CN102670485B - Method for researching and controlling hydrolysis impurity H in solid composition containing valsartan - Google Patents
Method for researching and controlling hydrolysis impurity H in solid composition containing valsartan Download PDFInfo
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Abstract
The invention relates to a method for researching and controlling hydrolysis impurity H in a solid composition containing valsartan. The property of the hydrolysis impurity H in the solid composition containing the valsartan is determined by researching the hydrolysis impurity H in the solid composition containing the valsartan; and a high-quality solid preparation product containing the valsartan is prepared by controlling the moisture of the solid composition containing the valsartan, wherein the moisture of the solid composition containing the valsartan is not more than 3.5 percent.
Description
Technical field:
The invention belongs to pharmaceutical field, relate to research and control method containing hydrolysis impurity H in the solid composite of valsartan.
Background technology:
Hypertension is modal cardiovascular disease, is the great public health difficult problem in global range.Statistics demonstration, China's Prevalence of Hypertension has reached 11.26%, and hyperpietic exceedes 1.3 hundred million.And the impetus of this rising is still continuing.According to WHO prediction, to the year two thousand twenty noninfectious, will account for 79% of China's cause of death, wherein cardiovascular diseases will account for first place.In order to contain the arrival on this cardiovascular diseases peak, the control of Efforts To Develop hypertension, active treatment hyperpietic, very urgent.
The eighties in 20th century, the ACE inhibitor of exploitation was the effectively Altace Ramipril of a class, but it has unsurmountable untoward reaction, zest dry cough (5%～20%) as relevant in dose, the mortality vasodilations such as pharynx, larynx, respiratory tract and lung etc.Valsartan is a kind of angiotensin (AT) II receptor antagonist of orally active high specificity, it optionally acts on AT1 type and is subject to hypotype, there is brand-new Hypotensive Mechanism, without the effect that promotes that Kallidin I and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 generate, thereby Angiotensin Ⅱ receptor antagonist can cause cough unlike ACE inhibitor; And hyperpietic's Administration of Valsartan does not affect heart rate when blood pressure drops.Therefore, the compound preparation of valsartan, valsartan and its active substance is widely used in hypertension therapeutic field, for extensive patients brings glad tidings and wishes; The sales volume in the whole world exceedes 6,000,000,000 dollars now.Diovan compound preparation embodies better controlling of blood pressure rate for the treatment of severe hypertension, and has reduced untoward reaction as valsartan and Hydrochlorothiade sheet, valsartan amlodipine sheet, valsartan and Hydrochlorothiade amlodipine.
Valsartan (valsartan, chemical formula is shown in Formula I), chemical name: N-(1-oxygen amyl group)-N-[4-[2-(1H-TETRAZOLE-5-yl) phenyl] benzyl]-Valine.Aspect the Control of Impurities of valsartan API, the Chinese patent CN101367772 of our company's application has made following restriction to related substance: VLSI-A is no more than 1.0%; VLSI-B and VLSI-D must not exceed respectively 0.2% and 0.1%, and other single unknown impuritie must not exceed 0.1%, and total impurities (not comprising VLSI-A) is no more than 0.3%; But the degradation impurity for valsartan does not have relevant regulations, just according to the pertinent regulations of ICH, as unknown impuritie, control.
About one piece of article Determination and Validtion of valsartan and itsdegration products by isocratic HPLC in the degradation impurity Jouranl of chemical metrology of valsartan, reported the hydrolysis impurity F(relative retention time 0.40 of valsartan) and oxidation impurities G(relative retention time 0.27).
These two impurity obtain under high-intensity degradation condition, but we do not find hydrolysis impurity F containing in preparation prescription accelerated stability (40 ℃/75%) sample of valsartan, one and the much the same impurity of oxidation impurities G retention time have just been found.The molecular weight of analyzing this impurity through liquid matter is 351, and through inferring that we judge that this impurity has following structure, we are called after hydrolysis impurity H.
Through directed synthetic above this hydrolysis impurity, and with sample in the impurity that produces carry out mass spectral analysis, we determine that this impurity is consistent with the impurity producing in accelerated stability sample.Valsartan hydrolysis impurity H is the impurity that we detect in preparation prescription stability sample, and the catabolite character producing under this and high strength degradation condition has larger difference.Under current conditions, our medicine can not be under high-intensity degradation condition, and the impurity therefore producing under high strength degradation condition not necessarily can produce in actual sample put procedure.And the degradation impurity producing in stability sample can badly influence safety and effectiveness containing valsartan solid compositions.Therefore, need to find a kind of control method, controlled hydrolysis impurity H is in the generation containing in valsartan solid combination.
Our surprised discovery in the research of actual prescription, this hydrolysis impurity H can adopt the mode of controlling solid composite moisture to be well controlled.
Summary of the invention:
The object of the present invention is to provide the method for hydrolysis impurity H in the solid composite medicament that a kind of control contains valsartan.
The present invention is that the moisture in the solid composite medicament that contains valsartan by control reaches the object of controlling impurity H.
The present invention's discovery, when the moisture in the solid composite medicament that contains valsartan is controlled in below 3.5%, in the solid composite medicament that contains valsartan, the content of impurity H is lower, meets the prescription of medicine.
For this reason, the invention provides the method for hydrolysis impurity H in the solid composite medicament that a kind of control contains valsartan, the method is applicable to prepare the process of the solid composite medicament that contains valsartan, and the process of the solid composite medicament that preparation contains valsartan comprises the following steps:
1) granule that preparation contains valsartan;
2) coating;
3) packing.
The wherein said solid composite medicament that contains valsartan can be any dosage form, as tablet, and capsule, granule etc.
The described solid composite medicament that contains valsartan comprises: the compound preparation of valsartan single preparations of ephedrine and valsartan, and as valsartan sheet, valsartan capsule, valsartan and Hydrochlorothiade sheet, valsartan amlodipine sheet etc.
Wherein, the granule that preparation contains valsartan described in step 1, is to control water content in granule, according to the present invention, controls water content in granule more few better, as below 3.5%.
Wherein coating described in step 2, that plain sheet or the granule of preparation are carried out to coating, make stabilisation, avoid directly contacting with air, according to the present invention, coating adopts conventional coating material and technology, coating material dissolves with solvent, and solvent is selected from alcohol-water mixture, adopts a high proportion of ethanol/water mixture as coating solvent according to the present invention, wherein ethanol: water volume ratio more than 65:35, preferred ethanol: water volume ratio is at 65-80:35-20.
Wherein packing described in step 3, that the solid composite medicament that contains valsartan after coating prepared by step 2 adopts drug packing material to carry out subpackage, the present invention, by the selection to drug packing material, controls medicine causes moisture in put procedure increase because of the moisture absorption.The present invention is through screening, adopts PVC/PVDC/ aluminium foil, bottled desiccant or the aluminum/aluminum packing packaging material as pharmaceutical composition that add.Preferably, adopt the packaging material of PVC/PVDC/ aluminium foil as solid composite.
The pharmaceutical composition of preparing through the present invention is under 6 months accelerated stability conditions, and hydrolysis impurity H is no more than 0.2%.
By following experiment, beneficial effect of the present invention is further detailed.
The present invention, by the research to containing hydrolysis impurity H in the solid composite of valsartan, determines containing hydrolysis impurity production process in valsartan solid group thing; Clear and definite moisture is containing Key Quality Indicator in the solid composite of valsartan.By the research to containing water quantities in the solid composite of valsartan, find suitable moisture Control scope, and by stability experiment, examine or check the amount of hydrolysis impurity H; For the stability of the solid composite containing valsartan provides quality control standard.
From the hydrolysis impurity H structural formula of valsartan, we can find, the impurity producing after the valeryl hydrolysis that this impurity is valsartan, and this degradation process is the process of an amide hydrolysis, the chemical reaction water of amide hydrolysis is a necessary chemical reaction condition.Therefore we are from studying as point of penetration containing moisture the solid composite of valsartan.We artificially prepare the valsartan granule of different in moisture content, carry out stability (60 ℃) research; Find that moisture and hydrolysis impurity H exist following relation.
| Moisture % | 0d hydrolysis impurity content | 10d hydrolysis impurity content |
| 1.45% | 0.01% | 0.09% |
| 2.59% | 0.01% | 0.10% |
| 3.54% | 0.01% | 0.16% |
| 3.87% | 0.01% | 0.25% |
The factor that has influence on moisture final in valsartan solid compositions may have: the 1) moisture of granule before tabletting; 2) in coating process, moisture increases; 3) sample moisture absorption (impact of packaging material) in put procedure.
Before tabletting, contain the control of valsartan pellet moisture.Because the mobility of valsartan API itself is poor, containing the solid composite of valsartan, need to granulate, meet the requirement of pill flow.The conventional mode of granulating is wet granulation.After adopting control dry, pellet moisture is controlled the content of moisture in solid composite, and we are preferably less than 3.5%.Can adopt fast tester for water content, karl Fischer moisture test apparatus to measure moisture.The moisture Control of this patent granule is not limited to the moisture of wet granulation, also comprises the pellet moisture of dry granulation, and the moisture at the total mixed powder of powder vertical compression end.
The control of moisture in coating process.Adopt water as solvent coating, can cause tablet to have certain moisture absorption weightening finish.Therefore we preferably adopt a high proportion of alcohol/aqueous mixtures to carry out coating.Coating temperature is no more than under 40 ℃ of conditions, and we adopt the alcohol/water of different proportion, as solvent, valsartan sheet is carried out to coating, investigates the situation of change of coating front and back moisture, and result is as follows:
| Solvent | Moisture % before coating | Moisture % after coating |
| Water | 3.2% | 3.8% |
| Alcohol: water=50:50 | 3.2% | 3.5% |
| Alcohol: water=65:35 | 3.2% | 3.3% |
| Alcohol: water=80:20 | 3.2% | 3.0% |
Result show when alcohol/water ratio is greater than 65/35 coating on the moisture of final finished without impact.
The impact of packaging material on moisture content of finished products content.After adopting the interior packaging material material of unlike material to pack valsartan sheet, the variation of moisture before and after measuring place 1 month under 95% super-humid conditions after, result is as follows.
| Packaging material | 0 month moisture % | January moisture % |
| PVC/ aluminium foil | 3.0% | 4.5% |
| PVC/PVDC/ aluminium foil | 3.0% | 3.1% |
| Aluminum/aluminum | 3.0% | 3.0% |
Result shows to adopt PVC/PVDC/ aluminium foil or aluminum/aluminum packing all can play good moisture-proof role, controls moisture.This patent is not limited to above several packaged form, also can adopt the packing of other form, as bottle adds the mode of desiccant.Packaging material according to our preferential PVC/PVDC/ aluminium foil of experiment as us.
The specific embodiment:
Further illustrate by the following examples the present invention, but not as restriction of the present invention.
The preparation (powder vertical compression) of embodiment 1. valsartan sheets
Prescription is (specification 320mg, every 1000 amount meters);
Material A and B are crossed to 30 eye mesh screens, and mix homogeneously, obtains mixture I; Microcrystalline Cellulose and polyvinylpolypyrrolidone are joined in mixture I, and mix homogeneously, obtains mixture II; Magnesium stearate is joined in mixture II, and mix homogeneously, obtains mixture III, and measuring angle of repose is 39.8 °, is pressed into plain sheet, hardness 30kg ± 5kg on Fitow tablet machine.Coating powder 03F640002 is dissolved with ethanol water mixed solvent, and described ethanol water mixed solvent is ethanol: water=65:35, and 35 ℃～40 ℃ are carried out coating, and weightening finish is 3%, makes coated tablet.Measuring moisture is 3.4%, and getting part slice, thin piece moisture absorption to moisture under super-humid conditions is 4.5%; Adopt respectively PVC/PVDC/ aluminium foil to pack.Under accelerated stability condition, investigate the amount of hydrolysis impurity H.
The preparation (dry granulation) of embodiment 2. valsartan sheets
Prescription is (specification 320mg, every 1000 amount meters);
Material A and B are crossed to 30 eye mesh screens, and mix homogeneously, obtains mixture I; Microcrystalline Cellulose and polyvinylpolypyrrolidone are joined in mixture I, and mix homogeneously, obtains mixture II; Magnesium stearate I is joined in mixture II, and mix homogeneously, obtains mixture III; Get mixture dry granulation, film-making pressure is 50kg, makes granule, adds magnesium stearate II mix homogeneously, is pressed into plain sheet, hardness 30kg ± 5kg on Fitow tablet machine.Coating powder 03F640002 is dissolved with ethanol water mixed solvent, and described ethanol water mixed solvent is ethanol: water=65:35,, 35 ℃～40 ℃ are carried out coating, and weightening finish is 3%, makes coated tablet.Measuring moisture is 3.3%, and getting part slice, thin piece moisture absorption to moisture under super-humid conditions is 4.7%; Adopt respectively PVC/PVDC/ aluminium foil to pack.Under accelerated stability condition, investigate the amount of hydrolysis impurity H.
Wherein, magnesium stearate I and magnesium stearate II are magnesium stearate, as adjuvant, are taken up in order of priority and add.The present invention, for the ease of distinguishing, is write as magnesium stearate I and magnesium stearate II.
In addition, polyvinylpolypyrrolidone I, II are in like manner.
The preparation (wet granulation) of embodiment 3. valsartan sheets
Prescription is (specification 320mg, every 1000 amount meters);
Material A and B are crossed to 30 eye mesh screens, and mix homogeneously, obtains mixture I; Microcrystalline Cellulose and polyvinylpolypyrrolidone I are joined in mixture I, and mix homogeneously, obtains mixture II; Polyvidone is dissolved in 450ml water as binding agent, joins in mixture II, in high speed wet granulation machine, granulate.By particle drying, measuring moisture is 3.3%, and magnesium stearate is joined in granule, and mix homogeneously, obtains mixture III; On Fitow tablet machine, be pressed into plain sheet, hardness 30kg ± 5kg.Coating powder 03F640002 is dissolved with ethanol water mixed solvent, and described ethanol water mixed solvent is ethanol: water=65:35, and 35 ℃～40 ℃ are carried out coating, and weightening finish is 3%, makes coated tablet.Measuring moisture is 3.6%, and getting part slice, thin piece moisture absorption to moisture under super-humid conditions is 4.9%; Adopt respectively PVC/PVDC/ aluminium foil to pack.Under accelerated stability condition, investigate the amount of hydrolysis impurity H.
The preparation (wet granulation) of embodiment 4 valsartan and Hydrochlorothiade sheets
Prescription is (specification 80mg/12.5mg, every 1000 amount meters);
By material A, B, C and D mix homogeneously, obtain mixture I; F is dissolved in 80ml water as binding agent, joins in mixture I, in high speed wet granulation machine, granulate.By particle drying, measuring moisture is 3.5%, and E, G and H are joined in granule, and mix homogeneously, obtains mixture II; On Fitow tablet machine, be pressed into plain sheet, hardness 30kg ± 5kg.Coating powder 03F640002 is dissolved with ethanol water mixed solvent, and described ethanol water mixed solvent is ethanol: water=65:35, and 35 ℃～40 ℃ are carried out coating, and weightening finish is 3%, makes coated tablet.Measuring moisture is 3.4%, and getting part slice, thin piece moisture absorption to moisture under super-humid conditions is 4.3%; Adopt respectively PVC/PVDC/ aluminium foil to pack.Under accelerated stability condition, investigate the amount of hydrolysis impurity H.
The preparation (wet granulation) of embodiment 5 valsartan and Hydrochlorothiade sheets
Prescription is (specification 80mg/12.5mg, every 1000 amount meters);
By material A, B, C and D mix homogeneously, obtain mixture I; F is dissolved in 80ml water as binding agent, joins in mixture I, in high speed wet granulation machine, granulate.By particle drying, measuring moisture is 3.5%, and E, G and H are joined in granule, and mix homogeneously, obtains mixture II; On Fitow tablet machine, be pressed into plain sheet, hardness 30kg ± 5kg.Coating powder 03F640002 is dissolved with ethanol water mixed solvent, and described ethanol water mixed solvent is ethanol: water=65:35, and 35 ℃～40 ℃ are carried out coating, and weightening finish is 3%, makes coated tablet.Measuring moisture is 3.4%, and getting part slice, thin piece moisture absorption to moisture under super-humid conditions is 5.0%; Adopt respectively PVC/PVDC/ aluminium foil to pack.Under accelerated stability condition, investigate the amount of hydrolysis impurity H.
The mensuration of embodiment 6 hydrolysis impurity H
Embodiment 1～5 prescription is measured respectively the amount of hydrolysis impurity H after accelerated stability condition (40 ℃/75%) placement 0 month, March and June.Result is as follows:
| Moisture | 0 month | March | June |
| Embodiment 1(3.4%) | 0.01% | 0.06% | 0.13% |
| Embodiment 1(4.5%) | 0.01% | 0.14% | 0.26% |
| Embodiment 2(3.3%) | 0.01% | 0.05% | 0.15% |
| Embodiment 2(4.7%) | 0.01% | 0.12% | 0.30% |
| Embodiment 3(3.6%) | 0.01% | 0.09% | 0.20% |
| Embodiment 3(4.9%) | 0.01% | 0.18% | 0.37% |
| Embodiment 4(3.4%) | 0.01% | 0.08% | 0.13% |
| Embodiment 4(4.3%) | 0.01% | 0.11 | 0.26% |
| Embodiment 5(3.4%) | 0.01% | 0.07% | 0.18% |
| Embodiment 5(5.0%) | 0.01% | 0.16% | 0.41% |
Result shows that the amount of the acceleration hydrolysis impurity H of 6 months is less than 0.2% under moisture Control is less than 3.5% condition; Meet ICH defines limit requirement to impurity.
The preparation (powder vertical compression) of embodiment 7. valsartan sheets
Prescription is (specification 320mg, every 1000 amount meters);
Material A and B are crossed to 30 eye mesh screens, and mix homogeneously, obtains mixture I; Microcrystalline Cellulose and polyvinylpolypyrrolidone are joined in mixture I, and mix homogeneously, obtains mixture II; Magnesium stearate is joined in mixture II, and mix homogeneously, obtains mixture III, and measuring angle of repose is 39.8 °, is pressed into plain sheet, hardness 30kg ± 5kg on Fitow tablet machine.By coating powder 03F640002 alcohol: after water=80:20 dissolves, 35 ℃～40 ℃ are carried out coating, and weightening finish is 3%, makes coated tablet, measuring moisture is 3.2%, adopts aluminum/aluminum to pack.
The chromatographic condition of the hydrolysis impurity H of attached 1. valsartan
Chromatographic column: (L1) Nucleosil100-10C18,25cm × 4.6mm, 5 μ m;
Mobile phase: methanol-pH7.2 buffer (500:500:1);
Buffer compound method: 0.2mol/L triethylamine is 7.2 with phosphoric acid adjust pH.
Detect wavelength: 250nm;
Flow velocity: 1.2ml per minute;
30 ℃ of column temperatures;
Sample size 10 μ l.
Claims (2)
1. the preparation method that contains the solid composite medicament of valsartan, comprises the following steps:
Material A and B are crossed to 30 eye mesh screens, and mix homogeneously, obtains mixture I; Microcrystalline Cellulose and polyvinylpolypyrrolidone are joined in mixture I, and mix homogeneously, obtains mixture II; Magnesium stearate is joined in mixture II, and mix homogeneously, obtains mixture III, and measuring angle of repose is 39.8 °, is pressed into plain sheet, hardness 30kg ± 5kg on Fitow tablet machine; Coating powder 03F640002 is dissolved with ethanol water mixed solvent, and described ethanol water mixed solvent is ethanol: water=65:35, and 35 ℃～40 ℃ are carried out coating, weightening finish is 3%, makes coated tablet, and measuring moisture is 3.4%, adopt PVC/PVDC/ aluminium foil to pack,
The solid composite medicament that contains valsartan is under 6 months accelerated stability conditions, and hydrolysis impurity H is no more than 0.2%, and wherein the molecular formula of impurity H is as follows:
2. the preparation method that contains the solid composite medicament of valsartan, comprises the following steps:
By material A, B, C and D mix homogeneously, obtain mixture I; F is dissolved in 80ml water as binding agent, joins in mixture I, in high speed wet granulation machine, granulate, by particle drying, measuring moisture is 3.5%, and E, G and H are joined in granule, and mix homogeneously, obtains mixture II; On Fitow tablet machine, be pressed into plain sheet, hardness 30kg ± 5kg, coating powder 03F640002 is dissolved with ethanol water mixed solvent, and described ethanol water mixed solvent is ethanol: water=65:35, and 35 ℃～40 ℃ are carried out coating, weightening finish is 3%, make coated tablet, measuring moisture is 3.4%, adopts PVC/PVDC/ aluminium foil to pack,
The solid composite medicament that contains valsartan is under 6 months accelerated stability conditions, and hydrolysis impurity H is no more than 0.2%, and wherein the molecular formula of impurity H is as follows:
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| CN104072433A (en) * | 2014-07-16 | 2014-10-01 | 南京正大天晴制药有限公司 | Hydrolysable impurity compound of valsartan and preparation method, detection method and use thereof |
| CN104887640B (en) * | 2015-06-30 | 2017-12-19 | 昆明医科大学 | A kind of solid composite medicament containing Valsartan |
| CN106176723A (en) * | 2015-07-11 | 2016-12-07 | 凌莉 | A kind of solid composite medicament and preparation method thereof |
| CN106176654A (en) * | 2015-07-11 | 2016-12-07 | 凌莉 | Solid composite medicament containing compound A and preparation method thereof |
| CN105596305A (en) * | 2015-12-25 | 2016-05-25 | 华润赛科药业有限责任公司 | High-stability valsartan preparation and preparation method thereof |
| CN105769788A (en) * | 2016-03-11 | 2016-07-20 | 江苏中邦制药有限公司 | Valsartan tablet and preparation method thereof |
| CN114814060B (en) * | 2021-01-28 | 2024-05-10 | 上海博志研新药物研究有限公司 | Detection method of valsartan amlodipine tablet related substances |
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| CN101820867A (en) * | 2007-08-10 | 2010-09-01 | 基因里克斯(英国)有限公司 | Solid valsartan composition |
| CN102204907A (en) * | 2011-03-31 | 2011-10-05 | 北京赛科药业有限责任公司 | Pharmaceutical composition containing valsartan, and preparation method thereof |
| CN102247376A (en) * | 2011-08-15 | 2011-11-23 | 北京赛科药业有限责任公司 | Compound solid preparation of valsartan and hydrochlorothiazide, and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101820867A (en) * | 2007-08-10 | 2010-09-01 | 基因里克斯(英国)有限公司 | Solid valsartan composition |
| CN102204907A (en) * | 2011-03-31 | 2011-10-05 | 北京赛科药业有限责任公司 | Pharmaceutical composition containing valsartan, and preparation method thereof |
| CN102247376A (en) * | 2011-08-15 | 2011-11-23 | 北京赛科药业有限责任公司 | Compound solid preparation of valsartan and hydrochlorothiazide, and preparation method thereof |
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