CN102108076A - Method for preparing amorphous dexlansoprazole - Google Patents
Method for preparing amorphous dexlansoprazole Download PDFInfo
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- CN102108076A CN102108076A CN2009102620686A CN200910262068A CN102108076A CN 102108076 A CN102108076 A CN 102108076A CN 2009102620686 A CN2009102620686 A CN 2009102620686A CN 200910262068 A CN200910262068 A CN 200910262068A CN 102108076 A CN102108076 A CN 102108076A
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- MJIHNNLFOKEZEW-RUZDIDTESA-N dexlansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1C[S@@](=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-RUZDIDTESA-N 0.000 title claims abstract description 45
- 229960003568 dexlansoprazole Drugs 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 24
- 239000007787 solid Substances 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 239000013078 crystal Substances 0.000 claims abstract description 5
- 239000012046 mixed solvent Substances 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 239000003021 water soluble solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 238000007605 air drying Methods 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003799 water insoluble solvent Substances 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 239000003759 ester based solvent Substances 0.000 claims 1
- 239000004210 ether based solvent Substances 0.000 claims 1
- 238000005406 washing Methods 0.000 abstract description 4
- 230000001376 precipitating effect Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- -1 glidants Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 6
- 206010063655 Erosive oesophagitis Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 5
- 229960003174 lansoprazole Drugs 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 201000006549 dyspepsia Diseases 0.000 description 4
- 208000024798 heartburn Diseases 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- IPJMZFJRPTWZTD-UHFFFAOYSA-N (4-chloro-3-methylpyridin-2-yl)methanol Chemical compound CC1=C(Cl)C=CN=C1CO IPJMZFJRPTWZTD-UHFFFAOYSA-N 0.000 description 3
- JHTAYQLERRPGDL-UHFFFAOYSA-N (4-chloro-3-methylpyridin-2-yl)methyl acetate Chemical compound CC(=O)OCC1=NC=CC(Cl)=C1C JHTAYQLERRPGDL-UHFFFAOYSA-N 0.000 description 3
- ZYUFKURTVOBEOQ-UHFFFAOYSA-N 4-chloro-2-(chloromethyl)-3-methylpyridine Chemical compound CC1=C(Cl)C=CN=C1CCl ZYUFKURTVOBEOQ-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000003628 erosive effect Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 3
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VQEDENJDYAWVOH-UHFFFAOYSA-N 2-methoxy-2-methylpropane;toluene Chemical compound COC(C)(C)C.CC1=CC=CC=C1 VQEDENJDYAWVOH-UHFFFAOYSA-N 0.000 description 1
- MCUYHRNUDDANSO-UHFFFAOYSA-N 4-chloro-2,3-dimethyl-1-oxidopyridin-1-ium Chemical compound CC1=C(C)[N+]([O-])=CC=C1Cl MCUYHRNUDDANSO-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- YSAVZVORKRDODB-PHDIDXHHSA-N diethyl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC YSAVZVORKRDODB-PHDIDXHHSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- AZLPEJUVWWGLHA-UHFFFAOYSA-N ethyl acetate;hexane;methanol Chemical compound OC.CCCCCC.CCOC(C)=O AZLPEJUVWWGLHA-UHFFFAOYSA-N 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical group CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing amorphous dexlansoprazole, which comprises the steps of dissolving dexlansoprazole or the crystal thereof in a single or mixed solvent, precipitating solids under alkaline conditions at a temperature of 5 DEG C below zero to 25 DEG C below zero, further filtering, washing and drying, and finally getting the amorphous dexlansoprazole.
Description
Technical Field
The invention relates to a method for preparing dexlansoprazole, in particular to a method for preparing amorphous dexlansoprazole.
Background
Dexlansoprazole is a new drug for treating gastroesophageal reflux disease which is superior to lansoprazole, and the structural formula of the drug is shown in the following figure.
Dexlansoprazole controlled release capsules (dexlansoprazole, kapadex) approved by wutian pharmaceutical north america are marketed for the treatment of heartburn in the stomach caused by non-erosive gastroesophageal reflux (GERD), Erosive Esophagitis (EE), and EE maintenance therapy, all 1 time a day. The product is the first double controlled release (DDR) proton pump inhibitor of 2-time drug release on the market. The preparation specification is 30 or 60mg per granule.
Proton pump inhibitors reduce the production of gastric acid by inhibiting H '/K' -ATP. The product contains 2 types of enteric-coated granules, and the 1 st peak appears 1-2 hours and the 2 nd peak appears 4-5 hours after 2 unique peaks are seen in a time curve. In addition, the product is not affected by oral food.
GERD patients suffer from heartburn during the day and at night. Research shows that the product prepared by DDR technology can relieve heartburn for 24 hours, and provides an exciting new treatment concept for GERD patients. The adverse reaction is similar to that of lansoprazole.
Dexlansoprazole is approved for the market based on results of a global efficacy evaluation study conducted in more than 20 countries for approximately 6000 erosive and non-erosive GERD patients. 2 8-week randomized, double-blind, control studies of the same design, which compared the efficacy of this product with lansoprazole for EE treatment. The results show that at 8 weeks, the cure rate of this product (60mg) group was higher than that of lansoprazole group (87% and 85% for both study 1, and 85% and 79% for both study 2), and patient tolerance was good. The data of the product for maintaining and treating EE at 30mg for 6 months show that the curative effect of treating EE and relieving heartburn is higher than that of a placebo.
CN1150186C discloses a crystal of dexlansoprazole and a method for preparing the crystal, the method relates to a method for obtaining amorphous dexlansoprazole by optical resolution, but the method can obtain a finished product with higher optical purity by multiple inclusion resolution, the operation is complex, and the method is not beneficial to scale-up production; and during the formulation of pharmaceutical compositions, crystalline form materials are inferior to amorphous materials in many respects, such as flowability.
Disclosure of Invention
The invention aims to provide a method for preparing amorphous dexlansoprazole, which comprises the steps of dissolving dexlansoprazole or crystals thereof in a single or mixed solvent, separating out solids at the temperature of-5 ℃ to-25 ℃ under an alkaline condition, and filtering, washing and drying to obtain the amorphous dexlansoprazole.
Wherein,
amorphous dexlansoprazole has an X-ray powder diffraction pattern as shown in figure 1, figure 2, figure 3, figure 4, or figure 5;
the single or mixed solvent comprises water soluble solvent and non-water soluble solvent, wherein the water soluble solvent is preferably ammonia water, methanol, ethanol, propanol, butanol, acetone or mixture thereof, more preferably ammonia water, and the non-water soluble solvent is preferably ester solvent, ether solvent, halogenated hydrocarbon solvent or mixture thereof;
the temperature is-5 ℃ to-25 ℃, preferably-10 ℃ to-20 ℃, more preferably-10 ℃;
the alkaline condition is selected from pH 8-10, preferably pH 9;
the drying is selected from vacuum drying, flow-through drying, heat drying or air drying, preferably vacuum drying, more preferably room temperature vacuum drying.
In the formulation of pharmaceutical compositions, it is important that the drug substance be in a form that is convenient to handle and handle. This is important not only from the point of view of obtaining a commercially viable process for the preparation, but also from the point of subsequent preparation of pharmaceutical preparations containing the active compound.
Furthermore, in the preparation of pharmaceutical compositions, it is important that a reliable, reproducible and constant plasma concentration profile of the drug is provided after administration to a patient.
Chemical stability, solid state stability and "shelf life" of the active ingredient are also very important factors. The drug substance, and compositions containing it, should preferably be capable of being effectively stored for a considerable period of time without exhibiting significant changes in the physicochemical properties of the active ingredient (e.g. its chemical composition, density, hygroscopicity and solubility).
Furthermore, it is also very important to provide the drug in as chemically pure a form as possible.
It will be appreciated by those skilled in the art that typically if a drug is readily available in a stable form, the following advantages are provided: easy handling, easy preparation of suitable pharmaceutical formulations and reliable dissolution characteristics.
It will be appreciated by those skilled in the art that the optimum number and spacing of individual doses of the active ingredient will depend upon the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimum will be determined by conventional techniques. It will also be appreciated by those skilled in the art that the optimal course of treatment, i.e. the number of doses of active ingredient administered per day over a given period of time, can be determined by those skilled in the art using routine tests for determining the course of treatment.
The amorphous dexlansoprazole prepared by the method can be orally or parenterally administered, and can be prepared into tablets, pills, powder and granules for various administration routes. In these solid formulations, the active ingredient is mixed with at least one inert diluent. Oral formulations may also include other substances besides the primary inert diluent, such as lubricants, glidants, and antioxidants, in accordance with conventional practice. In the form of capsule, tablet or pill, the preparation contains buffering agent. The tablet and pill can also be made into sustained release dosage form.
The parenteral formulations of the present invention include sterile aqueous solutions, although non-aqueous solutions of emulsions may also be employed. These dosage forms may also include adjuvants such as preserving, wetting, penetrating, buffering, emulsifying, and dispersing agents. The sterilization may be performed by filtering with a bacteria retaining filter (bacterio retaining filter), adding a sterilizing agent to the composition, irradiating the composition or heating the composition.
Compared with the method for obtaining amorphous dexlansoprazole disclosed in CN1150186C, the method disclosed by the invention can be used for preparing a finished product with higher optical purity, is simple to operate and is beneficial to large-scale production.
Compared with crystalline dexlansoprazole, the amorphous dexlansoprazole prepared by the method has the advantages that the physical properties are equivalent to those of the crystalline dexlansoprazole, the repeatability is strong, the optical purity is extremely high, the stability, the bioavailability, the dissolution speed and the hygroscopicity of the preparation are equivalent to those of the crystalline preparation, and the following advantages are achieved:
(1) the fluidity is better;
(2) the complex crystallization process is omitted, the process flow is simplified, and the method is more suitable for industrial production;
drawings
FIG. 1, FIG. 2, FIG. 3, FIG. 4 and FIG. 5 are X-ray powder diffraction patterns of amorphous dexlansoprazole.
Detailed Description
The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.
Example one
Crude dexlansoprazole (235.6g) obtained in the sixth step was dissolved in aqueous ammonia (12.5%, 5040ml) at room temperature, a little black insoluble matter was removed by filtration, and the mixture was washed with dichloromethane (1000 ml. times.3), and the pH of the aqueous layer was adjusted to about 9 with glacial acetic acid (1290ml) at-10 ℃ to precipitate a white solid. Stirring for 5min, filtering, washing the solid with ice water (1000ml), and vacuum drying at room temperature for 24h to obtain dexlansoprazole (off-white solid, 150.0 g). The product is amorphous dexlansoprazole as confirmed by attached figure 1.
Example two
The procedure is as described in example one, wherein the temperature is-5 ℃ and the pH is 8.
The product is amorphous dexlansoprazole as confirmed by the attached figure 2.
EXAMPLE III
The process is carried out as described in example one, wherein the temperature is-25 ℃ and the pH is 10.
The product is amorphous dexlansoprazole as confirmed by the attached figure 3.
Example four
The procedure is as described in example one, wherein the temperature is-10 ℃ and the pH is 8.
The product is amorphous dexlansoprazole as confirmed by the attached figure 4.
EXAMPLE five
The process is carried out as described in example one, wherein the temperature is-20 ℃ and the pH is 10.
The product is amorphous dexlansoprazole as confirmed by the attached figure 5.
Wherein, the crude product of dexlansoprazole is prepared by the following method:
step one Synthesis of 2-acetoxymethyl-4-chloro-3-methylpyridine
1083.7g and 6.88mol of 4-chloro-2, 3-dimethylpyridine-N-oxide (purchased from Sanyu Yu, Zhejiang and pharmaceutical chemical Co., Ltd.; specification: IG) were dissolved in toluene (7000ml), heated to 90 ℃ and acetic anhydride (2053.2g and 20.11mol) was slowly added dropwise at a temperature of 90-110 ℃. After the addition, the reaction is carried out for 1.5h at the temperature of 105 ℃ and 110 ℃, and the thin-layer chromatography detection is carried out to finish the reaction. The solvent was evaporated off under reduced pressure at 60 ℃ with slight cooling to give 2-acetoxymethyl-4-chloro-3-methylpyridine (yellow oil, 1627.2 g).
1HNMR(CDCl3)δ：2.12(s，3H，CH3CO)；2.48(s，3H，CH3)；5.18(s，2H，CH2)；7.20(d，1H，H-5)，8.22(d，1H，H-6)。
Synthesis of bis 2-hydroxymethyl-4-chloro-3-methylpyridine
Dissolving the 2-acetoxymethyl-4-chloro-3-methylpyridine in methanol (1450ml), cooling to 0-5 ℃, dropwise adding a solution of potassium hydroxide (1597.0g) and water (7000ml), controlling the temperature of the reaction solution to be below 10 ℃, completing dropping within about 30min, continuing to perform heat preservation reaction for 20min, and detecting the completion of the reaction by thin layer chromatography. Methanol was distilled off under reduced pressure, extracted with methylene chloride (2300 ml. times.3), and the organic phases were combined and dried over 973.4g of anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the synthesis of 2-hydroxymethyl-4-chloro-3-methylpyridine (yellow oil, 913.1 g).
1HNMR(DMSO-D6，500M，ppm)δ：2.42(s，3H，CH3)；4.93(s，2H，CH2)；8.08(d，1H，H-5)，8.62(d，1H，H-6)。
Step Synthesis of tris 2-chloromethyl-4-chloro-3-methylpyridine
Dissolving the 2-hydroxymethyl-4-chloro-3-methylpyridine in trichloromethane (4000ml), cooling to 0-5 ℃, dropwise adding thionyl chloride (590.3g, 4.96mol) under stirring, controlling the reaction temperature below 10 ℃, completing dropwise addition in about 40min, continuing to perform heat preservation reaction for 20min, and detecting the reaction completion by thin layer chromatography. Concentrating under reduced pressure to obtain brown solid, slowly adding ice water (3L), adjusting pH to 8-9 with saturated sodium bicarbonate (3000ml), extracting with dichloromethane (1700ml × 3), mixing organic phases, and washing with saturated sodium chloride solution (3L) once to obtain 2-chloromethyl-4-chloro-3-methylpyridine solution.
1HNMR(CDCl3)δ：2.49(s，3H，CH3)；5.06(s，2H，CH2)；7.82(d，1H，H-5)，8.53(d，1H，H-6)。
Step Synthesis of tetrakis 2- [ (4-chloro-3-methyl-2-pyridyl) methyl ] thio ] benzimidazole
Sodium hydroxide (487.6g, 12.19mol) was dissolved in water (4800ml), cooled to 10-15 ℃, 2-mercaptobenzimidazole (raw material B) (487.6g, 3.25mol) and triethylbenzylammonium chloride (146.6g, 0.63mol) were added, stirred for 15min, and then the above solution of 2-chloromethyl-4-chloro-3-methylpyridine was added dropwise, controlling the temperature below 15 ℃. After the addition was completed, the mixture was stirred at 25 to 30 ℃ for about 2 hours, and intermediate 4 was detected by thin layer chromatography to have reacted completely, the reaction mixture was concentrated to about 6300ml, cooled to 0 ℃ and stirred for 1 hour, filtered, and the solid was washed with methylene chloride (1150ml), water (1200 ml. times.3) and dried under vacuum at 40 ℃ for 8 hours to give 2- [ (4-chloro-3-methyl-2-pyridyl) methyl ] thio ] benzimidazole (off-white solid, 645.1 g).
1HNMR(DMSO-D6，500M，ppm)δ：8.29(d，1H)；7.46-7.44(m，3H)；7.11-7.14(m，2H)；4.80(s，2H)；2.45(s，3H)。
Step five Synthesis of [ (4-chloro-3-methyl-2-pyridyl) methyl ] sulfinyl ] benzimidazole
2- [ (4-chloro-3-methyl-2-pyridyl) methyl ] thio ] benzimidazole (645.1g), toluene (3600ml) and diethyl L- (+) tartrate (168ml) were mixed, heated to 50 to 60 ℃ and reacted for 0.5h, titanium tetraisopropoxide (131ml) was added, and the reaction was continued at this temperature for 1 h. The reaction solution was cooled to 20 ℃ and diisopropylethylamine (135ml) was added thereto, the temperature was lowered to-10 ℃ and 80% cumene hydroperoxide (1203ml) was added thereto at a temperature of-10 ℃ to 0 ℃ and the reaction was carried out at a temperature of-5 ℃ to 0 ℃ for 4 hours. After the basic reaction was completed by thin layer chromatography, 30% sodium thiosulfate solution (1600ml) was added, stirred for 10min, and then n-hexane (1550ml), t-butyl methyl ether (1550ml) and n-hexane (13000ml) were added dropwise in this order at 0 ℃ to 10 ℃ to precipitate a white solid, which was filtered and washed with t-butyl methyl ether-toluene (4: 1, 1250ml) 1 time. This solid was dissolved in acetone (15L), filtered, and water (40L) was added dropwise to the filtrate to precipitate a solid, which was filtered and dried under vacuum at 50 ℃ for 6 hours to give 2- [ (4-chloro-3-methyl-2-pyridyl) methyl ] sulfinyl ] benzimidazole (322.2g, HPLC normalization method: 99.6%, S isomer was not detected).
1HNMR(DMSO-D6，500M，ppm)δ：4.25(d，1H)；7.47(d，1H)；7.31-7.29(m，2H)；4.88(s，2H)；2.36(s，1H)。
Step six-right lansoprazole synthesis
2- [ (4-chloro-3-methyl-2-pyridyl) methyl ] sulfinyl ] benzimidazole (322.2g), dimethyl sulfoxide (2100ml), trifluoroethanol (727.8g) and sodium hydroxide (235.6g) were sequentially added to a reaction flask, and the reaction was allowed to warm to 60-70 ℃ for about 4 hours, followed by basic completion of the reaction by thin layer chromatography. The reaction solution was cooled to room temperature, water (20L) was added dropwise, the pH was adjusted to about 7 with 330ml of glacial acetic acid, and a solid was precipitated, stirred for 5min, and filtered to obtain an off-white solid. The solid was dissolved in ethyl acetate (5L) and dried over anhydrous magnesium sulfate (1000.0 g). Filtering, and concentrating the filtrate under reduced pressure to obtain brown oil. The oil was chromatographed on silica gel short column with ethyl acetate-n-hexane-methanol (10: 1) as eluent, and the qualified fractions were collected, concentrated and dried with n-hexane (2L) to give dexlansoprazole (foamy solid, 235.6 g).
MS-ESI：368.17(100)[M-H]+
1HNMR(CDCl3，400M)δ：4.784-4.904(d-d，2H，CF3 CH 2 O)，2.233(s，3H，-CH3)。
Claims (10)
1. A method for preparing amorphous dexlansoprazole is characterized in that dexlansoprazole or a crystal thereof is dissolved in a single or mixed solvent at the temperature of-5 ℃ to-25 ℃, solid is separated out under the alkaline condition, and the amorphous dexlansoprazole is obtained by filtering and drying.
2. The process for preparing amorphous dexlansoprazole of claim 1, wherein the amorphous dexlansoprazole has an X-ray powder diffraction pattern as shown in figure 1, figure 2, figure 3, figure 4, or figure 5.
3. The process for preparing amorphous dexlansoprazole of claim 1 or 2, wherein the single or mixed solvent comprises a water-soluble solvent and a water-insoluble solvent.
4. The process for preparing amorphous dexlansoprazole according to claim 3, wherein said water-soluble solvent is selected from the group consisting of ammonia, methanol, ethanol, propanol, butanol, acetone or mixtures thereof; and the water-insoluble solvent is selected from ester solvents, ether solvents, halogenated hydrocarbon solvents or a mixture thereof.
5. The process for preparing amorphous dexlansoprazole according to claim 4, wherein said water-soluble solvent is aqueous ammonia.
6. The process for preparing amorphous dexlansoprazole according to claim 1 or 2, wherein said temperature is between-10 ℃ and-20 ℃.
7. The process for preparing amorphous dexlansoprazole of claim 1 or 2, wherein the basic condition is a pH of 8-10.
8. The process for preparing amorphous dexlansoprazole of claim 7, wherein said basic condition is a pH of 9.
9. The process for preparing amorphous dexlansoprazole of claim 1 or 2, wherein the drying is selected from vacuum drying, flow-through drying, heat drying or air drying.
10. The process for preparing amorphous dexlansoprazole of claim 9, wherein said drying is room temperature vacuum drying.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108484578A (en) * | 2018-04-09 | 2018-09-04 | 珠海润都制药股份有限公司 | A kind of method prepared by esomeprazole impurity |
| CN108794450A (en) * | 2018-07-24 | 2018-11-13 | 浙江三门恒康制药有限公司 | The method for preparing unformed Dexlansoprazole |
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| CN1355798A (en) * | 1999-06-17 | 2002-06-26 | 武田药品工业株式会社 | Benzimidazole compound crystal |
| CN1681802A (en) * | 2002-03-27 | 2005-10-12 | 特瓦制药工业有限公司 | Lansoprazole polymorphs and processes for preparation thereof |
| US20060057195A1 (en) * | 2002-10-16 | 2006-03-16 | Takeda Pharmaceutical Company Limited | Stable solid preparations |
| WO2009117489A1 (en) * | 2008-03-18 | 2009-09-24 | Dr. Reddy's Laboratories Ltd. | Dexlansoprazole process and polymorphs |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1355798A (en) * | 1999-06-17 | 2002-06-26 | 武田药品工业株式会社 | Benzimidazole compound crystal |
| CN1681802A (en) * | 2002-03-27 | 2005-10-12 | 特瓦制药工业有限公司 | Lansoprazole polymorphs and processes for preparation thereof |
| US20060057195A1 (en) * | 2002-10-16 | 2006-03-16 | Takeda Pharmaceutical Company Limited | Stable solid preparations |
| WO2009117489A1 (en) * | 2008-03-18 | 2009-09-24 | Dr. Reddy's Laboratories Ltd. | Dexlansoprazole process and polymorphs |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108484578A (en) * | 2018-04-09 | 2018-09-04 | 珠海润都制药股份有限公司 | A kind of method prepared by esomeprazole impurity |
| CN108484578B (en) * | 2018-04-09 | 2019-03-26 | 珠海润都制药股份有限公司 | A kind of method of esomeprazole impurity preparation |
| CN108794450A (en) * | 2018-07-24 | 2018-11-13 | 浙江三门恒康制药有限公司 | The method for preparing unformed Dexlansoprazole |
| CN108794450B (en) * | 2018-07-24 | 2022-08-19 | 浙江恒康药业股份有限公司 | Method for preparing amorphous dexlansoprazole |
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