CN103127131A - Solid composition with valsartan and preparation method thereof - Google Patents
Solid composition with valsartan and preparation method thereof Download PDFInfo
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- CN103127131A CN103127131A CN2012102648062A CN201210264806A CN103127131A CN 103127131 A CN103127131 A CN 103127131A CN 2012102648062 A CN2012102648062 A CN 2012102648062A CN 201210264806 A CN201210264806 A CN 201210264806A CN 103127131 A CN103127131 A CN 103127131A
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Abstract
The invention discloses solid composition with valsartan and a preparation method of the solid composition with the valsartan. The solid composition with the valsartan comprises a compound preparation of the valsartan or a unilateral preparation of the valsartan. Quality content of ethyl acetate in valsartan atmospheric pressure ionization (API) residual solvent of the solid composition is smaller than 0.30%, and preferably, is smaller than 0.15%. Due to the fact that control of midbodies, such as particles, mixed powder, in the preparation process of the solid composition is adopted, final quality content of moisture of the solid composition is guaranteed to be smaller than 3.5%. Quality content of valsartan ethyl ester of the solid composition is less than 0.2% under the condition of quickened stability for 6 months. The solid composition with the valsartan and the preparation method of the solid composition with the valsartan have the advantages that due to the fact that the content of the ethyl acetate in valsartan API residual solvent is controlled, the solid composition with the valsartan with high quality is produced.
Description
Technical field
The present invention relates to medical technical field, relate in particular to a kind of solid composite that contains valsartan and preparation method thereof.
Background technology
Valsartan is a kind of angiotensin (AT) II receptor antagonist of orally active high specificity, it optionally acts on the AT1 type and is subjected to hypotype, has 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.At first this medicine was used in European countries such as Germany in 1996, went on the market in China in 1998, at present more than 70 country's listings in the world.Valsartan is more safer than captopril angiotensinⅠ receptor antagonist treatment hypertension, only need take 1 time in 1st.This medical instrument has the plurality of advantages that blood pressure lowering is steady, curative effect is strong, safety is good, side effect is low, patient compliance is good.In the hypertension therapeutic field, valsartan and compound preparation thereof are received numerous doctors and patient's welcome, and the global marketing volume rises year by year.
Valsartan (valsartan, chemical formula is seen 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 (crude drug), 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 distinguish over 0.2% and 0.1%, and other single unknown impuritie must not surpass 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 controls as unknown impuritie according to the pertinent regulations of ICH.
About the degradation impurity of valsartan, one piece of article in stoichiometry journal (Journal of chemical metrology) " determine and verify that valsartan and degradation product (Determination and Validtion of valsartan and its degration products by isocratic HPLC) thereof reported the hydrolysis impurity F(relative retention time 0.40 of valsartan by high performance liquid chromatograph) and oxidation impurities G(relative retention time 0.27).
Hydrolysis impurity F oxidation impurities G
And we find that hydrolysis impurity H and retention time were at 18min(minute in containing the preparation prescription accelerated stability of valsartan (40 ℃/75%) sample) unknown impuritie of left and right, determine that after deliberation the structural formula of hydrolysis impurity H and 18min unknown impuritie is as follows:
Hydrolysis impurity H valsartan ethyl ester.
About the control of hydrolysis impurity H, we have applied for Patents.After the impurity of valsartan ethyl ester was studied, we had found the source of this impurity, and found corresponding control method.
Summary of the invention
The purpose of this invention is to provide a kind of solid composite that contains valsartan and preparation method thereof, by the research to valsartan API residual solvent ethyl acetate in the solid composite that contains valsartan, find suitable span of control, and examine or check by stability experiment, detect the amount of valsartan ethyl ester; For the stability of the solid composite that contains valsartan provides method of quality control.
The technical scheme that realizes the object of the invention is as follows:
A kind of solid composite that contains valsartan, described solid composite comprise compound preparation or the valsartan single preparations of ephedrine of valsartan, and the mass content of the valsartan API residual solvent ethyl acetate in described solid composite is less than 0.30%, preferably less than 0.15%.
A kind of preparation method that contains the solid composite of valsartan, described solid composite comprises compound preparation or the valsartan single preparations of ephedrine of valsartan, described preparation method comprises that the mass content of controlling the valsartan API residual solvent ethyl acetate in described solid composite is less than 0.30%, preferably less than 0.15%.
Further, adopt and control the intermediate such as granule or mixed powder in the solid composite preparation process, guarantee that the biodiversity content of final solid composite is less than 3.5%.
Further, described solid composite is under 6 months accelerated stability conditions, and the mass content of valsartan ethyl ester is no more than 0.2%.
Preferably, described solid composite is valsartan amlodipine hydrochlorothiazide tablet, valsartan amlodipine sheet, valsartan and Hydrochlorothiade sheet, valsartan sheet or valsartan capsule.
Beneficial effect of the present invention: by the research to valsartan ethyl ester in the solid composite that contains valsartan, determine to contain the production process of valsartan ethyl ester in valsartan solid group thing; Clear and definite in valsartan API the residual solvent ethyl acetate be to contain Key Quality Indicator in the solid composite of valsartan; By the research to valsartan API residual solvent ethyl acetate in the solid composite that contains valsartan, find suitable span of control, and examine or check by stability experiment, detect the amount of valsartan ethyl ester; For the stability of the solid composite that contains valsartan provides method of quality control.
The specific embodiment
Further illustrate by the following examples the present invention, but not as restriction of the present invention
In the early stage we have prepared the valsartan amlodipine sheet, in the investigation of the accelerated stability (40 ℃/75%) of sample, find during related substance detects except hydrolysis impurity H, an impurity peaks occurs and present the trend of increase when retention time is about 18min.The measurement result of this impurity is as follows:
| Valsartan amlodipine sheet (40 ℃/75%) | Impurity level % |
| 0 month | Do not detect |
| January | 0.07% |
| February | 0.13% |
| March | 0.32% |
| June | 0.41% |
Result shows that 18 minutes (min) unknown impuritie peaks are along with stability increases standing time gradually.The pressure degradation experiment that we have carried out acid, alkali, high temperature, oxidation and illumination to valsartan and amlodipine respectively for the source of finding impurity, result does not find to occur the unknown peak of 18min; Then we are combined valsartan and amlodipine and force degradation experiment, and result is not still found the unknown peak of 18min.Adjuvant may produce impurity with the principal agent generation compatibility, so we force degraded not find also this impurity peaks the valsartan amlodipine sheet.Can't judge the source of impurity, our experimenter has carried out liquid chromatography mass coupling (HPLC-MS) ESI ion source, positive ion mode analysis to 6 months samples of accelerated stability, obtaining this impurity molecule amount is 464, and the molecular weight of valsartan is 435.52, and molecular weight differs 28.48.Infer it to be that valsartan and ethanol generate the valsartan ethyl ester from molecular weight; The molecular weight of ethanol is 46.07, is 463.59 with molecular weight after valsartan becomes ester.
Our orientation has synthesized the valsartan ethyl ester, and finishes the structure conclusive evidence.Analyze the position that the retention time of valsartan ethyl ester just occurs at unknown peak according to valsartan amlodipine sheet related substance detection method.We are for further confirmation, and we get the accelerated stability sample and carry out impurity application of sample mensuration, find that the application of sample sample with application of sample sample impurity peaks retention time is not consistent, other impurity peaks do not occur.It is consistent that HPLC-MS analyzes both molecular ion peak, so we judge that this impurity is the valsartan ethyl ester.
But why the valsartan ethyl ester can appear in valsartan? only have the coating process to introduce ethanol in the preparation technology of raw material and sheet, therefore our analysis is that the residual ethanol of coating causes valsartan to generate the valsartan ethyl ester, we adopt plain sheet and coated tablet to carry out respectively stability experiment, found that also to find onesize valsartan ethyl ester in plain sheet.Therefore we have got rid of the impact that the residual ethanol of art for coating causes.
In we surprised discovery valsartan API, the amount of residual solvent ethyl acetate is given birth to impact to the volume production of valsartan ethyl ester in follow-up experiment, and has larger association, and result is as follows:
| Stable standing time | Ethyl acetate residual solvent amount | Valsartan ethyl ester amount |
| 0 month | 0.42% | Do not detect |
| January | 0.42% | 0.07% |
| February | 0.41% | 0.13% |
| March | 0.38% | 0.32% |
| June | 0.36% | 0.41% |
By above result as can be known the amount of valsartan ethyl ester place gradually and increase along with stability, in valsartan, the amount of residual solvent reduces gradually.The molecular weight of valsartan ethyl ester is 463.59, and the molecular weight of ethyl acetate is 88, calculates according to the mol ratio of chemical reaction, and the minimizing trend of ethyl acetate is more much bigger than the increase trend of valsartan ethyl ester amount.Preliminary judgement may be that valsartan and ethyl acetate generation ester interchange generate the valsartan ethyl ester.Needing certain aqueous conditions and ester exchange occurs, is 4.5% through the stable biodiversity content with the valsartan amlodipine sheet of determination of water.We find that moisture also has a significant impact the dissolution that contains the valsartan solid compositions in the past experience, therefore in follow-up experiment we with moisture Control in 3.5%.
Embodiment 1
Prescription is for (specification 80mg/5mg, the ethyl acetate amount is 0.45%.)
A: valsartan 400g
B: Amlodipine Besylate Tablet 34.65g
C: starch (in add) 120g
D: starch (slurrying) 30g
E: add in microcrystalline Cellulose pH101() 300g
F: carboxymethylstach sodium (in add) 30g
G: carboxymethylstach sodium (adding) 20g
H: sodium lauryl sulphate 15g
I：PVP?K30 10g
J: magnesium stearate 5g
Preparation technology comprises the following steps:
Get starch (slurrying) and make 6% starch slurry, let cool to approximately 45～55 ℃, standby;
Get PVP K30 and add water and make 10% solution, then add sodium lauryl sulphate, be stirred to dissolve, standby;
Valsartan, hydrochlorothiazide, starch (in add), microcrystalline Cellulose pH101, carboxymethylstach sodium (in add) are put and mixed 2 minutes (min) in wet mixing pelletizer;
First add 10% PVP K30 solution, mix 2min in wet mixing pelletizer, then add starch slurry, put and mix 10min, soft material processed in mixing in wet mixing pelletizer;
Cross the wet granulate of 16 mesh sieves in oscillating granulator, fluid bed drying (60 ℃, controlling moisture is 1%～3.5%), 14 mesh sieve granulate;
Dried granule adds carboxymethylstach sodium (adding) and magnesium stearate mixing;
With the stamping of Φ 9mm scrobicula, 4 kilograms of hardness;
Coating is got 30g coating powder (material code name 1063), gets 85% ethanol 350g; Mix homogeneously, the high-efficiency coating pan coating.
Embodiment 2
Preparation method is with embodiment 1, and in the residual API of valsartan, the ethyl acetate amount is 0.30%.
Embodiment 3
Preparation method is with embodiment 1, and in the residual API of valsartan, the ethyl acetate amount is 0.15%.
Embodiment 4
With the sample of embodiment 1～3, put under accelerated stability (40 ℃/75%) condition and placed respectively 6 months, measure respectively the content of valsartan ethyl ester.Result such as following table:
| ? | March | June |
| Embodiment 1 | 0.34% | 0.49% |
| Embodiment 2 | 0.12% | 0.18% |
| Embodiment 3 | 0.04% | 0.13% |
Be controlled at 0.30% when following when valsartan API residual solvent ethyl acetate amount in the valsartan amlodipine sheet as can be known by above result, can satisfy under 6 months accelerated stability conditions, the amount of valsartan ethyl ester is below 0.2%.Therefore the amount of valsartan ethyl acetate can be controlled at below 0.3% preferred 0.15%.
The related substance chromatographic condition of valsartan:
Chromatographic column: (L1) Féraud door Gemini C18,25cm * 4.6mm, 10 μ m;
Mobile phase A: get triethylamine 10ml and add water to 1000ml, with phosphoric acid adjust pH to 2.8
Mobile phase B: methanol-acetonitrile (70:30)
Detect wavelength: 237nm;
Flow velocity: 1.0ml per minute;
30 ℃ of column temperatures;
Sample size 10 μ l.
The gradient elution program:
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 50 | 50 |
| 3 | 50 | 50 |
| 15 | 30 | 70 |
| 20 | 30 | 70 |
| 20.1 | 50 | 50 |
| 25 | 50 | 50 |
Claims (10)
1. solid composite that contains valsartan, described solid composite comprises compound preparation or the valsartan single preparations of ephedrine of valsartan, it is characterized in that: the mass content of the valsartan API residual solvent ethyl acetate in described solid composite is less than 0.30%.
2. the solid composite that contains Sha Tan according to claim 1, it is characterized in that: the mass content of the valsartan API residual solvent ethyl acetate in described solid composite is less than 0.15%.
3. the solid composite that contains valsartan according to claim 2, it is characterized in that: the biodiversity content of described solid composite is less than 3.5%.
4. the solid composite that contains valsartan according to claim 3 is characterized in that: described solid composite is under 6 months accelerated stability conditions, and valsartan ethyl ester mass content is no more than 0.2%, and wherein, the structural formula of described valsartan ethyl ester is as follows:
。
5. the described solid composite that contains valsartan of according to claim 1-4 any one, it is characterized in that: described solid composite is valsartan amlodipine hydrochlorothiazide tablet, valsartan amlodipine sheet, valsartan and Hydrochlorothiade sheet, valsartan sheet or valsartan capsule.
6. preparation method that contains the solid composite of valsartan, described solid composite comprises compound preparation or the valsartan single preparations of ephedrine of valsartan, it is characterized in that: control the mass content of the valsartan API residual solvent ethyl acetate in described solid composite less than 0.30%.
7. the preparation method that contains the solid composite of valsartan according to claim 6, is characterized in that: control the mass content of the valsartan API residual solvent ethyl acetate in described solid composite less than 0.15%.
8. the preparation method that contains the solid composite of valsartan according to claim 7, is characterized in that: control the biodiversity content of described solid composite less than 3.5%.
9. the preparation method that contains the solid composite of valsartan according to claim 8, it is characterized in that: described solid composite is under 6 months accelerated stability conditions, valsartan ethyl ester mass content is no more than 0.2%, and wherein, the structural formula of described valsartan ethyl ester is as follows:
。
10. the described preparation method that contains the solid composite of valsartan of according to claim 6-9 any one, it is characterized in that: described solid composite is valsartan amlodipine hydrochlorothiazide tablet, valsartan amlodipine sheet, valsartan and Hydrochlorothiade sheet, valsartan sheet or valsartan capsule.
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| CN2012102648062A CN103127131A (en) | 2012-07-27 | 2012-07-27 | Solid composition with valsartan and preparation method thereof |
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| CN2012102648062A CN103127131A (en) | 2012-07-27 | 2012-07-27 | Solid composition with valsartan and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114814060A (en) * | 2021-01-28 | 2022-07-29 | 上海博志研新药物技术有限公司 | Detection method of valsartan amlodipine tablet related substances |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362729A (en) * | 2008-08-22 | 2009-02-11 | 北京赛科药业有限责任公司 | Valsartan postprocessing method |
| CN101935308A (en) * | 2010-09-10 | 2011-01-05 | 北大国际医院集团西南合成制药股份有限公司 | New method for synthesizing valsartan |
| CN102391200A (en) * | 2011-09-30 | 2012-03-28 | 浙江新赛科药业有限公司 | Preparation method of high purity valsartan |
-
2012
- 2012-07-27 CN CN2012102648062A patent/CN103127131A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362729A (en) * | 2008-08-22 | 2009-02-11 | 北京赛科药业有限责任公司 | Valsartan postprocessing method |
| CN101935308A (en) * | 2010-09-10 | 2011-01-05 | 北大国际医院集团西南合成制药股份有限公司 | New method for synthesizing valsartan |
| CN102391200A (en) * | 2011-09-30 | 2012-03-28 | 浙江新赛科药业有限公司 | Preparation method of high purity valsartan |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN114814060A (en) * | 2021-01-28 | 2022-07-29 | 上海博志研新药物技术有限公司 | Detection method of valsartan amlodipine tablet related substances |
| 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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Application publication date: 20130605 |