CN104876866A - Alpha-crystal-form lappaconitine and preparation method thereof - Google Patents

Abstract

The invention discloses α-crystal form kinokine and its preparation method. Using Cu-Kα radiation, its X-ray powder diffraction in 2θ angle is 9.6±0.2°, 10.2±0.2°, 16.5±0.2°, 16.9° There are characteristic peaks at ±0.2°, 19.0±0.2°, and 19.3±0.2°. The α crystal form of the present invention has higher purity and better yield, its purity is more than 99.7%, and the content of single impurity is less than 0.1%. The reaction conditions are suitable for large-scale production.

Description

α-crystal form of uricine and its preparation method

technical field

The invention relates to a stable α-crystal form of uricine and a preparation method thereof, belonging to the technical field of medicine and chemical industry.

Background technique

Lappaconitine, whose chemical name is (1α, 14α, 16β)-20-ethyl-1,14,16-trimethoxyaconitane-4,8,9triol-4-2-( Acetylamino) benzoate, having the formula The chemical structure shown is produced and used in my country as a non-addictive analgesic. Gaowujiasu has a strong analgesic effect, the analgesic effect is equivalent to morphine, and its analgesic effect is 7 times that of the common analgesic drug aminopyrine, which is equivalent to that of pethidine, and the analgesic effect lasts for a longer period of time. Alternatives to tramadol. It has been clinically proven that the local anesthesia effect of homogenin is equivalent to that of cocaine, and the effect is long-lasting; the nerve conduction block effect of homogenin is 5.25 times that of cocaine, 13 times that of procaine, and the infiltration anesthesia effect of homogenin is far greater than that of cocaine. Stronger than procaine and cocaine. At the same time, high-level urine is also highly safe, non-addictive, mutagenic, and carcinogenic, and has no clinical advantages such as accumulation, stimulation, allergic reactions, and toxic effects on the immune system. It has been proved by clinical application that within the specified usage and dosage range, no case of poisoning has occurred in the use of gaurine. It has also been clinically confirmed that gaurine has a significant antipyretic effect on various types of fever, and its antipyretic effect is better than that of aminopyrine, and its cooling effect is equivalent to that of western medicine such as aspirin.

Crystalline forms (polymorphs) refer to the arrangement of molecules in the crystal lattice of crystalline substances. Due to the different crystal forms of the same drug, its physical and chemical properties (solubility, melting point, dissolution rate, bioavailability, etc.) may be significantly different, which directly affects the quality and efficacy of the drug. Therefore, research on drug crystal forms is also a new drug. One of the important contents in the research. At present, there is no relevant report on the research on the crystal form of homogenate and the patent on the crystal form of homogenate.

Contents of the invention

After a lot of experimental research, the inventors have found a stable crystal form α of homogenate, and the present invention is completed based on this discovery.

Implementation process of the present invention:

The present invention provides α-crystalline form of quinine, using Cu-Kα radiation, its X-ray powder diffraction represented by 2θ angle is 9.6±0.2°, 10.2±0.2°, 16.5±0.2°, 16.9±0.2°, 19.0 ±0.2°, there is a characteristic peak at 19.3±0.2°.

Further, the α crystalline form of guanidine, using Cu-Kα radiation, its X-ray powder diffraction in 2θ angles is 9.6±0.2°, 10.2±0.2°, 12.3±0.2°, 13.7±0.2° , There are characteristic peaks at 16.5±0.2°, 16.9±0.2°, 19.0±0.2°, 19.3±0.2°, 25.4±0.2°.

Furthermore, the α crystal form of guanidine, using Cu-Kα radiation, its X-ray powder diffraction in 2θ angles is 5.6±0.2°, 6.0±0.2°, 9.4±0.2°, 9.6±0.2 °, 10.2±0.2°, 11.2±0.2°, 12.0±0.2°, 12.3±0.2°, 13.7±0.2°, 15.2±0.2°, 16.5±0.2°, 16.9±0.2°, 17.4±0.2°, 18.2±0.2 °, 19.0±0.2°, 19.3±0.2°, 19.8±0.2°, 20.5±0.2°, 21.5±0.2°, 22.4±0.2°, 24.1±0.2°, 25.1±0.2°, 25.4±0.2°, 25.9±0.2 °, 26.4±0.2°, 27.0±0.2°, 29.2±0.2°, 29.6±0.2°, 31.1±0.2°, 42.0±0.2° have characteristic peaks.

In a specific embodiment, the X-ray powder diffraction of the α-crystalline form of quinolin using Cu-Kα radiation has the patterns and data shown in Figures 1 and 2 in terms of 2θ angles.

In the present invention, in the X-ray powder diffraction characteristic peak expressed by the 2θ angle of α-crystalline form of guanidine, “±0.2°” represents the reasonable measurement error range allowed by the position of the characteristic peak.

The differential scanning calorimetry (DSC) test results of the α-crystalline form of guanidine in the present invention show that there is an absorption peak in the range of 220-240°C; more specifically, there is a sharp melting point at 231±2°C Endothermic peak; in one embodiment, the α-crystalline form of gaurine has a DSC spectrum as shown in FIG. 3 .

The present invention also provides a method for preparing α-crystalline form of guanidine, the method comprising the following steps:

(1) Add the crude gluconate into the mixture of acetonitrile and other solvents, and heat to dissolve;

(2) cooling the organic solvent solution obtained in step (1) to the crystallization temperature, and naturally crystallizing;

(3) Filtrate and dry to obtain the crystalline form α of homougine.

Wherein said other solvents are selected from one or more of C1-5 saturated linear or branched chain alcohols, esters, ketones, ethers and C4-6 cyclic ethers; preferably methanol, ethanol, isopropanol, ethyl acetate One or more of ester, isopropyl acetate, acetone, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran; more preferably one or more of ethanol, ethyl acetate, acetone, tetrahydrofuran. The volume ratio of acetonitrile and other solvents is 1: 0.1-10, preferably 1: 0.1-2.0, more preferably 1: 0.5-1.0. The crystallization temperature is 0-20°C, preferably 0-10°C, more preferably 0-5°C; the crystallization time is 1-12h, preferably 1-3h.

The temperature for heating and dissolving in the above step (1) is a temperature capable of dissolving solids, preferably 60° C. to reflux temperature, more preferably 80° C. to reflux temperature; in one embodiment, the temperature for heating and dissolving is reflux temperature.

The present invention also provides the purposes of α-crystal form homogenin in the preparation of high-purity homogenin, which can be realized by the following method: heating and dissolving 10 g of homogenin in 250 ml of acetonitrile-ethanol solution (V Acetonitrile: V ethanol=1:0.5), cooling and crystallization, suction filtration, drying, obtains high-purity homougin; Wherein, described " high purity " refers to that its HPLC purity is more than 99.7%, and single impurity content is in Below 0.1%.

The α-crystal form gaokinasu provided by the present invention has relatively high purity and good yield, its purity is above 99.7%, and the content of a single impurity is below 0.1%, and its method is simple in process, convenient in operation and mild in condition. No special reaction conditions are required, so it is suitable for large-scale production.

Description of drawings

Fig. 1 is the X-ray powder diffraction pattern of α-crystal form gaokine;

Fig. 2 is the X-ray powder diffraction data of α-crystalline form of urine;

Figure 3 is the DSC spectrum of the α-crystalline form of homogenate.

specific embodiment

The present invention will be further elaborated below in conjunction with specific examples. These examples are for illustrative purposes only, and do not limit the scope and spirit of the present invention.

The reagents and methods used in the examples of the present invention are conventional reagents and conventional operating methods in the art. Hereinafter, if not specifically stated, the materials used and the operating methods of the present invention are well known in the art, but the present invention is still described in as much detail as possible. The crude homogenate amorphous used in the examples was prepared in Example 1 or by the same (similar) method.

The used test instrument of the present invention:

(1) X-ray powder diffractometer

Instrument model: Thermo X’TRA X-ray powder diffraction analyzer

Test method: according to the Chinese Pharmacopoeia 2010 Edition Part II (Appendix IX F X-ray powder diffraction method), fill the ground sample (100mg) in the groove of the glass plate, and use a glass slide to hang its plane flush with the glass surface Finally, the sample is placed in a Thermo X'TRA type X-ray powder diffraction analyzer, using a 40kV 40mA copper X-ray source, with a scanning range of 2 to 45° (2θ), a scanning speed of 8°/min, and a scanning time of 6 minute. Scanning errors are typically ±0.2° (2θ).

(2) Differential scanning calorimeter

Instrument model: METTLER TGA/DSCI.

Test method: according to JY/T014-1996 thermal analysis method general rules, put a sample weighing 3.10mg in a closed aluminum pan with a small pinhole, keep it balanced at 50°C, and then heat it at a scan rate of 10°C/min to 350°C. Dry nitrogen was used as purge gas.

Embodiment 1: Preparation of the crude product of amorphous homo-urine

According to the report of the relevant document CN1088919A, considering the energy consumption, pollution, reaction temperature and easy operation during the extraction process, our preparation process is as follows:

Take 0.25 kg of dried and crushed Aconitum root and put it in a 2.5L round bottom flask, add 0.850L ethanol (85% concentration) to soak for 12h, heat and reflux for 24h, filter and centrifuge (2500r/min, 10min), the supernatant is reduced Concentrate under pressure distillation until crystals appear, recover ethanol, let stand for 24 hours, and after the crystallization is complete, filter the obtained solid with suction, recrystallize with ethanol, filter, and then use phosphorus pentoxide as a desiccant to dry in a desiccator to remove water. Finally, 3.059 g of amorphous homo-orginine crude product was obtained, with a yield of 0.61%.

Example 2: Preparation of Polyurine Form α

Add 5.0 g of the crude amorphous homogenin into 100 ml of acetonitrile and 50 ml of ethanol mixed solvent, heat to dissolve, slowly cool down to 0~5°C for crystallization for 2 hours, suction filter, and vacuum dry at 50°C to obtain 4.1 g of white The crystalline form α of homogenate has a yield of about 82%, and a HLPC purity of 99.8%. After determination, its X-ray powder diffraction pattern is shown in Figure 1, and its DSC spectrum is shown in Figure 3.

Example 3: Preparation of homogenate crystal form α

Add 5.0g of the crude amorphous homogenin to 100ml of acetonitrile and 20ml of acetone, heat to dissolve, slowly cool down to 0~5°C for crystallization for 1 hour, filter with suction, and dry in vacuum at 50°C to obtain 3.6g of white homogenin Crystal form α, the yield is 72%, and the purity of HLPC is 99.7%. After determination, its X-ray powder diffraction pattern is basically consistent with Figure 1, and its DSC pattern is basically consistent with Figure 3.

Example 4: Preparation of homogenate crystal form α

Add 5.0 g of the crude amorphous gluconate into a mixed solvent of 100 ml of acetonitrile and 20 ml of methanol, heat to dissolve, slowly cool down to 0~5°C for crystallization for 1 hour, filter with suction, and dry in vacuum at 50°C to obtain 3.8 g of white kelp Form A α, the yield is 76%, and the purity of HLPC is 99.8%. After determination, its X-ray powder diffraction pattern is basically consistent with Figure 1, and its DSC pattern is basically consistent with Figure 3.

Example 5: Preparation of Polyurine Form α

Add 5.0g of crude saccharine into 150ml of acetonitrile and 50ml of isopropanol, heat to reflux to dissolve, slowly cool down to 0~5°C for crystallization for 1 hour, filter with suction, and dry in vacuum at 50°C to obtain 3.4g of white saccharine The yield of plain crystal form α is 68%, and the purity of HLPC is 99.8%. After determination, its X-ray powder diffraction pattern is basically consistent with Figure 1, and its DSC pattern is basically consistent with Figure 3.

Example 6: Preparation of Polyurine Form α

Add 5.0g of crude homogenin into 150ml of acetonitrile and 50ml of ethyl acetate, heat to dissolve, slowly cool down to 0~5°C for crystallization for 1 hour, filter with suction, and dry in vacuum at 50°C to obtain 3.0g of white homogenin crystals Type α, the yield is 65%, and the purity of HLPC is 99.9%. After determination, its X-ray powder diffraction pattern is basically consistent with Figure 1, and its DSC pattern is basically consistent with Figure 3.

Embodiment 7: stability test

Although amorphous drugs have higher solubility and dissolution rate than crystalline drugs in most cases, the main factors affecting the clinical use of amorphous drugs are their processing stability and storage stability. In addition, during the production process, some amorphous particles have low bulk density and high surface free energy, which may also easily cause a series of formulation problems such as aggregation, poor fluidity, and strong elastic deformation. Therefore, crystalline drugs have more advantages in terms of formulation stability.

The applicant inspected the stability of the crystalline form α of homogenate under different conditions. The specific stability inspection method can refer to the method in the second appendix XIX of the Chinese Pharmacopoeia 2010 edition; the HPLC method for purity detection can refer to the Chinese Pharmacopoeia. The method of Pharmacopoeia 2010 edition second appendix V D; The detection of crystal form is with the method of embodiment.

Take one part of the homogenate crystal form α prepared in Example 2 and Example 3, and place it under the condition of 45°C/humidity 75% for 30 days to investigate its stability. The results are shown in Table 1.

The above data show that the crystal form α of homouginine obtained in the present invention has good stability in both its purity and crystal form under normal conditions.

Embodiment 8: solubility test

The solubility of the drug directly affects the dissolution and oral bioavailability of the drug preparation. In order to investigate the solubility of the crystalline form α of homogenate, the inventors investigated its solubility (in water) under different conditions.

The test results showed that the solubility of both amorphous and α-crystalline homo-uricine in water increased with the increase of temperature. Shape-formed homogenate, which lays a good foundation for the use of α-crystal form homogenate in the preparation of pharmaceutical preparations with good dissolution.

Claims (10)

1. Alpha crystalline form of quinine, characterized in that: using Cu-Kα radiation, its X-ray powder diffraction represented by 2θ angle is at 9.6±0.2°, 10.2±0.2°, 16.5±0.2°, 16.9±0.2 °, there are characteristic peaks at 19.0±0.2° and 19.3±0.2°. 2. α-crystal form kinokine, characterized in that: using Cu-Kα radiation, its X-ray powder diffraction represented by 2θ angle is at 9.6±0.2°, 10.2±0.2°, 12.3±0.2°, 13.7±0.2 °, 16.5±0.2°, 16.9±0.2°, 19.0±0.2°, 19.3±0.2°, 25.4±0.2° have characteristic peaks. 3. Alpha crystalline form of quinine, characterized in that: using Cu-Kα radiation, its X-ray powder diffraction represented by 2θ angles is at 5.6±0.2°, 6.0±0.2°, 9.4±0.2°, 9.6±0.2 °, 10.2±0.2°, 11.2±0.2°, 12.0±0.2°, 12.3±0.2°, 13.7±0.2°, 15.2±0.2°, 16.5±0.2°, 16.9±0.2°, 17.4±0.2°, 18.2±0.2 °, 19.0±0.2°, 19.3±0.2°, 19.8±0.2°, 20.5±0.2°, 21.5±0.2°, 22.4±0.2°, 24.1±0.2°, 25.1±0.2°, 25.4±0.2°, 25.9±0.2 °, 26.4±0.2°, 27.0±0.2°, 29.2±0.2°, 29.6±0.2°, 31.1±0.2°, 42.0±0.2° have characteristic peaks. 4. The α-crystal form kinogenin according to claim 3 is characterized in that: α-crystal form kinogenine uses Cu-Kα radiation, and its X-ray powder diffraction represented by 2θ angle has the following characteristics as shown in Figure 1. the graph shown. 5. According to any one of claims 1-3, the α-crystalline form of glycoconate, characterized in that: the differential scanning calorimetry test result of the α-crystalline form of glycoconate is shown at 231±2°C Has a sharp melting endothermic peak. 6. The preparation method of α-crystal form kinogenin according to any one of claims 1-3, characterized in that it comprises the following steps: (1) Add the crude gluconate into the mixture of acetonitrile and other solvents, and heat to dissolve; (2) cooling the organic solvent solution obtained in step (1) to the crystallization temperature, and naturally crystallizing; (3) Filtrate and dry to obtain the α-crystal form of homogenate in the form of crystals; The other solvents are selected from one or more of C1-5 saturated linear or branched chain alcohols, esters, ketones, ethers and C4-6 cyclic ethers. 7. preparation method according to claim 6 is characterized in that: other solvent is selected from methyl alcohol, ethanol, Virahol, ethyl acetate, isopropyl acetate, acetone, isopropyl ether, methyl tert-butyl ether, One or more of tetrahydrofuran. 8. preparation method according to claim 6 is characterized in that: the volume ratio of acetonitrile and other solvents is 1: 0.1-10. 9. The preparation method according to claim 6, characterized in that: the crystallization temperature is 0-20°C, and the crystallization time is 1-12h. 10. The use of the α-crystalline form of homogenate according to claims 1-3 in the preparation of high-purity α-crystal form of homogenate, characterized in that: 10 g of the amorphous crude product of homogenate is heated and dissolved in a volume ratio of 250ml of acetonitrile-ethanol solution of 1:0.5, cooling and crystallization, suction filtration, and drying to obtain high-purity α-crystal form of goukacin, wherein, the high purity means that its HPLC purity is above 99.7%, and the content of a single impurity Below 0.1%.