CN105399665A - Deferiprone pharmaceutical cocrystal with p-hydroxybenzoic acid as precursor and preparation method thereof - Google Patents
Deferiprone pharmaceutical cocrystal with p-hydroxybenzoic acid as precursor and preparation method thereof Download PDFInfo
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- CN105399665A CN105399665A CN201510918275.8A CN201510918275A CN105399665A CN 105399665 A CN105399665 A CN 105399665A CN 201510918275 A CN201510918275 A CN 201510918275A CN 105399665 A CN105399665 A CN 105399665A
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- deferiprone
- hydroxybenzoic acid
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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
- C07C65/00—Compounds 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
- C07C65/01—Compounds 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
- C07C65/03—Compounds 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
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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
Abstract
The invention specifically relates to a novel deferiprone-p-hydroxybenzoic acid pharmaceutical cocrystal and a preparation method thereof, belonging to the technical field of pharmaceutical cocrystals. The space group of the deferiprone-p-hydroxybenzoic acid pharmaceutical cocrystal prepared in the invention belongs to a triclinic system; and a deferiprone molecule and a p-hydroxybenzoic acid molecule are bonded together through Pi-Pi accumulation and a hydrogen bond so as to form a basic constitutional unit of the deferiprone-p-hydroxybenzoic acid pharmaceutical cocrystal. A solvent selected in the preparation process of the pharmaceutical cocrystal is water; a solution cocrystallization method is employed; and a drug and a precursor are fully dissolved through stirring and heating and put in a baking oven for heat preservation for a period of time, 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
Technical field
The invention belongs to technical field of pharmaceutical co-crystal, being specifically related to a kind of take P-hydroxybenzoic 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 P-hydroxybenzoic acid as the Deferiprone pharmaceutical co-crystals of presoma and the preparation method of this pharmaceutical co-crystals.
The present invention selects bulk drug Deferiprone as the activeconstituents (API) of pharmaceutical co-crystals, selects P-hydroxybenzoic acid to be eutectic presoma, thus prepares the Deferiprone pharmaceutical co-crystals of novel texture.
Solvent selected by the present invention is water, is very clean resource.The preparation method adopted is solution cocrystallization method, under certain temperature and pressure, by heated and stirred, medicine and presoma is fully dissolved, and after baking oven is incubated for some time, namely cooling medicine crystal crystallizes 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 P-hydroxybenzoic acid, and molecular formula is: C
7h
6o
3, its structural formula is as shown in b formula.
Of the present invention a kind of take P-hydroxybenzoic acid as the Deferiprone pharmaceutical co-crystals of presoma, it is characterized in that: as shown in Figure 1, a Deferiprone molecule, a p-hydroxybenzoic acid form the basic structural unit of pharmaceutical co-crystals, there is the effect of π pi accumulation in z-axis direction in the pyridine ring in the phenyl ring in p-hydroxybenzoic acid and Deferiprone molecule, the distance between two planes of molecules is
meanwhile, between adjacent Deferiprone molecule, also there is the effect of π pi accumulation in z-axis direction in two pyridine rings, the distance between two planes of molecules is
in addition, the hydrogen atom in p-hydroxybenzoic acid on carboxyl forms O-HO hydrogen bond as the ketonic oxygen on hydrogen-bond donor and adjacent p-hydroxybenzoic acid carboxyl as hydrogen bond receptor; Hydrogen atom in Deferiprone molecule on hydroxyl forms O-HO hydrogen bond as the Sauerstoffatom on carbonyl in hydrogen-bond donor and adjacent Deferiprone molecule as hydrogen bond receptor, thus forms with P-hydroxybenzoic acid the reticulated structure of the Deferiprone pharmaceutical co-crystals being presoma.
Take P-hydroxybenzoic acid as the spacer of the Deferiprone pharmaceutical co-crystals of presoma be triclinic(crystalline)system, its axial length
shaft angle α=94.35 ~ 94.85 °, β=92.07 ~ 92.57 °, γ=110.79 ~ 111.29 °, and XRD spectrum signature peak value appears at 10.98 ° ~ 11.48 °, 12.61 ~ 13.11 °, 14.30 ° ~ 14.80 °, 18.40 ° ~ 18.90 °, 21.05 ° ~ 21.55 °, 25.35 ° ~ 25.85 °, 25.94 ° ~ 26.44 °.
Of the present invention a kind of take P-hydroxybenzoic acid as the preparation method of the Deferiprone pharmaceutical co-crystals of presoma, its step is as follows:
(1) Deferiprone and P-hydroxybenzoic acid 1:1 ~ 1:2 mixing are in molar ratio placed in reaction vessel, add deionized water 5 ~ 10mL, sealed by reaction vessel after putting into magnetic stir bar, in solution, solid content is 0.2 ~ 0.6mol/mL;
(2) be placed in by above-mentioned reaction vessel on 60 ~ 80 DEG C of magnetic stirring apparatuss, stir and raw material is dissolved in deionized water completely, constant temperature takes out stirrer rapidly after stirring 2 ~ 3h, is placed in rapidly 60 ~ 80 DEG C of baking ovens and places 2 ~ 4 days after being sealed by reaction vessel;
(3) at room temperature place 2 ~ 4 days after being taken out from baking oven by above-mentioned reaction vessel, have transparent needle-like crystal to generate, be described Deferiprone pharmaceutical co-crystals.
Further, described reaction vessel is vial.Volume is 20mL.Stopping property is good.
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;
As shown in Figure 1, the basic structural unit of a Deferiprone molecule, a p-hydroxybenzoic acid formation Deferiprone-P-hydroxybenzoic acid pharmaceutical co-crystals.There is the effect of π pi accumulation in z-axis direction in the pyridine ring in the phenyl ring in p-hydroxybenzoic acid and Deferiprone molecule, the distance between two planes of molecules is
meanwhile, between adjacent Deferiprone molecule, also there is the effect of π pi accumulation in z-axis direction in two pyridine rings, the distance between two planes of molecules is
in addition, hydrogen atom in p-hydroxybenzoic acid on carboxyl forms O-HO hydrogen bond as the ketonic oxygen on hydrogen-bond donor and adjacent P-hydroxybenzoic acid carboxyl as hydrogen bond receptor, hydrogen atom in Deferiprone molecule on hydroxyl forms O-HO hydrogen bond as the ketonic oxygen in hydrogen-bond donor and adjacent Deferiprone molecule as hydrogen bond receptor, thus forms the reticulated structure of Deferiprone-P-hydroxybenzoic 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=94.55 °, β=92.37 °, γ=111.09 °.
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 11.18 °, 12.91 °, 14.50 °, 18.70 °, 21.35 °, 25.65 °, 26.14 ° successively.
Embodiment
Embodiment 1:
(1) by Deferiprone and P-hydroxybenzoic acid in molar ratio 1:1 feed intake, accurately take 13.90mg Deferiprone with analytical balance, the P-hydroxybenzoic acid of 13.80mg is in vial; Add deionized water 6mL, 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 60 DEG C of magnetic stirring apparatuss, stir and raw material is dissolved in deionized water completely, constant temperature takes out stirrer rapidly after stirring 3h, is sealed by vial, is placed in rapidly 60 DEG C of baking ovens afterwards, place 4 days.
(3) taken out from baking oven by above-mentioned vial, at room temperature seal placement 3 days, have transparent needle-like crystal to generate, be described Deferiprone-P-hydroxybenzoic acid pharmaceutical co-crystals, drying quality of weighing is 21.50mg.
Embodiment 2:
(1) by Deferiprone and P-hydroxybenzoic acid in molar ratio 1:2 feed intake, accurately take 14.10mg Deferiprone with analytical balance, the P-hydroxybenzoic acid of 28.90mg is in vial; Add deionized water 8mL, 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 70 DEG C of magnetic stirring apparatuss, stir and raw material is dissolved in deionized water completely, constant temperature takes out stirrer rapidly after stirring 3h, is sealed by vial, is placed in rapidly 70 DEG C of baking ovens afterwards, place 2 days.
(3) taken out from baking oven by above-mentioned vial, at room temperature seal placement 4 days, have transparent needle-like crystal to generate, be described Deferiprone-P-hydroxybenzoic acid pharmaceutical co-crystals, drying quality of weighing is 39.70mg.
Embodiment 3:
(1) by Deferiprone and P-hydroxybenzoic acid in molar ratio 1:1 feed intake, accurately take 28.00mg Deferiprone with analytical balance, the P-hydroxybenzoic acid of 27.90mg is in vial; Add deionized water 10mL, 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 80 DEG C of magnetic stirring apparatuss, stir and raw material is dissolved in deionized water completely, constant temperature takes out stirrer rapidly after stirring 2h, is sealed by vial, is placed in rapidly 80 DEG C of baking ovens afterwards, place 3 days.
(3) taken out from baking oven by above-mentioned vial, at room temperature seal placement 2 days, have transparent needle-like crystal to generate, be described Deferiprone-P-hydroxybenzoic acid pharmaceutical co-crystals, drying quality of weighing is 43.60mg.
Claims (2)
1. one kind take P-hydroxybenzoic acid as the Deferiprone pharmaceutical co-crystals of presoma, it is characterized in that: a Deferiprone molecule, a p-hydroxybenzoic acid form the basic structural unit of pharmaceutical co-crystals, there is the effect of π pi accumulation in z-axis direction in the pyridine ring in the phenyl ring in p-hydroxybenzoic acid and Deferiprone molecule, the distance between two planes of molecules is
meanwhile, between adjacent Deferiprone molecule, also there is the effect of π pi accumulation in z-axis direction in two pyridine rings, the distance between two planes of molecules is
in addition, the hydrogen atom in p-hydroxybenzoic acid on carboxyl forms O-HO hydrogen bond as the ketonic oxygen on hydrogen-bond donor and adjacent p-hydroxybenzoic acid carboxyl as hydrogen bond receptor; Hydrogen atom in Deferiprone molecule on hydroxyl forms O-HO hydrogen bond as the Sauerstoffatom on carbonyl in hydrogen-bond donor and adjacent Deferiprone molecule as hydrogen bond receptor, thus forms the reticulated structure of Deferiprone-P-hydroxybenzoic acid pharmaceutical co-crystals; The spacer of this pharmaceutical co-crystals is triclinic(crystalline)system, its axial length
shaft angle α=94.35 ~ 94.75 °, β=92.07 ~ 92.57 °, γ=110.79 ~ 111.29 °, and XRD spectrum signature peak value appears at 10.98 ° ~ 11.48 °, 12.61 ~ 13.11 °, 14.30 ° ~ 14.80 °, 18.40 ° ~ 18.90 °, 21.05 ° ~ 21.55 °, 25.35 ° ~ 25.85 °, 25.94 ° ~ 26.44 °.
2. according to claim 1 a kind of take P-hydroxybenzoic acid as the preparation method of the Deferiprone pharmaceutical co-crystals of presoma, its step is as follows:
(1) Deferiprone and P-hydroxybenzoic acid 1:1 ~ 1:2 mixing are in molar ratio placed in reaction vessel, add deionized water 5 ~ 10mL, sealed by reaction vessel after putting into magnetic stir bar, in solution, solid content is 0.2 ~ 0.6mol/mL;
(2) be placed in by above-mentioned reaction vessel on 60 ~ 80 DEG C of magnetic stirring apparatuss, stir and raw material is dissolved in deionized water completely, constant temperature takes out stirrer rapidly after stirring 2 ~ 3h, is placed in rapidly 60 ~ 80 DEG C of baking ovens and places 2 ~ 4 days after being sealed by reaction vessel;
(3) at room temperature place 2 ~ 4 days after being taken out from baking oven by above-mentioned reaction vessel, have transparent needle-like crystal to generate, be described Deferiprone pharmaceutical co-crystals.
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Citations (1)
| 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 |
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| 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 |
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Application publication date: 20160316 |