CN105399664A - Deferiprone pharmaceutical cocrystal with 2,5-dihydroxybenzoic acid as precursor and preparation method thereof - Google Patents

Deferiprone pharmaceutical cocrystal with 2,5-dihydroxybenzoic acid as precursor and preparation method thereof Download PDF

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Publication number
CN105399664A
CN105399664A CN201510918190.XA CN201510918190A CN105399664A CN 105399664 A CN105399664 A CN 105399664A CN 201510918190 A CN201510918190 A CN 201510918190A CN 105399664 A CN105399664 A CN 105399664A
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deferiprone
pharmaceutical
crystals
dhb
molecule
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Inventor
张晓明
朱广山
王洪艳
张建会
杨东生
刘雨萌
李静
王静
王立英
张瑶
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Zhuhai College of Jilin University
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Zhuhai College of Jilin University
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62Oxygen or sulfur atoms
    • C07D213/69Two or more oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42Separation; Purification; Stabilisation; Use of additives
    • C07C51/43Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Abstract

The invention specifically relates to a deferiprone pharmaceutical cocrystal with 2,5-dihydroxybenzoic acid as a precursor and a preparation method thereof, belonging to the technical field of pharmaceutical cocrystals. The space group of the pharmaceutical cocrystal prepared in the invention belongs to a triclinic system; and a deferiprone molecule and a 2,5-dihydroxybenzoic acid molecule are bonded together through a hydrogen bond and Pi...Pi accumulation so as to form a basic constitutional unit of the pharmaceutical cocrystal. A solvent selected in the preparation process of the pharmaceutical cocrystal is a mixed solvent of ethanol and acetone; a solution cocrystallization method is employed; and a drug and the precursor are fully dissolved through stirring and heating, then cooling and standing at room temperature for a period of time are successively carried out, and crystals are produced through crystallization. The pharmaceutical cocrystal prepared in the invention inherits from a traditional bulk drug the characteristic of capcity of treating thalassemia which does not well response to conventional chelation therapy and is caused by excess iron load due to blood transfusion, and the pharmaceutical cocrystal is obviously improved in dissolvability, stability and bioavailability.

Description

Take DHB as Deferiprone pharmaceutical co-crystals of presoma and preparation method thereof
Technical field
The invention belongs to technical field of pharmaceutical co-crystal, being specifically related to a kind of take DHB as Deferiprone pharmaceutical co-crystals of presoma 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.Supramolecular chemistry has following notable feature: the strong bonding force that a. forms super molecular compound is weak interaction force superposition and collaborative result between differing molecular, is the general performance of multi-acting force; B. the super molecular compound of differing molecular self-assembly demonstrates New function diverse with former self assembly molecule.And the molecular recognition of being undertaken by the synergy of intermolecular weak interaction and Supramolecular self assembly are the cores of supramolecular chemistry research.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 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.With the active constituents of medicine (API) that crystalline form exists, be confined to salt, polymorph and solvate (comprising hydrate) traditionally always.From intellecture property and bioavailability, API itself has very high utility value, and wherein structure and composition are most important integral parts.Britain Camb structural database (CSD) is the main source of the structure of matter microscopic information about 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 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.
For imitation medicine company; 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 is introduced to the market, be a vital problem in recent years, will directly have 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.
Deferiprone (deferiprone, commodity are called Ao Beian can, Ferriprox) be the medicine developed in the Canadian ApoPharma company that on October 14th, 2011 is ratified by FDA, it be one can with iron with the bidentate ligand of 3:1 mol ratio bonding.Clinical trial confirms that Deferiprone can effectively promote that iron is got rid of, and stops the accumulation that the patients with thalassemia serum levels of iron of transfusion-independence meets.This medicine is used for the treatment of not good and due to the thalassemia causing iron load too much of transfusing blood to the past chelating therapy reaction.Thalassemia is that one leads anemogenic inherited blood disorders, and blood transfusion treats poor Main Means at present, but transfusion iron overload may occur in frequent blood transfusion, causes serious consequence even dead.Therefore, effectively treatment iron overload is the essential condition ensureing patients with thalassemia safety.The advantages such as Deferiprone is effective in cure definitely as single medical instrument for the treatment of major thalaseemia, untoward reaction is few, easy administration, patient compliance are high.
Summary of the invention
The object of the present invention is to provide a kind of take DHB as the Deferiprone pharmaceutical co-crystals of presoma and the preparation method of this pharmaceutical co-crystals thereof.
Bulk drug Deferiprone selected by the present invention, as the activeconstituents (API) of pharmaceutical co-crystals, is selected DHB to be eutectic presoma, thus is prepared the pharmaceutical co-crystals of novel texture Deferiprone.
Solvent selected by the present invention is the mixing solutions of ethanol and acetone.The preparation method adopted is solution cocrystallization method, under certain temperature and pressure, by heated and stirred, medicine and presoma is fully dissolved, and puts after baking oven is incubated for some time, cools and namely have crystal structure out.
The chemical name of active constituents of medicine (API) Deferiprone used in the present invention is: 1,2-Dimethyl-3-hydroxypyrid-4-one, molecular formula is: C 7h 9nO 2, its structural formula is as shown in a formula.
The eutectic precursor (cocrystalformer) used in the present invention is DHB, and molecular formula is: C 7h 6o 4, its structural formula is as shown in b formula.
Of the present invention a kind of take DHB as the Deferiprone pharmaceutical co-crystals of presoma, it is characterized in that: as shown in Figure 1, the basic structural unit of a Deferiprone molecule and a DHB molecular composition pharmaceutical co-crystals; Wherein, there is the effect of π pi accumulation between the pyridine ring of adjacent two Deferiprones along the z-axis direction, the distance in two faces is there is the effect of π pi accumulation between the phenyl ring of adjacent two DHBs along the y-axis direction, the distance between two faces is in addition, the double bond oxygen in DHB molecule on carboxyl to be combined as hydrogen-bond donor as the hydrogen atom of hydrogen bond receptor in Deferiprone molecule on hydroxyl and to form O-HO hydrogen bond; Ketonic oxygen in Deferiprone molecule to be combined as hydrogen-bond donor as the hydrogen atom of hydrogen bond receptor on DHB carboxyl and to form O-HO hydrogen bond, thus forms the tridimensional network of Deferiprone-DHB pharmaceutical co-crystals.
Take DHB as the spacer of the Deferiprone pharmaceutical co-crystals of presoma be oblique system, its axial length shaft angle α=89.80 ~ 90.30 °, β=105.50 ~ 106.00 °, γ=89.80 ~ 90.30 °, and XRD spectrum signature peak value appears at 6.54 ° ~ 7.04 °, 14.86 ~ 15.36 °, 16.40 ° ~ 16.90 °, 22.02 ° ~ 22.52 °, 22.55 ° ~ 23.05 °, 24.71 ° ~ 25.21 °, 25.98 ° ~ 26.48 °, 27.06 ° ~ 27.56 °.
Of the present invention a kind of take DHB as the preparation method of the Deferiprone pharmaceutical co-crystals of presoma, its step is as follows:
(1) by Deferiprone and 2,1:1 ~ 2:1 the mixing in molar ratio of 5-resorcylic acid is placed in reaction vessel, add the mixed solvent 5 ~ 10mL of ethanol and acetone, the volume ratio of ethanol and acetone is 1:2 ~ 2:1, in solution, solid content is 0.2 ~ 0.6mol/mL, is sealed by reaction vessel after putting into magnetic stir bar;
(2) above-mentioned reaction vessel is placed on 40 ~ 50 DEG C of magnetic stirring apparatuss, stirs and raw material is dissolved completely, then take out stirrer rapidly after constant temperature stirring 100 ~ 120min, then reaction vessel is sealed;
(3) reaction vessel after above-mentioned sealing is at room temperature placed 1 ~ 3 day, have flaxen tabular crystal to generate, being of the present invention take DHB as the Deferiprone pharmaceutical co-crystals of presoma.
In the present invention, the instrument of detection of drugs eutectic structure and performance is as follows:
1, eutectic structure is measured by Brooker ApexIICCDX-ray single crystal diffraction instrument, full name BrukerSMART-APEXCCDDiffractometer,
2, Shimadzu Corporation of X-RayDIFFRACTOMETER Japan produces, and model is XRD-6000, Cu-K α tube voltage 40kV, tube current 30mA, sweep velocity 2 °/min.
Pharmaceutical co-crystals prepared by the present invention, inheriting traditional raw material medicine in treatment to outside the past chelating therapy reaction thalassemic characteristic that is not good and that cause iron load too much owing to transfusing blood, its solvability, stability and bioavailability has had obvious change.
Accompanying drawing explanation
Fig. 1: Deferiprone pharmaceutical co-crystals structure iron; The basic structural unit of a Deferiprone molecule and a DHB molecular composition Deferiprone-DHB pharmaceutical co-crystals.Wherein, there is the effect of π pi accumulation between the pyridine ring of adjacent two Deferiprones along the z-axis direction, the distance in two faces is there is the effect of π pi accumulation between the phenyl ring of adjacent two DHBs along the y-axis direction, the distance between two faces is in addition, the double bond oxygen on the carboxyl in DHB molecule to be combined as hydrogen-bond donor as the hydrogen atom of hydrogen bond receptor in Deferiprone molecule on hydroxyl and to form O-HO hydrogen bond; Ketonic oxygen in Deferiprone molecule to be combined as hydrogen-bond donor as the hydrogen atom of hydrogen bond receptor on DHB carboxyl and to form O-HO hydrogen bond, thus forms the tridimensional network of Deferiprone-DHB pharmaceutical co-crystals.This pharmaceutical co-crystals spacer is oblique system, and its unit cell parameters is as follows: axial length shaft angle α=90 °, β=105.80 °, γ=90 °.
Fig. 2: Deferiprone pharmaceutical co-crystals XRD spectra;
As shown in Figure 2, also consistent with a few stack features peaks of the XRD (b) of the monocrystalline obtained under laboratory condition by the XRD spectra (a) of MaterialsStudio software simulation according to crystal information data, characteristic peak appears at 6.84 °, 15.16 °, 16.70 °, 22.22 °, 22.85 °, 24.91 °, 26.18 °, 27.26 ° successively.
Embodiment
Embodiment 1:
(1) by Deferiprone and DHB in molar ratio 1.25:1 feed intake, accurately take 14.10mg Deferiprone with analytical balance, the DHB of 15.80mg is in vial; Add 5mL ethanol and 5mL acetone, put into the magnetic stir bar of 1cm size, at vial bottleneck upper berth one deck masking foil, and tighten bottle cap bottle is sealed.
(2) be placed in by above-mentioned vial on 50 DEG C of magnetic stirring apparatuss, stir and raw material is dissolved in solvent completely, constant temperature takes out stirrer rapidly after stirring 115min, is sealed by vial..
(3) at room temperature sealed by above-mentioned vial and place 24h, have faint yellow tabular crystal to generate, be described Deferiprone-DHB pharmaceutical co-crystals, product drying quality of weighing is 25.60mg.
Embodiment 2:
(1) by Deferiprone and DHB in molar ratio 1.5:1 feed intake, accurately take 20.80mg Deferiprone with analytical balance, the DHB of 18.30mg is in vial; Add 3mL ethanol and 6mL acetone, put into the magnetic stir bar of 1cm size, at vial bottleneck upper berth one deck masking foil, and tighten bottle cap bottle is sealed.
(2) be placed in by above-mentioned vial on 50 DEG C of magnetic stirring apparatuss, stir and raw material is dissolved in solvent completely, constant temperature takes out stirrer rapidly after stirring 110min, is sealed by vial..
(3) above-mentioned vial is at room temperature sealed placement 51h, have faint yellow tabular crystal to generate, be described Deferiprone-DHB pharmaceutical co-crystals.Product drying quality of weighing is 31.40mg.
Embodiment 3:
(1) by Deferiprone and DHB in molar ratio 2:1 feed intake, accurately take 27.90mg Deferiprone with analytical balance, the DHB of 18.10mg is in vial; Add 6mL ethanol and 3mL acetone, put into the magnetic stir bar of 1cm size, at vial bottleneck upper berth one deck masking foil, and tighten bottle cap bottle is sealed.
(2) be placed in by above-mentioned vial on 45 DEG C of magnetic stirring apparatuss, stir and raw material is dissolved in solvent completely, constant temperature takes out stirrer rapidly after stirring 100min, is sealed by vial..
(3) above-mentioned vial is at room temperature sealed placement 72h, have faint yellow tabular crystal to generate, be described Deferiprone-DHB pharmaceutical co-crystals.Product drying quality of weighing is 36.50mg.

Claims (2)

1. be a Deferiprone pharmaceutical co-crystals for presoma with DHB, it is characterized in that: the basic structural unit of a Deferiprone molecule and a DHB molecular composition pharmaceutical co-crystals; Wherein, there is the effect of π pi accumulation between the pyridine ring of adjacent two Deferiprones along the z-axis direction, the distance in two faces is there is the effect of π pi accumulation between the phenyl ring of adjacent two DHBs along the y-axis direction, the distance between two faces is in addition, the double bond oxygen in DHB molecule on carboxyl to be combined as hydrogen-bond donor as the hydrogen atom of hydrogen bond receptor in Deferiprone molecule on hydroxyl and to form O-HO hydrogen bond; Ketonic oxygen in Deferiprone molecule to be combined as hydrogen-bond donor as the hydrogen atom of hydrogen bond receptor on DHB carboxyl and to form O-HO hydrogen bond, thus forms the tridimensional network of pharmaceutical co-crystals; The spacer of this pharmaceutical co-crystals is oblique system, its axial length shaft angle α=89.80 ~ 90.30 °, β=105.50 ~ 106.00 °, γ=89.80 ~ 90.30 °, and XRD spectrum signature peak value appears at 6.54 ° ~ 7.04 °, 14.86 ~ 15.36 °, 16.40 ° ~ 16.90 °, 22.02 ° ~ 22.52 °, 22.55 ° ~ 23.05 °, 24.71 ° ~ 25.21 °, 25.98 ° ~ 26.48 °, 27.06 ° ~ 27.56 °.
2. according to claim 1 a kind of take DHB as the preparation method of the Deferiprone pharmaceutical co-crystals of presoma, its step is as follows:
(1) by Deferiprone and 2,1:1 ~ 2:1 the mixing in molar ratio of 5-resorcylic acid is placed in reaction vessel, add the mixed solvent 5 ~ 10mL of ethanol and acetone, the volume ratio of ethanol and acetone is 1:2 ~ 2:1, in solution, solid content is 0.2 ~ 0.6mol/mL, is sealed by reaction vessel after putting into magnetic stir bar;
(2) above-mentioned reaction vessel is placed on 40 ~ 50 DEG C of magnetic stirring apparatuss, stirs and raw material is dissolved completely, then take out stirrer rapidly after constant temperature stirring 100 ~ 120min, then reaction vessel is sealed;
(3) reaction vessel after above-mentioned sealing is at room temperature placed 1 ~ 3 day, have flaxen tabular crystal to generate, being with DHB is the Deferiprone pharmaceutical co-crystals of presoma.
CN201510918190.XA 2015-12-11 2015-12-11 Deferiprone pharmaceutical cocrystal with 2,5-dihydroxybenzoic acid as precursor and preparation method thereof Pending CN105399664A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107827724A (en) * 2017-09-27 2018-03-23 湖南湘源美东医药科技有限公司 Dihydroxybenzoic acid cocrystal of curcumin 2,5 and preparation method thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078163A2 (en) * 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078163A2 (en) * 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107827724A (en) * 2017-09-27 2018-03-23 湖南湘源美东医药科技有限公司 Dihydroxybenzoic acid cocrystal of curcumin 2,5 and preparation method thereof

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