CN102924295A - Bromhexine hydrochloride crystal as well as preparation method and application of crystal - Google Patents
Bromhexine hydrochloride crystal as well as preparation method and application of crystal Download PDFInfo
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- YHXJLPRSAMJGSL-UHFFFAOYSA-N CCC(CC)N(C)Cc(cc(cc1Br)Br)c1N Chemical compound CCC(CC)N(C)Cc(cc(cc1Br)Br)c1N YHXJLPRSAMJGSL-UHFFFAOYSA-N 0.000 description 1
- RQJFMNQNCRVVFJ-UHFFFAOYSA-N O=C1OCc2cc(Br)cc(Br)c2N1 Chemical compound O=C1OCc2cc(Br)cc(Br)c2N1 RQJFMNQNCRVVFJ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides a bromhexine hydrochloride crystal as well as a preparation method and application of the bromhexine hydrochloride crystal. According to the crystal, an X-ray powder diffraction picture under the radiation of Cu KAlpha1 has diffraction peaks in a part with reflection angles 2 Theta of 7.29, 14.33 and 24.439. The crystal can obviously improve the water solubility of bromhexine hydrochloride, and is beneficial for the preparation of an injection; and relative materials can be further reduced, so that the safety of the preparation can be improved.
Description
Technical field
The present invention relates to a kind of bromhexine hydrochloride crystal and its production and use.
Background technology
Bromhexine hydrochloride (Bromhexine Hydrochloride) is white or off-white color crystalline powder, odorless, tasteless, slightly soluble in ethanol and trichloromethane, soluble,very slightly in water, its chemical name is Bromhexine Hydrochloride, and chemical structural formula is as follows:
Bromhexine hydrochloride is first-selected expectorant commonly used both at home and abroad, can make acidic mucopolysaccharide fiber decomposition fracture in the phlegm, and can suppress body of gland goblet cell synthetic acidic mucopolysaccharide, thereby make the sputum reduced viscosity, is easy to expectoration, there is no nauseating property phlegm-dispelling functions.Be mainly used in the adularescents such as chronic bronchitis, asthma, bronchiectasis, silicosis and glue the patient that phlegm is difficult for again expectoration, be particularly useful for surgical operation and urgent patient.
At present, medicinal hydrochloric acid bromhexine crystal (crystalline form I) usually adopts existing bibliographical information method (DE2411848A1 for example, GB1421580A, ZL 201010124730.4 etc.) prepare, these preparation methods normally the single solvent of water or lower alcohol (methyl alcohol, ethanol, Virahol) or the two component mixed solvents that contain a small amount of moisture (water content＜30%) (such as 95% ethanol, 90% ethanol) as recrystallisation solvent, after the heating for dissolving cooling crystallization or directly in bromhexine alkali and HCl salification process crystallization finish preparation to the bromhexine hydrochloride crystal.The X diffracting spectrum of the product that obtains is seen Fig. 3, and infrared absorption pattern is seen Fig. 4.
Above-mentioned crystallisation process, the solvent usage quantity is large, the purification step inefficiency, product purity is poor.For example ethanol is recrystallisation solvent, bromhexine hydrochloride and ethanol feed ratio (mass/volume)＜1:30, and the rate of recovery 40%, the primary crystallization product always mixes＞0.3%, and mass crystallization needs through overweight steaming recycling with solvent, and the production cycle is long, has strengthened production cost.
Chinese Pharmacopoeia 2010 editions has improved bromhexine hydrochloride related substance standard, is unfavorable for going out of impurity based on the crystallization method of prior art, needs can to obtain meeting through crystallization operation repeatedly the bromhexine hydrochloride product of pharmacopeia regulation in the production.
Summary of the invention
In order to overcome the defective of prior art, the invention provides a kind of bromhexine hydrochloride crystal and its production and use.Adopt preparation method of the present invention to prepare the bromhexine hydrochloride rate of recovery high, the product purity of preparation is high.
Above-mentioned purpose of the present invention is achieved through the following technical solutions.
On the one hand, the invention provides a kind of crystal (being the crystal II) of bromhexine hydrochloride, this crystal uses Cu K α
1The X-ray powder diffraction pattern of radiation is that 7.29,14.33,21.439 places have diffraction peak at reflection angle 2 θ.
Preferably, described crystal uses Cu K α
1The X-ray powder diffraction pattern of radiation is that 14.581,18.236,21.856 and 43.347 places have diffraction peak at reflection angle 2 θ also.
Preferably, described crystal uses Cu K α
1The X-ray powder diffraction pattern of radiation comprises corresponding to following reflection angle 2 θ, spacing d, intensity I and relative intensity I/I
0The peak:
| Reflection angle 2 θ | Spacing d | Intensity I | Relative intensity I/I 0 |
| 5.153 | 17.13526 | 15 | 0.3 |
| 7.29 | 12.11663 | 5389 | 100 |
| 11.019 | 8.02276 | 44 | 0.8 |
| 13.72 | 6.44906 | 56 | 1 |
| 14.33 | 6.17587 | 3308 | 61.4 |
| 14.581 | 6.07006 | 258 | 4.8 |
| 15.227 | 5.81391 | 27 | 0.5 |
| 17.448 | 5.07873 | 13 | 0.2 |
| 18.236 | 4.86087 | 444 | 8.2 |
| 19.925 | 4.4525 | 21 | 0.4 |
| 20.516 | 4.3256 | 23 | 0.4 |
| 21.439 | 4.14133 | 1094 | 20.3 |
| 21.856 | 4.06162 | 274 | 5.1 |
| 22.14 | 4.01181 | 50 | 0.9 |
| 23.165 | 3.83664 | 90 | 1.7 |
| 24.457 | 3.6368 | 30 | 0.6 |
| 26.354 | 3.37915 | 34 | 0.6 |
| 26.891 | 3.31286 | 60 | 1.1 |
| 28.618 | 3.11675 | 101 | 1.9 |
| 29.099 | 3.0663 | 148 | 2.7 |
| 29.478 | 3.02768 | 47 | 0.9 |
| 30.218 | 2.95527 | 62 | 1.2 |
| 30.768 | 2.90361 | 26 | 0.5 |
| 31.512 | 2.83674 | 21 | 0.4 |
| 32.974 | 2.71424 | 117 | 2.2 |
| 33.298 | 2.68868 | 60 | 1.1 |
| 35.548 | 2.52337 | 103 | 1.9 |
| 35.894 | 2.49986 | 70 | 1.3 |
| 36.165 | 2.48171 | 69 | 1.3 |
| 36.509 | 2.45913 | 61 | 1.1 |
| 36.8 | 2.44034 | 24 | 0.4 |
| 39.546 | 2.27699 | 85 | 1.6 |
| 40.451 | 2.22814 | 36 | 0.7 |
| 42.394 | 2.13041 | 84 | 1.6 |
| 43.347 | 2.08574 | 249 | 4.6 |
| 44.292 | 2.04341 | 16 | 0.3 |
| 46.484 | 1.95203 | 33 | 0.6 |
| 48.129 | 1.8891 | 32 | 0.6 |
| 50.298 | 1.81258 | 29 | 0.5 |
| 50.96 | 1.79058 | 58 | 1.1 |
| 56.055 | 1.6393 | 25 | 0.5 |
| 58.842 | 1.56811 | 104 | 1.9 |
More preferably, described crystal uses Cu K α
1The X-ray powder diffraction pattern of radiation as shown in Figure 1.
Preferably, the infrared spectrogram of described crystal is 3440.8,3325.1, and 3238.3,3209.6,2931.6,2673.2,2630.7,2578.7,1633.6,1456.2, there is charateristic avsorption band at 1305.7,871.8,854.4,690.5 places.
Preferably, the infrared spectrogram of described crystal as shown in Figure 2.
On the other hand, the invention provides a kind of preparation method (namely the bromhexine hydrochloride crude product being carried out the method for crystallization) of above-mentioned crystal, the method comprises the steps:
1) bromhexine hydrochloride is added to C
1To C
5In the recrystallisation solvent of lower alcohol-water, heating is dissolving fully;
2) add activated carbon decolorizing, filter, crystallization, ageing separates obtaining crystal and dry.
Preferably, described C
1To C
5Lower alcohol is selected from one or more in methyl alcohol, ethanol, propyl alcohol and the Virahol, is preferably ethanol.
Preferably, in volume percent, in the recrystallisation solvent volume content of water to be not less than 30%(be water content 〉=30%), be preferably 30%.
Preferably, in step 1), described bromhexine hydrochloride is 1:8 ~ 1:25(mass/volume with the ratio of described recrystallisation solvent consumption, g/ml), is preferably the 1:15(mass/volume, g/ml); Preferably, described Heating temperature is 50 ~ 85 ℃, is preferably 75 ℃.
Preferably, in step 2) in, the gac usage quantity is 1% ~ 10% of bromhexine hydrochloride quality, is preferably 5%; Preferably, recrystallization temperature is-20 ℃ ~ 30 ℃, is preferably 25 ℃; Preferably, digestion time is not less than 3h, is preferably 5h.
The bromhexine hydrochloride of using among the preparation method of the present invention can be bought acquisition or prepare with any method well known in the art, for example can prepare by the following method:
Syntheti c route 1:
With 2-amino-3, the 5-dibromobenzoic acid is raw material, through condensing agent dicyclohexylcarbodiimide (DCC) and catalyzer DMAP (DMAP) activation, direct and N-methylcyclohexylamine condensation makes N-methyl-N-cyclohexyl-2-amino-3,5-dibromobenzene methane amide makes bromhexine (free alkali) through the lithium borohydride reduction again.
Syntheti c route 2:
As starting raw material, with N-methylcyclohexylamine generation amination reaction, get 2-{[cyclohexyl (methyl) amido through the hydrazine hydrate reduction nitro again with 2-nitrobenzyl bromine first] methyl } aniline, again through the bromine bromo, the HCl salify gets the target compound bromhexine hydrochloride.
Syntheti c route 3:
Similar to syntheti c route 2, as starting raw material, first with N-methylcyclohexylamine generation amination reaction, get 2-{[cyclohexyl (methyl) amido through ni-mh reduction nitro again with 2-nitrobenzyl bromine] methyl } aniline, get the bromhexine free alkali through the bromine bromo again.
Syntheti c route 4:
[1,3] oxazine-2-ketone is raw material, and with bromine generation bromo-reaction, again through open loop, the N-methylcyclohexylamine amination makes the bromhexine free alkali first with 1H-benzo [d].
Syntheti c route 5:
With 2,4-, two bromo-6-{[cyclohexyl (methyl) amidos] methyl } phenylformic acid is raw material, makes the bromhexine free alkali with one step of sodium azide generation amination reaction.
Syntheti c route 6:
Amino-3 with 2-, 5-dibromobenzene methyl alcohol is starting raw material, under-70 ℃ of conditions through Tosyl chloride catalysis and N-methylcyclohexylamine reaction, and must the target compound bromhexine hydrochloride behind the HCl salify.
Syntheti c route 7:
With 2-amino-3, the 5-dibromo benzaldehyde is starting raw material, through sodium borohydride reduction, and the sulfur oxychloride chloro, the N-methylcyclohexylamine amination, the HCl salify gets the finished product bromhexine hydrochloride.
In the above-mentioned syntheti c route, route 1-5 exists starting raw material or intermediate to be not easy to obtain, severe reaction conditions, and yield is low, the problems such as poor product quality.In the suitability for industrialized production mainly with route 6 and route 7 as the method for preparing bromhexine hydrochloride, bromhexine hydrochloride is pressed route 6 and route 7 preparations, the related substances situation is similar, mainly comprise: (2-amino-3 for impurity A, the 5-dibromo benzaldehyde), (2-amino-3 for impurity B, 5-dibromobenzene methyl alcohol), impurity C(2-is amino-3, the 5-dibromobenzoic acid), impurity D, impurity E.
Preparation method's rate of recovery of the present invention is not less than 70%, and the bromhexine hydrochloride crystal maximum of preparation not notice of invitation mixes≤0.1%, always mixes≤0.3%, meets 2010 editions Chinese Pharmacopoeias to the relevant regulations of bromhexine hydrochloride related substance.
Another aspect the invention provides a kind of pharmaceutical composition, and it comprises described bromhexine hydrochloride crystal, and optional pharmaceutically acceptable vehicle and/or carrier.
Preferably, described pharmaceutical composition is the form of injection, sterile injection powder or frozen powder for injection.
Again on the one hand, the invention provides described bromhexine hydrochloride crystal and/or described pharmaceutical composition for the preparation of the purposes in the medicine for the treatment of chronic bronchitis and other respiratory tract diseases.
The bromhexine hydrochloride crystal of the present invention's preparation can obviously improve the water-soluble of bromhexine hydrochloride, more is conducive to the preparation of injection, and related substance is further reduced, and the security of preparation is improved.
Compared with prior art, bromhexine hydrochloride crystal of the present invention possesses following beneficial effect at least:
Use the finished product purity that crystallizing system of the present invention obtains good, be conducive to improve quality and the drug safety of bromhexine hydrochloride injection liquid.Related substance meets 2010 editions bromhexine hydrochloride relevant regulations of Chinese Pharmacopoeia, and namely total mixing is lower than 0.3%, and maximum is notice of invitation assorted≤0.1% not.And prior art uses single lower alcohol crystallizing system often to need repeatedly recrystallization just can reach this standard.
The inventive method crystallization rate of recovery is high, and the rate of recovery is more than 60%, and the crystallization condition rate of recovery through optimizing can reach more than 80%.
Crystallization method of the present invention, the low price of the few and partial solvent water that adds of recrystallisation solvent usage quantity, crystalline rate is high, and production cost is low.
New Crystal type stability and the solvability in water that the inventive method obtains are better than the prior art crystal formation, are beneficial to preparation bromhexine hydrochloride injection formulation.
Description of drawings
Fig. 1 is the powder X-ray-diffractogram of bromhexine hydrochloride crystal of the present invention (crystal II);
Fig. 2 is the infrared spectrogram of bromhexine hydrochloride crystal of the present invention (crystal II);
Fig. 3 is the powder X-ray-diffractogram by the crystal (crystal I) of published technical scheme (as: DE2411848A1, GB1421580A, ZL201010124730.4 etc.) preparation;
Fig. 4 is the infrared spectrogram by the crystal (crystal I) of published technical scheme (as: DE2411848A1, GB1421580A, ZL201010124730.4 etc.) preparation.
Embodiment
Embodiment 1: the preparation method of bromhexine hydrochloride alkali
(1) 2-is amino-3,5-dibromobenzene methyl alcohol synthetic
2-amino-3,5-dibromo benzaldehyde 11.2g(0.04mol) is suspended among the ethanol 20ml, 25 degree following (the ice-water bath cooling is lower), add sodium borohydride solids 0.95g(0.025mol in the 15min) in batches, finish, stir 1.5h under the room temperature, adding distil water 50ml dilution, 6% hydrochloric acid adjust pH to 6 under the room temperature, vigorous stirring 0.5h.Filter, distilled water (20ml * 3) washing is drained, and dry (70 degree 2h) gets off-white color solid 2-amino-3,5-dibromobenzene methyl alcohol.
Synthesizing of (2) 2,4-two bromo-6-chloromethyl aniline
Ice-water bath cooling lower (5-25 degree) is in the 10min, to 30mlSOCl
2In add 2-amino-3,5-dibromobenzene methyl alcohol 10g(0.0357mol in batches), finish, spend the night under the stirring at room.The excessive SOCl of the 30 following evaporated under reduced pressure of degree
2, steam a large amount of SOCl
2Rear adding 10mlCH
2Cl
2Continue distillation and take residual volume SOCl out of
2, add sherwood oil 15ml, filter to get faint yellow solid 2,4-two bromo-6-chloromethyl aniline (intermediate is unstable, and not adding purifies is directly used in the next step).
(3) bromhexine alkali is synthetic
Synthesizing of crude product
Ice-water bath cooling lower (0-25 degree), in the 10min to N-methylcyclohexylamine 11.3g(0.1mol) in add upper step reaction product in batches, finish the lower 2h of stirring of 35 degree, add dehydrated alcohol 30ml, after being heated to backflow, the gac 0.5g 20min that decolours, heat filtering is behind the evaporated under reduced pressure solvent, the remaining N-methylcyclohexylamine of oil pump evaporate to dryness, add ethyl acetate 40ml, stir 10min and filter, namely get the ethyl acetate solution of bromhexine alkali.
(4) the bromhexine hydrochloride crude product is synthetic
Above-mentioned filtrate is used the ethanol solution hydrochloride adjust pH to 6 of 2N, and refrigeration 2.5h filters, and the cold washing with alcohol of 10ml gets the bromhexine hydrochloride crude product.
Embodiment 2: by the crystallization of published technical scheme (DE2411848A1, example 3) preparation bromhexine hydrochloride
Press embodiment 1 operation, be evaporated to the ethyl acetate solution of the bromhexine alkali of gained among the embodiment 1 dried, the HCl ethanolic soln and the distilled water 2ml that add 40ml 17%, 70 ℃ of lower 1.5h that stir, stopped heating, add 25ml ethanol and stir lower cooling crystallization, filter to get bromhexine hydrochloride crystallization 10g, lot number: 110101-a.Through X diffraction and infrared analysis, the X diffracting spectrum of bromhexine hydrochloride crystallization 110101-a is consistent with Fig. 3, and infrared absorption pattern is consistent with Fig. 4, judges that thus according to said method the crystal formation of preparation is consistent with crystalline form I.
Embodiment 3: by the crystallization of published technical scheme (DE2411848A1, example 1) preparation bromhexine hydrochloride
Press embodiment 1 operation, the ethyl acetate solution of the bromhexine alkali of gained among the embodiment 1 is evaporated to dried, residuum is dissolved in the 80ml dehydrated alcohol, slowly is added dropwise to concentrated hydrochloric acid 6ml, and the dropping process has solid to separate out, and dropwises, and filters.Filter cake gets bromhexine hydrochloride crystallization 8.9g with 330ml dehydrated alcohol recrystallization.Lot number: 110101-b.Through X diffraction and infrared analysis, the X diffracting spectrum of bromhexine hydrochloride crystallization 110101-b is consistent with Fig. 3, and infrared absorption pattern is consistent with Fig. 4, judges that thus according to said method the crystal formation of preparation is consistent with crystalline form I.
Embodiment 4:: by the crystallization of published technical scheme (ZL 201010124730.4) preparation bromhexine hydrochloride
Press embodiment 1 operation, be evaporated to the ethyl acetate solution of the bromhexine alkali of gained among the embodiment 1 dried, residuum is dissolved in the 110ml dehydrated alcohol, slowly pass into dry HCl 5g, stir 2h, reaction solution is in 0 degree crystallization, filter, behind twice of the 10ml absolute ethanol washing filter cake, filter cake gets bromhexine hydrochloride crystallization 10.6g, lot number: 110101-c with 350ml dehydrated alcohol recrystallization.Through X diffraction and infrared analysis, the X diffracting spectrum of bromhexine hydrochloride crystallization 110101-c is consistent with Fig. 3, and infrared absorption pattern is consistent with Fig. 4, judges that thus according to said method the crystal formation of preparation is consistent with crystalline form I.
Embodiment 5: by the crystallization of published technical scheme (GB1421580A) preparation bromhexine hydrochloride
Press embodiment 1 operation, be evaporated to the ethyl acetate solution of the bromhexine alkali of gained among the embodiment 1 dried, residuum adds the 20ml concentrated hydrochloric acid, under the room temperature after the vigorous stirring, add 160ml distilled water, be heated to 50 degree and stir 1h, let cool rear filtration, get bromhexine hydrochloride crystallization 7.2g, lot number: 110101-d.
Through X diffraction and infrared analysis, the X diffracting spectrum of bromhexine hydrochloride crystallization 110101-d is consistent with Fig. 3, and infrared absorption pattern is consistent with Fig. 4, judges that thus according to said method the crystal formation of preparation is consistent with crystalline form I.
Embodiment 6: preparation method's research of bromhexine hydrochloride new crystal
Press embodiment 1 operation, with the ethyl acetate of the bromhexine alkali of gained among the embodiment 1 HCl ethanolic soln adjust pH to 6 with 2N, refrigeration 2.5h filters, and the cold washing with alcohol of 10ml gets the bromhexine hydrochloride crude product.
Prepare separately three batches of bromhexine hydrochloride crude products, lot number: 110101,110103,110105 with this method Chinese style scale.
The selection of recrystallisation solvent is great to the quality influence of product among the preparation method of the present invention, suitable recrystallisation solvent and reasonably crystallization operation played vital role to eliminating product impurity.Bromhexine hydrochloride belongs to the mono-hydrochloric salts structure of tertiary amine, under the normal temperature in majority of organic solvent solubleness limited, and contain the fat-soluble structures such as substituted benzene ring and hexa-atomic saturated carbon ring in its structure, therefore water-soluble also extreme difference.
For the bromhexine hydrochloride constructional feature, we at first select water and lower alcohols as recrystallisation solvent.Make respectively water, methyl alcohol, ethanol, propyl alcohol and Virahol as single solvent bromhexine hydrochloride be carried out the recrystallization experiment.Experimental result shows, by reflux is to fully dissolving in water, methyl alcohol, ethanol, propyl alcohol and Virahol respectively with bromhexine hydrochloride, activated carbon decolorizing leaves standstill under the room temperature, and the steps such as filtration all can realize the crystallization to bromhexine hydrochloride.But water, propyl alcohol and Virahol be owing to the excessive crystallization operation that is unsuitable for of heating for dissolving Solvent volume, and be not high as the crystallization experiment rate of recovery of solvent with methyl alcohol, ethanol one-component, all below 40%.The bromhexine hydrochloride crystallization crystal that obtains through Infrared spectroscopy and powder x-ray diffraction analysis as can be known, make water or single lower alcohol as recrystallisation solvent, the crystallization crystalline structure that obtains is consistent and consistent with present medicinal crystal, and (present medicinal crystal is take ethanol as recrystallisation solvent, crystalline form I), its powder X-ray-diffractogram is seen Fig. 3, and infrared spectrogram is seen Fig. 4.
In order to improve the crystallization rate of recovery, consider in crystallisation process, to select alcohol-water mixed solvent as the recrystallisation solvent system.Therefore, use 50 volume % methyl alcohol, 60 volume % methyl alcohol, 70 volume % methyl alcohol, 80 volume % methyl alcohol, 90 volume % methyl alcohol, 95 volume % methyl alcohol have been investigated respectively; 50 volume % ethanol, 60 volume % ethanol, 70 volume % ethanol, 75 volume % ethanol, 80 volume % ethanol, 90 volume % ethanol, 95 volume % ethanol; 50 volume % propyl alcohol, 60 volume % propyl alcohol, 70 volume % propyl alcohol, 80 volume % propyl alcohol, 90 volume % propyl alcohol, 95 volume % propyl alcohol; 50 volume % Virahols, 60 volume % Virahols, 70 volume % Virahols, 80 volume % Virahols, 90 volume % Virahols, 95 volume % Virahols carry out the situation of recrystallization to bromhexine hydrochloride crude product (lot number 110104) as recrystallisation solvent, the results are shown in Table 1.
Table 1 crystallization experiment result of study
Annotate: I represents the crystal that crystallization (ethanol, crystalline form I) that prior art obtains obtains; II represents new crystal of the present invention (crystal form II).
The result shows: use alcohol-water mixed solvent higher as the recrystallisation solvent rate of recovery, through infrared and powder X-ray-diffraction analysis as can be known, when water content is not less than the 30%(volume in small molecular alcohol and water mixed solvent) when above, the bromhexine hydrochloride crystallization crystal that obtains is new crystal of the present invention (crystal form II).
In addition, find through test of many times research: 70 volume % ethanol are the optimum proportion of recrystallisation solvent system, and under this ratio, used recrystallisation solvent volume is reasonable, and crystallization speed is moderate, and the product crystal outward appearance is good.After determining to use 70 volume % ethanol as the recrystallisation solvent system, by experiment other related process parameters are optimized, thereby determine solvent usage quantity, gac usage quantity, the type of cooling and crystallization digestion time.
Experimental result shows: take 70 volume % ethanol as the recrystallisation solvent system, bromhexine hydrochloride crude product quality and 70% ethanol volume ratio (mass volume ratio, W/V) should be between 1:8 ~ 1:25, preferred 1:15, the gac add-on is 1% ~ 10% of bromhexine hydrochloride quality, be preferably 5%, recrystallization temperature is-20 ℃ ~ 30 ℃, be preferably 25 ℃, digestion time is not less than 3h, is preferably 5h, under this crystallization condition, the bromhexine hydrochloride crystallization rate of recovery is more than 70%, and product purity reaches (HPLC area normalization method) more than 99.8%.
Embodiment 7
The charge ratio table
Add bromhexine hydrochloride crude product (lot number 110101) 2.60kg in the 50L crystallization kettle, 70 volume % ethanol 39L, reflux is to fully dissolving, slightly cold adding gac 0.08kg, continue backflow 20min, leave standstill cooling crystallization under the filtered while hot, room temperature, ageing 6h, filter methyl alcohol (1L * 3) washing, 85 ℃ of lower dry 2h, get bromhexine hydrochloride crystal (lot number JB 110201) 2.2kg, reaction yield 85%.
Use instrument to be D8ADVANCE type X-ray diffractometer, test condition: Cu K α 1 radiation, graphite monochromator, 40kV, 150mA, 2 θ sweep limit 5-60 degree, sweep velocity 8 degree/minute, step-length 0.02 degree.Bromhexine hydrochloride crystal to above preparation detects, and obtains powder X-ray-diffractogram (Fig. 1), and measurement result sees Table 2.
The new crystal powder X-of table 2 bromhexine hydrochloride diffraction detects data
| Reflection angle 2 θ | Spacing d | Intensity I | Relative intensity I/I 0 |
| 5.153 | 17.13526 | 15 | 0.3 |
| 7.29 | 12.11663 | 5389 | 100 |
| 11.019 | 8.02276 | 44 | 0.8 |
| 13.72 | 6.44906 | 56 | 1 |
| 14.33 | 6.17587 | 3308 | 61.4 |
| 14.581 | 6.07006 | 258 | 4.8 |
| 15.227 | 5.81391 | 27 | 0.5 |
| 17.448 | 5.07873 | 13 | 0.2 |
| 18.236 | 4.86087 | 444 | 8.2 |
| 19.925 | 4.4525 | 21 | 0.4 |
| 20.516 | 4.3256 | 23 | 0.4 |
| 21.439 | 4.14133 | 1094 | 20.3 |
| 21.856 | 4.06162 | 274 | 5.1 |
| 22.14 | 4.01181 | 50 | 0.9 |
| 23.165 | 3.83664 | 90 | 1.7 |
| 24.457 | 3.6368 | 30 | 0.6 |
| 26.354 | 3.37915 | 34 | 0.6 |
| 26.891 | 3.31286 | 60 | 1.1 |
| 28.618 | 3.11675 | 101 | 1.9 |
| 29.099 | 3.0663 | 148 | 2.7 |
| 29.478 | 3.02768 | 47 | 0.9 |
| 30.218 | 2.95527 | 62 | 1.2 |
| 30.768 | 2.90361 | 26 | 0.5 |
| 31.512 | 2.83674 | 21 | 0.4 |
| 32.974 | 2.71424 | 117 | 2.2 |
| 33.298 | 2.68868 | 60 | 1.1 |
| 35.548 | 2.52337 | 103 | 1.9 |
| 35.894 | 2.49986 | 70 | 1.3 |
| 36.165 | 2.48171 | 69 | 1.3 |
| 36.509 | 2.45913 | 61 | 1.1 |
| 36.8 | 2.44034 | 24 | 0.4 |
| 39.546 | 2.27699 | 85 | 1.6 |
| 40.451 | 2.22814 | 36 | 0.7 |
| 42.394 | 2.13041 | 84 | 1.6 |
| 43.347 | 2.08574 | 249 | 4.6 |
| 44.292 | 2.04341 | 16 | 0.3 |
| 46.484 | 1.95203 | 33 | 0.6 |
| 48.129 | 1.8891 | 32 | 0.6 |
| 50.298 | 1.81258 | 29 | 0.5 |
| 50.96 | 1.79058 | 58 | 1.1 |
| 56.055 | 1.6393 | 25 | 0.5 |
| 58.842 | 1.56811 | 104 | 1.9 |
Use instrument to be Shimadzu FTIR-8400s type Fourier transform infrared spectrometer, condition determination: the KBr compressing tablet, wave number is proofreaied and correct with polystyrene film, and the bromhexine hydrochloride crystal of above preparation is detected, obtain infrared spectrogram (Fig. 2), measurement result sees Table 3.
The new crystal infrared absorption peak of table 3 bromhexine hydrochloride and ownership thereof
Embodiment 8
The charge ratio table
Add bromhexine hydrochloride crude product (lot number: 110103) 2.60kg, 80 volume % ethanol 52L, extremely fully dissolving of reflux in the 50L crystallization kettle, slightly cold adding gac 0.08kg, continue backflow 20min, leave standstill cooling crystallization under the filtered while hot, room temperature, ageing 6h, filter methyl alcohol (1L * 3) washing, 85 ℃ of lower dry 2h, get bromhexine hydrochloride crystal (lot number JB 110203) 2.0kg, reaction yield 78%.Product X diffracting spectrum is consistent with Fig. 1, and infrared absorption pattern is consistent with Fig. 2, judges that thus according to said method the crystal formation of preparation is consistent with crystal form II.
Embodiment 9
The charge ratio table
Add bromhexine hydrochloride crude product (lot number: 110105) 2.60kg, 70 volume % methyl alcohol 47L, extremely fully dissolving of reflux in the 50L crystallization kettle, slightly cold adding gac 0.08kg, continue backflow 20min, leave standstill cooling crystallization under the filtered while hot, room temperature, ageing 6h, filter methyl alcohol (1L * 3) washing, 85 ℃ of lower dry 2h, get bromhexine hydrochloride crystal (lot number JB 110205) 1.9kg, reaction yield 74%.Product X diffracting spectrum is consistent with Fig. 1, and infrared absorption pattern is consistent with Fig. 2, judges that thus according to said method the crystal formation of preparation is consistent with crystal form II.
Embodiment 10: bromhexine hydrochloride related substance HPLC detection method
Related substance: measure according to high performance liquid chromatography (2010 editions two appendix V D of Chinese Pharmacopoeia).
Chromatographic condition and system suitability: the usefulness chromatographic column (Diamonsil C-185 μ 150mm * 4.6mm), take acetonitrile-0.1% potassium dihydrogen phosphate aqueous solution (80:20) as moving phase; Flow velocity is 1.0mL/min; Column temperature: 40 ℃; Detect wavelength: 245nm.Be about 2.5mg/mL bromhexine hydrochloride crude product take methyl alcohol as the solvent configuration concentration, precision measures 10 μ L injecting chromatographs, measure under above-mentioned chromatographic condition, main peak and each impurity peaks resolution meet the requirements, and theoretical plate number is pressed the bromhexine crude product and calculated greater than 8000.
Assay method: precision takes by weighing approximately 25mg of this product, places the 10ml measuring bottle, with moving phase dissolving and be diluted to scale, shake up, precision measures 10 μ l, injection liquid chromatography, the record color atlas, with calculated by peak area, maximum not assorted, the total impurities of notice of invitation should be no more than set quota by area normalization method.
Embodiment 11
The present embodiment has contrasted the content of related substance in the bromhexine hydrochloride of crystallization front and back.Wherein, bromhexine hydrochloride crystal (bromhexine hydrochloride after the crystallization) is prepared by embodiment 7-9.
This research adopts crystallization method of the present invention that the bromhexine hydrochloride crude product of different batches is carried out crystallization experiment, utilize the HPLC area normalization method method of embodiment 10 that related substance is measured, and compare with the bromhexine hydrochloride crude product that does not adopt crystallization method of the present invention, the results are shown in Table 4.Wherein, impurity A: 2-amino-3,5-dibromo benzaldehyde, impurity B: 2-amino-3,5-dibromobenzene methyl alcohol, impurity C:2-(N-cyclohexyl-N-methylamino methyl)-4-bromaniline, impurity D:2-(N-cyclohexyl-N-methylamino methyl)-aniline, impurity E: dl-6,8-two bromo-3-cyclohexyl-3-methyl isophthalic acids, 2,3,4 ,-tetrahydro quinazoline-3-quaternary amine.The structural formula of impurity A-E is as follows:
HPLC area normalization method detected result before and after the crystallization of table 4 bromhexine hydrochloride
Annotate: "-" expression does not detect.
The related substance detected result shows: the bromhexine hydrochloride crystal known impurities (A, B, C, D, E) of method preparation of the present invention obviously reduces, maximum not notice of invitation is mixed all≤0.1%, total mixing all≤0.3% meets 2010 editions Chinese Pharmacopoeias to the relevant regulations of bromhexine hydrochloride related substance.
Embodiment 12
The present embodiment is investigated the stability of the bromhexine hydrochloride crystal that adopts preparation method of the present invention (crystallization method) preparation, and with the bromhexine hydrochloride crystalline form I (available from the Beijing Double-Crane Pharmaceutical Co., Ltd, lot number: 100605) contrast.The results are shown in Table 5 and table 6.Table 5 crystalline form I 100605 and new crystal II JB110201(are by embodiment 7 preparations) permanent stability
The Experimental Comparison data
Long-term stable experiment is the result show: crystal form II JB110201 bromhexine hydrochloride crystal all increases significantly with present commercially available crystal formation product phase ratio content and related substance quality control level; And the test of long duration condition was placed 12 months, and each investigates the project indicator without considerable change, compared with present commercially available crystal formation product to have preferably stability.
Table 6 crystalline form I 100605 and new crystal II JB110201 accelerated test correlation data
Accelerated test result shows: crystal form II JB110201 bromhexine hydrochloride crystal acceleration environment was placed 6 months, and each investigates the project indicator without considerable change, and stability is better than commercially available crystal formation product.
Embodiment 13
The present embodiment is investigated the solvability of bromhexine hydrochloride crystal (crystal form II) in water that adopts preparation method of the present invention (crystallization method) preparation, and contrasts with the commercially available crystalline form I of bromhexine hydrochloride.Concrete experimentation and result are as follows:
1, sample source
Commercially available crystalline form I 1 and commercially available crystalline form I 2 be available from the Beijing Double-Crane Pharmaceutical Co., Ltd, lot number: 120401, and be two parallel sample setting up for the Elimination test operate miss;
Bromhexine hydrochloride new crystal II 1 and bromhexine hydrochloride new crystal II 2 are prepared from lot number by embodiment 7: JB110201 is two parallel sample setting up for the Elimination test operate miss.
2, experimentation:
2.1 precision takes by weighing totally 24 parts of the commercially available crystalline form I of bromhexine hydrochloride and each 1g of new crystal II sample; add respectively in 500ml, 700ml, 900ml, 1000ml, 1500ml and the 2000ml water for injection; under 25 ℃ ± 2 ℃ conditions; powerful jolting was 30 seconds every 5 minutes; observe the dissolving situation in 30 minutes; as without visual visible particles of solute or drop the time, namely be considered as dissolving fully.The result is as follows:
+ expression has visual visible particles of solute or drop
-expression is without visual visible particles of solute or drop
2.2 precision takes by weighing totally 4 parts of the commercially available crystalline form I of bromhexine hydrochloride and each 1g of new crystal II sample; add respectively in the 2000ml water for injection; under 25 ℃ ± 2 ℃ conditions; powerful jolting was 30 seconds every 5 minutes; observe the dissolving situation in 30 minutes; as without visual visible particles of solute or drop the time, namely be considered as dissolving fully.The result is as follows:
+ expression has visual visible particles of solute or drop
-expression is without visual visible particles of solute or drop
2.3 precision takes by weighing totally 4 parts of the commercially available crystalline form I of bromhexine hydrochloride and each 1g of new crystal II sample; add respectively in the 2000ml water for injection; under 25 ℃ ± 2 ℃ conditions; powerful jolting was 30 seconds every 5 minutes, observed the dissolving situation in 30 minutes, as without visual visible particles of solute or drop the time; namely be considered as dissolving fully; rear normal temperature was placed 72 hours, observed the dissolving situation, and the result is as follows:
+ expression has visual visible particles of solute or drop
-expression is without visual visible particles of solute or drop
Above test shows, the new crystal II of the present invention preparation in water after solvability, dissolution rate and the dissolving stability of solution be better than present commercially available crystal formation, more be conducive to prepare the commercially available bromhexine hydrochloride injection formulation products such as bromhexine hydrochloride injection liquid, hydrochloride for injection bromhexine and bromhexine hydrochloride glucose injection, guarantee stability and the security of product.
Embodiment 14Two kinds of crystal formation bioavailability simultaneous tests
To the commercially available crystalline form I of bromhexine hydrochloride (available from the Beijing Double-Crane Pharmaceutical Co., Ltd, lot number: 120401) and the new crystal II (be prepared from by embodiment 7, lot number: JB110201) sample carries out Evaluation On The Bioavailability, the gavage liquid for preparing respectively two kinds of crystal formations of bromhexine hydrochloride, successively (interval 7 days) is oral gives 6 beasle dogs, the LC-MS/MS method is measured respectively the Plasma Concentration that difference is got the bromhexine of blood point, draw drug-time curve, relatively medicine moves parameter, the results are shown in Table 7, the result shows: the bromhexine hydrochloride crystal form II is with respect to crystalline form I, area under the AUC(drug-time curve) increase, the drug bioavailability increase be described; The MRT(average retention time) increases, namely just can be eliminated in the longer time; t
1/2(eliminating the transformation period) increases the elimination of explanation medicine and slows down; T
Max(peak time) reduces the explanation uptake rate and increases; The CL(clearance rate) reduce, medicine is eliminated and is slowed down; C
Max(peak concentration) increases.
The commercially available crystalline form I of table 7 bromhexine hydrochloride and the non-compartment model statistical moment of new crystal II sample parameter
Claims (10)
1. the crystal of a bromhexine hydrochloride is characterized in that, this crystal uses Cu K α
1The X-ray powder diffraction pattern of radiation is that 7.29,14.33,21.439 places have diffraction peak at reflection angle 2 θ.
2. crystal according to claim 1 is characterized in that, described crystal uses Cu K α
1The X-ray powder diffraction pattern of radiation is that 14.581,18.236,21.856 and 43.347 places have diffraction peak at reflection angle 2 θ also;
Preferably, described crystal uses Cu K α
1The X-ray powder diffraction pattern of radiation comprises corresponding to following reflection angle 2 θ, spacing d, intensity I and relative intensity I/I
0The peak:
More preferably, described crystal uses Cu K α
1The X-ray powder diffraction pattern of radiation as shown in Figure 1.
3. crystal according to claim 1 and 2 is characterized in that, the infrared spectrogram of described crystal is 3440.8,3325.1,3238.3,3209.6,2931.6,2673.2,2630.7,2578.7,1633.6,1456.2 there is charateristic avsorption band at 1305.7,871.8,854.4,690.5 places; Preferably, the infrared spectrogram of described crystal as shown in Figure 2.
4. the preparation method of each described crystal in the claims 1 to 3, the method comprises the steps:
1) bromhexine hydrochloride is added to C
1To C
5In the recrystallisation solvent of lower alcohol-water, heating is dissolving fully;
2) add activated carbon decolorizing, filter, crystallization, ageing separates obtaining crystal and dry.
5. preparation method according to claim 4 is characterized in that, described C
1To C
5Lower alcohol is selected from one or more in methyl alcohol, ethanol, propyl alcohol and the Virahol, is preferably ethanol.
6. according to claim 4 or 5 described preparation methods, it is characterized in that, in volume percent, the volume content of water is not less than 30% in the recrystallisation solvent, is preferably 30%.
7. each described preparation method in 6 according to claim 4 is characterized in that, in step 1), described bromhexine hydrochloride is 1:8 ~ 1:25(mass/volume with the ratio of described recrystallisation solvent consumption, g/ml), be preferably the 1:15(mass/volume, g/ml); Preferably, described Heating temperature is 50 ~ 85 ℃, is preferably 75 ℃.
8. each described preparation method in 7 according to claim 4 is characterized in that, in step 2) in, the gac usage quantity is 1% ~ 10% of bromhexine hydrochloride quality, is preferably 5%; Preferably, recrystallization temperature is-20 ℃ ~ 30 ℃, is preferably 25 ℃; Preferably, digestion time is not less than 3h, is preferably 5h.
9. pharmaceutical composition, it comprises according to claim 1 each described bromhexine hydrochloride crystal in 3, and optional pharmaceutically acceptable vehicle and/or carrier;
Preferably, described pharmaceutical composition is the form of injection, sterile injection powder or frozen powder for injection.
According to claim 1 in 3 each described bromhexine hydrochloride crystal and/or pharmaceutical composition according to claim 9 for the preparation of the purposes in the medicine for the treatment of chronic bronchitis and other respiratory tract diseases.
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| CN103333074A (en) * | 2013-07-02 | 2013-10-02 | 浙江万邦药业股份有限公司 | Production method of bromhexine hydrochloride |
| CN103499647A (en) * | 2013-09-12 | 2014-01-08 | 江西科伦药业有限公司 | Detection method of intermediate or finished product of bromhexine hydrochloride glucose injection |
| CN105461659A (en) * | 2014-09-28 | 2016-04-06 | 韶远科技（上海)有限公司 | Amplifiable synthetic method of aminobenzylamine compounds |
| CN111662186A (en) * | 2020-07-20 | 2020-09-15 | 东南大学成贤学院 | Crystal form of salt formed by bromhexine and fumaric acid and preparation method thereof |
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| CN103333074A (en) * | 2013-07-02 | 2013-10-02 | 浙江万邦药业股份有限公司 | Production method of bromhexine hydrochloride |
| CN103499647A (en) * | 2013-09-12 | 2014-01-08 | 江西科伦药业有限公司 | Detection method of intermediate or finished product of bromhexine hydrochloride glucose injection |
| CN103499647B (en) * | 2013-09-12 | 2015-09-16 | 江西科伦药业有限公司 | The detection method of related substance in bromhexine hydrochloride glucose injection |
| CN105461659A (en) * | 2014-09-28 | 2016-04-06 | 韶远科技（上海)有限公司 | Amplifiable synthetic method of aminobenzylamine compounds |
| CN111662186A (en) * | 2020-07-20 | 2020-09-15 | 东南大学成贤学院 | Crystal form of salt formed by bromhexine and fumaric acid and preparation method thereof |
| CN111662186B (en) * | 2020-07-20 | 2022-03-29 | 东南大学成贤学院 | Crystal form of salt formed by bromhexine and fumaric acid and preparation method thereof |
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