CN104803983B - A kind of compound of pantoprazole sodium and preparation thereof - Google Patents
A kind of compound of pantoprazole sodium and preparation thereof Download PDFInfo
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- CN104803983B CN104803983B CN201510240574.0A CN201510240574A CN104803983B CN 104803983 B CN104803983 B CN 104803983B CN 201510240574 A CN201510240574 A CN 201510240574A CN 104803983 B CN104803983 B CN 104803983B
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- pantoprazole sodium
- compound
- pantoprazole
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- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229960004048 pantoprazole sodium Drugs 0.000 title claims abstract description 71
- 150000001875 compounds Chemical class 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 239000000843 powder Substances 0.000 claims abstract description 26
- 238000002347 injection Methods 0.000 claims abstract description 16
- 239000007924 injection Substances 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 230000005260 alpha ray Effects 0.000 claims abstract description 9
- 239000007788 liquid Substances 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 7
- 238000009472 formulation Methods 0.000 claims abstract description 7
- 238000005259 measurement Methods 0.000 claims abstract description 6
- 239000002552 dosage form Substances 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
- 239000013078 crystal Substances 0.000 claims description 22
- 239000012153 distilled water Substances 0.000 claims description 18
- 239000012046 mixed solvent Substances 0.000 claims description 18
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 12
- 238000010586 diagram Methods 0.000 claims description 10
- 229910017488 Cu K Inorganic materials 0.000 claims description 8
- 229910017541 Cu-K Inorganic materials 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 239000006185 dispersion Substances 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000012047 saturated solution Substances 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 10
- 238000013112 stability test Methods 0.000 abstract description 3
- 238000000634 powder X-ray diffraction Methods 0.000 abstract 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 46
- 229960005019 pantoprazole Drugs 0.000 description 46
- 238000012360 testing method Methods 0.000 description 33
- 238000007789 sealing Methods 0.000 description 14
- 238000004806 packaging method and process Methods 0.000 description 13
- 238000004088 simulation Methods 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 238000012552 review Methods 0.000 description 9
- 239000002245 particle Substances 0.000 description 8
- 239000000523 sample Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000002411 thermogravimetry Methods 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- IQPSEEYGBUAQFF-AREMUKBSSA-N 6-(difluoromethoxy)-2-[(r)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound COC1=CC=NC(C[S@@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-AREMUKBSSA-N 0.000 description 2
- IQPSEEYGBUAQFF-SANMLTNESA-N 6-(difluoromethoxy)-2-[(s)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound COC1=CC=NC(C[S@](=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-SANMLTNESA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004455 differential thermal analysis Methods 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- SIXIIKVOZAGHPV-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=C[CH]C2=N1 SIXIIKVOZAGHPV-UHFFFAOYSA-N 0.000 description 2
- 229960003174 lansoprazole Drugs 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 description 2
- 229960000381 omeprazole Drugs 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- YNWDKZIIWCEDEE-SNYZSRNZSA-N sodium;5-(difluoromethoxy)-2-[(s)-(3,4-dimethoxypyridin-2-yl)methylsulfinyl]benzimidazol-1-ide Chemical compound [Na+].COC1=CC=NC(C[S@](=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-SNYZSRNZSA-N 0.000 description 2
- PAYGMRRPBHYIMA-UHFFFAOYSA-N sodium;trihydrate Chemical compound O.O.O.[Na] PAYGMRRPBHYIMA-UHFFFAOYSA-N 0.000 description 2
- 239000008227 sterile water for injection Substances 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 150000003751 zinc Chemical class 0.000 description 2
- -1 3,4-dimethoxy-2-pyridinyl Chemical group 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009858 acid secretion Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000002467 anti-pepsin effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000007416 differential thermogravimetric analysis Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000012055 enteric layer Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000004457 water analysis Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of compound of pantoprazole sodium, it is characterised in that described Pantoprazole Sodium is pantoprazole sodium trihydrate, the X ray powder diffraction pattern that the use Cu K alpha ray measurement of this pantoprazole sodium trihydrate obtains is as shown in Figure 1.The invention still further relates to the pharmaceutical composition of this compound of pantoprazole sodium, the dosage form of this pharmaceutical composition is selected from oral formulations or ejection preparation, wherein, the preferred enteric coatel tablets of oral formulations, the preferred aseptic powder injection of ejection preparation, freeze-dried powder and liquid drugs injection.Confirm that through stability test having good stability of the Pantoprazole Sodium that the present invention prepares is suitable to clinical practice.Confirming through stability test, having good stability of the Pantoprazole Sodium that the present invention prepares, its enteric coatel tablets have good dissolution, are more suitable for clinical practice.
Description
Technical field
The present invention relates to field of medicaments, specifically, relate to a kind of compound of pantoprazole sodium and preparation thereof.
Background technology
Pantoprazole Sodium, English name: Pantoprazole Sodium, its chemical name is: 5-difluoro-methoxy-2-[[(3,4-bis-
Methoxyl group-2-pyridine radicals)-methyl] sulfinyl]-1H-benzimidazole sodium.Pantoprazole Sodium is proton pump inhibitor, by with coat of the stomach
The H of cell+-K+Two site covalent bond of ATP enzyme system and final step that gastric acid inhibitory produces.This effect is that dosage depends on
Rely property and make the gastric acid secretion under basis and stimulation state the most suppressed.H+-K+The combination of ATP enzyme may result in its anti-gastric acid secretion
Effect lasts more than 24 hours.Pantoprazole Sodium is the proton pump inhibitor of the 3rd listing after omeprazole and lansoprazole.
Owing to Pantoprazole Sodium substituted radical on pyridine ring and benzimidazole ring is different with omeprazole and lansoprazole, thus
Determine it in biochemical, pharmacokinetics and the difference of pharmacological property so that it is there is higher selectivity and specificity.
In prior art, for crystal formation and the hydrate of Pantoprazole Sodium, have and much studied:
ZL201110228921.X discloses a kind of compound of pantoprazole sodium, and this compound of pantoprazole sodium is crystal, uses
In the X-ray powder diagram that Cu-K alpha ray measurement obtains characteristic peak 2 θ be 12.5 °, 12.6 °, 13.2 °, 16.2 °,
17.3 ° display.
ZL201310093503.3 Pantoprazole Sodium crystalline compounds, pharmaceutical composition and preparation method thereof the present invention provides a kind of new
Pantoprazole Sodium crystalline compounds, its pharmaceutical preparation particularly enteric coated capsule, and their preparation method, described in dissolve Tuo La
Azoles sodium crystalline compounds dissolution is good, and stability is strong, is suitable for making pharmaceutical composition with conventional pharmaceutical carrier, has for preparation
The oral formulations of good dissolution.
ZL201210306449.1 relates to a kind of pantoprazole sodium crystal, uses X-diffraction powder diffraction, and its collection of illustrative plates is with 2 θ
The characteristic peak that angle represents be followed successively by 9.5 °, 10.4 °, 11.6 °, 13.1 °, 13.8 °, 14.2 °, 15.0 °, 15.3 °, 15.9 °, 16.5 °,
17.5 °, 18.0 ° and 18.2 °.
Patent application 201310096327.9 discloses one (S)-Pantoprazole Sodium dihydrate and is somebody's turn to do (S)-Pantoprazole Sodium two water
The preparation method of compound.
Patent application 02109182.X relate to anti-peptic ulcer medicine (±) 5-difluoro-methoxy-[[(3,4-dimethoxy-2-pyridinyl) first
Base] sulfinyl]-1H-benzimidazole left-handed (-) and dextrorotation (+) salt of enantiomer, i.e. S (-) pantoprazole potassium, sodium, magnesium, calcium,
Zinc salt R (+) pantoprazole potassium, sodium, magnesium, calcium, zinc salt.Additionally provide a kind of new of S (-) pantoprazole and R (+) pantoprazole
Preparation method, with chloroform or acetonitrile as solvents, carry out in the presence of Sharpless reagent chiral oxidization prepare, with potassium hydroxide,
The reaction such as potassium carbonate obtains.
Patent application 201310034866.X discloses a kind of novel compound of pantoprazole sodium and containing this compound of pantoprazole sodium
Pharmaceutical composition.Described pharmaceutical composition includes the component of following weight portion: Pantoprazole Sodium 45～80 parts, ethylenediamine tetrem
Acid disodium 3～20 parts, sodium tartrate 0.5～3 parts, mannitol 4～52 parts.
In order to improve the performance of Pantoprazole Sodium further, improve the effect of preparation clinical practice application, the special proposition present invention.
Summary of the invention
The primary goal of the invention of the present invention is to propose a kind of compound of pantoprazole sodium.
A second aspect of the present invention purpose is to propose the pharmaceutical composition containing this compound of pantoprazole sodium.
In order to realize the purpose of the present invention, the technical scheme of employing is:
A kind of compound of pantoprazole sodium, this compound of pantoprazole sodium is pantoprazole sodium trihydrate, its structural formula such as formula (I)
Shown in:
Wherein, the X-ray powder diagram that pantoprazole sodium trihydrate use Cu-K alpha ray measurement obtains is as shown in Figure 1；
This main particle diameter of pantoprazole sodium trihydrate is 650～850 μm, and the dispersion of distribution is 450～1050 μm.
The preparation method of this compound of pantoprazole sodium is:
(1) Pantoprazole Sodium crude product is ground, crosses 200～300 mesh sieves, be then dissolved in the mixed solution of distilled water and acetonitrile,
Prepare saturated solution；
(2) add dimethyl sulfoxide and mixed solvent that dichloroethanes volume ratio is 1:2～3 while stirring, be warming up to simultaneously 40～
45℃；
(3) after mixed solvent adds, it is cooled to-5 DEG C～5 DEG C, after obtaining crystal, stands crystallize；Filter, washing, vacuum drying 2～
4 hours, obtain compound of pantoprazole sodium.
Wherein, in step (1), distilled water is 1:0.4～1.6 with the volume ratio of acetonitrile.
In step (2), the speed of intensification is 5～8 DEG C/h；Mixing speed is 120～240 revs/min；Dimethyl is sub-
The weight of sulfone and dichloroethanes mixed solvent is 8～12 times of distilled water and acetonitrile mixed solution weight, and adding speed is 20～40
Ml/min.
In step (3), cooling rate is 0.5～2.5 DEG C/h.
The invention still further relates to the pharmaceutical composition of this compound of pantoprazole sodium a kind of, the dosage form of described pharmaceutical composition is selected from mouth
Formulation or ejection preparation, wherein, the preferred enteric coatel tablets of oral formulations, the preferred aseptic powder injection of ejection preparation, freeze-dried powder and liquid drugs injection.
Below technical scheme is made further explanation.
The present invention proposes the trihydrate of a kind of Pantoprazole Sodium, and character is white crystalline powder, and this hydrate is at air setting
Under the conditions of dry, the loss of water of crystallization will not occur.The Pantoprazole Sodium of the present invention confirms containing 3 water of crystallization, and carries out it
Following research:
1. elementary analysis
Take the pantoprazole sodium trihydrate that the present invention prepares and carry out elementary analysis, use Perkin-Elmer company of the U.S.
PE 2,400 II elemental analyser, elementary analysis (%) measured value: C (45.833), H (3.350), F (8.270), N (9.150), Na (5.010),
S (6.976), O (24.382)；It is consistent with the theoretical value of elementary analysis, elementary analysis (%) theoretical value: C (41.830), H (4.353),
F (8.272), N (9.149), Na (5.007), S (6.979), O (24.380).
2. differential thermal analysis and thermogravimetric analysis
Taking the pantoprazole sodium trihydrate that the present invention prepares and carry out differential thermal analysis, structure shows, the present invention at 140 DEG C～
Endothermic peak is had, it was demonstrated that containing water of crystallization in sample between 170 DEG C.Its thermogravimetric analysis figure shows that its about 150 DEG C quickly lose three
The water of crystallization of individual molecule, and changed without obvious weight before 150 DEG C, it was demonstrated that its hydrone lost is crystalline water molecules, and
Non-free hydrone.
3. loss on drying and water analysis
Taking the pantoprazole sodium trihydrate that the present invention prepares to be dried to constant weight at 230 DEG C, weightlessness is 11.74%；Use card
The weightlessness of the pantoprazole sodium trihydrate that formula moisture test apparatus measures the present invention is 11.74%, is consistent with theoretical value 11.755%.
4.HPLC purity detecting
Through HPLC purity detecting, the purity of the pantoprazole sodium hydrate of the present invention can reach 99.96～99.98%.
5. droplet measurement
Scanned electron microscope observation and particle size analyzer are measured, the main particle diameter of the pantoprazole sodium hydrate of the present invention be 650～
850 μm, the dispersion of distribution is 450～1050 μm.
6. crystal formation detection
The X-ray powder diagram that the pantoprazole sodium hydrate use Cu-K alpha ray measurement of the present invention obtains is as shown in Figure 1.
Its X-ray powder diagram represented with 2 θ ± 0.2 angles of diffraction 6.1 °, 8.0 °, 11.4 °, 15.0 °, 20.4 °, 26.9 °,
30.8 °, show characteristic peak at 34.0 °.
7. fusing point detection
The fusing point of the pantoprazole sodium hydrate of the present invention is 221～223 DEG C.
The present invention prepares the hydrate crystal of greater particle size, and Lens capsule is concentrated very much, size uniformity,
Thus advantageously in the collection of crystal, thus be suitable for large-scale industrialization and prepare, improve yield.The pantoprazole of the present invention
Solvent trace in sodium trihydrate (< 0.001%), clinical practice is safe and reliable.The crystal formation of the present invention is after water dissolution, no
The change of crystal formation can occur, be difficult to moisture absorption, place weight in wet condition unchanged.Confirm through stability test, the present invention
Having good stability of the Pantoprazole Sodium prepared, its enteric coatel tablets have good dissolution, are suitable to clinical practice.
Accompanying drawing illustrates:
Fig. 1 is the X-ray powder diagram of embodiment 1 hydrate；
Fig. 2 is the thermogravimetric analysis figure of embodiment 1 hydrate.
Detailed description of the invention
The detailed description of the invention of the present invention is only limitted to be explained further and the present invention is described, is not construed as limiting present disclosure.
The preparation of embodiment 1 pantoprazole sodium hydrate
1. Pantoprazole Sodium crude product is ground, crosses 200 mesh sieves, be then dissolved in the mixed solution of distilled water and acetonitrile, preparation
Saturated solution；Distilled water is 1:0.4 with the volume ratio of acetonitrile；
Add dimethyl sulfoxide the most while stirring and dichloroethanes volume ratio is the mixed solvent of 1:2, be warming up to 45 DEG C simultaneously；Heat up
Speed be 5 DEG C/h；Mixing speed is 120 revs/min；The weight of dimethyl sulfoxide and dichloroethanes mixed solvent is
8 times of distilled water and acetonitrile mixed solution weight, adding speed is 20 ml/min；
3. after mixed solvent adds, being cooled to 5 DEG C, cooling rate is 1.5 DEG C/h；Crystallize is stood after obtaining crystal；Filter, wash
Wash, be vacuum dried 4 hours, obtain compound of pantoprazole sodium.
This compound crystal detects through high performance liquid chromatography, and purity is 99.97%, yield 96.1%；Cu-K alpha ray is used to measure
The X-ray powder diagram that obtains as it is shown in figure 1, thermogravimetric analysis figure as shown in Figure 2；Scanned electron microscope observation and grain
Degree analyzer is measured, and the main particle diameter of crystal is 650～850 μm, and the dispersion of distribution is 450～1050 μm；The measured value of elementary analysis with
Theoretical value is consistent.
The preparation of embodiment 2 pantoprazole sodium hydrate
1. Pantoprazole Sodium crude product is ground, crosses 300 mesh sieves, be then dissolved in the mixed solution of distilled water and acetonitrile, preparation
Saturated solution；Distilled water is 1:1.6 with the volume ratio of acetonitrile；
Add dimethyl sulfoxide the most while stirring and dichloroethanes volume ratio is the mixed solvent of 1:3, be warming up to 40 DEG C simultaneously；Heat up
Speed be 8 DEG C/h, mixing speed is 240 revs/min；The weight of dimethyl sulfoxide and dichloroethanes mixed solvent is
12 times of distilled water and acetonitrile mixed solution weight, adding speed is 40 ml/min；
3. after mixed solvent adds, being cooled to-2 DEG C, cooling rate is 2.5 DEG C/h；Crystallize is stood after obtaining crystal；Filter, wash
Wash, be vacuum dried 2～4 hours, obtain compound of pantoprazole sodium.
This compound crystal detects through high performance liquid chromatography, and purity is 99.97%, yield 95.4%；Cu-K alpha ray is used to measure
The X-ray powder diagram that obtains as it is shown in figure 1, thermogravimetric analysis figure as shown in Figure 2；Scanned electron microscope observation and grain
Degree analyzer is measured, and the main particle diameter of crystal is 650～850 μm, and the dispersion of distribution is 450～1050 μm；The measured value of elementary analysis with
Theoretical value is consistent.
The preparation of embodiment 3 pantoprazole sodium hydrate
1. Pantoprazole Sodium crude product is ground, crosses 300 mesh sieves, be then dissolved in the mixed solution of distilled water and acetonitrile, preparation
Saturated solution；Distilled water is 1:0.8 with the volume ratio of acetonitrile；
Add dimethyl sulfoxide the most while stirring and dichloroethanes volume ratio is the mixed solvent of 1:2.5, be warming up to 42 DEG C simultaneously；Rise
The speed of temperature is 6 DEG C/h；Mixing speed is 240 revs/min；Dimethyl sulfoxide and the weight of dichloroethanes mixed solvent
For 9 times of distilled water and acetonitrile mixed solution weight, adding speed is 30 ml/min；
3. after mixed solvent adds, being cooled to 0 DEG C, cooling rate is 1.5 DEG C/h；Crystallize is stood after obtaining crystal；Filter, wash
Wash, be vacuum dried 3 hours, obtain compound of pantoprazole sodium.
This compound crystal detects through high performance liquid chromatography, and purity is 99.98%, yield 95.2%；Cu-K alpha ray is used to measure
The X-ray powder diagram that obtains as it is shown in figure 1, thermogravimetric analysis figure as shown in Figure 2；Scanned electron microscope observation and grain
Degree analyzer is measured, and the main particle diameter of crystal is 650～850 μm, and the dispersion of distribution is 450～1050 μm；The measured value of elementary analysis with
Theoretical value is consistent.
The preparation of embodiment 4 pantoprazole sodium hydrate
1. Pantoprazole Sodium crude product is ground, crosses 300 mesh sieves, be then dissolved in the mixed solution of distilled water and acetonitrile, preparation
Saturated solution；Distilled water is 1:1.2 with the volume ratio of acetonitrile.
Add dimethyl sulfoxide the most while stirring and dichloroethanes volume ratio is the mixed solvent of 1:2.4, be warming up to 43 DEG C simultaneously；Rise
The speed of temperature is 7 DEG C/h；Mixing speed is 240 revs/min；Dimethyl sulfoxide and the weight of dichloroethanes mixed solvent
For 10 times of distilled water and acetonitrile mixed solution weight, adding speed is 25 ml/min；
3. after mixed solvent adds, being cooled to 2 DEG C, cooling rate is 1.8 DEG C/h；Crystallize is stood after obtaining crystal；Filter, wash
Wash, be vacuum dried 4 hours, obtain compound of pantoprazole sodium.
This compound crystal detects through high performance liquid chromatography, and purity is 99.97%, yield 95.5%；Cu-K alpha ray is used to measure
The X-ray powder diagram that obtains as it is shown in figure 1, thermogravimetric analysis figure as shown in Figure 2；Scanned electron microscope observation and grain
Degree analyzer is measured, and the main particle diameter of crystal is 650～850 μm, and the dispersion of distribution is 450～1050 μm；The measured value of elementary analysis with
Theoretical value is consistent.
The preparation of embodiment 5 aseptic powder injection
Pantoprazole sodium hydrate embodiment 1 obtained, aseptically, direct packaging obtains sterile powder injection, and specification is
With C16H14F2N3NaO4S calculates 40mg.
The preparation of embodiment 6 freeze-dried powder
1. the pantoprazole sodium hydrate that Example 1 prepares is (with C16H14F2N3NaO4S counts) 40g, stirs with water for injection
Mix dissolving, add mannitol 60g, complement to 2L with water for injection；
2. regulation pH value is 6.5～7.5；Adding mass percent is the medicinal carbon of 0.01%, adsorbs 20～30 minutes, filters
De-charcoal；Fine straining, adds sterilized water for injection to full dose, fine straining；
3. lyophilization: filtrate lyophilization step 2 obtained, is aseptically distributed into 1000, and gland, aluminum seal,
Obtain.
Lyophilization is divided into pre-freeze, distils and be dried；
Pre-freeze: with the speed of 2.0 DEG C/min, shelf temperature is down to-20 DEG C, stops cooling, is incubated 3 hours, then with 1.5 DEG C
The speed of/min is cooled to-55 DEG C；
Distillation: be evacuated to 15Pa, rise to-15 DEG C with the speed of 3 DEG C/min, be incubated 2 hours；Again with the speed of 2 DEG C/min
Rise to 15 DEG C keep 3 hours；
It is dried: rise to 40 DEG C with the speed of 1.2 DEG C/min, is dried 2 hours.
The preparation of embodiment 7 liquid drugs injection
1. the pantoprazole sodium hydrate that Example 3 prepares is (with C16H14F2N3NaO4S counts) 40g, join injection
In water, add mannitol 30g, 80% added to the full amount of water for injection, be heated to 40 DEG C, stirring and dissolving；
2. regulation pH value is 6.5～7.0；Adding mass percent is the medicinal carbon of 0.01%, adsorbs 20～30 minutes, filters
De-charcoal；Fine straining, adds sterilized water for injection to full dose, fine straining；
3. sterilizing, sealing, packaging, to obtain final product.
The preparation of embodiment 8 enteric coatel tablets
Formula:
Sealing coat coating fluid prescription: 3% hydroxypropyl methylcellulose solution；
Enteric layer coating solution uses LE enteric coating agents.
Preparation method: use direct compression process to make sheet material after being mixed by raw material, carry out coating and the enteric of sealing coat the most respectively
The coating of layer.
Experimental example 1: mobility is tested
The mobility of the pantoprazole sodium hydrate of the embodiment of the present invention 1 is detected by this experimental example, uses fixed funnel method,
The suitable height being placed on graph paper by funnel, makes pantoprazole sodium hydrate freely flow down from bell mouth, until the circular cone formed
Body top contacts with bell mouth, measures hypotenuse and the horizontal angle (θ angle of repose) of pantoprazole sodium hydrate accumulation horizon.
Experimental result is as shown in table 1.
Table 1: mobility experimental result
| Batch | 1 | 2 | 3 | 4 | 5 | Meansigma methods |
| θ(°) | 25 | 24 | 25 | 24 | 24 | 24.4 |
From the interpretation of table 1, the mobility of the pantoprazole sodium hydrate that the embodiment of the present invention 1 prepares is fine,
The pantoprazole sodium hydrate of other embodiments of the invention is also carried out detection, obtains similar experimental result.
Experimental example 2: dissolution time measures
The dissolution time of the pantoprazole sodium hydrate of the embodiment of the present invention 1 is detected by this experimental example, dissolving of Example 1
Torr draws azoles sodium trihydrate compound 1g, and addition 20ml, the water for injection of 20 DEG C stand after carrying out shaking 3 times and observes dissolution time.
Experimental result is as shown in table 2.
Table 2: dissolution time experimental result
| Batch | 1 | 2 | 3 | 4 | 5 | Meansigma methods |
| Second | 34 | 33 | 35 | 34 | 33 | 33.8 |
From the interpretation of table 2, the dissolution velocity of the pantoprazole sodium hydrate that the embodiment of the present invention 1 prepares is fast,
It is more suitable for the needs of clinical practice, the pantoprazole sodium hydrate of other embodiments of the invention has been also carried out detection, has obtained
Similar experimental result.
Experimental example 3: influence factor tests
1. hot test
Three batches of the pantoprazole sodium hydrate that Example 1 prepares 101,102,103, according to joining of embodiment 5
Side and method prepare preparation, simulation listing packaging, put in sealing clean container, place 10 days at a temperature of 40 ± 2 DEG C, in the
Sampling in 5 days and the 10th day, is detected by stability high spot reviews project, and result of the test compared with 0 day.
2. high humility test
Three batches of the pantoprazole sodium hydrate that Example 1 prepares 101,102,103, according to joining of embodiment 5
Side and method prepare preparation, simulation listing packaging, put in sealing clean container, in the condition of 25 ± 2 DEG C of relative humiditys 90% ± 5%
Lower placement 10 days, in sampling in the 5th day and the 10th day, is detected by stability high spot reviews project, result of the test and 0 day
Relatively.
3. strong illumination test
Three batches of the Pantoprazole Sodium compound that Example 1 prepares 101,102,103, according to the formula of embodiment 5
Preparing preparation, simulation listing packaging with method, put in sealing clean container, being placed in illumination is placement 10 under conditions of 4500lx
My god, in sampling in the 5th day and the 10th day, detecting by stability high spot reviews project, result compared with 0 day.
Influence factor's result of the test is as shown in table 3.
Table 3:
Result shows: the aseptic powder injection that the pantoprazole sodium hydrate that the present invention prepares prepares, and its stability is good,
Under high temperature, high humidity, high light conditions, all keep stable performance.The pantoprazole that other embodiments of the invention are prepared
Sodium hydrate carries out influence factor's experiment, has obtained identical experimental result.
The freeze-dried powder, the liquid drugs injection that prepare the pantoprazole sodium hydrate of the present invention carry out influence factor's experiment, obtained with
The experimental result that the present embodiment is identical.
Experimental example 4: Acceleration study
Three batches 201,202,203 of the pantoprazole sodium hydrate of Example 1 gained, according to the formula of embodiment 6
Prepare preparation with method, simulation listing packaging, put in sealing clean container, in 42 DEG C, place 6 months under the conditions of 80%RH,
Sample once respectively at 1,2,3,6 the end of month during testing, each stability high spot reviews project is tested.Test knot
Fruit is as shown in table 4.
Table 4:
Result shows: what the formula of the pantoprazole sodium hydrate employing present invention that the present invention prepares and method prepared freezes
Dry powder pin, accelerated result of the test understands, and its stability is good.Pantoprazole Sodium water prepared by other embodiments of the present invention
Compound is accelerated experiment, has obtained identical experimental result.
The aseptic powder injection, the liquid drugs injection that prepare the pantoprazole sodium hydrate of the present invention carry out influence factor's experiment, obtained with
The experimental result that the present embodiment is identical.
Experimental example 5: long term test
Three batches 301,302,303 of the pantoprazole sodium hydrate of Example 1 gained, according to the formula of embodiment 7
Prepare preparation, simulation listing packaging with method, put in sealing clean container, place 18 months under the conditions of temperature 20 DEG C ± 2 DEG C,
Sample once respectively at the 3rd, 6,9,12,18 the end of month during testing, each inspection project is tested.Result of the test
As shown in table 5:
Table 5:
Result shows: the water that the formula of the pantoprazole sodium hydrate employing present invention that the present invention prepares and method prepare
Pin, understands through long-term test results, and its stability is good, all keeps stable performance.Prepared by other embodiments of the present invention
Pantoprazole sodium hydrate carries out long-term experiment, has obtained identical experimental result.
The aseptic powder injection, the liquid drugs injection that prepare the pantoprazole sodium hydrate of the present invention carry out influence factor's experiment, obtained with
The experimental result that the present embodiment is identical.
Experimental example 6: influence factor tests
1. hot test
Three batches of the pantoprazole sodium hydrate that Example 1 prepares 101,102,103, according to joining of embodiment 8
Side is prepared as tablet, simulation listing packaging, puts in sealing clean container, places 10 days, in the 5th day at a temperature of 40 ± 2 DEG C
With sampling in the 10th day, detecting by stability high spot reviews project, result of the test compared with 0 day.
2. high humility test
Three batches of the pantoprazole sodium hydrate that Example 1 prepares 101,102,103, according to joining of embodiment 8
Side is prepared as tablet, simulation listing packaging, puts in sealing clean container, puts under conditions of 25 ± 2 DEG C of relative humiditys 90% ± 5%
Putting 10 days, in sampling in the 5th day and the 10th day, detect by stability high spot reviews project, result of the test compared with 0 day.
3. strong illumination test
Three batches of the Pantoprazole Sodium crystalline compounds that Example 1 prepares 101,102,103, according to embodiment 8
Formula be prepared as tablet, simulation listing packaging, put in sealing clean container, being placed in illumination is to place 10 under conditions of 4500lx
My god, in sampling in the 5th day and the 10th day, detecting by stability high spot reviews project, result compared with 0 day.
Influence factor's result of the test is as shown in table 6.
Table 6:
Result shows: the intestinal that the formula of the pantoprazole sodium hydrate employing present invention that the present invention prepares and method prepare
Molten, its stability is good, under high temperature, high humidity, high light conditions, all keeps stable performance.To other reality of the present invention
Execute pantoprazole sodium hydrate prepared by example and carry out influence factor's experiment, obtain identical experimental result.
Experimental example 7: Acceleration study
Three batches 201,202,203 of the pantoprazole sodium hydrate of Example 2 gained, according to the formula of embodiment 8
Be prepared as tablet, simulation listing packaging, put in sealing clean container, in 42 DEG C, place 6 months under the conditions of 80%RH,
Sample once respectively at 1,2,3,6 the end of month during testing, each stability high spot reviews project is tested.Test knot
Fruit is as shown in table 7.
Table 7:
Result shows: the intestinal that the formula of the pantoprazole sodium hydrate employing present invention that the present invention prepares and method prepare
Molten, accelerated result of the test understands, and its stability is good.Pantoprazole Sodium hydration prepared by other embodiments of the present invention
Thing is accelerated experiment, has obtained identical experimental result.
Experimental example 8: long term test
Three batches 301,302,303 of the pantoprazole sodium hydrate of Example 1 gained, according to the formula of embodiment 8
Preparation, simulation listing packaging, put in sealing clean container, place 18 months under the conditions of temperature 20 DEG C ± 2 DEG C, in experimental period
Between sample once respectively at the 3rd, 6,9,12,18 the end of month, each inspection project is tested.Result of the test such as table 8 institute
Show:
Table 8:
Result shows: the intestinal that the formula of the pantoprazole sodium hydrate employing present invention that the present invention prepares and method prepare
Molten, understanding through long-term test results, its stability is good, all keeps stable performance.Prepared by other embodiments of the present invention
Pantoprazole sodium hydrate carry out long-term experiment, obtained identical experimental result.
Experimental example 9: contrast test
The pantoprazole sodium hydrate of Example 1 gained, and the formula and method according to embodiment 6 prepare preparation；
Comparative example 1: prepare pantoprazole sodium hydrate according to the method for patent application 201310014961.3 embodiment 1, and press
Formula and method according to embodiment 6 prepare preparation；
Comparative example 2: prepare pantoprazole sodium hydrate according to the method for patent application 201310096327.9 embodiment 1, and press
Formula and method according to embodiment 6 prepare preparation；
Simulation listing packaging, puts in sealing clean container, in 42 DEG C, place 6 months under the conditions of 80%RH, during testing
Sample once respectively at 1,2,3,6 the end of month, each stability high spot reviews project is tested.Result of the test such as table 9 institute
Show.
Table 9:
Experimental example 10:
Take the pantoprazole sodium enteric tablet 6 that the embodiment of the present invention 8 prepares, according to " Chinese Pharmacopoeia " version (two) in 2010
Annex XD release is determined method the first method and is used Rotating shaker, based on the 0.1mol/L hydrochloric acid solution 750mL of degassed process
Solvent, temperature controls in the range of (37 ± 0.5) DEG C, and rotating speed operates for (100 ± 5) r/min, immediately will through 120min stall
Turn basket emersion liquid level, must not have crack or disintegration phenomenon for test piece.The sodium radio-phosphate,P-32 solution of 0.2mol/L is added in above-mentioned acid solution
250mL (sodium hydroxide of the hydrochloric acid or 2mol/L that add 2mol/L if desired adjusts pH to 6.8 ± 0.05), rotating speed, temperature are not
Become, operate in accordance with the law, through 5,10,15,25,30,35,45,60,90,120min time respectively sample 10mL, and immediately
Supplementing synthermal phosphate buffer 1 0mL, sample solution is after less than 0.8 μm membrane filtration, at 288nm wavelength,
Measure trap with phosphate buffer solution for blank, calculate the mass concentration of solution, with medicine labelled amount as criterion calculation
The average accumulated release percentage rate of each time point.
Take 6 reference preparations (pantoprazole, Shenyang Sheng Yuan pharmaceutcal corporation, Ltd product) ibid method to measure and calculate.
Table 10: pantoprazole is discharged percentage rate (%) by the vitro cumulative of test preparation
Claims (9)
1. a compound of pantoprazole sodium, it is characterised in that described Pantoprazole Sodium is pantoprazole sodium trihydrate, its structure
Shown in formula such as formula (I):
The X-ray powder diagram that described pantoprazole sodium trihydrate use Cu-K alpha ray measurement obtains is as shown in Figure 1.
Compound of pantoprazole sodium the most according to claim 1, it is characterised in that the described main grain of pantoprazole sodium trihydrate
Footpath is 650～850 μm, and the dispersion of distribution is 450～1050 μm.
Compound of pantoprazole sodium the most according to claim 1, it is characterised in that the preparation of described compound of pantoprazole sodium
Method is:
(1) Pantoprazole Sodium crude product is ground, crosses 200～300 mesh sieves, be then dissolved in the mixed solution of distilled water and acetonitrile,
Prepare saturated solution；
(2) add dimethyl sulfoxide and mixed solvent that dichloroethanes volume ratio is 1:2～3 while stirring, be warming up to simultaneously 40～
45℃；
(3) after mixed solvent adds, it is cooled to-5 DEG C～5 DEG C, after obtaining crystal, stands crystallize；Filter, washing, vacuum drying 2～
4 hours, obtain compound of pantoprazole sodium.
Compound of pantoprazole sodium the most according to claim 3, it is characterised in that in step (1), distilled water and acetonitrile
Volume ratio be 1:0.4～1.6.
Compound of pantoprazole sodium the most according to claim 3, it is characterised in that in step (2), the speed of intensification be 5～
8 DEG C/h；Mixing speed is 120～240 revs/min.
Compound of pantoprazole sodium the most according to claim 3, it is characterised in that in step (2), dimethyl sulfoxide and
The weight of dichloroethanes mixed solvent is 8～12 times of distilled water and acetonitrile mixed solution weight, and adding speed is 20～40
Ml/min.
Compound of pantoprazole sodium the most according to claim 3, it is characterised in that in step (3), cooling rate be 0.5～
2.5 DEG C/h.
8. the pharmaceutical composition containing the compound of pantoprazole sodium described in claim 1, it is characterised in that described medicine group
The dosage form of compound is selected from oral formulations or ejection preparation.
Pharmaceutical composition the most according to claim 8, it is characterised in that described oral formulations is selected from enteric coatel tablets, described note
Penetrate preparation selected from aseptic powder injection, freeze-dried powder and liquid drugs injection.
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