CN104829467A - Ambroxol hydrochloride dihydrate compound - Google Patents
Ambroxol hydrochloride dihydrate compound Download PDFInfo
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- CN104829467A CN104829467A CN201510173852.5A CN201510173852A CN104829467A CN 104829467 A CN104829467 A CN 104829467A CN 201510173852 A CN201510173852 A CN 201510173852A CN 104829467 A CN104829467 A CN 104829467A
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Abstract
The present invention belongs to the technical field of medicine, and particularly relates to an ambroxol hydrochloride dihydrate compound, which has good stability, does not produce significant moisture absorption weight increase even under a high-humidity condition, does not increase related substances, and provides high solubility compared with the ambroxol hydrochloride with other crystalline states. The preparation method comprises: weighing ambroxol hydrochloride, placing into a reaction container, adding an appropriate volume of an isopropanol aqueous solution, stirring, carrying out heating reflux, naturally cooling to a room temperature, then cooling to a temperature of 20 DEG C, continuously carrying out stirring crystallization for 1 h, filtering, and drying at a temperature of 50 DEG C under a nitrogen atmosphere to obtain the ambroxol hydrochloride dihydrate compound, wherein the chemical purity is up to 99.9%, the impurity B is not more than 0.01%, the impurity E is not more than 0.002%, and the total impurity excluding the impurity B and the impurity E is not more than 0.02%.
Description
Technical field
The present invention relates to the medicine in field of medicaments, especially relate to a kind of Ambroxol HCl two hydrate and preparation method thereof.
Background technology
Respiratory system disease be people one of the disease kind be familiar with, such as catch a cold, cough, bronchitis, bronchial asthma etc. mostly are common disease and frequently-occurring disease.Respiratory system disease occurs in human respiratory tract's (comprising throat, tracheae, segmental bronchus and lung), and to cough, phlegm, breathes heavily, and is the symptom that it is common.These symptoms affect rest and the health of patient, if do not healed for a long time, also may develop into pulmonary emphysema, bronchiectasis and pulmonary heart disease etc.When respiratory tract is ill, cough, phlegm and to breathe heavily can be independent appearance, but also to exist often simultaneously, and can promote mutually or increase the weight of.Such as, phlegm can stimulate respiratory mucosa to cause cough; During phlegm many obstructions bronchiole, not only cause asthma, can also secondary infection be caused, damage respiratory tract further, increase the weight of cough, cough up phlegm and pant.
Sputum is secreted by the body of gland of trachea and bronchus (mucous gland, serous gland) and goblet cell.Under normal circumstances, body of gland and goblet cell are secreted a small amount of mucus and are covered in respiratory mucosa surface, and play protective effect, the particulates such as the dust of suction can be sticked by mucus, simultaneously discharge by cilium orientation movement.When respiratory inflammation, body of gland and goblet cell hyperplasia hypertrophy, secretory product increases, and viscosity increases, in addition ciliated cell's pathology, and ciliary movement is gone down, and mucus can not be discharged in time, so there is phlegm.Sputum can susceptor and afferent nerve endings under irritates nucous membrane, increases the weight of or causes cough, also can clogs airways, causes out of breathly even to suffocate.Stagnating again for secondary infection creates condition of sputum, the symptom of damage respiratory tissues further, make cough, coughing up phlegm and panting increases the weight of further, forms vicious cycle.So dispelling sputum is important measure of curing the disease to the ill.
In recent years the sickness rate of China's diseases of respiratory system and case fatality rate all high, at present, the third-largest factor of Yi Shi China human mortality.Therefore, the exploitation for the treatment of medicament for treating respiratory system thing also becomes an integral part of drug research.When respiratory tract infection (as respiratory tract diseases such as chronic bronchitiss), often produce a large amount of sputums, the existence blocking respiratory tract of phlegm, easily cause cough, pant, even cause expiratory dyspnea, especially often there is difficulty of spitting in children's and old man. so the application of expectorant is very necessary.Ambroxol HCl series acts on the strongest expectorant clinically at present, extremely affirms both at home and abroad to its curative effect.Ambroxol HCl is the derivative of methyl xanthine, and it is a kind of bronchodilator, can directly act on segmental bronchus, lax tracheal smooth muscle.Ambroxol HCl by suppressing the phosphodiesterase in smooth muscle cell, relaxing smooth muscle, thus reaches the effect suppressing asthma.
Ambroxol HCl is a kind of glutinous phlegm solvating agent, has another name called AMB, Eradicates phlegm and improve the features such as pulmonary function effect is strong and be widely used in clinical.This medicine can act on secretory cell, regulates the secretion of slurries and mucus, serous secretion is increased, and mucolytic dilutes, and can strengthen the swing of cilium, increases the Scavenging activity of mucus haulage system, makes sputum be easy to discharge.Ambroxol HCl is also a kind of respiratory system protective material, has anti-oxidant, inflammation-inhibiting medium release, lax airway smooth muscle, the effects such as the synthesis of promotion pulmonary surfactant and secretion.Ambroxol HCl can also increase the drug level of microbiotic in air flue, thus improves antibiotic curative effect.
The Ambroxol HCl of bibliographical information has multiple preparation method; as US Patent No. 3536713; domestic also have the synthesis technique on these thinking bases to report; the essential difference of each method is that phenyl ring part is with trans-different to the method for attachment of Trans-4-Amino Cyclohexanol; method 1: from 2-amino-3; 5-dibromobenzyl bromide or 2-acetamido-3; 5-dibromobenzyl bromide sets out; first and trans-to Trans-4-Amino Cyclohexanol or acetic acid trans-Transbroncho that aminocyclohexyl alcohol ester generation substitution reaction condensation dehydrohalogenation or hydroxyl have been acetylation, become Ambroxol HCl finally by acid hydrolysis.Method 2: set out from amino-3, the 5-dibromo benzaldehydes of 2-or 2 benzene methyl ethyl esters, first with trans-to Trans-4-Amino Cyclohexanol or trans-change into imines to isopropyl imido grpup hexalin amine condensation, then congratulate acidifying through hydro-reduction and become Ambroxol HCl.Route is comparatively loaded down with trivial details.
Chinese patent application CN02111561.3 relates to the ambroxol salt of chemical structural formula (I).This ambroxol salt is better than Ambroxol HCl solubleness, and dissolution rate is faster, and can use with T-1551 compatibility, it is characterized in that: the acid group of described salt is phosphoric acid, and a band crystal water.
The composition of Chinese patent application CN200510131121.0 Transbroncho or its salt and anti-infectives, belong to medical art, disclose a kind of pharmaceutical composition containing Transbroncho or its pharmacy acceptable salt and at least one anti-infectives and its production and use, wherein anti-infectives is selected from: baicalin and/or 14-deshydroxy-11,12-bis-dehydrogenation rographolide-3,19-disuccinic acid half ester salt, this pharmaceutical composition can be made into various pharmaceutically acceptable formulation; Composition disease in the thick sputum, dys-expectoration etc. that are caused by the microbial upper respiratory tract infection of sensitivity, chronic bronchitis, pneumonia and upper respiratory tract infection (as acute and chronic bronchitis, bronchial asthma, bronchiectasis, pulmonary tuberculosis etc.) for the preparation for the treatment of has synergistic function, and good stability, greatly improve than the Ambroxol HCl of alone same dosage or the effect of baicalin or potassium sodium dehydroandroan drographolide succinate, create beyond thought effect, be with a wide range of applications.
Chinese patent application CN200710128121.4 mono-kind prepares the method for Transbroncho and analogue or its salt, provides a kind of synthetic method of easy Ambroxol HCl, it is characterized in that the suitable method of reducing of precursor acyl ammonia of Transbroncho to obtain Transbroncho product easily.
Chinese patent application CN201110387736.5 relates to a kind of method for making comprising the ambroxol compound of following treatment step: 1, by a certain amount of Ambroxol HCl dissolving crude product in solvent, adds charcoal absorption, filters, and collects filtrate, concentrating under reduced pressure; 2, above-mentioned concentrated solution preparative scale chromatography post is carried out separation and purification, collects elutriant, concentrating under reduced pressure; 3, negative pressure crystallization is carried out to the Ambroxol HCl concentrated solution that above-mentioned steps 2 obtains, first concentrate at the temperature of negative pressure and rising, then reduce temperature, add Ambroxol HCl crystal seed, when there is tiny crystal grain, keep temperature until obtain desirable crystal, afterwards by the crystal of precipitation by filtering or being centrifugally separated, washing, drying, the Ambroxol HCl that final acquisition is refining.The Ambroxol HCl purity that method of the present invention obtains is high, uniform crystal particles, and crystal formation is complete, and mobility is better, and especially treatment capacity is large, and can carry out continuously, is therefore particularly suitable for carrying out suitability for industrialized production.Also improve the quality product of preparation simultaneously, decrease toxic side effect.
The process for purification of Chinese patent application CN201110048193.4 injection stage Ambroxol HCl and product and injection liquid thereof, relate to compound process for refining and purifying and products thereof field; The particularly process for refining and purifying and products thereof of Ambroxol HCl bulk drug and Application Areas.The process for purification of injection stage Ambroxol HCl, is characterized in that: get the Ambroxol HCl raw material that purity is more than 99.0%, with the ratio of 1: 5.5 ~ 9.2, add the aqueous ethanolic solution of 70.2% ~ 88% volume ratio, unit g/ml; Heat back and heat up in a steamer to abundant dissolving; Stop heating, crystallisation by cooling separates out Ambroxol HCl; Filtering solvent obtains crystallization, is drying to obtain.In the Ambroxol HCl raw material of the injection stage that the present invention obtains, impurity B is no more than 0.03%, and impurity E is no more than 0.002%, and the total impurities beyond the removal of impurity B and E is no more than 0.03%; Purity reaches more than 99.9%.
Chinese patent application CN201310045450.8 relates to a kind of process for purification of ambroxol compound, comprise the synthesis of Ambroxol HCl crude product and the refining of Ambroxol HCl, wherein refine and comprise: in reaction flask, 1) add water and Ambroxol HCl crude product, be warming up to 70-75 DEG C of stirring, dissolving crude product, obtains the crude product solution of Ambroxol HCl; In crude product solution, add gac, insulation decolouring, insulation is filtered, and collects filtrate; 2) filtrate temperature is down to 55-60 DEG C, insulation, stirs; 3) again filtrate is cooled to 45-48 DEG C, controls stirring velocity 15 revs/min, add crystal seed, control temperature and stirring velocity growing the grain 1h; 4) again by greenhouse cooling to 20-25 DEG C of growing the grain 20 minutes, growing the grain terminates again slow cooling to 10 DEG C growing the grain 1.5h, suction filtration, dry Ambroxol HCl fine work.The inventive method makes Ambroxol HCl only containing the impurity B in 5 known impurities, and the content of impurity B can be controlled below 0.005%.
In research process, repeat the method for the patent documentation of above-mentioned preparation, the Ambroxol HCl obtained has polymorphism, and different, and namely crystal formation is different.Because Ambroxol HCl is under oxidation or alkaline condition, in molecule, there is free Transbroncho, so related substance increases in storage process, affect quality and the security of medicine.The process for purification of Transbroncho two hydrate there is no and studies in great detail and disclose.
Ambroxol HCl two hydrate that the present invention obtains, purity is high, and impurity B is no more than 0.004%, and impurity E is no more than 0.002%, and the total impurities beyond the removal of impurity B and E is no more than 0.02%; Good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions; Related substance does not increase; Obtained injection good stability.
Summary of the invention
One object of the present invention, discloses a kind of Ambroxol HCl two hydrate.
Another object of the present invention, discloses the preparation method of Ambroxol HCl two hydrate.
The invention also discloses Ambroxol HCl two hydrate and treat acute, chronic lung disease with thick sputum and expectoration difficulties; The treatment of eliminating the phlegm of chronic bronchitis acute exacerbation, asthmatic bronchitis and bronchial asthma; The prophylactic treatment of Post operation pulmonary complication; Application in the medicines such as the treatment of premature infant and neonatal infant respiratory distress syndrome (IRDS).
Now in conjunction with object of the present invention, content of the present invention is specifically described.
This Ambroxol HCl two hydrate
Karl_Fischer method (Karl Fischer method) a kind ofly measures in all kinds of chemical processes of moisture in material,, the most accurately method the most single-minded to water, be listed in the standard method of moisture determination in many materials, especially organic compound, reliable results.Through 6 batches of mensuration, the moisture that described invention compound contains is between 8.50%-9.40% (weight percent).In Ambroxol HCl two hydrate, the theoretical content of water is 8.95%, can assert that invention compound contains two each and every one crystal water.
| Batch | 1 | 2 | 3 | 4 | 5 | 6 |
| Moisture (%) | 8.89 | 8.97 | 9.02 | 8.78 | 9.12 | 8.93 |
Ambroxol HCl two hydrate, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.With its powder x-ray diffraction collection of illustrative plates of 2 θ ± 0.2 °, see Fig. 1.
When infrared spectrogram measures, the correction polystyrene film of instrument, meets the regulation of Chinese Pharmacopoeia.
This Ambroxol HCl two hydrate infrared spectrogram (KBr pressed disc method mensuration) is at 3410 ± 5cm
-1; 3361 ± 5cm
-1; 2970 ± 5cm
-1; 2903 ± 5cm
-1; 2642 ± 5cm
-1; 1747 ± 2cm
-1; 1466 ± 2cm
-1there is characteristic peak at place, sees Fig. 2.Limit of error is determined according to Pharmacopoeia of People's Republic of China (2015 editions, two) annex IV C-infrared spectrophotometry.
Another object of the present invention, discloses the preparation method of Ambroxol HCl two hydrate, it is characterized in that comprising the following steps: to prepare isopropanol water solution (water: Virahol)=1:10-20, for subsequent use; Take the dimethyl formamide (DMF) of Ambroxol HCl and 0.3-0.8% in reaction vessel, add the isopropanol water solution of the above-mentioned preparation of 1-10 volume, stir, temperature rising reflux one hour, Temperature fall is to room temperature, cooling to 20 ± 5 DEG C, continue stirring and crystallizing 1 hour, filter, under nitrogen atmosphere, in 50 DEG C of dryings, obtain Ambroxol HCl two hydrate, chemical purity is up to 99.9%, and impurity B is no more than 0.004%, impurity E is no more than 0.002%, and the total impurities beyond the removal of impurity B and E is no more than 0.02%.
In above-mentioned preparation method, the dimethyl formamide (DMF) of 0.3-0.8% add the formation contributing to hydrate, the amount of mixed solution of isopropanol water solution (water: Virahol)=1:10-20 and the amount of crystal water about: the mixed solution using 10-20 times of isopropanol water solution (water: Virahol)=1:10-20, easily generates two hydrates; Use the mixed solution of 1-10 times of isopropanol water solution (water: Virahol)=1:1-10, easily generate monohydrate.
Above-mentioned monohydrate easily dries out when placement, drying, and poor stability, can not ensure the quality of pharmaceutical preparation.
Under 60 DEG C of hot conditionss, the mensuration of moisture in Ambroxol HCl two hydrate, monohydrate crystal:
| Inspection item | Ambroxol HCl two hydrate | Ambroxol HCl monohydrate |
| 0 hour | 8.94 | 4.68 |
| 12 hours | 8.96 | 3.23 |
| 24 hours | 8.97 | 2.31 |
| 36 hours | 8.98 | 1.45 |
Test-results shows: Ambroxol HCl monohydrate places 36 hours in the case of a high temperature, the volatile water that decrystallizes, and chemical structure is unstable, Ambroxol HCl two hydrate steady chemical structure.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 30% (weight) of composition.
Through animal (male rat) test, give ethanol-induced gastric lesion rat oral gavage, experimental result shows: observe visible a large amount of downright bad material bottom damage model group rat ulcer through stomach-tissue, in surrounding tissue, neutrophil infiltration is obvious; Bottom crystal formation of the present invention and Ambroxol HCl (obtaining with reference to US 3536713) group ulcer, in downright bad material and surrounding tissue, neutrophil infiltration all obviously reduces than damage model group; there is provide protection, the no significant difference (P>0.05) between two medication groups to gastric mucosa damage.
Ambroxol HCl used, the method provided according to document US 3536713 synthesis, the chemical structure of the Ambroxol HCl of synthesis through proton nmr spectra (
1h-NMR), ultimate analysis, proves that chemical structure is correct.
Present invention also offers Ambroxol HCl and treat acute, chronic lung disease with thick sputum and expectoration difficulties; The treatment of eliminating the phlegm of chronic bronchitis acute exacerbation, asthmatic bronchitis and bronchial asthma; The prophylactic treatment of Post operation pulmonary complication; Application in the medicines such as the treatment of premature infant and neonatal infant respiratory distress syndrome (IRDS).
Compared with prior art, tool of the present invention has the following advantages:
1) Ambroxol HCl two hydrate provided by the present invention thoroughly solves the problem of the poor stability of Ambroxol HCl.
2) Ambroxol HCl two hydrate purity provided by the present invention is high, good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions, related substance does not increase; High compared with the Ambroxol HCl solubleness of other crystalline state.
3) Ambroxol HCl two hydrate provided by the present invention is for improving the yield of this product, reducing the market risk of product, and being better applied to clinical treatment has very large help.
4) Ambroxol HCl two hydrate provided by the present invention is through industrialized production and study on the stability, and prove constant product quality, through pharmacology, toxicological test, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body fanout free region.
5) preparation method of Ambroxol HCl two hydrate provided by the present invention, the method is simple, prepared Ambroxol Hydrochloride for Injection good stability, reliable in quality.
Figure of description:
Fig. 1, the X-ray diffractogram of Ambroxol HCl two hydrate;
Fig. 2, the infrared spectrogram of Ambroxol HCl two hydrate;
Fig. 3, Ambroxol HCl two hydrate structure iron
Embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Ambroxol HCl used in the present invention, chemistry trans-4-[(2-amino 3 by name, 5-dibromo-benzyl) amino] cyclohexanol HCI, according to the method synthesis that document US 3536713 provides, purity 98.1% (HPLC normalization method), refine 1-3 times by the method for existing publication, purity about 98.6% (HPLC normalization method).Its chemical structure through proton nmr spectra (
1h-NMR), ultimate analysis confirmation, results of elemental analyses: measured value (calculated value),
C:37.66 (37.65), H:4.62 (4.65), Br:38.55 (38.50), N:6.76 (6.78), O:3.86 (3.79) Cl:8.55 (8.64), proves that chemical structure is correct.The moisture recorded with Karl_Fischer method is 0.54%.
Embodiment 1
In the 5000ml reaction flask that stirring, thermometer, condenser are housed, add 100 grams of Ambroxol HCls, the dimethyl formamide (DMF) of 0.3g and the mixed solution of 1000ml water-Virahol=1:10, start stirring, heat to 55 DEG C-60 DEG C, temperature rising reflux 1 hour, Temperature fall is to room temperature, then 20 DEG C are chilled to, continue stirring and crystallizing 1 hour, filter, under nitrogen atmosphere, in 50 DEG C of dryings 3 hours, obtain 90.3 grams, Ambroxol HCl two hydrate powder, the moisture recorded with Karl_Fischer method is 8.95%.
The X-ray diffractogram of this compound is shown in Fig. 1.INSTRUMENT MODEL and condition determination: Rigaku D/max 2500 type diffractometer; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50 °.
The infrared spectrogram of this compound is shown in Fig. 2, uses KBr compressing tablet during mensuration.
Embodiment 2
In the 5000ml reaction flask that stirring, thermometer, condenser are housed, add 100 grams of Ambroxol HCls, the dimethyl formamide (DMF) of 0.5g and the mixed solution of 800ml water-Virahol=1:12, start stirring, heat to 55 DEG C-60 DEG C, temperature rising reflux 1 hour, Temperature fall is to room temperature, then 20 DEG C are chilled to, continue stirring and crystallizing 1 hour, filter, under nitrogen atmosphere, in 50 DEG C of dryings 3 hours, obtain 91.4 grams, Ambroxol HCl two hydrate powder, the moisture recorded with Karl_Fischer method is 8.88%.
Embodiment 3
Granule containing embodiment 1 Ambroxol HCl two hydrate
Prescription:
Technique:
1) prepare: by lactose, pregelatinized Starch, aspartame, polyvinylpolypyrrolidone, Vltra tears, Magnesium Stearate under 80 DEG C of conditions dry 4 hours, for subsequent use;
2) weigh: Ambroxol HCl two hydrate, lactose, pregelatinized Starch, aspartame, polyvinylpolypyrrolidone, Vltra tears, the Magnesium Stearate that take recipe quantity;
3) mix: Ambroxol HCl two hydrate of recipe quantity, lactose, pregelatinized Starch, aspartame, polyvinylpolypyrrolidone, Vltra tears are inserted in high efficient mixed nodulizer, mixes;
4) granulate: in mixing machine, gradation adds appropriate water softwood, is inserted by softwood in nodulizer, adopts 16 eye mesh screens, the particle of the obtained suitable size that swings;
5) dry: to adopt boiling drier, in 60 ± 5 DEG C, be dried to moisture qualified;
6) Quality control of intermediates: according to intermediate quality inspection standard, carries out Quality control of intermediates;
7) pack: regulate suitable loading amount, carry out packing Ambroxol HCl two carbohydrate particles;
8) put in storage.
Embodiment 4
Injection containing embodiment 1 Ambroxol HCl two hydrate
Prescription:
Technique: get recipe quantity water for injection 90%, temperature, at 55-65 DEG C, adds the Citric Acid of recipe quantity, Sodium Citrate, after stirring and dissolving; Add Ambroxol HCl two hydrate of recipe quantity, after being stirred to dissolving, in solution, add the sodium-chlor of recipe quantity again, be stirred to and dissolve completely; Record initial pH value, according to initial pH value, by 10% CYSTEAMINE HCL acid solution adjust ph scope at 4.5-5.5; To adding Medicinal Charcoal 0.05%, stirring, placing 30 minutes; Suction filtration, adds water for injection to full dose, mixes; Essence filter; Filling; 121 DEG C of pressure sterilizings 15 minutes; Lamp is examined; Warehouse-in; Obtain ambroxol hydrochloride injection.
Test example 1
Stability test
The chemical stability of contriver to Ambroxol HCl two hydrate (embodiment 1) of the present invention is studied, investigation condition is high temperature (60 DEG C ± 2 DEG C), illumination (4500Lx ± 500lx), high humidity (92.5%, RH) inspection target is outward appearance, content and related substance.
Result: from 0-10 days under illumination, high temperature, super-humid conditions, outward appearance, related substance, content do not change, and illustrate that chemical stability is good, are applicable to manufacture and the standing storage of pharmaceutical preparation.
Test example 2
At 40 DEG C, under different relative humidity (RH) condition (75%), the mensuration of moisture in Ambroxol HCl (embodiment 1):
Result: at 40 DEG C, under different relative humidity (RH) condition (75%), change of soil water content is little, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
Test example 3
Solubility test
Solubleness is a kind of physical properties of medicine.The selection of solvent, should adopt with this medicine dissolution characteristics closely related as far as possible, formulated, prepare solution or purification operations the common solvent commonly used; Kind should simplify, and does not enumerate too much, and avoids using solvent that is expensive or that be of little use.Can not adopt and first add lower limit amount, then add to the method for upper limit amount, should again sample the solvent adding upper limit amount.Be arranged in order by solubleness size, " very easily dissolving ", front, is " Yi Rong ", " dissolving ", " slightly molten ", " slightly soluble ", " soluble,very slightly " and " almost insoluble or insoluble " thereafter; The solvent that wherein solubleness is similar, be then arranged in order (water, methyl alcohol, ethanol, the third heir, acetic acid second vinegar, chloroform, ether or hexanaphthene etc.) by its polarity size; Before hot water or hot ethanol (hot solvents without other) are placed on each solvent of same solubleness; Solubleness in acid or basic solution is placed on finally, and acid used or basic solution will indicate title (not using the nouns such as " ore deposit acid " or " alkali hydroxide ") preferably can write concentration exactly.
The approximate solubility of medicine is shown with following noun list:
Very easily dissolve and mean that solute 1g (ml) can dissolve in solvent is less than 1ml;
Yi Rong means that solute 1g (ml) can dissolve in solvent 1 ~ less than 10ml;
Dissolving means that solute 1g (ml) can dissolve in solvent 10 ~ less than 30ml;
Slightly moltenly mean that solute 1g (ml) can dissolve in solvent 30 ~ less than 100ml;
Slightly soluble means that solute 1g (ml) can dissolve in solvent 100 ~ less than 1000ml;
Soluble,very slightly means that solute 1g (ml) can dissolve in solvent 1000 ~ less than 10000ml;
Almost insolublely or insoluble mean that solute 1g (ml) can not dissolve completely in solvent 10000ml.
Test method(s): unless otherwise specified, takes the trial-product (embodiment 1) being ground into fine powder, is placed in the solvent of 25 DEG C ± 2 DEG C of certain capacities, powerful jolting 30 second every 5 minutes; Observing the dissolving situation in 30 minutes, during as cannot see particles of solute or drop, being namely considered as dissolving completely.
Solubility test result
Conclusion: be very easily dissolved in water, easily molten in methyl alcohol, dissolves in ethanol.
Comparison test example 1
This test example compares with the Ambroxol HCl solubleness of prior art for comparing Ambroxol HCl two hydrate of the present invention
Test 1: Ambroxol HCl two hydrate prepared by the embodiment of the present invention 1;
Test 2: Ambroxol HCl two hydrate prepared by the embodiment of the present invention 2;
Contrast 1: the traditional Chinese medicines accurate word H20000659 Ambroxol HCl bulk drug that Pharmaceutical Co Ltd, Changzhou Pharmaceutical Factory No.4 produces
Contrast 2: the traditional Chinese medicines accurate word H20074101 Ambroxol HCl bulk drug that PeKing University Healthcare Co., Ltd. produces
Contrast 3: the traditional Chinese medicines accurate word H20010424 Ambroxol HCl bulk drug that Shandong Luo Xin medicine company Group Plc produces
Contrast 4: Chinese patent application CN201310045450.8 embodiment 1
Contrast 5: Chinese patent application CN201110048193.4 embodiment 1
| Solvent | Test 1 | Test 2 | Contrast 1 | Contrast 2 | Contrast 3 | Contrast 4 | Contrast 5 |
| Water | Very easily dissolve | Very easily dissolve | Slightly molten | Slightly molten | Slightly molten | Slightly molten | Slightly molten |
| Methyl alcohol | Yi Rong | Yi Rong | Dissolve | Dissolve | Dissolve | Dissolve | Dissolve |
| Ethanol | Dissolve | Dissolve | Slightly soluble | Slightly soluble | Slightly soluble | Slightly soluble | Slightly soluble |
Above test-results shows: Ambroxol HCl two hydrate in the present invention has good solubility, and its solubleness is better than
The solubleness of the Ambroxol HCl that prior art is produced.
Comparison test example 2
This test example compares with the Ambroxol HCl related substance of prior art for comparing Ambroxol HCl two hydrate of the present invention
Test 1: Ambroxol HCl two hydrate prepared by the embodiment of the present invention 1;
Test 2: Ambroxol HCl two hydrate prepared by the embodiment of the present invention 2;
Contrast 1: the traditional Chinese medicines accurate word H20000659 Ambroxol HCl bulk drug that Pharmaceutical Co Ltd, Changzhou Pharmaceutical Factory No.4 produces
Contrast 2: the traditional Chinese medicines accurate word H20074101 Ambroxol HCl bulk drug that PeKing University Healthcare Co., Ltd. produces
Contrast 3: the traditional Chinese medicines accurate word H20010424 Ambroxol HCl bulk drug that Shandong Luo Xin medicine company Group Plc produces
Contrast 4: Chinese patent application CN201310045450.8 embodiment 1
Contrast 5: Chinese patent application CN201110048193.4 embodiment 1
Above test-results shows: the related substance of Ambroxol HCl two hydrate that the embodiment of the present invention is produced is less, is better than Ambroxol HCl prepared by prior art, and steady quality is reliable, and impurity is controlled, is beneficial to and is prepared into injection.
Claims (6)
1. Ambroxol HCl two hydrate shown in formula I,
Measure with Karl_Fischer method, described Ambroxol HCl two hydrate contains the moisture of 8.50%-9.40% (weight percent); Described Ambroxol HCl two hydrate, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle and D value,
The error of 2 θ diffraction angle is ± 0.2.
2. Ambroxol HCl two hydrate according to claim 1, infrared spectrogram, pellet technique measures, at 3410 ± 5cm
-1; 3361 ± 5cm
-1; 2970 ± 5cm
-1; 2903 ± 5cm
-1; 2642 ± 5cm
-1; 1747 ± 2cm
-1; 1466 ± 2cm
-1there is characteristic peak at place.
3. the preparation method of Ambroxol HCl two hydrate according to claim 1, is characterized in that comprising the following steps: to prepare isopropanol water solution (water: Virahol)=1:10-20, for subsequent use; Take the dimethyl formamide (DMF) of Ambroxol HCl and 0.3-0.8% in reaction vessel, add the isopropanol water solution of the above-mentioned preparation of 1-10 volume, stir, temperature rising reflux one hour, Temperature fall is to room temperature, cooling to 20 ± 5 DEG C, continue stirring and crystallizing 1 hour, filter, under nitrogen atmosphere, in 50 DEG C of dryings, obtain Ambroxol HCl two hydrate, chemical purity is up to 99.9%, and impurity B is no more than 0.004%, impurity E is no more than 0.002%, and the total impurities beyond the removal of impurity B and E is no more than 0.02%.
4. the composition of Ambroxol HCl two hydrate that forms of two hydrates of Ambroxol HCl and one or more pharmaceutically acceptable carriers according to claim 1.
5. the composition required by right described in 4, is characterized in that said composition is for the preparation of granule or injection.
6. Ambroxol HCl two hydrate is manufacturing acute, the chronic lung disease for the treatment of with thick sputum and expectoration difficulties according to claim 1; The treatment of eliminating the phlegm of chronic bronchitis acute exacerbation, asthmatic bronchitis and bronchial asthma; The prophylactic treatment of Post operation pulmonary complication; Application in the medicines such as the treatment of premature infant and neonatal infant respiratory distress syndrome (IRDS).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106631837A (en) * | 2016-12-22 | 2017-05-10 | 合肥久诺医药科技有限公司 | Method of refining ambroxol hydrochloride for injection |
| CN116199590A (en) * | 2022-12-26 | 2023-06-02 | 湖北美林药业有限公司 | Dobutamine hydrochloride and injection thereof |
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| CN102516096A (en) * | 2011-11-28 | 2012-06-27 | 海南灵康制药有限公司 | Hydrochloric acid ambroxol compound and novel preparation method thereof |
| CN102924302A (en) * | 2012-11-07 | 2013-02-13 | 陕西合成药业有限公司 | Injection-grade ambroxol hydrochloride and solution for inhalation of injection-grade ambroxol hydrochloride |
| CN103073438A (en) * | 2013-02-05 | 2013-05-01 | 山东罗欣药业股份有限公司 | Ambroxol hydrochloride compound refining method |
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| CN102516096A (en) * | 2011-11-28 | 2012-06-27 | 海南灵康制药有限公司 | Hydrochloric acid ambroxol compound and novel preparation method thereof |
| CN102924302A (en) * | 2012-11-07 | 2013-02-13 | 陕西合成药业有限公司 | Injection-grade ambroxol hydrochloride and solution for inhalation of injection-grade ambroxol hydrochloride |
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| CN106631837A (en) * | 2016-12-22 | 2017-05-10 | 合肥久诺医药科技有限公司 | Method of refining ambroxol hydrochloride for injection |
| CN106631837B (en) * | 2016-12-22 | 2019-04-16 | 合肥久诺医药科技有限公司 | A kind of refining methd of Ambroxol Hydrochloride for Injection |
| CN116199590A (en) * | 2022-12-26 | 2023-06-02 | 湖北美林药业有限公司 | Dobutamine hydrochloride and injection thereof |
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