CN114716433B - Crystal form of demethylenetetrahydroberberine hydrochloride and preparation method thereof - Google Patents
Crystal form of demethylenetetrahydroberberine hydrochloride and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to three crystal forms A, B, C of demethylenetetrahydroberberine hydrochloride and a preparation method thereof. The crystalline form X-ray powder diffraction has characteristic diffraction peaks of about 6.264, 9.603, 10.622, 11.933, 12.338, 13.206, 15.011, 15.409, 17.879, 18.273, 18.569, 18.844, 19.223, 19.865, 20.174, 21.348, 21.742, 22.393, 23.280, 24.699, 26.133, 26.700, 27.180, 27.630, 28.419, 29.088, 31.801 °. The invention also relates to a preparation method of the three crystal forms of the demethylenetetrahydroberberine hydrochloride. The preparation method has the advantages of simple process, high yield and low cost; the product has high purity and stable quality.
Description
The application is the application number: 2020106510592, filing date: 2020.07.08 the invention relates to a crystal form of demethylenetetrahydroberberine hydrochloride and a divisional application of a preparation method thereof.
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to three types of crystal forms of demethylenetetrahydroberberine hydrochloride and a preparation method thereof.
Background
Demethylenetetrahydroberberine hydrochloride, english name: demethylenetetrahydroberberine Hydrochloride, molecular formula: c (C) 19 H 22 NO 4 Cl, molecular weight: 363.7. the organic structural part of the demethyleneberberine is named as follows: 6H-dibenzo [ a, g]Quinolizine-2, 3-diol, 5,8,13 a-tetrahydro-9, 10-dimethoxy. Hydrochloric acid is removed inferiorThe structural formula of the methyltetrahydrophberberbamine is shown as the formula (I).
The biological activities of low toxicity, anti-inflammatory and anti-oxidation of the hydrochloric acid demethylenetetrahydroberberine are reported in the prior patent. And has stronger therapeutic potential in the fields of alcoholic liver injury, non-alcoholic fatty liver, thioacetamide-induced chemical liver injury and the like, and is a potential liver-protecting medicament. In addition, there is a report that the demethylenetetrahydroberberine hydrochloride has a tissue factor coagulation inhibiting activity. In summary, the use of the demethyleneberberine hydrochloride will provide a choice for the treatment of clinical diseases.
Tetrahydroberberine (THB) is derived from rhizoma corydalis tuber of Papaveraceae, belongs to tetrahydroisoquinoline alkaloid, can also be hydrogenated from berberine, and has various biological activities. The demethylenetetrahydroberberine can be obtained by metabolic or chemical modification of tetrahydroberberine. Because the content of the hydrochloric acid demethylenetetrahydroberberine in the natural plants is low, the extraction cost is high and the price is high. The chemical synthesis method is that cheap berberine is used as raw material, sodium borohydride and other reducing agents are used for reduction to obtain tetrahydroberberine, the tetrahydroberberine is subjected to demethyleneization through a sulfuric acid-phloroglucinol system to obtain the demethylenetetrahydroberberine hydrochloride, and then the demethylenetetrahydroberberine hydrochloride is recrystallized to obtain the pure product of the demethylenetetrahydroberberine hydrochloride.
The method obtains stable and high-purity products by utilizing a recrystallization method, improves related synthesis processes, reduces the synthesis cost of the hydrochloric acid demethylenetetrahydroberberine, and improves the yield of the hydrochloric acid demethylenetetrahydroberberine. At present, no patent report of literature relates to the preparation of a crystal form of the demethylenetetrahydroberberine hydrochloride, but the crystal form structure of the medicine is extremely important for the stability, dissolution and bioavailability of the medicine, and the proper crystal form of the medicine is extremely important for pharmaceutical research. In order to further study the pharmacological activity of the demethylenetetrahydroberberine hydrochloride, the crystal form of the demethylenetetrahydroberberine hydrochloride is very necessary to be studied.
Disclosure of Invention
The invention aims to provide three crystal forms of hydrochloric acid demethylenetetrahydroberberine and a preparation method thereof.
A crystalline form of demethylenetetrahydroberberine hydrochloride, designated as form a, characterized in that: characteristic diffraction peaks in the X-ray powder diffraction spectrum expressed in degrees 2 theta + 0.2 deg. diffraction of Cu-ka radiation are 6.264, 9.603, 10.622, 11.933, 12.338, 13.206, 15.011, 15.409, 17.879, 18.273, 18.569, 18.844, 19.223, 19.865, 20.174, 21.348, 21.742, 22.393, 23.280, 24.699, 26.133, 26.700, 27.180, 27.630, 28.419, 29.088, 31.801 deg.; the DSC spectrum contains 1 absorption peak of heat at 258.1+/-3 ℃; the infrared absorption characteristic peaks are: 422.3cm -1 、451.2cm -1 、513.8cm -1 、530.7cm -1 、554.3cm -1 、631.7cm -1 、677.6cm -1 、694.2cm -1 、732.7cm -1 、793.7cm -1 、810.0cm -1 、865.3cm -1 、882.9cm -1 、903.8cm -1 、927.9cm -1 、957.8cm -1 、983.5cm -1 、1008.2cm -1 、1040.1cm -1 、1092.9cm -1 、1115.2cm -1 、1161.5cm -1 、1188.1cm -1 、1232.0cm -1 、1279.7cm -1 、1302.1cm -1 、1318.5cm -1 、1333.8cm -1 、1358.3cm -1 、1373.4cm -1 、1391.9cm -1 、1426.6cm -1 、1443.7cm -1 、1501.3cm -1 、1524.0cm -1 、1587.1cm -1 、1605.8cm -1 、1622.3cm -1 、2402.8cm -1 、2458.7cm -1 、2585.4cm -1 、2668.0cm -1 、2689.3cm -1 、2689.3cm -1 、2791.9cm -1 、2833.3cm -1 、2908.4cm -1 、2937.5cm -1 、2976.8cm -1 、2995.5cm -1 、3019.7cm -1 、3142.2cm -1 、3293.4cm -1 。
A crystalline form of demethylenetetrahydroberberine hydrochloride, designated as form B, characterized in that: the characteristic diffraction peaks in the X-ray powder diffraction spectrum expressed in terms of Cu-K alpha radiation, 2 theta + -0.2 DEG diffraction angle are: 6.299, 10.644, 12.292, 12.559, 13.236, 15.034, 16.230, 18.604, 18.943, 19.912, 20.199, 21.381, 23.302, 24.738, 26.146, 27.137, 28.457, 29.106, 30.726, 31.862, 32.413, 36.198, 38.462 °; the DSC spectrum contains 1 endothermic peak, and the peak position is 253.7+/-3 ℃; the infrared characteristic absorption peaks are: 422.0cm -1 、450.2cm -1 、506.2cm -1 、530.4cm -1 、550.7cm -1 、631.9cm- 1 、678.1cm -1 、701.6cm -1 、733.5cm -1 、793.2cm -1 、808.4cm -1 、864.3cm -1 、882.7cm -1 、904.0cm -1 、923.8cm -1 、948.5cm -1 、958.8cm -1 、982.3cm -1 、1008.5cm -1 、1043.3cm -1 、1094.1cm -1 、1115.4cm -1 、1160.8cm- 1 、1187.7cm -1 、1230.9cm -1 、1286.8cm -1 、1319.5cm -1 、1333.1cm -1 、1358.2cm -1 、1373.7cm -1 、1391.1cm -1 、1424.8cm -1 、1446.6cm -1 、1502.8cm -1 、1523.8cm -1 、1586.8cm -1 、1606.8cm -1 、1624.0cm -1 、2403.1cm -1 、2457.8cm -1 、2589.9cm -1 、2670.0cm -1 、2691.6cm -1 。
A crystalline form of demethylenetetrahydroberberine hydrochloride, designated as form C, characterized in that: the characteristic diffraction peaks in the X-ray powder diffraction spectrum expressed in terms of Cu-K alpha radiation, 2 theta + -0.2 DEG diffraction angle are: 9.722, 12.030, 12.452, 15.555, 17.986, 18.366, 19.367, 20.328, 21.867, 22.501, 23.712, 24.090, 24.996, 26.226, 26.840, 27.747, 28.103, 28.521, 29.095, 30.944, 32.199, 33.527, 33.943, 38.700 °; the DSC spectrum contains 1 endothermic peak, the peak position is 250.8 (+ -)3 ℃; the infrared characteristic absorption peaks are: 424.0cm -1 、453.1cm -1 、514.8cm -1 、556.3cm -1 、613.1cm -1 、633.0cm -1 、652.2cm -1 、678.2cm -1 、692.3cm -1 、733.1cm -1 、741.4cm -1 、758.3cm -1 、797.8cm -1 、811.5cm -1 、867.3cm -1 、883.1cm -1 、904.0cm -1 、928.9cm -1 、957.6cm -1 、986.0cm -1 、1007.7cm -1 、1037.2cm -1 、1057.5cm -1 、1091.8cm -1 、1116.5cm -1 、1164.8cm -1 、1189.2cm -1 、1221.5cm -1 、1234.7cm -1 、1278.0cm -1 、1315.8cm -1 、1334.8cm -1 、1349.9cm -1 、1374.1cm -1 、1393.5cm -1 、1429.6cm -1 、1442.1cm -1 、1459.7cm -1 、1495.4cm -1 、1524.8cm -1 、1587.4cm -1 、1605.0cm -1 、1621.7cm -1 、2402.3cm -1 、2469.3cm -1 、2572.5cm -1 、2657.1cm -1 、2684.2cm -1 、2798.7cm -1 、2836.2cm -1 、2906.4cm -1 、2941.1cm -1 、2961.3cm -1 、2999.0cm -1 、3142.5cm -1 、3298.3cm -1 、3518.5cm -1 。
The method for preparing the crystal form of the demethylenetetrahydroberberine hydrochloride is characterized by comprising the following steps of: the method comprises the following steps:
(1) The tetrahydroberberine hydrochloride is subjected to a sulfuric acid-phloroglucinol system to obtain the demethylenetetrahydroberberine hydrochloride;
(2) Dissolving the hydrochloric acid demethylenetetrahydroberberine obtained in the step (1), and cooling and crystallizing to obtain a hydrochloric acid demethylenetetrahydroberberine A crystal form;
(3) Dissolving the hydrochloric acid demethylenetetrahydroberberine obtained in the step (1) by using ethanol or methanol, and recrystallizing to obtain a hydrochloric acid demethylenetetrahydroberberine B crystal form;
(4) Dissolving the mixed hydrochloric acid demethylenetetrahydroberberine obtained in the step (1) by using ethanol or methanol, adding ethyl acetate, and recrystallizing at 4 ℃ to obtain a hydrochloric acid demethylenetetrahydroberberine C crystal form;
the step (2) of the preparation method of the hydrochloric acid demethylenetetrahydroberberine crystal form also comprises the step of adding a small amount of seed crystal.
The preparation method of the hydrochloric acid demethylenetetrahydroberberine crystal form further comprises the step (4) of adding a small amount of seed crystal, adding 10-20% of diethyl ether by volume, adding 10-20% of dimethylbenzene by volume and adding 10-20% of methylbenzene by volume.
The crystal form A, B, C of the demethylenetetrahydroberberine hydrochloride is characterized in that the crystal form pharmaceutical composition of the demethylenetetrahydroberberine hydrochloride can be tablets, capsules, pills, injections, sustained release agents and various microparticle administration systems.
The three types of the crystal form pharmaceutical compositions of the demethylenetetrahydroberberine hydrochloride can be tablets, capsules, pills, injections, sustained release agents and various microparticle drug delivery systems.
The beneficial technical effects of the invention are as follows: the crystal form of the demethylenetetrahydroberberine hydrochloride provided by the invention has better stability. The preparation method has the advantages of simple process, high yield, good product quality and low preparation cost.
Drawings
FIG. 1 is an X-ray powder diffraction diagram of the form A of the demethylenetetrahydroberberine hydrochloride of the present invention;
FIG. 2 is a differential scanning calorimetric diagram of the form A of normethylene tetrahydroberberine hydrochloride;
FIG. 3 is an infrared spectrum of the form A of the normethylene tetrahydroberberine hydrochloride;
FIG. 4 is a thermogravimetric diagram of the form A of normethylene tetrahydroberberine hydrochloride;
FIG. 5 is an X-ray powder diffraction diagram of the B crystal form of the demethylenetetrahydroberberine hydrochloride of the present invention;
FIG. 6 is a differential scanning calorimetric diagram of the B crystal form of the demethylenetetrahydroberberine hydrochloride;
FIG. 7 is an infrared spectrum of the form B of the normethylene tetrahydroberberine hydrochloride;
FIG. 8 is a thermogravimetric diagram of the B crystal form of normethylene tetrahydroberberine hydrochloride;
FIG. 9 is an X-ray powder diffraction pattern of the C crystal form of the demethylenetetrahydroberberine hydrochloride of the present invention;
FIG. 10 is a differential scanning calorimetric diagram of the form C of the normethylene tetrahydroberberine hydrochloride;
FIG. 11 is an infrared spectrum of the C crystal form of the demethylenetetrahydroberberine hydrochloride;
FIG. 12 is a thermogravimetric diagram of the form C of normethylene tetrahydroberberine hydrochloride;
FIG. 13 is a HPLC detection chart of demethylenetetrahydroberberine hydrochloride;
FIG. 14 is a mass spectrum of demethylenetetrahydroberberine hydrochloride;
FIG. 15 is a hydrogen spectrum of demethylenetetrahydroberberine hydrochloride;
FIG. 16 is a graph showing the dissolution profile of the crystalline form of normethylene tetrahydroberberine hydrochloride A, B, C in water;
FIG. 17 is a graph showing the dissolution profile of the crystalline form ethanol system of normethylene tetrahydroberberine hydrochloride A, B, C.
FIG. 18 shows the detection of the blood concentration of the crystal form A, B, C of the demethylenetetrahydroberberine hydrochloride
Detailed Description
The following examples will assist those skilled in the art in a more complete understanding of the invention, but are not intended to limit the invention in any way.
The structural characterization of the crystal form of the demethylenetetrahydroberberine hydrochloride uses X-ray powder diffraction, differential scanning calorimetry, infrared spectrum and thermogravimetric analysis.
In the sulfuric acid-phloroglucinol system, the temperature range is as follows: 60-100 ℃, sulfuric acid concentration range: 40% -80%, and the proportion range of phloroglucinol and tetrahydroberberine is as follows: 1:3-3:1.
EXAMPLE 1 Synthesis of Demethylenetetrahydroberberine hydrochloride form A
Adding 5g of berberine hydrochloride into 50ml of ethanol, stirring, slowly adding 0.5g of sodium borohydride, reacting for 4 hours, and collecting tetrahydrochysene hydrochloride after the reaction is finishedBerberine. Adding tetrahydroberberine hydrochloride into phloroglucinol-H 2 SO 4 Stirring the mixture in the system to completely dissolve the mixture, and reacting for 0.5h under the catalysis of phloroglucinol to remove methylene to obtain the demethylenetetrahydroberberine hydrochloride. Dissolving the obtained product in water, recrystallizing, filtering, collecting filter cake, drying to obtain the crystal of hydrochloric acid demethylenetetrahydroberberine A, weighing, and detecting. The obtained solid has X-ray powder diffraction diagram shown in figure 1, DSC diagram shown in figure 2, infrared spectrum shown in figure 3, and thermogravimetric analysis diagram shown in figure 4.
EXAMPLE 2 Synthesis of Demethylenetetrahydroberberine hydrochloride form B
5g of berberine hydrochloride is added into 50ml of ethanol, and is stirred, 0.5g of sodium borohydride is slowly added, the reaction is carried out for 4 hours, and the product tetrahydroberberine hydrochloride is obtained after the reaction is finished. Adding tetrahydroberberine hydrochloride into phloroglucinol-H 2 SO 4 Stirring the mixture in the system to completely dissolve the mixture, and reacting for 0.5h under the catalysis of phloroglucinol to remove methylene to obtain the demethylenetetrahydroberberine hydrochloride. Dissolving the obtained product with methanol, adding ethyl acetate, recrystallizing, filtering, collecting filter cake, drying to obtain the crystal of hydrochloric acid demethylenetetrahydroberberine B, weighing, and detecting. The obtained solid has an X-ray powder diffraction pattern shown in FIG. 5, a DSC diagram shown in FIG. 6, an infrared spectrum shown in FIG. 7 and a thermogravimetric analysis diagram shown in FIG. 8.
EXAMPLE 3 Synthesis of Demethylenetetrahydroberberine hydrochloride form C
5g of berberine hydrochloride is added into 50ml of ethanol, and is stirred, 0.5g of sodium borohydride is slowly added, the reaction is carried out for 4 hours, and the product tetrahydroberberine hydrochloride is obtained after the reaction is finished. Adding tetrahydroberberine hydrochloride into phloroglucinol-H 2 SO 4 Stirring the mixture in the system to completely dissolve the mixture, and reacting for 0.5h under the catalysis of phloroglucinol to remove methylene to obtain the demethylenetetrahydroberberine hydrochloride. Dissolving the obtained product with ethanol, adding ethyl acetate, recrystallizing at 4deg.C overnight, filtering, collecting filter cake, drying to obtain demethylenetetrahydroberberine C crystal, weighing, and detecting. The obtained solid has an X-ray powder diffraction pattern shown in FIG. 9, a DSC diagram shown in FIG. 10, an infrared spectrum shown in FIG. 11, and a thermogravimetric analysis diagram shown in FIG. 12.
EXAMPLE 4 HPLC detection of normethylene tetrahydroberberine hydrochloride
The method comprises the following steps: the HPLC method is adopted for analysis, the hydrochloric acid demethylenetetrahydroberberine is dissolved by methanol, and the result is filtered, and finally the final concentration of 20 ng/. Mu.l sample is prepared for analysis. HPLC chromatograph: agilent 1100 high performance liquid chromatograph. Chromatographic column: agilent Eclipse XDB-C18 (4.6X105 mm,5 μm). Mobile phase (A) 20mM phosphate buffer salt solution, (B) acetonitrile. HPLC gradient elution conditions were 0min,20% B;0-13min,55% B;13-14min,55% B;14-15min,20% B;15-16min,20% B. The detection wavelength is 280nm, the speed is 1.0ml/min, and the sample injection volume is 5 μl.
Results: HPLC analysis results are shown in FIG. 13, retention time 3.817min, purity greater than 98.0%.
Example 5 structural identification and detection of normethylene tetrahydroberberine hydrochloride
The method comprises the following steps: molecular structure identification uses mass spectrometry and nuclear magnetic resonance spectroscopy. The mass spectrometer was a Waters Q-TOF MicroTM, ionization mode: ESI (+), mass scan range: m/z 80-1000, capillary voltage: 2500v, cone voltage: 25v, ion source temperature: 100 ℃, atomization temperature: 200 ℃, taper hole gas flow rate: 50L/hr, atomizing gas flow rate: 400L/hr. The nuclear magnetic resonance spectrometer (1H-NMR) was AVANCE AV-300, the irradiation frequency was 300MHz, and the solvent used was: deuterated dimethyl sulfoxide (DMSO-d 6), and Tetramethylsilane (TMS) was used as standard.
As a result, the positive ion mass spectrum analysis result of the demethylenetetrahydroberberine is shown in FIG. 14, ESI-MS (M/z): molecular ion group peak [ M-CI ]]+=327.1 and [ MH-Cl] + =328.1. This is consistent with the theoretical molecular weight of demethylenetetrahydroberberine, which chloride ions in the hydrochloride salt are not shown in mass spectrometry ESI (+). And (3) identifying chloride ions according to a reaction method related to identification (1) of chloride in Chinese pharmacopoeia. Taking 0.1 g of hydrochloric acid demethylenetetrahydroberberine, adding 10ml of water, slowly heating for dissolution, adding 0.5ml of nitric acid, cooling, standing for 10 minutes, filtering, dropwise adding silver nitrate test solution into filtrate to generate white curdlan precipitate, centrifuging, collecting precipitate, adding ammonia test solution into the precipitate for dissolution, and adding dilute nitric acid for acidification to generate the precipitate. Indicating that the experimentThe sample hydrochloric acid demethylenetetrahydroberberine contains chloride ions. Mass spectrometry and chemical analysis show that the molecular weight of the demethylenetetrahydroberberine hydrochloride is correct.
Demethylenetetrahydroberberine hydrochloride l The results of H-NMR (DMSO-d 6) hydrogen analysis are shown in FIG. 15, 1H NMR (DMSO-d 6,300 MHz) d:2.79 (m, 1H, 6-H), 3.04 (m, 1H, 13-H), 3.23 (m, 1H, 5-H), 3.41 (m, 2H,6-H, 5-H), 3.58 (m, 1H, 13-H), 3.77 (m, 1H, 8-H), 3.79 (s, 3H, -OCH 3), 3.82 (s, 3H, -OCH 3), 4.35 (m, 1H, 14-H), 4.59 (m, 1H, 8-H), 6.60 (s, 1H, 4-H), 6.79 (s, 1H, 1-H), 7.04 (d, J=8.5 Hz,1H, 12-H), 7.07 (d, J=8.5 Hz,1H, 11-H), 3.82 (s, 3H, 1H, 8-H), 4.35 (m, 1H, 14-H), 4.59 (m, 1H, 8-H).
EXAMPLE 6 stability test
And respectively taking a proper amount of hydrochloric acid demethylenetetrahydroberberine A, B and C crystals, placing the crystals in three parts respectively in plates with the numbers of A1, A2, A3, B1, B2, B3, C1, C2 and C3, and respectively placing the crystals in the following conditions (storage condition 1: high temperature at 60 ℃, storage condition 2: high humidity of 92.5 and storage condition 3:4500 lx+/-500 lx) for stability experiments. The experimental results are shown in tables 1, 2 and 3.
TABLE 1 high temperature experimental stability study of the Demethylenetetrahydroberberine hydrochloride Crystal (60+ -2 ℃ C.)
TABLE 2 high humidity experimental stability study of the Demethylenetetrahydroberberine hydrochloride Crystal (RH 90+ -5%)
TABLE 3 Strong light irradiation experimental stability study (RH 90+ -5%) of the normethylene tetrahydroberberine hydrochloride crystal
Conclusion: in the experimental study of high-temperature stability, the crystal B of the hydrochloric acid demethylenetetrahydroberberine shows better stability, and the crystal C of the hydrochloric acid demethylenetetrahydroberberine has poorer stability. In the experimental study of high wet stability, the crystal of the hydrochloric acid demethylenetetrahydroberberine C shows better stability, and the crystal of the hydrochloric acid demethylenetetrahydroberberine A has poorer stability. In experimental research on strong light irradiation stability, the normethylene tetrahydroberberine hydrochloride B crystal shows better stability, and the normethylene tetrahydroberberine hydrochloride A crystal and the normethylene tetrahydroberberine hydrochloride C crystal have poorer stability.
EXAMPLE 7 solubility Studies
And respectively taking a proper amount of crystals of the hydrochloric acid demethylenetetrahydroberberine A, B and C, and researching the solubility of the crystals of the hydrochloric acid demethylenetetrahydroberberine A, B and C at different temperatures by using water and ethanol as solvents.
1. Solubility study of hydrochloric acid demethylenetetrahydroberberine A, B, C crystal in water system
And respectively taking a proper amount of crystals of the hydrochloric acid demethylenetetrahydroberberine A, B and C, and researching the solubility of the crystals of the hydrochloric acid demethylenetetrahydroberberine A, B and C at different temperatures under an aqueous system. 20ul samples were taken at each temperature node and tested by HPLC and the experimental results are shown in FIG. 16.
Conclusion: the solubility of the crystal of the normethylene tetrahydroberberine A, B and C hydrochloride in an aqueous phase system is slowly increased along with the temperature rise. The solubility of the hydrochloric acid demethylenetetrahydroberberine C crystal is optimal, and the solubility of the hydrochloric acid demethylenetetrahydroberberine B crystal is worst.
2. Solubility study of hydrochloric acid demethylenetetrahydroberberine A, B, C crystal in ethanol system
And respectively taking a proper amount of crystals of the hydrochloric acid demethylenetetrahydroberberine A, B and C, and researching the solubility of the crystals of the hydrochloric acid demethylenetetrahydroberberine A, B and C at different temperatures under an ethanol system. 20ul samples were taken at each temperature node and tested by HPLC and the experimental results are shown in FIG. 17.
Conclusion: the solubility of the crystal of the hydrochloric acid demethylenetetrahydroberberine A, B and C in an ethanol system increases with the increase of the temperature. The solubility of the hydrochloric acid demethylenetetrahydroberberine A crystal is optimal, and the solubility of the hydrochloric acid demethylenetetrahydroberberine B crystal is worst.
EXAMPLE 8 detection of blood concentration of normethylene tetrahydroberberine hydrochloride A, B, C crystals
Male SD rats were adaptively bred for 3 days, and rats with a body weight of 220+ -20 g were selected and divided into 4 groups, which were a blank group, a demethylenetetrahydroberberine hydrochloride A crystal form group, a demethylenetetrahydroberberine hydrochloride B crystal form group, and a demethylenetetrahydroberberine hydrochloride C crystal form group, respectively. Fasted for 12h gastric emptying before the experiment, and the administration dose of the ig of the rats in the experimental group is 300mg/kg. Blood is taken from the eye sockets of rats ig for 5min, 15min, 30min, 1h, 2h, 6h and 12h respectively for 0.2ml, whole blood is centrifuged, and 100 μl of blood plasma is taken and frozen at-20deg.C for use. Taking 100 μl of plasma sample, adding 200 μl of methanol, swirling for 5min, centrifuging at 10000r/min in a centrifuge for 15min, collecting supernatant, detecting by HPLC, and testing with the experimental result shown in figure 18, and removing methylene tetrahydroberberine hydrochloride form A of crystal form C max ＝19.958μg×ml-1，T max =2h; crystal form C of hydrochloric acid demethylenetetrahydroberberine B max ＝10.38μg×ml-1，T max =0.5 h; demethylenetetrahydroberberine hydrochloride C crystal form C max ＝55.352μg×ml-1，T max =0.25 h. Calculating to obtain A according to experimental results AUC ＝91.67258μg×ml-1×h＞C AUC ＝47.50667μg×ml-1×h＞B AUC = 19.2071 μg×ml-1×h. The absorption of the crystal form A, C of the demethylenetetrahydroberberine hydrochloride is obviously better than that of the crystal form B of the demethylenetetrahydroberberine hydrochloride.
Claims (4)
1. A crystalline form of demethylenetetrahydroberberine hydrochloride, characterized in that: the crystal form is named as A type, and the characteristic diffraction peaks in the X-ray powder diffraction spectrum expressed in terms of Cu-K alpha radiation and 2 theta plus or minus 0.2 DEG diffraction angle are 6.264, 9.603, 10.622, 11.933, 12.338, 13.206, 15.011, 15.409, 17.879, 18.273, 18.569, 18.844, 19.223, 19.865, 20.174, 21.348, 21.742, 22.393, 23.280, 24.699, 26.133, 26.700, 27.180, 27.630, 28.419 and 29088, 31.801 °; the DSC spectrum contains 1 absorption peak of heat at 258.1+/-3 ℃, and the infrared absorption characteristic peak is as follows: 422.3cm -1 、451.2 cm -1 、513.8 cm -1 、530.7 cm -1 、554.3 cm -1 、631.7 cm -1 、677.6 cm -1 、694.2 cm -1 、732.7 cm -1 、793.7 cm -1 、810.0 cm -1 、865.3 cm -1 、882.9 cm -1 、903.8 cm -1 、927.9 cm -1 、957.8 cm -1 、983.5 cm -1 、1008.2 cm -1 、1040.1 cm -1 、1092.9 cm -1 、1115.2 cm -1 、1161.5 cm -1 、1188.1 cm -1 、1232.0 cm -1 、1279.7 cm -1 、1302.1 cm -1 、1318.5 cm -1 、1333.8 cm -1 、1358.3 cm -1 、1373.4 cm -1 、1391.9 cm -1 、1426.6 cm -1 、1443.7 cm -1 、1501.3 cm -1 、1524.0 cm -1 、1587.1 cm -1 、1605.8 cm -1 、1622.3 cm -1 、2402.8 cm -1 、2458.7 cm -1 、2585.4 cm -1 、2668.0 cm -1 、2689.3 cm -1 、2689.3 cm -1 、2791.9 cm -1 、2833.3 cm -1 、2908.4 cm -1 、2937.5 cm -1 、2976.8 cm -1 、2995.5 cm -1 、3019.7 cm -1 、3142.2 cm -1 、3293.4 cm -1 。
2. A process for preparing the crystalline form of normethylene tetrahydroberberine hydrochloride of claim 1, characterized in that: the method comprises the following steps:
(1) The tetrahydroberberine hydrochloride is subjected to a sulfuric acid-phloroglucinol system to obtain the demethylenetetrahydroberberine hydrochloride; wherein: the sulfuric acid-phloroglucinol system is: the concentration of sulfuric acid is 40% -80% at 60-100 ℃, and the mass ratio of phloroglucinol to tetrahydroberberine is 1:3-3:1;
(2) Dissolving the hydrochloric acid demethylenetetrahydroberberine obtained in the step (1), and cooling and crystallizing to obtain the hydrochloric acid demethylenetetrahydroberberine A crystal form.
3. The method for preparing the crystal form of the demethylenetetrahydroberberine hydrochloride according to claim 2, which is characterized in that: step (2) also includes adding a small amount of seed crystals.
4. A pharmaceutical composition containing a crystalline form of demethylenetetrahydroberberine hydrochloride according to claim 1, wherein the pharmaceutical composition is in the form of a tablet, capsule, pill, injection.
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| CN109293655A (en) * | 2018-02-06 | 2019-02-01 | 中国药科大学 | Demethyleneberberinehydrochloride hydrochloride crystal form and preparation method thereof |
| CN109432096A (en) * | 2018-11-12 | 2019-03-08 | 中国药科大学 | Hydrochloric acid goes application of the methylene N-1 in preparation prevention or treatment alcoholic liver disease and non-alcoholic fatty liver disease drug |
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