CN108752333B - Tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal and preparation method thereof - Google Patents
Tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal and preparation method thereof Download PDFInfo
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- CN108752333B CN108752333B CN201810577344.7A CN201810577344A CN108752333B CN 108752333 B CN108752333 B CN 108752333B CN 201810577344 A CN201810577344 A CN 201810577344A CN 108752333 B CN108752333 B CN 108752333B
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- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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Abstract
The invention relates to the technical field of pharmaceutical co-crystals, in particular to tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystals and a preparation method thereof. Dissolving tetrahydropalmatine and sulfosalicylic acid in a solution formed by mixing one, two or more than two solvents of isopropanol, ethanol, methanol and ethyl acetate according to a certain molar ratio, placing a glass container containing the mixed solution on a stirrer, stirring at room temperature for 1-5 hours, after full reaction, placing the mixed solution at room temperature for volatilization, and generating colorless blocky crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal. The molecular formula of the prepared tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal is C21H26O4N·C7H5O6S, the single crystal belongs to a triclinic system, and the space group is P1Axial length of
The shaft angle α is 74.399(10) °, β is 79.514(9) °, γ is 87.075(9) °,
Z＝1。
Description
Technical Field
The invention relates to the technical field of pharmaceutical co-crystals, in particular to tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystals and a preparation method thereof.
Background
Tetrahydropalmatine (THP), C21H25O4N, the chemical structural formula is as follows:
tetrahydropalmatine (THP) is protoberberine alkaloid, is derived from dried tuber of corydalis of Papaveraceae, has effects of tranquilizing, calming, relieving pain and central muscle relaxation, and is mainly used for treating dull pain, dysmenorrhea and childbirth pain caused by internal diseases. Researches show that the clinical pharmacological and pharmacodynamic effects of tetrahydropalmatine can be enhanced by improving the solubility of the tetrahydropalmatine in water, so that the current research on the tetrahydropalmatine mainly focuses on improving the solubility of the tetrahydropalmatine by modifying the structure of the original pharmaceutically active molecules, but the structure of the original pharmaceutically active molecules is changed into new compounds, and the toxic and side effects of the compounds are also changed unexpectedly. Therefore, it is a challenging problem how to effectively improve the solubility of the original pharmaceutically active molecule while maintaining the structure of the molecule unchanged.
Disclosure of Invention
The invention aims to provide a tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal and a preparation method thereof, and the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal is used for improving the solubility, the moisture absorption stability and the antibacterial capability on escherichia coli.
The raw material medicine tetrahydropalmatine selected by the invention has the chemical name of 2,3,9, 10-tetramethoxy-5, 8,13,13 a-tetrahydro-6H-dibenzo [ a, g]Quinolizine, known by the name Tetrahydropalmatine, has the molecular formula C21H25O4N, the molecular mass is 355.42, and the molecular structure is shown as a; sulfosalicylic acid has a molecular formula of C7H6O6S, the molecular mass is 218.18, and the molecular structure is shown as b.
The tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal disclosed by the invention has the following characteristics:
single crystal X-ray diffraction
Agilent 171CCD diffractometer, Mo-KαTarget
The crystal structure of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal prepared by the invention is simple and summarized as follows: the protonated tetrahydropalmatine cations and sulfosalicylic acid anions constitute asymmetric units of a eutectic single crystal structure. The monocrystals of tetrahydropalmatine pharmaceutical co-crystal are triclinic system, and the space group is P1Axial length of
The shaft angle α is 74.399(10) °, β is 79.514(9) °, γ is 87.075(9) °,
and Z is 1. The chemical structural formula is as follows:
x-ray powder diffraction (XRD)
X-ray diffractometer model D8Advance, Cu-K, Bruker, GermanyαTarget
The tube pressure is 20kV, the tube flow is 20mA, the step size is 0.02 degrees, and the scanning speed is 6 degrees/min. The results show that: the formed pharmaceutical co-crystal has diffraction peaks at 5.75-6.20 degrees, 6.62-6.93 degrees, 7.58-8.05 degrees, 10.01-10.75 degrees, 11.94-12.72 degrees, 17.14-17.78 degrees and 23.34-23.80 degrees.
Infrared spectroscopy
Alpha Centaurt FT/IR infrared spectrometer with wave number range of 400 and 4000cm, Mattson-1The sample adopts KBr solid tablet with the resolution of 1cm-1. The main characteristic peaks of the infrared spectrum of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal are as follows: 510, 962, 1088, 1151, 1352, 1435, 1614 and 3295cm-1。
A preparation method of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal comprises the steps of putting tetrahydropalmatine and sulfosalicylic acid in a transparent glass container together according to a molar ratio of 5:1-1:5, dissolving the tetrahydropalmatine and the sulfosalicylic acid together in 10mL of solution formed by mixing one or two or more than two solvents of isopropanol, ethanol, methanol and ethyl acetate (the mass concentration of the tetrahydropalmatine in the mixed solution is 2mg/mL-15mg/mL), putting the glass container containing the mixed solution on a stirrer, stirring at room temperature for 1-5 hours, after full reaction, slowly volatilizing at room temperature, and generating colorless blocky crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
Has the advantages that:
the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal prepared by the invention effectively improves the solubility of tetrahydropalmatine in water on the premise of keeping the structure of tetrahydropalmatine molecules unchanged, and is beneficial to absorption in vivo; the moisture absorption stability of tetrahydropalmatine is improved, so that the phenomena of deterioration, mildewing and the like of the medicine caused by moisture absorption are favorably avoided; and the bacteriostatic ability of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal on escherichia coli is obviously improved compared with that of tetrahydropalmatine, which is beneficial to improving the clinical medicinal value of the tetrahydropalmatine.
The tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal is prepared by a pharmaceutical co-crystal technology, so that the solubility of tetrahydropalmatine in water is effectively improved and the moisture absorption stability of tetrahydropalmatine is improved on the premise of keeping the original molecular structure of tetrahydropalmatine unchanged. In addition, the bacteriostatic ability of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal on escherichia coli is obviously enhanced compared with that of tetrahydropalmatine.
Drawings
Figure 1 is an asymmetric unit diagram of a tetrahydropalmatine-sulfosalicylic acid drug eutectic single crystal structure.
Figure 2 is a graph of hydrogen bonding of tetrahydropalmatine-sulfosalicylic acid drug co-crystals.
Figure 3 is an XRD spectrum of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
Figure 4 is an infrared spectrum of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
Figure 5 is a dissolution rate profile of tetrahydropalmatine-sulfosalicylic acid drug co-crystals.
Figure 6 is a moisture absorption stability curve for tetrahydropalmatine-sulfosalicylic acid drug co-crystals.
FIG. 7 shows the results of the bacteriostatic experiments of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal on Escherichia coli.
Detailed Description
The invention is further described below with reference to specific examples. These examples are illustrative only and do not limit the scope of the present invention in any way.
Example 1
The tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal uses tetrahydropalmatine as a pharmaceutical active ingredient, uses sulfosalicylic acid as a co-crystal ligand, and uses protonated tetrahydropalmatine cations and sulfosalicylic acid anions to jointly form an asymmetric unit of a pharmaceutical co-crystal single-crystal structure, and the analysis of the single-crystal X-ray diffraction structure shows that: the monocrystals of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal are triclinic system, and the space group is P1Axial length of
The shaft angle α is 74.399(10) °, β is 79.514(9) °, γ is 87.075(9) °,
and Z is 1. The chemical structural formula is as follows:
a tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal, wherein the characteristic peaks of an XRD spectrum of the pharmaceutical co-crystal appear as follows: 5.75-6.20 degrees, 6.62-6.93 degrees, 7.58-8.05 degrees, 10.01-10.75 degrees, 11.94-12.72 degrees, 17.14-17.78 degrees, 23.34-23.80 degrees.
Tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal having infrared absorption spectra measured with KBr pellet at 510, 962, 1088, 1151, 1352, 1435, 1614 and 3295cm-1Has characteristic absorption peaks.
A tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal is prepared by using tetrahydropalmatine and sulfosalicylic acid in an asymmetric unit of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal single crystal structure in a stoichiometric ratio of 1: 1.
A method for preparing tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal comprises the steps of putting tetrahydropalmatine and sulfosalicylic acid in a transparent glass container together according to a molar ratio of 5:1-1:5, dissolving the tetrahydropalmatine and the sulfosalicylic acid together in 10mL of solution formed by mixing one or two or more than two solvents of isopropanol, ethanol, methanol and ethyl acetate (the mass concentration of the tetrahydropalmatine in the mixed solution is 2mg/mL-15mg/mL), putting the glass container containing the mixed solution on a stirrer, stirring at room temperature for 1-5 hours, after full reaction, slowly volatilizing at room temperature, and generating colorless blocky crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
A preparation method of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal comprises the steps of putting 0.07mmol of tetrahydropalmatine and 0.21mmol of sulfosalicylic acid in a glass container together according to a molar ratio of 1:3, dissolving the tetrahydropalmatine and the sulfosalicylic acid together in a mixed solution of methanol (5mL) and ethyl acetate (5mL), putting the glass container containing the mixed solution on a stirrer, stirring for 3 hours at room temperature, slowly volatilizing at room temperature after full reaction, and generating colorless blocky crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
Example 2
A preparation method of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal comprises the steps of putting 0.07mmol of tetrahydropalmatine and 0.35mmol of sulfosalicylic acid in a glass container together according to a molar ratio of 1:5, dissolving the tetrahydropalmatine and the sulfosalicylic acid together in a mixed solution of ethanol (5mL) and ethyl acetate (5mL), putting the glass container containing the mixed solution on a stirrer, stirring for 3 hours at room temperature, slowly volatilizing at room temperature after full reaction, and generating colorless blocky crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
Example 3
A preparation method of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal comprises the steps of putting 0.07mmol of tetrahydropalmatine and 0.14mmol of sulfosalicylic acid in a glass container together according to a molar ratio of 1:2, dissolving the tetrahydropalmatine and the sulfosalicylic acid together in a mixed solution of ethyl acetate (5mL) and isopropanol (5mL), putting the glass container containing the mixed solution on a stirrer, stirring for 2 hours at room temperature, slowly volatilizing at room temperature after full reaction, and generating colorless blocky crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
Example 4
A preparation method of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal comprises the steps of putting 0.07mmol of tetrahydropalmatine and 0.07mmol of sulfosalicylic acid in a glass container together according to a molar ratio of 1:1, dissolving the tetrahydropalmatine and the sulfosalicylic acid together in a mixed solution of ethyl acetate (9mL) and methanol (1mL), putting the glass container containing the mixed solution on a stirrer, stirring for 5 hours at room temperature, slowly volatilizing at room temperature after full reaction, and generating colorless blocky crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
Example 5
A preparation method of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal comprises the steps of putting 0.07mmol of tetrahydropalmatine and 0.28mmol of sulfosalicylic acid in a glass container together according to a molar ratio of 1:4, dissolving the tetrahydropalmatine and the sulfosalicylic acid together in a mixed solution of ethyl acetate (6mL) and ethanol (4mL), putting the glass container containing the mixed solution on a stirrer, stirring for 5 hours at room temperature, slowly volatilizing at room temperature after full reaction, and generating colorless blocky crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
Example 6
A preparation method of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal comprises the steps of putting 0.07mmol of tetrahydropalmatine and 0.28mmol of sulfosalicylic acid in a glass container together according to a molar ratio of 1:4, dissolving the tetrahydropalmatine and the sulfosalicylic acid together in a mixed solution of methanol (7mL) and isopropanol (3mL), putting the glass container containing the mixed solution on a stirrer, stirring for 4 hours at room temperature, slowly volatilizing at room temperature after full reaction, and generating colorless blocky crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
Example 7
A preparation method of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal comprises the steps of putting 0.08mmol of tetrahydropalmatine and 0.04mmol of sulfosalicylic acid in a glass container together according to a molar ratio of 2:1, dissolving the tetrahydropalmatine and the sulfosalicylic acid together in a mixed solution of methanol (6mL) and isopropanol (4mL), putting the glass container containing the mixed solution on a stirrer, stirring for 2 hours at room temperature, slowly volatilizing at room temperature after full reaction, and generating colorless blocky crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
The tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal obtained by the method of the embodiment takes tetrahydropalmatine as a pharmaceutical active ingredient, sulfosalicylic acid as a co-crystal ligand, and the crystal characteristics are shown in figures 1-4:
as shown in fig. 1, the tetrahydropalmatine-sulfosalicylic acid drug cocrystal has an asymmetric unit comprising protonated tetrahydropalmatine cation and sulfosalicylic acid anion in a single crystal structure. The pharmaceutical co-crystal is triclinic, and the space group is P1Axial length of
The shaft angle α is 74.399(10) °, β is 79.514(9) °, γ is 87.075(9) °,
Z＝1。
as shown in fig. 2, the hydrogen bond in the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal is formed by using the N atom of tetrahydropalmatine as a hydrogen bond donor and respectively connecting with the sulfonic acid group in the adjacent sulfosalicylic acid as a hydrogen bond acceptor.
As shown in fig. 3, from the XRD spectrum of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal, diffraction peaks at 5.75-6.20 °, 6.62-6.93 °, 7.58-8.05 °, 10.01-10.75 °, 11.94-12.72 °, 17.14-17.78 °, 23.34-23.80 ° are observed, and these characteristic peaks are consistent with the characteristic peaks of the pharmaceutical co-crystal simulated by Mercury 3.8 software according to the crystal structure data.
As shown in fig. 4, the main characteristic peaks of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal infrared spectrum are as follows: 510, 962, 1088, 1151, 1352, 1435, 1614 and 3295cm-1。
The dissolution rate profile of tetrahydropalmatine-sulfosalicylic acid drug co-crystal in water is shown in fig. 5. As can be seen from the figure: the tetrahydropalmatine is almost insoluble in water, and the solubility of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal in water can reach 1.2mg/mL, so that the solubility of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal in water is remarkably improved compared with that of the tetrahydropalmatine, the absorption of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal in a body is facilitated, and the dosage of the pharmaceutical is saved.
The moisture absorption stability curve of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal is shown in fig. 6. As can be seen from the figure: the moisture absorption stability of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal provided by the invention is improved relative to that of tetrahydropalmatine, so that the phenomena of dilution, deliquescence, deterioration, mildewing and the like of a medicine caused by dampness introduction of the medicine can be favorably avoided.
The results of the bacteriostatic experiment of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal on escherichia coli are shown in fig. 7. As can be seen from the figure: the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal provided by the invention has obviously improved bacteriostatic ability on escherichia coli compared with tetrahydropalmatine, and is beneficial to improving the clinical medicinal value of tetrahydropalmatine.
Claims (5)
1. The tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal is characterized in that: the tetrahydropalmatine is used as a pharmaceutical active ingredient, the sulfosalicylic acid is used as a eutectic ligand, the protonated tetrahydropalmatine cation and the sulfosalicylic acid anion jointly form an asymmetric unit of a pharmaceutical eutectic single crystal structure, and the analysis of the single crystal X-ray diffraction structure shows that: the monocrystals of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal are triclinic system, and the space group is P1Axial length ofa = 8.5204(8) Å，b = 13.5001(15) Å，c= 15.3733(19) A, axial angleα= 74.399(10) °，β= 79.514(9) °，γ= 87.075(9) °，V = 1674.7(3) Å3，Z= 1, its chemical structural formula is as follows:
2. the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal of claim 1, wherein the characteristic peaks of the XRD spectrum of the pharmaceutical co-crystal appear as follows: 5.75-6.20 degrees, 6.62-6.93 degrees, 7.58-8.05 degrees, 10.01-10.75 degrees, 11.94-12.72 degrees, 17.14-17.78 degrees, 23.34-23.80 degrees.
3. The tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal of claim 1 wherein the infrared absorption spectrum of the pharmaceutical co-crystal is 510, 962, 1088, 1151, 1352, 1435, 1614 and 3295cm measured using KBr tablets-1Has characteristic absorption peaks.
4. A tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal according to any one of claims 1 to 3 wherein the stoichiometric ratio of tetrahydropalmatine to sulfosalicylic acid in the asymmetric unit of the single crystal structure of the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal is 1: 1.
5. The preparation method of tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal according to any one of claims 1 to 3, characterized in that the preparation method comprises putting tetrahydropalmatine and sulfosalicylic acid together in a transparent glass container according to a molar ratio of 5:1-1:5, dissolving in 10mL of a mixed solution of one, two or more of isopropanol, ethanol, methanol and ethyl acetate, putting the glass container with the mixed solution on a stirrer, stirring at room temperature for 1-5 hours, after full reaction, slowly volatilizing at room temperature, and generating colorless bulk crystals after 1-30 days, namely the tetrahydropalmatine-sulfosalicylic acid pharmaceutical co-crystal.
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| CN107586293A (en) * | 2016-07-06 | 2018-01-16 | 胡梨芳 | Sulfur-bearing dibenzothiazine alkaloid compound and application thereof |
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| CN107586293A (en) * | 2016-07-06 | 2018-01-16 | 胡梨芳 | Sulfur-bearing dibenzothiazine alkaloid compound and application thereof |
| CN106810547A (en) * | 2016-12-28 | 2017-06-09 | 佳木斯大学 | Phosphoric acid N-1 pharmaceutical co-crystals and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| Cocrystallization of N-donor type compounds with 5-sulfosalicylic acid: The effect of hydrogen-bonding supramolecular architectures;Wang, Lei等;《Science China: Chemistry》;20111012;第55卷(第1期);第138-144页，尤其是第139页2.2节，第140页第3节结论和讨论部分 * |
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