CN101987851B - Crystal forms of Acyclovir sodium dihydrate and preparation method thereof - Google Patents
Crystal forms of Acyclovir sodium dihydrate and preparation method thereof Download PDFInfo
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- CN101987851B CN101987851B CN200910090294.0A CN200910090294A CN101987851B CN 101987851 B CN101987851 B CN 101987851B CN 200910090294 A CN200910090294 A CN 200910090294A CN 101987851 B CN101987851 B CN 101987851B
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- acyclovir
- sodium
- crystal
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- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 title claims abstract description 29
- 239000013078 crystal Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229940008235 acyclovir sodium Drugs 0.000 title abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000003443 antiviral agent Substances 0.000 abstract description 2
- -1 nucleoside compound Chemical class 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229960004150 aciclovir Drugs 0.000 description 3
- 208000002352 blister Diseases 0.000 description 3
- 230000010354 integration Effects 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000009889 Herpes Simplex Diseases 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- 208000001688 Herpes Genitalis Diseases 0.000 description 1
- 208000000903 Herpes simplex encephalitis Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 201000004946 genital herpes Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses two novel crystal forms of antiviral drug, namely Acyclovir sodium dihydrate and a preparation method thereof. In the preparation method of the crystal forms, the common solvents such as water, carbinol, alcohol, isopropanol, acetone and the like are adopted.
Description
Technical field
The present invention relates to crystal forms of Acyclovir sodium dihydrate and preparation method thereof.
Background technology
Acyclovir is nucleoside compound, chemical name: 9-(2-'-hydroxyethoxy ylmethyl) guanine.As antiviral drug, be mainly used in clinically a series of diseases for the treatment of herpes simplex I, II type and causing thus, herpes simplex encephalitis, zoster, varicella, genital herpes etc. are all had to good curative effect.Preparation has freeze-dried powder, tablet, capsule.
Sodium acyclovir can be used as the bulk drug of injection powder pin.United States Patent (USP) 6040445 has carried out preliminary study to the preparation of Sodium acyclovir, find the form stable existence of Sodium acyclovir with dihydrate, lyophilize can obtain anhydrous Sodium acyclovir, absorbs water and changes into dihydrate soon but be exposed in damp atmosphere.In this patent, acyclovir is dissolved in diluted sodium hydroxide solution, be added dropwise in acetone, Virahol, crystallization, has obtained Sodium acyclovir dihydrate.The inventor, in the process of research Sodium acyclovir dihydrate, has found two kinds of stable new crystal, called after I type, II type.
Summary of the invention
Object of the present invention provides the new crystal of 2 kinds of Sodium acyclovir dihydrates.
The new crystal of the first Sodium acyclovir dihydrate of the present invention, this crystal formation is named the type into I, and its X-ray powder diffraction pattern is about 10.2,13.5 at reflection angle 2 θ, and 16.7,18.2,23.5,24.7, there is charateristic avsorption band at 26.8,29.0 places.
The new crystal of the second Sodium acyclovir dihydrate of the present invention, this crystal formation is named the type into II, and its X-ray powder diffraction pattern is about 4.3,8.8 at reflection angle 2 θ, and there is charateristic avsorption band at 13.2,22.3,26.8 places.
In the present invention, the mensuration of 2 θ values is used CuK α light source, precision is ± 0.2 °, therefore, " approximately " in above-mentioned " X-ray powder diffraction pattern charateristic avsorption band reflection angle 2 θ are about " should be defined as 2 θ ± 0.2 °, represent that 2 above-mentioned got θ values have allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Another object of the present invention is the preparation method who discloses Sodium acyclovir dihydrate new crystal.
The preparation method of crystal forms of Acyclovir sodium dihydrate I of the present invention, its process comprises: by Sodium acyclovir water dissolution, add methyl alcohol, leave standstill crystallization.It is characterized in that, the consumption of water is 2～20 times of Sodium acyclovir weight, methanol usage is water consumption 0.5～50 times, add methyl alcohol after solution clarify.
The preparation method of crystal forms of Acyclovir sodium dihydrate II of the present invention, its process comprises: by Sodium acyclovir water dissolution, add the solvent of another kind of little polarity, stirring and crystallizing.It is characterized in that, the solvent of little polarity can be ethanol, Virahol, acetone or the mixed solvent of any two or three composition wherein, and the consumption of water is 2～20 times of Sodium acyclovir weight, little polar solvent consumption is water consumption 0.5～50 times.
Embodiment
Can conduct further description the present invention by the following examples, but invention of the present invention is not limited to the following examples, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art has done within the scope of the claims and adjust and also should think and belong to scope of the present invention.
Embodiment 1
Acyclovir 90g (molecular weight: 225.2, document: 0.376mol, calculates: 0.400mol) be suspended in 480ml water 16.8g (0.42mol) sodium hydroxide (document: 15.9g, 0.397mol)-100ml aqueous solution drips at 20 DEG C, 0.8g activated carbon decolorizing, filters, washing, filtrate is slowly added drop-wise in 2800ml acetone at 10 DEG C, continue stirred for several hour, suction filtration, cold acetone washing.45 DEG C of vacuum-drying 16h, obtain product 83g, and karl-Fischer method is measured moisture content 12.45%.
The preparation of embodiment 2 brilliant I
1g Sodium acyclovir is dissolved in 5ml water, adds 50ml methyl alcohol, solution clarification, room temperature is placed 24 hours crystallizatioies.Crystallize out, filters 50 DEG C of drying under reduced pressure.Karl-Fischer method is measured moisture content 11.47%.
The preparation of embodiment 3 brilliant II
1g Sodium acyclovir is dissolved in 5ml water, adds 50ml ethanol, solution muddiness, stirs 24 hours.Crystallize out, filters 50 DEG C of drying under reduced pressure.Karl-Fischer method is measured moisture content 12.53%.
The mensuration of embodiment 4 Sodium acyclovir dihydrate new crystal physical propertys
By X-ray diffraction method, the Sodium acyclovir dihydrate powder of new crystal is placed on powder diffractometer, with 8 degree/point scanning speed scan between 2 θ angles at 2.6～40 degree, use Cu-Ka 40Kv～100mAX x radiation x.
The X-ray powder diffraction of accompanying drawing 1 crystal formation I
The X-ray powder diffraction of accompanying drawing 2 crystal form IIs
Embodiment 5 therapeutic evaluation experiments
40 of the cavys of herpes simplex infections.Be divided at random 4 groups: blank model control group, Sodium acyclovir control group, the brilliant I group of Sodium acyclovir, the brilliant II group of Sodium acyclovir.Medication is: administration group 200mg/ time, and gavage gives, and control group gives the physiological saline of equal volume, and gavage volume is 1.5mL/100g, administration 1 time in every 5 hours, successive administration 1 week.Efficacy determination: adopt integration to represent the different healings of bleb, 1 point: warts is withered. and have knot silly; 2 points: 50%-70% is silly, and piece comes off: 3 points: 70%～90% silly piece comes off; 4 points: silly piece comes off completely, bleb healing, records each medication group different time cavy bleb curative effect integration.
Result: each medication group curative effect integration is in table 1, after treatment, the 3rd day each medication group and negative control group are more effective in cure as seen from Table 1, have difference (P < 0.01); Sodium acyclovir and the comparison of acyclovir sodium crystal group, also have significant difference (P < 0.05). and acyclovir sodium crystal group more can effectively suppress the infection of simplexvirus.
Table 1 Sodium acyclovir and the comparison of crystal formation curative effect thereof
T inspection: with model control group comparison, * P < 0.01
With the comparison of Sodium acyclovir group, #P < 0.05
Claims (4)
1. a crystal formation I for Sodium acyclovir, is characterized in that the X-ray powder diffraction pattern of this crystal is about 10.2,13.5 at reflection angle 2 θ, 16.7,18.2,23.5,24.7, and there is charateristic avsorption band at 26.8,29.0 places.
2. a preparation method of crystal formation I as claimed in claim 1, is characterized in that: by by described compound water dissolution, add methyl alcohol, leave standstill crystallization.
3. preparation method claimed in claim 3, is characterized in that, the consumption of water is 2～20 times of Sodium acyclovir weight, methanol usage is water consumption 0.5～50 times.
4. preparation method claimed in claim 3, is characterized in that, add methyl alcohol after solution clarify.
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| Application Number | Priority Date | Filing Date | Title |
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| CN200910090294.0A CN101987851B (en) | 2009-08-04 | 2009-08-04 | Crystal forms of Acyclovir sodium dihydrate and preparation method thereof |
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| CN200910090294.0A CN101987851B (en) | 2009-08-04 | 2009-08-04 | Crystal forms of Acyclovir sodium dihydrate and preparation method thereof |
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| Publication Number | Publication Date |
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| CN101987851A CN101987851A (en) | 2011-03-23 |
| CN101987851B true CN101987851B (en) | 2014-06-18 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103113371B (en) * | 2012-10-22 | 2015-02-25 | 中山大学 | Acyclovir eutectic and preparation method thereof and preparation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1383827A (en) * | 2002-05-14 | 2002-12-11 | 刘万忠 | Prepn of antiviral N-9 substituted guanine medicine powder for injection |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1383827A (en) * | 2002-05-14 | 2002-12-11 | 刘万忠 | Prepn of antiviral N-9 substituted guanine medicine powder for injection |
Non-Patent Citations (1)
| Title |
|---|
| 姜国坤，陈承清.注射用阿昔洛韦钠的溶媒结晶法制备探讨.《中国医药工业杂志》.2002,第33卷(第2期),79-80. * |
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Effective date of registration: 20160414 Address after: Hangzhou City, Zhejiang province Yuhang District 310013 West Street warehouse before No. 1500 Building 1 room 237 Patentee after: Hangzhou Zhepu Taikang Biological Medicine Technology Co Ltd Address before: 100070 Beijing City, Fengtai District science and Technology Park Fung Fu Road No. 4 Building 16 layer 16A02 Federation of science and technology Patentee before: Beijing Lilesheng Pharmaceutical Technology Co., Ltd. |
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