CN102786513A - Omeprazole crystal E substance, its preparation method and its applications in medicines and healthcare products - Google Patents
Omeprazole crystal E substance, its preparation method and its applications in medicines and healthcare products Download PDFInfo
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- CN102786513A CN102786513A CN2011101284295A CN201110128429A CN102786513A CN 102786513 A CN102786513 A CN 102786513A CN 2011101284295 A CN2011101284295 A CN 2011101284295A CN 201110128429 A CN201110128429 A CN 201110128429A CN 102786513 A CN102786513 A CN 102786513A
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Abstract
The invention discloses an omeprazole crystal E substance with the structure represented by formula (I), a preparation method of an omeprazole crystal E sample, products prepared through treating the omeprazole crystal E substance as an active component, and applications of the omeprazole crystal E in the disease control and the healthcare, wherein the products comprise medicines and healthcare products.
Description
Technical field
The present invention relates to a kind of brilliant E type state of matter of omeprazole, the preparation method of the brilliant E type of omeprazole sample adopts the product of the brilliant E type of omeprazole material as activeconstituents, and the purposes of the brilliant E type of omeprazole, belongs to medical technical field.
Background technology
Omeprazole, English omeprazole by name, molecular structure is suc as formula shown in (I)
In English Patent WO2002/085889 (publication number), put down in writing " the Crystalform of omeprazole " of Mi La-people such as Na Tasha Sebastian Haffner invention
[1]Wherein, relate to a kind of new crystalline form of material of omeprazole, be called the omeprazole crystal C type.In addition; The preparation method of omeprazole crystal C type is also disclosed; The formula of medicine that contains the mixture of omeprazole crystal C type and the acceptable vehicle of pharmacy; And the omeprazole crystal C type is used to treat the purposes of gastrointestinal illness, and omeprazole crystal C type and crystal type A, the crystal B-type of existing report are contrasted.
In USP WO2009/066309 A2 (publication number), put down in writing Patel, Dhimant, " the Procee for preparation of omeprazole " of people such as Jasubhai invention
[2]Wherein, The method that relates to a kind of salt for preparing omeprazole and analogue thereof, hydrate, solvate; And in research process, obtain a kind of method for preparing the pure article of omeprazole crystal B-type; In addition, adopt powder x-ray diffraction analysis, differential scanning calorimetric analysis and IR spectroscopy that the pure article of omeprazole crystal B-type that prepare have been carried out the crystal formation sign.
In English Patent WO2004/076440 (publication number), put down in writing " polymorphic form of S-omeprazole " that Y storehouse horse, MS Kang Na, M Eswar Prasad are invented
[3]Wherein, related to omeprazole the polymorphic forms of S-enantiomorph, also relate to the method for preparing polymorphic forms.More specifically, the present invention relates to two kinds of polymorphic forms of S-omeprazole, be called " I type " and " II type " and comprise the I type and the pharmaceutical composition of II type.
In English Patent WO99/08500 (publication number), put down in writing " new crystal of omeprazole " that K Loew Qwest, D Nuo Leilande invent
[4]Wherein, relate to a kind of new crystal of omeprazole, be referred to as crystal type A.In addition; The invention still further relates to the application of omeprazole new crystal in the treatment gastrointestinal tract disease, contained the pharmaceutical composition of this new crystal compound and prepared the method for this new crystal compound, and adopted the X-ray diffraction method that this new crystal compound differentiated.
In Chinese patent CN1058211 (publication number), put down in writing " method of improved synthetic Aomei pula azoles " of people's inventions such as the special human relations of Ah Buddhist nun E cloth Lance
[5]Wherein, related to a kind of compound method of omeprazole, promptly in dichloromethane solution, remained on basically under the condition about 8.0-8.6 with pH; With 5-methoxyl group-2-[(4-methoxyl group-3; 5-dimethyl--2-pyridyl]-methylthio group]-1H-benzoglyoxaline (compound I) and metachloroperbenzoic acid reaction, with NaOH extraction with aqueous solution reaction mixture, water phase separated and organic phase; Alkyl formate is added to aqueous phase, generates the omeprazole crystallization.
In Chinese patent CN1136564 (publication number), put down in writing people such as Yan Yimin invention " Aomeilazole salt hydrate for gastric acid inhibitor and preparation method thereof "
[6]Wherein, related to Aomeilazole salt hydrate for gastric acid inhibitor and preparation method thereof.Form of omeprazole salts is a kind of good acid inhibitor, but because stability is bad bigger with residual solvent toxicity, clinical application is affected.Aomeilazole salt hydrate for gastric acid inhibitor provided by the invention, good stability, purity height do not contain the toxicity residual solvent, can be used for preparing the lyophilisate and the oral prepns of used for intravenous injection, treatment stomach ulcer and duodenal ulcer.Preparing method's technology of the present invention is simple, is suitable for suitability for industrialized production.
In Chinese patent CN1160050 (publication number), put down in writing " a kind of process for purification of omeprazole " of people such as Ge Jilong invention
[7]Wherein, a kind of process for purification that has related to omeprazole.Omeprazole stability of formulation and product gas purity receive the influence of crude product refining method very big, the invention provides new process for purification, are about to bullion and in water or organic solvent, react with highly basic; The omeprazole salts solution that obtains adds the stirring of organic solvent or water and adds solid hydrogen salt in batches after activated carbon decolorizing filters, and separates out crystallization; Final pH is 7.0-8.5, filters the washing crystallization; Dry below 40 ℃, get the omeprazole white crystals.Product stability is good, purity is high, process for purification is easy, is suitable for suitability for industrialized production.
In Chinese patent CN1379670 (publication number), put down in writing " the fourier transform raman spectroscopy art is measured the ratio of omeprazole isomer in the compsn " of people's inventions such as RR White reins in
[8]Wherein, related to the isomer proportion that employing fourier transform raman spectroscopy art (FT-Raman) is measured the chemical compsn of omeprazole.
In Chinese patent CN1467207 (publication number), put down in writing " the pure neutral S-of solid state optics (-)-and the preparation method of R-(+)-omeprazole " of people such as Deng Jingen invention
[9]Wherein, Related to the pure neutral S-of solid state optics (-)-and the preparation method of R-(+)-omeprazole; Relate to syrupy shape or buttery optical purity S-(-)-and the mixed system of R-(+)-omeprazole (Omeprazole) by water and a small amount of organic solvent in separate out; Obtain white amorphous powder; Recrystallization makes neutral S-(-) the specific crystalline state of optical purity, white-and the method for R-(+)-omeprazole in water (containing a small amount of organic solvent) again, and the application of neutral S-(-)-omeprazole in medicine of optical purity white solid state.Technology of the present invention is simple, and product stability is good, yield is high; The main water as solvent that uses in the method, the consumption of organic solvent seldom pollutes little; And omeprazole has good stability in alkaline aqueous solution, easy and simple to handle, is easy to industrial production.
In Chinese patent CN1810803 (publication number), put down in writing " method of high antimer selectivity preparation (S)-omeprazole " of people such as Jiang Biao invention
[10]Wherein, Related to the method that a kind of enantio-selectivity catalysed oxidation processes prepares optical activity enantiomorph or optical purity enantiomorph (S)-omeprazole; Metal titanium reagent and chiral diol part original position generate titanium-containing catalyst, enantio-selectivity catalyzed oxidation omeprazole thioether in the presence of oxygenant.Compare with titanium tetraisopropylate-diethyl tartrate system, this method avoids the use of expensive cumene hydroperoxide and diisopropyl ethyl amine, can obtain higher enantio-selectivity (92-99%ee) and productive rate.The invention still further relates to the neutral state of preparation (S)-omeprazole, partial crystallization or whole crystalline state.
In Chinese patent CN101070315 (publication number), put down in writing " a kind of preparation method of omeprazole " of people such as Song Guoqiang invention
[11]Wherein, The preparation method who has related to a kind of anti-ulcer medicament; Relating in particular to a kind of is starting raw material with pyrmetazole, and IBX is an oxygenant, and quaternary ammonium compound tetraethylammonium bromide or Tetrabutyl amonium bromide are catalyzer; The method of synthetic anti-ulcer medicament omeprazole has provided the measure that the oxygenant recovery set is used simultaneously.This method overcome above omeprazole synthetic in the existing problem of final step oxidizing reaction, have high yield, highly selective, simple, efficient and safe characteristics, satisfy the purpose and the demand of suitability for industrialized production.
In Chinese patent CN101914090A (publication number), put down in writing " preparation method of levo-omeprazole " of people such as Sun Zuguang invention
[12]Wherein, Related to a kind of method for preparing high purity levo-omeprazole or its metal-salt; In the presence of organic solvent; With (S)-binaphthol and tetraisopropoxy titanium under refluxad the complex compound that obtains of prepared in reaction be catalyzer, be oxygenant with tertbutyl peroxide decane solution, do not add any organic bases; Obtain the levo-omeprazole of high chromatographic purity high-optical-purity through asymmetric room temperature oxidation omeprazole thioether, and can be further through preparing the levo-omeprazole metal-salt with the alkali salify.The purity and the ee value of the present invention's purified back levo-omeprazole and salt thereof reach more than 99%, and yield is suitable for suitability for industrialized production more than 62%.
The 1921-1923 page or leaf of rolling up in 1989 the 45th at crystallography C volume
[13]In put down in writing the monocrystalline X ray diffracting data of omeprazole crystal formation and the molecular structure of being derived thereof, 1729 pages of 2000 the 11st of this external Tetrahedron:Asymmetry volumes
[14]With 2057 pages of 2007 the 5th of Chemical Communications volumes
[15]In all delivered the similar omeprazole single crystal structure of unit cell parameters.
The present invention is different with above-mentioned patent, and above-mentioned patent all is from preparing methods such as synthetic, the purifying of clinical application therapeutic action and compound.There are essential difference in point of penetration of the present invention and above-mentioned document and patent; Promptly be to start with from the research of omeprazole solid chemical substance existence; Study through the polymorphic triage techniques; On the raw material aspect of active constituents of medicine, seek, find the new crystal kind and the status flag of omeprazole solid material, and crystal formation research is combined with healthcare applications with clinical, for the omeprazole state of matter of seeking, finding, exploitation has optimal efficacy provides the basic scientific research data; Simultaneously, also for application country or international intellecture property invention patent protection provide scientific basis from omeprazole solid crystal formation raw material basis.
Summary of the invention
The technical problem that the present invention will solve provides a kind of new crystal formation of the omeprazole shown in the formula (I), promptly brilliant E type
Another technical problem that the present invention will solve provides the preparation method of the brilliant E type of omeprazole material.
Another technical problem that the present invention will solve provides the product of the brilliant E type of omeprazole composition as activeconstituents.
Another technical problem that the present invention will solve provides the application of the brilliant E type of omeprazole.
Particularly, the technical problem for solving, adopt following technical scheme:
1. the morphological specificity of the brilliant E type of omeprazole solid sample:
1.1 the brilliant E type of omeprazole solid matter, (CuK when using powder x-ray diffraction analysis
aRadiation), show as the Height%=100 peak position in 2-Theta=17.2 ± 0.2 ° or
The place and have 10 its positions of diffraction peak respectively 2-Theta (°) ± 0.2 ° of value or
Value has following expression:
And diffraction peak relative intensity value allows Height% ± 10% variation range (Fig. 1).
1.2 the brilliant E type of omeprazole solid matter, its infrared absorption spectrum (Fig. 2) 3063,3004,2944,2905,2834,2800,1627,1587,1567,1510,1473,1458,1428,1401,1310,1295,1269,1204,1186,1154,1119,1112,1076,1013,966,885,820,809,786,760,732,666cm
-1± 2cm
-1Absorption peak be the diffuse reflectance infrared spectroscopy peak position that the brilliant E type of omeprazole solid matter is appeared.
1.3 the brilliant E type of omeprazole solid matter, its melting point values is 145 ℃ ± 2 ℃.
1.4 the brilliant E type of omeprazole solid matter, (Fig. 3) contains 1 of Peak endotherm(ic)peak and 1 of exothermic peak in its DSC collection of illustrative plates, and transformation value is respectively 151 ℃ ± 3 ℃, 166 ℃ ± 3 ℃ positions.
2. the preparation method characteristic of the brilliant E type of omeprazole sample:
2.1 the invention provides the preparation method of the brilliant E type of a kind of omeprazole sample, the mixed solvent system that it is characterized in that using earlier THF, ethanol, methylene dichloride and water, hexanaphthene, normal hexane different sorts solvent to process through multiple proportioning combination dissolves the omeprazole sample fully under normal temperature or high temperature and obtains omeprazole crystalline substance E type sample fully through 4 ℃～80 ℃ of envrionment temperatures, ambient moisture 10%～75%, normal pressure or vacuum pressure condition.
2.2 the invention provides the preparation method of the brilliant E type of other a kind of omeprazole sample, it is characterized in that using the omeprazole sample as the preparation raw material and adopt the physical mechanics lattice damage and prepare brilliant E type solid matter or prepare omeprazole crystalline substance E type sample through pressure condition, the temperature condition that changes physics with the molecular transposition rotating crystal method.
3. the brilliant E type of omeprazole sample is as the using dosage and the purposes characteristic of active substance:
3.1 of the present invention a kind of product is provided also, with the brilliant E type of omeprazole composition as activeconstituents and contain other auxiliary materials.Product of the present invention comprises medicine, healthcare products.
The crystal formation purity of the brilliant E type of omeprazole is 1%～100% in the described product.
The formulation of said product is selected from tablet, capsule, pill, injection, slowly-releasing or control-released agent, pulvis.
Used the various products of the brilliant E type of omeprazole material as the activeconstituents exploitation 3.2 the invention provides, comprised medicine, healthcare products, it is characterized in that, the brilliant E type of omeprazole absorbs dosage in 1mg～30g scope its every day.
The various products of the brilliant E type of omeprazole material have been used 3.3 the invention provides as the activeconstituents exploitation; Comprise medicine, healthcare products; It is characterized in that, used the brilliant E type of omeprazole composition to guarantee its in vivo absorption characteristic, effectively bioavailability, effective blood drug concentration, the stable time that continues and reach prevention, treatment, health-care effect and the application of making the most of the advantage as active substance.
4. the absorption characteristic of the brilliant E type of omeprazole sample after oral:
The invention provides and use the various products of the brilliant E type of omeprazole material as the activeconstituents exploitation; Comprise medicine, healthcare products; And the bio-absorbable effect after the oral administration, it is characterized in that the brilliant E type of omeprazole material can reach the peak concentration value as activeconstituents in about 15 minutes through gi tract and play a role in blood.Accompanying drawing 4 provides after the brilliant E type of the omeprazole sample oral absorption at the intravital plasma concentration curve of rat.
5. the application of the brilliant E type of omeprazole in pharmacy.
The brilliant E type of omeprazole of the present invention can be used for preparing the medicine of treating gastrointestinal tract disease.Preferred gastrointestinal tract disease is selected from the gastrointestinal ulceration disease.Preferred gastrointestinal ulceration disease is to be selected from stomach ulcer, duodenal ulcer.
Description of drawings
The x-ray diffractogram of powder spectrum of the brilliant E type of accompanying drawing 1 omeprazole sample
The infrared absorpting light spectra of the brilliant E type of accompanying drawing 2 omeprazoles sample
The DSC collection of illustrative plates of the brilliant E type of accompanying drawing 3 omeprazoles sample
After the brilliant E type of the accompanying drawing 4 omeprazoles sample oral absorption at the intravital plasma concentration curve of rat
Embodiment
Be better explanation technical scheme of the present invention, the spy provides following examples, but the present invention is not limited to this.
The preparation method of the brilliant E type of omeprazole sample:
The preparation method of the brilliant E type of omeprazole sample; It is characterized in that using the 30mL THF to add the 20mL cyclohexane give earlier as under the solvent room temperature condition 210mg omeprazole sample being dissolved fully; Remove solvent 40 ℃ vacuum pressure condition, prepare the omeprazole crystal form samples.
The x-ray diffractogram of powder spectrum of gained omeprazole crystal form samples is shown in accompanying drawing 1
The infrared absorpting light spectra of gained omeprazole crystal form samples is shown in accompanying drawing 2
The DSC collection of illustrative plates of gained omeprazole crystal form samples is shown in accompanying drawing 3
Above spectrum data result shows that present embodiment gained crystalline crystal formation is the brilliant E type of omeprazole.
The problem that needs explanation: have 6 kinds owing to can be used for preparing the organic solvent of the brilliant E type of omeprazole sample; Every kind of organic solvent boiling point value is different, different to omeprazole sample dissolution degree, variate-values such as the envrionment temperature of its experiment, humidity, time there is some difference property and constant interval scope when causing under the using the different solvents condition brilliant E type of preparation omeprazole sample.
The preparation method of the brilliant E type of omeprazole sample:
The preparation method of the brilliant E type of omeprazole sample is characterized in that adopting the physical grinding technology, prepares the omeprazole crystal form samples.
The x-ray diffractogram of powder spectrum of gained omeprazole crystal form samples is shown in accompanying drawing 1
The infrared absorpting light spectra of gained omeprazole crystal form samples is shown in accompanying drawing 2
The DSC collection of illustrative plates of gained omeprazole crystal form samples is shown in accompanying drawing 3
Above spectrum data result shows that present embodiment gained crystalline crystal formation is the brilliant E type of omeprazole.
The brilliant E type of omeprazole absorbs characteristic and Plasma Concentration characteristic in the rat body:
Adopt the conventional raising condition of SD male rat of body weight 200～270g to raise, freely drink water, behind the fasting 12h, irritate stomach by 200mg/kg and give medicine; 2min, 5min, 15min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h before administration and after the administration get blood in the heparinization test tube by the eye socket venous plexus, and be centrifugal, gets blood plasma 0.2ml; After mark 10 μ l are mixed in adding, add 1ml ETHYLE ACETATE, the 3min that is mixed vibrates; 13, the centrifugal 10min of 400rpm gets supernatant 900 μ l nitrogen and blows and volatilize; Redissolve with moving phase 100 μ l, last appearance 30 μ l carry out HPLC and detect, and carry out quantitative analysis with sample and interior mark peak area ratio.The HPLC detection system is Aligent 1200 highly effective liquid phase chromatographic systems, and chromatographic column is Agilent Eclipse XDB-C
18(250 * 4.6mm, 5 μ m), moving phase is methyl alcohol: water=65: 35, sample size are 30 μ l, and flow velocity is 0.8ml/min, and the detection wavelength is 302nm, and column temperature is 30 ℃.The result shows that the brilliant E type of the oral omeprazole of rat sample can detect activeconstituents in the blood after 5-15 minute, shows that the brilliant E type of omeprazole has the fast biological property of absorption rate (Fig. 4).
The brilliant E type of omeprazole Plasma Concentration data
The brilliant E type of omeprazole material is as the medicine dosage of activeconstituents:
The medicinal tablet or other preparations that use the brilliant E type of omeprazole sample to manufacture as active constituents of medicine; It is characterized in that containing the activeconstituents of the brilliant E type of omeprazole as medicine; Every day, dosage was 300mg; Can be prepared into 3 times/each 1 100mg conventional tablet every day respectively, every day 2 times/each 1 150mg conventional tablet or every day 1 time/each 1 300mg the tablet type.
The problem that needs explanation: the brilliant E type of the omeprazole that the present invention relates to pharmaceutical composition has many factor affecting on the dosage of effective constituent, for example: be used to prevent different with the purposes of treating and cause the difference of dosage every day; Ill character is different with ill severity and cause the different of dosage every day; The difference of patient's sex, age, body surface area, route of administration, administration number of times, therapeutic purpose are different and cause the difference of dosage every day; In addition, absorption that exists between crystal form samples and Plasma Concentration are not equal, and also causing the present invention is 0.01～200mg/kg body weight in appropriate dose scope every day of using the brilliant E type of omeprazole composition, is preferably 1～100mg/kg body weight.Should formulate the brilliant E type of omeprazole effective constituent total dose scheme according to the prevention of reality and treatment different situations demand during use, and can be divided into repeatedly or the single administration mode is accomplished.
Embodiment 5
The brilliant E type of omeprazole material is as the healthcare products dosage of activeconstituents:
Use the brilliant E type of omeprazole material as the functional health product that activeconstituents manufactures, it is characterized in that containing in the healthcare products the brilliant E type of omeprazole as the health active component substances, its consumption is from 1mg～30g.
Reference
1, English Patent, publication number WO 2002/085889.
2, USP, publication number WO 2009/066309A2.
3, English Patent, publication number WO 2004/076440.
4, English Patent, publication number WO 99/08500.
5, Chinese patent, publication number CN 1058211.
6, Chinese patent, publication number CN 1136564.
7, Chinese patent, publication number CN 1160050.
8, Chinese patent, publication number CN 1379670.
9, Chinese patent, publication number CN 1467207.
10, Chinese patent, publication number CN 1810803.
11, Chinese patent, publication number CN 101070315.
12, Chinese patent, publication number CN 101914090A.
13、Acta?Crystallography，Section?C，1989(45)：1921-1923。
14、Tetrahedron：Asymmetry，2000(11)：1729。
15、Chemical?Communications，2007(5)：2057。
Claims (10)
1. the brilliant E type of the omeprazole shown in the formula (I),
It is characterized in that (CuK when using powder x-ray diffraction analysis
αRadiation) show as the Height%=100 peak position in 2-Theta=17.2 ± 0.2 ° or
The place and have 10 its positions of diffraction peak respectively 2-Theta (°) ± 0.2 ° of value or
Value has following expression:
And diffraction peak relative intensity value allows Height% ± 10% variation range.
2. the preparation method of the brilliant E type of the described omeprazole of claim 1 sample; It is characterized in that the mixed solvent system that uses THF, ethanol, methylene dichloride and water, hexanaphthene, normal hexane different sorts solvent to process through multiple proportioning combination earlier dissolves the omeprazole sample fully and obtains the brilliant E type of omeprazole sample fully through 4 ℃～80 ℃ of envrionment temperatures, ambient moisture 10%～75%, normal pressure or vacuum pressure condition under normal temperature or high temperature.
3. the preparation method of the brilliant E type of the described omeprazole of claim 1 sample; It is characterized in that, use the omeprazole sample as the preparation raw material and adopt the physical mechanics lattice damage and prepare brilliant E type solid matter or prepare omeprazole crystalline substance E type sample through pressure condition, the temperature condition that changes physics with the molecular transposition rotating crystal method.
4. a product is characterized in that, as activeconstituents, and contains other auxiliary materials with the brilliant E type of the described omeprazole of claim 1 composition.
5. according to the product of claim 4, it is characterized in that the crystal formation purity of the brilliant E type of described omeprazole is 1%～100%.
6. according to the product of claim 4, it is characterized in that said product is selected from medicine, healthcare products.
7. according to each product among the claim 4-6, the formulation of said product is selected from tablet, capsule, pill, injection, slowly-releasing or control-released agent, pulvis.
8. the application of the brilliant E type of the omeprazole of claim 1 in the medicine of preparation treatment gastrointestinal tract disease.
9. according to Claim 8 application is characterized in that described gastrointestinal tract disease is the gastrointestinal ulceration disease.
10. according to the application of claim 9, it is characterized in that described gastrointestinal ulceration disease is to be selected from stomach ulcer, duodenal ulcer.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1058211A (en) * | 1990-06-07 | 1992-01-29 | 阿斯特拉公司 | Improved method for synthesizing benzoimidazole |
| CN1160050A (en) * | 1996-03-20 | 1997-09-24 | 常州市第四制药厂 | Process for refining omeprazole |
| CN1531533A (en) * | 2001-04-25 | 2004-09-22 | ������ҩ�뻯ѧ��˾ | Crystalline form of omeprazole |
-
2011
- 2011-05-18 CN CN2011101284295A patent/CN102786513A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1058211A (en) * | 1990-06-07 | 1992-01-29 | 阿斯特拉公司 | Improved method for synthesizing benzoimidazole |
| CN1160050A (en) * | 1996-03-20 | 1997-09-24 | 常州市第四制药厂 | Process for refining omeprazole |
| CN1531533A (en) * | 2001-04-25 | 2004-09-22 | ������ҩ�뻯ѧ��˾ | Crystalline form of omeprazole |
Non-Patent Citations (1)
| Title |
|---|
| 李洪运: "奥美拉唑合成工艺的优化", 《安徽医药》, vol. 9, no. 12, 31 December 2005 (2005-12-31), pages 894 - 895 * |
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Application publication date: 20121121 |