CN102633785A - Novel iloperidone pharmaceutical cocrystal and preparation method thereof - Google Patents
Novel iloperidone pharmaceutical cocrystal and preparation method thereof Download PDFInfo
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- CN102633785A CN102633785A CN2012101151372A CN201210115137A CN102633785A CN 102633785 A CN102633785 A CN 102633785A CN 2012101151372 A CN2012101151372 A CN 2012101151372A CN 201210115137 A CN201210115137 A CN 201210115137A CN 102633785 A CN102633785 A CN 102633785A
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- XMXHEBAFVSFQEX-UHFFFAOYSA-N CC(c(cc1)cc(OC)c1OCCCN(CC1)CCC1c1n[o]c2cc(F)ccc12)=O Chemical compound CC(c(cc1)cc(OC)c1OCCCN(CC1)CCC1c1n[o]c2cc(F)ccc12)=O XMXHEBAFVSFQEX-UHFFFAOYSA-N 0.000 description 1
- UYEMGAFJOZZIFP-UHFFFAOYSA-N OC(c1cc(O)cc(O)c1)=O Chemical compound OC(c1cc(O)cc(O)c1)=O UYEMGAFJOZZIFP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of pharmaceutical cocrystals and in particular relates to a novel iloperidone pharmaceutical cocrystal and a preparation method thereof. The pharmaceutical cocrystal is characterized in that iloperidone is taken as the active pharmaceutical ingredient, 3,5-dihydroxy-benzoic acid is taken as the former, and an iloperidone molecule, a 3,5-dihydroxy-benzoic acid molecule and a water molecule jointly form a basic structural unit of the iloperidone pharmaceutical cocrystal through hydrogen bonds and deposition. The pharmaceutical cocrystal is prepared by taking ethanol as the solvent and adopting the method of reflux-room temperature diffusion and volatilization. As the selected organic solvent has lower boiling point, crystals are prepared in the process of solvent volatilization after reflux and filtration. The prepared pharmaceutical cocrystal carries forward the characteristic of the traditional active pharmaceutical ingredients in treating schizophrenia and the dissolubility, stability and bioavailability of the pharmaceutical cocrystal are also obviously improved.
Description
Technical field
The invention belongs to medicine eutectic technical field, be specifically related to a kind of novel Zomaril medicine eutectic and preparation method thereof.
Background technology
1894, German E.Fischer proposed " lock-key " model based on the thought of " intermolecular selectivity effect ", promptly is the blank of modern supramolecule scientific theory.Nineteen thirty-seven; Germany K.L.Wolf etc. has created " supramolecule " speech, and the entity of the high-sequential that forms in order to describe molecular association is said from universal significance; All there is interaction in the set of any molecule, so people usually are called " supramolecule " with this layer of structure of material aggregation attitude.Up to 1978, the J.M.Lehn professor of France just finally proposed the complete concept of " supramolecular chemistry " based on traditional Subjective and Objective architectural study that is planted in the organic chemistry.Supramolecular chemistry be the research molecular interaction conclude and form complicated in order and have a science of the molecule aggregates of ad hoc structure and function, it is " chemistry that surmounts the branch subcategory " and this molecule aggregates abbreviation supramolecule.So the basis of supramolecular chemistry is intermolecular non-covalent interaction, through studying the science of the ergasia that a plurality of intermolecular non-covalent interactions not of the same race form.The strong bonding force that supramolecular chemistry has following notable feature: a. formation super molecular compound is weak interaction force stack and collaborative result between differing mol, is the general performance of multiple reactive force; B. the super molecular compound that forms of differing mol self-assembly demonstrates and the diverse new function of former self assembly molecule.And molecular recognition of carrying out through the synergy of intermolecular weak interaction and supramolecule self-assembly are the cores of supramolecular chemistry research.
Crystal engineering is applied to crystalline design and growth with the principle and the method for supramolecular chemistry, through the acting in conjunction of molecular recognition and self assembling process, obtains the Adjustable structure control, has the new crystal of specific physico-chemical property.The approach of the Design Theory medicine eutectic of utilization crystal engineering is feasible, utilizes the principle of crystal engineering to be connected to form new crystal through active constituents of medicine and other eutectic precursor through hydrogen bond.
Active constituents of medicine (API) so that crystalline form exists is confined to salt, polymorph and solvolyte (comprising hydrate) traditionally always.On intellecture property and bioavailability, API itself has very high utility value, and wherein structure and moity are most important component.Britain Camb structural database (CSD) is the main source about the structure of matter microscopic information of molecular designing and material design.
Research of medicine crystal formation and the solid-state pharmacy industry that is characterized in of medicine have very important meaning.On the one hand, the same medicine of different crystal forms may there were significant differences aspect biochemical properties such as stability, solubleness and bioavailability, thereby influence the curative effect of medicine.If there is well assessment to select best medicine crystal formation to research and develop, may produces the variation of crystal formation in the clinical later stage, thereby cause the extension of medicine listing and produce enormous economic loss.
For imitation medicine company; Thereby new crystal how to develop medicine can be broken the patent protection of original medicine company to crystal formation; Ahead of time imitation medicine being introduced to the market, is vital problem in recent years, will directly have influence on imitation medicine and bulk drug company's market and international competitiveness.It has been comparative maturity and dark valued field that medicine crystal formation research and medicine solid-state is characterized in American-European pharmaceutical industry, but pharmaceutical industry still belongs to the starting stage at home.
Summary of the invention
The object of the present invention is to provide Zomaril medicine eutectic of a kind of novel texture and preparation method thereof, and its crystalline structure is tested, its performance is characterized.
The present invention selects for use the bulk drug Zomaril as active constituents of medicine (API), and the presoma of selecting for use is 3, the 5-resorcylic acid, thus obtain a kind of medicine eutectic of novel texture.
The active constituents of medicine of using in the invention (API) is a Zomaril, and chemical name is 6,7; 8,9-tetrahydrochysene-3-(2-(4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino) ethyl)-9-hydroxy-2-methyl-4H-pyrido [2; 1-a] pyrimidin-4-one, molecular formula is C
24H
27FN
2O
4, its structural formula is shown in a.The eutectic precursor of using in the invention (cocrystal former) is 3, the 5-resorcylic acid, and molecular formula is C
7H
6O
4, its structural formula is shown in b.
New crystal is a Zomaril molecule, one 3; 5-resorcylic acid molecule and water molecules are through the basic structural unit of hydrogen bond with accumulation formation Zomaril medicine eutectic; The Zomaril molecule forms Z type chain through the pi-pi accumulation effect; Promptly the six-ring of the six-ring in five-ring and the six-ring dicyclo and another Zomaril molecule is piled up at directions X and is formed in Zomaril molecule; 3,5-resorcylic acid molecule connects water molecules and the Zomaril molecule stretches and the three-dimensional structure of formation Zomaril eutectic molecule at the YZ face; Wherein, 3, the O atom in the 5-resorcylic acid molecule on hydroxyl forms hydrogen bond as the H atom on hydrogen bond receptor and the water molecules as hydrogen-bond donor; 3, the H atom in the 5-resorcylic acid molecule on the carboxyl forms hydrogen bond as the N atom on the pyrimidine ring in hydrogen-bond donor and the Zomaril molecule as hydrogen bond receptor; 3, the Wasserstoffatoms in the 5-resorcylic acid molecule on another hydroxyl forms hydrogen bond as O atom on the flexible chain in hydrogen-bond donor and the Zomaril molecule and the ketonic oxygen on the six-ring as hydrogen bond receptor, and this hydrogen bond belongs to dual hydrogen bond.
The Zomaril medicine eutectic spacer that the present invention prepares is an oblique system; Its axial length a=7.8024～7.9024; B=13.8145～13.9145, c=13.9711～14.0711, shaft angle α=89.950 °～90.050 °; β=105.237 °～105.337 °, y=89.950 °～90.050 °.XRD spectrum signature peak value appears at 9.092 °～9.192 °, and 13.043 °～13.143 °, 14.247 °～14.347 °, 17.295 °～17.395 °, 18.292 °～18.392 °, 19.609 °～19.709 °, 23.353 °～23.453 °.
Zomaril medicine eutectic of the present invention is solvent with ethanol, adopts the method for backflow-room temperature dispensing volatile to prepare, because the boiling point of the organic solvent of being selected for use is lower, so after reflux and filter, promptly there is crystal structure to come out in the process of solvent evaporates.Its step is following:
(1) with mass ratio be 1: 1～1: 4 Zomaril and 3,5-resorcylic acid, etoh solvent place round-bottomed flask in the lump, and the solid content of reaction system is 8～20mg/ml;
(2) at the round-bottomed flask reflux of having put on the shelf, the temperature to 85 of rising reaction system～95 ℃, reaction system begins to reflux, and opens water of condensation then and opens magnetic stirring apparatus simultaneously, stirs refluxed reaction 2～4h;
(3) stir stop after with reacting liquid filtering, place the transparent glass bottle to have crystal to generate Zomaril medicine eutectic promptly of the present invention after 5～10 hours filtrating after leaching insolubles in the room temperature environment held.
The instrument of detection of drugs eutectic structure and performance is following among the present invention:
1, eutectic structure is measured by Brooker Apex II CCD X-ray single crystal diffractometer, full name Bruker SMART-APEX CCD Diffractometer
2, X-Ray DIFFRACTOMETER day island proper Tianjin company produces; Model is XRD-6000; Cu-K α
tube voltage 40kV; Tube current 30mA, 8 °/min of sweep velocity.
The Zomaril bulk drug is to obtain the drugs approved by FDA listing in 2009, the acute schizophrenia that is used to be grown up treatment.It possibly become first personalized psychotherapeutic drug, and its listing might become schizoid first gene target property medicine of treatment.The medication of spirit neural system is being played the part of very important role as the important class of clinical application in global pharmaceutical market always, accounts for 10% of global pharmaceutical market.Along with a large amount of novel therapeutic medicines are widely used in clinically, driven the rapid growth of whole market, spiritual neural field also becomes the research and development focus of domestic and international pharmaceuticals new drug.
Zomaril is mixed type dopamine D 2/serotonin 5HT2A receptor blocking agent, belongs to the atypia Antipsychotic drug.Be incorporated into serotonin 5HT2A and dopamine D 2, D3 acceptor its high-affinity; To dopamine d 4 and serotonin 5HT6,5HT7 and sympathin NE α 1 acceptor moderate affinity; To the low affinity of 5HT1A, dopamine D 1 and histamine H1-receptor, the cholinergic muscarinic receptor there is not detectable affinity.It is through playing a role to dopamine D 2, D3, serotonin 5HT1A and sympathin NE α 1/ α 2c receptor blocking.
The medicine eutectic of the present invention's preparation all has had tangible change having inherited the traditional raw material medicine outside treatment schizophrenia characteristic on its solvability, stability and bioavailability!
Description of drawings
Fig. 1: Zomaril medicine eutectic structure cell schematics;
As shown in the figure; A Zomaril molecule (1), one 3; A 5-resorcylic acid molecule (2) and a water molecules (3) constitute the basic structural unit of Zomaril medicine eutectic through hydrogen bond and accumulation; The Zomaril molecule forms Z type chain through the pi-pi accumulation effect; Promptly the six-ring of the six-ring in five-ring and the six-ring dicyclo and another Zomaril molecule is piled up at directions X and is formed in Zomaril molecule, and 3,5-resorcylic acid molecule connects water molecules and stretches and the three-dimensional structure of formation Zomaril eutectic molecule at the YZ face with the Zomaril molecule; Wherein, 3, the O atom in the 5-resorcylic acid molecule on hydroxyl forms hydrogen bond as the H atom on hydrogen bond receptor and the water molecules as hydrogen-bond donor; 3, the H atom in the 5-resorcylic acid molecule on the carboxyl forms hydrogen bond as the N atom on the pyrimidine ring in hydrogen-bond donor and the Zomaril molecule as hydrogen bond receptor; 3, the Wasserstoffatoms in the 5-resorcylic acid molecule on another hydroxyl forms hydrogen bond as O atom on the flexible chain in hydrogen-bond donor and the Zomaril molecule and the ketonic oxygen on the six-ring as hydrogen bond receptor, and this hydrogen bond belongs to dual hydrogen bond.
The unit cell parameters of the medicine eutectic of embodiment 1 preparation is following: axial length a=7.8524, b=13.8645, c=14.0211, shaft angle α=90.000 °, β=105.287, γ=90.000 °.
Fig. 2: the crystal XRD spectra that the XRD spectra of the eutectic that the Zomaril experiment obtains and simulation obtain.
As shown in the figure; Can find out from the x-ray diffraction pattern peak of this eutectic of synthetic 9.1429 °, 13.093 °, 14.297 °, 17.345 °, 18.342 °, 19.659 ° and 23.403 ° of positions the series of features peak to occur that these characteristic peaks conform to the characteristic peak of the medicine eutectic of simulating out according to the crystalline structure data and through Materials Studio software.
Embodiment
Embodiment 1:
Use Zomaril and 3, the 5-resorcylic acid synthesizes eutectic:
Weighing:
Reactant is pressed Zomaril: 3, and the 5-resorcylic acid=mass ratio fed intake in 1: 1.Accurately take by weighing 20.00mg Zomaril and 20mg3 with analytical balance, the 5-resorcylic acid is in the 25ml single necked round bottom flask.
The dissolving of bulk drug:
Accurately measure 5ml ethanol respectively in the 25ml single necked round bottom flask with the 5ml transfer pipet.
Heating method refluxes-waves:
Put into stirrer in the uniform Zomaril of above-mentioned dissolving and 3, in the round-bottomed flask of 5-resorcylic acid, the good reflux of frame, return time is 2h, reflux temperature is 90 ℃, opens magnetic stirring apparatus and water of condensation.
With reacting liquid filtering, filtrating is placed 25ml transparent glass bottle, room temperature held after the backflow.Slowly volatilizing through solvent promptly has behind the 6h transparent bulk crystals to generate, and the gained eutectic quality of weighing is 0.02g.
Claims (2)
1. Zomaril medicine eutectic; It is characterized in that: with Zomaril as active constituents of medicine; With 3; The 5-resorcylic acid is a presoma, Zomaril molecule, 3, and 5-resorcylic acid molecule and a water molecules are through the basic structural unit of hydrogen bond with accumulation formation Zomaril medicine eutectic; The Zomaril molecule forms Z type chain through the pi-pi accumulation effect; Promptly the six-ring of the six-ring in five-ring and the six-ring dicyclo and another Zomaril molecule is piled up at directions X and is formed in Zomaril molecule, and 3,5-resorcylic acid molecule connects water molecules and stretches and the three-dimensional structure of formation Zomaril eutectic molecule at the YZ face with the Zomaril molecule; Wherein, 3, the O atom in the 5-resorcylic acid molecule on hydroxyl forms hydrogen bond as the H atom on hydrogen bond receptor and the water molecules as hydrogen-bond donor; 3, the H atom in the 5-resorcylic acid molecule on the carboxyl forms hydrogen bond as the N atom on the pyrimidine ring in hydrogen-bond donor and the Zomaril molecule as hydrogen bond receptor; 3, the Wasserstoffatoms in the 5-resorcylic acid molecule on another hydroxyl forms hydrogen bond as O atom on the flexible chain in hydrogen-bond donor and the Zomaril molecule and the ketonic oxygen on the six-ring as hydrogen bond receptor, and this hydrogen bond belongs to dual hydrogen bond; This medicine eutectic spacer is an oblique system, its axial length a=7.8024～7.9024, b=13.8145～13.9145, c=13.9711～14.0711, shaft angle α=89.950～90.050, β=105.237～105.337, γ=89.950～90.050.
2. the preparation method of the described a kind of Zomaril medicine eutectic of claim 1, its step is following:
(1) with mass ratio be 1: 1～1: 4 Zomaril and 3,5-resorcylic acid, etoh solvent place round-bottomed flask in the lump, and the solid content of reaction system is 8～20mg/ml;
(2) at the round-bottomed flask reflux of having put on the shelf, the temperature to 85 of rising reaction system～95 ℃, reaction system begins to reflux, and opens water of condensation then and opens magnetic stirring apparatus simultaneously, stirs refluxed reaction 2～4h;
(3) stir stop after with reacting liquid filtering, place the transparent glass bottle to have crystal to generate after 5～10 hours filtrating after leaching insolubles, i.e. Zomaril medicine eutectic in the room temperature environment held.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210115137.2A CN102633785B (en) | 2012-04-18 | 2012-04-18 | Novel iloperidone pharmaceutical cocrystal and preparation method thereof |
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| CN201210115137.2A CN102633785B (en) | 2012-04-18 | 2012-04-18 | Novel iloperidone pharmaceutical cocrystal and preparation method thereof |
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| CN102633785B CN102633785B (en) | 2014-07-30 |
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Cited By (5)
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| CN103044411A (en) * | 2013-01-09 | 2013-04-17 | 吉林三善恩科技开发有限公司 | Iloperidone drug cocrystal and preparation method thereof |
| CN103113363A (en) * | 2013-03-06 | 2013-05-22 | 吉林三善恩科技开发有限公司 | Iloperidone-benzoic acid organic pharmaceutical co-crystal and preparation method thereof |
| CN103113362A (en) * | 2013-03-06 | 2013-05-22 | 吉林三善恩科技开发有限公司 | Iloperidone-p-hydroxybenzoic acid organic pharmaceutical co-crystal and preparation method thereof |
| CN106083743A (en) * | 2016-06-20 | 2016-11-09 | 广州大学 | A kind of glycine anhydride eutectic as medicinal premixing auxiliary material and preparation method and application |
| CN115785065A (en) * | 2022-12-02 | 2023-03-14 | 山东达因海洋生物制药股份有限公司 | Desloratadine eutectic crystal and preparation method and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044411A (en) * | 2013-01-09 | 2013-04-17 | 吉林三善恩科技开发有限公司 | Iloperidone drug cocrystal and preparation method thereof |
| CN103044411B (en) * | 2013-01-09 | 2015-02-18 | 吉林三善恩科技开发有限公司 | Iloperidone drug cocrystal and preparation method thereof |
| CN103113363A (en) * | 2013-03-06 | 2013-05-22 | 吉林三善恩科技开发有限公司 | Iloperidone-benzoic acid organic pharmaceutical co-crystal and preparation method thereof |
| CN103113362A (en) * | 2013-03-06 | 2013-05-22 | 吉林三善恩科技开发有限公司 | Iloperidone-p-hydroxybenzoic acid organic pharmaceutical co-crystal and preparation method thereof |
| CN103113362B (en) * | 2013-03-06 | 2015-03-04 | 吉林三善恩科技开发有限公司 | Iloperidone-p-hydroxybenzoic acid organic pharmaceutical co-crystal and preparation method thereof |
| CN106083743A (en) * | 2016-06-20 | 2016-11-09 | 广州大学 | A kind of glycine anhydride eutectic as medicinal premixing auxiliary material and preparation method and application |
| CN115785065A (en) * | 2022-12-02 | 2023-03-14 | 山东达因海洋生物制药股份有限公司 | Desloratadine eutectic crystal and preparation method and application thereof |
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| CN102633785B (en) | 2014-07-30 |
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