CN102827165B - Method for directionally preparing theophylline-saccharin eutectic through membrane technology - Google Patents
Method for directionally preparing theophylline-saccharin eutectic through membrane technology Download PDFInfo
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- CN102827165B CN102827165B CN201210333271.XA CN201210333271A CN102827165B CN 102827165 B CN102827165 B CN 102827165B CN 201210333271 A CN201210333271 A CN 201210333271A CN 102827165 B CN102827165 B CN 102827165B
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Abstract
The invention discloses a method for directionally preparing theophylline-saccharin eutectic through a membrane technology. The method comprises the steps of: 1) dipping a glass sheet in Piranha solution, heating the solution, taking out the glass sheet, washing the glass sheet, drying the glass sheet to obtain a hydroxylated glass sheet, placing the hydroxylated glass sheet in water solution containing silane coupling agent, and hermetically placing at room temperature to obtain a glass sheet with a silanized surface; and washing and drying the glass sheet to obtain a silane single-molecule self-assembled monolayer on the surface of the glass sheet; and 2) adding theophylline and saccharin into a container containing methanol or ethanol, heating to dissolve solids; and cooling the solution, placing the glass sheet with the single-molecule self-assembled monolayer on the surface, slowly evaporating solvent at constant temperature being 25-40DEG C, growing a large quantity of theophylline-saccharin eutectic crystals on the surface of the single-molecule self-assembled monolayer within 2-7 days, taking out the glass sheet on which the eutectic crystals grow, washing the glass sheet, and taking the theophylline-saccharin eutectic crystals down after the surface of the glass sheet is dried. According verification through XRD (X-Ray Diffraction), by adopting the method, pure theophylline-saccharin eutectic can be obtained within a wider concentration range.
Description
Technical field
The present invention relates to a kind of method of utilizing membrane orienting technology to prepare eutectic, belong to the preparing technical field of theophylline-asccharin eutectic.
Background technology
Eutectic, as a kind of novel solid form of current medicine, has the unique physico-chemical property and the bioavailability that are different from conventional medicament.In fact, in the eutectic of specific system, the selection of ligand molecular need to be followed solubleness principle of similarity, and the solubleness of ligand molecular can not be too higher than active constituents of medicine.Otherwise, will produce asymmetric phasor.Fully understanding on the basis of the two solution phase Balance, the method that adopts solvent evaporation and be suspended crystallization can be processed the asymmetric case of phasor.But this is based on binary or the known situation of ternary phase diagrams.Therefore, obtaining sterling eutectic need to carefully control the thermodynamics and kinetics factor of system, and this acquisition for sterling eutectic has produced very large obstacle.
Departing from present thermodynamics phasor for asymmetric system prepares the method for eutectic and mainly contains spray crystallization and surface active agent solubilization crystallization.Utilizing self-assembled film (self-assembled monolayers is called for short SAMs) to carry out eutectic selective growth does not report at present.Because mainly leaning on Intermolecular Forces (being mainly hydrogen bond) and intermolecular accumulation to carry out intermolecular self-assembly, eutectic forms.In addition, hydrogen bond is also often formed between the active constituents of medicine/part and solvent molecule in solution.Be adsorbed on unimolecular film surface in order to make pharmaceutical activity molecule or ligand molecular can overcome this hydrogen bond action, the Intermolecular Forces between these two kinds of molecules and unimolecular film should be greater than the Intermolecular Forces in solution.For example, in conventional non covalent bond (hydrogen bond, halogen key and pi-pi accumulation), halogen key is as a large class non covalent bond, and its bond energy is between 10-200kJ/mol.Therefore, its bond energy size has determined that in some molecular self-assembling and molecular recognition process, can be better than hydrogen bond first forms.
Theophylline, as a kind of medicine, is the inhibitor of a kind of phosphodiesterase (PDE), is therefore widely used in the treatment of respiratory system disease.Asccharin is a kind of ancient sweeting agent, but not containing nutrition.In theophylline-asccharin eutectic, in theophylline-carbonylic oxygen atom that NH serves as in hydrogen bond donor and asccharin carries out hydrogen bonding.Simultaneously in asccharin-carbonyl in NH and theophylline also formed N-H ... O.Theophylline-asccharin eutectic is all typical asymmetric phasor system at conventional solvent in as methyl alcohol, ethanol, utilizes solution evaporation method cannot obtain sterling eutectic.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of method of membrane technique directional preparation theophylline-asccharin eutectic is provided.
Technical scheme of the present invention is summarized as follows:
A method for membrane technique directional preparation theophylline-asccharin eutectic, comprises the steps:
(1) need big or small sheet glass to immerse in fresh Piranha solution by being cut into, thermostatically heating 90～120min at 70 ℃～90 ℃, sheet glass is taken out, successively with deionized water, Virahol, dehydrated alcohol and normal hexane washing, dry, obtain hydroxylation sheet glass, described hydroxylation sheet glass is put into the aqueous solution that contains silane coupling agent that concentration is 10～20mM, under room temperature, air tight condition, place 100～150min, obtain the sheet glass of surface silicon alkanisation; The sheet glass of described silanization is rinsed with fresh normal hexane, put into the ultrasonic 5-20min of anhydrous methanol; With anhydrous methanol cleaning, in 50 ℃～80 ℃ oven dry 8～12h, obtain silane self-assembled monolayer in glass sheet surface;
(2) theophylline that is 1:1～5 by mol ratio and asccharin altogether 3.0g～5.0g join in the container that is contained with 100mL methyl alcohol or ethanol, be heated to 50 ℃ solid is all dissolved; Be cooled to 25～40 ℃, put into surface with the sheet glass of silane self-assembled monolayer and make it and container inner wall angle is 70 °-80 °, the container cover that is coated with adjustable open degree at container upper end opening part can be evaporated by Slow Isothermal the solvent in container at 25～40 ℃, grow a large amount of theophylline-asccharin eutectic crystal on film surface described in 2-7 angel, the long sheet glass that has crystal is taken out, with the anhydrous methanol washing surface of 2-4mL, after surface drying, theophylline-asccharin eutectic crystal is taken off.
Described silane coupling agent is 3-r-chloropropyl trimethoxyl silane, 3-aminopropyl trimethoxysilane or n-propyl Trimethoxy silane.
The present invention uses silane coupling agent on sheet glass, to grow silane self-assembled monolayer, recycle the local composition of solution that intermolecular reactive force and membrane crystallization change eutectic system, the growth of directional induction eutectic, in wider concentration range, through XRD checking, all can obtain pure theophylline-asccharin eutectic.In addition, the method can be applied to other asymmetric ternary phase diagrams system to obtain highly purified pharmaceutical co-crystals.
Accompanying drawing explanation
Fig. 1 is the eutectic XRD figure that theophylline, asccharin and theophylline and asccharin form.
Embodiment
The present invention selects silane self-assembled monolayer (SAMs) to carry out the eutectic selective growth under asymmetric system phasor, its mechanism is: thereby because the reactive force each other on ligand molecular and film surface can cause the subjective environment that is different from solution in the solution microenvironment on film surface, cause at the ligand concentration in this region too high, make the partial concn ratio of pharmaceutical activity molecule and ligand molecular higher than main body concentration ratio, this can make pilot wire in ternary phase diagrams to pharmaceutical activity molecule one side shifting, thereby the single phase region that enters eutectic is more conducive to the generation of eutectic.
Below by specific embodiment, the present invention is described further.Described herein, embodiment is just in order to enable those skilled in the art to better understand the present invention, not to doing any restriction.
The dense H that the present invention's Piranha solution used is is 7:3 by volume ratio
2sO
4with 30% H
2o
2formulated.
Embodiment 1
(1) in large beaker, add the Piranha solution that 50ml is fresh, the sheet glass cutting (20X20mm) is put into wherein, thermostatically heating 120min under 70 ℃ of conditions, sheet glass is taken out, carefully wash with deionized water, Virahol, dehydrated alcohol and normal hexane successively, dry, obtain hydroxylation sheet glass, described hydroxylation sheet glass is put into the aqueous solution that contains 3-r-chloropropyl trimethoxyl silane that 60mL concentration is 10mM, under room temperature, air tight condition, place 100min, obtain the sheet glass of surface silicon alkanisation; The sheet glass of described silanization is rinsed with fresh normal hexane, put into the ultrasonic 10min of anhydrous methanol; With anhydrous methanol cleaning, in 50 ℃ of oven dry 12h, obtain silane self-assembled monolayer in glass sheet surface;
(2) theophylline that is 1:1 by mol ratio and asccharin altogether 3.0g join in the container that is contained with 100mL methyl alcohol, be heated to 50 ℃ solid is all dissolved; Be cooled to 25 ℃, put into surface with the sheet glass of silane self-assembled monolayer and make it and container inner wall angle is 70 °, the container cover that is coated with adjustable open degree at container upper end opening part can be evaporated by Slow Isothermal the solvent in container at 25 ℃, grow a large amount of theophylline-asccharin eutectic crystal on film surface described in 7 angels, the long sheet glass that has crystal is taken out, with the anhydrous methanol washing surface of 2mL, after surface drying, theophylline-asccharin eutectic crystal is taken off.
Theophylline-asccharin eutectic crystal XRD is shown in Fig. 1.
(1) in large beaker, add the Piranha solution that 50ml is fresh, the sheet glass cutting (20X20mm) is put into wherein, thermostatically heating 90min under 90 ℃ of conditions, sheet glass is taken out, carefully wash with deionized water, Virahol, dehydrated alcohol and normal hexane successively, dry, obtain hydroxylation sheet glass, described hydroxylation sheet glass is put into the aqueous solution that contains 3-aminopropyl trimethoxysilane that 60mL concentration is 15mM, under room temperature, air tight condition, place 150min, obtain the sheet glass of surface silicon alkanisation; The sheet glass of described silanization is rinsed with fresh normal hexane, put into the ultrasonic 5min of anhydrous methanol; With anhydrous methanol cleaning, in 80 ℃ of oven dry 8h, obtain silane self-assembled monolayer in glass sheet surface;
(2) theophylline that is 1:3 by mol ratio and asccharin altogether 4.0g join in the container that is contained with 100mL ethanol, be heated to 50 ℃ solid is all dissolved; Be cooled to 30 ℃, put into surface with the sheet glass of silane self-assembled monolayer and make it and container inner wall angle is 80 °, the container cover that is coated with adjustable open degree at container upper end opening part can be evaporated by Slow Isothermal the solvent in container at 30 ℃, grow a large amount of theophylline-asccharin eutectic crystal on film surface described in 4 angels, the long sheet glass that has crystal is taken out, with the anhydrous methanol washing surface of 4mL, after surface drying, theophylline-asccharin eutectic crystal is taken off.
Theophylline is similar to embodiment 1 to the eutectic XRD figure that asccharin forms.
Embodiment 3
(1) in large beaker, add the Piranha solution that 50ml is fresh, the sheet glass cutting (20X20mm) is put into wherein, thermostatically heating 100min under 80 ℃ of conditions, sheet glass is taken out, carefully wash with deionized water, Virahol, dehydrated alcohol and normal hexane successively, dry, obtain hydroxylation sheet glass, described hydroxylation sheet glass is put into the aqueous solution that contains n-propyl Trimethoxy silane that 60mL concentration is 20mM, under room temperature, air tight condition, place 150min, obtain the sheet glass of surface silicon alkanisation; The sheet glass of described silanization is rinsed with fresh normal hexane, put into the ultrasonic 20min of anhydrous methanol; With anhydrous methanol cleaning, in 70 ℃ of oven dry 10h, obtain silane self-assembled monolayer in glass sheet surface;
(2) theophylline that is 1:5 by mol ratio and asccharin altogether 5.0g join in the container that is contained with 100mL ethanol, be heated to 50 ℃ solid is all dissolved; Be cooled to 40 ℃, put into surface with the sheet glass of silane self-assembled monolayer and make it and container inner wall angle is 75 °, the container cover that is coated with adjustable open degree at container upper end opening part can be evaporated by Slow Isothermal the solvent in container at 40 ℃, grow a large amount of theophylline-asccharin eutectic crystal on film surface described in 2 angels, the long sheet glass that has crystal is taken out, with the anhydrous methanol washing surface of 3mL, after surface drying, theophylline-asccharin eutectic crystal is taken off.
Theophylline is similar to embodiment 1 to the eutectic XRD figure that asccharin forms.
Claims (1)
1. a method for membrane technique directional preparation theophylline-asccharin eutectic, is characterized in that comprising the steps:
(1) need big or small sheet glass to immerse in fresh Piranha solution by being cut into, thermostatically heating 90～120min at 70 ℃～90 ℃, sheet glass is taken out, successively with deionized water, Virahol, dehydrated alcohol and normal hexane washing, dry, obtain hydroxylation sheet glass, described hydroxylation sheet glass is put into the aqueous solution that contains silane coupling agent that concentration is 10～20mM, under room temperature, air tight condition, place 100～150min, obtain the sheet glass of surface silicon alkanisation; The sheet glass of described silanization is rinsed with fresh normal hexane, put into the ultrasonic 5-20min of anhydrous methanol; With anhydrous methanol cleaning, in 50 ℃～80 ℃ oven dry 8～12h, obtain silane self-assembled monolayer in glass sheet surface;
(2) theophylline that is 1:1～5 by mol ratio and asccharin altogether 3.0g～5.0g join in the container that is contained with 100mL methyl alcohol or ethanol, be heated to 50 ℃ solid is all dissolved, be cooled to 25～40 ℃, put into surface with the sheet glass of silane self-assembled monolayer and make it and container inner wall angle is 70 °-80 °, the container cover that is coated with adjustable open degree at container upper end opening part can be evaporated by Slow Isothermal the solvent in container at 25～40 ℃, grow a large amount of theophylline-asccharin eutectic crystal on film surface described in 2-7 angel, the long sheet glass that has crystal is taken out, with the anhydrous methanol washing surface of 2-4mL, after surface drying, theophylline-asccharin eutectic crystal is taken off, described silane coupling agent is 3-r-chloropropyl trimethoxyl silane, 3-aminopropyl trimethoxysilane or n-propyl Trimethoxy silane.
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| CN105396474B (en) * | 2014-09-05 | 2017-12-19 | 中国石油化工股份有限公司 | A method of modifying polyolefin hollow fiber membrane with special hydrophilic organosilicon |
| CN105381723B (en) * | 2014-09-05 | 2017-11-07 | 中国石油化工股份有限公司 | Preparation method of super-hydrophobic flat membrane |
| CN115925708B (en) * | 2022-11-22 | 2024-11-26 | 天津大学 | A belinastatin eutectic and its preparation method and application |
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| WO2008153945A2 (en) * | 2007-06-06 | 2008-12-18 | University Of South Florida | Nutraceutical co-crystal compositions |
| CN102202753A (en) * | 2008-07-26 | 2011-09-28 | 布拉德福德大学 | method and product |
| CN102276652A (en) * | 2011-06-27 | 2011-12-14 | 中国药科大学 | New crystal form of saccharine adefovir dipivoxil eutectic |
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| JPH03193733A (en) * | 1989-12-25 | 1991-08-23 | Nikken Chem Co Ltd | Sustained release preparation of theopylline |
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| WO2008153945A2 (en) * | 2007-06-06 | 2008-12-18 | University Of South Florida | Nutraceutical co-crystal compositions |
| CN102202753A (en) * | 2008-07-26 | 2011-09-28 | 布拉德福德大学 | method and product |
| CN102276652A (en) * | 2011-06-27 | 2011-12-14 | 中国药科大学 | New crystal form of saccharine adefovir dipivoxil eutectic |
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