CN103044411B - 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 pharmaceutical new crystal form 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 ", was namely the blank of modern supramolecule scientific theory.Nineteen thirty-seven, Germany K.L.Wolf etc. creates " supramolecule " word, and the entity of the high-sequential formed in order to describe molecular association, from universal significance, all there is interaction in the set of any molecule, so this layer of structure of material aggregation state is usually called " supramolecule " by people.Until 1978, the J.M.Lehn professor of France just finally proposes the complete concept of " supramolecular chemistry " based on traditional guest-host system research be planted in organic chemistry.Supramolecular chemistry be research molecular interaction conclude and the complexity that formed in order and there is the science of the molecule aggregates of ad hoc structure and function, it is " chemistry surmounting point 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 multiple noncovalent intermolecular interactions not of the same race is formed.The molecule with ad hoc structure and group is spontaneously assembled into the supramolecular structure with specific function according to the mode that specifically it is expected to.To the understanding of molecule, Supramolecular self assembly and the just constantly progress of manipulation ability, by the design of functional materials and molecule etc. and preparation, molecule, supramolecule, self-assembly field are just continuing to bring out new model.The molecular recognition of being undertaken by the synergy of intermolecular weak interaction and Supramolecular self assembly are the cores of supramolecular chemistry research.

According to crystal engineering for instructing, the supramolecular chemistry of molecule aggregates is formed based on 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, progressively develop into 21 century new ideas and one of the important source of new technology.The principle of supramolecular chemistry and method are applied to design and the growth of crystal by crystal engineering, by the acting in conjunction of molecular recognition and self assembling process, obtain structure controllable, have the new crystal of specific physico-chemical property.The widespread use of crystal engineering, by non-covalent interaction, controls functional materials and molecule and handles from molecular level, also reaches expectation function and application further to prepare and to assemble the macromolecular architecture with predetermined structure.The approach using the Design Theory pharmaceutical co-crystals of crystal engineering is feasible, 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.

For drug crystal forms research and the solid-state pharmacy industry that is characterized in of medicine, there is very important meaning.On the one hand, the same medicine of different crystal forms, may there were significant differences in the biochemical properties such as stability, solubleness and bioavailability, thus affect the curative effect of medicine.If well assessment selects best drug crystal forms to research and develop, the change of crystal formation may be produced at clinical late, thus the extension causing medicine to go on the market and produce huge financial loss.How to develop the new crystal of medicine thus original medicine company can be broken to the patent protection of crystal formation, ahead of time imitation medicine being introduced to the market, being a vital problem in recent years, will directly having influence on market and the international competitiveness of imitation medicine and bulk drug company.Drug crystal forms research is characterized in American-European pharmaceutical industry with medicine solid-state and has been comparative maturity and dark valued field, but pharmaceutical industry still belongs to the starting stage at home.Because hydrogen bond has selectivity, directivity and the character such as moderate strength, so when changing extraneous solvent or hydrogen bond number, the intensity of hydrogen bond can well be controlled.This handiness makes it have a wide range of applications in crystal engineering, can be used for controlling molecular orientation.Simultaneously hydrogen bond or other non covalent bond are present in molecular structure, and the properties of molecule itself can not change, also can not the covalent linkage of saboteur inside.When these superior character of hydrogen bond are applied in connection drug molecule by us, just can reach the object of modified medicaments molecular property, new crystalline phase can formed to a greater extent simultaneously.Hydrogen bond be formed in retain medicine itself pharmacological properties while, reach the object 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 organic pharmaceutical co-crystal has very large magnetism to be to pharmaceutical industry, and it providing one does not need destruction and produces covalent linkage just to reach the physics of modified medicaments activeconstituents (API) or the chance of chemical property.Show by after the studying in great detail of the physical properties to organic pharmaceutical co-crystal, really there is difference to a certain extent with the character of pure active constituents of medicine in it, for API, due to a lot of all with the functional group that can form hydrogen bond, there is the ability of the non covalent bond of very strong formation hydrogen bond or directivity, major part drug molecule or ion also have and comprise foreign molecules recognizing site, mean that they tend to form polymorphic and solvate, exactly because but the existence of also these functional groups, make them become the ideal chose forming organic pharmaceutical co-crystal.

Summary of the invention

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

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

Solvent selected by the present invention is methylene dichloride and acetone, and adopt the method for room temperature volatilization, the boiling point of selected organic solvent is lower, in the process of organic solvent volatilization, namely have amorphous material to separate out from mother liquor.

The active constituents of medicine (API) used in invention is Zomaril, and chemical name is 4-[3-(4-(fluoro-1, the 2-benzoisoxazole-3-base of 6-)-piperidino) propoxy-]-3-methoxyacetophenone, and molecular formula is C ₂₄h ₂₇fN ₂o ₄, its structural formula is as shown in a.The eutectic precursor (cocrystal former) used in invention 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 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 room temperature volatilization method, and specific experiment process is as follows:

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

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

(3) room temperature is placed: stop stirring, take out stirrer, sealed by transparent glass bottle with masking foil, is put in surrounding environment peace and quiet place;

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

In the present invention, the instrument of detection of drugs eutectic structure and performance is as follows:

1, eutectic structure is measured by Brooker Apex II CCD X-ray single crystal diffraction instrument, full name BrukerSMART-APEX CCD Diffractometer

2, Shimadzu Corporation of X-Ray DIFFRACTOMETER Japan produces, and model is XRD-6000, tube voltage 40kV, tube current 30mA, sweep velocity 8 °/min.

This bulk drug is within 2009, obtain U.S. FDA approval listing, for adult acute's treatment of schizophrenia.It may become first personalized psychotherapeutic drug, and its listing likely becomes schizoid first the gene target medicine for the treatment of.Zomaril is mixed type dopamine D 2/serotonin 5HT2A receptor blocking agent, belongs to Atypical anti-psychotic drugs.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 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, Neurotoxicity medication, as the important class of clinical application, plays very important role in global pharmaceutical market always, accounts for 10% of global pharmaceutical market.Along with a large amount of new types of therapeutic agents is widely used in clinical, driven the rapid growth of whole market, spiritual neural field also becomes the research and development focus of domestic and international pharmaceuticals new drug.

Pharmaceutical co-crystals prepared by the present invention, inheriting traditional raw material medicine outside treatment schizophrenia characteristic, its solvability, stability and bioavailability has had obvious change!

Accompanying drawing explanation

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

As shown in Figure 1, Zomaril 1 and PABA 2 form three-dimensional net structure by hydrogen bond and pi-pi accumulation effect.Wherein, YZ face, there is hydrogen bond and pi-pi accumulation effect, namely PABA molecule passes through N-H ... O hydrogen bond is that wave stretches in YZ face along Y-direction, and Zomaril molecule to be piled up in YZ face with accumulation mode end to end and stretched along Y-direction; In X-direction, there is hydrogen bond and pi-pi accumulation effect, namely Zomaril molecule and PABA molecule pass through O-H ... N forms hydrogen bond, and Zomaril molecule is piled up in the X direction with accumulation mode end to end.This pharmaceutical co-crystals spacer is oblique system, and its unit cell parameters is as follows: axial length 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, 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 from the x-ray diffraction pattern peak of this eutectic of synthesis, occur series of features peak (curve 2).These characteristic peaks with according to crystal structural data and by Materials Studio software the characteristic peak (curve 1) of pharmaceutical co-crystals of simulating out conform to.

Embodiment

The invention will be further elaborated for Application Example below, and experiment detailed process prepared by Zomaril-PABA eutectic is as follows:

Embodiment 1:

Zomaril and PABA is used to be Material synthesis eutectic:

Accurately take 40.00mg Zomaril and 40.00mg PABA with analytical balance, accurately measure 1ml methylene dichloride and 3ml acetone with 5ml transfer pipet, be together placed in 20ml transparent glass bottle.

Room temperature is volatilized:

Transparent glass bottle is added a cover and is placed on agitator and stir 30 minutes, make the dissolution of solid in transparent glass bottle complete, take out stirrer, with masking foil, bottleneck is sealed, room temperature is positioned over surrounding environment peace and quiet place, along with solvent constantly slowly volatilizees, separate out with or without look bulk crystals bottom transparent vials after 5 days, i.e. Zomaril-PABA pharmaceutical co-crystals.

Claims (2)

1. an iloperidone medicinal cocrystal, is characterized in that: using Zomaril as active constituents of medicine, take PABA as presoma, and Zomaril and PABA form three-dimensional net structure by hydrogen bond and pi-pi accumulation effect; On YZ face, PABA molecule passes through N-H ... O hydrogen bond is that wave stretches in YZ face along Y-direction, and Zomaril molecule stretches along Y-direction at YZ face pi-pi accumulation with accumulation mode end to end; In X-direction, Zomaril molecule and PABA molecule pass through O-H ... N forms hydrogen bond, and Zomaril molecule is with accumulation mode pi-pi accumulation in the X direction end to end; This eutectic spacer is oblique system, its axial length 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 ° places.

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

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

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

(3) room temperature is placed: stop stirring, take out stirrer, sealed by transparent glass bottle with masking foil, is put in surrounding environment peace and quiet place;

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