CN102276594B - Iloperidone medicinal cocrystal and preparation method thereof - Google Patents

Iloperidone medicinal cocrystal and preparation method thereof Download PDF

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Publication number
CN102276594B
CN102276594B CN 201110162654 CN201110162654A CN102276594B CN 102276594 B CN102276594 B CN 102276594B CN 201110162654 CN201110162654 CN 201110162654 CN 201110162654 A CN201110162654 A CN 201110162654A CN 102276594 B CN102276594 B CN 102276594B
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iloperidone
cocrystal
zomaril
medicinal cocrystal
dicarboxylic acid
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CN 201110162654
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Chinese (zh)
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CN102276594A (en
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张婷
朱广山
邢娇娇
韩冰
苏红敏
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吉林大学
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Abstract

The invention belongs to the technical field of medicinal cocrystal, and particularly relates to a novel iloperidone medicinal cocrystal and a preparation method thereof. An N atom in a piperidine ring of iloperidone is used as a hydrogen bond donor, and an H atom on a carboxyl group in 3,5-pyridine dicarboxylic acid is used as a hydrogen bond receptor to form a hydrogen bond; an iloperidone molecule is combined with a 3,5-pyridine dicarboxylic acid molecule through the hydrogen bond to form a basic structural unit of the iloperidone medicinal cocrystal; and a space group of the medicinal cocrystal is a triclinic system. The preparation method of the iloperidone medicinal cocrystal is a reflux-room temperature volatilization method. The medicinal cocrystal prepared by using the preparation method disclosed by the invention has the characteristics of inheriting the conventional raw material medicament on treatment of schizophrenia; and the dissolubility, the stability and the bioavailability of the medicinal cocrystal are obviously improved.

Description

A kind of iloperidone medicinal cocrystal and preparation method thereof

Technical field

The invention belongs to the pharmaceutical co-crystals technical field, be specifically related to a kind of iloperidone medicinal cocrystal and preparation method thereof.

Background technology

1894, German E.Fischer proposed " lock-key " model based on the thought of " intermolecular selectivity effect ", namely is the blank of modern supramolecule scientific theory.Nineteen thirty-seven, Germany K.L.Wolf etc. has created " supramolecule " word, and the entity of the high-sequential that forms in order to describe molecular association is on 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.Until 1978, the J.M.Lehn of France professor has just finally proposed the complete concept of " supramolecular chemistry " based on traditional guest-host system research 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 minute subcategory " and this molecule aggregates abbreviation supramolecule.So the basis of supramolecular chemistry is noncovalent intermolecular interactions, by studying the science of the ergasia that a plurality of noncovalent intermolecular 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 molecular, is the general performance of multi-acting force; B. the super molecular compound that forms of differing molecular self-assembly demonstrates and the diverse new function of former self assembly molecule.And the molecular recognition of being undertaken by the synergy of intermolecular weak interaction and supramolecule self-assembly are the cores of supramolecular chemistry research.Design and growth that crystal engineering is applied to crystal with principle and the method for supramolecular chemistry, by the acting in conjunction of molecular recognition and self assembling process, obtaining structure can regulate and control, and has the new crystal of specific physico-chemical property.It is feasible using the approach of the Design Theory pharmaceutical co-crystals of crystal engineering, utilizes the principle of crystal engineering to be connected to form new crystal by active constituents of medicine and other eutectic precursor by hydrogen bond.Active constituents of medicine (API) so that crystalline form exists is confined to salt, polymorph and solvate (comprising hydrate) traditionally always.On intellecture property and bioavailability, API itself has very high utility value, and wherein the structure and composition composition is most important integral part.Britain Camb structural database (CSD) is the main source about the structure of matter microscopic information of molecular designing and design of material.

Drug crystal forms research 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 the biochemical properties such as stability, solubleness and bioavailability, thereby affect the curative effect of medicine.If there is well assessment to select best drug crystal forms to research and develop, may produces in the clinical later stage variation of crystal formation, thereby cause the extension of medicine listing and produce huge financial loss.

For imitation medicine company; thereby new crystal how to develop medicine can be broken original medicine company to the patent protection of crystal formation; ahead of time imitation medicine being introduced to the market, is vital problem in recent years, will directly have influence on market and the international competitiveness of imitation medicine and bulk drug company.It has been comparative maturity and dark valued field that drug crystal forms 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 iloperidone medicinal cocrystal of a kind of novel texture and preparation method thereof, and its crystalline structure is tested, its performance is characterized.

The selected bulk drug Zomaril of the present invention is as active constituents of medicine (API), and the eutectic presoma of selecting is 3,5-pyridine dicarboxylic acid, thereby obtains a kind of pharmaceutical co-crystals of novel texture.

The selected solvent of the present invention is ethanol, adopts the method for backflow-room temperature dispensing volatile, because the boiling point of selected organic solvent is lower, so crystal structure is namely arranged out in the process of solvent evaporates after reflux and filter.

The active constituents of medicine of using in the invention (API) is 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 3,5-pyridine dicarboxylic acid, and molecular formula is C 7H 5O 4N, its structural formula is shown as b.

The iloperidone medicinal cocrystal that the present invention prepares is characterized in that: the N atom in the Zomaril in the piperidine ring is as the hydrogen-bond donating body, and the H atom in 3, the 5-pyridine dicarboxylic acid on the carboxyl forms hydrogen bond as hydrogen bond receptor; Zomaril molecule and one 3,5-pyridine dicarboxylic acid molecule consists of the basic structural unit of iloperidone medicinal cocrystal together by hydrogen bonded, the spacer of this pharmaceutical co-crystals is triclinic(crystalline)system, its axial length a=9.4398~9.9398, b=9.6102~10.1102, c=16.3628~16.8628, shaft angle α=89.363~89.863, β=78.521~79.021, γ=74.130~74.630; XRD spectrum signature peak value appears at 12.72 °~13.22 °, 14.30 °~14.80 °, 17.24 °~17.74 °, 19.98 °~20.48 °, locate for 20.36 °~20.86,21.58 °~22.08 °, Zomaril eutectic thermogravimetric curve (air atmosphere test condition), begin weightlessness 40~45% at 180 ° of C~240 ° C, to 240 ° of C~600 ° C weightlessness 60~55%, then decompose fully at 500 ° of C~650 ° C.

The preparation method of iloperidone medicinal cocrystal of the present invention is backflow-room temperature volatilization method, and concrete steps are as follows:

(1) with Zomaril and 3,5-pyridine dicarboxylic acid 1:1~3:1 in mass ratio, the volume of ethanol is 4~6ml, places in the lump round-bottomed flask, and the solid content of reaction system is 10~20mg/ml;

(2) at the added good reflux of round-bottomed flask, the temperature to 90 of rising reaction system~95 ℃, reaction system begins to reflux, and then opens water of condensation and opens simultaneously magnetic stirring apparatus, stirs lower reaction 2~4h;

(3) stir stop after with reacting liquid filtering, place the transparent glass bottle after placing 20~40 hours under the room temperature environment, to have crystal to generate filtrate after leaching insolubles, i.e. iloperidone medicinal cocrystal of the present invention.

The instrument of detection of drugs eutectic structure and performance is as follows 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 Japan Shimadzu company produces, and model is XRD-6000, Cu-K α Tube voltage 40kV, tube current 30mA, 8 °/min of sweep velocity;

3, SIMULTANEOUS DTA-TG APPARATUS, Japanese Shimadzu company, the thermal weight loss of model DTG-60 (TGA) and differential thermal analyzer (DTA), the present invention adopts air atmosphere, and temperature rise rate is 10 ° of C/min.

This bulk drug Zomaril is to obtain the drugs approved by FDA listing in 2009, is used for the treatment of adult's acute schizophrenia.It may become first personalized psychotherapeutic drug, and its listing might become schizoid first gene target medicine for the treatment of.In addition, the Neurotoxicity 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 pharmaceutical co-crystals of the present invention's preparation has had obvious change having inherited the traditional raw material medicine outside treatment schizophrenia characteristic on its solvability, stability and bioavailability!

Description of drawings

The iloperidone medicinal cocrystal basic structural unit synoptic diagram of Fig. 1: embodiment 1 preparation;

As shown in the figure, a Zomaril molecule (1) and one 3,5-pyridine dicarboxylic acid molecule (2) consists of the basic structural unit of iloperidone medicinal cocrystal together by hydrogen bonded, wherein in the Zomaril N atom in the piperidine ring as the hydrogen-bond donating body, H atom in 3, the 5-pyridine dicarboxylic acid on the carboxyl forms hydrogen bond as hydrogen bond receptor; This pharmaceutical co-crystals spacer is triclinic(crystalline)system, and its unit cell parameters is as follows: axial length a=9.4398, b=9.6102, c=16.3628, shaft angle α=89.363, β=78.521, γ=74.130

The crystal XRD spectra that the XRD spectra of the paliperidone eutectic of Fig. 2: embodiment 1 preparation and simulation obtain;

As shown in the figure, can find out at 9.21 °, 18.50 °, 16.70 °, 22.49 °, 23.00 ° from the x-ray diffraction pattern peak of this pharmaceutical co-crystals of preparing the series of features peak to occur that these characteristic peaks conform to the characteristic peak of the pharmaceutical co-crystals of simulating out according to the crystalline structure data and by Materials Studio software.

The thermogravimetric spectrogram of the paliperidone eutectic of Fig. 3: embodiment 1 preparation;

This figure is under the air atmosphere test condition, Zomaril eutectic thermogravimetric curve: begin weightlessness at 240 ° of C, to 450 ° of C weightlessness 45%, then 600 ° of C weightlessness 55%.

Embodiment

The invention will be further elaborated for following Application Example, and the experiment detailed process of Zomaril and the preparation of 3,5-pyridine dicarboxylic acid eutectic is as follows:

Embodiment 1:

Use the synthetic eutectic of Zomaril and 3,5-pyridine dicarboxylic acid:

Weighing:

Reactant is pressed Zomaril: the mass ratio of 3,5-pyridine dicarboxylic acid=1:1 feeds intake.Accurately take by weighing 3 of 40.00mg Zomaril and 40.00mg with analytical balance, the 5-pyridine dicarboxylic acid.

The dissolving of bulk drug:

Accurately measure 4ml ethanol in the 25ml single necked round bottom flask with the 5ml transfer pipet.

Backflow-solvent room temperature hot the method for volatilizing:

Put into magnetic stir bar in round-bottomed flask, the good reflux of frame.It is 90 ℃ that reflux temperature is set, and opens and stirs and water of condensation, behind the backflow 3h, filters, and filtrate is placed under the 25ml beaker room temperature place.Slowly volatilize by the solvent room temperature afterwards, namely have transparent strip crystal to generate behind the 30h, the gained Zomaril eutectic quality of weighing after solvent evaporates is 0.06g.

Embodiment 2:

Use the synthetic eutectic of Zomaril and 3,5-pyridine dicarboxylic acid:

Weighing:

Reactant is pressed Zomaril: the mass ratio of 3,5-pyridine dicarboxylic acid=3:1 feeds intake.Accurately take by weighing 3 of 30.00mg Zomaril and 10.00mg with analytical balance, the 5-pyridine dicarboxylic acid.

The dissolving of bulk drug:

Accurately measure 4ml ethanol in the 25ml single necked round bottom flask with the 5ml transfer pipet.

Backflow-solvent room temperature hot the method for volatilizing:

Put into magnetic stir bar in round-bottomed flask, the good reflux of frame.It is 90 ℃ that reflux temperature is set, and opens and stirs and water of condensation, behind the backflow 3h, filters, and filtrate is placed under the 25ml beaker room temperature place.Slowly volatilize by the solvent room temperature afterwards, namely have transparent strip and laminar two-phase crystal to generate behind the 30h, the gained Zomaril eutectic quality of weighing after solvent evaporates is 0.02g.

On the purity of phase and output, compare slightly difference among the Zomaril eutectic that this method generates and the embodiment 1 with the former.

Claims (2)

1. iloperidone medicinal cocrystal, it is characterized in that: the N atom in the Zomaril in the piperidine ring is as the hydrogen-bond donating body, and the H atom in 3, the 5-pyridine dicarboxylic acid on the carboxyl forms hydrogen bond as hydrogen bond receptor; Zomaril molecule and one 3,5-pyridine dicarboxylic acid molecule consists of the basic structural unit of iloperidone medicinal cocrystal together by hydrogen bonded, the spacer of this pharmaceutical co-crystals is triclinic(crystalline)system, its axial length a=9.4398~9.9398, b=9.6102~10.1102, c=16.3628~16.8628, shaft angle α=89.363~89.863, β=78.521~79.021, γ=74.130~74.630; XRD spectrum signature peak value appears at 12.72 °~13.22 °, 14.30 °~14.80 °, 17.24 °~17.74 °, 19.98 °~20.48 °, 20.36 °~20.86 °, locate for 21.58 °~22.08 °, Zomaril eutectic thermogravimetric curve, begin weightlessness 40~45% at 180 ° of C~240 ° C, to 240 ° of C~600 ° C weightlessness 60~55%, then decompose fully at 500 ° of C~650 ° C.
2. the preparation method of a kind of iloperidone medicinal cocrystal claimed in claim 1, its step is as follows:
(1) with Zomaril and 3,5-pyridine dicarboxylic acid 1:1~3:1 in mass ratio, and the ethanol of 4~6ml places round-bottomed flask in the lump, and the solid content of reaction system is 10~20mg/ml;
(2) at the added good reflux of round-bottomed flask, the temperature to 90 of rising reaction system~95 ℃, reaction system begins to reflux, and then opens water of condensation and opens simultaneously magnetic stirring apparatus, stirs lower reaction 2~4h;
(3) stir stop after with reacting liquid filtering, place the transparent glass bottle after placing 20~40 hours under the room temperature environment, to have crystal to generate filtrate after leaching insolubles, namely prepare iloperidone medicinal cocrystal.
CN 201110162654 2011-06-17 2011-06-17 Iloperidone medicinal cocrystal and preparation method thereof CN102276594B (en)

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Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102584818A (en) * 2012-01-11 2012-07-18 吉林三善恩科技开发有限公司 Novel paliperidone medicinal eutectic and preparation method thereof
CN102659771B (en) * 2012-04-18 2013-11-27 吉林三善恩科技开发有限公司 Lloperidone pharmaceutical co-crystal and preparation method thereof
CN102633785B (en) * 2012-04-18 2014-07-30 吉林三善恩科技开发有限公司 Novel iloperidone pharmaceutical cocrystal and preparation method thereof
CN102633786B (en) * 2012-04-18 2013-11-27 吉林三善恩科技开发有限公司 Iloperidone pharmaceutical 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
CN103113363B (en) * 2013-03-06 2015-02-18 吉林三善恩科技开发有限公司 Iloperidone-benzoic acid organic pharmaceutical co-crystal and preparation method thereof
CN103113361B (en) * 2013-03-06 2015-03-04 吉林三善恩科技开发有限公司 Iloperidone-saccharin 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

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CN102030744A (en) * 2009-09-30 2011-04-27 天津药物研究院 Iloperidone crystal and preparation method and medicinal composition thereof
WO2011055188A1 (en) * 2009-11-05 2011-05-12 Orchid Chemicals And Pharmaceuticals Limited An improved process for the preparation of iloperidone
CN102070625A (en) * 2009-11-21 2011-05-25 浙江华海药业股份有限公司 Iloperidone crystallizing method

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Publication number Priority date Publication date Assignee Title
CN102030744A (en) * 2009-09-30 2011-04-27 天津药物研究院 Iloperidone crystal and preparation method and medicinal composition thereof
WO2011055188A1 (en) * 2009-11-05 2011-05-12 Orchid Chemicals And Pharmaceuticals Limited An improved process for the preparation of iloperidone
CN102070625A (en) * 2009-11-21 2011-05-25 浙江华海药业股份有限公司 Iloperidone crystallizing method

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