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Etoricoxib-resorcinol pharmaceutical co-crystal and preparation method thereof

A technology of etoricoxib and resorcinol, which is applied in the field of etoricoxib-resorcinol drug co-crystal and its preparation, can solve the problems of low maximum dissolution concentration, complicated method, high energy consumption, etc., and achieve the improvement of biological Utilization, good product reproducibility, and good application prospects

Pending Publication Date: 2022-01-28
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is operated at low temperature for a long time, which consumes a lot of energy; the methanol solvent is highly toxic and poses a safety hazard to the production operator; the continuous stirring of the solution to become turbid is the process of explosive nucleation, which will directly cause the crystal particle size to be small, coalesce, and explode. Nucleation is a consequence of high supersaturation and can result in the precipitation of etoricoxib Form I rather than the eutectic
In the above etoricoxib-glutaric acid, etoricoxib-adipic acid, etoricoxib-suberic acid, etoricoxib-phthalic acid, etoricoxib-p-toluenesulfonic acid, etoricoxib-furancarboxylic acid In the process of co-crystal preparation, methanol is used as a solvent. Methanol is highly toxic and extremely harmful to the nervous system and blood system, and there are health risks for production operators and patients taking medicine.
In addition, the co-crystal ligands glutaric acid, phthalic acid, p-toluenesulfonic acid, and furancarboxylic acid are not listed as GRAS by the FDA, and are extremely harmful to the body after being inhaled, ingested, or absorbed through the skin. The co-crystal formed by etoricoxib does not belong to the category of drug co-crystal and cannot be used in medicine
[0008] At present, there are problems such as low maximum dissolution concentration, low dissolution rate, small crystal particle size, poor thermal stability, and potential safety hazards of cocrystal ligands in the pharmaceutical crystal form of etoricoxib and its cocrystal, which affect the bioavailability, and there are problems in the preparation method. Problems such as high solvent toxicity, complicated method, high energy consumption, and poor reproducibility

Method used

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  • Etoricoxib-resorcinol pharmaceutical co-crystal and preparation method thereof
  • Etoricoxib-resorcinol pharmaceutical co-crystal and preparation method thereof
  • Etoricoxib-resorcinol pharmaceutical co-crystal and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Adopt cooling crystallization method to prepare etoricoxib-resorcinol drug co-crystal, the specific steps are as follows:

[0058] (1) Add 0.71g of etoricoxib crystal form I and 0.22g of resorcinol to 15.5mL of n-propanol, and heat to 60°C to form a clear solution;

[0059] (2) Cool the solution to 40°C at a rate of 30°C / h and maintain it for 10 minutes;

[0060] (3) Cool down to 0°C at a rate of 10°C / h and maintain for 2 hours;

[0061] (4) Then filter and dry the filter cake at 80°C.

[0062] The mol ratio of etoricoxib and resorcinol in the obtained etoricoxib-resorcinol drug cocrystal is 1:1, and cocrystal X-ray powder diffraction spectrum figure is as attached Figure 4 As shown, the diffraction angle 2θ is 5.68°, 9.42°, 15.56°, 15.88°, 17.14°, 17.74°, 18.26°, 20.06°, 20.40°, 20.94°, 21.32°, 21.58°, 22.56°, 23.16°, 23.48 °, 23.76°, 24.68°, 25.76°, 26.22°, 27.84°, 28.34°, 29.48°, 30.06° have characteristic peaks; its DSC spectrum is as attached Figure 5 As show...

Embodiment 2

[0064] Adopt cooling crystallization method to prepare etoricoxib-resorcinol drug co-crystal, the specific steps are as follows:

[0065] (1) Add 0.71g of the mixture of etoricoxib crystal form I and crystal form III, and 0.22g resorcinol to 10mL ethanol, and heat to 50°C to form a clear solution;

[0066] (2) Cool the solution to 30°C at a rate of 25°C / h and maintain it for 15 minutes;

[0067] (3) Cool down to 5°C at a rate of 8°C / h and maintain for 1.5h;

[0068] (4) Then filter and dry the filter cake at 65°C.

[0069] The mol ratio of etoricoxib and resorcinol in the gained etoricoxib-resorcinol drug cocrystal is 1:1, and the X-ray powder diffraction spectrum figure of cocrystal is as attached Figure 4 As shown, the diffraction angle 2θ is 5.58°, 9.32°, 15.36°, 15.78°, 17.04°, 17.54°, 18.19°, 20.00°, 20.30°, 20.90°, 21.30°, 21.68°, 22.32°, 23.11°, 23.40 °, 23.70 °, 24.88 °, 25.55 °, 26.22 °, 27.74 °, 28.25 °, 29.37 °, 30.01 ° have characteristic peaks; its DSC spectru...

Embodiment 3

[0071] Adopt cooling crystallization method to prepare etoricoxib-resorcinol drug co-crystal, the specific steps are as follows:

[0072] (1) Add 1.80 g of etoricoxib crystalline form I and crystalline form V mixture, 0.58 g resorcinol to 6.0 mL dimethyl carbonate, and heat to 40°C to form a clear solution;

[0073] (2) Cool the solution to 35°C at a rate of 20°C / h and maintain it for 20 minutes;

[0074] (3) Cool down to 10°C at a rate of 5°C / h and maintain for 1h;

[0075] (4) Then filter and dry the filter cake at 50°C.

[0076] The mol ratio of etoricoxib and resorcinol in the gained etoricoxib-resorcinol drug cocrystal is 1:1, and the X-ray powder diffraction spectrum figure of cocrystal is as attached Figure 4 As shown, the diffraction angle 2θ is 5.88°, 9.62°, 15.61°, 15.98°, 1.94°, 17.94°, 18.35°, 20.24°, 20.40°, 20.74°, 21.32°, 21.78°, 22.52°, 23.16°, 23.48 °, 23.76 °, 24.78 °, 25.63 °, 26.29 °, 27.64 °, 28.54 °, 29.53 °, and 30.16 ° have characteristic peaks; its...

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Abstract

The invention relates to an etoricoxib-resorcinol pharmaceutical co-crystal and a preparation method thereof. Etoricoxib, resorcinol and a non-toxic solvent are mixed, and the etoricoxib-resorcinol pharmaceutical co-crystal is prepared through a cooling crystallization method, a volatile solvent crystallization method or a suspension crystallization method. The structural formula of the eutectic crystal is shown in the description, the molar ratio of etoricoxib to resorcinol is 1: 1, a differential scanning calorimetry spectrogram has an endothermic peak at 141.7 + / -2 DEG C, an X-ray photoelectron spectroscopy of pyridine nitrogen has a characteristic peak at 398.60 + / -0.2 eV, and the particle size of the eutectic crystal exceeds 1000 microns; and the etoricoxib-resorcinol pharmaceutical co-crystal can reach the maximum dissolution concentration of 40.88 + / -0.2 mg / mL in 5 minutes (based on etoricoxib). The obtained etoricoxib-resorcinol eutectic crystal is high in thermal stability, large in particle size and remarkable in solubilizing effect, and the bioavailability is remarkably improved. Meanwhile, the preparation operation is simple, the energy consumption is low, the solvent dosage is small, and the product reproducibility is good.

Description

technical field [0001] The invention belongs to the field of pharmaceutical technology crystallization, and in particular relates to an etoricoxib-resorcinol drug co-crystal and a preparation method thereof. Background technique [0002] Etoricoxib (Etoricoxib), chemical name is 2,3'-bipyridine, 5-chloro-6'-methyl-3-[4-(methylsulfonyl)phenyl], molecular formula C 18 h 15 ClN 2 o 2 S has a relative molecular mass of 358.84, and its structural formula is shown in formula (I). Etoricoxib is a selective COX-2 non-steroidal anti-inflammatory drug, which has anti-inflammatory, analgesic and antipyretic effects, and is often used in the treatment of chronic / acute osteoarthritis and acute gouty arthritis. [0003] [0004] Etoricoxib Form V is a medicinal crystal form. Form V has a melting point of 133.9°C and a small particle size of about 10-20 μm. figure 1 shown. Etoricoxib belongs to the BCS class II drug, which has the characteristics of low solubility and high perme...

Claims

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Application Information

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IPC IPC(8): C07D213/61C07C39/08C07C37/84
CPCC07D213/61C07C39/08C07C37/84C07B2200/13
Inventor 鲍颖王源源侯宝红李欣周丽娜
Owner TIANJIN UNIV
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