CN101744777B - Omeprazole sodium freeze-dried powder injection, as well as preparation method and quality control method thereof - Google Patents
Omeprazole sodium freeze-dried powder injection, as well as preparation method and quality control method thereof Download PDFInfo
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Abstract
The invention relates to omeprazole sodium freeze-dried powder injection, as well as a preparation method and a quality control method thereof, belonging to the technical field of medicines. In the invention, the stability of the medicament is improved by utilizing the combined application of an antioxidant and a chelator, adjusting the pH value of an intermediate solution in the preparation process to be in a certain range and controlling the temperature in each phase of the freeze-drying process. In addition, the quality control method of the omeprazole sodium freeze-dried powder injection is researched, and a quality control method with high sensitivity and strong specificity is established so that the quality of the omeprazole sodium freeze-dried powder injection can be well controlled.
Description
Technical field
The present invention relates to a kind of proton pump and suppress medicine and method for preparing and method of quality control, particularly omeprazole freeze-dried powder injection and method for preparing and method of quality control belong to medical technical field.
Background technology
Omeprazole Sodium is 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.Because H
+, K
+-ATP enzyme is last process that parietal cell secretes acid, so but these article sour ability are powerful.It can not only suppress the gastric acid secretion that gastrin, histamine, choline and food, vagus nerve stimulation etc. cause by noncompetitive, and can suppress not receive choline or H
2The part basal gastric acid secretion of receptor blocking agent influence is to H
2Receptor antagonist is untamed to stimulate the gastric acid secretion that causes that strong and persistent inhibitory action is also arranged by dibutyl cyclic adenosine monophosphate (DcAMP).These article also have inhibitory action to pepsinia, and are not obvious to the change of gastric mucosa blood flow, also do not influence body temperature, gastral cavity temperature, arteriotony, vein hemoglobin, art pO2, partial pressure of carbon dioxide and arterial blood ph.
Main Ingredients and Appearance is an Omeprazole Sodium, its chemical name: 5-methoxyl group-2-{ [(4-methoxyl group-3,5-dimethyl-2-pyridine radicals) methyl]-sulfinyl }-1H-benzimidazole sodium-hydrate.Molecular formula: C
17H
18N
3NaO
3SH
2O; Molecular weight: 385.41.
200610042004.1 in " a kind of stable omeprazol sodium preparation for injection " disclosed, point out to make adjuvant with mannitol and disodiumedetate, invented a kind of stable bland and need not be furnished with the injection omeprazole sodium of dedicated solvent.Use mannitol to make excipient in the said preparation, the solution particulate matter exceeded standard after the preparation that obtains redissolved, and did not meet existing injection basic standard.
200810001181.4 in " a kind of omeprazole freeze-dried powder injection and preparation method thereof " disclosed, protection be the method for preparing of its product, add sodium citrate solution and regulate pH value.
200810062160.3 in " a kind of omeprazole freeze-dried powder injection and method for preparing " disclosed; Guaranteed stability of formulation through adjuvant beta-schardinger dextrin-or HP-and sodium sulfite; Clarity; Variation with Borax-sodium carbonate buffer has been stablized pH value replaces disodiumedetate to alleviate the bone calcium loss with calcium disodium edetate.It is adjuvant that beta-schardinger dextrin-is adopted in this patent application; Be to guarantee stability of formulation through the effective ingredient Omeprazole Sodium of enclose medicine; But the effective ingredient of medicine is difficult for being released after getting into human body simultaneously, and the result causes the curative effect of medicine to reduce, and side effect strengthens.
The problem of the particulate matter of the omeprazole freeze-dried powder injection of listing and related substance perplexs the use of this product always at present; Adjuvant is the key factor that influences its particulate matter; Like mannitol, beta-schardinger dextrin-etc., if but be difficult to again guarantee without the mouldability of its medicine of adjuvant, stability.The inventor is surprised to find that and does not add excipient; Through antioxidant and chelating agen Combined application; Regulate in the preparation process midbody solution pH value in certain scope, and each phase temperature in the control freeze-drying process, Omeprazole Sodium the problems referred to above can be solved well.
Summary of the invention
An object of the present invention is to provide omeprazole freeze-dried powder injection;
Another object of the present invention provides the method for preparing of omeprazole freeze-dried powder injection;
Another object of the present invention provides the method for quality control of omeprazole freeze-dried powder injection.
The present invention mainly realizes through following technical scheme:
The injection omeprazole sodium lyophilized injectable powder is made up of active constituents of medicine Omeprazole Sodium, disodium edetate and anhydrous sodium sulfite.
Wherein the weight ratio of Omeprazole Sodium and disodium edetate is 28-85: 1, and preferred weight ratio is 56.8: 1.
Wherein the weight ratio of Omeprazole Sodium and anhydrous sodium sulfite is 21-85: 1, and preferred weight ratio is 42.6: 1.
The method for preparing of omeprazole freeze-dried powder injection is following:
Get the room temperature water for injection of recipe quantity about 90%, add disodium edetate and anhydrous sodium sulfite, be stirred to dissolving fully; Raw material is added, be stirred to dissolving fully; Detect the pH value of solution, and regulate pH value with NaOH solution; Add needle-use activated carbon, stirring and adsorbing is taken off charcoal, aseptic filtration; Add water for injection to recipe quantity; Intermediate check, fill; Lyophilizing, tamponade.
Its intermediate pH value of solution value scope is controlled at 9.5-12.0, is preferably between the 10.1-11.1, most preferably is 10.7-10.9.
The pre-freeze temperature is controlled at below-35 ℃ in the wherein cold dried process, and the temperature that once heats up is controlled at-3 ℃～8 ℃, and the secondary temperature elevation temperature is controlled at 28 ℃～42 ℃.
The method of quality control of omeprazole freeze-dried powder injection of the present invention is following:
Detection method of content:
Use octadecylsilane chemically bonded silica to be filler according to HPLC chromatographic condition and system suitability test; With acetonitrile-4-butyl ammonium hydrogen sulfate buffer (pH7.4)-phosphate buffer (pH7.4) (33-37: 4-8: 63-55) be mobile phase; The detection wavelength is 280nm; Theoretical cam curve is calculated by the omeprazole peak should be not less than 2000, and the separating degree of omeprazole peak and H168/66 impurity peaks should be not less than 3.0;
Algoscopy is got 5 preparation units of medicine of the present invention, and accurate the title decides, and inclining content; The accurate title, decided empty bottle weight, obtains average loading amount; It is an amount of that precision takes by weighing content, adds the diluent dissolving, processes need testing solution; It is an amount of to get the Omeprazole Sodium reference substance, and accurate the title decides, and adds diluent and processes reference substance solution; Get above-mentioned two kinds of solution, inject chromatograph of liquid respectively, the record chromatogram, promptly gets with calculated by peak area by external standard method.
Calculate by average loading amount, contain Omeprazole Sodium with omeprazole (C
17H
19N
3O
3S) meter should be 93.0%～107.0% of labelled amount.
The related substance detection method:
Use octadecylsilane chemically bonded silica to be filler; With acetonitrile-4-butyl ammonium hydrogen sulfate buffer (pH7.4)-phosphate buffer (pH7.4) (33-37: 4-8: 63-55) be mobile phase; The detection wavelength is 280nm; Theoretical cam curve is calculated by the omeprazole peak should be not less than 2000, and the separating degree of omeprazole peak and H168/66 impurity peaks should be not less than 3.0;
It is an amount of that precision takes by weighing medicine of the present invention, adds the diluent dissolving and process need testing solution; It is an amount of to measure need testing solution, adds diluent and processes prerun solution; Get prerun solution and inject chromatograph of liquid, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be about 10% of monitor full scale; Get need testing solution again and inject chromatograph of liquid, the 2-4 of record chromatogram to main constituent peak retention time doubly; Need testing solution chromatogram H168/66 impurity peaks must not be greater than 0.3% of total peak area; The peak area of maximum contaminant all must not be greater than 1.0% of total peak area; The peak area of total impurities must not be greater than 2.5% of total peak area.
The method of quality control of omeprazole sodium medicinal composition for injection lyophilized injectable powder of the present invention is preferably following:
Detection method of content:
Use octadecylsilane chemically bonded silica to be filler according to HPLC chromatographic condition and system suitability test; With acetonitrile-4-butyl ammonium hydrogen sulfate buffer (pH7.4)-phosphate buffer (pH7.4) (35: 6: 59) is mobile phase; The detection wavelength is 280nm; Theoretical cam curve is calculated by the omeprazole peak should be not less than 2000, and the separating degree of omeprazole peak and H168/66 impurity peaks should be not less than 3.0;
Algoscopy is got 5 bottles of medicines of the present invention, and accurate the title decides, and inclining content; The accurate title, decided empty bottle weight, obtains average loading amount; It is an amount of that precision takes by weighing content, adds the diluent dissolving and process the solution that contains omeprazole 0.1mg among every 1ml approximately, as need testing solution; It is an amount of to get the Omeprazole Sodium reference substance, and accurate the title decides, and adds diluent and processes the solution that contains 0.1mg among every 1ml approximately, as reference substance solution; Get each 20 μ l of above-mentioned two kinds of solution, inject chromatograph of liquid respectively, the record chromatogram, with calculated by peak area, the result multiply by 0.940 again, promptly gets by external standard method;
Calculate by average loading amount, contain Omeprazole Sodium with omeprazole (C
17H
19N
3O
3S) meter should be 93.0%～107.0% of labelled amount.
Related substance:
Use octadecylsilane chemically bonded silica to be filler; With acetonitrile-4-butyl ammonium hydrogen sulfate buffer (pH7.4)-phosphate buffer (pH7.4) (35: 6: 59) is mobile phase; The detection wavelength is 280nm; Theoretical cam curve is calculated by the omeprazole peak should be not less than 2000, and the separating degree of omeprazole peak and H168/66 impurity peaks should be not less than 3.0;
It is an amount of that precision takes by weighing drug substance contents of the present invention, adds the diluent dissolving and process the solution that contains omeprazole 0.1mg among every 1ml approximately, as need testing solution; It is an amount of to measure need testing solution, adds diluent and processes the solution that contains omeprazole 1 μ g among every 1ml, as prerun solution; Get prerun solution 20 μ l and inject chromatograph of liquid, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be about 10% of monitor full scale; Get need testing solution 20 μ l injection chromatograph of liquid again, 3 times of writing down chromatogram to main constituent peak retention time.Need testing solution chromatogram H168/66 impurity peaks must not be greater than 0.3% of total peak area; The peak area of maximum contaminant all must not be greater than 1.0% of total peak area; The peak area of total impurities must not be greater than 2.5% of total peak area.
Wherein test used buffer:
(1) phosphate buffer (pH7.4): get sodium dihydrogen phosphate (NaH
2PO
4H
2O) 0.166g and sodium hydrogen phosphate (Na
2HPO
412H
2O) 1.074g adds water and makes dissolving and be diluted to 1000ml, and pH value should be 7.4, promptly gets.
(2) 4-butyl ammonium hydrogen sulfate buffer (pH7.4): get 4-butyl ammonium hydrogen sulfate 6.78g and sodium hydroxide 0.8g, add phosphate buffer (pH7.4) and make dissolving and be diluted to 1000ml, promptly get.
(3) phosphate buffer (pH11.0): get sodium dihydrogen phosphate (NaH
2PO
4H
2O) 0.34g and sodium hydrogen phosphate (Na
2HPO
412H
2O) 0.63g is dissolved in water and is diluted to 1000ml, regulates pH value to 11.0 with phosphoric acid, promptly gets.
(4) diluent: get acetonitrile 200ml, add phosphate buffer (pH11.0) and be diluted to 1000ml, promptly get (needing fresh).
The screening of the inventor through writing out a prescription in the omeprazole freeze-dried powder injection; The Combined application of antioxidant and chelating agen; The control of midbody solution pH value, lowest total of the melting point gropes creative works such as the control of lyophilisation condition in the freeze-drying process; Solved omeprazole freeze-dried powder injection particulate matter and related substance problem well, made its formulation content, related substance all better than prior art.And invented a kind of highly sensitive, specificity is strong, precision good, the method for quality control of good stability, can control the quality of medicine of the present invention well.
Beneficial technical effects
Following experimental example and embodiment are used to further specify but are not limited to the present invention.
The selection of Test Example 1 excipient
The condition held of quickening (at 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%) 3 months, investigate the variation of each item indexs such as content, related substance, character, mouldability, particulate matter of sample.
By following prescription, take by weighing supplementary material respectively, get the room temperature water for injection of recipe quantity about 90%, adds following shown in adjuvant, be stirred to fully and dissolve.Add Omeprazole Sodium, be stirred to dissolving fully.Detect the pH value of solution, and with NaOH solution adjust pH to 10.5; Add the needle-use activated carbon of 0.1% (W/V), stirring and adsorbing 20 minutes is taken off charcoal, aseptic filtration; Add water for injection to recipe quantity; Intermediate check, fill; Lyophilizing, check.The result sees the following form:
The selection of excipient
Can be known by result of the test: it is all defective that prescription 1-6 contains the particulate matter of preparation of mannitol, dextran, lactose.Prescription 7 does not add the particulate matter that adjuvant then obviously improves preparation; And do not influence its dried frozen aquatic products mouldability; But there are problems such as unstable, easy oxidation in the Omeprazole Sodium medicine; Therefore, do not add excipient in the preliminary affirmation prescription, further investigate the improvement situation of antioxidant that add content, related substance.
The selection of Test Example 2 antioxidant
The condition held of quickening (at 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%) 3 months, investigate the variation of each item indexs such as content, related substance, character, particulate matter of sample.
By following prescription, take by weighing supplementary material respectively, get the room temperature water for injection of recipe quantity about 90%, adds following shown in adjuvant, be stirred to fully and dissolve.Add Omeprazole Sodium, be stirred to dissolving fully.Detect the pH value of solution, and with NaOH solution adjust pH to 10.5; Add the needle-use activated carbon of 0.1% (W/V), stirring and adsorbing 20 minutes is taken off charcoal, aseptic filtration; Add water for injection to recipe quantity; Intermediate check, fill; Lyophilizing, check.The result sees the following form:
The selection of antioxidant
Can know by result of the test: acceleration environment held 3 months; Preparation related substance and changes of contents that prescription 1-5 adding antioxidant obtains are not obvious; The variation of 2,5 related substances of wherein writing out a prescription is less, writes out a prescription 5 to add mannitol to obtain preparation particulate matter item against regulation, though prescription 6 is unqualified with the preparation particulate matter that mannitol and antioxidant obtain; But through the acceleration environment held after 3 months related substance increase obviously, verify that further particulate matter is relevant with the adding excipient.Comprehensive above explanation adds antioxidant and can obviously improve medicine stability in prescription, the variation that wherein adds the preparation related substance that anhydrous sodium sulfite obtains is less, therefore, best with anhydrous sodium sulfite.
The selection of Test Example 3 metal ion chelation agents
The condition held of quickening (at 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%) 3 months, investigate the variation of each item indexs such as content, related substance, character, particulate matter of sample.
Medicine of the present invention is a sterile freeze-drying preparation, and in order to prevent the catalytic action of metal ion to the medicine autoxidation, we have added a certain amount of metal ion chelation agent in preparation of the present invention.
By following prescription, take by weighing supplementary material respectively, get the room temperature water for injection of recipe quantity about 90%, adds following shown in adjuvant, be stirred to fully and dissolve.Add Omeprazole Sodium, be stirred to dissolving fully.Detect the pH value of solution, and with NaOH solution adjust pH to 10.5; Add the needle-use activated carbon of 0.1% (W/V), stirring and adsorbing 20 minutes is taken off charcoal, aseptic filtration; Add water for injection to recipe quantity; Intermediate check, fill; Lyophilizing, check.The result sees the following form:
The selection of metal ion chelation agent
Can be known by result of the test: add the prescription 1,2 of chelating agen, 3 months related substances of acceleration environment held remain unchanged basically, and 2 optimums of writing out a prescription; And that prescription 5 related substances that only add the prescription 3,4 of chelating agen and only add antioxidant change is comparatively obvious, surpasses 3%, so medicament selection disodium edetate of the present invention is optimum as chelating agen, and with antioxidant anhydrous sodium sulfite Combined application.
The selection of Test Example 4 antioxidant consumptions
The condition held of quickening (at 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%) 3 months, investigate the variation of each item indexs such as pH value, content, related substance, character of sample.
Shown in Omeprazole Sodium 42.6g, disodium edetate 1.0g, the anhydrous sodium sulfite according to the form below, water for injection 1000ml.Get the room temperature water for injection of recipe quantity about 90%, add disodium edetate and anhydrous sodium sulfite, be stirred to dissolving fully.Add Omeprazole Sodium, be stirred to dissolving fully.Detect the pH value of solution, and with NaOH solution adjust pH to 10.5; Add the needle-use activated carbon of 0.1% (W/V), stirring and adsorbing 20 minutes is taken off charcoal, aseptic filtration; Add water for injection to recipe quantity; Intermediate check, fill; Lyophilizing, check.The result sees the following form
The selection of antioxidant consumption
Can be known by result of the test: adding 3 months related substances of anhydrous sodium sulfite 0.1g prescription acceleration environment held increases obviously, surpasses 2.5%.Add other amount anhydrous sodium sulfite preparation related substances and do not have significant change.Take all factors into consideration clinical drug safety property, the weight ratio of Omeprazole Sodium and anhydrous sodium sulfite is 21-85: 1, and preferred weight ratio is 42.6: 1.
The selection of Test Example 5 metal ion chelation agent consumptions
The condition held of quickening (at 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%) 3 months, investigate the variation of each item indexs such as pH value, content, related substance, character of sample.
Shown in Omeprazole Sodium 42.6g, the disodium edetate according to the form below, anhydrous sodium sulfite 1.0g, water for injection 1000ml.Get the room temperature water for injection of recipe quantity about 90%, add disodium edetate and anhydrous sodium sulfite, be stirred to dissolving fully.Add Omeprazole Sodium, be stirred to dissolving fully.Detect the pH value of solution, and with NaOH solution adjust pH to 10.5; Add the needle-use activated carbon of 0.1% (W/V), stirring and adsorbing 20 minutes is taken off charcoal, aseptic filtration; Add water for injection to recipe quantity; Intermediate check, fill; Lyophilizing, check.The result sees the following form
The selection of metal ion chelation agent consumption
Can know by result of the test: acceleration environment held 3 months, add the 0.1g disodium edetate, its related substance increases obviously, surpasses 2.5%.0.5-1.5g the disodium edetate related substance change little.Take all factors into consideration clinical drug safety property, the weight ratio of Omeprazole Sodium and disodium edetate is 28-85: 1, and preferred weight ratio is 56.8: 1.
The selection of Test Example 6 needle-use activated carbons
Omeprazole Sodium 42.6g, disodium edetate 0.75g, anhydrous sodium sulfite 1.0g, water for injection 1000ml.Get the room temperature water for injection of recipe quantity about 90%, add disodium edetate and anhydrous sodium sulfite, be stirred to dissolving fully.Add Omeprazole Sodium, be stirred to dissolving fully.Detect the pH value of solution, and with NaOH solution adjust pH to 10.5; The needle-use activated carbon that adds dosing amount 0.1%, 0.2% (W/V) respectively makes an experiment, and stirring and adsorbing 20 minutes is taken off charcoal, aseptic filtration; Add water for injection to recipe quantity; Intermediate check, fill; Lyophilizing, check.Investigate it to the improvement situation of clarity and whether obvious to principal agent absorption.
The screening of needle-use activated carbon consumption
Can be known by result of the test: the active carbon of two kinds of consumptions all has absorption to principal agent; Wherein use 0.2% active carbon more obvious; For the clarity that guarantees pyrogen and solution is qualified, we select to use 0.1% active carbon to remove pyrogen and improve the clarity of solution.
Confirming of Test Example 7pH value scope
The condition held of quickening (at 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%) 3 months, investigate the variation of each item indexs such as pH value, content, related substance, character of sample.
Omeprazole Sodium 42.6g, disodium edetate 0.75g, anhydrous sodium sulfite 1.0g, water for injection 1000ml.Get the room temperature water for injection of recipe quantity about 90%, add disodium edetate and anhydrous sodium sulfite, be stirred to dissolving fully.Add Omeprazole Sodium, be stirred to dissolving fully.Detect the pH value of solution, and with NaOH solution adjust pH to shown in the following table; Add the needle-use activated carbon of 0.1% (W/V), stirring and adsorbing 20 minutes is taken off charcoal, aseptic filtration; Add water for injection to recipe quantity; Intermediate check, fill; Lyophilizing, check.The result sees the following form:
Confirming of pH value scope
Can be known by result of the test: omeprazole freeze-dried powder injection surpasses prescribed limit when pH value is lower than 9.5 related substances, and better in 9.5 above each item indexs at pH value, related substance does not have significant change in the pH value 10.7-10.9 scope.Comprehensive human tolerance controls its pH value between 9.5-12.0, and between the preferred 10.1-11.1, most preferably pH value is 10.7-10.9.
Through hemolytic test and vascular stimulation test, prove that this preparation does not have haemolysis in this pH value scope, blood vessel there is not any zest.
The mensuration of Test Example 8 lowest total of the melting point
Adopt the method for cooling reheat earlier, can avoid occurring surfusion like this, the eutectic point of being surveyed is more accurate.Through test determination, the lowest total of the melting point of Omeprazole Sodium is-4.5 ℃, thereby the pre-freeze investigation temperature of confirming freeze-dry process is below-35 ℃.
The screening of Test Example 9 freeze-dry process
Lyophilization is divided into three phases: pre-freeze, cryogenic vacuum distillation, high temperature drying.Designed the selection that experimentizes of three kinds of lyophilization conditions according to freeze-drying process, freeze drying box vacuum is evacuated to below the 10Pa, different lyophilizing results see the following form:
Can be known by result of the test: the sample each item index according to freeze-dry process 3 preparation is better, and sample mouldability, the dissolubility of technology 1,2 preparations are relatively poor, so our preferred freeze-dry process 3, and its freeze-dry process is:
The case refrigeration is reduced to below-25 ℃ products temperature before opening, and the time is about 2～3hr; Open the rear cabinet refrigeration and condenser temperature is reduced to-35 ℃; Freeze drying box vacuum is evacuated to below the 10Pa; Once heat up: setting the conduction oil temperature is-3 ℃～8 ℃; After the conduction oil temperature reached design temperature 2～5hr, every separated 2hr improved 1 ℃～2 ℃ of conduction oil temperature, all crosses 0 ℃ up to all products temperatures, continues insulation 2～6hr, once distils and finishes; It is 28 ℃～42 ℃ that secondary temperature elevation is set the conduction oil temperature; When the conduction oil temperature curve is parallel with the products temperature curve, continue insulation 2～3hr, lyophilizing finishes; Lyophilizing is carried out tamponade after finishing.
The selection of Test Example 10 related substance detection methods
For the end product quality that makes is controlled better, plan employing high-efficient liquid phase technique (two appendix V of Chinese Pharmacopoeia version in 2005 D) is checked the related substance of the sample that the embodiment of the invention 1 makes, and has been carried out relevant methodological study.
1 chromatographic condition
Instrument: Tianjin, island LC-10Atvp high performance liquid chromatograph, SPD-10Avp UV, visible light detector, Anastar chromatographic work station.
Reagent: acetonitrile (chromatographically pure); Sodium dihydrogen phosphate (analytical pure); Sodium hydrogen phosphate (analytical pure); Sodium phosphate (analytical pure); 4-butyl ammonium hydrogen sulfate (analytical pure); Redistilled water.
Chromatographic condition: (4.6mm * 150mm, 5 μ m) are immobile phase with octadecylsilane chemically bonded silica, are mobile phase with acetonitrile-4-butyl ammonium hydrogen sulfate buffer (pH7.4)-phosphate buffer (pH7.4) (35: 6: 59), and the detection wavelength is 280nm.
The used buffer of 2 tests
(1) phosphate buffer (pH7.4): get sodium dihydrogen phosphate (NaH
2PO
4H
2O) 0.166g and sodium hydrogen phosphate (Na
2HPO
412H
2O) 1.074g adds water and makes dissolving and be diluted to 1000ml, and pH value should be 7.4, promptly gets.
(2) 4-butyl ammonium hydrogen sulfate buffer (pH7.4): get 4-butyl ammonium hydrogen sulfate 6.78g and sodium hydroxide 0.8g, add phosphate buffer (pH7.4) and make dissolving and be diluted to 1000ml, promptly get.
(3) phosphate buffer (pH11.0): get sodium dihydrogen phosphate (NaH
2PO
4H
2O) 0.34g and sodium hydrogen phosphate (Na
2HPO
412H
2O) 0.627g is dissolved in water and is diluted to 1000ml, regulates pH value to 11.0 with phosphoric acid, promptly gets.
(4) diluent: get acetonitrile 200ml, add phosphate buffer (pH11.0) and be diluted to 1000ml, promptly get (needing fresh).
The test of 3 system suitabilitys
It is an amount of to get the embodiment of the invention 1 sample, processes the solution that contains 0.1mg/ml approximately with diluent, by above-mentioned chromatographic condition, and sample introduction 20 μ l.Omeprazole peak retention time is 6.497 minutes, and number of theoretical plate is 6676, and the separating degree of main peak and adjacent impurity peaks is respectively 3.404,7.452.
The regulation number of theoretical plate calculates by the omeprazole peak should be not less than 2000, and main peak and adjacent impurity peaks separating degree are greater than 3.0.
4.1 the failure test of raw material
It is an amount of to get the omeprazole sodium raw materials, adds diluent and processes the solution that 1ml contains 0.2mg approximately, as need testing solution A.
Acid destroys: get need testing solution A5ml, drip 5 of concentrated hydrochloric acid, in 60 ℃ of baking ovens, placed 3 hours, taking-up is put cold, regulates pH value to neutral with saturated sodium hydroxide solution, filters sample introduction 20 μ l.
Alkali destroys: get need testing solution A5ml, drip 5 of saturated sodium hydroxide solutions, in 60 ℃ of baking ovens, placed 3 hours, taking-up is put cold, regulates pH value to neutral with concentrated hydrochloric acid, filters sample introduction 20 μ l.
Oxidation destroys: get need testing solution A5ml, drip 5 of potassium permanganate solutions, in 60 ℃ of baking ovens, placed 3 hours, taking-up is put cold, filters sample introduction 20 μ l.
High temperature destroys: get need testing solution A5ml, be positioned over 60 ℃ of baking ovens interior 8 hours, taking-up is put cold, filters, and gets subsequent filtrate 20 μ l sample introductions.
Illumination destroys: get need testing solution A5ml, 4500LX illumination held 12 hours, take out and put coldly, filter, get subsequent filtrate 20 μ l sample introductions.
4.2 the failure test of sample:
It is an amount of to get the sample that the embodiment of the invention 1 makes, and adds diluent and processes and contain 0.2mg solution among every 1ml approximately, as need testing solution B.
Sample acid destroys the product preparation: get need testing solution B 10ml, add 5 of concentrated hydrochloric acid, be positioned over 60 ℃ of baking ovens interior 3 hours, taking-up is put cold, regulates pH value to neutral with saturated sodium hydroxide solution, and subsequent filtrate 20 μ l sample introductions are got in filtration.
Sample alkali destroys the product preparation: get need testing solution B 10ml, add 5 of saturated sodium hydroxide solutions, be positioned over 60 ℃ of baking ovens interior 3 hours, taking-up is put cold, regulates pH value to neutral with concentrated hydrochloric acid, and subsequent filtrate 20 μ l sample introductions are got in filtration.
The sample oxidation destroys the product preparation: get need testing solution B 10ml, add 5 of potassium permanganate solutions, be positioned over 60 ℃ of baking ovens interior 3 hours, taking-up is put cold, filters, and gets subsequent filtrate 20 μ l sample introductions.
High-temperature sample destroys the product preparation: get need testing solution B 10ml, be positioned over 60 ℃ of baking ovens interior 8 hours, taking-up is put cold, filters, and gets subsequent filtrate 20 μ l sample introductions.
Sample illumination destroys the product preparation: get need testing solution B 10ml, 4500LX illumination held 12 hours, take out and put coldly, filter, get subsequent filtrate 20 μ l sample introductions.
The preparation of soda acid blank solvent: get the about 5ml of diluent, add 5 of concentrated hydrochloric acid, be positioned over 60 ℃ of baking ovens interior 3 hours, taking-up is put cold, regulates pH value to neutral with saturated sodium hydroxide solution, and subsequent filtrate 20 μ l sample introductions are got in filtration.
The preparation of adjuvant blank solution: press the preparation prescription amount, remove outside the principal agent, add diluent and process blank adjuvant solution, sample introduction 20 μ l, record chromatogram.Know that by chromatogram adjuvant does not have absorption basically.See accompanying drawing 18.
The preparation of blank solvent: get diluent 20 μ l sample introductions.
Can be known that by above-mentioned destruction product raw material and sample all have catabolite to generate under acid, alkali, oxidation, high temperature, illumination condition, each catabolite all can reach preferably with the main constituent peak and separate.Blank assay shows that adjuvant does not disturb the mensuration of principal agent.Result of the test shows that this chromatographic condition can satisfy the requirement of the related substance inspection of pharmaceutical composition of the present invention.
Analyze above-mentioned blank solvent and adjuvant; The result shows that blank solvent and adjuvant peak are all before 2min; And the catabolite of omeprazole is all after 2min; Adjuvant does not disturb the determination of related substances of main constituent, so when calculating related substance, be about except the blank solvent and adjuvant peak before 0.31 with the RRT of Omeprazole Sodium peak.
5 minimum detectable activities detect
Precision takes by weighing Omeprazole Sodium 10.8mg, by omeprazole 9.6mg, adds the concentration that diluent dissolves and process about 0.002mg/ml; Precision is measured 5ml and is put in the 100ml volumetric flask, with the diluent dissolving and be diluted to scale, shakes up; Get this solution 20 μ l sample introductions, the record chromatogram.Winner's peak-to-peak area is 1754, and peak height is about 3 times of baseline noise, and therefore calculating minimum detectable activity is 1.92ng.
The location of 6H168/66 impurity peaks
It is an amount of that precision takes by weighing H168/66 impurity reference substance, add diluent dissolving and process the concentration of 1mg/ml, precision measure in right amount with diluent process contain 0.6 μ g among every 1ml solution as contrast solution, get contrast solution 20 μ l and inject chromatograph of liquid.The appearance time at H 168/66 peak is 9.162min, and it is an amount of that other gets the omeprazole sodium raw materials, add diluent process contain omeprazole 0.1mg among every 1ml solution as need testing solution, get need testing solution 20 μ l and inject chromatograph of liquid.The retention time at omeprazole peak is at 6.360min.Get H168/66 reference substance solution (concentration of 1mg/ml) and add in right amount in the need testing solution, get this solution sample introduction 20 μ l.The retention time at omeprazole peak is at 6.317min, and the retention time at H168/66 peak is 9.108min, calculates the peak of H168/66 and the RRT of main peak and is about 1.44, and the separating degree of the two is 4.771.
The minimum detectable activity of 7H168/66 impurity peaks
Precision takes by weighing H168/66 impurity reference substance 10.2mg; Add the concentration that diluent dissolves and process 1mg/ml; Precision measure in right amount with diluent process contain 0.6 μ g among every 1ml solution as contrast solution, precision is measured 1ml and is put in the 10ml volumetric flask, with the diluent dissolving and be diluted to scale; Shake up, get this solution 20 μ l sample introductions.Winner's peak-to-peak area is 1070, and peak height is about 3 times of baseline noise, and therefore calculating minimum detectable activity is 1.224ng.
The limit of 8H168/66 impurity
Stipulate in the omeprazole freeze-dried powder injection method of quality control: the H168/66 peak area must not be greater than 1.0% of total peak area; Greater than 0.3% of total peak area, then use external standard method like the peak area of H168/66 with calculated by peak area.Pharmaceutical composition accelerated test and long term test are investigated the result according to the present invention, and limit is decided to be: be about 1.44 places as showing impurity peaks with the main peak RRT, its peak area must not be greater than 0.3% of total peak area.
9 determination of related substances methods
It is an amount of to get the sample contents that the embodiment of the invention 1 makes, and adds the diluent dissolving and processes the solution that contains omeprazole 0.1mg among every 1ml approximately, as need testing solution; It is an amount of to measure need testing solution, adds diluent and processes the solution that contains 1 μ g among every 1ml approximately, as prerun solution.Get prerun solution 20 μ l and inject chromatograph of liquid, regulate detection sensitivity, make the peak height of main constituent chromatographic peak be about 10% of full scale; Get need testing solution 20 μ l injection chromatograph of liquid again, 3 times of writing down chromatogram to main constituent peak retention time.The need testing solution chromatogram is as showing impurity peaks (being about except the adjuvant peak before 0.31 with the main peak RRT), and H 168/66 impurity peaks (being about 1.44 impurity peaks with the main peak RRT) must not be greater than 0.3% of total peak area; The peak area of other single impurity all must not be greater than 1.0% of total peak area; The peak area of total impurities must not be greater than 2.5% of total peak area.
The selection of Test Example 11 content assaying methods
The employing high-efficient liquid phase technique is checked the content of the sample that the embodiment of the invention 1 makes, and has been carried out methodological study.
1 content measuring standard curve
Precision takes by weighing Omeprazole Sodium reference substance 28.2mg (moisture 5.26%, content 100.02%), by omeprazole 25.1mg; Put in the 50ml measuring bottle; Add the diluent dissolving and be diluted to scale, shake up, accurately measure 0.5ml, 1.0ml, 1.5ml, 2.0ml, 3.0ml, 4.0ml respectively and place the 10ml volumetric flask respectively; Add diluent to scale, shake up.Get each solution 20 μ l respectively, inject chromatograph of liquid.The result sees the following form.
Assay linear relationship result of the test
| Concentration C (μ g/ml) | 25.1 | 50.2 | 75.3 | 100.4 | 150.6 | 200.8 |
| Peak area 1 | 693283 | 1404651 | 2107357 | 2882945 | 4332152 | 5772401 |
| Peak area 2 | 694794 | 1407875 | 2112694 | 2876575 | 4341302 | 5786550 |
| Average peak area | 694039 | 1406263 | 2118031 | 2879760 | 4336727 | 5779476 |
With peak area A concentration C (μ g/ml) is carried out linear regression, must linear equation be:
A＝2.9042×104C-47607 R＝0.9999
Result of the test shows omeprazole peak area A and solution concentration C in 25.1～200.8 μ g/ml scope internal linear relation better.
The test of 2 precision
It is an amount of that precision takes by weighing the sample that the embodiment of the invention 1 makes, and adds diluent dissolving and dilution and process the solution that every 1ml contains omeprazole 0.1mg approximately, shakes up, as need testing solution; Precision is measured 20 μ l and is injected chromatograph of liquid, and sample introduction is 6 times respectively.Mensuration result sees the following form.
Assay precision test data
| Number of times | ?1 | 2 | 3 | 4 | 5 | 6 |
| Peak area | ?2853994 | 2827125 | 2835598 | 2863500 | 2828980 | 2833289 |
Average peak area is 2840414, and RSD is 0.52%.Explain that the method precision is better.
3 stability tests
It is an amount of that precision takes by weighing the sample that the embodiment of the invention 1 makes, and adds diluent dissolving and dilution and process the solution that every 1ml contains omeprazole 0.1mg approximately, shakes up, as need testing solution; Respectively at 0,1,2,4,6,8 hour, precision was measured 20 μ l, injected chromatograph of liquid.Mensuration result sees the following form.
Assay stability test data
| Time (h) | 0 | 1 | 2 | 4 | 6 | 8 |
| Peak area A | 2857224 | 2856715 | 2837542 | 2845554 | 2878286 | 2857088 |
Meansigma methods is 2855402, and RSD=0.48% shows this law repeatability better.
4 recovery tests
By recipe quantity 80.0%, 100.0% and 120.0% respectively precision take by weighing Omeprazole Sodium reference substance and other adjuvants, put in the 250ml volumetric flask, add diluent dissolving and be diluted to scale, shake up, as need testing solution; It is an amount of that other precision takes by weighing the Omeprazole Sodium reference substance, adds diluent and process the solution that the every 1ml of concentration contains omeprazole 0.1mg approximately, gets each 20 μ l of above-mentioned solution respectively, injects chromatograph of liquid, calculates by external standard method, gets the Omeprazole Sodium response rate.
Assay recovery test data
Mensuration average recovery rate as a result is 100.04%, and RSD is 0.35%, and it is better that the result shows that high-efficient liquid phase technique is measured the pharmaceutical composition response rate of the present invention, and adjuvant does not influence principal agent and measures.
Experimental example 12 stability tests
1, sample and reagent source: injection omeprazole sodium, make 3 batches by oneself according to embodiment 1 said prescription and technology, lot number is respectively: AZ1, AZ2, AZ3; The Omeprazole Sodium reference substance is available from Nat'l Pharmaceutical & Biological Products Control Institute.
2, test method:
(1) accelerated stability test: get 3 lot sample article respectively, press commercially available back, 40 ℃ ± 2 ℃ of temperature, the condition held of relative humidity 75% ± 5% 6 months respectively at sampling in 1,2,3,6 month, is investigated character, pH value, related substance, content.The result sees the following form
The accelerated stability test result
Can be known by result of the test: medicine of the present invention is through accelerated test 6 months, the testing result of investigating project with relatively had no significant change in 0 month, explain that medicine of the present invention stablizes under above-mentioned experimental condition.
(2) long-term stable experiment: press commercially available back, 25 ℃ ± 2 ℃ of temperature, the condition held of relative humidity 60% ± 10% 12 months respectively at sampling in 0,3,6,9,12,18,24 month, is investigated character, pH value, related substance, content with sample.The result sees the following form
The long-term stable experiment result
Can be known by result of the test: medicine of the present invention is investigated 24 months through long term test, the testing result of investigating project with relatively had no significant change in 0 month, explain that medicine of the present invention stablizes under above-mentioned experimental condition.
(3) stability test of compatibility
Get the finished product that makes by embodiment 1 prescription and technology, join respectively among 5% glucose solution and the 0.9% sodium chloride injection 100ml, shake up, as simulation compatibility solution A, B.
Behind the character of checking simulation compatibility solution A in 0,1,2,4,6,8 hour, clarity, pH value, precision is measured simulation solution A 2.5ml, is diluted to 10ml with 5% glucose, shakes up, as need testing solution A; Get 5% glucose injection as blank solution A.
Behind the character of checking simulation compatibility solution B in 0,1,2,4,6,8 hour, clarity, pH value, precision is measured simulation solution B 2.5ml, is diluted to 10ml with 0.9% sodium chloride, shakes up, as need testing solution B.Get 0.9% sodium chloride injection as blank solution B.
Get above-mentioned each solution 20 μ l sample introduction respectively.The relatively variation of its character, clarity, pH value, main peak area, related substance (area normalization method), 5 hydroxymethyl furfural is as the index of weighing stability.
5 hydroxymethyl furfural: it is an amount of that precision takes by weighing the 5 hydroxymethyl furfural reference substance; Water is processed the solution that contains 3 μ g among every 1ml; As reference substance solution, get this solution 20 μ l sample introductions, the retention time of 5 hydroxymethyl furfural chromatographic peak is at 2.148min; Do not disturb the mensuration of main constituent, the 5 hydroxymethyl furfural peak area is 848573.Investigate 5 hydroxymethyl furfural so adopt high-efficient liquid phase technique.Assay method: get need testing solution 20 μ l sample introductions, as showing the chromatographic peak of 5 hydroxymethyl furfural, its peak area must not be greater than 5 times (reference substance solution be converted to 5% glucose injection) of reference substance solution main peak peak area among the need testing solution A.
5% glucose injection compatibility stability test data
0.9% sodium chloride injection compatibility stability test data
The average main peak area of the compatibility solution of 5% glucose injection is 3082598, and RSD is 0.30%; Average related substance is 1.997%; Average 5 hydroxymethyl furfural peak area is 292522, and RSD is 2.83%; It is basicly stable that other investigates index.The result shows that omeprazole freeze-dried powder injection is basicly stable in 6 hours in 5% glucose injection.Its compatibility can satisfy the clinical compatibility needs.
The average main peak area of the compatibility solution of sodium chloride injection is 2752755, and RSD is 0.27%; Average related substance is 2.085%.The result shows that omeprazole freeze-dried powder injection is basicly stable in 8 hours in sodium chloride injection.Its compatibility can satisfy the clinical compatibility needs.
Test Example 13 contrast tests
Comparative sample 1
Omeprazole Sodium 40g
Water for injection adds to 2000ml
Process 1000 bottles after the lyophilizing
The Omeprazole Sodium of recipe quantity is added in the dosing cylinder, add 1500ml water for injection and be stirred to dissolving fully, reuse 0.05mol/L sodium citrate solution is regulated pH to 10.5, adds water for injection to recipe quantity.Add the needle-use activated carbon of total amount 0.05%, stirred 15 minutes, filter decarburization, medicinal liquid with 0.22 μ m degerming microporous filter membrane fine straining, is measured pH value, content, false add plug.Carry out lyophilization at last: earlier medicine is reduced to-22.5 ℃ from room temperature, be incubated after 30 minutes, continued to be cooled under-45 ℃ the temperature conditions pre-freeze then 3 hours; Then medicine is warming up to-25 ℃ from-45 ℃, is incubated 12 hours, reduced vacuum is dry under-25 ℃～10 ℃ conditions then, this process altogether the time be 24 hours, at last 35 ℃ of high temperature dryings 7 hours, tamponade, roll lid, examine and be packaged into warehouse for finished product after qualified entirely.
Comparative sample 2
Omeprazole Sodium 44.63g
Mannitol 200g
Water for injection adds to 3000ml
Process 1000 bottles after the lyophilizing
The Omeprazole Sodium and the mannitol supplementary material of recipe quantity are added in the dosing cylinder, add 2500ml water for injection and be stirred to dissolving fully, reuse 0.1mol/L sodium citrate solution is regulated pH to 10.3, adds water for injection to 3000ml, the solution after obtaining diluting.In said solution, add the needle-use activated carbon that accounts for dilution back solution weight 0.05%, stirred 20 minutes, filter decarburization, obtain filtrating, will filtrate again, measure pH value, content, false add plug with 0.22 μ m degerming microporous filter membrane fine straining.Lyophilization: earlier medicine is reduced to-22.5 ℃ from room temperature, be incubated after 45 minutes, continued to be cooled under-45 ℃ the temperature conditions pre-freeze then 2 hours; Then medicine is warming up to-26 ℃ from-45 ℃, is incubated 10 hours, reduced vacuum is dry under-26 ℃～10 ℃ conditions then, this process altogether the time be 28 hours, at last 35 ℃ of high temperature dryings 8 hours, tamponade, roll lid, examine and be packaged into warehouse for finished product after qualified entirely.
Comparative sample 3
According to embodiment 1 prescription and prepared sample, obtain comparative sample 3.
Can be known by result of the test: comparative sample 1,2 long-term 12 months content and related substances have significant change; Comparative sample 3 accelerated tests 6 months, 12 months related substance of long term test do not have significant change.
Following embodiment all can realize the described effect of above-mentioned experimental example
Following concrete embodiment further describes the present invention, but described embodiment only is used to explain the present invention rather than restriction the present invention.
Embodiment 1
Omeprazole Sodium 42.6g
Disodium edetate 0.75g
Anhydrous sodium sulfite 1.0g
Water for injection adds to: 1000ml
Make 1000 altogether
Prepare, get the room temperature water for injection of recipe quantity about 90%, add disodium edetate and anhydrous sodium sulfite, be stirred to dissolving fully.Raw material is added, be stirred to dissolving fully.Detect the pH value of solution, and transfer in the scope 10.7 with NaOH solution; Add the needle-use activated carbon of 0.1% (W/V), stirring and adsorbing 20 minutes is taken off charcoal, aseptic filtration; Add water for injection to recipe quantity; Intermediate check, fill;
The case refrigeration is reduced to below-25 ℃ products temperature before opening, and the time is about 2～3hr; Opening the rear cabinet refrigeration is reduced to condenser temperature below-35 ℃; Freeze drying box vacuum is evacuated to below the 10Pa; Once heat up: setting the conduction oil temperature is-3 ℃～8 ℃; After the conduction oil temperature reached design temperature 2～5hr, every separated 2hr improved 1 ℃～2 ℃ of conduction oil temperature, all crosses 0 ℃ up to all products temperatures, continues insulation 2～6hr, once distils and finishes; It is 28 ℃～42 ℃ that secondary temperature elevation is set the conduction oil temperature; When the conduction oil temperature curve is parallel with the products temperature curve, continue insulation 2～3hr, lyophilizing finishes; Lyophilizing is carried out tamponade after finishing.
Detection method of content:
Use octadecylsilane chemically bonded silica to be filler according to HPLC chromatographic condition and system suitability test; With acetonitrile-4-butyl ammonium hydrogen sulfate buffer (pH7.4)-phosphate buffer (pH7.4) (35: 6: 59) is mobile phase.The detection wavelength is 280nm.Theoretical cam curve is calculated by the omeprazole peak should be not less than 2000, and the separating degree of omeprazole peak and H168/66 impurity peaks should be not less than 3.0.
Algoscopy is got 5 bottles of these article, and accurate the title decides, and inclining content; The accurate title, decided empty bottle weight, obtains average loading amount; It is an amount of that precision takes by weighing content, adds the diluent dissolving and process the solution that contains omeprazole 0.1mg among every 1ml approximately, as need testing solution; It is an amount of to get the Omeprazole Sodium reference substance, and accurate the title decides, and adds diluent and processes the solution that contains 0.1mg among every 1ml approximately, as reference substance solution.Get each 20 μ l of above-mentioned two kinds of solution, inject chromatograph of liquid respectively, the record chromatogram, with calculated by peak area, the result multiply by 0.940 again, promptly gets by external standard method.
Calculate by average loading amount, contain Omeprazole Sodium with omeprazole (C
17H
19N
3O
3S) meter should be 93.0%～107.0% of labelled amount.
Related substance:
It is an amount of that precision takes by weighing drug substance contents of the present invention, adds the diluent dissolving and process the solution that contains omeprazole 0.1mg among every 1ml approximately, as need testing solution; It is an amount of to measure need testing solution, adds diluent and processes the solution that contains omeprazole 1 μ g among every 1ml, as prerun solution.Chromatographic condition according under the assay item makes an experiment, and gets prerun solution 20 μ l and injects chromatograph of liquid, regulates detection sensitivity, makes the peak height of main constituent chromatographic peak be about 10% of monitor full scale; Get need testing solution 20 μ l injection chromatograph of liquid again, 3 times of writing down chromatogram to main constituent peak retention time.Need testing solution chromatogram H168/66 impurity peaks must not be greater than 0.3% of total peak area; The peak area of maximum contaminant all must not be greater than 1.0% of total peak area; The peak area of total impurities must not be greater than 2.5% of total peak area.
Wherein test used buffer:
(1) phosphate buffer (pH7.4): get sodium dihydrogen phosphate (NaH
2PO
4H
2O) 0.166g and sodium hydrogen phosphate (Na
2HPO
412H
2O) 1.074g adds water and makes dissolving and be diluted to 1000ml, and pH value should be 7.4, promptly gets.
(2) 4-butyl ammonium hydrogen sulfate buffer (pH7.4): get 4-butyl ammonium hydrogen sulfate 6.78g and sodium hydroxide 0.8g, add phosphate buffer (pH7.4) and make dissolving and be diluted to 1000ml, promptly get.
(3) phosphate buffer (pH11.0): get sodium dihydrogen phosphate (NaH
2PO
4H
2O) 0.34g and sodium hydrogen phosphate (Na
2HPO
412H
2O) 0.63g is dissolved in water and is diluted to 1000ml, regulates pH value to 11.0 with phosphoric acid, promptly gets.
(4) diluent: get acetonitrile 200ml, add phosphate buffer (pH11.0) and be diluted to 1000ml, promptly get (needing fresh).
Get the midbody solution and the finished product of said method, each item indexs such as the content of investigation sample, related substance, character.
Embodiment 2
Omeprazole Sodium 42.6g
Disodium edetate 1.8g
Anhydrous sodium sulfite 0.6g
Water for injection adds to: 1000ml
Make 1000 altogether
Preparation technology is with embodiment 1, and wherein the midbody solution pH value is adjusted to 10.9, and the pre-freeze temperature is at-50 ℃.
Get the midbody solution and the finished product of said method, each item indexs such as the content of investigation sample, related substance, character.
Embodiment 3
Omeprazole Sodium 42.6g
Disodium edetate 0.5g
Anhydrous sodium sulfite 1.5g
Water for injection adds to: 1000ml
Make 1000 altogether
Preparation technology is with embodiment 1, and wherein the midbody solution pH value is adjusted to 10.7, and the pre-freeze temperature is at-48 ℃.
Midbody solution and the finished product of getting said method are investigated each item indexs such as the content of sample, related substance, character.
Embodiment 4
Omeprazole Sodium 50g
Disodium edetate 1.2g
Anhydrous sodium sulfite 0.9g
Water for injection adds to: 1000ml
Make 1000 altogether
Preparation technology is with embodiment 1, and wherein the midbody solution pH value is adjusted to 10.3, and the pre-freeze temperature is at-42 ℃.
Get the midbody solution and the finished product of said method, each item indexs such as the content of investigation sample, related substance, character.
Embodiment 5
Omeprazole Sodium 40g
Disodium edetate 1.4g
Anhydrous sodium sulfite 1.2g
Water for injection adds to: 1000ml
Make 1000 altogether
Preparation technology is with embodiment 1, and wherein the midbody solution pH value is adjusted to 10.5, and the pre-freeze temperature is at-45 ℃.
Get the midbody solution and the finished product of said method, each item indexs such as the content of investigation sample, related substance, character.
Embodiment 6
Omeprazole Sodium 60g
Disodium edetate 0.8g
Anhydrous sodium sulfite 1.1g
Water for injection adds to: 1000ml
Make 1000 altogether
Preparation technology is with embodiment 1, and wherein the midbody solution pH value is adjusted to 11.1, and the pre-freeze temperature is at-38 ℃.
Get the midbody solution and the finished product of said method, each item indexs such as the content of investigation sample, related substance, character.
Embodiment 7
Omeprazole Sodium 45g
Disodium edetate 1.1g
Anhydrous sodium sulfite 0.8g
Water for injection adds to: 1000ml
Make 1000 altogether
Preparation technology is with embodiment 1, and wherein the midbody solution pH value is adjusted to 10.1, and the pre-freeze temperature is at-40 ℃.
Get the midbody solution and the finished product of said method, each item indexs such as the content of investigation sample, related substance, character.
Embodiment 8
Omeprazole Sodium 20g
Disodium edetate 0.3g
Anhydrous sodium sulfite 0.9g
Water for injection adds to: 1000ml
Make 1000 altogether
Preparation technology is with embodiment 1, and wherein the midbody solution pH value is adjusted to 10.4, and the pre-freeze temperature is at-50 ℃.
Get the midbody solution and the finished product of said method, each item indexs such as the content of investigation sample, related substance, character.
Embodiment 9
Omeprazole Sodium 80g
Disodium edetate 2.8g
Anhydrous sodium sulfite 1.0g
Water for injection adds to: 1000ml
Make 1000 altogether
Preparation technology is with embodiment 1, and wherein the midbody solution pH value is adjusted to 10.8, and the pre-freeze temperature is at-35 ℃.
Get the midbody solution and the finished product of said method, each item indexs such as the content of investigation sample, related substance, character.
Claims (12)
1. omeprazole freeze-dried powder injection; It is characterized in that this lyophilized injectable powder is made up of active constituents of medicine Omeprazole Sodium, disodium edetate and anhydrous sodium sulfite; Wherein the weight ratio of Omeprazole Sodium and disodium edetate is 28-85: 1; The weight ratio of Omeprazole Sodium and anhydrous sodium sulfite is 21-85: 1, and midbody solution pH value scope is controlled at 9.5-12.0 in the process for preparation, and the pre-freeze temperature is controlled at below-35 ℃ in the cold dried process; The temperature that once heats up is controlled at-3 ℃～8 ℃, and the secondary temperature elevation temperature is controlled at 28 ℃～42 ℃.
2. omeprazole freeze-dried powder injection according to claim 1, it is characterized in that this lyophilized injectable powder form in the weight ratio of Omeprazole Sodium and disodium edetate be 56.8: 1.
3. omeprazole freeze-dried powder injection according to claim 1, it is characterized in that this lyophilized injectable powder form in the weight ratio of Omeprazole Sodium and anhydrous sodium sulfite be 42.6: 1
4. the method for preparing of omeprazole freeze-dried powder injection according to claim 1 is characterized in that method for preparing is to get the room temperature water for injection of recipe quantity 90%, adds disodium edetate and anhydrous sodium sulfite, is stirred to dissolving fully; Crude drug is added, be stirred to dissolving fully; Detect the pH value of solution, and regulate pH value with NaOH solution; Add needle-use activated carbon, stirring and adsorbing is taken off charcoal, aseptic filtration; Add water for injection to recipe quantity; Intermediate check, fill; Lyophilizing, tamponade.
5. like the method for preparing of the said omeprazole freeze-dried powder injection of claim 4, it is characterized in that midbody solution pH value scope is controlled at 9.5-12.
6. like the method for preparing of the said omeprazole freeze-dried powder injection of claim 5, it is characterized in that midbody solution pH value scope is controlled at 10.1-11.1.
7. like the method for preparing of the said omeprazole freeze-dried powder injection of claim 6, it is characterized in that midbody solution pH value scope is controlled at 10.7-10.9.
8. like the method for preparing of the said omeprazole freeze-dried powder injection of claim 4, it is characterized in that the pre-freeze temperature is controlled at below-35 ℃ in the cold dried process, the temperature that once heats up is controlled at-3 ℃～8 ℃, and the secondary temperature elevation temperature is controlled at 28 ℃～42 ℃.
9. the detection method of omeprazole freeze-dried powder injection according to claim 1 is characterized in that comprising in the following detection method one or more:
Detection method of content:
Use octadecylsilane chemically bonded silica to be filler according to HPLC chromatographic condition and system suitability test; With acetonitrile-pH7.4 4-butyl ammonium hydrogen sulfate buffer-pH7.4 phosphate buffer 33-37: 4-8: 63-55 is a mobile phase; The detection wavelength is 280nm; Theoretical cam curve is calculated by the omeprazole peak should be not less than 2000, and the separating degree of omeprazole peak and H168/66 impurity peaks should be not less than 3.0;
Algoscopy is got 5 preparation units of omeprazole freeze-dried powder injection, and accurate the title decides, and inclining content; The accurate title, decided empty bottle weight, obtains average loading amount; It is an amount of that precision takes by weighing content, adds the diluent dissolving, processes need testing solution; It is an amount of to get the Omeprazole Sodium reference substance, and accurate the title decides, and adds diluent and processes reference substance solution; Get above-mentioned two kinds of solution, inject chromatograph of liquid respectively, the record chromatogram, promptly gets with calculated by peak area by external standard method;
Calculate by average loading amount, contain Omeprazole Sodium with omeprazole (C
17H
19N
3O
3S) meter should be 93.0%～107.0% of labelled amount;
The related substance detection method:
Use octadecylsilane chemically bonded silica to be filler; With acetonitrile-pH7.4 4-butyl ammonium hydrogen sulfate buffer-pH7.4 phosphate buffer 33-37: 4-8: 63-55 is a mobile phase; The detection wavelength is 280nm; Theoretical cam curve is calculated by the omeprazole peak should be not less than 2000, and the separating degree of omeprazole peak and H168/66 impurity peaks should be not less than 3.0;
It is an amount of that precision takes by weighing the Omeprazole Sodium medicine, adds the diluent dissolving and process need testing solution; It is an amount of to measure need testing solution, adds diluent and processes prerun solution; Get prerun solution and inject chromatograph of liquid, regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is 10% of a monitor full scale; Get need testing solution again and inject chromatograph of liquid, the 2-4 of record chromatogram to main constituent peak retention time doubly; Need testing solution chromatogram H168/66 impurity peaks must not be greater than 0.3% of total peak area; The peak area of maximum contaminant all must not be greater than 1.0% of total peak area; The peak area of total impurities must not be greater than 2.5% of total peak area.
10. like the detection method of the said omeprazole freeze-dried powder injection of claim 9, it is characterized in that content assaying method is following:
Use octadecylsilane chemically bonded silica to be filler according to high effective liquid chromatography for measuring chromatographic condition and system suitability test; With acetonitrile-pH7.4 4-butyl ammonium hydrogen sulfate buffer-pH7.4 phosphate buffer is mobile phase at 35: 6: 59; The detection wavelength is 280nm; Theoretical cam curve is calculated by the omeprazole peak should be not less than 2000, and the separating degree of omeprazole peak and H168/66 impurity peaks should be not less than 3.0;
Algoscopy is got 5 preparation units of omeprazole freeze-dried powder injection, and accurate the title decides, and inclining content; The accurate title, decided empty bottle weight, obtains average loading amount; It is an amount of that precision takes by weighing content, adds the diluent dissolving and process the solution that contains omeprazole 0.1mg among every 1ml, as need testing solution; It is an amount of to get the Omeprazole Sodium reference substance, and accurate the title decides, and adds diluent and processes the solution that contains 0.1mg among every 1ml, as reference substance solution; Get each 20 μ l of above-mentioned two kinds of solution, inject chromatograph of liquid respectively, the record chromatogram, with calculated by peak area, the result multiply by 0.940 again, promptly gets by external standard method;
Calculate by average loading amount, contain Omeprazole Sodium with omeprazole (C
17H
19N
3O
3S) meter should be 93.0%～107.0% of labelled amount.
11., it is characterized in that the determination of related substances method is following like the detection method of the said omeprazole freeze-dried powder injection of claim 9:
Use octadecylsilane chemically bonded silica to be filler according to high effective liquid chromatography for measuring chromatographic condition and system suitability test; With acetonitrile-pH7.4 4-butyl ammonium hydrogen sulfate buffer-pH7.4 phosphate buffer is mobile phase at 35: 6: 59; The detection wavelength is 280nm; Theoretical cam curve is calculated by the omeprazole peak should be not less than 2000, and the separating degree of omeprazole peak and H168/66 impurity peaks should be not less than 3.0;
It is an amount of that precision takes by weighing these article content, adds the diluent dissolving and process the solution that contains omeprazole 0.1mg among every 1ml, as need testing solution; It is an amount of to measure need testing solution, adds diluent and processes the solution that contains omeprazole 1 μ g among every 1ml, as prerun solution; Get prerun solution 20 μ l and inject chromatograph of liquid, regulate detection sensitivity, the peak height that makes the main constituent chromatographic peak is 10% of a monitor full scale; Get need testing solution 20 μ l injection chromatograph of liquid again, 3 times of writing down chromatogram to main constituent peak retention time; Need testing solution chromatogram H168/66 impurity peaks must not be greater than 0.3% of total peak area; The peak area of maximum contaminant all must not be greater than 1.0% of total peak area; The peak area of total impurities must not be greater than 2.5% of total peak area.
12. omeprazole freeze-dried powder injection by each described method for preparing preparation of claim 4-8.
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| CN103054863B (en) * | 2012-12-28 | 2014-05-14 | 海南锦瑞制药股份有限公司 | Pharmaceutical composition of omeprazole sodium, and preparation method of pharmaceutical composition |
| CN103592379B (en) * | 2013-09-29 | 2015-02-11 | 山东省医药工业研究所 | Analytic method of omeprazole related substance |
| CN107561195A (en) * | 2017-07-26 | 2018-01-09 | 郑州泰丰制药有限公司 | The preparation method of reference substance and need testing solution used in a kind of Omeprazole dissolution measure |
| CN111904937A (en) * | 2020-09-18 | 2020-11-10 | 开封康诺药业有限公司 | Omeprazole sodium freeze-dried powder injection for injection and preparation method thereof |
| CN112807282A (en) * | 2021-01-13 | 2021-05-18 | 海南葫芦娃药业集团股份有限公司 | Omeprazole sodium freeze-dried powder injection and preparation method thereof |
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