CN102659771A - Novel lloperidone pharmaceutical co-crystal and preparation method thereof - Google Patents
Novel lloperidone pharmaceutical co-crystal and preparation method thereof Download PDFInfo
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- CN102659771A CN102659771A CN2012101151391A CN201210115139A CN102659771A CN 102659771 A CN102659771 A CN 102659771A CN 2012101151391 A CN2012101151391 A CN 2012101151391A CN 201210115139 A CN201210115139 A CN 201210115139A CN 102659771 A CN102659771 A CN 102659771A
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Abstract
The invention belongs to the technical field of pharmaceutical co-crystals, in particular to a novel lloperidone pharmaceutical co-crystal and a preparation method thereof. The pharmaceutical co-crystal takes lloperidone as an active pharmaceutical ingredient and takes 2, 3-dihydroxy-benzoic acid as a precursor; one lloperidone molecule, one 2, 3-dihydroxy-benzoic acid molecule and one water molecule commonly form a basic structural unit of the lloperidone pharmaceutical co-crystal under the hydrogen bond and accumulation actions. A solvent selected by the pharmaceutical co-crystal is ethanol and is prepared by adopting a backflow-diffused evaporation method; and as the selected organic solvent is lower in boiling point, the crystal is crystallized out in the solvent evaporation process after backflow filtering. The pharmaceutical co-crystal prepared by the invention not only inherits the characteristic of traditional raw medicine in treating schizophrenia, but also is remarkably improved on dissolubility, stability and bioavailability of the pharmaceutical co-crystal.
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 2, the 3-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 2, the 3-resorcylic acid, and molecular formula is C
7H
6O
4, its structural formula is shown in b.
Its crystalline structure is summarized as follows: Zomaril molecule, 2; 3-resorcylic acid molecule, a water molecules constitute the basic structural unit of Zomaril medicine eutectic jointly through hydrogen bond and accumulation; The Zomaril molecule forms Z type chain through the pi-pi accumulation effect; Promptly in Zomaril molecule in the six-ring in five-ring and the six-ring dicyclo and another Zomaril molecule independent six-ring pile up at directions X and form; Water molecules and 2,3-resorcylic acid molecule stretches the three-dimensional structure that constitutes the Zomaril eutectic at the YZ face jointly through the chain that hydrogen bond forms; Wherein, at the YZ face, the O atom in the water molecules is as hydrogen bond receptor and 2, and the H atom in the 3-resorcylic acid molecule on the hydroxyl forms hydrogen bond as hydrogen-bond donor; H atom in the water molecules forms hydrogen bond as the O atom on the carbonyl in the six-ring in hydrogen-bond donor and the Zomaril molecule as hydrogen bond receptor; 2, the H atom in the 3-resorcylic acid molecule on the carboxyl forms hydrogen bond as the N atom in the pyrimidine ring in hydrogen-bond donor and the Zomaril molecule as hydrogen bond receptor.
The Zomaril medicine eutectic spacer that the present invention prepares is an oblique system; Its axial length a=7.7302～7.8302; B=13.7442～13.8442, c=13.8764～13.9764, shaft angle α=89.950 °～90.050 °; β=103.539 °～103.639 °, Y=89.950 °～90.050 °; XRD spectrum signature peak value appears at 6.635 °～6.735 °, and 9.173 °～9.273 °, 13.057 °～13.157 °, 14.320 °～14.420 ° and 19.915 °～20.015 °.
The selected solvent of Zomaril medicine eutectic of the present invention is an ethanol, adopts the method for backflow-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 Zomaril and 2, the 3-resorcylic acid adds in the round-bottomed flask by mass ratio 1: 1～1: 4 and etoh solvent 3ml～6ml 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 90 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 in the room temperature environment held, be Zomaril medicine eutectic of the present invention.
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.
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.In addition, spiritual neural system medication 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.
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 2; 3-resorcylic acid molecule (2), a water molecules (3) constitute the basic structural unit of Zomaril medicine eutectic jointly through hydrogen bond and accumulation; The Zomaril molecule forms Z type chain through the pi-pi accumulation effect; Promptly in Zomaril molecule in the six-ring in five-ring and the six-ring dicyclo and another Zomaril molecule independent six-ring pile up at directions X and form, water molecules and 2,3-resorcylic acid molecule stretches the three-dimensional structure that constitutes the Zomaril eutectic at the YZ face jointly through the chain that hydrogen bond forms; Wherein, at the YZ face, the O atom in the water molecules is as hydrogen bond receptor and 2, and the H atom in the 3-resorcylic acid molecule on the hydroxyl forms hydrogen bond as hydrogen-bond donor; H atom in the water molecules forms hydrogen bond as the O atom on the carbonyl in the six-ring in hydrogen-bond donor and the Zomaril molecule as hydrogen bond receptor; 2, the H atom in the 3-resorcylic acid molecule on the carboxyl forms hydrogen bond as the N atom in the pyrimidine ring in hydrogen-bond donor and the Zomaril molecule as hydrogen bond receptor.
The unit cell parameters of the medicine eutectic of embodiment 1 preparation is following: axial length a=7.7802, b=13.7942, c=13.9264, shaft angle α=90.000 °, β=103.589 °, Y=90.000 °.
Fig. 2: the crystal XRD spectra that the XRD spectra of Zomaril eutectic and simulation obtain;
As shown in the figure; Can find out from the x-ray diffraction pattern peak of this eutectic of synthetic 6.685 °, 9.223 °, 13.107 °, 14.370 ° and 19.965 ° 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 2, the 3-resorcylic acid synthesizes eutectic:
Weighing:
Reactant is pressed Zomaril: 2, and the mass ratio of 3-resorcylic acid=1: 1 feeds intake.Accurately take by weighing 2 of 20.00mg Zomaril and 20.00mg with analytical balance, the 3-resorcylic acid.
The dissolving of bulk drug:
Accurately measure 5ml ethanol in the 25ml single necked round bottom flask with the 5ml transfer pipet.
Heating method refluxes-waves:
Put into the round-bottomed flask of magnetic agitation in the above-mentioned uniform medicine of back dissolving of weighing, the good reflux of frame, return time is 2h, 90 ℃ of reflux temperatures are opened magnetic stirring apparatus and water of condensation.
With reacting liquid filtering, filtrating is placed 25ml transparent glass bottle 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: as active constituents of medicine, with 2, the 3-resorcylic acid is a presoma to this medicine eutectic with Zomaril; Zomaril molecule, one 2; 3-resorcylic acid molecule, a water molecules constitute the basic structural unit of Zomaril medicine eutectic jointly through hydrogen bond and accumulation; The Zomaril molecule forms Z type chain through the pi-pi accumulation effect; Promptly in Zomaril molecule in the six-ring in five-ring and the six-ring dicyclo and another Zomaril molecule independent six-ring pile up at directions X and form; Water molecules and 2,3-resorcylic acid molecule stretches the three-dimensional structure that constitutes the Zomaril eutectic at the YZ face jointly through the chain that hydrogen bond forms; Wherein, at the YZ face, the O atom in the water molecules is as hydrogen bond receptor and 2, and the H atom in the 3-resorcylic acid molecule on the hydroxyl forms hydrogen bond as hydrogen-bond donor; H atom in the water molecules forms hydrogen bond as the O atom on the carbonyl in the six-ring in hydrogen-bond donor and the Zomaril molecule as hydrogen bond receptor; 2, the H atom in the 3-resorcylic acid molecule on the carboxyl forms hydrogen bond as the N atom in the pyrimidine ring in hydrogen-bond donor and the Zomaril molecule as hydrogen bond receptor; This medicine eutectic spacer is an oblique system, its axial length a=7.7302～7.8302, b=13.7442～13.8442; C=13.8764～13.9764; Shaft angle α=89.950 °～90.050 °, β=103.539 °～103.639 °, Y=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 Zomaril and 2, the 3-resorcylic acid places round-bottomed flask in the lump by mass ratio 1: 1～1: 4 and etoh solvent, 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 90 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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| CN2012101151391A CN102659771B (en) | 2012-04-18 | 2012-04-18 | Lloperidone pharmaceutical co-crystal and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| WO2004006886A2 (en) * | 2002-07-15 | 2004-01-22 | Novartis Ag | Injectable depot formulation comprising crystals of iloperidone |
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| WO2011055188A1 (en) * | 2009-11-05 | 2011-05-12 | Orchid Chemicals And Pharmaceuticals Limited | An improved process for the preparation of iloperidone |
| CN102276594A (en) * | 2011-06-17 | 2011-12-14 | 吉林大学 | Novel iloperidone medicinal cocrystal and preparation method thereof |
| CN102311430A (en) * | 2010-06-29 | 2012-01-11 | 大道隆达（北京）医药科技发展有限公司 | Novel crystalline state of iloperidone and preparation method thereof |
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2012
- 2012-04-18 CN CN2012101151391A patent/CN102659771B/en not_active Expired - Fee Related
Patent Citations (6)
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| WO2004006886A2 (en) * | 2002-07-15 | 2004-01-22 | Novartis Ag | Injectable depot formulation comprising crystals of iloperidone |
| US20100076196A1 (en) * | 2008-09-19 | 2010-03-25 | Vertessy Miklos | Process for the preparation of iloperidone |
| WO2011032404A1 (en) * | 2009-09-19 | 2011-03-24 | 浙江华海药业股份有限公司 | Method for preparation of iloperidone and crystallization method thereof |
| WO2011055188A1 (en) * | 2009-11-05 | 2011-05-12 | Orchid Chemicals And Pharmaceuticals Limited | An improved process for the preparation of iloperidone |
| CN102311430A (en) * | 2010-06-29 | 2012-01-11 | 大道隆达（北京）医药科技发展有限公司 | Novel crystalline state of iloperidone and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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