CN102267936A - Preparation method of arbidol methanesulfonate crystal - Google Patents
Preparation method of arbidol methanesulfonate crystal Download PDFInfo
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- CN102267936A CN102267936A CN2011102563642A CN201110256364A CN102267936A CN 102267936 A CN102267936 A CN 102267936A CN 2011102563642 A CN2011102563642 A CN 2011102563642A CN 201110256364 A CN201110256364 A CN 201110256364A CN 102267936 A CN102267936 A CN 102267936A
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Abstract
The invention discloses a preparation method of an arbidol methanesulfonate crystal, which comprises the following steps: dissolving active pharmaceutical ingredient arbidol in an organic solvent, heating to 45-55 DEG C, adding methanesulfonic acid, stirring to react for 0.5-1.5 hours, cooling, continuing stirring for 10-14 hours until the crystal precipitates, filtering to collect the precipitate crystal, washing the crystal with isopropanol 1-3 times, and carrying out vacuum drying to obtain the low-hygroscopicity arbidol methanesulfonate crystal which can satisfy the demand for pharmaceutical preparation stability. The purity of the arbidol methanesulfonate crystal is higher than 99.5%.
Description
Technical field
The present invention relates to the preparing technical field of medicine crystal formation, be specifically related to the preparation method of suitable medicinal crystal formation of the medicine methylsulfonic acid Arbidol of a kind of treatment and flu-prevention virus.
Background technology
The antiviral chemicals that uses clinically both at home and abroad mainly contains Arbidol, ribavirin, amantadine, Rimantadine, Oseltamivir and zanamivir etc. at present.Wherein, when ribavirin uses in heavy dose, first type and Influenza B virus are all had activity, but its have nucleoside medicine teratogenesis, cause change toxicity, can cause anaemia and immunosuppression.Amantadine and Rimantadine are only effective to influenza A, and are prone to resistance.Such medicine also can cause the toxic reaction of central nervous system, thereby has reduced clinical use value.The determined curative effect of neuraminidase inhibitor Oseltamivir and zanamivir, but price is very expensive.
Be a kind of resisiting influenza virus new drug in Russia and Chinese arbidol HCl and the oral solid formulation (sheet, capsule, dispersible tablet, granule) thereof that goes on the market at present.Its mechanism of action is by activating 2 ', 5 '-oligo-adenylate synthetase, and specificity suppresses the fusion of viral lipid cyst membrane and host cell membrane, thus the duplicating of blocking virus.Arbidol HCl successfully goes on the market in Russia and China, is mainly used in and prevents and treats the upper respiratory tract infection that first, Influenza B virus causes.It has following advantage and characteristics: 1, to influenza virus A type and B-mode all effective.2, existing therapeutic action also has prophylactic effect.3, have the direct dual function that suppresses virus and induce endogenous interferon concurrently.Arbidol HCl toxicity is very low, foreign literature report rat and the oral 2000mg/kg of the single agent of cavy, and well-tolerated shows that oral acute toxicity is very low, estimates LD
50＞3000mg/kg.The oral LD of mouse
50=340mg/kg.Chronic toxicity test: rat 100-125mg/kg, dog 25mg/kg, oral administration 6 months pathology all do not occur and changes, and is safer to rabbit and cavy long-term prescription yet.
The physico-chemical property characteristics of arbidol HCl are its almost insoluble in water (1g this product can not be dissolved in 10000mL water), and the preparation stripping is slower, might influence in its body to absorb.
Russia has carried out the research of methylsulfonic acid Arbidol again after hydrochloric acid Ah Bill listing, studies show that the methylsulfonic acid Arbidol has preferably resisiting influenza virus curative effect and toxicity low, is a kind of product innovation that DEVELOPMENT PROSPECT is arranged.
The methylsulfonic acid Arbidol is 6-bromo-4-(dimethyl aminomethyl)-5-hydroxyl-1-methyl-2-(benzene thiomethyl)-1H-Indole-3-Carboxylic Acid second fat mesylate, English name Abidol Mesylate.Structural formula is as follows:
Russ P RU2394618C2 mentions the methylsulfonic acid Arbidol, but does not relate to concrete crystal formation.The methylsulfonic acid Arbidol does not have the powder of crystal formation, suction easily, and instability is difficult for preserving.The methylsulfonic acid Arbidol crystal of the present invention's preparation is a kind of crystal habit of not moisture substantially and other solvents newly.
Summary of the invention
At the deficiencies in the prior art, the object of the present invention is to provide a kind of preparation method of methylsulfonic acid Arbidol crystal formation of not moisture and other solvents.Prepared methylsulfonic acid Arbidol stable crystal form, water absorbability is low, preserves solvability good (1g this product dissolves in the 27mL water) easily.The preparation method is easy, and is easy to operate, is fit to suitability for industrialized production.
In order to realize purpose of the present invention, the present invention has taked following technical scheme, a kind of preparation method of methylsulfonic acid Arbidol crystal formation, and its step is as follows:
The Arbidol bulk drug is dissolved in organic solvent and is heated to 45-55 ℃, add methylsulfonic acid then, stirring reaction 0.5-1.5h, after the cooling, continue to stir 10-14h crystallization is separated out, the crystallization that the filter collection is separated out, use washed with isopropyl alcohol crystallization 1-3 time then, after the vacuum-drying, it is low and can satisfy the methylsulfonic acid Arbidol crystal formation of pharmaceutical preparation stability requirement promptly to obtain a kind of water absorbability, and purity reaches more than 99.5%.
Described organic solvent is methylene dichloride, dehydrated alcohol or acetone;
Described Arbidol bulk drug and consumption of organic solvent ratio are 1g: (5-10) mL;
The mol ratio of described Arbidol bulk drug and methylsulfonic acid is 1: 0.8-1: 1.5;
The speed of described stirring is 100-750rpm.
This crystallization processes need not special operation, time-saving energy-saving.
The crystal characteristic of the methylsulfonic acid Arbidol that the inventive method makes:
(1) melting range is 167.5-168.5 ℃;
(2) differential thermal analysis (DSC) collection of illustrative plates is seen Fig. 1, and an endotherm(ic)peak is arranged near 206.27 ℃;
(3) infared spectrum is seen collection of illustrative plates 2, and the collection of illustrative plates that methylsulfonic acid Arbidol crystal records with the KBr compressing tablet is 3414,3065,2981,2361,1691,1481,1437,1326,1175,1039,955,773,736 and 553cm
-1There is strong absorption peak at the place;
(4) the X-ray powder diffraction is seen collection of illustrative plates 3, and 2 θ that show with kilsyth basalt have characteristic peak at 10.18,11.88,12.36,14.09,14.32,16.85,19.08,20.05,20.10,36.33 places.
The preparation method's of a kind of methylsulfonic acid Arbidol crystal formation of the present invention advantage and beneficial effect are as follows:
1, step is few, and agents useful for same is few, meets the requirement of environmental protection and energy saving.
2, the methylsulfonic acid Arbidol crystalline for preparing of the inventive method has good stability, and has guaranteed the stability that it is medicinal.
Description of drawings
Fig. 1 is the differential scanning calorimetric figure (DSC figure) of methylsulfonic acid Arbidol crystal of the present invention (being made by embodiment 1).
Fig. 2 is the infrared absorpting light spectra of methylsulfonic acid Arbidol crystal of the present invention (being made by embodiment 2).
Fig. 3 is the x-ray diffraction pattern of methylsulfonic acid Arbidol crystal of the present invention (being made by embodiment 3).
Embodiment
Below in conjunction with specific embodiment the inventive method is described in further detail.
Embodiment 1
A kind of preparation method of methylsulfonic acid Arbidol crystal formation, its step is as follows:
Arbidol 5.7g is dissolved in the acetone of 50mL, is heated to 50 ℃, add methylsulfonic acid 1.49g then, stirring reaction 1h, be chilled to room temperature, 500rpm stirs and spends the night (12h) suction filtration, solid is washed 2 times with Virahol, get methylsulfonic acid Arbidol crystal 5 .5g after the vacuum-drying, yield is 80.2%, detects through HPLC, product purity is 99.6%, fusing point 167.5-168.5 ℃.
Embodiment 2
A kind of preparation method of methylsulfonic acid Arbidol crystal formation, its step is as follows:
Arbidol 5.7g is dissolved in the dehydrated alcohol of 40mL, is heated to 45 ℃, add methylsulfonic acid 1.49g then, stirring reaction 0.5h, be chilled to room temperature, 300rpm stirs and spends the night (14h) suction filtration, solid is washed 3 times with Virahol, get methylsulfonic acid Arbidol crystal 5 .1g after the vacuum-drying, yield is 74.4%, detects through HPLC, product purity is 99.6%, fusing point 167.5-168.5 ℃.
Embodiment 3
A kind of preparation method of methylsulfonic acid Arbidol crystal formation, its step is as follows:
Arbidol 5.7g is dissolved in the methylene dichloride of 40mL, is heated to 55 ℃, add methylsulfonic acid 1.49g then, stirring reaction 1.5h, be chilled to room temperature, 700rpm stirs and spends the night (10h) suction filtration, solid is washed 2 times with Virahol, get methylsulfonic acid Arbidol crystal 5 .8g after the vacuum-drying, yield is 84.6%, detects through HPLC, product purity is 99.7%, fusing point 167.5-168.5 ℃.
The methylsulfonic acid Arbidol crystalline property testing that the inventive method makes
One, solvability:
Test with reference to 2010 editions notes on the use of Chinese Pharmacopoeia, method: it is an amount of that precision takes by weighing methylsulfonic acid Arbidol crystal (being made by embodiment 1), slowly adds certain amount of solvent, and powerful jolting was 30 seconds every 5 minutes, observe the dissolving situation in 30 minutes, the results are shown in Table 1.
The solubility test of table 1 methylsulfonic acid Arbidol
Test result is that this product is easily molten in methyl alcohol, in water, dissolves, and slightly soluble in Glacial acetic acid, almost insoluble in dilute hydrochloric acid and sodium hydroxide solution.Illustrate that this product solubleness in water compared large increase with arbidol HCl.
| Solvent | Solute amount (g) | Quantity of solvent (mL) | Phenomenon | Conclusion |
| Water | ?1 | 27 | Dissolving | Dissolving |
| Methyl alcohol | ?1 | 10 | Dissolving | Yi Rong |
| Glacial acetic acid | ?1 | 110 | Dissolving | Slightly soluble |
| 0.1mol/L?HCl | ?0.1 | 1000 | Insoluble | Almost insoluble |
| 0.1mol/L?NaOH | ?0.11 | 1000 | Insoluble | Almost insoluble |
Embodiment 2 and 3 obtained crystalline solubility experiment operations and result and embodiment 1 do not display one by one at this together.
Two, stability
1, exposure experiments to light
Methylsulfonic acid Arbidol crystal (embodiment 1-3 is obtained) is evenly spread out to uncovered culture dish, thickness is less than 5mm, place under the 4500lx illumination and shine, sampling detects during respectively at 5 days, 10 days, and compares, the results are shown in Table 2-1,2-2 and 2-3 with 0 day result.
The crystalline exposure experiments to light (4500LX) that table 2-1 embodiment 1 makes
| Time (my god) | Proterties | Content (%) | Related substance (%) | Solubleness in the water (g/100mL) |
| 0 | The off-white color crystalline powder | 99.62 | 0.38 | 3.7 |
| 5 | The off-white color crystalline powder | 99.64 | 0.36 | 3.7 |
| 10 | The off-white color crystalline powder | 99.62 | 0.38 | 3.7 |
The crystalline exposure experiments to light (4500LX) that table 2-2 embodiment 2 makes
| Time (my god) | Proterties | Content (%) | Related substance (%) | Solubleness in the water (g/100mL) |
| 0 | The off-white color crystalline powder | 99.64 | 0.36 | 3.7 |
| 5 | The off-white color crystalline powder | 99.63 | 0.37 | 3.7 |
| 10 | The off-white color crystalline powder | 99.62 | 0.38 | 3.7 |
The crystalline exposure experiments to light (4500LX) that table 2-3 embodiment 3 makes
| Time (my god) | Proterties | Content (%) | Related substance (%) | Solubleness in the water (g/100mL) |
| 0 | The off-white color crystalline powder | 99.71 | 0.29 | 3.7 |
| 5 | The off-white color crystalline powder | 99.69 | 0.31 | 3.7 |
| 10 | The off-white color crystalline powder | 99.68 | 0.32 | 3.7 |
2, high temperature test
Be positioned under 60 ℃ of conditions methylsulfonic acid Arbidol crystal (embodiment 1-3 is obtained) is uncovered, sampling detects during respectively at 5 days, 10 days, and compares with 0 day result, the results are shown in Table 3-1,3-2 and 3-3.
The crystalline high temperature test (60 ℃) that table 3-1 embodiment 1 makes
| Time (my god) | Proterties | Content (%) | Related substance (%) | Solubleness in the water (g/100mL) |
| 0 | The off-white color crystalline powder | 99.62 | 0.38 | 3.7 |
| 5 | The off-white color crystalline powder | 99.63 | 0.37 | 3.7 |
| 10 | The off-white color crystalline powder | 99.64 | 0.36 | 3.7 |
The crystalline high temperature test (60 ℃) that table 3-2 embodiment 2 makes
| Time (my god) | Proterties | Content (%) | Related substance (%) | Solubleness in the water (g/100mL) |
| 0 | The off-white color crystalline powder | 99.64 | 0.36 | 3.7 |
| 5 | The off-white color crystalline powder | 99.65 | 0.35 | 3.7 |
| 10 | The off-white color crystalline powder | 99.66 | 0.34 | 3.7 |
The crystalline high temperature test (60 ℃) that table 3-3 embodiment 3 makes
| Time (my god) | Proterties | Content (%) | Related substance (%) | Solubleness in the water (g/100mL) |
| 0 | The off-white color crystalline powder | 99.71 | 0.29 | 3.7 |
| 5 | The off-white color crystalline powder | 99.71 | 0.29 | 3.7 |
| 10 | The off-white color crystalline powder | 99.72 | 0.28 | 3.7 |
3, high wet test
Methylsulfonic acid Arbidol crystal (embodiment 1-3 is obtained) is evenly shared uncovered being positioned in the culture dish, thickness is less than 5mm, place 25 ℃ of room temperatures, under the environment of relative humidity 92.5%, sampling detects during respectively at 5 days, 10 days, and compare during with 0 day, the results are shown in Table 4-1,4-2 and 4-3.
The high wet test of crystalline (25 ℃, relative humidity 92.5%) that table 4-1 embodiment 1 makes
| Time (my god) | Proterties | Content (%) | Related substance (%) | Solubleness in the water (g/100mL) |
| 0 | The off-white color crystalline powder | 99.62 | 0.38 | 3.7 |
| 5 | The off-white color crystalline powder | 99.63 | 0.37 | 3.7 |
| 10 | The off-white color crystalline powder | 99.64 | 0.36 | 3.7 |
The high wet test of crystalline (25 ℃, relative humidity 92.5%) that table 4-2 embodiment 2 makes
| Time (my god) | Proterties | Content (%) | Related substance (%) | Solubleness in the water (g/100mL) |
| 0 | The off-white color crystalline powder | 99.64 | 0.36 | 3.7 |
| 5 | The off-white color crystalline powder | 99.64 | 0.36 | 3.7 |
| 10 | The off-white color crystalline powder | 99.65 | 0.35 | 3.7 |
The high wet test of crystalline (25 ℃, relative humidity 92.5%) that table 4-3 embodiment 3 makes
| Time (my god) | Proterties | Content (%) | Related substance (%) | Solubleness in the water (g/100mL) |
| 0 | The off-white color crystalline powder | 99.71 | 0.29 | 3.7 |
| 5 | The off-white color crystalline powder | 99.72 | 0.28 | 3.7 |
| 10 | The off-white color crystalline powder | 99.73 | 0.27 | 3.7 |
By The above results as can be known, the methylsulfonic acid Arbidol crystal that the present invention obtains is at exposure experiments to light, and in high temperature test (60 ℃) and the high humidity experiment, outward appearance and content all do not have bigger variation, and its stable in properties is described.Detect by XRD, before and after above-mentioned test, find no the transformation of crystal formation.
Our company entrusts effect experiment unit to carry out the external test of pesticide effectiveness (product of embodiment 3): in the safe concentration scope, methylsulfonic acid Arbidol and arbidol HCl are chosen 6 concentration gradients respectively, each concentration repeats 3 holes, adds pastille and keeps substratum, 35 ℃, 5%CO
2Cultivate, establish normal cell contrast and the contrast of first influenza virus H1N1 virus simultaneously.Every day, observation of cell changed under inverted microscope, treat that first influenza virus H1N1 virus control group CPE reaches more than 80%, and the cell control group just often, with MTT viable cell dyeed, and reads the A590 light absorption value.Calculate the inhibiting rate of medicine,, draw the probit regression curve, calculate medicine IC50 according to inhibiting rate and corresponding concentration relation to virus.At last, calculate the therapeutic index TI (TI=TC50/IC50) of medicine according to TC50 (median toxic concentration) and IC50 (medium effective concentration).It carries out three tests, and the result is as follows:
External resisiting influenza virus results of pharmacodynamic test shows that the methylsulfonic acid Arbidol is better than arbidol HCl to first influenza virus H1N1 and its clinical separation strain effect, and cytotoxicity is lower.
Claims (4)
1. the preparation method of a methylsulfonic acid Arbidol crystal formation, its step is as follows:
The Arbidol bulk drug is dissolved in organic solvent and is heated to 45-55 ℃, add methylsulfonic acid then, stirring reaction 0.5-1.5h, after the cooling, continue to stir 10-14h crystallization is separated out, the crystallization that the filter collection is separated out, use washed with isopropyl alcohol crystallization 1-3 time then, after the vacuum-drying, promptly;
Described organic solvent is methylene dichloride, dehydrated alcohol or acetone.
2. preparation method according to claim 1 is characterized in that: described Arbidol bulk drug and consumption of organic solvent ratio are 1g:5mL-1g:10mL.
3. preparation method according to claim 1 is characterized in that: the mol ratio of described Arbidol bulk drug and methylsulfonic acid is 1:0.8-1:1.5.
4. preparation method according to claim 1 is characterized in that: the speed of described stirring is 100-750rpm.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106366029A (en) * | 2016-08-19 | 2017-02-01 | 江苏吴中医药集团有限公司苏州制药厂 | Arbidol mesylate monohydrate crystal C and its preparation method and use |
| CN116102486A (en) * | 2022-10-31 | 2023-05-12 | 盈科瑞（天津）创新医药研究有限公司 | Arbidol mesylate crystal form IV and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2255086C1 (en) * | 2004-04-21 | 2005-06-27 | Закрытое Акционерное Общество "Мастерклон" | 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5- hydroxy-6 -bromoindole mesylate eliciting antiviral activity and pharmaceutical composition with its usage |
| WO2005102320A1 (en) * | 2004-04-21 | 2005-11-03 | Zakrytoe Aktsionernoe Obschestvo 'masterklon' | Medicinal agent for treating viral infections |
| CN1792362A (en) * | 2005-11-29 | 2006-06-28 | 沈阳中海生物技术开发有限公司 | Intravenous administration preparation of arbidol and salt thereof and preparation method |
-
2011
- 2011-09-01 CN CN 201110256364 patent/CN102267936B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2255086C1 (en) * | 2004-04-21 | 2005-06-27 | Закрытое Акционерное Общество "Мастерклон" | 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5- hydroxy-6 -bromoindole mesylate eliciting antiviral activity and pharmaceutical composition with its usage |
| WO2005102320A1 (en) * | 2004-04-21 | 2005-11-03 | Zakrytoe Aktsionernoe Obschestvo 'masterklon' | Medicinal agent for treating viral infections |
| CN1792362A (en) * | 2005-11-29 | 2006-06-28 | 沈阳中海生物技术开发有限公司 | Intravenous administration preparation of arbidol and salt thereof and preparation method |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106366029A (en) * | 2016-08-19 | 2017-02-01 | 江苏吴中医药集团有限公司苏州制药厂 | Arbidol mesylate monohydrate crystal C and its preparation method and use |
| CN116102486A (en) * | 2022-10-31 | 2023-05-12 | 盈科瑞（天津）创新医药研究有限公司 | Arbidol mesylate crystal form IV and preparation method and application thereof |
| CN116102486B (en) * | 2022-10-31 | 2024-02-13 | 盈科瑞（天津）创新医药研究有限公司 | Arbidol mesylate crystal form IV and preparation method and application thereof |
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