CN104876866A - Alpha-crystal-form lappaconitine and preparation method thereof - Google Patents
Alpha-crystal-form lappaconitine and preparation method thereof Download PDFInfo
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- CN104876866A CN104876866A CN201510217463.8A CN201510217463A CN104876866A CN 104876866 A CN104876866 A CN 104876866A CN 201510217463 A CN201510217463 A CN 201510217463A CN 104876866 A CN104876866 A CN 104876866A
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Abstract
The invention discloses alpha-crystal-form lappaconitine and a preparation method thereof. By virtue of Cu-Kalpha radiation, characteristic peaks are formed in an X-ray powder diffraction pattern represented by a 2theta angle at 9.6+/-0.2 degrees, 10.2+/-0.2 degrees, 16.5+/-0.2 degrees, 16.9+/-0.2 degrees, 19.0+/-0.2 degrees and 19.3+/-0.2 degrees. The alpha-crystal-form lappaconitine disclosed by the invention has relatively high purity and relatively good yield; the purity is 99.7% or above; the single impurity content is 0.1% or below; and the reparation method is simple in process, convenient to operate and mild in condition, does not need a special reaction condition and therefore is suitable for large-scale production.
Description
Technical field
The present invention relates to stable alpha-crystal form lappaconitine and preparation method thereof, belong to pharmaceutical chemistry technical field.
Background technology
Lappaconitine (Lappaconitine), its chemical name is (1 α, 14 α, 16 β)-20-ethyl-1,14,16-trimethoxy aconitane-4,8,9 triol-4-2-(kharophen) benzoic ether, there is formula
shown chemical structure, in China as non-addicted analgesics production and application.Lappaconitine has potent analgesic effect, and analgesic effect is equivalent to morphine, and its analgesic activity is 7 times of common anodyne pyramidon, suitable with dolantin, and analgesic effect is held time longer, the substitute species of U-26225A especially.Clinical proof lappaconitine toponarcosis effect is equal to Cocaine, persistent; The effect of lappaconitine nerve block is 5.25 times of Cocaine, be 13 times of PROCAINE HCL, PHARMA GRADE, and the effect of lappaconitine infiltration anesthesia is better than PROCAINE HCL, PHARMA GRADE and Cocaine far away.Simultaneously lappaconitine also has tight security, without additive, mutagenesis and carcinogenesis, to immunity system also without accumulation, stimulation, and the clinical advantage such as transformation reactions and toxic action.Prove through clinical application, in the usage and amount ranges of regulation, use none routine poisoning case of lappaconitine to occur.Clinical also confirmation lappaconitine has significant refrigeration function to various heating, and its refrigeration function is better than pyramidon, and cooling effect is equal to the Western medicine such as acetylsalicylic acid.
Crystal formation (crystalline forms, polymorphs) refers to the spread pattern of molecule in crystalline material lattice.Same medicine is due to the difference of drug crystal forms, its physics, chemistry (aspect such as solubleness, fusing point, dissolution rate, biological effectiveness) character may have remarkable difference, direct quality and the drug effect affecting medicine, therefore drug crystal forms research is also one of important content in new drug research.Lappaconitine crystal formation is not also had to study the relevant report with lappaconitine crystal formation patent at present.
Summary of the invention
Contriver studies through lot of experiments, has found the crystalline form α that a kind of lappaconitine is stable, the present invention is based on this and finds and complete.
Implementation procedure of the present invention:
The invention provides alpha-crystal form lappaconitine, use Cu-K α radiation, its X-ray powder diffraction represented with 2 θ angles is at 9.6 ± 0.2 °, and 10.2 ± 0.2 °, 16.5 ± 0.2 °, 16.9 ± 0.2 °, 19.0 ± 0.2 °, there is characteristic peak at 19.3 ± 0.2 ° of places.
Further, described alpha-crystal form lappaconitine, uses Cu-K α radiation, and its X-ray powder diffraction represented with 2 θ angles 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 °, there is characteristic peak at 25.4 ± 0.2 ° of places.
Further, described alpha-crystal form lappaconitine, use Cu-K α radiation, its X-ray powder diffraction represented with 2 θ 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 °, there is characteristic peak at 42.0 ± 0.2 ° of places.
In a specific embodiment, described alpha-crystal form lappaconitine, uses Cu-K α radiation, and it has collection of illustrative plates as illustrated in fig. 1 and 2 and data with the X-ray powder diffraction that 2 θ angles represent.
In the present invention, alpha-crystal form lappaconitine in the X-ray powder diffraction characteristic peak represented with 2 θ angles, the reasonable measuring error scope that " ± 0.2 ° " representation feature peak position allows.
Differential scanning calorimetric analysis (DSC) detected result of alpha-crystal form lappaconitine of the present invention is presented within the scope of 220-240 DEG C absorption peak; More specifically, sharp-pointed melting endotherm(ic)peak is had at 231 soil 2 DEG C of places; In one embodiment, described alpha-crystal form lappaconitine has DSC collection of illustrative plates as shown in Figure 3.
Present invention also offers a kind of method preparing alpha-crystal form lappaconitine, the method comprises the following steps:
(1) lappaconitine crude product is joined in the mixed solution of acetonitrile and other solvents, heating for dissolving;
(2) step (1) gained organic solvent solution is cooled to recrystallization temperature, natural crystallization;
(3) filter, dry, obtain the lappaconitine crystal formation α of crystalline form.
Other solvents wherein said be selected from the saturated straight chain of C1-5 or the cyclic ethers of branched-chain alcoho, ester, ketone, ether and C4-6 one or more; One or more in particular methanol, ethanol, Virahol, ethyl acetate, isopropyl acetate, acetone, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF); More preferably one or more in ethanol, ethyl acetate, acetone, tetrahydrofuran (THF).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.Recrystallization temperature is 0-20 DEG C, preferred 0-10 DEG C, more preferably 0-5 DEG C; The crystallization time is 1-12h, preferred 1-3h.
The temperature of heating for dissolving is the temperature that can make dissolution of solid in above-mentioned steps (1), and preferably 60 DEG C to reflux temperature, and more preferably 80 DEG C to reflux temperature; The temperature of heating for dissolving is reflux temperature in one embodiment.
The present invention also provides the purposes of alpha-crystal form lappaconitine in preparation high purity lappaconitine, this purposes can realize by the following method: unformed for 10g lappaconitine crude product heating is dissolved in 250ml acetonitrile-ethanol solution (V acetonitrile: V ethanol=1:0.5), cooling crystallization, suction filtration, drying, obtains highly purified lappaconitine; Wherein, described " high purity " refers to that its HPLC purity is more than 99.7%, and single foreign matter content is below 0.1%.
Alpha-crystal form lappaconitine provided by the invention has higher purity and good yield, and its purity is more than 99.7%, and single foreign matter content is below 0.1%; and its method technique is simple, easy to operate, mild condition; do not need special reaction conditions, be therefore applicable to large-scale production.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of alpha-crystal form lappaconitine;
Fig. 2 is the X-ray powder diffraction data of alpha-crystal form lappaconitine;
Fig. 3 is the DSC collection of illustrative plates of alpha-crystal form lappaconitine.
Specific embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.These embodiments are only for purpose of explanation, and do not limit the scope of the invention and essence.
The reagent used in the embodiment of the present invention and the method for employing are all the conventional reagent of this area and conventional working method.Hereinafter, if not specified, material therefor of the present invention and working method are well known in the art, but the present invention still describes in detail as far as possible.The unformed crude product of embodiment lappaconitine used is that obtained or identical with it (seemingly) the method for embodiment 1 obtains.
The testing tool that the present invention is used:
(1) X-ray powder diffractometer
INSTRUMENT MODEL: Thermo X ' TRA type X-ray powder diffraction analyser
Testing method: the sample (l00mg) after porphyrize is filled out in sheet glass groove according to Chinese Pharmacopoeia 2010 editions two (annex IX F x-ray powder diffraction), after its plane and glass surface hung flushing with slide glass, sample is placed in Thermo X ' TRA type X-ray powder diffraction analyser, use the copper X-ray source of 40kV 40mA, sweep limit is 2 ~ 45 ° (2 θ), sweep velocity 8 °/minute, 6 minutes sweep times.Scanning errors is generally soil 0.2 ° (2 θ).
(2) differential scanning calorimeter
INSTRUMENT MODEL: METTLER TGA/DSCI.
Testing method: according to JY/T014-1996 heat analysis method general rule, is placed in the sealed aluminum pan with little pin hole by the sample of heavy 3.10mg, keeps balance, be then heated to 350 DEG C with the scanning speed of 10 DEG C/min at 50 DEG C.Drying nitrogen is used as sweeping gas.
Embodiment 1: the preparation of unformed lappaconitine crude product
According to the report of related documents CN1088919A, consider the energy consumption in leaching process, pollution, temperature of reaction and easy and simple to handle etc., the technological process that we prepare is as follows:
Get the dry Aconitum sinomontanum Nakai root 0.25kg through pulverizing as in 2.5L round-bottomed flask, add ethanol 0.850L(85% concentration) soak 12h, filter centrifugation (2500r/min, 10min) after reflux 24h, supernatant liquor has been concentrated into crystallization through underpressure distillation and has occurred, reclaim ethanol, after standing 24h crystallization is complete, suction filtration gained solid, again through ethyl alcohol recrystallization, filters, then use Vanadium Pentoxide in FLAKES as siccative, in moisture eliminator, drying dewaters.Finally obtain unformed lappaconitine crude product 3.059g, productive rate is 0.61%.
Embodiment 2: the preparation of lappaconitine crystal formation α
Unformed for 5.0g lappaconitine crude product is joined in 100ml acetonitrile and 50ml alcohol mixed solvent, is heated to dissolve, slow cooling to 0 ~ 5 DEG C crystallization 2h, suction filtration, 50 DEG C of vacuum-dryings, obtain 4.l g white lappaconitine crystal formation α, yield about 82%, HLPC purity 99.8%; After measured, as shown in Figure 1, its DSC collection of illustrative plates as shown in Figure 3 for its X-ray powder diffraction.
Embodiment 3: the preparation of lappaconitine crystal formation α
Unformed for 5.0g lappaconitine crude product is joined in 100ml acetonitrile and 20ml acetone, is heated to dissolve, slow cooling to 0 ~ 5 DEG C crystallization 1h, suction filtration, 50 DEG C of vacuum-dryings, obtain 3.6g white lappaconitine crystal formation α, yield 72%, HLPC purity 99.7%; After measured, its X-ray powder diffraction and Fig. 1 basically identical, its DSC collection of illustrative plates and Fig. 3 basically identical.
Embodiment 4: the preparation of lappaconitine crystal formation α
Unformed for 5.0g lappaconitine crude product is joined in the mixed solvent of 100ml acetonitrile and 20ml methyl alcohol, heating for dissolving, slow cooling to 0 ~ 5 DEG C crystallization 1h, suction filtration, 50 DEG C of vacuum-dryings, obtain 3.8g white lappaconitine crystal formation α, yield 76%, HLPC purity 99.8%; After measured, its X-ray powder diffraction and Fig. 1 basically identical, its DSC collection of illustrative plates and Fig. 3 basically identical.
Embodiment 5: the preparation of lappaconitine crystal formation α
5.0g lappaconitine crude product is joined in 150ml acetonitrile and 50ml Virahol, is heated to backflow and dissolves, slow cooling to 0 ~ 5 DEG C crystallization 1h, suction filtration, 50 DEG C of vacuum-dryings, obtain 3.4g white lappaconitine crystal formation α, yield 68%, HLPC purity 99.8%; After measured, its X-ray powder diffraction and Fig. 1 basically identical, its DSC collection of illustrative plates and Fig. 3 basically identical.
Embodiment 6: the preparation of lappaconitine crystal formation α
5.0g lappaconitine crude product is joined in 150ml acetonitrile and 50ml ethyl acetate, heating for dissolving, slow cooling to 0 ~ 5 DEG C crystallization 1h, suction filtration, 50 DEG C of vacuum-dryings, obtain 3.0g white lappaconitine crystal formation α, yield 65%, HLPC purity 99.9%; After measured, its X-ray powder diffraction and Fig. 1 basically identical, its DSC collection of illustrative plates and Fig. 3 basically identical.
Embodiment 7: stability test
Although amorphous drug all has higher solubleness and dissolution rate compared with crystal formation medicine in most of occasion, the principal element affecting amorphous drug Clinical practice is their processing stability and storage stability.In addition, in process of production, the loose density of some amorphous particle is less, and surface free energy is high, a series of formulation problems such as also easily cause cohesion, poor fluidity, elastic deformability strong.Therefore, crystal formation medicine has more advantage in preparation stability.
Applicant investigates lappaconitine crystal formation α stability at different conditions, and the method for concrete study on the stability can with reference to the method for Chinese Pharmacopoeia 2010 editions second annex XIX; Purity detecting HPLC method, can with reference to the method for Chinese Pharmacopoeia 2010 editions second annex V D; The detection of crystal formation is with the method for embodiment.
The each portion of lappaconitine crystal formation α of Example 2, embodiment 3 preparation, is placed on 45 DEG C/humidity 75% condition lower 30 days, investigates its stability, the results are shown in Table 1.
Above data show, its purity and crystal formation all have satisfactory stability to the lappaconitine crystal formation α that the present invention obtains at typical condition.
Embodiment 8: dissolubility test
The solvability of medicine directly affects stripping and the oral administration biaavailability of pharmaceutical preparation, and for investigating the solvability of lappaconitine crystal formation α, contriver investigates its solvability in different condition (in water),
Test-results shows, amorphous lappaconitine and the solubleness of alpha-crystal form lappaconitine in water all raise with the rising of temperature, at identical temperature, the water-soluble of alpha-crystal form lappaconitine is better than amorphous lappaconitine, and this is that alpha-crystal form lappaconitine has established good basis for the preparation of the pharmaceutical preparation that stripping is good.
Claims (10)
1. alpha-crystal form lappaconitine, is characterized in that: use Cu-K α radiation, and its X-ray powder diffraction represented with 2 θ angles is at 9.6 ± 0.2 °, and 10.2 ± 0.2 °, 16.5 ± 0.2 °, 16.9 ± 0.2 °, 19.0 ± 0.2 °, there is characteristic peak at 19.3 ± 0.2 ° of places.
2. alpha-crystal form lappaconitine, it is characterized in that: use Cu-K α radiation, its X-ray powder diffraction represented with 2 θ angles 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 °, there is characteristic peak at 25.4 ± 0.2 ° of places.
3. alpha-crystal form lappaconitine, it is characterized in that: use Cu-K α radiation, its X-ray powder diffraction represented with 2 θ 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 °, there is characteristic peak at 42.0 ± 0.2 ° of places.
4. alpha-crystal form lappaconitine according to claim 3, is characterized in that: alpha-crystal form lappaconitine uses Cu-K α radiation, and it has collection of illustrative plates as shown in Figure 1 with the X-ray powder diffraction that 2 θ angles represent.
5. according to one of any described alpha-crystal form lappaconitine of claim 1-3, it is characterized in that: the differential scanning calorimetric analysis detected result of described alpha-crystal form lappaconitine is presented at 231 soil 2 DEG C of places sharp-pointed melting endotherm(ic)peak.
6. the preparation method of one of any described alpha-crystal form lappaconitine of claim 1-3, is characterized in that comprising the following steps:
(1) lappaconitine crude product is joined in the mixed solution of acetonitrile and other solvents, heating for dissolving;
(2) step (1) gained organic solvent solution is cooled to recrystallization temperature, natural crystallization;
(3) filter, dry, obtain the alpha-crystal form lappaconitine of crystalline form;
Other solvents described be selected from the saturated straight chain of C1-5 or the cyclic ethers of branched-chain alcoho, ester, ketone, ether and C4-6 one or more.
7. preparation method according to claim 6, is characterized in that: one or more in other solvent selected from methanol, ethanol, Virahol, ethyl acetate, isopropyl acetate, acetone, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF).
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. preparation method according to claim 6, is characterized in that: described recrystallization temperature is 0-20 DEG C, and the crystallization time is 1-12h.
10. alpha-crystal form lappaconitine described in claim 1-3 is preparing the purposes in high-purity alpha crystal formation lappaconitine, it is characterized in that: unformed for 10g lappaconitine crude product heating is dissolved in the 250ml acetonitrile-ethanol solution that volume ratio is 1:0.5, cooling crystallization, suction filtration, drying, obtains highly purified alpha-crystal form lappaconitine, wherein, described high purity refers to that its HPLC purity is more than 99.7%, and single foreign matter content is below 0.1%.
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Cited By (2)
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| RU2624240C1 (en) * | 2016-06-01 | 2017-07-03 | Закрытое акционерное общество "Фармцентр ВИЛАР" (ЗАО "Фармцентр ВИЛАР") | Method for obtaining means with anti-arithmal action |
| CN108997216A (en) * | 2018-07-20 | 2018-12-14 | 西安惠博生物科技有限公司 | Lappaconitine crystal, preparation method, lappaconitine freeze-dried powder and preparation method |
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