CN105622497A - Isoliquiritigenin pyrazinamide eutectic crystal and preparation method thereof - Google Patents
Isoliquiritigenin pyrazinamide eutectic crystal and preparation method thereof Download PDFInfo
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- CN105622497A CN105622497A CN201511029394.4A CN201511029394A CN105622497A CN 105622497 A CN105622497 A CN 105622497A CN 201511029394 A CN201511029394 A CN 201511029394A CN 105622497 A CN105622497 A CN 105622497A
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- isoliquiritigenin
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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
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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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Abstract
The invention belongs to the technical field of medicine eutectic crystal, and concretely discloses an isoliquiritigenin pyrazinamide eutectic crystal and a preparation method thereof. According to the method, isoliquiritigenin and pyrazinamide are used as raw materials; a solvent auxiliary grinding method or a solvent suspension method is used for preparing the isoliquiritigenin pyrazinamide eutectic crystal. The obtained eutectic crystal has a novel crystal form, is favorable for novel preparation development, and promotes the application of the isoliquiritigenin to medicine clinics.
Description
Technical field
The present invention relates to isoliquiritigenin Pyrazinamide eutectic and preparation method thereof, belong to pharmaceutical co-crystals field.
Background technology
Supramolecular chemistry is in fast development in recent decades, it is believed that be one of the important source of 21 century new ideas and new technique. It is as a branch of chemistry, it is absorbed in the non-covalent bond combination between molecule, compared to the covalent bond studied on traditional chemical, the object of study of supramolecular chemistry is that some are more weak and relatively have the intermolecular interaction of restorability, such as, hydrogen bond, metal-complexing, hydrophobicity effect, Van der Waals force and overlap action etc. The molecular recognition and Supramolecular self assembly that are to be undertaken by the synergism of intermolecular weak interaction are acted the leading role in its research core.
The principle of supramolecular chemistry and method are applied to design and the growth of crystal by crystal engineering, by the combined effect of molecular recognition and self assembling process, obtain structure controllable, have the new crystal of specific physico-chemical property. Crystal engineering is the effective means of oriented control compound structure, character and function, it is an important component part of molecular engineering, relate to the control of the behavior in crystal of material and molecular radical, the design of crystal, structure and performance and the prediction of crystal structure, be realize an important channel from molecule to material.
Development in an all-round way and people's further investigation to crystal product structure activity relationship along with crystallization technique, the chemical purity of drug products and chemical composition are not only produced impact by the factors in crystallization process, also determine the internal structure (polymorphic) of drug products, particle size distribution and the critical nature such as brilliant habit and defect concentration (degree of crystallinity), significant difference is produced, thus affecting the performance of the stability of medicine, bioavailability and curative effect in the dissolubility of medicine, dissolution rate, fusing point, density, hardness, outward appearance and biological effectiveness etc. Mostly pharmaceutical co-crystals is formation based on hydrogen bond, the pharmaceutical co-crystals formed by hydrogen bond need not form new covalent bond, covalent bond is had also without destroying oneself, and can well the series of physicochemical character of modified medicaments and pharmacological properties, change the whole course of dissolution of API, have also been changed the process of the absorption of medicine and distribution in vivo.
Isoliquiritigenin is to extract from Chinese crude drug Radix Glycyrrhizae to separate the natural flavone compounds obtained, it is that liquorice chalcone constituent class composition studies more important compound, showing stronger physiologically active in multiple pharmacological effect, its antitumor, antioxidation, freeradical etc. act on and have obtained experimental verification. But isoliquiritigenin dissolubility is relatively low, causes that its oral suction is undesirable, greatly limit its application in disease treatment. If in conjunction with the theory of pharmacy eutectic, improve isoliquiritigenin druggability by preparing eutectic, provide broader space for isoliquiritigenin in the application of medicine clinicing aspect.
Summary of the invention
The purpose of the present invention aims to provide a kind of isoliquiritigenin Pyrazinamide eutectic and preparation method thereof.
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 such as shown in a. The eutectic precursor (cocrystalformer) used in invention is Pyrazinamide, and molecular formula is C6H6N2O, its structural formula is shown as b.
Crystal structure of the present invention is summarized as follows: an isoliquiritigenin molecule and Pyrazinamide molecule collectively form the basic structural unit of isoliquiritigenin Pyrazinamide pharmaceutical co-crystals by hydrogen bond and sedimentation. Wherein the hydroxyl in isoliquiritigenin molecule is as hydrogen-bond donor, and the pyridine ring nitrogen atom in Pyrazinamide molecule forms intermolecular hydrogen bonding as hydrogen bond receptor; In addition in isoliquiritigenin molecule, carbonylic oxygen atom is as hydrogen bond receptor, and the amide groups hydrogen in Pyrazinamide molecule also form intermolecular hydrogen bonding as hydrogen-bond donor, defines a kind of layer structure by hydrogen bond. Pi-pi accumulation effect results from ring 1 (isoliquiritigenin C1-C6) to ring 1, ring 1 to ring 3 (Pyrazinamide) and ring 2 (another ring of isoliquiritigenin) to ring 3, and stacked direction is amass along b uranium pile. Formed pharmaceutical co-crystals belong to anorthic system, the space group of P-1 (2), its cell parameter is: axial length Shaft angle ��=79.871 (5) ��, ��=78.545 (4) ��, ��=82.818 (5) ��,Z=2. Not any and both allied substances arbitrarily all can effectively be combined into eutectic.
Therefore it is an object of the invention to be accomplished by:
A kind of isoliquiritigenin Pyrazinamide eutectic, this eutectic is with isoliquiritigenin for activity characteristic composition (API), and Pyrazinamide is eutectic presoma (CCF), adopts solvent assisted milling method or solvent suspendible method to prepare; Formed pharmaceutical co-crystals belong to anorthic system, the space group of P-1 (2), its cell parameter is: axial length Shaft angle ��=79.871 (5) ��, ��=78.545 (4) ��, ��=82.818 (5) ��,Z=2, the powder X-ray diffraction characteristic peak of this eutectic occurs in 11.325 ��, 13.281 ��, 15.269 ��, 15.709 ��, 17.000 ��, 19.559 ��, 21.969 ��, 25.707 ��, 26.773 ��, 27.188 ��, 28.441 �� and 28.775 �� of places.
The DSC figure of this eutectic has highly endothermic peak at 186.37 DEG C, Raman spectrum 1628.62,1606.34,1552.96,1528.60,1381.53,1316.94,1294.18,1218.24,1175.17,1029.85,970.99,889.42,762.54,749.71,536.18,404.18,328.33,196.57,102.89cm-1 place have absworption peak.
This eutectic bond principle is an isoliquiritigenin molecule and the basic structural unit of a Pyrazinamide molecular composition isoliquiritigenin pharmaceutical co-crystals; Wherein the hydroxyl in isoliquiritigenin molecule is as hydrogen-bond donor, and the pyridine ring nitrogen atom in Pyrazinamide molecule forms intermolecular hydrogen bonding as hydrogen bond receptor.
The mol ratio that preferred isoliquiritigenin mixes with Pyrazinamide is 1:2��2:1.
The above-mentioned method preparing isoliquiritigenin Pyrazinamide eutectic, the method includes solvent assisted milling method or solvent suspendible method.
Described solvent assisted milling method specifically includes following steps: takes the crude drug isoliquiritigenin that mol ratio is 1:2��2:1 and is placed in mortar with Pyrazinamide, add organic solvent, mixed grinding 20��60min under room temperature, obtaining isoliquiritigenin Pyrazinamide eutectic, isoliquiritigenin and Pyrazinamide gross mass with solvent solid-to-liquid ratio is (40��150) mg/ (0.015��0.300) ml. Wherein, organic solvent is methanol or ethanol.
Described solvent suspendible method specifically includes following steps: takes the crude drug isoliquiritigenin that mol ratio is 1:2��2:1 and mixes with Pyrazinamide, add organic solvent, after being stirred at room temperature 2��4 days, the suspension of gained is filtered, filter cake vacuum drying, obtaining isoliquiritigenin pharmaceutical co-crystals, isoliquiritigenin and Pyrazinamide gross mass with neat solvent solid-to-liquid ratio is (50��120) mg/ml. Described organic solvent is methanol, ethanol or isopropanol, it is preferable that organic solvent is isopropanol.
Beneficial effects of the present invention compared with the prior art: the present invention relates to isoliquiritigenin Pyrazinamide eutectic and preparation method thereof, select crude drug isoliquiritigenin as active medicine component API, Pyrazinamide is medicine presoma, adopt solvent assisted milling method or solvent suspendible method to prepare eutectic, and carry out the relevant characterization such as DSC, Raman, powder X-ray RD. It is shown that described eutectic crystallization form is totally different from the isoliquiritigenin of prior art or the crystal habit of Pyrazinamide, the eutectic obtained can significantly improve the dissolubility of medicine, bioavailability, stability. Additionally, synthetic method preparation technology used by this cocrystalization compound is simple, with low cost, improve the productivity of eutectic, it is adaptable to extensive line production.
Accompanying drawing explanation
Fig. 1 is the construction unit schematic diagram of isoliquiritigenin Pyrazinamide eutectic.
As it can be seen, the basic structural unit of an isoliquiritigenin molecule and a Pyrazinamide molecular composition isoliquiritigenin pharmaceutical co-crystals; Wherein the hydroxyl in isoliquiritigenin molecule is as hydrogen-bond donor, and the pyridine ring nitrogen atom in Pyrazinamide molecule forms intermolecular hydrogen bonding as hydrogen bond receptor; Formed pharmaceutical co-crystals belong to anorthic system, the space group of P-1 (2), its cell parameter is: axial lengthShaft angle ��=79.871 (5) ��, ��=78.545 (4) ��, ��=82.818 (5) ��,Z=2.
Fig. 2 is the DSC figure of isoliquiritigenin Pyrazinamide eutectic.
Wherein: a is isoliquiritigenin, b is isoliquiritigenin Pyrazinamide eutectic, and c is Pyrazinamide, and d is isoliquiritigenin and Pyrazinamide physical mixture; In figure, DSC figure has highly endothermic peak at 186.37 DEG C.
Fig. 3 is the Raman figure of isoliquiritigenin Pyrazinamide eutectic.
Wherein: a is isoliquiritigenin, b is isoliquiritigenin Pyrazinamide eutectic, and c is Pyrazinamide; In figure, Raman spectrum 1628.62,1606.34,1552.96,1528.60,1381.53,1316.94,1294.18,1218.24,1175.17,1029.85,970.99,889.42,762.54,749.71,536.18,404.18,328.33,196.57,102.89cm-1 place have absworption peak.
Fig. 4 is the PXRD figure of isoliquiritigenin Pyrazinamide eutectic.
Wherein: a is isoliquiritigenin, b is isoliquiritigenin Pyrazinamide eutectic, and c is the isoliquiritigenin Pyrazinamide eutectic predicted by mono-crystalline structures, and d is Pyrazinamide. In figure, isoliquiritigenin Pyrazinamide eutectic, under powder X-ray diffraction, has characteristic peak at 11.325 ��, 13.281 ��, 15.269 ��, 15.709 ��, 17.000 ��, 19.559 ��, 21.969 ��, 25.707 ��, 26.773 ��, 27.188 ��, 28.441 ��, 28.775 �� places.
Detailed description of the invention
Below by way of specific embodiment, technical solution of the present invention is further expalined explanation:
Embodiment 1
Precision weighs 128.17mg isoliquiritigenin and 61.06mg Pyrazinamide is placed in mortar, adds 75 �� l methanol, grinds 20min, obtains isoliquiritigenin Pyrazinamide eutectic.
Embodiment 2
Precision weighs 135.49mg isoliquiritigenin and 64.56mg Pyrazinamide is placed in mortar, adds 90 �� l ethanol, grinds 40min, obtains isoliquiritigenin Pyrazinamide eutectic.
Embodiment 3
Precision weighs 89.79mg isoliquiritigenin and 42.76mg Pyrazinamide is placed in mortar, adds 60 �� l methanol, grinds 35min, obtains isoliquiritigenin Pyrazinamide eutectic.
Embodiment 4
Precision weighs 130.87mg isoliquiritigenin with 62.38mg Pyrazinamide in 5ml Brown Glass Brown glass bottles and jars only, addition 2ml isopropanol solvent, seals, magnetic agitation 48h (500r/min) at 25 DEG C, stopped reaction, filters, filter cake vacuum drying, obtains isoliquiritigenin Pyrazinamide eutectic.
Embodiment 5
Precision weighs 152.36mg isoliquiritigenin with 72.62mg Pyrazinamide in 5ml Brown Glass Brown glass bottles and jars only, addition 2ml methanol solvate, seals, magnetic agitation 80h (500r/min) at 25 DEG C, stopped reaction, filters, filter cake vacuum drying, obtains isoliquiritigenin Pyrazinamide eutectic.
Embodiment 6
Precision weighs 201.66mg isoliquiritigenin with 96.13mg Pyrazinamide in 5ml Brown Glass Brown glass bottles and jars only, addition 2ml alcohol solvent, seals, magnetic agitation 72h (500r/min) at 25 DEG C, stopped reaction, filters, filter cake vacuum drying, obtains isoliquiritigenin Pyrazinamide eutectic.
According to the isoliquiritigenin Pyrazinamide eutectic that above-described embodiment method obtains, using isoliquiritigenin as active constituents of medicine (API), Pyrazinamide as eutectic precursor (CCF), crystal characteristic as Figure 1-4:
In Fig. 2, DSC figure has highly endothermic peak at 186.37 DEG C.
In Fig. 3, Raman spectrum 1628.62,1606.34,1552.96,1528.60,1381.53,1316.94,1294.18,1218.24,1175.17,1029.85,970.99,889.42,762.54,749.71,536.18,404.18,328.33,196.57,102.89cm-1 place have absworption peak.
In Fig. 4, isoliquiritigenin Pyrazinamide eutectic, under powder X-ray diffraction, has characteristic peak at 11.325 ��, 13.281 ��, 15.269 ��, 15.709 ��, 17.000 ��, 19.559 ��, 21.969 ��, 25.707 ��, 26.773 ��, 27.188 ��, 28.441 ��, 28.775 �� places.
Claims (10)
1. an isoliquiritigenin Pyrazinamide eutectic, it is characterised in that: this eutectic is with isoliquiritigenin for activity characteristic composition, and Pyrazinamide is eutectic presoma, adopts solvent assisted milling method or solvent suspendible method to prepare; Formed pharmaceutical co-crystals belong to anorthic system, the space group of P-1 (2), its cell parameter is: axial length Shaft angle ��=79.871 (5) ��, ��=78.545 (4) ��, ��=82.818 (5) ��,Z=2, the powder X-ray diffraction characteristic peak of this eutectic occurs in 11.325 ��, 13.281 ��, 15.269 ��, 15.709 ��, 17.000 ��, 19.559 ��, 21.969 ��, 25.707 ��, 26.773 ��, 27.188 ��, 28.441 �� and 28.775 �� of places.
2. isoliquiritigenin Pyrazinamide eutectic according to claim 1, it is characterized in that: the DSC figure of this eutectic has highly endothermic peak at 186.37 DEG C, Raman spectrum 1628.62,1606.34,1552.96,1528.60,1381.53,1316.94,1294.18,1218.24,1175.17,1029.85,970.99,889.42,762.54,749.71,536.18,404.18,328.33,196.57,102.89cm-1 place have absworption peak.
3. isoliquiritigenin Pyrazinamide eutectic according to claim 1, it is characterised in that the mol ratio that isoliquiritigenin mixes with Pyrazinamide is 1:2��2:1.
4. isoliquiritigenin Pyrazinamide eutectic according to claim 1, it is characterised in that the basic structural unit of this eutectic specifically isoliquiritigenin molecule and a Pyrazinamide molecular composition isoliquiritigenin pharmaceutical co-crystals; Wherein the hydroxyl in isoliquiritigenin molecule is as hydrogen-bond donor, and the pyridine ring nitrogen atom in Pyrazinamide molecule forms intermolecular hydrogen bonding as hydrogen bond receptor.
5. the method for the isoliquiritigenin Pyrazinamide eutectic that a kind is prepared described in claim 1, it is characterised in that the method includes solvent assisted milling method or solvent suspendible method.
6. the method preparing isoliquiritigenin Pyrazinamide eutectic according to claim 5, it is characterised in that described solvent assisted milling method comprises the following steps:
For 1:2��2:1, crude drug isoliquiritigenin and Pyrazinamide are placed in mortar in molar ratio, add organic solvent, mixed grinding 20��60min under room temperature, obtaining isoliquiritigenin Pyrazinamide eutectic, isoliquiritigenin and Pyrazinamide gross mass with organic solvent solid-to-liquid ratio is (40��150) mg/ (0.015��0.300) ml.
7. the preparation method of isoliquiritigenin Pyrazinamide eutectic according to claim 6, it is characterised in that described organic solvent is methanol or ethanol.
8. the method for isoliquiritigenin Pyrazinamide eutectic as claimed in claim 5, it is characterised in that described solvent suspendible method comprises the following steps:
Take the crude drug isoliquiritigenin that mol ratio is 1:2��2:1 to mix with Pyrazinamide, add organic solvent, after being stirred at room temperature 2��4 days, the suspension of gained is filtered, filter cake vacuum drying, obtaining isoliquiritigenin pharmaceutical co-crystals, isoliquiritigenin and Pyrazinamide gross mass with organic solvent solid-to-liquid ratio is (50��120) mg/ml.
9. the preparation method of isoliquiritigenin Pyrazinamide eutectic according to claim 8, it is characterised in that described organic solvent is methanol, ethanol or isopropanol.
10. the preparation method of isoliquiritigenin Pyrazinamide eutectic according to claim 9, it is characterised in that described organic solvent is isopropanol.
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| CN107056607A (en) * | 2016-12-01 | 2017-08-18 | 北京理工大学 | Gemfibrozil Capsules eutectic and preparation method thereof |
| CN107629010A (en) * | 2017-11-17 | 2018-01-26 | 中国海洋大学 | A kind of eutectic of pyrazinamide and Quercetin and preparation method thereof |
| 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 |
| CN114409560A (en) * | 2022-01-26 | 2022-04-29 | 东南大学 | Actalli pharmaceutical co-crystal and preparation method thereof |
| CN115724775A (en) * | 2022-11-22 | 2023-03-03 | 天津大学 | Belinostat pharmaceutical co-crystal as well as preparation method and application thereof |
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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 |
| CN114409560A (en) * | 2022-01-26 | 2022-04-29 | 东南大学 | Actalli pharmaceutical co-crystal and preparation method thereof |
| CN114409560B (en) * | 2022-01-26 | 2024-05-10 | 东南大学 | Axoliti pharmaceutical co-crystal and preparation method thereof |
| CN115724775A (en) * | 2022-11-22 | 2023-03-03 | 天津大学 | Belinostat pharmaceutical co-crystal as well as preparation method and application thereof |
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Application publication date: 20160601 |