ratio of (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadizaotetradecahyric-3-carbonitrile to water is 1: 13-13 1:14 (v/v).
5. A pharmaceutical composition comprising the crystal of claim 1 or 2.
6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition comprises 1 to 200mg of the crystalline (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15,16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4,3-H ] [2,5,11] benzoxadiazepin-3-carbonitrile according to claim 1 or 2 in a unit dose.
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