CN104292128A - Safinamide of crystasl form A - Google Patents
Safinamide of crystasl form A Download PDFInfo
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- CN104292128A CN104292128A CN201410308151.3A CN201410308151A CN104292128A CN 104292128 A CN104292128 A CN 104292128A CN 201410308151 A CN201410308151 A CN 201410308151A CN 104292128 A CN104292128 A CN 104292128A
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Abstract
The invention relates to the technical field of medicines, and concretely relates to safinamide of crystal form A, its preparation method, a medicinal composition containing it, and its use in the treatment of the Parkinson disease and the Alzheimer's disease. An X-raw powder diffraction pattern of the safinamide of crystal form A under the radiation of Cu-Kalpha has peaks at 2theta values of 9.018, 11.575, 13.988, 14.553, 15.239, 15.611, 16.567, 17.235, 17.491, 18.859, 19.671, 20.915, 21.349, 22.074, 23.663, 24.311, 27.468, 28.432 and 30.302.
Description
Technical field
The present invention relates to medical art, relate to FCE-26743A crystal form A and preparation method thereof particularly, containing its pharmaceutical composition and the purposes at treatment treatment Parkinson's disease, alzheimer disease thereof.
Background technology
FCE-26743A (safinamide) praises the exploitation of nation (Zambon) joint research and development by the drugmaker's knob grand (Newron) and marketing partner thereof being devoted to exploitation central nervous system disease medicine.FCE-26743A is a kind of sodium channel and calcium channel complex blocking agent, and release glutamate is again selectivity MAO-B inhibitor, selectivity can affect the abnormal neurone of electric discharge and do not change the activity of normal neurons.
FCE-26743A has two advantages compared with its competing product.The first, it has high degree of specificity to MAO-B, therefore can limit or eliminate dietary restrictions (dietary restrictions), and this remains a very large problem in other similar medicine; Second; FCE-26743A has double action mechanism, except can suppressing MAO-B, also has the additional function of suppression glutamic neuron (glutamate release); in theory; this may produce neuroprotective, and compare the situation only providing symptomatic treatment at present, the FCE-26743A more key that can meet on market is not met demand; current MAO-B inhibitor; rasagiline particularly, also been proposed and have neuroprotective, but clinical data can not fully support this hypothesis.Therefore, FCE-26743A becomes possibly more by the medicine of doctor's favor.In any case doctor places high hopes to this medicine medicine, believe that it can slow down the progress of disease.
This product have submitted application for quotation respectively on December 5th, 2013, on May 29th, 2014 to EMA, FDA, and its formulation of declaring is tablet, and technique adopts direct compression, but FCE-26743A has the feature of poor stability.Thus a kind of stable FCE-26743A crystal formation is sought extremely urgent.The present inventor, in the process of constantly research, is groped by test, has prepared a kind of stable FCE-26743A crystal form A newly unexpectedly.
Summary of the invention
The object of this invention is to provide stable FCE-26743A crystal form A.
FCE-26743A crystal form A structural formula of the present invention is as follows:
FCE-26743A crystal form A provided by the present invention, determines its feature through X-powder diffraction method, and it has following spectrum characteristic.Adopt Bruker D8 Advance X-ray diffractometer to analyze to the crystalline phase of sample, Cu K α target, tube voltage 40KV, tube current 40mA, slit is 1.0/1.0/Ni/0.2, and step-length is 0.02 °; Its X-ray powder diffraction pattern characterizes and represents, specifically in table 1 with 2 θ diffraction angle (Angle), spacing (d-value) and diffraction relative intensity (Intensity%).
The X-ray powder diffraction pattern characterization data of table 1 FCE-26743A crystal form A
| Peak no | Angle | d-value | Intensity% |
| 1 | 9.018 | 9.798 | 10.4 |
| 2 | 11.575 | 7.639 | 32.9 |
| 3 | 13.988 | 6.326 | 344.0 |
| 4 | 14.553 | 6.082 | 10.4 |
| 5 | 15.239 | 5.809 | 48.0 |
| 6 | 15.611 | 5.672 | 25.9 |
| 7 | 16.567 | 5.347 | 24.4 |
| 8 | 17.235 | 5.141 | 64.6 |
| 9 | 17.491 | 5.066 | 19.5 |
| 10 | 18.859 | 4.702 | 11.9 |
| 11 | 19.671 | 4.509 | 100.0 |
| 12 | 20.915 | 4.244 | 33.8 |
| 13 | 21.349 | 4.159 | 14.7 |
| 14 | 22.074 | 4.024 | 39.4 |
| 15 | 23.663 | 3.757 | 10.8 |
| 16 | 24.311 | 3.658 | 11.1 |
| 17 | 27.468 | 3.245 | 19.4 |
| 18 | 28.432 | 3.137 | 12.1 |
| 19 | 30.302 | 2.947 | 11.4 |
Those skilled in the art are to be understood that, each crystal formation data listed by the present invention, owing to being subject to the impact of many factors, X-ray powder diffraction measured by same crystal formation go out that peak position or intensity can there is some difference, therefore, the experimental error value of the diffraction peak Angle value in its X-ray powder diffraction of crystal formation of the present invention can be ± and 0.2.
Another object of the present invention is the preparation method providing FCE-26743A crystal form A:
FCE-26743A is joined in acetone, under stirring, be heated to backflow, and keep return stirring 1h, heat filtering, solution is cooled to-10 ~ 10 DEG C, leaves standstill crystallization, suction filtration, collect the crystal grain obtained, at 60 DEG C, vacuum-drying is to constant weight, obtains FCE-26743A crystal form A.More detailed, preparation method of the present invention in an embodiment.
The present invention also further provides the application of FCE-26743A crystal form A in pharmaceutical preparation.
FCE-26743A crystal form A of the present invention and pharmaceutical carrier make pharmaceutical preparation, and described preparation can be made into any pharmaceutically useful formulation.These formulations comprise: tablet, capsule, granule, dry suspensoid, pulvis.
Preparation of the present invention, is preferably tablet, capsule and particle.Wherein containing FCE-26743A crystal form A of the present invention in per unit preparation is 50 ~ 200mg.
The preparation method of above-mentioned preparation normally those skilled in that art knows conventional method, outstandingly generally includes FCE-26743A crystal form A of the present invention and pharmaceutical excipient mixed pressuring plate, filled capsules or makes particle.
FCE-26743A crystal form A of the present invention, its good stability, preparation method is easy, easy handling, used time are short, and cost is low, is easy to suitability for industrialized production.
Advantage of the present invention is further illustrated below by way of testing data:
Amorphous powder prepared by the FCE-26743A crystal form A prepared by the method for the embodiment of the present invention 1 and prior art carries out the study on the stability of accelerated test, and result shows, the amorphous powder that the stability of crystal formation of the present invention is prepared than prior art is more stable.
Table 2 FCE-26743A crystal form A study on the stability
accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of FCE-26743A crystal form A;
Fig. 2 is the DSC differential thermal analysis curve of FCE-26743A crystal form A.
embodiment
For a better understanding of the present invention, below by the description to invention preferred embodiment, explain the present invention in detail, but do not limit the present invention in any form.
Embodiment 1 FCE-26743A crystal form A and preparation thereof
10g FCE-26743A is joined in 100ml acetone, under stirring, be heated to backflow, and keep return stirring 2h, heat filtering, solution is cooled to-10 ~-5 DEG C, leaves standstill crystallization, suction filtration, collect the crystal grain obtained, at 60 DEG C, vacuum-drying is to constant weight, obtains clear crystals body.Its X-ray powder diffraction is shown in that accompanying drawing 1, DSC differential thermal analysis curve is shown in accompanying drawing 2.
Embodiment 2 FCE-26743A crystal form A and preparation thereof
10g FCE-26743A is joined in 50ml acetone, under stirring, be heated to backflow, and keep return stirring 1h, heat filtering, solution is cooled to-5 ~ 0 DEG C, leaves standstill crystallization, suction filtration, collect the crystal grain obtained, at 60 DEG C, vacuum-drying is to constant weight, obtains clear crystals body.Its X-ray powder diffraction is shown in that accompanying drawing 1, DSC differential thermal analysis curve is shown in accompanying drawing 2.
Embodiment 3 FCE-26743A crystal form A and preparation thereof
10g FCE-26743A is joined in 80ml acetone, under stirring, be heated to backflow, and keep return stirring 6h, heat filtering, solution is cooled to-5 ~ 5 DEG C, leaves standstill crystallization, suction filtration, collect the crystal grain obtained, at 60 DEG C, vacuum-drying is to constant weight, obtains clear crystals body.Its X-ray powder diffraction is shown in that accompanying drawing 1, DSC differential thermal analysis curve is shown in accompanying drawing 2.
Embodiment 4 FCE-26743A crystal form A and preparation thereof
10g FCE-26743A is joined in 75ml acetone, under stirring, be heated to backflow, and keep return stirring 3h, heat filtering, solution is cooled to 5 ~ 10 DEG C, leaves standstill crystallization, suction filtration, collect the crystal grain obtained, at 60 DEG C, vacuum-drying is to constant weight, obtains clear crystals body.Its X-ray powder diffraction is shown in that accompanying drawing 1, DSC differential thermal analysis curve is shown in accompanying drawing 2.
Embodiment 5 FCE-26743A crystal form A of the present invention tablet
Every sheet is containing the preparation of the FCE-26743A sheet of 50mg crystal form A:
FCE-26743A is crossed 100 mesh sieves, lactose, starch, sodium starch glycolate cross 80 mesh sieves, and FCE-26743A mixes with sodium starch glycolate (inside adding), starch, lactose, add binder solution 30ml and prepare softwood, 30 orders are granulated, 60 DEG C of dry 85min, obtain dry material, add additional sodium starch glycolate (additional), Magnesium Stearate, after mixing 5min, the whole grain of 24 order, compressing tablet, to obtain final product.
Embodiment 6 FCE-26743A crystal form A of the present invention tablet
Every sheet is containing the preparation of the FCE-26743A sheet of 100mg crystal form A:
FCE-26743A is crossed 100 mesh sieves, lactose, starch, sodium starch glycolate cross 80 mesh sieves, and FCE-26743A mixes with sodium starch glycolate, starch, lactose, add binder solution 40ml and prepare softwood, 30 orders are granulated, 60 DEG C of dry 95min, obtain dry material, add Magnesium Stearate, after mixing 5min, the whole grain of 24 order, compressing tablet, to obtain final product.
Embodiment 7 FCE-26743A crystal form A of the present invention tablet
Every sheet is containing the preparation of the FCE-26743A sheet of 200mg crystal form A:
FCE-26743A is crossed 100 mesh sieves, lactose, starch, sodium starch glycolate cross 80 mesh sieves, and FCE-26743A mixes with sodium starch glycolate (inside adding), starch, lactose, add binder solution 50ml and prepare softwood, 30 orders are granulated, 60 DEG C of dry 75min, obtain dry material, add additional sodium starch glycolate (additional), Magnesium Stearate, after mixing 5min, the whole grain of 24 order, compressing tablet, to obtain final product.
The tablet of embodiment 8 FCE-26743A crystal form A of the present invention
Every sheet is containing the preparation of the FCE-26743A sheet of 100mg crystal form A:
FCE-26743A is crossed 100 mesh sieves, lactose, starch, sodium starch glycolate cross 80 mesh sieves, and FCE-26743A mixes with sodium starch glycolate (inside adding), starch, lactose, add binder solution 50ml and prepare softwood, 30 orders are granulated, 60 DEG C of dry 75min, obtain dry material, add additional sodium starch glycolate (additional), Magnesium Stearate, after mixing 5min, the whole grain of 24 order, compressing tablet, to obtain final product.
Embodiment 9 FCE-26743A crystal form A of the present invention capsule
Every preparation containing the FCE-26743A capsule of 100mg crystal form A:
FCE-26743A is crossed 100 mesh sieves, lactose, Microcrystalline Cellulose, sodium starch glycolate cross 80 mesh sieves, FCE-26743A mixes with sodium starch glycolate, Microcrystalline Cellulose, lactose, adds binder solution 50ml and prepares softwood, and 40 orders are granulated, 60 DEG C of dry 65min, must particle be done, add Magnesium Stearate, after mixing 5min, fill No. 1 capsule, to obtain final product.
Embodiment 9 FCE-26743A crystal form A of the present invention capsule
Every preparation containing the FCE-26743A capsule of 100mg crystal form A:
FCE-26743A is crossed 100 mesh sieves, lactose, Microcrystalline Cellulose, sodium starch glycolate cross 80 mesh sieves, FCE-26743A mixes with sodium starch glycolate, Microcrystalline Cellulose, lactose, adds binder solution 50ml and prepares softwood, and 40 orders are granulated, 60 DEG C of dry 65min, must particle be done, add Magnesium Stearate, after mixing 5min, fill No. 0 capsule, to obtain final product.
Embodiment 9: FCE-26743A crystal form A particle of the present invention
Every bag of preparation containing the FCE-26743A particle of 100mg crystal form A:
FCE-26743A is crossed 100 mesh sieves, lactose, N.F,USP MANNITOL, sodium starch glycolate cross 80 mesh sieves, FCE-26743A mixes with sodium starch glycolate, N.F,USP MANNITOL, lactose, adds binder solution 60ml and prepares softwood, and 40 orders are granulated, 60 DEG C of dry 65min, must particle be done, add sodium stearyl fumarate, after mixing 5min, filling, to obtain final product.
Claims (3)
1. a FCE-26743A crystal form A, its X-ray powder diffraction pattern characterizes as follows:
。
2. the preparation method of FCE-26743A crystal form A according to claim 1, it comprises: joined by FCE-26743A in acetone, under stirring, be heated to backflow, and keep return stirring 1h, heat filtering, solution is cooled to-10 ~ 10 DEG C, leave standstill crystallization, suction filtration, collect the crystal grain obtained, at 60 DEG C, vacuum-drying is to constant weight, to obtain final product.
3. FCE-26743A crystal form A can make tablet, capsule and particle with pharmaceutical carrier according to claim 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410308151.3A CN104292128A (en) | 2014-07-01 | 2014-07-01 | Safinamide of crystasl form A |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410308151.3A CN104292128A (en) | 2014-07-01 | 2014-07-01 | Safinamide of crystasl form A |
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| CN104292128A true CN104292128A (en) | 2015-01-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410308151.3A Pending CN104292128A (en) | 2014-07-01 | 2014-07-01 | Safinamide of crystasl form A |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017060A (en) * | 2015-07-03 | 2015-11-04 | 南京正大天晴制药有限公司 | Novel polymorph of safinamide and preparation method therefor |
| CN105399643A (en) * | 2015-12-17 | 2016-03-16 | 浙江美诺华药物化学有限公司 | Preparation method of safinamide mesilate A1 crystal form |
| CN106361711A (en) * | 2016-09-26 | 2017-02-01 | 扬子江药业集团有限公司 | Methanesulfonic acid safinamide tablet and preparation method thereof |
| CN106580900A (en) * | 2017-02-22 | 2017-04-26 | 佛山市弘泰药物研发有限公司 | Safinamide tablets and preparation method thereof |
| CN106619513A (en) * | 2017-02-22 | 2017-05-10 | 佛山市弘泰药物研发有限公司 | Safinamide self-microemulsion preparation and preparation method thereof |
| CN106667957A (en) * | 2017-02-22 | 2017-05-17 | 佛山市弘泰药物研发有限公司 | Safinamide soft capsules and preparation method thereof |
| CN106667940A (en) * | 2017-02-22 | 2017-05-17 | 佛山市弘泰药物研发有限公司 | Safinamide dispersible tablet and preparation method thereof |
| CN106983730A (en) * | 2017-02-22 | 2017-07-28 | 佛山市弘泰药物研发有限公司 | A kind of FCE-26743A stomach dissolution type pellet tablet and preparation method thereof |
| WO2019167085A1 (en) * | 2018-03-01 | 2019-09-06 | Msn Laboratories Private Limited, R&D Center | Process for the preparation of (s)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide methanesulfonate |
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| CN101896456A (en) * | 2007-12-11 | 2010-11-24 | 纽朗制药有限公司 | Process for the production of 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamides with high purity degree |
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105017060A (en) * | 2015-07-03 | 2015-11-04 | 南京正大天晴制药有限公司 | Novel polymorph of safinamide and preparation method therefor |
| CN105399643A (en) * | 2015-12-17 | 2016-03-16 | 浙江美诺华药物化学有限公司 | Preparation method of safinamide mesilate A1 crystal form |
| CN106361711A (en) * | 2016-09-26 | 2017-02-01 | 扬子江药业集团有限公司 | Methanesulfonic acid safinamide tablet and preparation method thereof |
| CN106361711B (en) * | 2016-09-26 | 2019-06-21 | 扬子江药业集团有限公司 | Methanesulfonic acid FCE-26743A piece and preparation method thereof |
| CN106580900A (en) * | 2017-02-22 | 2017-04-26 | 佛山市弘泰药物研发有限公司 | Safinamide tablets and preparation method thereof |
| CN106619513A (en) * | 2017-02-22 | 2017-05-10 | 佛山市弘泰药物研发有限公司 | Safinamide self-microemulsion preparation and preparation method thereof |
| CN106667957A (en) * | 2017-02-22 | 2017-05-17 | 佛山市弘泰药物研发有限公司 | Safinamide soft capsules and preparation method thereof |
| CN106667940A (en) * | 2017-02-22 | 2017-05-17 | 佛山市弘泰药物研发有限公司 | Safinamide dispersible tablet and preparation method thereof |
| CN106983730A (en) * | 2017-02-22 | 2017-07-28 | 佛山市弘泰药物研发有限公司 | A kind of FCE-26743A stomach dissolution type pellet tablet and preparation method thereof |
| WO2019167085A1 (en) * | 2018-03-01 | 2019-09-06 | Msn Laboratories Private Limited, R&D Center | Process for the preparation of (s)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide methanesulfonate |
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Application publication date: 20150121 |