CN104496972A - Novel pharmaceutical tegafur co-crystal and preparation method thereof - Google Patents

Novel pharmaceutical tegafur co-crystal and preparation method thereof Download PDF

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CN104496972A
CN104496972A CN201410733457.3A CN201410733457A CN104496972A CN 104496972 A CN104496972 A CN 104496972A CN 201410733457 A CN201410733457 A CN 201410733457A CN 104496972 A CN104496972 A CN 104496972A
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tegafur
pharmaceutical
eutectic
crystal
crystals
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汤谷平
吴敏
胡秀荣
沈洁
赵蒙蒙
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of pharmaceutical co-crystals, particularly relates to a novel pharmaceutical tegafur co-crystal and a preparation method thereof, and more particularly relates to a novel co-crystal consisting of tegafur and an organic matter of 4-phenol benzamide. The co-crystal takes the tegafur as a pharmaceutical effective component (API); the selected matter for forming the co-crystal is the 4-phenol benzamide; the tegafur is connected with the 4-phenol benzamide by hydrogen bonds and a pi-pi accumulation effect; and the stoichiometric ratio (mole ratio) of both the tegafur and the 4-phenol benzamide is 1:1. The method for preparing the co-crystal disclosed by the invention is a temperature reduction type crystallization method which is simple and convenient to operate and easy to implement; used solvents are organic solvents which are low in boiling point and low in cost, such as acetonitrile and ketone; and convenience is provided for realizing industrial production.

Description

A kind of novel Tegafur pharmaceutical co-crystals and preparation method thereof
Technical field
The invention belongs to technical field of organic pharmaceutical co-crystal, be specifically related to the new eutectic of Tegafur and the preparation method of new eutectic.
Background technology
Tegafur is anti-metabolism chemotherapy of tumors s-generation fluorouracil drug, and it is successfully synthesized in nineteen sixty-eight by USSR (Union of Soviet Socialist Republics) scientist doctor Hiller.Tegafur is the inactive precursor of 5-FU, in vivo by liver drug metabolism enzyme and cytochrome P-450 system degrade, change 5-FU into gradually and work, its antitumor machanism is identical with 5-FU.Tegafur has fat-soluble height, can be oral, and gastrointestinal absorption is rapid, and the advantages such as long half time, its side effect is 1/7th of 5-FU, and its therapeutic index is then high 2 times.
Tegafur is widely used in the treatment of intestinal cancer and transitivity intestinal cancer, but because Tegafur has certain toxicity, there is more serious bone marrow depression, intestines and stomach reaction and lesions of liver and kidney etc., so reduce its toxicity or improve the focus that its bioavailability becomes research.Such as, the racemization isomer that Tegafur exists 2 ' R and 2 ' S is described in belgian patent No.855121, but the research such as Yasumoto M shows that two kinds of isomer biological activitys are consistent, and toxicity the same (YasumotoM.et al.; " J.Med.Chem. ", 1977, vol.41; No.9,1632-1635); Afterwards, the crystal formation of people to Tegafur such as Uchida T was studied and obtained its α, β, γ, δ tetra-kinds of crystal formations (" Chem.Pharm.Bull. ", Vol.41, No.9,1623-1625).Tegafur is dissolved in low temperature crystallization after in the acetone of heat and obtains alpha-crystal form; Saturated Tegafur methanol solution is by obtaining beta crystal after rotary evaporation; Beta crystal is heated to 130 DEG C and can obtains γ crystal formation; Slow evaporation obtains δ crystal formation by recrystallization in methanol solution and under room temperature.Above crystal formation does not have significant difference in result for the treatment of.
Well do not improve the curative effect of Tegafur from described above learning by configuration or crystal formation screening or reduce its toxicity, having synergistic compound to be the focus studied at present so search out with Tegafur.Such as, KagawaY. etc. confirm the curative effect (" Cancer Investigation ", Vol.13, No.5,470-474.) that effectively can improve Tegafur after Tegafur mixes with mol ratio 1:4 with uridylic; Sanchiz F etc. has invented the compound (" Jpn.Journal Clin.Oncol. ", 1994, vol.24, No.6,322-326) of Tegafur, folic acid and uridylic composition, to improve the bioavailability of Tegafur.Because uridylic itself has certain toxicity, when Fujita H etc. points out the conbined usage such as Tegafur and thymus pyrimidine, adenosine, thymidine, toxicity reduces more obviously (Experimental andClinical Pharmacotherapy, Issue 12, Riga, 1983, p.205).US Patent No. 6,538,001 report can improve solvability and the bioavailability of Tegafur after Tegafur and 6-Methyl Uracil form molecular complex (i.e. eutectic) with 1:2 or 1:1.In sum, drug combination is the effective ways of the bioavailability improving Tegafur.
Pharmaceutical co-crystals is by medicine activity component (active pharmaceuticalingredient according to crystal engineering principle, API) with the acceptable molecule of other physiology, the crystal in same lattice is combined according to certain stoichiometric ratio with non covalent bond forms such as hydrogen bonds.Significantly can improve the physicochemical property of medicine, solubleness, dissolution rate and stability through the pharmaceutical co-crystals of appropriate design, and then improve the bioavailability of medicine.In November, 2011, FDA has issued " pharmaceutical co-crystals management classification guide " (Guidance for Industry:RegulatoryClassification ofPharmaceutical Cocrystals), point out after medicine and certain auxiliary material form eutectic, pharmaceutical co-crystals can be managed as " preparation intermediate " and controls, so eutectic is without the need to registering as medicine separately.Therefore, obtain and morely there is novelty, practicality and creationary pharmaceutical co-crystals have important practical significance, particularly more meaningful for some water-insoluble drugs.In recent years, pharmaceutical co-crystals research more and more received the concern of people.Present stage, abroad start increase gradually and go deep into the research of pharmaceutical co-crystals; And it is domestic also relatively less to its research.For imitation medicine, the research of pharmaceutical co-crystals also can break Yuan Yan medicine company to the patent protection of drug crystal forms, is beneficial to and is introduced to the market by imitation medicine.
The design of pharmaceutical co-crystals is the prerequisite that eutectic is successfully prepared, and uses supramolecular chemistry principle and self-assembly principle to be the features that crystal engineering prepares eutectic to supramolecular structure design.The intensity that potential molecular interaction is mainly assessed in cocrystallization experimental design becomes key principle with consideration hydrogen bond.Current eutectic internus can be divided into following a few class structure: amides pharmaceutical co-crystals, carboxylic-acid pharmaceutical co-crystals, alcohol phenols pharmaceutical co-crystals, heterocyclic drug eutectic.Wherein amides medicine be pharmaceutical co-crystals research in relate to a more class active constituents of medicine, the carbonyl O atom in its molecule is proton acceptor, and amino N atom is proton donor, can and eutectic auxiliary material in proton acceptor or form hydrogen bond between different kinds of molecules to body.From the structural analysis of Tegafur, it also belongs to amides medicine, and its structure is simple, is easier to form eutectic with other medicines or pharmaceutical excipient.The present invention's exploration obtains Tegafur and can form eutectic with 4-hydroxybenzamide as eutectic formation (Cocrystal former, CCF), and this is for we select drug-drug eutectic to provide foundation later.
Summary of the invention
The present invention seeks to for the improvement done by the deficiencies in the prior art part, a kind of eutectic and preparation method of Tegafur medicine are provided, and characterization research is carried out to its structure.For the raising of Tegafur bioavailability, the reduction of toxic side effect provide an approach.
The present invention is achieved by the following technical solutions:
A kind of Tegafur pharmaceutical co-crystals, eutectic is made up of Tegafur (I) and 4-hydroxybenzamide (II), and described Tegafur (I) is as follows with the structural formula of 4-hydroxybenzamide (II):
As improving further, the present invention take Tegafur as active constituents of medicine, and 4-hydroxybenzamide is eutectic formation; The basic structural unit of a Tegafur molecule and a 4-hydroxybenzamide molecular composition eutectic, its crystallographic parameters is: oblique system, P 21/n spacer, unit cell parameters: b= α=90.000 °, (3) 9 °, β=36.304, γ=90.000 ° unit cell volume z=4, molecular formula: C 8h 9fN 2o 3c 7h 7nO 2.
As further improvement, the X-ray powder diffraction pattern had as shown in Figure 3 of eutectic of the present invention, is expressed as with diffraction angle 2 θ ° ± 0.1: 4.30 °, 4.88 °, 9.75 °, 10.99 °, 11.78 °, 12.99 °, 14.65 °, 16.27 °, 18.19 °, 19.59 °, 20.54 °, 20.88 °, 21.67 °, 22.10 °, 22.78 °, 23.20 °, 23.46 °, 23.85 °, 24.47 °, 24.794 °, 25.89 °, 26.16 °, 28.06 °, 28.48 °, 29.19 °, 29.60 °, 29.93 ° etc.
The invention also discloses a kind of preparation method of Tegafur pharmaceutical co-crystals, be characterised in that:
In organic solvent Tegafur and eutectic formation are fed intake according to equimolar ratio, the weight g of Tegafur and the volume ml of solvent are than being 1:5 ~ 1:30, under high temperature bath condition, backflow is stirred to solution clarification and Keep agitation certain hour, above-mentioned settled solution is put into ice-water bath cooling crystallization fast, spend the night, the throw out obtained, filter, drying obtains described Tegafur eutectic.
As improving further, organic solvent of the present invention is acetone and acetonitrile.
Meanwhile, invention also discloses a kind of application of Tegafur pharmaceutical co-crystals, eutectic can be applicable to treatment digestive tract tumor or treatment mammary cancer or lung bronchogenic carcinoma or liver cancer, and described digestive tract tumor is cancer of the stomach or colorectal carcinoma or rectum or carcinoma of the pancreas.
Beneficial effect of the present invention is as follows:
Tegafur is the derivative of Fluracil, change Fluracil gradually into through liver activation in vivo and play antitumor action, interference, blocking dna, RNA and protein synthesis in vivo, it is anti-miazines medicine, for cell cycle specific agents, chemotherapeutic index is 2 times of Fluracil, and toxicity is only 1/4 ~ 1/7 of Fluracil.
Eutectic prepared by the present invention inherits the pharmacologically active of Tegafur itself, and all has some improvement in stability and bioavailability.Thermal analyses result shows that the starting temperature that eutectic decomposes is 207.4 DEG C, and the initial decomposition temperature of Tegafur bulk drug is 185.69 DEG C, illustrate Tegafur and 4-hydroxybenzamide form eutectic after thermostability significantly improve to some extent.The crystal structure analysis of eutectic prepared by the present invention shows, abundant hydrogen bond network is there is between Tegafur and 4-hydroxybenzamide in eutectic, with intermolecular hydrogen bonding, eutectic molecule is formed a helical molecular chain infinitely extended in molecule, this molecular chain infinitely extends along b direction, this coiled strand is similar to a chain in the double-spiral structure of DNA from structure, consider that this structure may be conducive to the synthesis of Tegafur blocking dna from biology angle, thus improve the activity of Tegafur as anti-miazines medicine.
Accompanying drawing explanation
Fig. 1 is the crystalline structure figure of the organic pharmaceutical co-crystal of Tegafur and 4-hydroxybenzamide;
Fig. 2 is the hydrogen bond interface chart of the organic pharmaceutical co-crystal of Tegafur and 4-hydroxybenzamide;
Fig. 3 is X-ray powder diffraction (XRD) figure of the organic pharmaceutical co-crystal of Tegafur and 4-hydroxybenzamide;
Fig. 4 is thermogravimetric analysis (TG) figure of the organic pharmaceutical co-crystal of Tegafur and 4-hydroxybenzamide;
Fig. 5 is differential scanning analysis (DSC) figure of the organic pharmaceutical co-crystal of Tegafur and 4-hydroxybenzamide.
Embodiment
The invention provides a kind of Tegafur pharmaceutical co-crystals and preparation method thereof, the active constituents of medicine (API) selected is Tegafur, and eutectic formation (CCF) is 4-hydroxybenzamide, has prepared a kind of eutectic of novel texture.
Tegafur (Tegafur) is as active constituents of medicine of the present invention, and chemical name is 1-(tetrahydrochysene-2-furyl)-5-fluoro-2, and 4 (1H, 3H)-pyrimidine dione, its molecular formula is C 8h 9fN 2o 3, its structure is as schemed the crystalline structure figure of the organic pharmaceutical co-crystal of I Tegafur and 4-hydroxybenzamide.
The eutectic formation (CCF) that the present invention selects is 4-hydroxybenzamide, molecular formula C 7h 7nO 2structure is as schemed the hydrogen bond interface chart of the organic pharmaceutical co-crystal of II Tegafur and 4-hydroxybenzamide.
Tegafur pharmaceutical co-crystals of the present invention is by a Tegafur molecule and 4-hydroxybenzamide molecular composition Tegafur pharmaceutical co-crystals (Fig. 1), belong to oblique system, P21/n spacer, crystallographic parameters is as shown in table 1, atomic coordinate and temperature factor as shown in table 2.Hydroxyl on 4-hydroxybenzamide forms hydrogen bond as the carbonyl on the pyrimidone of body and Tegafur of giving of hydrogen bond, and the carbonyl on Tegafur pyrimidone has strong hydrogen bond action with the hydroxyl of 4-hydroxybenzamide, with intermolecular this hydrogen bond, eutectic molecule is formed a helical molecular chain (Fig. 2) infinitely extended in molecule, this molecular chain infinitely extends along b direction.X-ray powder diffraction (XRD) figure (Fig. 3) of eutectic, its X-ray feature diffract spectral line diffraction angle 2 θ represents that (2 θ, ± 0.1 °) is: 4.30 °, 4.88 °, 9.75 °, 10.99 °, 11.78 °, 12.99 °, 14.65 °, 16.27 °, 18.19 °, 19.59 °, 20.54 °, 20.88 °, 21.67 °, 22.10 °, 22.78 °, 23.20 °, 23.46 °, 23.85 °, 24.47 °, 24.794 °, 25.89 °, 26.16 °, 28.06 °, 28.48 °, 29.19 °, 29.60 °, 29.93.Thermogravimetric (TG) the analytical results display of eutectic from room temperature within the scope of 150 DEG C without weightless, show eutectic 1 not containing crystal water and solvent (Fig. 4), differential thermal analysis (DSC) is presented at 145.4 DEG C of (summit value) places an endotherm(ic)peak, shows that the fusing point (summit value) of eutectic is 145.4 DEG C (Fig. 5).
The crystallographic parameters of table 1 Tegafur-4-hydroxybenzamide eutectic
Each atom (non-hydrogen atom) atomic coordinate and temperature factor in table 2 Tegafur-4-hydroxybenzamide eutectic
Atom X Y Z Ueq
C1 0.4166(8) 0.3702(6) 0.07429(12) 0.0464(11)
C2 0.5316(11) 0.2202(8) 0.09098(17) 0.0823(18)
C3 0.6229(11) 0.1289(8) 0.05732(19) 0.0817(15)
C4 0.4246(10) 0.1745(6) 0.02841(15) 0.0621(14)
C5 0.6017(7) 0.6032(5) 0.10857(10) 0.0344(9)
C6 0.9646(7) 0.7670(5) 0.08608(10) 0.0337(9)
C7 0.9434(7) 0.6652(5) 0.05380(10) 0.0381(10)
C8 0.7709(8) 0.5453(5) 0.04984(11) 0.0400(10)
C9 0.5220(7) 0.9200(5) 0.19087(10) 0.0352(9)
C10 0.5074(6) 0.9221(5) 0.23150(10) 0.0323(9)
C11 0.6910(7) 0.8374(5) 0.25351(11) 0.0389(10)
C12 0.6793(7) 0.8316(6) 0.29111(11) 0.0419(10)
C13 0.4820(7) 0.9165(5) 0.30808(10) 0.0363(9)
C14 0.3015(7) 1.0053(5) 0.28680(11) 0.0387(10)
C15 0.3129(7) 1.0083(5) 0.24866(11) 0.0376(9)
F1 1.1100(5) 0.6990(4) 0.02700(7) 0.0613(8)
N1 0.6017(6) 0.5122(4) 0.07711(8) 0.0375(8)
N3 0.3014(6) 0.9428(5) 0.17083(9) 0.0465(10)
O1 0.3538(6) 0.3379(4) 0.03746(8) 0.0536(8)
O2 0.4474(5) 0.5798(4) 0.13276(8) 0.0493(8)
O3 1.1231(5) 0.8782(4) 0.09103(8) 0.0468(8)
O4 0.7368(5) 0.8967(4) 0.17628(8) 0.0472(8)
O5 0.4717(5) 0.9055(4) 0.34531(7) 0.0527(9)
In the present invention, the instrument of detection of drugs eutectic structure is as follows:
Single crystal diffraction: Rigaku R-AXIS-RAPID single crystal diffractometer, adopts MoK α ray, carries out structure elucidation and correction with SHELXS97 and SHELXL97.Diamond and Mercury software is used to obtain structure iron.
Powder x-ray diffraction (XRD) characterizes: instrument: Rigaku D/Max-2550PC, CuK α radiation, power 40kV × 250mA, sweep limit 2 θ 3 ~ 40 °, walk wide (step width) 0.02 °, sweep velocity 5 °/min.
Thermogravimetric analysis (TG) characterizes: instrument: TA company SDT Q600, sweep gas: nitrogen 120ml/min, heat-up rate: 10 DEG C/min, temperature range: room temperature ~ 380 DEG C.
Differential scanning calorimetric analysis (DSC) characterizes: instrument: TA company DSC Q100, sweep gas: nitrogen 50ml/min, heat-up rate: 10 DEG C/min, temperature range: room temperature ~ 200 DEG C.
Under by specific embodiment, technical scheme of the present invention is further described:
Embodiment 1
Get 0.40g Tegafur, 0.27g 4-hydroxybenzamide, adds 2ml acetonitrile solution, is heated to 60 DEG C of backflows, stir molten clear after, continue backflow 20-30 minute, put into ice-water bath fast, slowly separate out white crystal, after 24 hours, filter, obtain the Tegafur organic pharmaceutical co-crystal of white.
Embodiment 2
Get 0.40g Tegafur, 0.27g 4-hydroxybenzamide, adds 4ml acetonitrile solution, is heated to 60 DEG C of backflows, stir molten clear after, continue backflow 20-30 minute, put into ice-water bath fast, slowly separate out white crystal, after 24 hours, filter, obtain the Tegafur organic pharmaceutical co-crystal of white.
Embodiment 3
Get 0.80g Tegafur, 0.54g 4-hydroxybenzamide, adds 5ml acetonitrile solution, is heated to 60 DEG C of backflows, stir molten clear after, continue backflow 20-30 minute, put into ice-water bath fast, slowly separate out white crystal, after 24 hours, filter, obtain the Tegafur organic pharmaceutical co-crystal of white.
Embodiment 4
Get 0.40g Tegafur, 0.27g4-hydroxybenzamide, add 4ml acetone soln, be heated to 60 DEG C of backflows, stir molten clear after, continue backflow 20-30 minute, put into ice-water bath fast, slowly separate out white crystal, after 24 hours, filter, obtain the Tegafur organic pharmaceutical co-crystal of white.
Embodiment 5
Get 4.0g Tegafur, 2.7g4-hydroxybenzamide, adds 50ml acetone soln, is heated to 60 DEG C of backflows, stir molten clear after, continue backflow 20-30 minute, put into ice-water bath fast, slowly separate out white crystal, after 24 hours, filter, obtain the Tegafur organic pharmaceutical co-crystal of white, weigh to obtain 5.2g.
Powder X-ray powder diffraction that embodiment 1-5 obtains measures, and its diffractogram is consistent, with spacing d, diffraction angle 2 θ (with ° ± 0.2 to represent) and relative intensity (being expressed as the percentage ratio relative to most intense line) represent.
Finally, it is also to be noted that what enumerate above is only several specific embodiment of the present invention and comparative example.Obviously, the invention is not restricted to above embodiment, many distortion can also be had.All distortion that those of ordinary skill in the art can directly derive from content disclosed by the invention or associate, all should think protection scope of the present invention.

Claims (7)

1. a Tegafur pharmaceutical co-crystals, it is characterized in that, described eutectic is made up of Tegafur (I) and 4-hydroxybenzamide (II), and described Tegafur (I) is as follows with the structural formula of 4-hydroxybenzamide (II):
2. a Tegafur pharmaceutical co-crystals according to claim 1, is characterized in that, take Tegafur as active constituents of medicine, and 4-hydroxybenzamide is eutectic formation; The basic structural unit of a Tegafur molecule and a 4-hydroxybenzamide molecular composition eutectic, its crystallographic parameters is: oblique system, P 21/n spacer, unit cell parameters: α=90.000 °, (3) 9 °, β=36.304, γ=90.000 ° unit cell volume z=4, molecular formula: C 8h 9fN 2o 3c 7h 7nO 2.
3. a Tegafur pharmaceutical co-crystals according to claim 2, it is characterized in that, described eutectic has X-ray powder diffraction pattern as shown in Figure 3, be expressed as with diffraction angle 2 θ ° ± 0.1: 4.30 °, 4.88 °, 9.75 °, 10.99 °, 11.78 °, 12.99 °, 14.65 °, 16.27 °, 18.19 °, 19.59 °, 20.54 °, 20.88 °, 21.67 °, 22.10 °, 22.78 °, 23.20 °, 23.46 °, 23.85 °, 24.47 °, 24.794 °, 25.89 °, 26.16 °, 28.06 °, 28.48 °, 29.19 °, 29.60 °, 29.93 ° etc.
4. a preparation method for the Tegafur pharmaceutical co-crystals as described in claim 1 or 2 or 3, is characterised in that:
In organic solvent Tegafur and eutectic formation are fed intake according to equimolar ratio, the weight g of Tegafur and the volume ml of solvent are than being 1:5 ~ 1:30, under high temperature bath condition, backflow is stirred to solution clarification and Keep agitation certain hour, above-mentioned settled solution is put into ice-water bath cooling crystallization fast, spend the night, the throw out obtained, filter, drying obtains described Tegafur eutectic.
5. a preparation method for Tegafur pharmaceutical co-crystals according to claim 4, is characterized in that, described organic solvent is acetone and acetonitrile.
6. an application for the Tegafur pharmaceutical co-crystals as described in 1 or 2 or 3, is characterized in that, described eutectic can be applicable to treatment digestive tract tumor or treatment mammary cancer or lung bronchogenic carcinoma or liver cancer.
7. the application of Tegafur pharmaceutical co-crystals according to claim 6, is characterized in that, described digestive tract tumor is cancer of the stomach or colorectal carcinoma or rectum or carcinoma of the pancreas.
CN201410733457.3A 2014-12-04 2014-12-04 Novel pharmaceutical tegafur co-crystal and preparation method thereof Pending CN104496972A (en)

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Application publication date: 20150408