CN104177274B - The preparation method of ethenzamide-saccharin eutectic crystal form II - Google Patents
The preparation method of ethenzamide-saccharin eutectic crystal form II Download PDFInfo
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- CN104177274B CN104177274B CN201410353998.3A CN201410353998A CN104177274B CN 104177274 B CN104177274 B CN 104177274B CN 201410353998 A CN201410353998 A CN 201410353998A CN 104177274 B CN104177274 B CN 104177274B
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Abstract
The preparation method that the invention discloses a kind of ethenzamide-saccharin eutectic crystal form II, step is: (1), by aluminium substrate sand paper brighten, is cleaned, dry, immerses in the solution of fatty acid, surface self-organization；Clean, dry；Put into MgCl2Aqueous solution impregnates, cleans, dry；(2) mixture of ethenzamide Yu saccharin is made mixed liquor, the one end of substrate step (1) obtained is fixing to be put in mixed liquor, cover container finish, evaporating under room temperature, make the ethenzamide-saccharin eutectic crystal of precipitation adhere on the substrate, ethenzamide, saccharin crystal sink to container bottom, take out substrate, clean, dry, ethenzamide-saccharin eutectic crystal is taken off from substrate.The present invention makes the self-assembled monolayer that fatty acid produces at aluminum surface self-organization, makes the growth of interaction force directional induction eutectic between membrane molecule and drug molecule, in relatively wide concentration range, all can obtain ethenzamide-saccharin eutectic crystal form II.
Description
Technical field
The preparation method that the present invention relates to a kind of ethenzamide-saccharin eutectic crystal form II, belongs to the technology of preparing of ethenzamide-saccharin eutectic.
Background technology
Under the premise not changing medicine pharmacology behavior, design and synthesize pharmaceutical co-crystals by introducing the multiple active medicine component with difference in functionality.Cocrystallization is a difference in that the crystalline state homogeneous mixture that heterogeneity crystallization together with the material of character, can form various ingredients, i.e. eutectic with conventional crystallization method.As a kind of novel solid form of current medicine, eutectic has the unique physico-chemical property and bioavailability that are different from conventional medicament, is the new direction of drug development.
Currently, in the world some experts of the state such as American-European at the research work being actively working to active drug molecule design.The research of Nehm and Trask shows, eutectic can improve many performances of active medicine, such as dissolubility, bioavailability, hygroscopicity and physical and chemical stability.For the research of eutectic, pharmaceutical science man focuses on two crucial aspects: the first improves the physical property of medicine, and it two is the exploitation of medicine new crystalline form.In the most of eutectic structure reported at present, the intermolecular of eutectic ligand component forms eutectic supermolecule by active forces such as hydrogen bond, pi-pi accumulation power, Van der Waals forces, maintains the Stability Analysis of Structures of crystal.One of Main Means as eutectic crystal preparation, solution crystal process has the advantage that other method is incomparable.In solution crystallization process, due to the impact by conditions such as solute composition, solvent and crystallization temperatures, polymorphism and the stoichiometric proportion multiformity of eutectic crystal often occur.But, asymmetric phasor can be produced when the dissolubility of ligand molecular is too below or above active constituents of medicine, utilize the solution evaporation method of routine cannot obtain sterling eutectic in this case.Depart from thermodynamics phasor restriction at present to prepare the method for eutectic mainly have spray crystallization and a surface active agent solubilization crystallization for asymmetric systems, but the shortcoming that spray crystallization has energy consumption height, poor crystal form；Surface active agent solubilization crystallization then easily remains non-medical ingredients.
Ethenzamide is a kind of antipyretic analgesic, is used for treating the diseases such as heating, headache, neuralgia, arthralgia, rheumatoid arthritis, toothache, dysmenorrhea.Saccharin is a kind of sweeting agent, without nutrition.Under different operating conditions, ethenzamide forms eutectic with saccharin molecule with the ratio of 1:1, owing to eutectic molecule there are differences in steric configuration, defines two kinds of crystal formations, respectively crystal formation I and crystal form II.Wherein, in ethenzamide-saccharin eutectic (crystal form II), with C-H between ethenzamide and saccharin molecule ... O and C-H ... π key interacts and defines " tetramer " shape space structure.Ethenzamide-saccharin eutectic is typical asymmetric phasor system in conventional alcohols, ketones solvent, utilizes solution evaporation method cannot obtain sterling eutectic.
Summary of the invention
It is an object of the invention to overcome the deficiencies in the prior art, it is provided that the preparation method of a kind of ethenzamide-saccharin eutectic crystal form II.
Technical scheme is summarized as follows:
The preparation method of a kind of ethenzamide-saccharin eutectic crystal form II, comprises the steps:
(1) by aluminium substrate 400# that purity is 99.99%～600# sand papering light, put into ultrasonic degreasing in ethanol or acetone and clean 5-10min, take out, put into the inorganic alkaline compound aqueous cleaning 4-6min that mass concentration is 4%～8%, washing, dry, obtain surface and form one layer of Al2O3The aluminium substrate of thin film, called after Al2O3/ Al substrate；By described Al2O3It is the C of 10～50mM that/Al substrate immerses concentration14-C22In the hexadecane solution of fatty acid, or immerse C14-C22In the hexadecane solution of monounsaturated fatty acid, airtight under room temperature carry out surface self-organization 24～72 hours；Ultrasonic 10 minutes are put in absolute methanol to remove surface physics absorption and the C deposited after being rinsed with fresh normal hexane by substrate after self assembly14-C22Fatty acid or C14-C22Monounsaturated fatty acid；Clean with absolute methanol, dry 3～5h for 50～80 DEG C；Put into the MgCl of 0.1～0.8M2Aqueous solution, AlCl3Aqueous solution or CaCl2Impregnating 1h～2h in aqueous solution, taking-up deionized water cleans, and dries 7～12h for 50～80 DEG C；
(2) in proportion, by ethenzamide and the mixture of saccharin that the stoichiometric proportion of 4.0g～8.0g is 1～6:1, add in the container filling 150mL methanol or ethanol, be heated to 45～50 DEG C and make to be completely dissolved；It is cooled to room temperature, obtain mixed solution, the one end of substrate step (1) obtained is fixed on foam and makes described substrate be lowered in mixed solution, container finish is covered with aluminium foil, solvent is evaporated under room temperature, ethenzamide-saccharin eutectic the crystal making precipitation adheres on the substrate, ethenzamide crystal, saccharin crystal sinks to container bottom by gravity, take out the substrate of attachment ethenzamide-saccharin eutectic crystal, with 5～8ml absolute methanol or absolute ethanol washing, place air drying 1h-2h, ethenzamide-saccharin eutectic crystal is ethenzamide-saccharin eutectic crystal form II from taking off substrate.
C14-C22Monounsaturated fatty acid is preferably the double bond C at end14-C22Monounsaturated fatty acid, or three keys are at the C of end14-C22Monounsaturated fatty acid.
Inorganic alkaline compound is preferably sodium hydroxide, sodium carbonate or sodium bicarbonate.
Advantages of the present invention:
The present invention uses the self-assembled monolayer that fatty acid or derivative of fatty acid produce at aluminum surface self-organization, make the growth of interaction force directional induction eutectic between membrane molecule and drug molecule, in relatively wide concentration range, all can obtain ethenzamide-saccharin eutectic crystal form II.Further, owing to single pharmaceutical co-crystals component molecular is insoluble in two-dimensional structure, therefore the single crystal of the two can reach high efficiency separation by action of gravity with being grown in film surface eutectic, to obtain highly purified ethenzamide-saccharin eutectic crystal form II product.
Additionally, the method can apply to other asymmetric ternary phase diagrams system to obtain highly purified pharmaceutical co-crystals.
Accompanying drawing explanation
Fig. 1 is ethenzamide-saccharin eutectic (crystal form II) product comparison figure.
Detailed description of the invention
The present invention selects the self-assembled film of fatty acid or derivative of fatty acid to carry out the eutectic selective growth under asymmetric systems phasor, its mechanism is: owing to the active force each other on ligand molecular and film surface is thus can cause the solution microenvironment on film surface to be different from the subjective environment of solution, causing the ligand concentration in this region too high, entering the monophase field of eutectic thus being more beneficial for the generation of eutectic.
Below in conjunction with specific embodiment, the present invention is further illustrated.
Embodiment 1
The preparation method of a kind of ethenzamide-saccharin eutectic crystal form II, comprises the steps:
(1) by the aluminium substrate 400# sand papering light that purity is 99.99%, put into ultrasonic degreasing in ethanol and clean 5min, take out, put into the sodium hydrate aqueous solution that mass concentration is 4% and clean 5min, wash, dry, obtain surface and form one layer of Al2O3The aluminium substrate of thin film, called after Al2O3/ Al substrate；By Al2O3/ Al substrate immerses the arachic acid (CH that concentration is 10mM3(CH2)18COOH), in hexadecane solution, airtight under room temperature surface self-organization is carried out 24 hours；Ultrasonic 10 minutes are put in absolute methanol to remove surface physics absorption and the arachic acid deposited after being rinsed with fresh normal hexane by substrate after self assembly；Clean with absolute methanol, dry 5h for 50 DEG C；Put into the MgCl of 0.1M2Impregnating 1h in aqueous solution, taking-up deionized water cleans, and dries 12h for 50 DEG C；
(2) by the mixture of ethenzamide that the stoichiometric proportion of 4.0g is 1:1 with saccharin, add in the container filling 150mL methanol, be heated to 45 DEG C and make to be completely dissolved；It is cooled to room temperature, obtain mixed solution, the one end of substrate step (1) obtained is fixed on foam and makes substrate be lowered in mixed solution, container finish is covered with aluminium foil, solvent is evaporated under room temperature, ethenzamide-saccharin eutectic the crystal making precipitation adheres on the substrate, ethenzamide crystal, saccharin crystal sinks to container bottom by gravity, it is slowly withdrawn the substrate of ethenzamide-saccharin eutectic crystal, wash with 5ml absolute methanol, place air drying 1h, ethenzamide-saccharin eutectic crystal is ethenzamide-saccharin eutectic crystal form II from taking off substrate.XRD figure spectrum is shown in Fig. 1.
Embodiment 2
The preparation method of a kind of ethenzamide-saccharin eutectic crystal form II, comprises the steps:
(1) by the aluminium substrate 600# sand papering light that purity is 99.99%, put into ultrasonic degreasing in acetone and clean 10min, take out, put into the aqueous sodium carbonate that mass concentration is 8% and clean 4min, wash, dry, obtain surface and form one layer of Al2O3The aluminium substrate of thin film, called after Al2O3/ Al substrate；By Al2O3/ Al substrate immerses the tetradecanoic acid (CH that concentration is 50mM3(CH2)12COOH), in hexadecane solution, airtight under room temperature surface self-organization is carried out 72 hours；Ultrasonic 10 minutes are put in absolute methanol to remove surface physics absorption and the tetradecanoic acid deposited after being rinsed with fresh normal hexane by substrate after self assembly；Clean with absolute methanol, dry 3h for 80 DEG C；Put into the AlCl of 0.8M3Impregnating 2h in aqueous solution, taking-up deionized water cleans, and dries 7h for 80 DEG C；
(2) by the mixture of ethenzamide that the stoichiometric proportion of 8.0g is 6:1 with saccharin, add in the container filling 150mL ethanol, be heated to 50 DEG C and make to be completely dissolved；It is cooled to room temperature, obtain mixed solution, the one end of substrate step (1) obtained is fixed on foam and makes substrate be lowered in mixed solution, container finish is covered with aluminium foil, solvent is evaporated under room temperature, ethenzamide-saccharin eutectic the crystal making precipitation adheres on the substrate, ethenzamide crystal, saccharin crystal sinks to container bottom by gravity, after 7 days, it is slowly withdrawn the substrate of attached ethenzamide-saccharin eutectic crystal, use 8ml absolute ethanol washing, place air drying 2h, ethenzamide-saccharin eutectic crystal is ethenzamide-saccharin eutectic crystal form II from taking off substrate.
XRD figure spectrum is similar to embodiment 1.
Embodiment 3
The preparation method of a kind of ethenzamide-saccharin eutectic crystal form II, comprises the steps:
(1) by the aluminium substrate 500# sand papering light that purity is 99.99%, put into ultrasonic degreasing in ethanol and clean 6min, take out, put into the sodium hydrate aqueous solution that mass concentration is 8% and clean 6min, wash, dry, obtain surface and form one layer of Al2O3The aluminium substrate of thin film, called after Al2O3/ Al substrate；By Al2O3/ Al substrate immerses the behenic acid (CH that concentration is 35mM3(CH2)20COOH), in hexadecane solution, airtight under room temperature surface self-organization is carried out 36 hours；Ultrasonic 10 minutes are put in absolute methanol to remove surface physics absorption and the CH deposited after being rinsed with fresh normal hexane by substrate after self assembly3(CH2)20COOH；Clean with absolute methanol, dry 4h for 70 DEG C；Put into the CaCl of 0.6M2Impregnating 1h in aqueous solution, taking-up deionized water cleans, and dries 9h for 60 DEG C；
(2) by the mixture of ethenzamide that the stoichiometric proportion of 5.0g is 3:1 with saccharin, add in the container filling 150mL methanol, be heated to 48 DEG C and make to be completely dissolved；It is cooled to room temperature, obtain mixed solution, the one end of substrate step (1) obtained is fixed on foam and makes substrate be lowered in mixed solution, container finish is covered with aluminium foil, solvent is evaporated under room temperature, ethenzamide-saccharin eutectic the crystal making precipitation adheres on the substrate, ethenzamide crystal, saccharin crystal sinks to container bottom by gravity, after 5 days, it is slowly withdrawn the substrate of attachment ethenzamide-saccharin eutectic crystal, wash with 6ml absolute methanol, place air drying 2h, ethenzamide-saccharin eutectic crystal is ethenzamide-saccharin eutectic crystal form II from taking off substrate.
XRD figure spectrum is similar to embodiment 1.
Embodiment 4
The preparation method of a kind of ethenzamide-saccharin eutectic crystal form II, comprises the steps:
(1) by the aluminium substrate 500# sand papering light that purity is 99.99%, put into ultrasonic degreasing in ethanol and clean 5min, take out, put into the sodium bicarbonate aqueous solution that mass concentration is 5% and clean 6min, wash, dry, obtain surface and form one layer of Al2O3The aluminium substrate of thin film, called after Al2O3/ Al substrate；By Al2O3It is the CH of 30mM that/Al substrate immerses concentration2=CH (CH2)16In the hexadecane solution of COOH, airtight under room temperature carry out surface self-organization 48 hours；Ultrasonic 10 minutes are put in absolute methanol to remove surface physics absorption and the CH deposited after being rinsed with fresh normal hexane by substrate after self assembly2=CH (CH2)16COOH；Clean with absolute methanol, dry 4h for 60 DEG C；Put into the CaCl of 0.5M2Impregnating 1.5h in aqueous solution, taking-up deionized water cleans, and dries 9h for 60 DEG C；
(2) by the mixture of ethenzamide that the stoichiometric proportion of 5.0g is 4:1 with saccharin, add in the container filling 150mL methanol, be heated to 48 DEG C and make to be completely dissolved；It is cooled to room temperature, obtain mixed solution, the one end of substrate step (1) obtained is fixed on foam and makes substrate be lowered in mixed solution, container finish is covered with aluminium foil, solvent is evaporated under room temperature, ethenzamide-saccharin eutectic the crystal making precipitation adheres on the substrate, ethenzamide crystal, saccharin crystal sinks to container bottom by gravity, after 5 days, it is slowly withdrawn the substrate of attachment ethenzamide-saccharin eutectic crystal, wash with 6ml absolute methanol, place air drying 2h, ethenzamide-saccharin eutectic crystal is ethenzamide-saccharin eutectic crystal form II from taking off substrate.
XRD figure spectrum is similar to embodiment 1.
Embodiment 5
The preparation method of a kind of ethenzamide-saccharin eutectic crystal form II, comprises the steps:
(1) by the aluminium substrate 400# sand papering light that purity is 99.99%, put into ultrasonic degreasing in ethanol and clean 10min, take out, put into the sodium hydrate aqueous solution that mass concentration is 8% and clean 4min, wash, dry, obtain surface and form one layer of Al2O3The aluminium substrate of thin film, called after Al2O3/ Al substrate；By Al2O3It is the CH of 50mM that/Al substrate immerses concentration2=CH (CH2)11In the hexadecane solution of COOH, airtight under room temperature carry out surface self-organization 48 hours；Ultrasonic 10 minutes are put in absolute methanol to remove surface physics absorption and the CH deposited after being rinsed with fresh normal hexane by substrate after self assembly2=CH (CH2)11COOH；Clean with absolute methanol, dry 4h for 80 DEG C；Put into the CaCl of 0.3M2Impregnating 2h in aqueous solution, taking-up deionized water cleans, and dries 12h for 50 DEG C；
(2) by the mixture of ethenzamide that the stoichiometric proportion of 5.0g is 4:1 with saccharin, add in the container filling 150mL methanol, be heated to 50 DEG C and make to be completely dissolved；Being cooled to room temperature, obtain mixed solution, the one end of substrate step (1) obtained is fixed on foam and makes substrate be lowered in mixed solution, covers container finish with aluminium foil, evaporates solvent under room temperature,
Ethenzamide-saccharin eutectic the crystal making precipitation adheres on the substrate, ethenzamide crystal, saccharin crystal sink to container bottom by gravity, after 6 days, it is slowly withdrawn the substrate of attachment ethenzamide-saccharin eutectic crystal, wash with 8ml absolute methanol, place air drying 2h, ethenzamide-saccharin eutectic crystal is ethenzamide-saccharin eutectic crystal form II from taking off substrate.
XRD figure spectrum is similar to embodiment 1.
Embodiment 6
The preparation method of a kind of ethenzamide-saccharin eutectic crystal form II, comprises the steps:
(1) by the aluminium substrate 600# sand papering light that purity is 99.99%, put into ultrasonic degreasing in ethanol and clean 10min, take out, put into the sodium hydrate aqueous solution that mass concentration is 6% and clean 5min, wash, dry, obtain surface and form one layer of Al2O3The aluminium substrate of thin film, called after Al2O3/ Al substrate；By Al2O3It is the CH of 20mM that/Al substrate immerses concentration2=CH (CH2)19In the hexadecane solution of COOH, airtight under room temperature carry out surface self-organization 72 hours；Ultrasonic 10 minutes are put in absolute methanol to remove surface physics absorption and the CH deposited after being rinsed with fresh normal hexane by substrate after self assembly2=CH (CH2)19COOH；Clean with absolute methanol, dry 3h for 80 DEG C；Put into the MgCl of 0.7M2Impregnating 1h in aqueous solution, taking-up deionized water cleans, and dries 7h for 80 DEG C；
(2) by the mixture of ethenzamide that the stoichiometric proportion of 5.0g is 6:1 with saccharin, add in the container filling 150mL methanol, be heated to 45 DEG C and make to be completely dissolved；It is cooled to room temperature, obtain mixed solution, the one end of substrate step (1) obtained is fixed on foam and makes substrate be lowered in mixed solution, container finish is covered with aluminium foil, solvent is evaporated under room temperature, ethenzamide-saccharin eutectic the crystal making precipitation adheres on the substrate, ethenzamide crystal, saccharin crystal sinks to container bottom by gravity, after 4 days, it is slowly withdrawn the substrate of attachment ethenzamide-saccharin eutectic crystal, wash with 5ml absolute methanol, place air drying 2h, ethenzamide-saccharin eutectic crystal is ethenzamide-saccharin eutectic crystal form II from taking off substrate.
XRD figure spectrum is similar to embodiment 1.
Embodiment 7
The preparation method of a kind of ethenzamide-saccharin eutectic crystal form II, comprises the steps:
(1) by the aluminium substrate 400# sand papering light that purity is 99.99%, put into ultrasonic degreasing in acetone and clean 5min, take out, put into the sodium bicarbonate aqueous solution that mass concentration is 5% and clean 5min, wash, dry, obtain surface and form one layer of Al2O3The aluminium substrate of thin film, called after Al2O3/ Al substrate；By Al2O3/ Al substrate immerses the CH ≡ C (CH that concentration is 40mM2)19In the hexadecane solution of COOH, airtight under room temperature carry out surface self-organization 36 hours；Ultrasonic 10 minutes are put in absolute methanol to remove surface physics absorption and the CH ≡ C (CH deposited after being rinsed with fresh normal hexane by substrate after self assembly2)19COOH；Clean with absolute methanol, dry 4h for 70 DEG C；Put into the AlCl of 0.4M3Impregnating 2h in aqueous solution, taking-up deionized water cleans, and dries 10h for 70 DEG C；
(2) by the mixture of ethenzamide that the stoichiometric proportion of 6.0g is 3:1 with saccharin, add in the container filling 150mL ethanol, be heated to 50 DEG C and make to be completely dissolved；It is cooled to room temperature, obtain mixed solution, the one end of substrate step (1) obtained is fixed on foam and makes substrate be lowered in mixed solution, container finish is covered with aluminium foil, solvent is evaporated under room temperature, ethenzamide-saccharin eutectic the crystal making precipitation adheres on the substrate, ethenzamide crystal, saccharin crystal sinks to container bottom by gravity, after 6 days, it is slowly withdrawn the substrate of attachment ethenzamide-saccharin eutectic crystal, use 7ml absolute ethanol washing, place air drying 1h, ethenzamide-saccharin eutectic crystal is ethenzamide-saccharin eutectic crystal form II from taking off substrate.
XRD figure spectrum is similar to embodiment 1.
Embodiment 8
The preparation method of a kind of ethenzamide-saccharin eutectic crystal form II, comprises the steps:
(1) by the aluminium substrate 500# sand papering light that purity is 99.99%, put into ultrasonic degreasing in ethanol and clean 8min, take out, put into the sodium hydrate aqueous solution that mass concentration is 6% and clean 6min, wash, dry, obtain surface and form one layer of Al2O3The aluminium substrate of thin film, called after Al2O3/ Al substrate；By Al2O3/ Al substrate immerses the CH ≡ C (CH that concentration is 45mM2)11In the hexadecane solution of COOH, airtight under room temperature carry out surface self-organization 48 hours；Ultrasonic 10 minutes are put in absolute methanol to remove surface physics absorption and the CH ≡ C (CH deposited after being rinsed with fresh normal hexane by substrate after self assembly2)11COOH；Clean with absolute methanol, dry 5h for 50 DEG C；Put into the MgCl of 0.4M2Impregnating 1.5h in aqueous solution, taking-up deionized water cleans, and dries 10h for 70 DEG C；
(2) by the mixture of ethenzamide that the stoichiometric proportion of 5.0g is 5:1 with saccharin, add in the container filling 150mL methanol, be heated to 50 DEG C and make to be completely dissolved；It is cooled to room temperature, obtain mixed solution, the one end of substrate step (1) obtained is fixed on foam and makes substrate be lowered in mixed solution, container finish is covered with aluminium foil, solvent is evaporated under room temperature, ethenzamide-saccharin eutectic the crystal making precipitation adheres on the substrate, ethenzamide crystal, saccharin crystal sinks to container bottom by gravity, after 6 days, it is slowly withdrawn the substrate of attachment ethenzamide-saccharin eutectic crystal, wash with 8ml absolute methanol, place air drying 1.5h, ethenzamide-saccharin eutectic crystal is ethenzamide-saccharin eutectic crystal form II from taking off substrate.
XRD figure spectrum is similar to embodiment 1.
Claims (2)
1. a preparation method for ethenzamide-saccharin eutectic crystal form II, is characterized in that comprising the steps:
(1) by aluminium substrate 400# that purity is 99.99%～600# sand papering light, put into ultrasonic degreasing in ethanol or acetone and clean 5-10min, take out, put into the inorganic alkaline compound aqueous cleaning 4-6min that mass concentration is 4%～8%, washing, dry, obtain surface and form one layer of Al2O3The aluminium substrate of thin film, called after Al2O3/ Al substrate；By described Al2O3It is the C of 10～50mM that/Al substrate immerses concentration14-C22In the hexadecane solution of fatty acid, airtight under room temperature carry out surface self-organization 24～72 hours；Ultrasonic 10 minutes are put in absolute methanol to remove surface physics absorption and the C deposited after being rinsed with fresh normal hexane by substrate after self assembly14-C22Fatty acid；Clean with absolute methanol, dry 3～5h for 50～80 DEG C；Put into the MgCl of 0.1～0.8M2Aqueous solution, AlCl3Aqueous solution or CaCl2Impregnating 1h～2h in aqueous solution, taking-up deionized water cleans, and dries 7～12h for 50～80 DEG C；
(2) in proportion, by ethenzamide and the mixture of saccharin that the stoichiometric proportion of 4.0g～8.0g is 1～6:1, add in the container filling 150mL methanol or ethanol, be heated to 45～50 DEG C and make to be completely dissolved；It is cooled to room temperature, obtain mixed solution, the one end of substrate step (1) obtained is fixed on foam and makes described substrate be lowered in mixed solution, container finish is covered with aluminium foil, solvent is evaporated under room temperature, ethenzamide-saccharin eutectic the crystal making precipitation adheres on the substrate, ethenzamide crystal, saccharin crystal sinks to container bottom by gravity, take out the substrate of attachment ethenzamide-saccharin eutectic crystal, with 5～8ml absolute methanol or absolute ethanol washing, place air drying 1h-2h, ethenzamide-saccharin eutectic crystal is ethenzamide-saccharin eutectic crystal form II from taking off substrate, described ethenzamide-saccharin eutectic crystal form II XRD spectra is as shown in Figure 1.
2. the preparation method of a kind of ethenzamide according to claim 1-saccharin eutectic crystal form II, is characterized in that described inorganic alkaline compound is sodium hydroxide, sodium carbonate or sodium bicarbonate.
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