CN111303041A - Method for preparing mixed crystal form phenytoin sodium - Google Patents
Method for preparing mixed crystal form phenytoin sodium Download PDFInfo
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- CN111303041A CN111303041A CN202010263714.7A CN202010263714A CN111303041A CN 111303041 A CN111303041 A CN 111303041A CN 202010263714 A CN202010263714 A CN 202010263714A CN 111303041 A CN111303041 A CN 111303041A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
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Abstract
The invention provides a method for preparing phenytoin sodium in a mixed crystal form, which comprises the following steps: 1) preparing phenytoin: taking a reaction kettle, adding water and diphenylethanedione, adjusting to be alkaline, adding urea, heating to reflux, filtering after the reaction is finished, dropwise adding concentrated hydrochloric acid, crystallizing and stirring, performing spin filtration, washing a filter cake, discharging to obtain a phenytoin crude product tide product, pulping, performing spin filtration, and discharging to obtain a phenytoin tide product; 2) preparing phenytoin sodium: taking another reaction kettle, putting the phenytoin tide product into the reaction kettle, adding water, heating, dropwise adding a sodium hydroxide solution, adjusting the pH value, decoloring, finely filtering, cooling to room temperature, stirring and crystallizing, performing spin filtration, washing a filter cake, drying the washed solid, and discharging to obtain the phenytoin sodium in a mixed crystal form. The mixed crystal proportion of the phenytoin sodium, the anhydride and the monohydrate prepared by the preparation method is consistent with that of a reference preparation, and the tablets prepared from the mixed crystal phenytoin sodium produced by the method are consistent with that of the reference preparation in vitro dissolution and in vivo bioequivalence.
Description
Technical Field
The invention belongs to the technical field of phenytoin sodium preparation, and particularly relates to a method for preparing phenytoin sodium in a mixed crystal form.
Background
Phenytoin sodium is an antiepileptic drug suitable for the treatment of grand mal seizures, as well as trigeminal neuralgia and certain types of arrhythmias. The chemical name of the phenytoin sodium is 5, 5-diphenylhydantoin, and the chemical structural formula is as follows:
the phenytoin sodium is white powder, odorless, bitter, soluble in water, soluble in ethanol, and almost insoluble in diethyl ether and chloroform. Slightly hygroscopic, carbon dioxide is gradually absorbed in the air and decomposed into phenytoin.
Phenytoin sodium (Phenytoin sodium) has a highly selective inhibitory effect on the motor zone of the cerebral cortex, and is thought to have an anti-epileptic effect by preventing the spread of abnormal discharges by stabilizing the function of the cerebral cell membrane and increasing the effects of the inhibitory neurotransmitters 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) in the brain.
The mechanism of action of anti-neuropathic pain may be related to a decrease in synaptic transmission or a decrease in transient stimuli that cause neuronal firing. It also has effects in inhibiting ectopic rhythm of atrium and ventricle, accelerating atrioventricular conduction, reducing myocardial autonomy, and resisting arrhythmia.
The sodium phenytoin disclosed in US6245917B1 has two crystal forms, one is sodium phenytoin monohydrate (sodium phenytoin monohydrate), and the X-ray diffraction pattern of the sodium phenytoin monohydrate is shown in fig. 1; the other is sodium phenytoin anhydride (sodium phenytoin anhydride), the X-crystal diffraction pattern of the sodium phenytoin anhydride is shown in figure 2, however, the patent only discloses the two crystal forms, but does not describe the mixed crystal ratio in the original preparation.
In the process of consistent evaluation and development, crystal form research finds that the crystal form of the raw material medicine in the reference preparation is a mixed crystal form, wherein the mixed crystal ratio of an anhydride and a monohydrate is 80: 20-95: 5 (an X-crystal form diffraction pattern of the reference preparation is shown in figure 3), and in order to ensure that a self-made product can be consistent with the reference preparation in quality and curative effect, the raw material medicine of the mixed crystal form consistent with the reference preparation must be prepared.
Disclosure of Invention
In order to solve the existing problems, the invention aims to provide a method for preparing mixed crystal form phenytoin sodium, the mixed crystal proportion of the phenytoin sodium, anhydrous substance and monohydrate prepared by the preparation method is consistent with that of a reference preparation, and tablets prepared from the mixed crystal form phenytoin sodium produced by the method are consistent with that of the reference preparation in vitro dissolution and in vivo bioequivalence.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a process for preparing a mixed crystalline form of sodium phenytoin comprising the steps of:
1) preparation of phenytoin
Adding water and benzil diketone into a reaction kettle, adjusting to be alkaline, adding urea, heating to reflux, reacting the benzil diketone and the urea for 1-3 hours under an alkaline condition, filtering after the reaction is finished, dropwise adding concentrated hydrochloric acid into filtrate to adjust the pH value to 4-5, crystallizing, stirring for 1-3 hours, performing throw filtration, washing filter cakes, discharging to obtain a phenytoin crude product tide product, pulping the phenytoin crude product tide product for 1-3 hours at normal temperature, performing throw filtration, and discharging to obtain a phenytoin tide product;
2) preparation of phenytoin sodium
Taking another reaction kettle, putting the phenytoin tide product prepared in the step 1) into the reaction kettle, adding water, heating to 70-75 ℃, dropwise adding a sodium hydroxide solution, adjusting the pH value to 11-12, decoloring, finely filtering, cooling to room temperature, stirring and crystallizing for 6-10 hours, performing filter spinning, washing a filter cake, drying and drying the washed solid until the water content in the solid is 2.5-3.5 wt%, and discharging to obtain the phenytoin sodium in a mixed crystal form.
Furthermore, in the obtained mixed crystal form of the phenytoin sodium, the mixed crystal ratio of the phenytoin sodium anhydride to the phenytoin sodium monohydrate is 80:20 to 95:5
Further, the mass ratio of the water to the benzil in the step 1) is 3-5: 1, the mass ratio of urea to diphenylethanedione is 1: 2 to 3.
Further, adding sodium hydroxide to adjust to be alkaline, wherein the mass ratio of the sodium hydroxide to the urea is (1-1.5): 1.
further, cooling the filtrate obtained in the step 1) to 25-35 ℃, and dropwise adding concentrated hydrochloric acid.
Further, putting the phenytoin crude product damp product obtained in the step 1) into a pulping kettle, adding purified water, pulping for 1-3 hours at normal temperature, wherein the mass ratio of the purified water to the benzidine is 2-3: 1.
further, the water added in the step 2) is purified water, and the mass ratio of the addition amount of the purified water to the benzil diketone is 4-6: 1.
further, the sodium hydroxide solution added dropwise in the step 2) is a 30% sodium hydroxide solution.
Further, activated carbon is adopted for decolorization in the step 2).
Further, the drying step in the step 2) is to place the washed solid in a hot air circulation drying oven for drying, firstly dry the solid at 50-60 ℃ for 3-5 hours, then heat the solid to 80-90 ℃ for 3-5 hours until the water content in the solid is 2.5-3.5 wt%, and stop drying.
The invention has the beneficial effects that:
the mixed crystal proportion of the phenytoin sodium, the anhydride and the monohydrate prepared by the preparation method is consistent with that of a reference preparation, and is 80:20 to 95: 5; the tablet prepared from the mixed crystal phenytoin sodium produced by the method is consistent with a reference preparation in vitro dissolution and in vivo bioequivalence.
The total yield of the prepared phenytoin sodium in a mixed crystal form is 85-90%, and the purity is not lower than 99.95%.
Drawings
FIG. 1 is an X-ray diffraction pattern of sodium phenytoin monohydrate in mixed crystal form of sodium phenytoin provided in U.S. patent;
FIG. 2 is an X-ray diffraction pattern of the anhydrous sodium phenytoin in mixed crystal form of sodium phenytoin provided in the U.S. patent;
FIG. 3 is a diffractogram of the X-form of the reference formulation;
fig. 4 is an X-crystal diffraction pattern of phenytoin sodium prepared by the method for preparing mixed crystal form phenytoin sodium provided by embodiment 1 of the invention.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
The invention relates to a method for preparing phenytoin sodium in a mixed crystal form, which comprises the following steps:
1) preparation of phenytoin
Adding water and benzil diketone into a reaction kettle, adjusting to be alkaline, adding urea, heating to reflux, reacting the benzil diketone and the urea for 1-3 hours under an alkaline condition, filtering after the reaction is finished, dropwise adding concentrated hydrochloric acid into filtrate to adjust the pH value to 4-5, crystallizing, stirring for 1-3 hours, performing throw filtration, washing filter cakes, discharging to obtain a phenytoin crude product tide product, pulping the phenytoin crude product tide product for 1-3 hours at normal temperature, performing throw filtration, and discharging to obtain a phenytoin tide product;
2) preparation of phenytoin sodium
Taking another reaction kettle, putting the phenytoin tide product prepared in the step 1) into the reaction kettle, adding water, heating to 70-75 ℃, dropwise adding a sodium hydroxide solution, adjusting the pH value to 11-12, decoloring, finely filtering, cooling to room temperature, stirring and crystallizing for 6-10 hours, performing filter spinning, washing a filter cake, drying and drying the washed solid until the water content in the solid is 2.5-3.5 wt%, and discharging to obtain the phenytoin sodium in a mixed crystal form.
Further, the mass ratio of the water to the benzil in the step 1) is 3-5: 1, the mass ratio of urea to diphenylethanedione is 1: 2 to 3.
Further, adding sodium hydroxide to adjust to be alkaline, wherein the mass ratio of the sodium hydroxide to the urea is (1-1.5): 1.
further, cooling the filtrate obtained in the step 1) to 25-35 ℃, and dropwise adding concentrated hydrochloric acid.
Further, putting the phenytoin crude product damp product obtained in the step 1) into a pulping kettle, adding purified water, pulping for 1-3 hours at normal temperature, wherein the mass ratio of the purified water to the benzidine is 2-3: 1.
further, the water added in the step 2) is purified water, and the mass ratio of the addition amount of the purified water to the benzil diketone is 4-6: 1.
further, the sodium hydroxide solution added dropwise in the step 2) is a 30% sodium hydroxide solution.
Further, activated carbon is adopted for decolorization in the step 2).
Further, the drying step in the step 2) is to place the washed solid in a hot air circulation drying oven for drying, firstly dry the solid at 50-60 ℃ for 3-5 hours, then heat the solid to 80-90 ℃ for 3-5 hours until the water content in the solid is 2.5-3.5 wt%, and stop drying.
Example 1
The method for preparing the mixed crystal form of sodium phenytoin in example 1 comprises the following steps:
1) preparation of phenytoin
Adding 800kg of water, 200kg of diphenylethanedione, 85kg of urea and 80kg of sodium hydroxide into a 2000L reaction kettle, heating to reflux for reaction for 2 hours, filtering after the reaction is finished, cooling the filtrate to about 30 ℃, dropwise adding concentrated hydrochloric acid to adjust the pH value to 4-5, crystallizing and stirring for 2 hours, performing spin filtration, washing a filter cake with a large amount of water, discharging to obtain a phenytoin crude product tide product, putting the obtained tide product into a pulping kettle, adding 500kg of purified water, pulping at normal temperature for 2 hours, performing spin filtration, and discharging to obtain a phenytoin tide product;
2) preparation of phenytoin sodium
Putting the phenytoin tide product obtained in the step into a 2000L reaction kettle, adding 1000kg of purified water, heating to 70-75 ℃, dropwise adding a 30% sodium hydroxide solution, adjusting the pH value of the system to 11-12, adding activated carbon for decolorization, finely filtering, cooling the filtrate to room temperature, stirring and crystallizing for 8 hours, carrying out filtration, washing a filter cake with a small amount of purified water, discharging, drying the solid in a hot air circulation drying oven, drying for 4 hours at 50-60 ℃, heating to 80-90 ℃ for 4 hours, and discharging to obtain phenytoin sodium in a mixed crystal form, wherein the water content is 2.5% -3.5%.
According to the method for preparing the mixed crystal form phenytoin sodium, in the process of preparing the intermediate 1, tetrahydrofuran is adopted to replace liquid bromine or other brominating agents to prepare the intermediate 1, and in the process of preparing the intermediate 2, tetrahydrofuran solution of tert-butylamine is adopted, so that the generation of similar genotoxic impurities with an α -bromo structure is avoided, the synthetic method is environment-friendly and non-toxic, and the clinical use risk of the synthesized clenbuterol hydrochloride as a raw material medicine is effectively reduced.
It should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and are not limited. Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the present invention.
Claims (10)
1. A process for preparing a mixed crystal form of sodium phenytoin comprising the steps of:
1) preparation of phenytoin
Adding water and benzil diketone into a reaction kettle, adjusting to be alkaline, adding urea, heating to reflux, reacting the benzil diketone and the urea for 1-3 hours under an alkaline condition, filtering after the reaction is finished, dropwise adding concentrated hydrochloric acid into filtrate to adjust the pH value to 4-5, crystallizing, stirring for 1-3 hours, performing throw filtration, washing filter cakes, discharging to obtain a phenytoin crude product tide product, pulping the phenytoin crude product tide product for 1-3 hours at normal temperature, performing throw filtration, and discharging to obtain a phenytoin tide product;
2) preparation of phenytoin sodium
Taking another reaction kettle, putting the phenytoin tide product prepared in the step 1) into the reaction kettle, adding water, heating to 70-75 ℃, dropwise adding a sodium hydroxide solution, adjusting the pH value to 11-12, decoloring, finely filtering, cooling to room temperature, stirring and crystallizing for 6-10 hours, performing filter spinning, washing a filter cake, drying and drying the washed solid until the water content in the solid is 2.5-3.5 wt%, and discharging to obtain the phenytoin sodium in a mixed crystal form.
2. The method for preparing the mixed crystal form of sodium phenytoin according to claim 1, wherein the mixed crystal ratio of the anhydrous phenytoin sodium and the monohydrate of phenytoin sodium in the obtained mixed crystal form of sodium phenytoin is 80:20 to 95: 5.
3. The method for preparing the mixed crystal form of sodium phenytoin according to claim 1, wherein the mass ratio of water to diphenylethanedione in step 1) is 3-5: 1, the mass ratio of urea to diphenylethanedione is 1: 2 to 3.
4. The method for preparing the mixed crystal form of sodium phenytoin according to claim 2, characterized in that in the step 1), sodium hydroxide is added to adjust to be alkaline, and the mass ratio of sodium hydroxide to urea is 1-1.5: 1.
5. the method for preparing phenytoin sodium in mixed crystal form according to claim 1, wherein concentrated hydrochloric acid is added dropwise after the temperature of the filtrate in step 1) is reduced to 25-35 ℃.
6. The method for preparing phenytoin sodium in mixed crystal form according to claim 5, characterized in that the wet phenytoin crude product obtained in step 1) is put into a pulping kettle, purified water is added, and pulping is carried out at normal temperature for 1-3 hours, wherein the mass ratio of the purified water to the diphenylethanedione is 2-3: 1.
7. the method for preparing the phenytoin sodium in mixed crystal form according to claim 1, wherein the water added in the step 2) is purified water, and the mass ratio of the added amount of the purified water to the diphenylethanedione is 4-6: 1.
8. the method for preparing phenytoin sodium in mixed crystal form according to claim 1, wherein the sodium hydroxide solution added dropwise in step 2) is 30% sodium hydroxide solution.
9. The method for preparing the mixed crystal form of sodium phenytoin according to claim 1, characterized in that activated carbon is used for decolorization in step 2).
10. The method for preparing phenytoin sodium in mixed crystal form according to claim 1, wherein the drying step in step 2) is to dry the washed solid in a hot air circulation drying oven, and the drying step comprises drying the solid at 50-60 ℃ for 3-5 hours, then heating the solid to 80-90 ℃ for 3-5 hours until the water content in the solid is 2.5-3.5 wt%, and stopping drying.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111978258A (en) * | 2020-08-13 | 2020-11-24 | 山西新宝源制药有限公司 | Method for preparing phenytoin sodium |
| CN113943254A (en) * | 2021-11-23 | 2022-01-18 | 宁夏医科大学 | Preparation method of phenytoin sodium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6245917B1 (en) * | 1998-03-20 | 2001-06-12 | Warner-Lambert Company | Crystalline sodium phenytoin monohydrate |
| CN109456271A (en) * | 2018-11-20 | 2019-03-12 | 宁波职业技术学院 | A kind of synthetic method of dilantin sodium |
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2020
- 2020-04-07 CN CN202010263714.7A patent/CN111303041B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6245917B1 (en) * | 1998-03-20 | 2001-06-12 | Warner-Lambert Company | Crystalline sodium phenytoin monohydrate |
| CN109456271A (en) * | 2018-11-20 | 2019-03-12 | 宁波职业技术学院 | A kind of synthetic method of dilantin sodium |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111978258A (en) * | 2020-08-13 | 2020-11-24 | 山西新宝源制药有限公司 | Method for preparing phenytoin sodium |
| CN111978258B (en) * | 2020-08-13 | 2021-05-25 | 山西新宝源制药有限公司 | Method for preparing phenytoin sodium |
| CN113943254A (en) * | 2021-11-23 | 2022-01-18 | 宁夏医科大学 | Preparation method of phenytoin sodium |
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