CN102351846B - Novel omeprazole sodium compound and medicinal composition thereof - Google Patents
Novel omeprazole sodium compound and medicinal composition thereof Download PDFInfo
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- CN102351846B CN102351846B CN2011102647760A CN201110264776A CN102351846B CN 102351846 B CN102351846 B CN 102351846B CN 2011102647760 A CN2011102647760 A CN 2011102647760A CN 201110264776 A CN201110264776 A CN 201110264776A CN 102351846 B CN102351846 B CN 102351846B
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- 229940063517 omeprazole sodium Drugs 0.000 title claims abstract description 142
- KNVABRFVZVESIL-UHFFFAOYSA-N sodium;6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound [Na+].N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C KNVABRFVZVESIL-UHFFFAOYSA-N 0.000 title claims abstract description 141
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 22
- 229960000381 omeprazole Drugs 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 20
- 238000009472 formulation Methods 0.000 claims description 19
- 239000000047 product Substances 0.000 claims description 17
- 239000011734 sodium Substances 0.000 claims description 15
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 claims description 14
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 239000002662 enteric coated tablet Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
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Abstract
The invention discloses a novel omeprazole sodium compound. Characteristic peaks of the omeprazole sodium compound in an X-ray powder diffraction pattern obtained through Cu-K alpha-ray measurement are displayed when 2 theta is 3.2, 5.9, 7.6, 9.2, 10.5, 10.6, 12.3, 16.2, 18.2, 20.8, 23.4, 27.1, 30.4, 32.3 and 34.6. The omeprazole sodium compound has a new crystal form different from the prior art, has the thermodynamic stability higher than that with known crystal form, and has the advantage of not absorbing moisture basically. The invention also discloses a medicinal composition, which comprises the novel omeprazole sodium compound. Omeprazole sodium freeze-dried powder injection can be directly prepared under the condition of not adding lyoprotectants, and the omeprazole sodium freeze-dried powder injection has the advantages of high stability and high re-dissolubility.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of new omeprazole sodium compound and pharmaceutical composition thereof.
Background technology
Omeprazole Sodium, chemical name is: 5-methoxyl group-2-{ [(4-methoxyl group-3,5-dimethyl--2-pyridyl)-methyl]-sulfinyl }-1H-benzoglyoxaline sodium-hydrate, molecular formula is C
17H
18N
3NaO
3SH
2O, molecular weight are 385.41.Omeprazole Sodium is the weakly alkaline material, and the parietal cell proton pump inhibitor can suppress the secreted microtubule of parietal cell top film formation and the H on the intracytoplasmic tubular foam specifically
+, K
+-ATP enzyme, thereby the secretion of gastric acid inhibitory effectively.Omeprazole Sodium all has significant curative effect to duodenal ulcer, stomach ulcer, reflux esophagitis, Zhuo-Emhorn syndromes etc.
CN1134432C discloses a kind of Type B Omeprazole Sodium; And confirm that through the X-ray powder diffraction pattern this Type B Omeprazole Sodium of its preparation is different from disclosed A type Omeprazole Sodium among the EP124495, wherein, the preparation method of Type B Omeprazole Sodium is: in container, add 26.7 gram water, 480ml Virahol, 13.2g sodium hydroxide and 120g omeprazole; After the stirring at room 40 minutes; Filtering, collect filtrating, is that crystal seed carries out crystallization with 6gB type Omeprazole Sodium; At last product is filtered and be drying to obtain at 40 ℃, productive rate is 84.5%.In addition, the document also discloses the preparation method of A type Omeprazole Sodium, comprising: the 120kg omeprazole is dissolved in the 927L Virahol, adds aqueous sodium hydroxide solution again; Filter, add hot filtrate, and add 228L methyl alcohol startup crystallization at 50 ℃; The Omeprazole Sodium soup compound moistening with 1.2kg methyl alcohol is crystal seed, is cooled to-8 ℃, keeps 4 hours under the moderate agitation; Centrifugal, washing is drying to obtain.This patent inventor thinks, the Type B Omeprazole Sodium is than A type Omeprazole Sodium Thermodynamically stable, and non-hygroscopic basically, but lacks the support of concrete experimental data.
CN101412710B discloses a kind of omeprazole sodium compound and method for making thereof, comprising: the Omeprazole Sodium bullion is water-soluble, add the solid acid salt solution; The solid that collection is separated out is behind organic solvent dissolution, through macroporous adsorbent resin wash-out purifying; Collect elutriant; Add basic soln again and regulate pH, collect the solid of separating out, be drying to obtain to alkalescence.This invention is mainly used in through acid-base method carries out purification to the Omeprazole Sodium bullion, thereby improves the purity of the Omeprazole Sodium for preparing, and does not relate to the problem of preparation omeprazole sodium novel crystal form.
CN1347413A discloses a kind of new crystal of omeprazole, and CN1531533A also discloses a kind of crystalline form of omeprazole, and the disclosed omeprazole crystal formation of these two pieces of patents all characterizes through the X-ray powder diffraction pattern.But the omeprazole crystal formation that these two pieces of patents are introduced is different from the prepared omeprazole sodium crystal of the present invention; Because chemical property such as omeprazole and Omeprazole Sodium solvability have significant difference; So these two pieces of patents do not have the enlightenment effect to the present invention.
The inventor is a raw material with existing Omeprazole Sodium bullion, through experiment in a large number, all of a sudden prepares a kind of omeprazole sodium compound that is different from the new crystal of prior art; And through experiment confirm, the thermostability of the omeprazole sodium compound of this kind crystal formation is superior to existing crystal formation, and non-hygroscopic basically; And solubleness is superior to existing crystal formation, and yield is higher, and technology is simple; Repeatability is strong, is suitable for suitability for industrialized production.Omeprazole sodium compound with this new crystal is a raw material; Need not add frozen-dried supporting agent and just can directly prepare omeprazole sodium freeze-dried powder pin; And this omeprazole sodium freeze-dried powder needle set has good stability, advantage that solubility is good, thereby has accomplished the present invention.
Summary of the invention
The present invention's first purpose is to provide a kind of new omeprazole sodium compound, and this omeprazole sodium compound is a kind of omeprazole sodium compound that is different from the new crystal of prior art, and passes through experiment confirm; The thermodynamic stability of the omeprazole sodium compound of this kind crystal formation is superior to existing crystal formation; And non-hygroscopic basically, and yield is higher, and technology is simple; Repeatability is strong, is suitable for suitability for industrialized production.
The present invention's second purpose is to provide a kind of pharmaceutical composition that comprises above-mentioned new omeprazole sodium compound, and the formulation of this pharmaceutical composition comprises: powder injection, enteric coated tablet, little liquid drugs injection or infusion solutions.Especially just can directly prepare omeprazole sodium freeze-dried powder pin need not adding under the frozen-dried supporting agent situation, and this omeprazole sodium freeze-dried powder needle set there are good stability, advantage that solubility is good.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
It is a kind of suc as formula the new omeprazole sodium compound shown in (I) that the present invention provides
Said new omeprazole sodium compound is a crystal, and characteristic peak is 3.2,5.9,7.6,9.2,10.5,10.6,12.3,16.2,18.2,20.8,23.4,27.1,30.4,32.3,34.6 demonstrations at 2 θ in the X-ray powder diffraction pattern that use Cu-K alpha-ray measures.
According to aforesaid new omeprazole sodium compound, wherein, the fusing point of this omeprazole sodium compound is 260-262 ℃.
According to aforesaid new omeprazole sodium compound, wherein, the particle diameter of this omeprazole sodium compound is 70～100 μ m.
According to aforesaid new omeprazole sodium compound, wherein, the preparation method of this omeprazole sodium compound may further comprise the steps:
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 5-10 weight part, and 20-30 ℃ of needle-use activated carbon that adds 0.1% weight part stirs 1-1.5 hour after-filtration, obtains solution 1;
(2) nucleus generative process: at rotating speed is that 40-60 rev/min, temperature are under 20-30 ℃; And in frequency is that 15-20KHz, output rating are under the sound field of 100-150W; Under the pressure of 2-3Mpa, the speed of in solution 1, dividing with 1-2ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2-3 hour: rotating speed is 10-20 rev/min, and temperature is 10-20 ℃, and to be in frequency be that 8-12KHz, output rating are under the sound field of 200-250W, pressure 0.5-1Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 20-25 ℃ promptly got product in vacuum-drying 1-2 days.
According to aforesaid new omeprazole sodium compound, wherein the preparation method of this omeprazole sodium compound may further comprise the steps:
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 7-8 weight part, and 22-28 ℃ of needle-use activated carbon that adds 0.1% weight part stirs 1.1-1.4 hour after-filtration, obtains solution 1;
(2) nucleus generative process: at rotating speed is that 45-55 rev/min, temperature are under 22-28 ℃; And in frequency is that 17-18KHz, output rating are under the sound field of 110-140W; Under the pressure of 2.2-2.8Mpa; The speed of in solution 1, dividing with 1.3-1.7ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2.3-2.7 hour: rotating speed is 13-17 rev/min, and temperature is 13-17 ℃, and to be in frequency be that 9-11KHz, output rating are under the sound field of 220-230W, pressure 0.7-0.8Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 21-24 ℃ promptly got product in vacuum-drying 1.3-1.7 days.
According to aforesaid new omeprazole sodium compound, wherein the preparation method of this omeprazole sodium compound may further comprise the steps:
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 7.5 weight parts, and 25 ℃ of needle-use activated carbons that add 0.1% weight part stir 1.2 hours after-filtration, obtain solution 1;
(2) nucleus generative process: at rotating speed is that 50 rev/mins, temperature are under 25 ℃; And in frequency is that 17.5KHz, output rating are under the sound field of 125W; Under the pressure of 2.5Mpa, the speed of in solution 1, dividing with 1.5ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2.5 hours: rotating speed is 15 rev/mins, and temperature is 15 ℃, and to be in frequency be that 10KHz, output rating are under the sound field of 225W, pressure 0.75Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 22.5 ℃ of vacuum-dryings promptly got product in 1.5 days.
Crystallization is the heat transfer-mass transfer process of a complicacy, and under different physicochemical environments, the change of any controlled step of crystallisation process all can form different crystallization effects.Among the present invention, at first for guaranteeing effective crystallization, step (1) is taken off bacterium through gac and is removed the look raw material of purifying; Step (2) and step (3) have mainly been investigated temperature, mixing speed, sound field frequency and processing parameters such as output rating and pressure in nucleus generative process and the nucleus growth process.Wherein, the temperature of nucleus generative process is higher than the temperature of crystal growing process in the step (3) in the step (2), and major cause is: in the nucleus generative process, can suppress effectively that crystallization is too fast to make a certain amount of impurity of parcel in the crystal thereby temperature is high slightly.In a word; The inventor is through a large amount of experiments; Through strictness control to the crystallization processes parameter; Obtained the omeprazole sodium compound of the new crystal all different unexpectedly with prior art; And the omeprazole sodium compound of this new crystal carried out the XRD sign, the X-ray powder diffraction pattern of disclosed A type Omeprazole Sodium among disclosed Type B Omeprazole Sodium and the EP124495 can find out very significantly that the omeprazole sodium compound that the present invention prepares is a kind of omeprazole sodium compound that is different from the new crystal of prior art among the omeprazole sodium compound for preparing through the present invention relatively, the CN1134432C.1-3 can find out through the The compounds of this invention comparative example, and the prepared new omeprazole sodium compound solubleness in water that obtains of the present invention is better, and better heat stability; And water cut is stable; Basically non-hygroscopic, more can satisfy the requirement that pharmaceutical prepn is learned, be more suitable for preparing various medicines.
For realizing second purpose of the present invention, the present invention adopts following technical scheme:
The present invention provides a kind of omeprazole composition of sodium, and said omeprazole composition of sodium comprises acceptable auxiliary on above-mentioned omeprazole sodium compound and the pharmaceutics.
According to aforesaid omeprazole composition of sodium, wherein, the formulation of this omeprazole composition of sodium comprises: powder injection, enteric coated tablet, little liquid drugs injection or infusion solutions.
According to aforesaid omeprazole composition of sodium, wherein, when the formulation of this omeprazole composition of sodium is lyophilized injectable powder, comprise following composition:
Omeprazole sodium compound 1 weight part (in omeprazole)
The pH regulator agent is an amount of
pH 10.0-12.0
Wherein, the pH regulator agent is selected from one or more in sodium hydroxide, sodium hydrogencarbonate, Pottasium Hydroxide, the Sodium phosphate, dibasic;
Wherein, the pH value is preferably 10.5-11.5; More preferably 11.0.
According to aforesaid omeprazole composition of sodium, wherein, this Omeprazole Sodium preparation of compositions method may further comprise the steps:
1) takes by weighing the recipe quantity omeprazole sodium compound, add the sterile water for injection dissolving, obtain solution 1;
2) with the pH to 10.0-12.0 of pH regulator agent regulator solution 1, obtain solution 2;
3) add the gac of prescription total amount 0.1-0.3%, heating 10-30min filters, and successively through 0.45 μ m millipore filtration once filter, 0.22 μ m millipore filtration carries out secondary filtration, obtains filtrating 4, benefit adds to the full amount of water for injection;
4) determination step 3) pH, content, the false add plug of gained solution, carry out lyophilize and get product.
Compared with prior art, the present invention has the following advantages:
(1) new omeprazole sodium compound provided by the present invention is a kind of omeprazole sodium compound that is different from the new crystal of prior art, and passes through experiment confirm; The thermodynamic stability of the omeprazole sodium compound of this kind crystal formation is superior to existing crystal formation; And non-hygroscopic basically, and yield is higher, and technology is simple; Repeatability is strong, is suitable for suitability for industrialized production.
(2) pharmaceutical composition stability and the solubility that contains this omeprazole sodium compound provided by the present invention is fine, thereby has improved drug safety and validity, avoids incidence rate of adverse reaction.
Description of drawings
Fig. 1 is the X-ray powder diffraction pattern of the prepared new omeprazole sodium compound of the embodiment of the invention 1.
Embodiment
Following embodiment will do to explain more specifically to the present invention, but the present invention is not limited only to these embodiment, and these embodiment do not limit the present invention in any way yet equally.
The preparation of the omeprazole sodium compound that [embodiment 1] is new
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 7.5 weight parts, and 25 ℃ of needle-use activated carbons that add 0.1% weight part stir 1.2 hours after-filtration, obtain solution 1;
(2) nucleus generative process: at rotating speed is that 50 rev/mins, temperature are under 25 ℃; And in frequency is that 17.5KHz, output rating are under the sound field of 125W; Under the pressure of 2.5Mpa, the speed of in solution 1, dividing with 1.5ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2.5 hours: rotating speed is 15 rev/mins, and temperature is 15 ℃, and to be in frequency be that 10KHz, output rating are under the sound field of 225W, pressure 0.75Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 22.5 ℃ of vacuum-dryings promptly got product in 1.5 days.
The particle diameter of prepared new omeprazole sodium compound is 85 μ m, and using in the X-ray powder diffraction pattern (see figure 1) that the Cu-K alpha-ray measures characteristic peak is 3.2,5.9,7.6,9.2,10.5,10.6,12.3,16.2,18.2,20.8,23.4,27.1,30.4,32.3,34.6 to show at 2 θ.Fusing point is 260-262 ℃.Yield 98.5%.
The preparation of the omeprazole sodium compound that [embodiment 2] are new
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 7 weight parts, and 28 ℃ of needle-use activated carbons that add 0.1% weight part stir 1.4 hours after-filtration, obtain solution 1;
(2) nucleus generative process: at rotating speed is that 45 rev/mins, temperature are under 28 ℃; And in frequency is that 18KHz, output rating are under 110 the sound field; Under the pressure of 2.8Mpa, the speed of in solution 1, dividing with 1.7ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2.7 hours: rotating speed is 17 rev/mins, and temperature is 13 ℃, and to be in frequency be that 11KHz, output rating are under the sound field of 230W, pressure 0.8Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 24 ℃ of vacuum-dryings promptly got product in 1.7 days.
The particle diameter of prepared new omeprazole sodium compound is 75 μ m, and fusing point is 260-262 ℃.Yield 98.8%.The X-ray powder diffraction pattern that use Cu-K alpha-ray measures is consistent with embodiment's 1.
The preparation of the omeprazole sodium compound that [embodiment 3] are new
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 8 weight parts, and 22 ℃ of needle-use activated carbons that add 0.1% weight part stir 11 hours after-filtration, obtain solution 1;
(2) nucleus generative process: at rotating speed is that 55 rev/mins, temperature are under 28 ℃; And in frequency is that 17KHz, output rating are under the sound field of 140W; Under the pressure of 2.2Mpa, the speed of in solution 1, dividing with 1.3ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2.3 hours: rotating speed is 13 rev/mins, and temperature is 17 ℃, and to be in frequency be that 9KHz, output rating are under the sound field of 220W, pressure 0.7Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 21 ℃ of vacuum-dryings promptly got product in 1.3 days.
The particle diameter of prepared new omeprazole sodium compound is 90 μ m, and fusing point is 260-262 ℃.Yield 97.9%.The X-ray powder diffraction pattern that use Cu-K alpha-ray measures is consistent with embodiment's 1.
The preparation of [embodiment 4] omeprazole sodium compound
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 5 weight parts, and 20 ℃ of needle-use activated carbons that add 0.1% weight part stir 1.5 hours after-filtration, obtain solution 1;
(2) nucleus generative process: at rotating speed is that 40 rev/mins, temperature are under 30 ℃; And in frequency is that 20KHz, output rating are under 100 the sound field; Under the pressure of 2Mpa, the speed of in solution 1, dividing with 2ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2 hours: rotating speed is 20 rev/mins, and temperature is 10 ℃, and to be in frequency be that 12KHz, output rating are under the sound field of 250W, pressure 1Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 25 ℃ of vacuum-dryings promptly got product in 2 days.
The particle diameter of prepared new omeprazole sodium compound is 80 μ m, and fusing point is 260-262 ℃.Yield 98.1%.The X-ray powder diffraction pattern that use Cu-K alpha-ray measures is consistent with embodiment's 1.
The preparation of [embodiment 5] omeprazole sodium compound
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 10 weight parts, and 30 ℃ of needle-use activated carbons that add 0.1% weight part stir 1 hour after-filtration, obtain solution 1;
(2) nucleus generative process: at rotating speed is that 60 rev/mins, temperature are under 20 ℃; And in frequency is that 15KHz, output rating are under the sound field of 150W; Under the pressure of 3Mpa, the speed of in solution 1, dividing with 1ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 3 hours: rotating speed is 10 rev/mins, and temperature is 20 ℃, and to be in frequency be that 8KHz, output rating are under the sound field of 200W, pressure 0.5Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 20 ℃ of vacuum-dryings promptly got product in 1 day.
The particle diameter of prepared new omeprazole sodium compound is 100 μ m, and fusing point is 260-262 ℃.Yield 97.8%.The X-ray powder diffraction pattern that use Cu-K alpha-ray measures is consistent with embodiment's 1.
The preparation of [embodiment 6] omeprazole sodium compound
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 8 weight parts, and 22 ℃ of needle-use activated carbons that add 0.1% weight part stir 14 hours after-filtration, obtain solution 1;
(2) nucleus generative process: at rotating speed is that 48 rev/mins, temperature are under 26 ℃; And in frequency is that 19KHz, output rating are under the sound field of 120W; Under the pressure of 2.8Mpa, the speed of in solution 1, dividing with 1.4ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2.2 hours: rotating speed is 18 rev/mins, and temperature is 17 ℃, and to be in frequency be that 10KHz, output rating are under the sound field of 210W, pressure 0.7Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 21 ℃ of vacuum-dryings promptly got product in 1.4 days.
The particle diameter of prepared new omeprazole sodium compound is 70 μ m, and fusing point is 260-262 ℃.Yield 98.3%.The X-ray powder diffraction pattern that use Cu-K alpha-ray measures is consistent with embodiment's 1.
The preparation of [FORMULATION EXAMPLE 1] omeprazole sodium freeze-dried powder pin
Prescription:
The preparation method:
1) takes by weighing the recipe quantity omeprazole sodium compound, add the sterile water for injection dissolving, obtain solution 1;
2) with the pH to 11.0 of pH regulator agent regulator solution 1, obtain solution 2;
3) add the gac of prescription total amount 0.1%, heating 30min filters, and successively through 0.45 μ m millipore filtration once filter, 0.22 μ m millipore filtration carries out secondary filtration, obtains filtrating 4, benefit adds to the full amount of water for injection;
4) determination step 3) pH, content, the false add plug of gained solution, carry out lyophilize and get product.
The preparation of [FORMULATION EXAMPLE 2] omeprazole sodium freeze-dried powder pin
Prescription:
The preparation method:
The preparation method is with FORMULATION EXAMPLE 1, and different is:
(1) the PH regulator replaces with sodium hydroxide;
(2) PH regulator adjusting pH value is 11.5 in the step (2).
(3) 0.3% of the middle gac add-on of step (3), be 20min heat-up time.
The preparation of [FORMULATION EXAMPLE 3] omeprazole sodium freeze-dried powder pin
Prescription:
The preparation method is with FORMULATION EXAMPLE 1, and different is:
(1) the PH regulator replaces with Pottasium Hydroxide;
(2) PH regulator adjusting pH value is 10.5 in the step (2).
The preparation of [FORMULATION EXAMPLE 4] omeprazole sodium freeze-dried powder pin
Prescription:
The preparation method:
The preparation method is with FORMULATION EXAMPLE 1, and different is:
(1) the PH regulator replaces with Sodium phosphate, dibasic;
(2) PH regulator adjusting pH value is 10.5 in the step (2).
(3) 0.2% of the middle gac add-on of step (3), be 15min heat-up time.
The preparation of [FORMULATION EXAMPLE 5] omeprazole sodium freeze-dried powder pin
Prescription:
The preparation method:
The preparation method is with FORMULATION EXAMPLE 1, and different is:
(1) the PH regulator replaces with sodium hydroxide;
(2) PH regulator adjusting pH value is 10.0 in the step (2).
(3) 0.3% of the middle gac add-on of step (3), be 20min heat-up time.
The preparation of [FORMULATION EXAMPLE 6] omeprazole sodium freeze-dried powder pin
Prescription:
The preparation method:
The preparation method is with FORMULATION EXAMPLE 1, and different is:
(1) PH regulator adjusting pH value is 12.0 in the step (2).
(2) 0.3% of the middle gac add-on of step (3), be 26min heat-up time.
Comparative example 1
This comparative example is used for investigating the dissolubility difference of the Omeprazole Sodium of prepared new omeprazole sodium compound of the present invention and the existing crystal formation of prior art.
Each sample is numbered in this comparative example: the omeprazole sodium compound for preparing with experimental example 1 of the present invention is a sample 1; The omeprazole sodium compound for preparing with experimental example 3 of the present invention is a sample 2; With disclosed Type B Omeprazole Sodium among the patented claim CN1134432C is sample 3; With disclosed A type Omeprazole Sodium among the patented claim EP124495 is sample 4.
Be dissolved in deionized water respectively until saturated with under 25 ℃ in above-mentioned each sample, analyze the solubleness of each saturated solution through the HPLC method, wherein, the HPLC test condition is: post: Zorbax C8XDB, 5 μ m (150mm*4.6mm); Detect wavelength: 281nm; Flow velocity: 1.0ml/min; Elution requirement: Na
2HPO
4-NaH
2PO
4Buffered soln/CH
3CN=75/25 (v/v).The result sees table 1.
Table 1
Can find out from last table, the new omeprazole sodium compound that the present invention prepares in water solubleness apparently higher than the solubleness of the Omeprazole Sodium of existing crystal formation.
Comparative example 2
This comparative example is used for investigating the water absorbability difference of the Omeprazole Sodium of prepared new omeprazole sodium compound of the present invention and the existing crystal formation of prior art.
The classes of compounds of sample 1-4 numbering representative is with comparative example 1.
It is that through the water cut of each sample of weight loss on drying experiment measuring at different time, the result sees table 2 under 40%, 60%, 75%, 90% the environment that each sample is exposed to relative humidity respectively.
Table 2
Can find out that from last table the new omeprazole sodium compound that the present invention prepares is non-hygroscopic basically under high humidity, and under low, keep its initial water content basically.Therefore, the stability of the new omeprazole sodium compound water cut for preparing of the present invention is superior to the Omeprazole Sodium of existing crystal formation.
Comparative example 3
This comparative example is used for investigating the thermal stability difference of the Omeprazole Sodium of prepared new omeprazole sodium compound of the present invention and the existing crystal formation of prior art.
The classes of compounds of sample 1-4 numbering representative and HPLC method test condition are with comparative example 1.
With each sample be exposed to respectively that relative humidity is 75%, temperature is that through the content of active substance Omeprazole Sodium behind the HPLC method test different time, the result sees table 3 under 60 ℃ the environment.
Table 3
Can find out that from last table the new omeprazole sodium compound thermostability that the present invention prepares is superior to the Omeprazole Sodium of existing crystal formation.
Comparative example 4
This comparative example is used for investigating respectively the proterties of the prepared lyophilized injectable powder of FORMULATION EXAMPLE 1-6 of the present invention, and the result sees table 4.
Table 4
Comparative example 5
This comparative example is used to investigate the omeprazole sodium freeze-dried powder pin that the present invention prepares and the stability of omeprazole sodium freeze-dried powder pin of the prior art.
Trial-product: the omeprazole sodium freeze-dried powder pin that FORMULATION EXAMPLE 1 of the present invention makes.
Reference substance: commercially available omeprazole sodium freeze-dried powder pin, manufacturer: Dandong doctor's wound medicine company Ltd, the accurate word H20054327 of traditional Chinese medicines, specification: 40mg/ props up.
Respectively sample is placed high light (4500 ± 500) LX, high temperature (60 degree), high humidity (75%), high humidity (93%) condition held 10d, respectively at 0,5, the 10d sampling investigates clarity and color, related substance, the content of proterties, pH value, the solution of sample.The result sees the following form 4.
Table 5
Can find out that from last table the stability of the prepared omeprazole sodium freeze-dried powder pin of the present invention is superior to commercially available omeprazole sodium freeze-dried powder pin.
The omeprazole sodium freeze-dried powder pin that other FORMULATION EXAMPLE of the present invention is made has also carried out identical test, and the result of its acquisition is similar.
More than disclosedly be merely several specific embodiment of the present invention, still, the present invention is not limited thereto, any those skilled in the art can think variation all should fall into protection scope of the present invention.
Claims (10)
1. omeprazole sodium compound shown in formula I
It is characterized in that; Said omeprazole sodium compound is a crystal, and characteristic peak is 3.2,5.9,7.6,9.2,10.5,10.6,12.3,16.2,18.2,20.8,23.4,27.1,30.4,32.3,34.6 demonstrations at 2 θ in the X-ray powder diffraction pattern that use Cu-K alpha-ray measures.
2. omeprazole sodium compound according to claim 1 is characterized in that, the fusing point of this omeprazole sodium compound is 260-262 ℃.
3. omeprazole sodium compound according to claim 1 is characterized in that, the particle diameter of this omeprazole sodium compound is 70 ~ 100 μ m.
4. the preparation method of the described omeprazole sodium compound of claim 1 is characterized in that, the preparation method of this omeprazole sodium compound may further comprise the steps:
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 5-10 weight part, and 20-30 ℃ of needle-use activated carbon that adds 0.1% weight part stirs 1-1.5 hour after-filtration, obtains solution 1;
(2) nucleus generative process: at rotating speed is that 40-60 rev/min, temperature are under 20-30 ℃; And in frequency is that 15-20KHz, output rating are under the sound field of 100-150W; Under the pressure of 2-3Mpa; The speed of in solution 1, dividing with 1-2ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2-3 hour: rotating speed is 10-20 rev/min, and temperature is 10-20 ℃, and to be in frequency be that 8-12KHz, output rating are under the sound field of 200-250W, pressure 0.5-1Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 20-25 ℃ promptly got product in vacuum-drying 1-2 days.
5. preparation method according to claim 4 is characterized in that, the preparation method of this omeprazole sodium compound may further comprise the steps:
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 7-8 weight part, and 22-28 ℃ of needle-use activated carbon that adds 0.1% weight part stirs 1.1-1.4 hour after-filtration, obtains solution 1;
(2) nucleus generative process: at rotating speed is that 45-55 rev/min, temperature are under 22-28 ℃; And in frequency is that 17-18KHz, output rating are under the sound field of 110-140W; Under the pressure of 2.2-2.8Mpa; The speed of in solution 1, dividing with 1.3-1.7ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2.3-2.7 hour: rotating speed is 13-17 rev/min, and temperature is 13-17 ℃, and to be in frequency be that 9-11KHz, output rating are under the sound field of 220-230W, pressure 0.7-0.8Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 21-24 ℃ promptly got product in vacuum-drying 1.3-1.7 days.
6. preparation method according to claim 5 is characterized in that, the preparation method of this omeprazole sodium compound may further comprise the steps:
(1) the Omeprazole Sodium bullion with 1 weight part is dissolved in the water of 7.5 weight parts, and 25 ℃ of needle-use activated carbons that add 0.1% weight part stir 1.2 hours after-filtration, obtain solution 1;
(2) nucleus generative process: at rotating speed is that 50 rev/mins, temperature are under 25 ℃; And in frequency is that 17.5KHz, output rating are under the sound field of 125W; Under the pressure of 2.5Mpa, the speed of in solution 1, dividing with 1.5ml/ at the uniform velocity flows and adds Virahol to solution feculence, gets solution 2;
(3) crystal growing process: solution 2 was placed the atmosphere growing the grain 2.5 hours: rotating speed is 15 rev/mins, and temperature is 15 ℃, and to be in frequency be that 10KHz, output rating are under the sound field of 225W, pressure 0.75Mpa;
(4) step with centrifugal separation 3 gained solution, filter cake is used washed with isopropyl alcohol, and 22.5 ℃ of vacuum-dryings promptly got product in 1.5 days.
7. an omeprazole composition of sodium is characterized in that, said omeprazole composition of sodium comprises acceptable auxiliary on each described omeprazole sodium compound of claim 1-3 and the pharmaceutics.
8. omeprazole composition of sodium according to claim 7 is characterized in that, the formulation of this omeprazole composition of sodium comprises: powder injection, enteric coated tablet, little liquid drugs injection or infusion solutions.
9. omeprazole composition of sodium according to claim 8 is characterized in that, when the formulation of this omeprazole composition of sodium is lyophilized injectable powder, comprises following composition:
Omeprazole sodium compound is counted 1 weight part with omeprazole
The pH regulator agent is an amount of
The pH of said omeprazole composition of sodium is 10.0-12.0,
Wherein, the pH regulator agent is selected from one or more in sodium hydroxide, sodium hydrogencarbonate, Pottasium Hydroxide, the Sodium phosphate, dibasic.
10. the described Omeprazole Sodium preparation of compositions of claim 9 method is characterized in that, this Omeprazole Sodium preparation of compositions method may further comprise the steps:
1) takes by weighing the recipe quantity omeprazole sodium compound, add the sterile water for injection dissolving, obtain solution 1;
2) with the pH to 10.0-12.0 of pH regulator agent regulator solution 1, obtain solution 2;
3) add the gac of prescription total amount 0.1-0.3%, heating 10-30min filters, and successively through 0.45 μ m millipore filtration once filter, 0.22 μ m millipore filtration carries out secondary filtration, obtains filtrating 4, benefit adds to the full amount of water for injection;
4) determination step 3) pH, content, the false add plug of gained solution, carry out lyophilize and get product.
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| CN103570687B (en) * | 2013-11-15 | 2015-01-07 | 悦康药业集团有限公司 | Crystalline compound of omeprazole sodium |
| CN107982261B (en) * | 2017-11-30 | 2020-01-10 | 乐普药业股份有限公司 | Esomeprazole sodium freeze-dried powder and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0124495A2 (en) * | 1983-03-04 | 1984-11-07 | Aktiebolaget Hässle | Omeprazole salts |
| CN1261362A (en) * | 1997-06-27 | 2000-07-26 | 阿斯特拉公司 | Omeprazole sodium salt |
| CN1531533A (en) * | 2001-04-25 | 2004-09-22 | ������ҩ�뻯ѧ��˾ | Crystalline form of omeprazole |
-
2011
- 2011-09-07 CN CN2011102647760A patent/CN102351846B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0124495A2 (en) * | 1983-03-04 | 1984-11-07 | Aktiebolaget Hässle | Omeprazole salts |
| CN1261362A (en) * | 1997-06-27 | 2000-07-26 | 阿斯特拉公司 | Omeprazole sodium salt |
| CN1531533A (en) * | 2001-04-25 | 2004-09-22 | ������ҩ�뻯ѧ��˾ | Crystalline form of omeprazole |
Non-Patent Citations (2)
| Title |
|---|
| Fabio S. Murakami等.Physico-chemical solid-state characterization of omeprazole sodium: Thermal,spectroscopic and crystallinity studies.《Journal of Pharmaceutical and Biomedical Analysis》.2009,第49卷(第1期),72-80. * |
| FabioS.Murakami等.Physico-chemicalsolid-statecharacterizationofomeprazolesodium:Thermal spectroscopic and crystallinity studies.《Journal of Pharmaceutical and Biomedical Analysis》.2009 |
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