CN104592009B - Naproxen pharmaceutical co-crystal and preparation method thereof - Google Patents

Abstract

Naproxen drug co-crystal and preparation method thereof, the invention relates to the field of drug co-crystal, which aims to solve the problem of the low solubility of naproxen drug in aqueous solution. The structural formula of the naproxen drug co-crystal is [2(C ₁₄ H ₁₄ O ₃ )·C ₄ H ₅ N ₃ ], two naproxen molecules and one 2-aminopyrazine molecule are bonded together to form The basic structural unit, the naproxen pharmaceutical co-crystal is a monoclinic crystal system. Using naproxen and 2-aminopyrazine as raw materials, the naproxen drug co-crystal is prepared by liquid-phase assisted grinding method and solvent evaporation method respectively. The naproxen drug co-crystal of the present invention has a relatively large solubility in aqueous solution, reaching 0.308g/L. Since there is no crystallized solvent molecule in the co-crystal structure, it can still maintain its solubility for one year at room temperature. The skeletal structure of the crystal is chemically stable.

Description

Naproxen pharmaceutical co-crystal and preparation method thereof

technical field

The invention relates to the field of drug co-crystals, in particular to naproxen drug co-crystals and a preparation method thereof.

Background technique

In recent years, the preparation of drug co-crystals using supramolecular chemistry and crystal engineering has become a research hotspot in the fields of chemistry and medicine. Drug co-crystals are favored due to their unique physical and chemical properties. Pharmaceutical co-crystals refer to co-crystal formers (CCFs) between active pharmaceutical ingredients (API) and other physiologically acceptable acids, bases or non-ionic compounds, through hydrogen bonds, van der Waals forces, etc. , π-π stacking, halogen bonds and other non-covalent bonding forces, in which the pure state of API and CCFs are solid at room temperature. The drug co-crystal formed by the active drug molecule and the appropriate compound has many advantages: (1) Due to the introduction of CCFs, the three-dimensional packing structure of the drug active molecule itself is changed, thereby changing its solubility and dissolution rate, and finally improving the drug in vivo. (2) Since the main driving forces in the formation of drug co-crystals are non-covalent interactions such as hydrogen bonds and van der Waals forces, which do not change the covalent structure of the drug compound itself, it retains the drug to the greatest extent. (3) According to research findings, the melting point of drug co-crystals is often between the melting points of pharmaceutical active components and co-crystal formers, therefore, it can be appropriately improved by selecting co-crystal formers with higher melting points. Drug stability; (4) For some chiral drug molecules, the enantiomers have large differences in physiological activity, and the separation of enantiomers can be achieved by selecting appropriate co-crystal formers , which greatly simplifies the production and preparation process of chiral drugs. Based on the above characteristics, the synthesis and properties of drug co-crystals show attractive application prospects in the fields of pharmacology and biomedicine. Naproxen, as a class of antipyretic and analgesic non-steroidal anti-inflammatory drugs, has been used in the synthesis of drug co-crystal compounds.

Contents of the invention

The purpose of the present invention is to solve the problem of low solubility of naproxen drug in aqueous solution, and provide a novel naproxen drug co-crystal and a preparation method thereof.

The structural formula of the naproxen pharmaceutical co-crystal of the present invention is [2(C ₁₄ H ₁₄ O ₃ )·C ₄ H ₅ N ₃ ], two naproxen molecules and one 2-aminopyrazine molecule are bound together by hydrogen bonds Forming the basic structural unit, the naproxen drug co-crystal is a monoclinic system, the space group is P2 ₁ , and the unit cell parameters are: axial length β=91.65(3)°, Its XRD characteristic diffraction peaks appear at 9.64°, 11.84°, 15.28°, 16.68°, 18.00°, 19.02°, 20.04°, 22.33°, 23.30°, 24.74°, 26.35°.

The preparation method of naproxen drug co-crystal of the present invention is realized by the following steps:

The raw material naproxen and 2-aminopyrazine are placed in an agate mortar with a molar ratio of 2:1, acetonitrile is added to the agate mortar, and then ground, and acetonitrile is continuously added during the grinding process, and the ground After 30-60 minutes, the drug co-crystal of naproxen was obtained.

The preparation method of naproxen drug co-crystal of the present invention is realized by the following steps:

The crude drug naproxen and 2-aminopyrazine were ground in an agate mortar with a molar ratio of 2:1, ethanol and acetonitrile were added to the ground mixed powder, stirred at room temperature for 30-40 min, and then filtered. After the filtrate is placed for 8-12 days, the solid phase is collected to obtain the drug co-crystal of naproxen.

The present invention relates to the preparation method of novel naproxen medicine co-crystal, select raw material drug naproxen as active drug component API, the molecular structural formula of naproxen is: 2-aminopyrazine is a drug precursor, and the molecular structural formula of 2-aminopyrazine is High-quality single crystals were prepared by liquid phase assisted grinding method and solvent evaporation method, and related characterizations such as single crystal structure analysis, infrared, melting point, DSC, fluorescence, powder XRD and solubility in aqueous solution were carried out. The results showed that the structural formula of the naproxen pharmaceutical co-crystal compound was [2(C ₁₄ H ₁₄ O ₃ )·C ₄ H ₅ N ₃ ], and the naproxen-2-aminopyrazine powders prepared by the two methods had Very high purity and crystallinity, and this eutectic compound has bigger solubility in aqueous solution, reaches 0.308g/L, far exceeds the solubility (0.0159g) of the pure state naproxen drug that The Human Metabolome Database provides in water /L).

The invention adopts a liquid-phase assisted grinding method and a solvent volatilization method to prepare drug eutectics of naproxen and 2-aminopyrazine. The synthetic method used for the eutectic compound has simple preparation process, high yield and high purity, is suitable for large-scale assembly line operation, and has low cost.

Description of drawings

Fig. 1 is the molecular structure figure of naproxen medicine co-crystal of the present invention, wherein A and B represent naproxen molecule;

Fig. 2 is the XRD spectrogram of the naproxen drug cocrystal that naproxen, 2-aminopyrazine and embodiment one obtain, wherein 1-naproxen drug cocrystal, 2-naproxen, 3-2-amino pyrazine;

Fig. 3 is the XRD spectrogram of the naproxen drug cocrystal that simulation and embodiment one obtain, wherein 1—naproxen drug cocrystal, 2—software simulation;

Fig. 4 is the infrared spectrogram of the naproxen pharmaceutical co-crystal compound that embodiment obtains;

Fig. 5 is the DSC curve of the naproxen pharmaceutical co-crystal compound that embodiment obtains;

Fig. 6 is the solid-state fluorescence curve of naproxen, 2-aminopyrazine and naproxen drug cocrystal, wherein 1-naproxen;

Fig. 7 is the enlarged view of place A in Fig. 6, wherein 2-2-aminopyrazine, 3-naproxen drug eutectic;

Fig. 8 is the standard curve of solubility experiment;

Fig. 9 is the solubility curve of naproxen pharmaceutical co-crystal compound.

detailed description

Specific embodiment 1: The structural formula of the naproxen drug co-crystal in this embodiment is [2(C ₁₄ H ₁₄ O ₃ )·C ₄ H ₅ N ₃ ], two naproxen molecules and one 2-aminopyrazine molecule The basic structural unit is formed by hydrogen bonding. The naproxen drug co-crystal is monoclinic, the space group is P2 ₁ , and the unit cell parameters are: axial length β=91.65(3)°, Its XRD characteristic diffraction peaks appear at 9.64°, 11.84°, 15.28°, 16.68°, 18.00°, 19.02°, 20.04°, 22.33°, 23.30°, 24.74°, 26.35°.

The naproxen drug co-crystal described in this embodiment is formed by combining two naproxen molecules and one 2-aminopyrazine molecule through an intermolecular O/NH...N/O hydrogen bond to form a naproxen drug co-crystal Crystallographic asymmetric unit, in which, naproxen molecule A is connected with amino hydrogen (-N1H2) in 2-aminopyrazine and pyrazine ring N2 atoms to form a hydrogen bonded ring, while naproxen molecule B is connected with pyrazine ring The remaining N3 atoms on the top form a single hydrogen bond, as shown in Figure 1. The carboxyl bond lengths in the two naproxen molecules are 1.297(4), and 1.326(4), It shows that the carboxyl groups in both naproxen molecules are not dehydrogenated. In addition, the remaining hydrogen atoms in the amino group form hydrogen bonds with the carbonyl group of naproxen molecule B in the next repeating unit, thereby forming a one-dimensional hydrogen bond chain along the a-axis direction.

Specific embodiment two: the preparation method of naproxen drug co-crystal of this embodiment is implemented according to the following steps:

The raw material naproxen and 2-aminopyrazine are placed in an agate mortar with a molar ratio of 2:1, acetonitrile is added to the agate mortar, and then ground, and acetonitrile is continuously added during the grinding process, and the ground After 30-60 minutes, the drug co-crystal of naproxen was obtained.

Embodiment 3: This embodiment is different from Embodiment 2 in that acetonitrile is continuously added during the grinding process, and the grinding lasts for 40-50 minutes. Other steps and parameters are the same as in the second embodiment.

Specific embodiment four: the preparation method of naproxen drug co-crystal of the present embodiment is implemented according to the following steps:

The crude drug naproxen and 2-aminopyrazine were ground in an agate mortar with a molar ratio of 2:1, ethanol and acetonitrile were added to the ground mixed powder, stirred at room temperature for 30-40 min, and then filtered. After the filtrate is placed for 8-12 days, the solid phase is collected to obtain the drug co-crystal of naproxen.

This embodiment and specific embodiment 2 prepare a drug co-crystal of naproxen with good chemical stability, high purity, and high yield, and through the introduction of CCF, while effectively reducing the melting point of naproxen, it improves its water solubility. It provides preliminary theoretical and experimental basis for the application of such drug co-crystals.

Embodiment 5: This embodiment is different from Embodiment 4 in that the volume ratio of ethanol to acetonitrile is 1:1. Other steps and parameters are the same as those in Embodiment 4.

Embodiment 6: This embodiment differs from Embodiment 4 or Embodiment 5 in that the solid-to-liquid ratio of the mixed powder to ethanol and acetonitrile is (0.550-0.555) g: (8-10) mL. Other steps and parameters are the same as those in Embodiment 4 or 5.

Embodiment 7: This embodiment is different from Embodiment 4 to Embodiment 6 in that the solid phase is collected after the filtrate is placed at room temperature for 10 days. Other steps and parameters are the same as one of the fourth to sixth specific embodiments.

Embodiment one: the preparation method of the present embodiment naproxen drug co-crystal is implemented according to the following steps:

Put 0.460g of naproxen and 0.095g of 2-aminopyrazine in the agate mortar with a molar ratio of 2:1, add 3 to 5 drops of acetonitrile in the agate mortar, then grind, and grind During the process, 1 mL of acetonitrile was continuously added, and the mixture was ground for 40 min to obtain the naproxen drug co-crystal.

In this example, a drug co-crystal of naproxen was prepared by a liquid phase assisted grinding method, and the co-crystal compound [2(C ₁₄ H ₁₄ O ₃ )·C ₄ H ₅ N ₃ ] had good chemical stability. Since there are no crystallized solvent molecules in the co-crystal structure of the drug, it can still maintain its crystal skeleton structure without any deterioration after being placed at room temperature for one year.

Embodiment two: the preparation method of the present embodiment naproxen drug co-crystal is implemented according to the following steps:

Put the naproxen of 0.460g of the crude drug and the 2-aminopyrazine of 0.095g in an agate mortar and grind it at a molar ratio of 2:1, and then add 5mL of ethanol and 5mL of acetonitrile to the ground mixed powder , stirred at room temperature for 30 minutes and then filtered, and the filtrate was left to stand for 10 days to collect the solid phase to obtain the naproxen drug co-crystal.

The drug co-crystal of naproxen prepared by the solvent evaporation method in this example is a colorless massive crystal, its chemical formula is C ₃₂ H ₃₃ N ₃ O ₆ , and the yield is 90% (calculated by element N).

Purity Determination of Naproxen Drug Cocrystal Compound:

A powder XRD diffraction experiment was carried out on the powder sample obtained by the liquid-phase assisted grinding method in Example 1. The powder X-ray diffraction data were measured on a D8 X-ray diffractometer of BRUKER Company in Germany. Test conditions: Cu-Kα target The tube voltage is 40kV, the tube current is 10mA, and the scanning speed is 0.2°/min. By comparing the ground sample with the pure state of the two raw materials, it can be seen that the position of the characteristic diffraction peak and the diffraction intensity have undergone significant changes. phase, as shown in Figure 2. At the same time, the single crystal X-ray diffraction experiment was carried out on the single crystal obtained by the solvent evaporation method. The single crystal structure was determined on the Xcalibur Eos diffractometer of Agilent Corporation in the United States, at a temperature of 293K, using MoK _α -rays monochromated by a graphite monochromator The scan mode is ω scan. The current and voltage required for the diffraction experiment are set to 40mA and 50kV.

In order to further determine the phase and purity of the sample after grinding, this example uses the crystal data obtained from the single crystal diffraction experiment to simulate the theoretical powder XRD spectrum of the above-mentioned naproxen drug co-crystal through Mercury software, and finds that its characteristic diffraction peaks appear at 9.64, 11.84, 15.28, 16.68, 18.00, 19.02, 20.04, 22.33, 23.30, 24.74, 26.35°, which are basically consistent with the sample peaks after grinding, indicating that the naproxen drug co-crystal prepared by the grinding method has a high Purity (Figure 3).

Infrared Characterization of Naproxen Pharmaceutical Co-crystal Compound:

Infrared spectroscopy was performed on an Equinox 55 Fourier transform infrared spectrometer from BRUKER, Germany. The scanning band is 4000～400cm ^-1 , the sample is pressed by KBr solid, and the resolution is 1cm ^-1 . Its infrared spectrum presents a series of characteristic absorption peaks of amino, carbonyl, hydroxyl and aromatic rings (Figure 4). The absorption peaks at 3420cm ^-1 and 3210cm ^-1 of the infrared spectrum of the eutectic compound can be regarded as the vibration absorption peaks of carboxyl OH, amino NH and hydrogen bonds, and the strong and sharp peak at 1697cm ^-1 is the vibration absorption of C=O The peaks at 1633 and 1420cm ^-1 are the vibration absorption peaks of the aromatic skeleton. A series of absorption peaks in the range of 1275-1020cm ^-1 are stretching vibration peaks of CO single bond in naproxen molecule.

Differential Scanning Calorimetry (DSC) Test of Naproxen Drug Cocrystal Compound:

The DSC curve of the eutectic compound was measured on a DSC4000 differential scanning calorimeter from PE Company in the United States. The test atmosphere is nitrogen, the gas flow rate is 20.0cm ³ /min, the heating rate is 10.00°C/min, and the test temperature range is 30-300°C. In the temperature range of 30-300°C, the DSC curve only appears a sharp exothermic peak in the range of 96-109°C (Figure 5), corresponding to the thermal decomposition process of the compound.

Melting point determination of naproxen pharmaceutical co-crystal compound:

The melting point test of the eutectic compound was completed on the X-5 micro melting point tester of Gongyi Yuhua Instrument Company. The test results show that the melting point of the eutectic compound is 97.4-99.7° C., and the melting range is 2.3° C., indicating that the drug eutectic prepared by the grinding method has high purity.

Fluorescence performance test of naproxen pharmaceutical co-crystal compound:

The fluorescence spectra of the raw materials and co-crystal compounds were analyzed using a LS-55 fluorescence spectrometer from Perkin Elmer, USA. The test uses a solid sample holder, resolution: 0.5nm, slit width: incident 15nm, outgoing 2.5nm, scanning speed: 700nm/min. As shown in Figures 6 and 7, the co-crystal compound exhibited lower blue-violet fluorescence emission compared to naproxen and 2-aminopyrazine. The fluorescence emission peak of 2-aminopyrazine is located at 428nm. The fluorescence emission peak of naproxen is located at 355nm, while that of the eutectic compound is located at 382nm, and the fluorescence intensity is significantly lower than that of the raw materials.

Solubility Determination of Naproxen Drug Cocrystal Compound:

The solubility of the eutectic compound was determined by the standard curve method, and the absorbance value of each sample was measured by a UV-2550 ultraviolet-visible spectrophotometer from Shimadzu Corporation of Japan.

(1) Selection of the best absorption wavelength

Saturated aqueous solutions of 2-aminopyrazine and naproxen were prepared respectively, and ultraviolet absorption spectrum scanning was carried out in the wavelength range of 200-800nm. The results show that 2-aminopyrazine has a strong absorption peak at 228nm, and naproxen has no obvious absorption at this wavelength, and there is no interference between them. Therefore, this wavelength is selected for the solubility determination experiment of drug cocrystals.

(2) Drawing of quasi-curve

Accurately weigh 0.0478g of 2-aminopyrazine in a 50mL volumetric flask, add water to prepare a 10.00mmol/L stock solution, take 10.00mL of the stock solution in a 100mL volumetric flask and dilute it into a 1mmol/L use solution, respectively Pipette 0.50, 1.00, 2.00, 3.00, 4.00mL of the use solution and dilute it into standard solutions with different concentration gradients, measure the absorbance values respectively, and then obtain the standard curve equation as y=11.43377x+0.00176, R ² =0.99994 , the standard curve is shown in Figure 8.

(3) Solubility determination of eutectic compounds

Take 0.16g of the eutectic compound and add it into 500mL of deionized water, and stir on a magnetic stirrer. When the sample is stirred to 0, 60, 120, 180, 240, 260, 280, 300 and 320min, draw 20mL solution with a syringe respectively, filter through a microporous membrane (0.45μm), pipette 10.00mL filtrate into 100mL capacity bottle, then add water to dilute to the mark, after mixing evenly, measure its absorbance value (A) at 228nm, the equilibration time of the eutectic compound is corresponding to when the absorbance (A) value measured by adjacent samples begins to differ less than ±0.004 The time, the solubility curve is shown in Figure 9. The results showed that the naproxen co-crystal compound reached the dissolution equilibrium in 240min, and its solubility was about 0.555mmol/L (about 0.308g/L).

Claims (7)

1. Naproxen drug co-crystal, the structural formula of the naproxen drug co-crystal is [2(C ₁₄ H ₁₄ O ₃ )·C ₄ H ₅ N ₃ ], two naproxen molecules and one 2-aminopyridine The oxazine molecules are bonded together by hydrogen bonds to form basic structural units. The naproxen drug co-crystal is a monoclinic crystal system, the space group is P2 ₁ , and the unit cell parameters are: axial length β=91.65(3)°, Its XRD characteristic diffraction peaks appear at 9.64°, 11.84°, 15.28°, 16.68°, 18.00°, 19.02°, 20.04°, 22.33°, 23.30°, 24.74°, 26.35°. 2. the preparation method of naproxen drug co-crystal as claimed in claim 1 is characterized in that the preparation method of naproxen drug co-crystal is realized by the following steps: The raw material naproxen and 2-aminopyrazine are placed in an agate mortar with a molar ratio of 2:1, acetonitrile is added to the agate mortar, and then ground, and acetonitrile is continuously added during the grinding process, and the ground After 30-60 minutes, the drug co-crystal of naproxen was obtained. 3. the preparation method of naproxen drug co-crystal according to claim 2 is characterized in that acetonitrile is added continuously again in the process of grinding, grinding 40～50min. 4. the preparation method of naproxen drug co-crystal as claimed in claim 1 is characterized in that the preparation method of naproxen drug co-crystal is realized by the following steps: The crude drug naproxen and 2-aminopyrazine were ground in an agate mortar with a molar ratio of 2:1, ethanol and acetonitrile were added to the ground mixed powder, stirred at room temperature for 30-40 min, and then filtered. After the filtrate is placed for 8-12 days, the solid phase is collected to obtain the drug co-crystal of naproxen. 5. the preparation method of naproxen drug co-crystal according to claim 4, is characterized in that the volume ratio of ethanol and acetonitrile is 1:1. 6. The preparation method of naproxen drug co-crystal according to claim 4, characterized in that the solid-to-liquid ratio of the mixed powder and ethanol and acetonitrile is (0.550～0.555) g: (8～10) mL. 7. the preparation method of naproxen drug co-crystal according to claim 4 is characterized in that at room temperature the filtrate is placed after 10 days and collects solid phase thing.