CN102850333A - Olmesartan medoxomil crystal and preparation method thereof - Google Patents
Olmesartan medoxomil crystal and preparation method thereof Download PDFInfo
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- CN102850333A CN102850333A CN2012100493461A CN201210049346A CN102850333A CN 102850333 A CN102850333 A CN 102850333A CN 2012100493461 A CN2012100493461 A CN 2012100493461A CN 201210049346 A CN201210049346 A CN 201210049346A CN 102850333 A CN102850333 A CN 102850333A
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Abstract
The invention provides a new olmesartan medoxomil crystal and a preparation method thereof; the crystal has good crystallinity and stability; the preparation method is realized by recrystallization of olmesartan medoxomil in a mixed solvent. The olmesartan medoxomil crystal prepared by the method has good crystallinity and stability; the method is simple; the used organic solvent is a Class III solvent, which has low toxicity, and is beneficial to environmental protection; and the method is suitable for large-scale production.
Description
Technical field
The present invention relates to new crystal of a kind of olmesartan medoxomill and preparation method thereof, comprise the pharmaceutical composition of Olmesartan crystalline esters and described pharmaceutical composition in the preparation prevention or treat application in the hypertensive medicine.
Background technology
Olmesartan medoxomill, chemical name is (5-methyl-2-oxo-1, the 3-Dioxol-4-yl) methyl-4-(1-hydroxyl-1-methylethyl)-and 2-propyl group-1-{4-[2-(tetrazolium-5-yl) phenyl] phenyl } Methylimidazole-5-carboxylicesters, it is a kind of prodrug, in absorption process, be hydrolyzed, block the vasoconstriction effect of angiotensinⅡ by the combination of selective exclusion angiotensinⅡ and vascular smooth muscle AT1 acceptor, be used for the diseases such as prevention or treatment hypertension, its structural formula is:
Those skilled in the art can prepare olmesartan medoxomill by disclosed method among US5616599, WO2004/085428, WO2007/017135, CN101778843, the WO2011/036674.
Material owing to affected by various factors, changes intramolecule or intermolecular bonding mode when crystallization, causes molecule or atom to be arranged at lattice vacancy different, forms different crystalline structure.The different crystal forms of same medicine all may be significantly different at aspects such as outward appearance, solubleness, fusing point, dissolution rate, bioavailabilities, thereby affect stability and the curative effect of medicine.
Medicine will pass through the processes such as absorption, distribution in vivo usually, especially oral administration, because GI physiological situation is complicated, the speed of drug absorption and degree are subject to the impact of factors, particularly medicine was dissolved in first in the pipe intestinal digesting liquid before absorbing, could enter blood circulation by gastrointestinal mucosal with mechanism of absorption such as passive diffusion or active transports, therefore, the solubleness of medicine and dissolution rate are usually by the basis as drug absorption.
The olmesartan medoxomill solvability is relatively poor, enters to be difficult to behind the human body absorb, and causes bioavailability lower.Arrange by changing its lattice vacancy, make different crystal formations, improving its solvability, thereby improve its bioavailability.
CN101238119 discloses a kind of crystal formation of olmesartan medoxomill, by olmesartan medoxomill slow crystallization from Virahol or tetrahydrofuran (THF) is prepared the Olmesartan crystalline esters.
US2006/0281800 discloses the polymorphic G of olmesartan medoxomill, and by olmesartan medoxomill being dissolved in alcohol, nitrile or its mixed solvent, behind the remove portion solvent, cooling crystallization prepares olmesartan medoxomill polymorphic G.
WO2008/149155 discloses the crystal form B of olmesartan medoxomill, by olmesartan medoxomill being dissolved in or being suspended in tetrahydrofuran (THF), methylene dichloride, acetone or its mixture, prepares the olmesartan medoxomill crystal form B take water and hexanaphthene as anti-solvent.
Disclose the polymorphic R of olmesartan medoxomill among the WO2011/013096, by olmesartan medoxomill being dissolved in the organic solvent that contains alkaline matter, stirred time enough, separating obtained crystal prepares olmesartan medoxomill polymorphic R.
Summary of the invention
The inventor finds a kind of new Olmesartan crystalline esters, and develops the method that can prepare high yield, high purity Olmesartan crystalline esters through great many of experiments.New crystal has following feature through the X-powdery diffractometry:
| 2θ(°) | d（?） | Relative intensity |
| 11.62 | 7.61 | 30 |
| 12.70 | 6.96 | 47 |
| 14.50 | 6.10 | 33 |
| 14.88 | 5.95 | 29 |
| 16.52 | 5.36 | 94 |
| 19.60 | 4.52 | 49 |
| 20.58 | 4.31 | 38 |
| 21.86 | 4.06 | 100 |
| 22.08 | 4.02 | 64 |
| 22.52 | 3.95 | 26 |
| 23.30 | 3.82 | 32 |
| 24.60 | 3.62 | 47 |
| 25.24 | 3.53 | 35 |
Measure through differential scanning calorimetric analysis, this crystal has higher fusing point, is 182-185 ℃, determine that by analysis this is the new crystal of olmesartan medoxomill, and this crystal has good crystallinity and solvability.
Another object of the present invention has provided the preparation method of Olmesartan crystalline esters, and the method is by realizing olmesartan medoxomill recrystallization in mixed solvent.
Recrystallization is pharmaceutical industry be used to a to purify important technology of target substance, and its principle is to utilize the solubility with temperature of solid matter in certain solvent to change the notable difference that produces, thereby realizes the purpose of separating-purifying.Affect the recrystallization effect and mainly contain two factors: the 1. selection of solvent; 2. the process control of recrystallization.In recrystallization technology, select suitable solvent extremely important, the effect of single solvent recrystallization is often undesirable, can consider to select the mixed solvent recrystallization, and mixed solvent is the solvent composition that is dissolved each other by two or more; Simultaneously, desolventize outside the selection, usage ratio of all kinds of SOLVENTS etc. also all becomes the important factor that affects the recrystallization effect in the mixed solvent.In addition, recrystallization temperature, crystallization time etc. also can affect the formation of crystal in the recrystallization process, so process control is also particularly important.
The preparation method of the new crystal of olmesartan medoxomill provided by the invention is included in the step of recrystallization in the mixed solvent, and described mixed solvent is the mixture of organic solvent and water.The step of recrystallization comprises olmesartan medoxomill is dissolved in the organic solvent, gets drug solution; In above-mentioned drug solution, splash into water; Cooling crystallization; Reclaim the Olmesartan crystalline esters.Verified, organic solvent dissolves olmesartan medoxomill fully, obtain drug solution after, splash into water, organic solvent fully mixes with water, namely has crystal to separate out after the cooling, the crystallinity of this crystal is good, the purity conformance with standard.
In the above-mentioned re-crystallization step, because olmesartan medoxomill is poorly soluble, preferred olmesartan medoxomill is dissolved in the organic solvent under reflux state.
Further, constantly have crystal to separate out with the temperature reduction, preferred cooling crystallization temperature is 0-5 ℃.
By great many of experiments, the present invention has determined described in the preparation method of Olmesartan crystalline esters that the preferred volume ratio of organic solvent and water is 20:1-6 in the mixed solvent, can prepare the higher Olmesartan crystalline esters of productive rate and purity under this ratio.
Further, the preferred acetone of described organic solvent or Virahol, prepared Olmesartan crystalline esters have good crystallinity, higher productive rate and purity.
Further, the preferred acetone of described organic solvent.
Another object of the present invention provides the pharmaceutical composition that contains the new crystal of olmesartan medoxomill, and described pharmaceutical composition also contains one or more pharmaceutically acceptable auxiliary material or vehicle.This pharmaceutical composition can be with oral such as tablet, granule, capsule, powder, pill, solution, suspensoid, emulsion, non-enteron aisle such as injection, rectum such as suppository, the form administrations such as respiratory tract such as aerosol.
Be suitable for oral solid preparation and can contain thinner, tackiness agent, lubricant, disintegrating agent etc., can contain in case of necessity stablizer, pH adjusting agent; Described thinner is selected from lactose, Microcrystalline Cellulose, N.F,USP MANNITOL, sucrose etc.; Described tackiness agent is selected from polyvidone, hypromellose, Xylo-Mucine, Vltra tears sodium etc.; Described lubricant is selected from Magnesium Stearate, talcum powder, micropowder silica gel, sodium laurylsulfate, poly(oxyethylene glycol) 400 etc.; Described disintegrating agent is selected from croscarmellose sodium, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose etc.; Described stablizer is selected from butylated hydroxy anisole (BHA), 2,6 di tert butyl 4 methyl phenol (BHT) etc.; Described pH adjusting agent is selected from citric acid, fumaric acid, oxysuccinic acid etc.
Be suitable for oral liquid preparation and can contain solvent, suspending agent, emulsifying agent etc.; Described solvent is selected from water, glycerine, ethanol etc.; Described suspending agent is selected from gum arabic, Xylo-Mucine etc.; Described emulsifying agent is selected from gelatin, sodium stearate, poloxamer, polysorbate etc.
The injection that is suitable for parenterai administration can contain solvent for injection, buffer reagent, antioxidant etc.; Described solvent for injection is selected from water for injection, ethanol, glycerine etc.; Described buffer reagent is selected from citrate, acetate, dihydrogen phosphate etc.; Described antioxidant is selected from S-WAT, sodium ascorbate etc.
The suppository that is suitable for rectal administration can contain the matrix such as cocoa butter, glycogelatin, poloxamer, the additives such as stearic acid, glycerol monostearate, butylhydroxy anisole.
The aerosol that is suitable for respiratory tract administration can contain the vehicle such as freon hydro carbons, hydrocarbon polymer.
Aforementioned pharmaceutical compositions can prepare according to the method for this area routine.
The pharmaceutical composition that contains the Olmesartan crystalline esters provided by the invention, it is in preparation prevention or treat application in the hypertensive medicine.
The invention provides new crystal of a kind of olmesartan medoxomill that is more suitable for pharmaceutical preparation and preparation method thereof; namely adopt the mixed solvent recrystallization method to prepare the new crystal of olmesartan medoxomill; not only has good crystallinity and stability; and this preparation method is simple, and the organic solvent that adopts is three kind solvents, and toxicity is low; be beneficial to environmental protection; be fit to large-scale production, the products obtained therefrom particle is thinner, is conducive to improve the result of extraction of preparation.
Description of drawings
The X-ray powder diffraction of Fig. 1 Olmesartan crystalline esters
Rigaku D/max-RC X-ray powder diffraction instrument, condition determination: voltage: 50KV, electric current: 60mA, sweep velocity: 4 degree/minute, step-length 0.02 degree.
Embodiment
Embodiment 1
Get the 1.0g olmesartan medoxomill and place three-necked bottle, add acetone 20mL, reflux is to all dissolvings, in mentioned solution, splash into water 1mL, be cooled to 0-5 ℃ under stirring, keep this temperature to stir 2h, separate out solid, suction filtration, the cold washing with acetone of 2mL 2 times of gained white powder solid, cryodrying gets Olmesartan crystalline esters 0.871g, productive rate 87.1%, purity 99.8%, prepared Olmesartan crystalline esters has X-ray powder diffraction as follows:
| 2θ(°) | d（?） | Relative intensity |
| 11.62 | 7.61 | 30 |
| 12.70 | 6.96 | 47 |
| 14.50 | 6.10 | 33 |
| 14.88 | 5.95 | 29 |
| 16.52 | 5.36 | 94 |
| 19.60 | 4.52 | 49 |
| 20.58 | 4.31 | 38 |
| 21.86 | 4.06 | 100 |
| 22.08 | 4.02 | 64 |
| 22.52 | 3.95 | 26 |
| 23.30 | 3.82 | 32 |
| 24.60 | 3.62 | 47 |
| 25.24 | 3.53 | 35 |
Embodiment 2
Get the 1.0g olmesartan medoxomill and place three-necked bottle, add Virahol 10mL, reflux is to all dissolvings, in mentioned solution, splash into water 0.5mL, be cooled to 0-5 ℃ under stirring, keep this temperature to stir 2h, separate out solid, suction filtration, the cold washed with isopropyl alcohol of 2mL 2 times of gained white powder solid, cryodrying gets Olmesartan crystalline esters 0.834g, productive rate 83.4%, purity 99.7% is identical among products obtained therefrom crystal habit and the embodiment 1.
Embodiment 3 acetone and water mixed solvent proportioning test
Press the method for embodiment 1, adopt acetone and two kinds of solvent of water to carry out recrystallization, solvent burden ratio is respectively 20:1,20:2,20:3,20:4,20:5,20:6, and operation steps is the same, the results are shown in Table 1, identical among products obtained therefrom crystal habit and the embodiment 1.
Table 1 acetone and water mixed solvent proportioning test result
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 |
| Acetone: water (V:V) | 20：1 | 20：2 | 20：3 | 20：4 | 20：5 | 20：6 |
| Productive rate (%) | 87.1 | 87.3 | 87.8 | 87.9 | 88.2 | 88.5 |
| Purity (%) | 99.8 | 99.8 | 99.7 | 99.7 | 99.6 | 99.5 |
Embodiment 4 Virahols and water mixed solvent proportioning test
Press the method for embodiment 2, adopt two kinds of solvent of isopropyl alcohol and water to carry out recrystallization, solvent burden ratio is respectively 20:1,20:2,20:3,20:4,20:5,20:6, and operation steps is the same, the results are shown in Table 2, identical among products obtained therefrom crystal habit and the embodiment 1.
Table 2 Virahol and water mixed solvent proportioning test result
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 |
| Virahol: water (V:V) | 20：1 | 20：2 | 20：3 | 20：4 | 20：5 | 20：6 |
| Productive rate (%) | 83.4 | 83.6 | 83.7 | 83.8 | 84.0 | 84.3 |
| Purity (%) | 99.7 | 99.6 | 99.6 | 99.6 | 99.5 | 99.4 |
Embodiment 5 contains the pharmaceutical composition of Olmesartan crystalline esters
| The Olmesartan crystalline esters | 20mg |
| Citric acid | 2g |
| BHA | 1g |
| Lactose | 60g |
| Microcrystalline Cellulose | 100g |
| Sodium starch glycolate | 10g |
| Polyvidone | 4.5g |
| Magnesium Stearate | 2g |
The Olmesartan crystalline esters, citric acid, BHA, lactose, Microcrystalline Cellulose, sodium starch glycolate, the polyvidone that take by weighing recipe quantity sieve, mix, and wet granulation, drying, whole grain adds Magnesium Stearate, mixes compressing tablet.
Embodiment 6
| The Olmesartan crystalline esters | 20mg |
| Fumaric acid | 2.5g |
| BHA | 2g |
| Lactose | 30g |
| Microcrystalline Cellulose | 130g |
| Croscarmellose sodium | 19g |
| Hypromellose | 4.5g |
| Magnesium Stearate | 2g |
The Olmesartan crystalline esters, fumaric acid, BHA, lactose, Microcrystalline Cellulose, croscarmellose sodium, the hypromellose that take by weighing recipe quantity sieve, mix, and wet granulation, drying, whole grain adds Magnesium Stearate, mixes, and incapsulates.
Claims (9)
1. an Olmesartan crystalline esters is characterized in that, described Olmesartan crystalline esters has X-ray diffracting spectrum as follows:
。
2. a method for preparing Olmesartan crystalline esters claimed in claim 1 is characterized in that, described method comprises that wherein said organic solvent is acetone or Virahol with olmesartan medoxomill recrystallization in the mixed solvent of organic solvent and water.
3. the preparation method of Olmesartan crystalline esters according to claim 2 is characterized in that, the volume ratio of organic solvent and water is 20:1-6 in the described mixed solvent.
4. the preparation method of Olmesartan crystalline esters according to claim 2 is characterized in that, described organic solvent is acetone.
5. the preparation method of Olmesartan crystalline esters according to claim 2 is characterized in that, the step of recrystallization comprises in the described method:
A. olmesartan medoxomill is dissolved in the organic solvent, gets drug solution;
B. in above-mentioned drug solution, splash into water;
C. cooling crystallization;
D. reclaim the Olmesartan crystalline esters.
6. the preparation method of Olmesartan crystalline esters according to claim 5 is characterized in that, olmesartan medoxomill is dissolved in the organic solvent under reflux state among the described method steps a.
7. the preparation method of Olmesartan crystalline esters according to claim 5 is characterized in that, the cooling crystallization temperature is 0-5 ℃ among the described method steps c.
8. a pharmaceutical composition that contains Olmesartan crystalline esters claimed in claim 1 is characterized in that, comprises Olmesartan crystalline esters and pharmaceutically acceptable auxiliary material or vehicle.
9. pharmaceutical composition that contains Olmesartan crystalline esters claimed in claim 1, it is in the preparation prevention or treat application in the hypertensive medicine.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817546A (en) * | 2015-05-20 | 2015-08-05 | 浙江华海药业股份有限公司 | Method for recovering olmesartan medoxomil mother solution |
| CN108658954A (en) * | 2018-06-12 | 2018-10-16 | 广州小桔生物科技有限公司 | A kind of process for purification of high-purity olmesartan medoxomil |
| CN112321575A (en) * | 2020-11-18 | 2021-02-05 | 福建天泉药业股份有限公司 | Olmesartan medoxomil refining method suitable for industrial production |
| CN113105439A (en) * | 2021-04-15 | 2021-07-13 | 迪嘉药业集团有限公司 | Method for preparing small-particle-size olmesartan medoxomil crystals |
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| CN1381453A (en) * | 2002-05-17 | 2002-11-27 | 浙江省医学科学院 | Process for preparing Aomeishatan |
| US20060074117A1 (en) * | 2004-09-02 | 2006-04-06 | Lilach Hedvati | Purification of olmesartan medoxomil |
| WO2008149155A1 (en) * | 2007-06-05 | 2008-12-11 | Generics [Uk] Limited | Crystalline form b of olmesartan medoxomil |
| CN101602760A (en) * | 2009-04-07 | 2009-12-16 | 无锡好芳德药业有限公司 | A kind of preparation method of olmesartan medoxomill |
| WO2011007368A2 (en) * | 2009-07-14 | 2011-01-20 | Cadila Healthcare Limited | An improved process for preparation of olmesartan |
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2012
- 2012-02-29 CN CN2012100493461A patent/CN102850333A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1381453A (en) * | 2002-05-17 | 2002-11-27 | 浙江省医学科学院 | Process for preparing Aomeishatan |
| US20060074117A1 (en) * | 2004-09-02 | 2006-04-06 | Lilach Hedvati | Purification of olmesartan medoxomil |
| WO2008149155A1 (en) * | 2007-06-05 | 2008-12-11 | Generics [Uk] Limited | Crystalline form b of olmesartan medoxomil |
| CN101602760A (en) * | 2009-04-07 | 2009-12-16 | 无锡好芳德药业有限公司 | A kind of preparation method of olmesartan medoxomill |
| WO2011007368A2 (en) * | 2009-07-14 | 2011-01-20 | Cadila Healthcare Limited | An improved process for preparation of olmesartan |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817546A (en) * | 2015-05-20 | 2015-08-05 | 浙江华海药业股份有限公司 | Method for recovering olmesartan medoxomil mother solution |
| CN104817546B (en) * | 2015-05-20 | 2020-02-07 | 浙江华海药业股份有限公司 | Method for recovering olmesartan medoxomil mother liquor |
| CN108658954A (en) * | 2018-06-12 | 2018-10-16 | 广州小桔生物科技有限公司 | A kind of process for purification of high-purity olmesartan medoxomil |
| CN112321575A (en) * | 2020-11-18 | 2021-02-05 | 福建天泉药业股份有限公司 | Olmesartan medoxomil refining method suitable for industrial production |
| CN112321575B (en) * | 2020-11-18 | 2023-07-21 | 福建天泉药业股份有限公司 | Olmesartan medoxomil refining method suitable for industrial production |
| CN113105439A (en) * | 2021-04-15 | 2021-07-13 | 迪嘉药业集团有限公司 | Method for preparing small-particle-size olmesartan medoxomil crystals |
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Application publication date: 20130102 |