CN105541701A - Pharmaceutical cocrystal of deferiprone with maleic acid as precursor, and preparation method thereof - Google Patents
Pharmaceutical cocrystal of deferiprone with maleic acid as precursor, and preparation method thereof Download PDFInfo
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- CN105541701A CN105541701A CN201510918148.8A CN201510918148A CN105541701A CN 105541701 A CN105541701 A CN 105541701A CN 201510918148 A CN201510918148 A CN 201510918148A CN 105541701 A CN105541701 A CN 105541701A
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- deferiprone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic 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
- C07D213/02—Heterocyclic 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
- C07D213/04—Heterocyclic 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
- C07D213/60—Heterocyclic 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Crystallography & Structural Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical cocrystals, specifically to a pharmaceutical cocrystal of deferiprone with maleic acid as a precursor, and a preparation method thereof. The prepared pharmaceutical cocrystal in the invention has a space group belonging a triclinic system, wherein a deferiprone molecule and a maleic acid molecule are bonded together to constitute a basic structural unit of the pharmaceutical cocrystal through a hydrogen bond and pi-pi stacking interaction. 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 capacity 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
Technical field
The invention belongs to technical field of pharmaceutical co-crystal, being specifically related to a kind of take maleic acid 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 maleic acid 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 maleic acid 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 maleic acid, and molecular formula is: C
4h
4o
4, its structural formula is as shown in b formula.
Of the present invention a kind of take maleic acid 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 this pharmaceutical co-crystals of maleic acid molecular composition; Wherein, there is the effect of π pi accumulation between the pyridine ring of adjacent two Deferiprone molecules along the x-axis direction, the distance in two faces is
simultaneously, hydrogen atom in maleic acid molecule on carboxyl forms O-HO hydrogen bond as the ketonic oxygen in hydrogen-bond donor and Deferiprone molecule as hydrogen bond receptor, hydroxyl hydrogen in Deferiprone molecule forms O-HO hydrogen bond as the Sauerstoffatom in hydrogen-bond donor and maleic acid carboxyl as hydrogen bond receptor, thus forms the two-dimentional chain-like structure of Deferiprone-maleic acid pharmaceutical co-crystals.
Take maleic acid as the spacer of the Deferiprone pharmaceutical co-crystals of presoma be triclinic(crystalline)system, its axial length
shaft angle α=81.42 ~ 81.92 °, β=87.78 ~ 88.28 °, γ=83.49 ~ 83.99 °, and XRD spectrum signature peak value appears at 8.80 ° ~ 9.30 °, 13.01 ~ 13.51 °, 14.87 ° ~ 15.37 °, 18.39 ° ~ 18.89 °, 23.38 ° ~ 23.88 °, 27.00 ° ~ 27.50 °, 30.13 ° ~ 30.63 °.
Of the present invention a kind of take maleic acid as the preparation method of the Deferiprone pharmaceutical co-crystals of presoma, its step is as follows:
(1) Deferiprone and maleic acid 1:1 ~ 1:2 mixing are in molar ratio placed in reaction vessel, add the mixed solvent 5 ~ 10mL of ethanol and acetone, ethanol and acetone volume ratio are 1:2 ~ 2:1, 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 of above-mentioned sealing is at room temperature placed 1 ~ 3 day, have flaxen tabular crystal to generate, being of the present invention take maleic acid 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
As shown in Figure 1, the basic structural unit of a Deferiprone molecule and this pharmaceutical co-crystals of maleic acid molecular composition; Wherein, there is the effect of π pi accumulation between the pyridine ring of adjacent two Deferiprone molecules along the x-axis direction, the distance in two faces is
simultaneously, hydrogen atom in maleic acid molecule on carboxyl forms O-HO hydrogen bond as the ketonic oxygen in hydrogen-bond donor and Deferiprone molecule as hydrogen bond receptor, hydroxyl hydrogen in Deferiprone molecule forms O-HO hydrogen bond as the Sauerstoffatom in hydrogen-bond donor and maleic acid carboxyl as hydrogen bond receptor, thus forms the two-dimentional chain-like structure of Deferiprone-maleic acid pharmaceutical co-crystals.This pharmaceutical co-crystals spacer is triclinic(crystalline)system, and its unit cell parameters is as follows: axial length
shaft angle α=81.72 °, β=87.98 °, γ=83.79 °.
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 9.00 °, 13.21 °, 15.07 °, 18.59 °, 23.68 °, 27.20 °, 30.33 ° successively.
Embodiment
Embodiment 1:
(1) by Deferiprone and maleic acid in molar ratio 0.75:1 feed intake, accurately take Deferiprone 42.50mg and maleic acid 51.20mg mixing and be placed 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 120min, is sealed by vial.
(3) above-mentioned vial is at room temperature sealed placement 24h, have flaxen tabular crystal to generate, be described Deferiprone-maleic acid pharmaceutical co-crystals.Product drying quality of weighing is 61.20mg.
Embodiment 2:
(1) by Deferiprone and maleic acid in molar ratio 1:1 feed intake, accurately take Deferiprone 41.70mg and maleic acid 34.80mg mixing and be placed in vial, add 4mL ethanol and 4mL 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 40 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 72h, have flaxen tabular crystal to generate, be described Deferiprone-maleic acid pharmaceutical co-crystals.Product drying quality of weighing is 56.10mg.
Embodiment 3:
(1) by Deferiprone and maleic acid in molar ratio 1:2 feed intake, accurately take Deferiprone 28.00mg and maleic acid 23.20mg mixing and be placed 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 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) above-mentioned vial is at room temperature sealed placement 48h, have flaxen tabular crystal to generate, be described Deferiprone-maleic acid pharmaceutical co-crystals.Product drying quality of weighing is 39.50mg.
Claims (2)
1. be a Deferiprone pharmaceutical co-crystals for presoma with maleic acid, it is characterized in that: the basic structural unit of a Deferiprone molecule and this pharmaceutical co-crystals of maleic acid molecular composition; Wherein, there is the effect of π pi accumulation between the pyridine ring of adjacent two Deferiprone molecules along the x-axis direction, the distance in two faces is
simultaneously, hydrogen atom in maleic acid molecule on carboxyl forms O-HO hydrogen bond as the ketonic oxygen in hydrogen-bond donor and Deferiprone molecule as hydrogen bond receptor, hydroxyl hydrogen in Deferiprone molecule forms O-HO hydrogen bond as the Sauerstoffatom in hydrogen-bond donor and maleic acid carboxyl as hydrogen bond receptor, thus forms the two-dimentional chain-like structure of pharmaceutical co-crystals; The spacer of this pharmaceutical co-crystals is triclinic(crystalline)system, its axial length
shaft angle α=81.42 ~ 81.92 °, β=87.78 ~ 88.28 °, γ=83.49 ~ 83.99 °, and XRD spectrum signature peak value appears at 8.80 ° ~ 9.30 °, 13.01 ~ 13.51 °, 14.87 ° ~ 15.37 °, 18.39 ° ~ 18.89 °, 23.38 ° ~ 23.88 °, 27.00 ° ~ 27.50 °, 30.13 ° ~ 30.63 °.
2. a kind of as claimed in claim 1 take maleic acid as the preparation method of the Deferiprone pharmaceutical co-crystals of presoma, and its step is as follows:
(1) Deferiprone and maleic acid 1:1 ~ 1:2 mixing are in molar ratio placed in reaction vessel, add the mixed solvent 5 ~ 10mL of ethanol and acetone, ethanol and acetone volume ratio are 1:2 ~ 2:1, 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 of above-mentioned sealing at room temperature being placed 1 ~ 3 day, have flaxen tabular crystal to generate, is namely the Deferiprone pharmaceutical co-crystals of presoma with maleic acid.
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Citations (10)
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 |
CN1874993A (en) * | 2003-09-04 | 2006-12-06 | 赛福伦公司 | Modafinil compositionsc |
CN102060755A (en) * | 2010-12-28 | 2011-05-18 | 吉林大学 | Novel acetaminophen pharmaceutical co-crystals and preparation method thereof |
CN102093307A (en) * | 2010-11-16 | 2011-06-15 | 中国药科大学 | Famotidine eutectic crystal |
CN102153588A (en) * | 2011-03-01 | 2011-08-17 | 吉林大学 | Adefovir pharmaceutical co-crystal and preparation method thereof |
CN103333208A (en) * | 2013-06-04 | 2013-10-02 | 广州晶莱医药科技有限公司 | Adefovir dipivoxil maleate and preparation method and composition thereof |
CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
CN103864850A (en) * | 2014-03-20 | 2014-06-18 | 吉林大学珠海学院 | Adefovir drug cocrystal with 3,5-dihydroxy-benzoic acid as former and preparation method thereof |
CN103864849A (en) * | 2014-03-20 | 2014-06-18 | 吉林大学珠海学院 | Adefovir drug cocrystal with para-aminobenzoic acid as former and preparation method thereof |
WO2014138812A1 (en) * | 2013-03-15 | 2014-09-18 | Bionomics Limited | Salts, co-crystals, and polymorphs of an anxiolytic compound |
-
2015
- 2015-12-11 CN CN201510918148.8A patent/CN105541701A/en active Pending
Patent Citations (10)
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 |
CN1874993A (en) * | 2003-09-04 | 2006-12-06 | 赛福伦公司 | Modafinil compositionsc |
CN102093307A (en) * | 2010-11-16 | 2011-06-15 | 中国药科大学 | Famotidine eutectic crystal |
CN102060755A (en) * | 2010-12-28 | 2011-05-18 | 吉林大学 | Novel acetaminophen pharmaceutical co-crystals and preparation method thereof |
CN102153588A (en) * | 2011-03-01 | 2011-08-17 | 吉林大学 | Adefovir pharmaceutical co-crystal and preparation method thereof |
CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
WO2014138812A1 (en) * | 2013-03-15 | 2014-09-18 | Bionomics Limited | Salts, co-crystals, and polymorphs of an anxiolytic compound |
CN103333208A (en) * | 2013-06-04 | 2013-10-02 | 广州晶莱医药科技有限公司 | Adefovir dipivoxil maleate and preparation method and composition thereof |
CN103864850A (en) * | 2014-03-20 | 2014-06-18 | 吉林大学珠海学院 | Adefovir drug cocrystal with 3,5-dihydroxy-benzoic acid as former and preparation method thereof |
CN103864849A (en) * | 2014-03-20 | 2014-06-18 | 吉林大学珠海学院 | Adefovir drug cocrystal with para-aminobenzoic acid as former and preparation method thereof |
Non-Patent Citations (5)
Title |
---|
弋东旭,等: "药物共晶研究进展及应用", 《中国抗生素杂志》 * |
张晓明,等: "药物共晶制备及表征方法研究进展", 《广东化工》 * |
闻聪,等: "药物共晶在药学中的应用", 《中国新药杂志》 * |
陈嘉媚,等: "超分子化学在药物共晶中的应用", 《高等学校化学学报》 * |
高缘,等: "药物共晶研究进展", 《化学进展》 * |
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Application publication date: 20160504 |