CN105669543A - Isoliquiritigenin nicotinamide eutectic crystal and preparation method thereof - Google Patents
Isoliquiritigenin nicotinamide eutectic crystal and preparation method thereof Download PDFInfo
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- CN105669543A CN105669543A CN201511030893.5A CN201511030893A CN105669543A CN 105669543 A CN105669543 A CN 105669543A CN 201511030893 A CN201511030893 A CN 201511030893A CN 105669543 A CN105669543 A CN 105669543A
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic 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 belongs to the technical field of medicine eutectic crystals, and concretely discloses an isoliquiritigenin nicotinamide eutectic crystal and a preparation method thereof. The above medicinal eutectic crystal preparation method adopts isoliquiritigenin as a medicinal active component and nicotinamide as an eutectic precursor, and adopts a solvent assisted grinding technology or a solvent suspension technology to crystallize, and the obtained eutectic crystal has a brand new crystallization form, and is completely different from isoliquiritigenin and nicotinamide crystals in characteristics.
Description
Technical field
The invention belongs to technical field of pharmaceutical co-crystal, it is specifically related to isoliquiritigenin nicotinamide eutectic and its preparation method.
Background technology
Supramolecular chemistry is proposed in 1987 first by French scientist Jean-MarieLehn, and it is based on intermolecular non covalent bond, taking supramolecule and molecule aggregates as the chemistry of object, is the subject of a research molecule assembling and inter-molecular linkage. Main research intermolecular non-covalent interaction not of the same race, its core content is molecular recognition, and namely main body is to the process forming secondary key optimum matching between substrate molecule, is that non covalent bond weak interaction works in coordination with the embodiment adding sum; Supramolecular self assembly, namely refers to construct the process that base unit is spontaneously formed with sequence structure under certain condition, is the important means created novel substance and produce New function.
Inherently seeing, eutectic is a kind of Supramolecular self assembly system (supermolecularsynthon), is the result of balance mutually between thermodynamics, kinetics and molecular recognition three. In the process of molecular self-assembling, intermolecular interaction and steric effect affect the formation of supramolecule network, and supramolecule network directly affects the formation of crystal. In eutectic system, the interaction between differing molecular is mainly divided into these four kinds of Intermolecular Forcess of hydrogen bond, halogen key, pi accumulation effect and Van der Waals force.
Biomass Biopharmaceutics Classification system (thebiopharmaceuticsclassificationsystem, it is called for short BCS) according to solubleness and the perviousness of medicine, the oral absorption of medicine is divided, wherein the medicine of BCSII level accounts for the 30% of all commercialities and explorative total number of drugs, and their oral absorption is subject to the restriction of solubleness to a great extent. Brilliant type medicine is in preparation process, and for improving the activity of API, common methods is exactly that compound becomes salt or forms complex compound. At present, only there are 10 kinds of acid ligand molecule rate of utilization that can be used for into salt more than 1%, can be used for into the rate of utilization of the alkaline ligand molecule of salt then lower. And form the CCF in medicine eutectic and can comprise physiologically acceptable acid-alkali salt and non-ionic molecule, such as foodstuff additive, sanitas, pharmaceutical excipient, VITAMIN, mineral substance, amino acid and other bioactive molecules, or even other API etc., they can be connected and be combined in same lattice with other non covalent bonds with hydrogen bond, π pi accumulation, Van der Waals force with API. Chemically angle is said, API molecule itself does not change, and therefore also keeps original drug effect; and the solubleness of eutectic medicine; bioavailability, the aspects such as stability but have great improvement, and especially development for some oral drug preparations has very positive effect.Therefore medicine eutectic has advantage more more than conventional medicament as a kind of novel medical solid kenel.
Isoliquiritigenin (isoliquiritigenin) is the isoflavonoid that two phenyl ring are formed by connecting by α, β unsaturated carbonyl, is yellow needle crystal, is insoluble in water, is dissolved in the solvent that polarity is little, such as ether, chloroform etc. In recent years, isoliquiritigenin causes the interest of numerous investigators, because it has various pharmacologically active, such as anti-inflammation, anti-oxidant, anticancer, angiogenesis inhibitor, and antianaphylaxis etc. act on. Along with a large amount of new types of therapeutic agents is widely used in clinical, having driven the rapid growth of whole market, the natural drug that isoliquiritigenin is representative also will become the focus of attention that medicine is clinical both at home and abroad.
Summary of the invention
The object of the present invention aims to provide a kind of isoliquiritigenin nicotinamide eutectic and its preparation method.
The active pharmaceutical ingredient (API) used in invention is isoliquiritigenin, and chemical name is (E)-1-(2,4-dihydroxy phenyl)-3-(4-hydroxy phenyl)-2-propylene-1-ketone, and molecular formula is C15H12O4, its structural formula is as shown in a. The eutectic precursor (cocrystalformer) used in invention is niacinamide, and molecular formula is C6H6N2O, its structural formula is shown as b.
Crystalline structure of the present invention is summarized as follows: two isoliquiritigenin molecules and two niacinamide molecules jointly consist of the basic structural unit of isoliquiritigenin niacinamide medicine eutectic hydrogen bond and accumulation. Wherein the hydroxyl in isoliquiritigenin molecule is as hydrogen-bond donor, and the pyridine ring nitrogen atom in niacinamide molecule forms intermolecular hydrogen bonding as hydrogen bond receptor; In addition in isoliquiritigenin molecule hydroxyl oxygen atom as hydrogen bond receptor, amide group hydrogen in niacinamide molecule also form intermolecular hydrogen bonding as hydrogen-bond donor, and two isoliquiritigenin molecules and two niacinamide molecules define the tetramer being made up of 3 hydrogen bond rings by hydrogen bond. Pi-pi accumulation effect results from ring 1 (isoliquiritigenin C1-C6) to ring 1, and ring 1 to ring 3 (Isonicotinamide), ring 2 (another ring of isoliquiritigenin) is to ring 2 and ring 3 to ring 3, and stacked direction is amass along b uranium pile. Formed medicine eutectic belong to oblique system, the spacer of P2/n (13), its unit cell parameters is: axial lengthα=90 °, axle angle, β=114.968 (7) °, γ=90 °,Z=4. Not any and both allied substances arbitrarily all can effectively be combined into eutectic.
Therefore it is an object of the invention to realize in the following manner:
A kind of isoliquiritigenin nicotinamide eutectic, this eutectic take isoliquiritigenin as active constituents of medicine (API), and niacinamide is presoma (CCF), adopts solvent assisted milling method or the mixed outstanding method of solvent to prepare; Formed medicine eutectic belong to oblique system, the spacer of P2/n (13), its unit cell parameters is: axial lengthα=90 °, axle angle, β=114.968 (7) °, γ=90 °,Z=4, the powder x-ray diffraction characteristic peak of this eutectic appears at 4.604 °, 7.207 °, 14.420 °, 14.739 °, 15.000 °, 15.534 °, 16.143 °, 16.400 °, 18.433 °, 19.075 °, 22.793 °, 23.652 °, 24.613 °, 25.837 °, 26.288 °, 27.742 °, 32.627 ° and 37.015 ° of places. The DSC figure of this eutectic has strong endotherm(ic)peak at 164.42 DEG C, Raman spectrum 1626.97,1611.04,1569.52,1520.20,1371.29,1316.52,1202.62,1164.41,1127.30,1031.78,892.19,538.38,411.64,382.89,332.67,115.89cm-1There is absorption peak at place.
This eutectic bond principle is two isoliquiritigenin molecules and the basic structural unit of two niacinamide molecule composition isoliquiritigenin medicine eutectics; Wherein the hydroxyl in isoliquiritigenin molecule is as hydrogen-bond donor, and the pyridine ring nitrogen atom in niacinamide molecule forms intermolecular hydrogen bonding as hydrogen bond receptor.
The mol ratio 1:2 of preferred isoliquiritigenin and niacinamide～2:1.
The above-mentioned method preparing isoliquiritigenin Isonicotinamide eutectic, the method comprises solvent assisted milling method or the mixed outstanding method of solvent.
Described solvent assisted milling method specifically comprises the following steps: be that bulk drug isoliquiritigenin and niacinamide are put into mortar and mixed by 1:2～2:1 by mol ratio, mixed powder adds organic solvent, collect after grinding 10～60min under room temperature, obtaining isoliquiritigenin nicotinamide eutectic, isoliquiritigenin and niacinamide total mass and organic solvent solid-to-liquid ratio are (50～150) mg/ (0.015～0.200) ml. Wherein, organic solvent is methyl alcohol or ethanol.
The mixed outstanding method of described solvent specifically comprises the following steps: by the isoliquiritigenin of mol ratio 1:2～2:1 and niacinamide and organic solvent stirring at room temperature 4～6 days, the suspension of gained is filtered, filter cake vacuum-drying, or room temperature placement solvent volatilizes, obtaining isoliquiritigenin nicotinamide eutectic, isoliquiritigenin and niacinamide total mass and organic solvent solid-to-liquid ratio are (30～120) mg/ml. Described organic solvent is methyl alcohol, ethanol or Virahol, it is preferable that organic solvent is Virahol.
The useful effect of the present invention compared with the prior art: the present invention relates to isoliquiritigenin nicotinamide eutectic and its preparation method, select bulk drug isoliquiritigenin as active medicine component API, Isonicotinamide is medicine presoma, adopt solvent assisted milling method or the mixed outstanding method of solvent to prepare eutectic, and carry out the relevant characterization such as DSC, La Man, powder X-ray RD. Result shows, described eutectic crystallization form is different from the isoliquiritigenin of prior art or the crystal habit of nicotinoyl completely, and the eutectic obtained can significantly improve the solubleness of medicine, bioavailability, stability. In addition, this cocrystalization compound synthetic method preparation technology used is simple, with low cost, it is to increase the product rate of eutectic, is applicable to extensive streamline operration.
Accompanying drawing explanation
Fig. 1 is the structural unit schematic diagram of isoliquiritigenin nicotinamide eutectic.
In figure, the basic structural unit of two isoliquiritigenin molecules and two niacinamide molecule composition isoliquiritigenin medicine eutectics; Wherein the hydroxyl in isoliquiritigenin molecule is as hydrogen-bond donor, and the pyridine ring nitrogen atom in niacinamide molecule forms intermolecular hydrogen bonding as hydrogen bond receptor; Formed medicine eutectic belong to oblique system, the spacer of P2/n (13), its unit cell parameters is: axial lengthα=90 °, axle angle, β=114.968 (7) °, γ=90 °,Z=4.
Fig. 2 is the DSC figure of isoliquiritigenin nicotinamide eutectic.
Wherein: a is isoliquiritigenin, b is isoliquiritigenin nicotinamide eutectic, and c is niacinamide, and d is isoliquiritigenin and niacinamide physical mixture; In figure, DSC figure has strong endotherm(ic)peak at 164.42 DEG C.
Fig. 3 is the Raman figure of isoliquiritigenin nicotinamide eutectic.
Wherein: a is isoliquiritigenin, b is isoliquiritigenin nicotinamide eutectic, and c is niacinamide; In figure, Raman spectrum 1626.97,1611.04,1569.52,1520.20,1371.29,1316.52,1202.62,1164.41,1127.30,1031.78,892.19,538.38,411.64,382.89,332.67,115.89cm-1 place have absorption peak.
Fig. 4 is the PXRD figure of isoliquiritigenin nicotinamide eutectic.
Wherein: a is isoliquiritigenin, b is isoliquiritigenin nicotinamide eutectic, and c is the isoliquiritigenin nicotinamide eutectic of prediction, and d is niacinamide. In figure, isoliquiritigenin nicotinamide eutectic is under powder x-ray diffraction, and its characteristic peak appears at 4.604 °, 7.207 °, 14.420 °, 14.739 °, 15.000 °, 15.534 °, 16.143 °, 16.400 °, 18.433 °, 19.075 °, 22.793 °, 23.652 °, 24.613 °, 25.837 °, 26.288 °, 27.742 °, 32.627 ° and 37.015 ° of places.
Embodiment
Below by way of specific embodiment, technical solution of the present invention is further expalined explanation:
Embodiment 1
Precision takes 54.18mg isoliquiritigenin and 25.82mg niacinamide mixes in agate mortar, adds 65 μ l methyl alcohol, collects, obtain isoliquiritigenin nicotinamide eutectic after grinding at room temperature 10min.
Embodiment 2
Precision takes 100.51mg isoliquiritigenin and 47.91mg niacinamide mixes in agate mortar, adds 100 μ l ethanol, collects, obtain isoliquiritigenin nicotinamide eutectic after grinding at room temperature 15min.
Embodiment 3
Precision takes 60.17mg isoliquiritigenin and 28.53mg niacinamide is placed in mortar, adds 75 μ l methyl alcohol, and grinding 30min, obtains isoliquiritigenin nicotinamide eutectic.
Embodiment 4
Precision takes 300.21mg isoliquiritigenin and 143.24mg niacinamide in 10ml Brown Glass Brown glass bottles and jars only, adds 5ml isopropanol solvent, sealing, stir 4 days (500r/min) at 25 DEG C of lower magnetic forces, stopped reaction, filter, filter cake vacuum-drying, obtains isoliquiritigenin nicotinamide eutectic.
Embodiment 5
Precision takes 203.17mg isoliquiritigenin and 96.84mg niacinamide in 5ml Brown Glass Brown glass bottles and jars only, adds 2ml methanol solvate, sealing, stir 6 days (500r/min) at 25 DEG C of lower magnetic forces, stopped reaction, filter, filter cake vacuum-drying, obtains isoliquiritigenin Isonicotinamide eutectic.
Embodiment 6
Precision takes 115.13mg isoliquiritigenin and 54.88mg niacinamide in 5ml Brown Glass Brown glass bottles and jars only, adds 2ml alcohol solvent, sealing, stir 4 days (500r/min) at 25 DEG C of lower magnetic forces, stopped reaction, room temperature is placed and is volatilized solvent, obtains isoliquiritigenin nicotinamide eutectic.
The isoliquiritigenin nicotinamide eutectic obtained according to above-described embodiment method, using isoliquiritigenin as active constituents of medicine (API), Isonicotinamide as eutectic precursor (CCF), crystal characteristic as Figure 1-4:
In Fig. 2, DSC figure has strong endotherm(ic)peak at 164.42 DEG C.
In Fig. 3, Raman spectrum 1626.97,1611.04,1569.52,1520.20,1371.29,1316.52,1202.62,1164.41,1127.30,1031.78,892.19,538.38,411.64,382.89,332.67,115.89cm-1 place have absorption peak.
In Fig. 4, isoliquiritigenin nicotinamide eutectic, under powder x-ray diffraction, has characteristic peak at 4.604 °, 7.207 °, 14.420 °, 14.739 °, 15.000 °, 15.534 °, 16.143 °, 16.400 °, 18.433 °, 19.075 °, 22.793 °, 23.652 °, 24.613 °, 25.837 °, 26.288 °, 27.742 °, 32.627 ° and 37.015 ° of places.
Claims (10)
1. an isoliquiritigenin nicotinamide eutectic, it is characterised in that: this eutectic take isoliquiritigenin as active constituents of medicine, and niacinamide is presoma, adopts solvent assisted milling method or the mixed outstanding method of solvent to prepare;Formed medicine eutectic belong to oblique system, the spacer of P2/n (13), its unit cell parameters is: axial lengthα=90 °, axle angle, β=114.968 (7) °, γ=90 °,Z=4, the powder x-ray diffraction characteristic peak of this eutectic appears at 4.604 °, 7.207 °, 14.420 °, 14.739 °, 15.000 °, 15.534 °, 16.143 °, 16.400 °, 18.433 °, 19.075 °, 22.793 °, 23.652 °, 24.613 °, 25.837 °, 26.288 °, 27.742 °, 32.627 ° and 37.015 ° of places.
2. isoliquiritigenin nicotinamide eutectic according to claim 1, it is characterized in that: the DSC figure of this eutectic has strong endotherm(ic)peak at 164.42 DEG C, Raman spectrum 1626.97,1611.04,1569.52,1520.20,1371.29,1316.52,1202.62,1164.41,1127.30,1031.78,892.19,538.38,411.64,382.89,332.67,115.89cm-1 place have absorption peak.
3. isoliquiritigenin nicotinamide eutectic according to claim 1, it is characterised in that: the mol ratio that isoliquiritigenin mixes with niacinamide is 1:2～2:1.
4. isoliquiritigenin nicotinamide eutectic according to claim 1, it is characterised in that: the basic structural unit of this eutectic specifically two isoliquiritigenin molecules and two niacinamide molecules composition isoliquiritigenin medicine eutectics; Wherein the hydroxyl in isoliquiritigenin molecule is as hydrogen-bond donor, and the pyridine ring nitrogen atom in niacinamide molecule forms intermolecular hydrogen bonding as hydrogen bond receptor.
5. prepare the method for isoliquiritigenin nicotinamide eutectic according to claim 1 for one kind, it is characterised in that the method comprises solvent assisted milling method or the mixed outstanding method of solvent.
6. the preparation method of isoliquiritigenin nicotinamide eutectic as claimed in claim 5, it is characterised in that described solvent assisted milling method step is as follows:
Mix for bulk drug isoliquiritigenin and niacinamide are put into mortar by 1:2～2:1 in molar ratio, mixed powder adds organic solvent, collect after grinding 10～60min under room temperature, obtaining isoliquiritigenin nicotinamide eutectic, isoliquiritigenin and niacinamide total mass and organic solvent solid-to-liquid ratio are (50～150) mg/ (0.015～0.200) ml.
7. the preparation method of isoliquiritigenin nicotinamide eutectic according to claim 6, it is characterised in that described organic solvent is methyl alcohol or ethanol.
8. the method for isoliquiritigenin nicotinamide eutectic as claimed in claim 5, it is characterised in that the mixed outstanding method of described solvent comprises the following steps:
By the isoliquiritigenin of mol ratio 1:2～2:1 and niacinamide and organic solvent stirring at room temperature 4～6 days, the suspension of gained is filtered, filter cake vacuum-drying, or room temperature placement solvent volatilizes, obtaining isoliquiritigenin nicotinamide eutectic, isoliquiritigenin and niacinamide total mass and organic solvent solid-to-liquid ratio are (30～120) mg/ml.
9. the preparation method of isoliquiritigenin nicotinamide eutectic according to claim 8, it is characterised in that described organic solvent is methyl alcohol, ethanol or Virahol.
10. the preparation method of isoliquiritigenin nicotinamide eutectic according to claim 9, it is characterised in that described organic solvent is Virahol.
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| CN108558748A (en) * | 2018-05-15 | 2018-09-21 | 辽宁大学 | Drug molecule Pyrazinamide crystallizes into polymorphism of salt and preparation method thereof with sulfosalicylic acid |
| CN113004198A (en) * | 2021-03-05 | 2021-06-22 | 中国科学院上海药物研究所 | Hydroxytyrosol nicotinamide eutectic crystal, preparation method and composition thereof |
| WO2024037138A1 (en) * | 2022-08-18 | 2024-02-22 | 广州青岚生物科技有限公司 | Phloretin-isoniazid cocrystal and preparation method therefor |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108558748A (en) * | 2018-05-15 | 2018-09-21 | 辽宁大学 | Drug molecule Pyrazinamide crystallizes into polymorphism of salt and preparation method thereof with sulfosalicylic acid |
| CN113004198A (en) * | 2021-03-05 | 2021-06-22 | 中国科学院上海药物研究所 | Hydroxytyrosol nicotinamide eutectic crystal, preparation method and composition thereof |
| CN113004198B (en) * | 2021-03-05 | 2022-06-10 | 中国科学院上海药物研究所 | Hydroxytyrosol nicotinamide eutectic crystal, preparation method and composition thereof |
| WO2022184120A1 (en) * | 2021-03-05 | 2022-09-09 | 中国科学院上海药物研究所 | Hydroxytyrosol nicotinamide eutectic crystal, and preparation method therefor and composition thereof |
| WO2024037138A1 (en) * | 2022-08-18 | 2024-02-22 | 广州青岚生物科技有限公司 | Phloretin-isoniazid cocrystal and preparation method therefor |
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Application publication date: 20160615 |