CN101693713B - New crystal system of entecavir, preparation process and medicament application thereof - Google Patents
New crystal system of entecavir, preparation process and medicament application thereof Download PDFInfo
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- CN101693713B CN101693713B CN2009102364088A CN200910236408A CN101693713B CN 101693713 B CN101693713 B CN 101693713B CN 2009102364088 A CN2009102364088 A CN 2009102364088A CN 200910236408 A CN200910236408 A CN 200910236408A CN 101693713 B CN101693713 B CN 101693713B
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Abstract
The present invention relates to a crystal form of entecavir, a preparation process and a medicament application thereof, wherein the crystal form starts to generate a dehydration heat absorption melting peak in 75.4 DEG C, can generate a heat absorption melting peak in 138.9 DEG C, and can generate two sharp heat absorption melting peaks in 244.6 DEG C and 258.5 DEG C.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of new crystal and preparation method thereof of Entecavir and in medicine, use.
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.
We improve through continuous research, have invented a kind of new crystal and preparation method thereof of Entecavir and use in medicine.
Summary of the invention
The object of the present invention is to provide a kind of bioavailability height, good stability, yield height, the new crystal of the Entecavir that purity is high.
By following experiment and detection method, the new crystal of detailed explanation Entecavir of the present invention.
One, powder x-ray diffraction: (table 1)
The new crystal of Entecavir of the present invention, its condition determination: 40KV, 50mA, beam wavelength CuKa
DS=SS=1 °, RS=0.3mm, 0～35 ° of sweep limit under the condition of 5 °/min of scanning speed, has the peak of the suction of following feature: table 1
| The peak | Diffraction angle | 2 θ (pact) | Crystal face is apart from d (pact) | Relative intensity (pact) |
| 1 | 14.800 | 5.981 | 13 | |
| 2 | 15.480 | 5.719 | 100 | |
| 3 | 16.200 | 5.467 | 17 | |
| 4 | 16.540 | 5.355 | 17 | |
| 5 | 17.260 | 5.133 | 48 | |
| 6 | 17.960 | 4.935 | 16 | |
| 7 | 19.660 | 4.512 | 28 | |
| 8 | 21.080 | 4.211 | 24 | |
| 9 | 21.520 | 4.126 | 23 | |
| 10 | 22.140 | 4.012 | 21 | |
| 11 | 23.580 | 3.770 | 30 | |
| 12 | 24.060 | 3.696 | 23 | |
| 13 | 24.960 | 3.565 | 70 | |
| 14 | 25.480 | 3.493 | 66 | |
| 15 | 26.240 | 3.393 | 47 | |
| 16 | 27.160 | 3.281 | 31 | |
| 17 | 27.540 | 3.236 | 46 | |
| 18 | 28.420 | 3.138 | 25 | |
| 19 | 29.640 | 3.012 | 25 | |
| 20 | 30.920 | 2.890 | 21 | |
| 21 | 32.000 | 2.795 | 25 | |
| 22 | 32.380 | 2.763 | 33 | |
| 23 | 32.840 | 2.725 | 25 | |
| 24 | 35.060 | 2.557 | 20 | |
| 25 | 35.840 | 2.503 | 19 | |
| 26 | 36.380 | 2.468 | 13 | |
| 27 | 37.800 | 2.378 | 13 | |
| 28 | 38.720 | 2.324 | 19 |
Infrared absorption spectrum: table 2
Condition determination: measure infrared absorption spectrum with the KBr pressed disc method,, can make following ownership according to the infrared absorption spectrum data:
(1) 3446cm
-1, 3371cm
-1, 3301cm
-1: for hydroxyl, amino, secondary amide and crystal water-OH ,-the NH stretching vibration;
1723cm
-1Carbonylic stretching vibration for secondary amide;
1686cm
-1For-NH
2Flexural vibration;
1537cm
-1For secondary amide-the NH in-plane bending vibration;
1166cm
-1C-N stretching vibration for primary amino;
1062cm
-1, 1016cm
-1Be the C-O stretching vibration of hydroxyl, prove to have crystal water, hydroxyl, primary amino, secondary amide structure in the molecular structure.
(2) 3184cm
-1: for carbon-carbon double bond=the C-H stretching vibration;
1634cm
-1Be the C=C stretching vibration of carbon-carbon double bond, illustrate to have the carbon-carbon double bond structure in the molecule.
(3) 3184cm
-1: for purine skeleton=the C-H stretching vibration;
1601cm
-1, 1482cm
-1Be 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) 2946cm
-1, 2895cm
-1, 2857cm
-1: be the C-H stretching vibration of methylene radical, methyne;
1398cm
-1, 1327cm
-1Be the C-H flexural vibration of methylene radical, methyne, illustrate to have methylene radical, methyne structure in the molecule.
Three, differential thermal analysis (DSC):
Entecavir new crystal of the present invention, its differential thermal analysis (DSC) is the result show, begin to occur a dehydration endothermic melting peak at 75.4 ℃ (onset), an endothermic melting peak occurs at 138.9 ℃ (onset), occur two sharp-pointed endothermic melting peaks again at 244.6 ℃ (onset) and 258.5 ℃ (onset).
Another object of the present invention is to provide a kind of preparation simple easy handling, the preparation method of the new crystal of the Entecavir of suitable scale operation.
The preparation method of the new crystal of described Entecavir, concrete steps are as follows:
Get Entecavir, after the mixing solutions heating for dissolving with 20～24 times of amounts, stir 30min, be chilled to 0 ℃ and place crystallization, suction filtration, with small amount of methanol washing 2 times, vacuum-drying is promptly;
Wherein said mixing solutions is: volume ratio is (5.5～6): 1 the anhydrous methanol and the mixing solutions of dimethyl formamide, mix the mixing solutions of gained with the dimethyl formamide proportioning of 1ml as the anhydrous methanol of 5.5ml to 6ml.
The present invention also further provides the application of Entecavir new crystal in pharmaceutical preparation.
Entecavir new crystal and pharmaceutical carrier are made pharmaceutical preparation, and described preparation can be made into 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 vehicle 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.
Wherein containing new crystal Entecavir of the present invention in the per unit preparation is 0.5～1mg.
Preparing such formulations normally those skilled in that art is known conventional method.
The new crystal of Entecavir of the present invention has the bioavailability height, and drug effect is remarkable, good stability, yield height, characteristics such as purity height.The new crystal of Entecavir 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 crystal formation of the method for the embodiment of the invention 1 preparation and the crystal formation of prior art for preparing, the result shows,
The stability of crystal formation of the present invention is more stable than prior art.
Table 3 study on the stability
Description of drawings
Accompanying drawing 1: the x-ray diffraction pattern of Entecavir new crystal;
Accompanying drawing 2: the infrared absorpting light spectra of Entecavir new crystal;
Accompanying drawing 3: the differential thermal analysis curve of Entecavir new crystal.
Embodiment:
By following examples the present invention is done step explanation, but not as restriction of the present invention.
In the 50ml reaction flask, add the 1.0g Entecavir, 18.8ml anhydrous methanol and 3.2ml DMF are heated to 70 ℃, stir 30min, be chilled to 0 ℃ and place 8hr, suction filtration, get white crystalline powder, with small amount of methanol washing 2 times, vacuum-drying promptly gets Entecavir new crystal of the present invention.
Its x-ray diffraction pattern, infrared absorpting light spectra, differential thermal analysis curve are seen accompanying drawing 1,2 and 3.
In the 50ml reaction flask, add the 1.0g Entecavir, 18ml anhydrous methanol and 3ml DMF are heated to 70 ℃, stir 30min, be chilled to 0 ℃ and place 8hr, suction filtration, get white crystalline powder, with small amount of methanol washing 2 times, vacuum-drying promptly gets Entecavir new crystal of the present invention.
In the 50ml reaction flask, add the 1.0g Entecavir, 16.5ml anhydrous methanol and 3ml DMF are heated to 70 ℃, stir 30min, be chilled to 0 ℃ and place 8hr, suction filtration, get white crystalline powder, with small amount of methanol washing 2 times, vacuum-drying promptly gets Entecavir new crystal of the present invention.
Prescription: Entecavir new crystal 12g of the present invention, hydroxypropylcellulose 100g, sodium starch glycolate 30g.
Method for making: back two kinds of material separated pulverizing are crossed 100 orders in above-mentioned, more than 10 hours, are chilled to room temperature in 100 ℃ of drying under reduced pressure, mix with the Entecavir new crystal, and dry granulation mechanism grain is pressed into 1000, promptly.
Prescription: Entecavir new crystal 8g of the present invention, lactose 55g, Microcrystalline Cellulose 70g, sodium starch glycolate 25g, Magnesium Stearate 1.5g.
Method for making: the lactose in above-mentioned, Microcrystalline Cellulose, sodium starch glycolate separated pulverizing are crossed 100 orders; in 100 ℃ of drying under reduced pressure more than 10 hours; be chilled to room temperature; mix with the Entecavir new crystal; dry granulation mechanism grain adds Magnesium Stearate, mixing; be filled in 1000 Capsuleses, promptly get the Entecavir capsule.
Prescription: Entecavir new crystal 10g of the present invention, lactose 45g, Microcrystalline Cellulose 50g, sodium starch glycolate 20g, Magnesium Stearate 1.5g.Make particle according to the ordinary method on the technology of pharmaceutics.
Other formulations of embodiment 7. Entecavirs
Make other formulations according to the ordinary method on the technology of pharmaceutics.
Claims (2)
1. the preparation method of an Entecavir crystal formation is characterized in that, step is as follows:
Get Entecavir, after the mixing solutions heating for dissolving with 20～24 times of amounts, stir 30min, be chilled to 0 ℃ and place crystallization, suction filtration, with small amount of methanol washing 2 times, vacuum-drying is promptly; Wherein said mixing solutions is: volume ratio is 5.5～6: 1 the anhydrous methanol and the mixing solutions of dimethyl formamide;
Described Entecavir crystal formation, its powder x-ray diffraction figure is as shown in Figure 1; Its infrared absorpting light spectra as shown in Figure 2; Its differential thermal analysis curve as shown in Figure 3.
2. preparation method according to claim 1 is characterized in that step is as follows:
In the 50ml reaction flask, add the 1.0g Entecavir, 18.8ml anhydrous methanol and 3.2ml dimethyl formamide are heated to 70 ℃, stir 30min, are chilled to 0 ℃ and place 8hr, and suction filtration gets white crystalline powder, and with small amount of methanol washing 2 times, vacuum-drying is promptly.
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| CN103304566B (en) * | 2013-07-09 | 2015-11-04 | 北京凯因科技股份有限公司 | A kind of crystallization type Entecavir |
| CN105001223B (en) * | 2015-06-30 | 2016-08-17 | 湖南三清药业有限公司 | A kind of Entecavir crystalline compounds and capsule preparations thereof |
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|---|---|---|---|---|
| WO1998009964A1 (en) * | 1996-09-03 | 1998-03-12 | Bristol-Myers Squibb Company | IMPROVED PROCESS FOR PREPARING THE ANTIVIRAL AGENT [1S-(1α, 3α, 4β)]-2-AMINO-1,9-DIHYDRO-9-[4-HYDROXY-3-(HYDROXYMETHYL)-2-METHYLENECYCLOPENTYL]-6H-PURIN-6-ONE |
| CN1747959A (en) * | 2002-12-11 | 2006-03-15 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing the antiviral agent [1s-(1alpha,3 alpha,4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6h-purin-6-one |
| CN1861602A (en) * | 2005-05-13 | 2006-11-15 | 上海仲夏化学有限公司 | Preparation process of entecavir |
| CN101050216A (en) * | 2006-04-05 | 2007-10-10 | 杭州容立医药科技有限公司 | Method for synthesizing medication Entecavir of anti hepatitis B |
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-
2009
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|---|---|---|---|---|
| WO1998009964A1 (en) * | 1996-09-03 | 1998-03-12 | Bristol-Myers Squibb Company | IMPROVED PROCESS FOR PREPARING THE ANTIVIRAL AGENT [1S-(1α, 3α, 4β)]-2-AMINO-1,9-DIHYDRO-9-[4-HYDROXY-3-(HYDROXYMETHYL)-2-METHYLENECYCLOPENTYL]-6H-PURIN-6-ONE |
| CN1747959A (en) * | 2002-12-11 | 2006-03-15 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing the antiviral agent [1s-(1alpha,3 alpha,4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6h-purin-6-one |
| CN1861602A (en) * | 2005-05-13 | 2006-11-15 | 上海仲夏化学有限公司 | Preparation process of entecavir |
| CN101050216A (en) * | 2006-04-05 | 2007-10-10 | 杭州容立医药科技有限公司 | Method for synthesizing medication Entecavir of anti hepatitis B |
| CN101210015A (en) * | 2006-12-26 | 2008-07-02 | 杭州盛友医药技术开发有限公司 | Method for preparing hepatitis B therapeutic medicament entecavir |
| CN101245068A (en) * | 2007-02-14 | 2008-08-20 | 浙江医药股份有限公司新昌制药厂 | Crystallization type entecavir, method of producing the same, pharmaceutical composition and uses thereof |
| CN101182322A (en) * | 2007-12-06 | 2008-05-21 | 福建广生堂药业有限公司 | Method for preparing antiviral drug of Entecavir |
Non-Patent Citations (1)
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| 李荣东，乔娟，王福东，黄萍.抗乙肝病毒药物恩替卡韦的合成.《中南药学》.2008,第6卷(第3期), * |
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