CN116023313A - Docalcitol compound crystal and capsule thereof - Google Patents
Docalcitol compound crystal and capsule thereof Download PDFInfo
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- CN116023313A CN116023313A CN202211688113.6A CN202211688113A CN116023313A CN 116023313 A CN116023313 A CN 116023313A CN 202211688113 A CN202211688113 A CN 202211688113A CN 116023313 A CN116023313 A CN 116023313A
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- calcitol
- compound
- ethyl acetate
- methanol
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 26
- 239000013078 crystal Substances 0.000 title claims abstract description 26
- 239000002775 capsule Substances 0.000 title claims abstract description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 78
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 57
- 238000003756 stirring Methods 0.000 claims abstract description 34
- 239000002904 solvent Substances 0.000 claims abstract description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000002425 crystallisation Methods 0.000 claims abstract description 20
- 230000008025 crystallization Effects 0.000 claims abstract description 20
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000012043 crude product Substances 0.000 claims abstract description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 dulcitol compound Chemical class 0.000 claims abstract description 11
- 239000012074 organic phase Substances 0.000 claims abstract description 11
- 239000000463 material Substances 0.000 claims abstract description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 7
- 238000004090 dissolution Methods 0.000 claims abstract description 7
- 239000012065 filter cake Substances 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- 238000001291 vacuum drying Methods 0.000 claims abstract description 7
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 4
- 238000001816 cooling Methods 0.000 claims abstract description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 21
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 20
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 108010010803 Gelatin Proteins 0.000 claims description 11
- 239000008273 gelatin Substances 0.000 claims description 11
- 229920000159 gelatin Polymers 0.000 claims description 11
- 235000019322 gelatine Nutrition 0.000 claims description 11
- 235000011852 gelatine desserts Nutrition 0.000 claims description 11
- 239000008213 purified water Substances 0.000 claims description 10
- 239000004408 titanium dioxide Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 239000000499 gel Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 5
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical group COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 230000008034 disappearance Effects 0.000 claims description 3
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 229920001971 elastomer Polymers 0.000 claims description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000008346 aqueous phase Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 238000000605 extraction Methods 0.000 abstract description 8
- 208000020832 chronic kidney disease Diseases 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 210000001685 thyroid gland Anatomy 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 abstract description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000006187 pill Substances 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 229960003276 erythromycin Drugs 0.000 description 5
- 238000000071 blow moulding Methods 0.000 description 4
- 229960003722 doxycycline Drugs 0.000 description 4
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 4
- DWDQDGVEPVITJL-UHFFFAOYSA-N 5-butyl-2-methoxyphenol Chemical compound CCCCC1=CC=C(OC)C(O)=C1 DWDQDGVEPVITJL-UHFFFAOYSA-N 0.000 description 3
- 229960000413 doxercalciferol Drugs 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000001728 nano-filtration Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- 229930006677 Erythromycin A Natural products 0.000 description 2
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 2
- 230000005260 alpha ray Effects 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 239000002932 luster Substances 0.000 description 2
- 229940057917 medium chain triglycerides Drugs 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- PGNYNCTUBKSHHL-UHFFFAOYSA-N 2,3-diaminobutanedioic acid Chemical compound OC(=O)C(N)C(N)C(O)=O PGNYNCTUBKSHHL-UHFFFAOYSA-N 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- HKXBNHCUPKIYDM-CGMHZMFXSA-N doxercalciferol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C HKXBNHCUPKIYDM-CGMHZMFXSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 210000002990 parathyroid gland Anatomy 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003703 vitamin D2 derivatives Chemical class 0.000 description 1
Images
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The utility model discloses a dulcitol compound crystal and a capsule thereof, relates to the technical field of compound crystal medicines, and aims to solve the problem that the existing dulcitol crystal medicine has no good treatment effect on chronic kidney disease patients and secondary thyroid patients. Step one: dispersing the crude product of the calcitol in a solvent, heating to 60+/-5 ℃ for dissolution, then cooling to 0+/-5 ℃ for crystallization for more than 5 hours, filtering, transferring a filter cake to 30+/-5 ℃ for vacuum drying, and collecting the material to obtain the calcitol, wherein the purity of the calcitol crude product is not less than 99.0%; the solvent for crystallization can be one or more of methanol, isopropanol, acetone and 2-butanone; step two: the compound crystals (0.02 mol,7.9 g) were dissolved in 8mL of ethyl acetate, stirred and fully dissolved, 16mL of acetic acid was added, reacted at room temperature for 24 hours, stirring was stopped, the pH of the system was adjusted to 7 by saturated sodium bicarbonate, the organic phases were combined after extraction with 30mL of ethyl acetate 2, and the organic phases were washed with 20mL of saturated sodium chloride.
Description
Technical Field
The utility model relates to the technical field of compound crystal medicines, in particular to a dulcitol compound crystal and a capsule thereof, and also relates to a pharmaceutical composition of the dulcitol compound crystal and application thereof in the aspect of secondary hyperparathyroidism of chronic kidney disease patients receiving dialysis treatment or stage 3 or 4.
Background
The chemical name of the calcitol (Doxercalciferol) is 9, 10-secergosta-5, 7, 10 (19), 22-tetraene-1 alpha, 3 beta-diol, and the chemical structural formula is as follows:
the calcitol is white to off-white powder, is a synthetic analogue of vitamin D2, and can inhibit synthesis and secretion of parathyroid gland.
For example, bulletin number "CN105237452B", entitled (a new crystalline form of calcitol and process for its preparation), comprising: the pharmaceutical composition of the novel crystalline form A of the doxycycline and the application thereof in treating osteoporosis or secondary hyperparathyroidism. The novel crystal form A of the calcitol adopts Cu-K alpha radiation, and X-ray powder diffraction expressed by 2 theta angles has diffraction peaks at 7.82, 8.51, 12.06, 13.01, 15.60, 17.05, 17.82, 18.71, 19.35, 20.06, 20.37, 20.62, 21.98, 22.68, 22.90, 23.81 and 24.79. The utility model also discloses a process improvement scheme for preparing high-purity calcitol, which has the advantages of simple steps, easy operation, short time, low cost and suitability for industrial mass production.
For example, the publication number "CN204162637U", entitled (an erythromycin thiocyanate extraction apparatus), includes: the erythromycin fermentation liquid treating device comprises an ultrafiltration membrane, a nanofiltration membrane and an extraction tower, wherein a conveying pipeline of erythromycin fermentation liquid is connected to an inlet of the interception side of the ultrafiltration membrane, a permeation side of the ultrafiltration membrane is connected to an inlet of the nanofiltration membrane, an outlet of the interception side of the nanofiltration membrane is connected to the extraction tower, the bottom of the extraction tower is connected to an inlet of a ceramic membrane, the permeation side of the ceramic membrane is connected to a middle tank, and a sodium thiocyanate storage tank is arranged on the middle tank and sequentially connected with a crystallization kettle, a solid-liquid separation device and a drying device. Compared with the traditional erythromycin extraction device, the erythromycin A extraction device has high erythromycin A extraction yield; the purity is high; the operation process is simplified; reducing the cost of solvent and reducing industrial pollution.
The existing calcitol crystallization medicine has no problem of good treatment effect on chronic kidney disease patients and secondary thyroid patients; to this end, we provide a crystalline form of a calcitol compound and a capsule thereof.
Disclosure of Invention
The utility model aims to provide a dulcitol compound crystal and a capsule thereof, which are used for solving the problem that the traditional dulcitol crystal medicine provided in the background art has no good treatment effect on chronic kidney disease patients and secondary thyroid patients.
In order to achieve the above purpose, the present utility model provides the following technical solutions: a crystalline of a calcitol compound, which uses a Cu target K alpha ray, has a powder X-ray powder diffraction pattern having characteristic peaks at 5.63.+ -. 0.2, 10.32.+ -. 0.2, 11.24.+ -. 0.2, 12.08.+ -. 0.2, 14.86.+ -. 0.2, 15.05.+ -. 0.2, 15.42.+ -. 0.2, 16.30.+ -. 0.2, 16.70.+ -. 0.2, 16.89.+ -. 0.2, 18.00.+ -. 0.2, 20.03.+ -. 0.2, 20.56.+ -. 0.2, 22.5.+ -. 0.27 and 24.26.+ -. 0.2.
Further, the DSC spectrum has an endothermic peak at 163.0 + -3deg.C.
The utility model also provides a preparation method of the doxercalciferol compound crystal, which specifically comprises the following steps:
step one: dispersing the crude product of the calcitol in a solvent, heating to 60+/-5 ℃ for dissolution, then cooling to 0+/-5 ℃ for crystallization for more than 5 hours, filtering, transferring a filter cake to 30+/-5 ℃ for vacuum drying, and collecting the material to obtain the calcitol, wherein the purity of the calcitol crude product is not less than 99.0%; the solvent for crystallization can be one or more of methanol, isopropanol, acetone and 2-butanone.
Step two: dissolving compound crystals (0.02 mol,7.9 g) in 8mL of ethyl acetate, stirring for complete dissolution, adding 16mL of acetic acid, reacting for 24 hours at room temperature, stopping stirring, regulating the pH of a system to 7 by saturated sodium bicarbonate, extracting with 30mLx2 of ethyl acetate, merging organic phases, washing the organic phases with 20mL of saturated sodium chloride, and distilling the ethyl acetate under reduced pressure until no liquid is distilled off to obtain light red oily substance which is compound crystal 2;
step three: compound crystal 2 was dissolved in 16mL of tetrahydrofuran, and tetrabutylammonium fluoride (1.0 mol. L) -1 ) (0.02 mol,16 mL), stirring at room temperature for 24h, TLC detection of disappearance of starting material;
step four: saturated sodium bicarbonate was adjusted to ph=7, extracted with ethyl acetate 30mL x2, the organic phases were combined, washed with saturated sodium chloride 10mL, separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove ethyl acetate until no liquid distilled off to give a red oil;
step five: the oil was dissolved in 34mL of methanol, and 8mL of potassium hydroxide solution (2.0 mol. L -1 ) Stirring at room temperature for 3h, and reacting 1.0mol.L -1 Hydrochloric acid adjusts pH=7, methanol is distilled under reduced pressure, water phase is extracted with 20mL of ethyl acetate, anhydrous sodium sulfate is dried, maleic anhydride 0.4g is added, ethyl acetate is distilled under reduced pressure after shaking fully until no liquid is distilled off, oily substance column chromatography (petroleum ether: ethyl acetate=5:1-1:1) is carried out, and white granular solid 1.4g is the calcitol, and the yield is: 22.4%.
The crystallization solvent is preferably a mixed system of methanol/2-butanone, the dosage of the methanol is 1-2 ml/g, the dosage of the acetone is 8-9 ml/g, the dosage of the methanol is preferably 1.5ml/g, and the dosage of the 2-butanone is preferably 8.5ml/g.
As a preferred embodiment, the solvent for crystallization may be one or more of methanol, isopropanol, acetone and 2-butanone, wherein a mixed system of methanol/acetone is preferred.
As a preferred technical scheme, the solvent for crystallization is preferably a mixed system of methanol/acetone, the dosage of the methanol is 1-2 ml/g and the dosage of the acetone is 8-9 ml/g, wherein the dosage of the methanol is preferably 1.5ml/g, and the dosage of the acetone is preferably 8.5ml/g.
The utility model also provides a preparation method of the domino alcoholization capsule, which comprises the following steps:
weighing absolute ethyl alcohol and medium-chain triglyceride in a container with a proper volume, adding p-butyl hydroxyanisole under stirring, and stirring until the mixture is completely dissolved; weighing the raw materials of the doxycycline, adding into the container under stirring, charging nitrogen, and stirring until the raw materials are completely dissolved.
Taking out part of purified water, adding the weighed titanium dioxide and the yellow ferric oxide into a container with a proper volume, stirring until the titanium dioxide and the yellow ferric oxide are completely dispersed, adding the mixture into a gel melting tank, adding the glycerol and the rest of purified water into the gel melting tank, heating to 80 ℃ with stirring, slowly adding gelatin, stirring at the constant temperature of 80 ℃ for 30min, vacuumizing, and ending the sol after the vacuum defoaming is complete.
According to the theoretical loading of 100 mg/pill, performing pelleting; and (3) using an intelligent rotating cage, performing cold blow molding, and transferring the capsule into a drying room for drying to obtain the capsule.
As a preferred embodiment, the contents comprise absolute ethanol, butyl hydroxyanisole and medium chain triglycerides.
As a preferred embodiment, the gelatin skin comprises gelatin, glycerol, iron oxide yellow, titanium dioxide and purified water.
Compared with the prior art, the utility model has the beneficial effects that:
1. according to the utility model, the intermediate (compound) is silanized, crystallized and separated to obtain the intermediate with single configuration, so that the industrialized production of the route can be realized, and the reaction is more stable and controllable. The reaction is increased by 2 steps, but the final yield is still slightly improved. The existing yield is 5.80%, the yield of the route is 6.87%, the material cost is reduced, the batch can directly meet the requirements of preparation production at present, the compound crystal 2 can be used as a key intermediate of a plurality of calcitol analogues, and the crude product of the calcitol is dissolved in a solvent, so that the application of the chronic kidney disease patients receiving dialysis treatment or stage 3 or 4 in the aspect of secondary parathyroid hyperfunction is finally realized.
Drawings
FIG. 1 is an X-ray powder diffraction pattern of a crystalline form of a calcitol compound of the present utility model;
FIG. 2 is a DSC chart of a crystal of a dulcitol compound of the present utility model;
Detailed Description
The following description of the embodiments of the present utility model will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present utility model, but not all embodiments.
Example 1
Referring to fig. 1-2, an embodiment of the present utility model is provided: a crystalline of a calcitol compound, which uses a Cu target K alpha ray, has a powder X-ray powder diffraction pattern having characteristic peaks at 5.63.+ -. 0.2, 10.32.+ -. 0.2, 11.24.+ -. 0.2, 12.08.+ -. 0.2, 14.86.+ -. 0.2, 15.05.+ -. 0.2, 15.42.+ -. 0.2, 16.30.+ -. 0.2, 16.70.+ -. 0.2, 16.89.+ -. 0.2, 18.00.+ -. 0.2, 20.03.+ -. 0.2, 20.56.+ -. 0.2, 22.5.+ -. 0.27 and 24.26.+ -. 0.2.
Further, the DSC spectrum has an endothermic peak at 163.0 + -3deg.C.
The utility model also provides a preparation method of the doxercalciferol compound crystal, which specifically comprises the following steps:
step one: dispersing the crude product of the calcitol in a solvent, heating to 60+/-5 ℃ for dissolution, then cooling to 0+/-5 ℃ for crystallization for more than 5 hours, filtering, transferring a filter cake to 30+/-5 ℃ for vacuum drying, and collecting the material to obtain the calcitol, wherein the purity of the calcitol crude product is not less than 99.0%; the solvent for crystallization can be one or more of methanol, isopropanol, acetone and 2-butanone.
Step two: dissolving compound crystals (0.02 mol,7.9 g) in 8mL of ethyl acetate, stirring for complete dissolution, adding 16mL of acetic acid, reacting for 24 hours at room temperature, stopping stirring, regulating the pH of a system to 7 by saturated sodium bicarbonate, extracting with 30mLx2 of ethyl acetate, merging organic phases, washing the organic phases with 20mL of saturated sodium chloride, and distilling the ethyl acetate under reduced pressure until no liquid is distilled off to obtain light red oily substance which is compound crystal 2;
step three: compound crystal 2 was dissolved in 16mL of tetrahydrofuran, and tetrabutylammonium fluoride (1.0 mol. L) -1 ) (0.02 mol,16 mL), stirring at room temperature for 24h, TLC detection of disappearance of starting material;
step four: saturated sodium bicarbonate was adjusted to ph=7, extracted with ethyl acetate 30mL x2, the organic phases were combined, washed with saturated sodium chloride 10mL, separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove ethyl acetate until no liquid distilled off to give a red oil;
step five: the oil was dissolved in 34mL of methanol, and 8mL of potassium hydroxide solution (2.0 mol. L -1 ) Stirring at room temperature for 3h, and reacting 1.0mol.L -1 Hydrochloric acid adjusts pH=7, methanol is distilled under reduced pressure, water phase is extracted with 20mL of ethyl acetate, anhydrous sodium sulfate is dried, maleic anhydride 0.4g is added, ethyl acetate is distilled under reduced pressure after shaking fully until no liquid is distilled off, oily substance column chromatography (petroleum ether: ethyl acetate=5:1-1:1) is carried out, and white granular solid 1.4g is the calcitol, and the yield is: 22.4%.
The mixed system of the crystallization solvent, preferably methanol/2-butanone, has the dosage of 1-2 ml/g of methanol and 8-9 ml/g of acetone, wherein the dosage of the methanol, preferably the solvent, is 1.5ml/g, and the dosage of the 2-butanone, preferably the solvent, is 8.5ml/g
As a preferable technical scheme, the solvent for crystallization can be one or more of methanol, isopropanol, acetone and 2-butanone. Among them, a mixed system of methanol/acetone is preferable.
As a preferred embodiment, the crystallization solvent is preferably a methanol/acetone mixed system. The dosage of methanol is 1-2 ml/g and the dosage of acetone is 8-9 ml/g calculated by the weight of the crude product. Wherein the preferred solvent dosage of methanol is 1.5ml/g, and the preferred solvent dosage of acetone is 8.5ml/g.
The utility model also provides a preparation method of the domino alcoholization capsule, which comprises the following steps:
weighing absolute ethyl alcohol and medium-chain triglyceride in a container with a proper volume, adding p-butyl hydroxyanisole under stirring, and stirring until the mixture is completely dissolved; weighing the raw materials of the doxycycline, adding into the container under stirring, charging nitrogen, and stirring until the raw materials are completely dissolved.
Taking out part of purified water, adding the weighed titanium dioxide and the yellow ferric oxide into a container with a proper volume, stirring until the titanium dioxide and the yellow ferric oxide are completely dispersed, adding the mixture into a gel melting tank, adding the glycerol and the rest of purified water into the gel melting tank, heating to 80 ℃ with stirring, slowly adding gelatin, stirring at the constant temperature of 80 ℃ for 30min, vacuumizing, and ending the sol after the vacuum defoaming is complete.
According to the theoretical loading of 100 mg/pill, performing pelleting; and (3) using an intelligent rotating cage, performing cold blow molding, and transferring the capsule into a drying room for drying to obtain the capsule.
As a preferred embodiment, the contents comprise absolute ethanol, butyl hydroxyanisole and medium chain triglycerides.
As a preferred embodiment, the gelatin skin comprises gelatin, glycerol, iron oxide yellow, titanium dioxide and purified water.
EXAMPLE 2 preparation of crystalline of the calcitol Compound
1.90g of isopropanol is weighed and added into 10.74g of 2-butanone for uniform mixing, 2g of calcitol crude product with the degree is weighed and added into a flask, isopropanol/2-butanone solution is added, the temperature is raised to 60+/-5 ℃, the temperature is slowly reduced to-15+/-5 ℃ for crystallization for 6 hours, filtration is carried out, the filter cake is transferred to 30+/-5 ℃ for vacuum drying, 0.84g of calcitol with the purity of 99.8% is obtained after material collection.
EXAMPLE 3 preparation of crystalline calcitol Compound
1.90g of isopropanol is weighed and added into 10.74g of acetone for uniform mixing, 2g of calcitol crude product with the degree of weighing is added into a flask, isopropanol/acetone solution is added, the temperature is raised to 60+/-5 ℃, the temperature is slowly reduced to-15+/-5 ℃ for crystallization for 6 hours, filtration is carried out, a filter cake is transferred to 30+/-5 ℃ for vacuum drying, 1.08g of calcitol with the purity of 99.9% is obtained after material collection.
EXAMPLE 4 preparation of crystalline calcitol Compound
1.90g of methanol is weighed and added into 10.74g of 2-butanone for even mixing, 2g of calcitol crude product with the degree of weighing is added into a flask, methanol/2-butanone solution is added, the temperature is raised to 60+/-5 ℃, the temperature is slowly reduced to minus 15+/-5 ℃ for crystallization for 6 hours, filtration is carried out, the filter cake is transferred to 30+/-5 ℃ for vacuum drying, and 0.85g of calcitol with the degree of purity of 99.8% is obtained after material collection.
Application example 1 degree calcitol soft capsule preparation
Prescription:
the composition of the content is as follows: 2.5g of calcitol, 1.16kg of absolute ethyl alcohol, 29g of butyl hydroxyanisole and 98.81kg of medium-chain triglyceride.
Rubber composition: 42.98kg of gelatin, 17.19kg of glycerol, 150g of yellow ferric oxide, 1.0kg of titanium dioxide and 6.68kg of purified water.
The preparation method comprises the following steps:
(1) The preparation process of the content comprises the following steps:
weighing absolute ethyl alcohol and medium-chain triglyceride in a container with a proper volume, adding p-butyl hydroxyanisole under stirring, and stirring until the mixture is completely dissolved; weighing the raw materials of the doxycycline, adding into the container under stirring, charging nitrogen, and stirring until the raw materials are completely dissolved. Vacuumizing to remove bubbles, and hermetically preserving in a dark place for later use.
(2) The glue solution preparation process comprises the following steps:
taking out part of purified water, adding the weighed titanium dioxide and the iron oxide yellow into a container with a proper volume, stirring for 10-20 min until the titanium dioxide and the iron oxide yellow are completely dispersed, ensuring uniform color and luster, adding the mixture into a gel melting tank, adding glycerol and the rest of purified water into the gel melting tank, stirring, heating to 80 ℃, slowly adding gelatin, stirring at the constant temperature of 80 ℃ for 30min, vacuumizing, completely dissolving gelatin, ensuring uniform color and luster of the gelatin, stopping stirring and vacuum, and ending the sol. And (5) using a 100-mesh filter screen to discharge glue to a stainless steel heat-preserving barrel, and preserving heat at 60+/-5 ℃ for later use.
(3) Pill pressing and shaping
According to the theoretical loading of 100 mg/pill, performing pelleting; and (3) using an intelligent rotating cage, performing cold blow molding, wherein oil marks on the surface of the capsule are basically removed, the appearance is normal, the capsule is elastic, and the capsule is not sticky and is dispersible, so that the molding can be finished.
(4) Drying (Red light environment)
After cold blow molding, the capsule is transferred into a drying room for drying.
(5) Pill (Red light environment)
And (3) sorting out unqualified products such as leakage pills, big and small pills, special-shaped pills and the like, controlling the exposure time of the capsules within 1h, and transferring the qualified products into a transfer frame of an inner sleeve double-layer clean material bag for light-shielding temporary storage.
(6) Packaging to obtain the final product.
It will be evident to those skilled in the art that the utility model is not limited to the details of the foregoing illustrative embodiments, and that the present utility model may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the utility model being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Claims (5)
1. A crystalline of a calcitol compound characterized by having a characteristic peak at 5.63±0.2, 10.32±0.2, 11.24±0.2, 12.08±0.2, 14.86±0.2, 15.05±0.2, 15.42±0.2, 16.30±0.2, 16.70±0.2, 16.89±0.2, 18.00±0.2, 20.03±0.2, 20.56±0.2, 22.5±0.27 and 24.26±0.2 in a powder X-ray powder diffraction pattern and having an endothermic peak at 163.0 ±3 ℃ in a DSC pattern, which is prepared by a method comprising the steps of:
step one: dispersing the crude product of the calcitol in a solvent, heating to 60+/-5 ℃ for dissolution, then cooling to-15+/-5 ℃ for crystallization for 6 hours, filtering, transferring a filter cake to 30+/-5 ℃ for vacuum drying, and collecting the material to obtain the calcitol, wherein the purity of the crude product of the calcitol is 99.3%; the solvent for crystallization can be one or more of methanol, isopropanol, acetone, 2-butanone and methyl formate;
step two: dissolving compound crystals (0.02 mol,7.9 g) in 8mL of ethyl acetate, stirring for complete dissolution, adding 16mL of acetic acid, reacting for 24 hours at room temperature, stopping stirring, regulating the pH of a system to 7 by saturated sodium bicarbonate, extracting with 30mLx2 of ethyl acetate, merging organic phases, washing the organic phases with 20mL of saturated sodium chloride, and distilling the ethyl acetate under reduced pressure until no liquid is distilled off to obtain light red oily substance which is compound crystal 2;
step three: compound crystal 2 was dissolved in 16mL of tetrahydrofuran, and tetrabutylammonium fluoride (1.0 mol. L) -1 ) (0.02 mol,16 mL), stirred at RT for 24h, TLC detects the disappearance of the raw material;
step four: saturated sodium bicarbonate was adjusted to ph=7, extracted with ethyl acetate 30mL x2, the organic phases were combined, washed with saturated sodium chloride 10mL, separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to remove ethyl acetate until no liquid distilled off to give a red oil;
step five: the oil was dissolved in 34mL of methanol, and 8mL of potassium hydroxide solution (2.0 mol. L -1 ) Stirring at room temperature for 3h, and reacting 1.0mol.L -1 Adjusting pH to 7 by hydrochloric acid, distilling methanol under reduced pressure, extracting an aqueous phase with 20mL of ethyl acetate, drying by anhydrous sodium sulfate, adding 0.4g of maleic anhydride, fully shaking, distilling the ethyl acetate under reduced pressure until no liquid is distilled off, and performing oil column chromatography (petroleum ether: ethyl acetate=5:1-1:1) to obtain 1.4g of white granular solid, namely the calcitol, wherein the yield is 22.4%.
2. A crystalline of a calcitol compound according to claim 1 characterized in that: the crystallization solvent is preferably a mixed system of methanol/2-butanone, the dosage of the methanol is 1-2 ml/g, the dosage of the acetone is 8-9 ml/g, the dosage of the methanol is preferably 1.5ml/g, and the dosage of the 2-butanone is preferably 8.5ml/g.
3. A pharmaceutical capsule of a dulcitol compound, characterized in that: the pharmaceutical composition comprises a dulcitol compound crystal and pharmaceutical excipients, wherein the preparation form of the pharmaceutical composition is selected from capsules.
4. A capsule of a dulcitol compound as claimed in claim 3, wherein: the gel comprises a content and a gel skin, wherein the content comprises a crystalline of a calcitol compound as an active ingredient.
5. A capsule of a dulcitol compound as claimed in claim 3, wherein: the content also comprises absolute ethyl alcohol, butyl hydroxyanisole and medium chain triglyceride, and the rubber further comprises gelatin, glycerol, ferric oxide, titanium dioxide and purified water.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863809A (en) * | 2010-05-12 | 2010-10-20 | 重庆泰濠制药有限公司 | Method for purifying doxercalciferol |
| US20120108554A1 (en) * | 2010-10-28 | 2012-05-03 | Formosa Laboratories, Inc. | PROCESS FOR PREPARING HIGH PURITY 1alpha-HYDROXY VITAMIN D2 |
| CN105237452A (en) * | 2015-11-01 | 2016-01-13 | 南京海融制药有限公司 | Novel crystalline form of doxercalciferol and preparation method for novel crystalline form |
| CN105254548A (en) * | 2015-10-29 | 2016-01-20 | 无锡福祈制药有限公司 | Doxercalciferol purification method |
-
2022
- 2022-12-27 CN CN202211688113.6A patent/CN116023313A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863809A (en) * | 2010-05-12 | 2010-10-20 | 重庆泰濠制药有限公司 | Method for purifying doxercalciferol |
| US20120108554A1 (en) * | 2010-10-28 | 2012-05-03 | Formosa Laboratories, Inc. | PROCESS FOR PREPARING HIGH PURITY 1alpha-HYDROXY VITAMIN D2 |
| CN105254548A (en) * | 2015-10-29 | 2016-01-20 | 无锡福祈制药有限公司 | Doxercalciferol purification method |
| CN105237452A (en) * | 2015-11-01 | 2016-01-13 | 南京海融制药有限公司 | Novel crystalline form of doxercalciferol and preparation method for novel crystalline form |
Non-Patent Citations (1)
| Title |
|---|
| 孙博 等: "度骨化醇的合成", 《中国新药杂志》, 31 December 2009 (2009-12-31), pages 1243 - 1244 * |
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