CN101787026A - Amorphous entecavir p-toluenesulfonate salt and preparation method and medicament application thereof - Google Patents
Amorphous entecavir p-toluenesulfonate salt and preparation method and medicament application thereof Download PDFInfo
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- CN101787026A CN101787026A CN201010000444A CN201010000444A CN101787026A CN 101787026 A CN101787026 A CN 101787026A CN 201010000444 A CN201010000444 A CN 201010000444A CN 201010000444 A CN201010000444 A CN 201010000444A CN 101787026 A CN101787026 A CN 101787026A
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- entecavir
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- tosilate
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- ethyl acetate
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Abstract
The invention provides amorphous entecavir p-toluenesulfonate salt with high bioavailability, high stability, high yield and high purity. The amorphous entecavir p-toluenesulfonate salt is determined as an amorphous state of entecavir p-toluenesulfonate salt through detections such as X-ray diffraction, infrared absorption spectrum determined by a KBr tablet method, differential scanning calorimetry (DSC) and the like. The invention also relates to a preparation method and medicament application of the amorphous salt.
Description
Technical field
The invention belongs to field of medicaments, particularly a kind of antiviral drug of Entecavir tosylate, imperfect crystal formation and preparation method thereof and medicinal application.
Technical background
Entecavir (Entecavir) is a kind of 2,-penta ring deoxyguanosine analogue, chemical name is [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene radical cyclopentyl]-the 6H-purine-6-one, monohydrate normally, molecular structural formula is as follows:
Entecavir is a kind of chipal compounds, and [1S-(1 α, 3 α, 4 β)] optically active isomer has extremely strong resistance of hepatitis B disease (HBV) toxic action.
Entecavir is a kind of antiviral agent efficiently, clinical study has shown the hepatitis B virus good inhibition effect, because the activity of Entecavir hepatitis B virus resisting is very high, low-down dosage just is enough to reach the treatment effect of expectation, and the every day of generally being grown up, oral 0.5mg or 1mg Entecavir can reach good therapeutic action.
At present, publication number is: the Chinese patent of CN101245068A discloses a kind of crystalline form of Entecavir, and its crystal habit Entecavir is the desolvation product or contains the crystal water product.
The polymorph that one skilled in the art will appreciate that medicine has become the drug research process and has become the important component part that must lack in yield and quality control and the testing process with medicine.Polymorphic research helps the bioactive selection of new drug compound to medicine, help to improve bioavailability, promote clinical efficacy, help the selection and the design of drug administration approach, and the determining of pharmaceutical preparation technology parameter, thereby improve the pharmaceutical production quality.Same medicine crystalline form difference, its bioavailability may significant difference.With a kind of medicine, some crystalline form may possess higher biological activity than other crystalline forms.
The present invention finds that by the research to the Entecavir tosylate a kind of unformed Entecavir tosylate form has special advantages of excellent stability and bioavailability.
Summary of the invention
The object of the present invention is to provide a kind of bioavailability height, good stability, yield height, the unformed Entecavir tosilate that purity is high.
Unformed Entecavir tosilate of the present invention improves the water-soluble of Entecavir under the prerequisite of the compound pharmacological properties that does not change Entecavir.
Unformed Entecavir tosilate of the present invention has following feature:
One, powder x-ray diffraction:
The unformed tosic acid Entecavir of the present invention does not have the absorption peak of feature, is amorphous powder.
Its condition determination is: 40KV, 50mA, beam wavelength CuKa
DS=SS=1 °, RS=0.3mm, 0～40 ° of sweep limit, 5 °/min of scanning speed;
Two, infrared absorption spectrum:
The unformed tosic acid Entecavir of the present invention, its infrared signature absorption peak such as following table:
Table 1
| Absorption peak (cm -1) | Functional group |
| ??3388，3333 | Hydroxyl, secondary amide-OH ,-NH |
| ??3100～2800 | ??-N+H 3-NH |
| ??1169，1033 | ??-SO 3The SO of H 2 |
| ??1708 | Carbonyl |
| ??1533 | ??-NH |
| ??1122 | ??C-N |
| ??1009 | Hydroxyl |
| ??3191 | Carbon-carbon double bond=C-H |
| ??1641 | ??C＝C |
| ??3191 | Purine skeleton=C-H |
| ??1603，1474 | Purine skeleton |
| ??2925 | ??C-H |
| ??1411，1374 | ??C-H |
| ??3137 | The C-H of phenyl ring |
| ??1603，1556，1474 | Phenyl ring |
Condition determination is: measure infrared absorption spectrum with the KBr pressed disc method,
According to the infrared absorption spectrum data, each characteristic peak can be made following ownership:
(1) 3388cm
-1, 3333cm
-1: for hydroxyl, secondary amide-OH ,-the NH stretching vibration;
3100～2800cm
-1N-H stretching vibration for ammonium salt;
1169cm
-1, 1033cm
-1-be-SO
3The SO of H
2Stretching vibration;
1708cm
-1Carbonylic stretching vibration for secondary amide;
1533cm
-1For secondary amide-the NH in-plane bending vibration;
1122cm
-1C-N stretching vibration for primary amino;
1009cm
-1Be the C-O stretching vibration of hydroxyl, prove exist in the molecular structure hydroxyl, uncle ammonium salt, secondary amide ,-SO
3The H structure.
(2) 3191cm
-1: for carbon-carbon double bond=the C-H stretching vibration;
1641cm
-1Be the C=C stretching vibration of carbon-carbon double bond, illustrate to have the carbon-carbon double bond structure in the molecule.
(3) 3191cm
-1: for purine skeleton=the C-H stretching vibration;
1603cm
-1, 1474cm
-1: be skeleton carbon-carbon double bond, the carbon-to-nitrogen double bon stretching vibration of purine skeleton, therefore, prove to have the purine skeleton structure in the molecule.
(4) 2925cm
-1: be the C-H stretching vibration of methylene radical, methyne;
1411cm
-1, 1374cm
-1: be the C-H flexural vibration of methylene radical, methyne, illustrate to have methylene radical, methyne structure in the molecule.
(5) 3137cm
-1: for phenyl ring=the C-H stretching vibration;
1603cm
-1, 1556cm
-1, 1474cm
-1: be the skeleton carbon-carbon double bond stretching vibration of phenyl ring, therefore, prove to have benzene ring structure in the molecule.
Three, differential thermal analysis (DSC):
Unformed Entecavir tosilate of the present invention melting peak occurs at 198.6 ℃ (onset), does not contain crystal water.
Another object of the present invention is to provide a kind of preparation simple easy handling, be fit to the preparation method of the unformed Entecavir tosilate of scale operation.
Concrete steps are as follows:
Get equimolar Entecavir and tosic acid, behind dissolve with methanol, reaction concentrates, and adds the ethyl acetate crystallization, and with the ethyl acetate washing, vacuum-drying promptly;
Preferable methods is as follows:
Entecavir hydrate is placed reaction flask, add methyl alcohol, stir,, add the solution that tosic acid and methyl alcohol are made in batches the reaction solution heating, finish reaction, concentrating under reduced pressure, cooling, add ethyl acetate, separate out solid, again with the washing of 4.0ml ethyl acetate, residue vacuum-drying.
The present invention also further provides the pharmaceutical preparation that contains unformed Entecavir tosilate of the present invention.
Unformed Entecavir tosilate and pharmaceutical carrier are made pharmaceutical preparation, and described preparation can be any pharmaceutically useful formulation.These formulations comprise: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, pulvis, solution, injection, suppository, ointment, plaster, creme, sprays, drops, patch.Preparation of the present invention is preferably oral solid preparation, as tablet, capsule, granule etc.
Described pharmaceutical carrier comprises and is selected from the following carrier one or more: meglumine, N.F,USP MANNITOL, sorbyl alcohol, Sodium Pyrosulfite, sodium bisulfite, Sulfothiorine, cysteine hydrochloride, Thiovanic acid, methionine(Met), vitamins C, the EDTA disodium, EDTA calcium sodium, the alkali-metal carbonate of monovalence, acetate, phosphoric acid salt or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium-chlor, Repone K, Sodium.alpha.-hydroxypropionate, Xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, ethanol, Sucralose, citric acid, silicon derivative, Mierocrystalline cellulose and derivative thereof, alginate, gelatin, polyvinylpyrrolidone, glycerine, soil temperature 80, agar, lime carbonate, Calcium hydrogen carbonate, tensio-active agent, polyoxyethylene glycol, cyclodextrin, beta-cyclodextrin, the phospholipid material, kaolin, talcum powder, calcium stearate, Magnesium Stearate, essence, Microcrystalline Cellulose, N.F,USP MANNITOL, hydroxypropylcellulose, sodium starch glycolate.
Preparing such formulations is the ordinary method that those skilled in that art know.
The present invention also provides the application of unformed Entecavir tosilate of the present invention in the hepatitis b virus infected medicine of preparation treatment.And the application of pharmaceutical preparation of the present invention in the hepatitis b virus infected medicine of preparation treatment.
Unformed Entecavir tosilate of the present invention has the bioavailability height, and drug effect is remarkable, good stability, yield height, characteristics such as purity height.Unformed Entecavir tosilate of the present invention helps the selection and the design of drug administration approach, and the determining of pharmaceutical preparation technology parameter, thereby improves the pharmaceutical production quality.
Below further specify advantage of the present invention by testing data:
Carry out study on the stability with the unformed Entecavir tosilate of the method for the embodiment of the invention 1 preparation and the Entecavir form of prior art for preparing, the result shows that the stability of crystal formation of the present invention is more stable than prior art.
Table 2 study on the stability
Table 3 bioavailability is investigated
Under the normal temperature and pressure, unformed Entecavir tosilate water-soluble greater than 160mg/ml, and the water-soluble of Entecavir is 2.4mg/ml, visible unformed Entecavir tosilate water-soluble are far longer than the water-soluble of Entecavir.
Description of drawings
Accompanying drawing 1: the x-ray diffraction pattern of unformed Entecavir tosilate;
Accompanying drawing 2: the infrared absorpting light spectra of unformed Entecavir tosilate;
Accompanying drawing 3: the differential thermal analysis curve of unformed Entecavir tosilate.
Embodiment:
By following examples the present invention is done step explanation, but not as restriction of the present invention.
Embodiment 1:
The 2.95g Entecavir hydrate is placed reaction flask, add methyl alcohol 30.0ml, stir, reaction solution is heated to 40 ℃, adds the solution of making by 2.0g tosic acid and 5.0ml methyl alcohol in batches, finish, 65 ℃ of reaction 3h, be evaporated to 12.5ml, be cooled to 0 ℃, add ethyl acetate 130.0ml, separate out thick solid, come down in torrents and desolvate, with the washing of 4.0ml ethyl acetate, residue vacuum-drying gets white foam shape solid to unformed Entecavir tosilate 4.45g again.
Claims (10)
1. unformed Entecavir tosilate, it is characterized in that powder x-ray diffraction: do not have the absorption peak of feature, be amorphous powder, its condition determination is: 40KV, 50mA, beam wavelength CuKa
DS=SS=1 °, RS=0.3mm, 0～40 ° of sweep limit, 5 °/min of scanning speed; Measure infrared absorption spectrum with the KBr pressed disc method, its absorption peak is characterized as:
Its differential thermal analysis: melting peak occurs at 198.6 ℃, do not contain crystal water.
2. the preparation method of the described unformed Entecavir tosilate of claim 1 is characterized in that step is as follows: get equimolar Entecavir and tosic acid, behind dissolve with methanol, reaction concentrates, add the ethyl acetate crystallization, with the ethyl acetate washing, vacuum-drying promptly.
3. preparation method according to claim 2 is characterized in that step is as follows: Entecavir hydrate is placed reaction flask, add methyl alcohol, stir, reaction solution is heated, add the solution that tosic acid and methyl alcohol are made in batches, finish, reaction, concentrating under reduced pressure, cooling adds ethyl acetate, separates out solid, again with the washing of 4.0ml ethyl acetate, residue vacuum-drying.
4. preparation method according to claim 3, it is characterized in that, step is as follows: the 2.95g Entecavir hydrate is placed reaction flask, add methyl alcohol 30.0ml, stir, reaction solution is heated to 40 ℃, adds the solution of making by 2.0g tosic acid and 5.0ml methyl alcohol in batches, finish, 65 ℃ of reaction 3h, be evaporated to 12.5ml, be cooled to 0 ℃, add ethyl acetate 130.0ml, separate out thick solid, come down in torrents and desolvate, with the washing of 4.0ml ethyl acetate, residue vacuum-drying gets white foam shape solid to unformed Entecavir tosilate again.
5. pharmaceutical preparation that comprises the described unformed Entecavir tosilate of claim 1.
6. preparation according to claim 5 wherein contains the medicine acceptable carrier.
7. preparation according to claim 6 is any pharmaceutical dosage form.
8. preparation according to claim 7, described pharmaceutical dosage form is selected from: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, pulvis, solution, injection, suppository, ointment, plaster, creme, sprays, drops, patch.
9. according to the application of the described unformed Entecavir tosilate of claim 1 in the hepatitis b virus infected medicine of preparation treatment.
10. the application of preparation according to claim 5 in the hepatitis b virus infected medicine of preparation treatment.
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| CN201010000444A CN101787026A (en) | 2010-01-08 | 2010-01-08 | Amorphous entecavir p-toluenesulfonate salt and preparation method and medicament application thereof |
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| CN201010000444A CN101787026A (en) | 2010-01-08 | 2010-01-08 | Amorphous entecavir p-toluenesulfonate salt and preparation method and medicament application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107441066A (en) * | 2017-08-09 | 2017-12-08 | 润和生物医药科技(汕头)有限公司 | A kind of percutaneous absorption patch and its preparation method and application |
| CN114105987A (en) * | 2020-08-26 | 2022-03-01 | 上海博志研新药物技术有限公司 | Entecavir medicinal salt and preparation method, pharmaceutical composition and application thereof |
| CN116650497A (en) * | 2022-09-30 | 2023-08-29 | 广州帝奇医药技术有限公司 | Antiviral pharmaceutical composition and preparation process and application thereof |
-
2010
- 2010-01-08 CN CN201010000444A patent/CN101787026A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107441066A (en) * | 2017-08-09 | 2017-12-08 | 润和生物医药科技(汕头)有限公司 | A kind of percutaneous absorption patch and its preparation method and application |
| CN107441066B (en) * | 2017-08-09 | 2019-03-15 | 润和生物医药科技(汕头)有限公司 | A kind of percutaneous absorption patch and its preparation method and application |
| CN114105987A (en) * | 2020-08-26 | 2022-03-01 | 上海博志研新药物技术有限公司 | Entecavir medicinal salt and preparation method, pharmaceutical composition and application thereof |
| WO2022042641A1 (en) * | 2020-08-26 | 2022-03-03 | 上海博志研新药物技术有限公司 | Entecavir medicinal salt, preparation method therefor, pharmaceutical composition thereof, and application thereof |
| CN114105987B (en) * | 2020-08-26 | 2022-12-27 | 上海博志研新药物技术有限公司 | Entecavir medicinal salt, preparation method, pharmaceutical composition and application thereof |
| CN116650497A (en) * | 2022-09-30 | 2023-08-29 | 广州帝奇医药技术有限公司 | Antiviral pharmaceutical composition and preparation process and application thereof |
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Address after: 350003, 32 floor, global Plaza, No. 54, 158, Gulou District, Fujian, Fuzhou Applicant after: Fujian Cosunter Pharmaceutical Co., Ltd. Address before: 350003, 32 floor, global Plaza, No. 54, 158, Gulou District, Fujian, Fuzhou Applicant before: Guangshengtang pharmaceutical Industry Co., Ltd. Fujian |
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Application publication date: 20100728 |