CN102827165A - 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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- CN102827165A CN102827165A CN201210333271XA CN201210333271A CN102827165A CN 102827165 A CN102827165 A CN 102827165A CN 201210333271X A CN201210333271X A CN 201210333271XA CN 201210333271 A CN201210333271 A CN 201210333271A CN 102827165 A CN102827165 A CN 102827165A
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- theophylline
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- asccharin
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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 the membrane orienting technology to prepare eutectic, belong to the preparing technical field of theophylline-asccharin eutectic.
Background technology
Eutectic has the unique physico-chemical property and the bioavailability that are different from conventional medicament as a kind of novel solid form of current medicine.In fact, the selection of ligand molecular need be followed the solubleness principle of similarity in the eutectic of specific system, and promptly the solubleness of ligand molecular can not too be higher than active constituents of medicine.Otherwise, will produce asymmetric phasor.Balance each other on the basis of rule fully understanding the two solution, adopt solvent evaporation and outstanding turbid crystalline method can handle the asymmetric case of phasor.But this is based on binary or the known situation of ternary phase diagrams.Therefore, obtaining pure article eutectic need carefully control the thermodynamics and kinetics factor of system, and this acquisition for pure article eutectic has produced very big obstacle.
Break away from the method that the thermodynamics phasor prepares eutectic at present to asymmetric system and mainly contain spray crystallization and surface active agent solubilization crystallization.Utilizing self-assembled film (self-assembled monolayers is called for short SAMs) to carry out the eutectic selective growth does not report at present.Owing to mainly leaning on Intermolecular Forces (being mainly hydrogen bond) and intermolecular accumulation to carry out intermolecular self-assembly, eutectic forms.In addition, hydrogen bond also often is formed between the active constituents of medicine/part and solvent molecule in the solution.Be adsorbed on the 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 the unimolecular film should be greater than the Intermolecular Forces in the solution.In non covalent bond commonly used (for example hydrogen bond, halogen key and pi-pi accumulation), the halogen key is as one big type of non covalent bond, and its bond energy is between 10-200kJ/mol.Therefore, its bond energy size has determined in some molecule self-assembly and molecular recognition process, can be superior to hydrogen bond formation earlier.
Theophylline is the suppressor factor of a kind of phosphodiesterase (PDE) as a kind of medicine, therefore is widely used in the treatment of respiratory system disease.Asccharin is a kind of ancient sweeting agent, but does not contain nutrition.In theophylline-asccharin eutectic, in the theophylline--carbonylic oxygen atom that NH serves as in hydrogen bond donor and the asccharin carries out hydrogen bonding.NH and the carbonyl in the theophylline in the asccharin also formed N-H simultaneously ... O.Theophylline-asccharin eutectic all is typical asymmetric phasor system in conventional solvent such as methyl alcohol, ethanol, utilizes the solution evaporation method can't obtain pure article eutectic.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art, provide a kind of membrane technique the directed method for preparing theophylline-asccharin eutectic.
Technical scheme of the present invention is summarized as follows:
The directed method for preparing theophylline-asccharin eutectic of a kind of membrane technique comprises the steps:
(1) will be cut into the sheet glass that needs size and immerse in the fresh Piranha solution,, sheet glass taken out in 70 ℃ ~ 90 ℃ following thermostatically heating 90～120min; Successively with deionized water, Virahol, absolute ethyl alcohol and normal hexane washing; Drying obtains the hydroxylation sheet glass, and said hydroxylation sheet glass is put into the aqueous solution that contains silane coupling agent that concentration is 10 ~ 20mM; Room temperature, air tight condition held 100 ~ 150 minutes obtain the sheet glass of surface silicon alkanisation; The sheet glass of said silylanization is washed with fresh normal hexane, put into the ultrasonic 5-20 of anhydrous methanol minute; Clean with anhydrous methanol,, obtain the silane self-assembled monolayer in glass sheet surface in 50 ℃ ~ 80 ℃ oven dry 8 ~ 12h;
(2) with mol ratio be 1:1 ~ 5 theophylline and asccharin altogether 3.0g ~ 5.0g join and be contained with in 100mL methyl alcohol or the alcoholic acid container, be heated to 50 ℃ solid all dissolved; Be cooled to 25 ~ 40 ° ℃; Putting into the surface has the sheet glass of silane self-assembled monolayer and makes it and the container inner wall angle is 70 °-80 °; The container cover that is coated with the adjustable open degree at the container upper end opening part can slowly be evaporated the solvent in the container at 25 ~ 40 ℃ of following constant temperature; Grow a large amount of theophylline-asccharin eutectic crystal on the said film of 2-7 angel surface; There is the crystalline sheet glass to take out length,, treats after the surface drying theophylline-asccharin eutectic crystal to be taken off with the anhydrous methanol washing surface of 2-4mL.
Said 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 the silane self-assembled monolayer; Utilize intermolecular reactive force and membrane crystallization to change local composition of solution of eutectic system again; The growth of directional induction eutectic; In concentration range,, all can obtain pure theophylline-asccharin eutectic through XRD checking than broad.In addition, this method can be applied to other asymmetric ternary phase diagrams system to obtain highly purified medicine eutectic.
Description of drawings
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 the 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 this regional ligand concentration too high; Make the partial concn ratio of pharmaceutical activity molecule and ligand molecular be higher than the main body concentration ratio; This can make pilot wire in the ternary phase diagrams to pharmaceutical activity molecule one side shifting, thereby the single phase region that gets into eutectic more helps the generation of eutectic.
Through specific embodiment the present invention is done further explanation below.In this explanation is that embodiment is just in order to enable those skilled in the art to better understand the present invention, not to doing any restriction.
The used Piranha solution of the present invention is to be the dense H of 7:3 by volume ratio
2SO
4With 30% H
2O
2Formulated.
Embodiment 1
(1) in large beaker, adds the fresh Piranha solution of 50ml; (20X20mm) puts into wherein with the sheet glass that cuts, and thermostatically heating is 120 minutes under 70 ° of ℃ of conditions, and sheet glass is taken out; Carefully wash with deionized water, Virahol, absolute ethyl alcohol and normal hexane successively; Drying obtains the hydroxylation sheet glass, and said hydroxylation sheet glass is put into the aqueous solution that contains the 3-r-chloropropyl trimethoxyl silane that 60mL concentration is 10mM; Room temperature, air tight condition held 100 minutes obtain the sheet glass of surface silicon alkanisation; The sheet glass of said silylanization is washed with fresh normal hexane, put into anhydrous methanol ultrasonic 10 minutes; Clean with anhydrous methanol,, obtain the silane self-assembled monolayer in glass sheet surface in 50 ℃ of oven dry 12h;
(2) with mol ratio be 1:1 theophylline and asccharin altogether 3.0g join in the container that is contained with 100mL methyl alcohol, be heated to 50 ℃ solid all dissolved; Be cooled to 25 ° ℃; Putting into the surface has the sheet glass of silane self-assembled monolayer and makes it and the container inner wall angle is 70 °; The container cover that is coated with the adjustable open degree at the container upper end opening part can slowly be evaporated the solvent in the container at 25 ℃ of following constant temperature, grows a large amount of theophylline-asccharin eutectic crystal on the said film of 7 angels surface, has the crystalline sheet glass to take out length; With the anhydrous methanol washing surface of 2mL, treat after the surface drying theophylline-asccharin eutectic crystal to be taken off.
Theophylline-asccharin eutectic crystal XRD sees Fig. 1.
(1) in large beaker, adds the fresh Piranha solution of 50ml; (20X20mm) puts into wherein with the sheet glass that cuts, and thermostatically heating is 90 minutes under 90 ° of ℃ of conditions, and sheet glass is taken out; Carefully wash with deionized water, Virahol, absolute ethyl alcohol and normal hexane successively; Drying obtains the hydroxylation sheet glass, and said hydroxylation sheet glass is put into the aqueous solution that contains the 3-aminopropyl trimethoxysilane that 60mL concentration is 15mM; Room temperature, air tight condition held 150 minutes obtain the sheet glass of surface silicon alkanisation; The sheet glass of said silylanization is washed with fresh normal hexane, put into anhydrous methanol ultrasonic 5 minutes; Clean with anhydrous methanol,, obtain the silane self-assembled monolayer in glass sheet surface in 80 ℃ of oven dry 8h;
(2) with mol ratio be 1:3 theophylline and asccharin altogether 4.0g join and be contained with in the 100mL alcoholic acid container, be heated to 50 ℃ solid all dissolved; Be cooled to 30 ° ℃; Putting into the surface has the sheet glass of silane self-assembled monolayer and makes it and the container inner wall angle is 80 °; The container cover that is coated with the adjustable open degree at the container upper end opening part can slowly be evaporated the solvent in the container at 30 ℃ of following constant temperature, grows a large amount of theophylline-asccharin eutectic crystal on the said film of 4 angels surface, has the crystalline sheet glass to take out length; With the anhydrous methanol washing surface of 4mL, treat after the surface drying theophylline-asccharin eutectic crystal to be taken off.
Theophylline is similar with embodiment 1 with the eutectic XRD figure that asccharin forms.
Embodiment 3
(1) in large beaker, adds the fresh Piranha solution of 50ml; (20X20mm) puts into wherein with the sheet glass that cuts, and thermostatically heating is 100 minutes under 80 ° of ℃ of conditions, and sheet glass is taken out; Carefully wash with deionized water, Virahol, absolute ethyl alcohol and normal hexane successively; Drying obtains the hydroxylation sheet glass, and said hydroxylation sheet glass is put into the aqueous solution that contains the n-propyl Trimethoxy silane that 60mL concentration is 20mM; Room temperature, air tight condition held 150 minutes obtain the sheet glass of surface silicon alkanisation; The sheet glass of said silylanization is washed with fresh normal hexane, put into anhydrous methanol ultrasonic 20 minutes; Clean with anhydrous methanol,, obtain the silane self-assembled monolayer in glass sheet surface in 70 ℃ of oven dry 10h;
(2) with mol ratio be 1:5 theophylline and asccharin altogether 5.0g join and be contained with in the 100mL alcoholic acid container, be heated to 50 ℃ solid all dissolved; Be cooled to 40 ° ℃; Putting into the surface has the sheet glass of silane self-assembled monolayer and makes it and the container inner wall angle is 75 °; The container cover that is coated with the adjustable open degree at the container upper end opening part can slowly be evaporated the solvent in the container at 40 ℃ of following constant temperature, grows a large amount of theophylline-asccharin eutectic crystal on the said film of 2 angels surface, has the crystalline sheet glass to take out length; With the anhydrous methanol washing surface of 3mL, treat after the surface drying theophylline-asccharin eutectic crystal to be taken off.
Theophylline is similar with embodiment 1 with the eutectic XRD figure that asccharin forms.
Claims (2)
1. the directed method for preparing theophylline-asccharin eutectic of membrane technique is characterized in that comprising the steps:
(1) will be cut into the sheet glass that needs size and immerse in the fresh Piranha solution,, sheet glass taken out in 70 ℃ ~ 90 ℃ following thermostatically heating 90 ~ 120min; Successively with deionized water, Virahol, absolute ethyl alcohol and normal hexane washing; Drying obtains the hydroxylation sheet glass, and said hydroxylation sheet glass is put into the aqueous solution that contains silane coupling agent that concentration is 10 ~ 20mM; Room temperature, air tight condition held 100 ~ 150 minutes obtain the sheet glass of surface silicon alkanisation; The sheet glass of said silylanization is washed with fresh normal hexane, put into the ultrasonic 5-20 of anhydrous methanol minute; Clean with anhydrous methanol,, obtain the silane self-assembled monolayer in glass sheet surface in 50 ℃ ~ 80 ℃ oven dry 8 ~ 12h;
(2) with mol ratio be 1:1 ~ 5 theophylline and asccharin altogether 3.0g ~ 5.0g join and be contained with in 100mL methyl alcohol or the alcoholic acid container, be heated to 50 ℃ solid all dissolved; Be cooled to 25 ~ 40 ° ℃; Putting into the surface has the sheet glass of silane self-assembled monolayer and makes it and the container inner wall angle is 70 °-80 °; The container cover that is coated with the adjustable open degree at the container upper end opening part can slowly be evaporated the solvent in the container at 25 ~ 40 ℃ of following constant temperature; Grow a large amount of theophylline-asccharin eutectic crystal on the said film of 2-7 angel surface; There is the crystalline sheet glass to take out length,, treats after the surface drying theophylline-asccharin eutectic crystal to be taken off with the anhydrous methanol washing surface of 2-4mL.
2. the directed method for preparing theophylline-asccharin eutectic of a kind of membrane technique according to claim 1 is characterized in that said silane coupling agent is 3-r-chloropropyl trimethoxyl silane, 3-aminopropyl trimethoxysilane or n-propyl Trimethoxy silane.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105381723A (en) * | 2014-09-05 | 2016-03-09 | 中国石油化工股份有限公司 | Super-hydrophobic flat plate membrane preparation method |
| CN105396474A (en) * | 2014-09-05 | 2016-03-16 | 中国石油化工股份有限公司 | Method for modifying polyolefin hollow fiber membrane with specially-moistening organosilicon |
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| JPH03193733A (en) * | 1989-12-25 | 1991-08-23 | Nikken Chem Co Ltd | Sustained release preparation of theopylline |
| 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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2012
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Patent Citations (4)
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| JPH03193733A (en) * | 1989-12-25 | 1991-08-23 | Nikken Chem Co Ltd | Sustained release preparation of theopylline |
| 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 |
Non-Patent Citations (5)
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| 《CrystEngComm》 20120424 Shuo Zhang 等 The theophylline-oxalic acid co-crystal system: solid phases, thermodynamics and crystallisation 第4644-4655页 1-2 第14卷, 第14期 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105381723A (en) * | 2014-09-05 | 2016-03-09 | 中国石油化工股份有限公司 | Super-hydrophobic flat plate membrane preparation method |
| CN105396474A (en) * | 2014-09-05 | 2016-03-16 | 中国石油化工股份有限公司 | Method for modifying polyolefin hollow fiber membrane with specially-moistening organosilicon |
| CN105381723B (en) * | 2014-09-05 | 2017-11-07 | 中国石油化工股份有限公司 | A kind of preparation method of super-hydrophobic Flat Membrane |
| CN105396474B (en) * | 2014-09-05 | 2017-12-19 | 中国石油化工股份有限公司 | A kind of method for moistening organic-silicon-modified Polyolefin Hollow Fiber with special parent |
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