CN104761453A - Dimethyl fumarate crystal form and preparation method thereof - Google Patents
Dimethyl fumarate crystal form and preparation method thereof Download PDFInfo
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- CN104761453A CN104761453A CN201510193140.XA CN201510193140A CN104761453A CN 104761453 A CN104761453 A CN 104761453A CN 201510193140 A CN201510193140 A CN 201510193140A CN 104761453 A CN104761453 A CN 104761453A
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- dimethyl fumarate
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Abstract
The invention relates to a dimethyl fumarate crystal form and a preparation method thereof. The X-ray powder diffraction spectrum of the crystal form has characteristic peaks at the following d values: 7.431, 3.872, 3.553 and 3.142. The method for preparing the crystal form comprises the following steps: dissolving dimethyl fumarate in an organic solvent, and crystallizing, thereby obtaining the crystal form. The novel crystal form disclosed by the invention is high in stability, and the preparation method is high in controllability and high in reproducibility and is suitable for large-scale pharmaceutical production.
Description
Technical field
The present invention relates to a kind of new crystal, be specifically related to a kind of dimethyl fumarate crystal formation and preparation method thereof.
Background technology
Dimethyl fumarate (DMF) is a kind of excellent antisepsis antistaling agent, there is wide spectrum, efficiently antibacterial, germicidal action, and there is insecticidal action, toxicity is low, chemical stability is good, the pH value range be suitable for is wider, and fungistatic effect is obviously better than preservative benzoic acid, Sorbic Acid, dehydro-acetic acid, propionic acid and other salt etc., can be widely used in food, feed, grain, fruit, vegetables, textiles, the mildew-resistant of makeup and medicine, insect protected.But existing dimethyl fumarate stability and bioavailability poor, growing market demand can not be met, and up to the present, also not have the crystal formation of dimethyl fumarate to report.
Summary of the invention
The invention provides a kind of dimethyl fumarate crystal formation and preparation method thereof, described new crystal good stability, its preparation method controllability is good, favorable reproducibility, is suitable for mass-producing pharmaceutical manufacturing.
For solving the problem, the present invention by the following technical solutions:
Design a kind of dimethyl fumarate crystal formation, the X-ray powder diffraction of described crystal formation has characteristic peak in following d value: 7.431,3.872,3.553,3.142.
Preferably, the X-ray powder diffraction of described crystal formation also has characteristic peak in following d value: 4.787,2.616,2.562.
Preferred, the X-ray powder diffraction of described crystal formation as shown in Figure 1.
Preferably, the differential thermal/thermogravimetric analysis collection of illustrative plates of described crystal formation as shown in Figure 2.
The present invention also designs a kind of preparation method of above-mentioned dimethyl fumarate crystal formation, is dissolved in by dimethyl fumarate in organic solvent, carries out crystallization, obtain described crystal formation.
Preferably, described organic solvent is methyl alcohol.
Preferred, dimethyl fumarate and methyl alcohol are joined in container, is heated to backflow, after stirring 0.5 ~ 1.5h, naturally cool to 25 DEG C, crystallization, filter, methanol wash twice, collect filter cake, dry and get final product.
Preferred, described methanol usage is 10 ~ 15 times of dimethyl fumarate weight.
positive beneficial effect of the present invention:
The different crystal forms of same compound may have remarkable difference in outward appearance, solubleness, fusing point, dissolution rate, biological effectiveness etc., thus has influence on the drug effect of the stability of compound, bioavailability and mildew-resistant, insect protected, and this kind of phenomenon clearly.Compound polymorphism is one of important factor affecting anti-corrosive fresh-keeping quality and practical application.Dimethyl fumarate stability of crystal form of the present invention is good, and its preparation method is stablized controlled, favorable reproducibility, is suitable for large-scale production.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRPD) collection of illustrative plates of dimethyl fumarate crystal formation of the present invention.
Fig. 2 is differential thermal/thermogravimetric analysis (DSC/TG/DTG) collection of illustrative plates of dimethyl fumarate crystal formation of the present invention.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in more detail.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Dimethyl fumarate crude product used in following examples of the present invention, also prepare by following methods by commercial: 116g fumaric acid and 600mL methyl alcohol are joined 2L single port bottle, carry out mechanical stirring, then add 14.1g boron trifluoride diethyl etherate, be warming up to backflow, after stirring 8h, HPLC detection is carried out in sampling, disappears to raw material, cooling, crystallization, filters to obtain crude product.
embodiment 1
A kind of preparation method of dimethyl fumarate crystal formation, comprise the following steps: 130g dimethyl fumarate and 1300g methyl alcohol are joined in 3L there-necked flask, be heated to backflow, stir 1h, naturally cool to 25 DEG C, crystallization, filter, anhydrous methanol washes twice, collect filter cake, dry to obtain white solid 115g, as shown in Figure 1, its differential thermal/thermogravimetric analysis (DSC/TG/DTG) collection of illustrative plates as shown in Figure 2 for its X-ray powder diffraction (XRPD) collection of illustrative plates.
embodiment 2
A kind of preparation method of dimethyl fumarate crystal formation, comprise the following steps: 130g dimethyl fumarate and 1600g methyl alcohol are joined in 3L there-necked flask, be heated to backflow, stir 0.5h, naturally cool to 25 DEG C, crystallization, filter, anhydrous methanol washes twice, and collects filter cake, dry to obtain white solid 110g, its XRPD, DSC, TG, DTG collection of illustrative plates is identical with embodiment 1.
embodiment 3
A kind of preparation method of dimethyl fumarate crystal formation, comprise the following steps: 130g dimethyl fumarate and 1950g methyl alcohol are joined in 3L there-necked flask, be heated to backflow, stir 1.5h, naturally cool to 25 DEG C, crystallization, filter, anhydrous methanol washes twice, and collects filter cake, dry to obtain white solid 102g, its XRPD, DSC, TG, DTG collection of illustrative plates is identical with embodiment 1.
The present invention is not limited to above-mentioned embodiment, and those skilled in the art also can make multiple change accordingly, but to be anyly equal to the present invention or similar change all should be encompassed in the scope of the claims in the present invention.
Claims (8)
1. a dimethyl fumarate crystal formation, is characterized in that: the X-ray powder diffraction of described crystal formation has characteristic peak in following d value: 7.431,3.872,3.553,3.142.
2. dimethyl fumarate crystal formation according to claim 1, is characterized in that: the X-ray powder diffraction of described crystal formation also has characteristic peak in following d value: 4.787,2.616,2.562.
3. dimethyl fumarate crystal formation according to claim 2, is characterized in that: the X-ray powder diffraction of described crystal formation as shown in Figure 1.
4. dimethyl fumarate crystal formation according to claim 1, is characterized in that: the differential thermal/thermogravimetric analysis collection of illustrative plates of described crystal formation as shown in Figure 2.
5. a preparation method for dimethyl fumarate crystal formation described in claim 1, is characterized in that: be dissolved in by dimethyl fumarate in organic solvent, carries out crystallization, obtain described crystal formation.
6. preparation method according to claim 5, is characterized in that: described organic solvent is methyl alcohol.
7. preparation method according to claim 6, is characterized in that: join in container by dimethyl fumarate and methyl alcohol, is heated to backflow, after stirring 0.5 ~ 1.5h, naturally cool to 25 DEG C, crystallization, filter, methanol wash twice, collects filter cake, dries and get final product.
8. preparation method according to claim 7, is characterized in that: described methanol usage is 10 ~ 15 times of dimethyl fumarate weight.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510193140.XA CN104761453A (en) | 2015-04-22 | 2015-04-22 | Dimethyl fumarate crystal form and preparation method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432464A (en) * | 2011-12-14 | 2012-05-02 | 费近峰 | Continuous production process of dimethyl fumarate |
| CN102766050A (en) * | 2012-08-10 | 2012-11-07 | 太仓市运通化工厂 | Method for synthesizing dimethyl fumarate |
| CN103649041A (en) * | 2011-06-08 | 2014-03-19 | 比奥根艾迪克Ma公司 | Process for preparing high purity and crystalline dimethyl fumarate |
| CN103848739A (en) * | 2014-03-20 | 2014-06-11 | 徐晓宁 | Production method of high-purity dimethyl fumarate |
| CN104151165A (en) * | 2014-08-11 | 2014-11-19 | 广东东阳光药业有限公司 | Preparation method of dimethyl fumarate |
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2015
- 2015-04-22 CN CN201510193140.XA patent/CN104761453A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103649041A (en) * | 2011-06-08 | 2014-03-19 | 比奥根艾迪克Ma公司 | Process for preparing high purity and crystalline dimethyl fumarate |
| CN102432464A (en) * | 2011-12-14 | 2012-05-02 | 费近峰 | Continuous production process of dimethyl fumarate |
| CN102766050A (en) * | 2012-08-10 | 2012-11-07 | 太仓市运通化工厂 | Method for synthesizing dimethyl fumarate |
| CN103848739A (en) * | 2014-03-20 | 2014-06-11 | 徐晓宁 | Production method of high-purity dimethyl fumarate |
| CN104151165A (en) * | 2014-08-11 | 2014-11-19 | 广东东阳光药业有限公司 | Preparation method of dimethyl fumarate |
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Application publication date: 20150708 |