CN103044411A - Iloperidone drug cocrystal and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of new crystal forms of organic drugs, and particularly relates to an iloperidone drug cocrystal and a preparation method of the iloperidone drug cocrystal. The method comprises the steps that iloperidone is taken as an active drug ingredient; 4-aminobenzoic acid is taken as a precursor; a three-dimensional net structure is formed by iloperidone and 4-aminobenzoic acid through hydrogen bonds and by the action of pi-pi accumulation; on a YZ plane, 4-aminobenzoic acid molecules stretch in a wave manner in a Y direction on the YZ plane through N-H...O hydrogen bonds; iloperidone molecules conduct the pi-pi accumulation on the YZ plane in an end-to-end accumulation manner and stretch in the Y direction; in an X direction, the iloperidone molecules and 4-aminobenzoic acid molecules form the hydrogen bonds through O-H...N, and the iloperidone molecules conduct the pi-pi accumulation in the X direction in an end-to-end accumulation manner. A crystal space group is a monoclinic system. The drug cocrystal carries on the characteristics of a traditional raw material drug in treating schizophrenia, and has obvious improvement in solubility, stability and bioavailability.

Description

A kind of iloperidone medicinal cocrystal and preparation method thereof

Technical field

The invention belongs to organic drug new crystal 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 the 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.Has the molecule of ad hoc structure and group according to specifically can spontaneously being assembled into by way of expectations the supramolecular structure with specific function.The understanding of molecule, supramolecule self-assembly and the ability of controlling are just constantly improved, and by design and preparation to functional materials and molecule etc., molecule, supramolecule, self-assembly field are just continuing to bring out new model.Molecular recognition and the supramolecule self-assembly undertaken by the synergy of intermolecular weak interaction are the cores of supramolecular chemistry research.

Be guidance according to crystal engineering, form the supramolecular chemistry of molecule aggregates as the basis take intermolecular hydrogen bonding or non-covalent interaction, with the mixing together of Materials science, physical science, bio-science, life science, environmental science, information technology science, medicine and pharmacology, nano science and other each subjects in, progressively develop into 21 century new ideas and one of the important source of new technology.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.The widespread use of crystal engineering by non-covalent interaction, is controlled and is handled functional materials and molecule from molecular level, has the macromolecular architecture of predetermined structure and further reaches expectation function and application with preparation and assembling.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.

Has very important meaning for drug crystal forms research and the solid-state pharmacy industry that is characterized in of medicine.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.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 is 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.Because hydrogen bond has the character such as selectivity, directivity and moderate strength, so when changing extraneous solvent or hydrogen bond number, can well control the intensity of hydrogen bond.This handiness has widely it and uses in crystal engineering, can be used for controlling molecular orientation.Simultaneously hydrogen bond or other non covalent bond are present in the molecular structure, and the properties of molecule itself can not change, covalent linkage that also can saboteur inside.When we are applied in these superior character of hydrogen bond when connecting drug molecule, just can reach the purpose of modified medicaments molecular property, the while can form new crystalline phase to a greater extent.Hydrogen bond be formed on the pharmacological properties that keeps medicine itself time, reached the purpose of the physicochemical property of modified medicaments.The crystallized form of API has a great impact its physical and chemical properties of drugs, comprises solvability, stability, dispersion rate, metabolic stability and bioavailability etc.

Why the organic drug eutectic has very large magnetism to be that it provides a kind of and has not needed destruction and produce covalent linkage just to reach the physics of modified medicaments activeconstituents (API) or the chance of chemical property to pharmaceutical industry.Show afterwards by the studying in great detail of physical properties to the organic drug eutectic, there is difference to a certain extent in the character of the active constituents of medicine that it is certain and pure, for API, because a lot of all with the functional group that can form hydrogen bond, ability with non covalent bond of very strong formation hydrogen bond or directivity, most of drug molecule or ion also have the foreign molecules of comprising recognizing site, mean that they tend to form polymorphic and solvate, exactly because but the also existence of these functional groups, so that they become the ideal chose that forms organic pharmaceutical co-crystals.

Summary of the invention

The object of the present invention is to provide a kind of iloperidone medicinal cocrystal and preparation method thereof.

The selected bulk drug Zomaril of the present invention is as active constituents of medicine (API), and the presoma of selecting is PABA, thereby obtains a kind of pharmaceutical co-crystals new crystal.Its crystalline structure simplified summary is as follows: Zomaril and PABA consist of three-dimensional net structure by hydrogen bond and pi-pi accumulation effect; On the YZ face, the PABA molecule passes through N-H ... the O hydrogen bond is wave at the YZ face along Y-direction and stretches, and the Zomaril molecule stretches along Y-direction at YZ face pi-pi accumulation with accumulation mode end to end; On the directions X, Zomaril molecule and PABA molecule pass through O-H ... N forms hydrogen bond, and the Zomaril molecule is with accumulation mode pi-pi accumulation on directions X end to end.

The selected solvent of the present invention is methylene dichloride and acetone, adopts the method for room temperature volatilization, and the boiling point of selected organic solvent is lower, namely has the crystalline state material to separate out from mother liquor in the process of organic solvent volatilization.

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 PABA, and molecular formula is C ₇H ₇O ₂N, its structural formula is shown as b.

The iloperidone medicinal cocrystal spacer that the present invention prepares is oblique system, its axial length a=7.4085～7.6085, b=12.6665～14.6665, c=13.4528～15.4528, shaft angle α=90, β=104.06～106.06, γ=90.XRD spectrum signature peak value appears at 9.0116 °～9.2116 °, 12.6403 °～12.8403 °, 14.2060 °～14.4060 °, 14.9961 °～15.1961 °, 16.3423 °～16.5423 °, 17.6738 °～17.8738 °, 19.7954 °～19.9954 °, 20.7465 °～20.9465 °, 24.5216 °～24.7216 ° and 25.2386 °～25.4386 °.

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

(1) weighing: be that the Zomaril of 1:1～1:5 and methylene dichloride and acetone that PABA, volume ratio are 1:1～1:5 are put into 20mL transparent glass bottle with mass ratio, wherein, the usage ratio of Zomaril and methylene dichloride is 40～60mg/mL;

(2) stir: the transparent glass bottle is added a cover and is placed on stir 30～50 minutes on the magnetic stirring apparatus;

(3) room temperature is placed: stop to stir, take out stirrer, with masking foil the transparent glass bottle is sealed, be put in the quiet place of surrounding environment;

(4) volatilization crystallization: after 3～5 days, along with the volatilization of organic solvent, crystalline state material crystallization from mother liquor is arranged, i.e. iloperidone medicinal cocrystal.

The instrument of detection of drugs eutectic structure and performance is as follows among the present invention:

1, eutectic structure is measured by Brooker ApexIICCD X-ray single crystal diffractometer, full name BrukerSMART-APEX CCD Diffractometer

2, X-Ray DIFFRACTOMETER Japan Shimadzu company produces, and model is XRD-6000,

Tube voltage 40kV, tube current 30mA, 8 °/min of sweep velocity.

This bulk drug 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.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 norepinephrine NE α 1 acceptor moderate affinity, to the low affinity of 5HT1A, dopamine D 1 and histamine H1-receptor, to the cholinergic muscarinic receptor without detectable affinity.It is by playing a role to dopamine D 2, D3, serotonin 5HT1A and norepinephrine NE α 1/ α 2c receptor blocking.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

Fig. 1: paliperidone medicinal eutectic crystalline structure synoptic diagram;

As shown in Figure 1, Zomaril 1 and PABA 2 consist of three-dimensional net structure by hydrogen bond and pi-pi accumulation effect.Wherein, the YZ face exists hydrogen bond and pi-pi accumulation effect, and namely the PABA molecule passes through N-H ... the O hydrogen bond is wave at the YZ face along Y-direction and stretches, and the Zomaril molecule is piled up at the YZ face with accumulation mode end to end and stretched along Y-direction; On the directions X, have hydrogen bond and pi-pi accumulation effect, namely Zomaril molecule and PABA molecule pass through O-H ... N forms hydrogen bond, and the Zomaril molecule is piled up at directions X with accumulation mode end to end.This pharmaceutical co-crystals spacer is oblique system, and its unit cell parameters is as follows: axial length a=7.5085, b=13.6665, c=14.4528, shaft angle α=90, β=105.06, γ=90.

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

As shown in Figure 2, from the x-ray diffraction pattern peak of this synthetic eutectic, can find out 9.1116 °, 12.7403 °, 14.3060 °, 15.0961 °, 16.4423 °, 17.7738 °, 19.8954 °, 20.8465 °, 24.6216 ° and 25.3386 ° of positions, series of features peak (curve 2) occur.These characteristic peaks conform to the characteristic peak (curve 1) of the pharmaceutical co-crystals of simulating out according to the crystalline structure data and by Materials Studio software.

Embodiment

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

Embodiment 1:

Use Zomaril and PABA to be the synthetic eutectic of raw material:

Accurately take by weighing 40.00mg Zomaril and 40.00mg4-benzaminic acid with analytical balance, accurately measure 1ml methylene dichloride and 3ml acetone with the 5ml transfer pipet, together place 20ml transparent glass bottle.

The room temperature volatilization:

The transparent glass bottle added a cover and be placed on the agitator stirred 30 minutes, so that the dissolution of solid in the transparent glass bottle is complete, take out stirrer, with masking foil bottleneck is sealed, room temperature is positioned over the quiet place of surrounding environment, along with constantly slowly volatilization of solvent, transparent bottle bottom has or not color lump shape crystal to separate out after 5 days, i.e. Zomaril-PABA pharmaceutical co-crystals.

Claims (2)

1. iloperidone medicinal cocrystal is characterized in that: as active constituents of medicine, take PABA as presoma, Zomaril and PABA consist of three-dimensional net structure by hydrogen bond and pi-pi accumulation effect with Zomaril; On the YZ face, the PABA molecule passes through N-H ... the O hydrogen bond is wave at the YZ face along Y-direction and stretches, and the Zomaril molecule stretches along Y-direction at YZ face pi-pi accumulation with accumulation mode end to end; On the directions X, Zomaril molecule and PABA molecule pass through O-H ... N forms hydrogen bond, and the Zomaril molecule is with accumulation mode pi-pi accumulation on directions X end to end; This eutectic spacer is oblique system, its axial length a=7.4085～7.6085, b=12.6665～14.6665, c=13.4528～15.4528, shaft angle α=90, β=104.06～106.06, γ=90; XRD spectrum signature peak value appears at 9.0116 °～9.2116 °, 12.6403 °～12.8403 °, 14.2060 °～14.4060 °, 14.9961 °～15.1961 °, 16.3423 °～16.5423 °, 17.6738 °～17.8738 °, 19.7954 °～19.9954 °, 20.7465 °～20.9465 °, locate for 24.5216 °～24.7216 ° and 25.2386 °～25.4386 °.

2. the preparation method of iloperidone medicinal cocrystal claimed in claim 1, its step is as follows:

(1) weighing: be that the Zomaril of 1:1～1:5 and methylene dichloride and acetone that PABA, volume ratio are 1:1～1:5 are put into 20mL transparent glass bottle with mass ratio, wherein, the usage ratio of Zomaril and methylene dichloride is 40～60mg/mL;

(2) stir: the transparent glass bottle is added a cover and is placed on stir 30～50 minutes on the magnetic stirring apparatus;

(3) room temperature is placed: stop to stir, take out stirrer, with masking foil the transparent glass bottle is sealed, be put in the quiet place of surrounding environment;

(4) volatilization crystallization: after 3～5 days, along with the volatilization of organic solvent, crystalline state material crystallization from mother liquor is arranged, i.e. iloperidone medicinal cocrystal.

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