CN106278907B - A kind of Syprine Hydrochloride compound - Google Patents
A kind of Syprine Hydrochloride compound Download PDFInfo
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- CN106278907B CN106278907B CN201610642758.4A CN201610642758A CN106278907B CN 106278907 B CN106278907 B CN 106278907B CN 201610642758 A CN201610642758 A CN 201610642758A CN 106278907 B CN106278907 B CN 106278907B
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- syprine hydrochloride
- syprine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/86—Separation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a kind of Syprine Hydrochloride compounds, it is characterised in that the compound is existed in the form of crystal form, and the preparation method and purposes of the compound, and the pharmaceutical composition comprising the compound are also disclosed in text.The crystal form feature of Syprine Hydrochloride of the present invention are as follows: stability is good, hygroscopicity is low, with high purity, impurity content is low.
Description
The application is the divisional application of Chinese No. 201410787042.4 application for a patent for invention, and the applying date of this application is
On December 17th, 2014, a kind of entitled Syprine Hydrochloride compound.
Technical field
The present invention provides a kind of Syprine Hydrochloride compounds, specifically provide the crystal form I of the Syprine Hydrochloride compound
With crystal form II, belong to drug field.
Background technique
Hepatolenticular degeneration is also known as hepatolenticular degeneration, belongs to a kind of copper dysbolism disease of autosomal recessive inheritance, is
As caused by the ATP 7B gene mutation of patient.Clinically, which has liver type, brain type, mixed type and asymptomatic, main
Show as the symptom of psychoneural and liver etc., specially extrapyramidal symptoms, the cirrhosis, spirit of progressive exacerbation
Symptom, kidney function damage and Kayser-Fleischer ring.
The illness rate of hepatolenticular degeneration worldwide is 3/,100,000 people, and wherein gene carrier accounts for 1/90.Such
The therapeutic scheme of illness follows the principle of early diagnosis and early treatment, still, before mutated gene fails thoroughly to correct, drug
The purpose for the treatment of can only be the excretion for promoting internal copper and the absorption for reducing copper, and this is that the physiology for needing to maintain for a long time is raw
Change process, therefore patient needs to receive lifelong drug therapy, including drives copper drug, prevents enteron aisle to Copper uptakie and promote row's copper
Drug and symptomatic treatment.
Currently, the drug for the treatment of hepatolenticular degeneration is mostly using penicillamine, but the clinical data of many years shows
25%~30% may occur in which various adverse reactions in the patient for receiving penicillamine treatment, such as: fash, fever immediate allergic are anti-
It answers；The reaction of the subacute toxicities such as bone marrow suppression, albuminuria；And the slow poisoning reaction of collagen and immune system may be influenced,
Such as wrinkle of skin, abdomen scar formed, boring shape elastosis skin lesion of crawling, empsyxis, nephritic syndrome,
The more serious disease of immune system such as systemic loupus erythematosus and myasthenia gravis, and can therefore occur being discontinued, be reduced or need to add
With glucocorticoid etc..More seriously, nervous system type patient carries out initial treatment, about 20%~50% patient using penicillamine
Early stage occurs brain symptom and deteriorates, though wherein about 25% patient is through active treatment, the nervous symptoms deteriorated still cannot be extensive
Therefore the multiple level to before treatment, many patients cause serious deformity.Therefore, American-European Neurological Clinics doctors most of in recent years
Teacher does not recommend initial treatment drug of the penicillamine as nervous system type patient.
Syprine Hydrochloride mechanism of action is similar to penicillamine, and copper is mobilized from tissue, works fast compared with penicillamine.This
Outside, Syprine Hydrochloride can also prevent and stop the rapid clinical deterioration rates after penicillamine treatment, therefore, can be used for generating penicillamine
The patient of serious toxicity reaction.It is at present choice drug in the treatment of liver type patient, can be additionally used in combination with zinc preparation.
For penicillamine earlier, the side effect of Syprine Hydrochloride is seldom, and also there is no the anaphylactoid report about the medicine
Road.
The entitled triethylene tetramine dihydrochloride of chemistry of Syprine Hydrochloride, also there is no the crystal form report about the drug at present
Road.
Summary of the invention
The purpose of the present invention is to provide the low Syprine Hydrochloride compounds of a kind of stability height, hygroscopicity.
The present invention also provides the preparation method of the compound and purposes.
Syprine Hydrochloride compound provided by the invention, it is characterised in that it is existed in the form of crystal form I.
When the compounds of this invention carries out X-ray powder diffraction using Cu K α radiation source, in diffraction in X-ray powder diffraction
2 θ=13.3 ° ± 0.2 ° of angle, 19.9 ° ± 0.2 °, 24.5 ° ± 0.2 °, 27.0 ° ± 0.2 °, 27.7 ° ± 0.2 °, 30.0 ° ±
0.2 °, 31.7 ° ± 0.2 °, 37.4 ° ± 0.2 °, 40.7 ° ± 0.2 ° has characteristic absorption peak；
Further, also 2 θ=16.6 ° ± 0.2 ° of angle of diffraction, 24.0 ° in the X-ray powder diffraction of the compound
± 0.2 °, 25.8 ° ± 0.2 °, 28.8 ° ± 0.2 °, 31.2 ° ± 0.2 °, 38.0 ° ± 0.2 ° has characteristic absorption peak.Its structural formula
Are as follows:
Further, in the X-ray powder diffraction collection of the compound, the relative intensity of 2 θ angle of diffraction characteristic peaks
Value are as follows:
Further, the compound is in 3342.7 ± 3cm-1、3236.3±3cm-1、3217.0±3cm-1、2993.3±
3cm-1、2918.1±3cm-1、2902.7±3cm-1、2856.4±3cm-1、2833.2±3cm-1、2590.2±3cm-1、
2524.6±3cm-1、2486.1±3cm-1、2127.3±3cm-1、1641.3±3cm-1、1620.1±3cm-1、1556.5±
3cm-1、1502.4±3cm-1、1475.4±3cm-1、1458.1±3cm-1There is infrared absorption at place.
The preparation method of Syprine Hydrochloride compound of the present invention, steps are as follows:
Suitable quantity of water is added into load weighted trientine, stirs, hydrochloric acid is added and adjusts pH value, appropriate organic solvent is added
It stirs and evenly mixs, crystallization, obtained Syprine Hydrochloride is dried under reduced pressure.
Wherein, the organic solvent is alcohols, ketone；
Further, the alcohol organic solvent is selected from: methanol, ethyl alcohol, ethylene glycol, isopropanol；The ketones solvent
For acetone.
Further, the pH value is 7.5~10.0；Preferably 8.0~9.5.
Further, the temperature that is dried under reduced pressure is 60 DEG C~80 DEG C.
Further, the crystallization is to stir or stand crystallization.
Further, the crystallization temperature is 0 DEG C~room temperature.
The present invention also provides a kind of pharmaceutical composition, it is by above-mentioned Syprine Hydrochloride as active constituent, addition or
Pharmaceutically acceptable auxiliary material is not added to be prepared.
What pharmaceutically acceptable carrier of the present invention was well known in the art is used to prepare the common figuration of above-mentioned preparation
Agent or auxiliary material.Oral preparation or the common excipient of external preparation or auxiliary material include but are not limited to filler (diluent), profit
Lubrication prescription (glidant or antitack agent), dispersing agent, wetting agent, adhesive, regulator, solubilizer, antioxidant, bacteriostatic agent, emulsification
Agent, disintegrating agent etc..Adhesive, such as syrup, Arabic gum, gelatin, sorbierite, tragacanth, cellulose and its derivates are (such as micro-
Crystalline cellulose, sodium carboxymethylcellulose, ethyl cellulose or hypromellose etc.), gelatine size, syrup, starch slurry or poly-
Vinylpyrrolidone etc.；Filler, for example, it is lactose, Icing Sugar, dextrin, starch and its derivative, cellulose and its derivates, inorganic
Calcium salt (such as calcium sulfate, calcium phosphate, calcium monohydrogen phosphate, precipitated calcium carbonate), sorbierite or glycine；Lubricant, such as micro mist silicon
Glue, magnesium stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol；Disintegrating agent, such as starch and its derivative
Object (such as sodium carboxymethyl starch, Explotab, pregelatinized starch, modified starch, hydroxypropul starch, cornstarch) gathers
Vinylpyrrolidone or microcrystalline cellulose；Wetting agent, such as lauryl sodium sulfate, water or alcohol etc..
The common excipient of injection of the present invention or auxiliary material include but are not limited to: antioxidant, such as sodium sulfite,
Sodium hydrogensulfite, sodium pyrosulfite, dibutyl benzoic acid etc.；Bacteriostatic agent, such as 0.5% phenol, 0.3% cresols, 0.5% trichlorine uncle
Butanol；Regulator, such as hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate and buffer (including phosphoric acid dioxy sodium and phosphorus
Sour disodium hydrogen etc.)；Emulsifier, such as Tween-80, do not have that sour sorb is smooth, pluronic gram F-68, lecithin, Fabaceous Lecithin；Increase
Solvent, such as Tween-80, bile, glycerol etc..
It is subject in addition, also active constituent can be prepared requirement by it with pharmaceutically acceptable slow-released carrier or controlled release carrier
Retarding agent coating is such as added or by active principle microcapsules according still further to the preparation method of sustained-release preparation well known in the art in mixing
Pellet, including sustained release pellet or controlled release micro pill etc. is made after change again；The slow controlled release carrier includes but are not limited to oil
Dopant, hydrophilic colloid or coating retarding agent etc., the oil dopant is selected from glycerin monostearate, hydrogenated castor
Oil, dormant oil, polysiloxanes or dimethyl siloxane it is any or combinations thereof；The hydrophilic colloid is selected from carboxymethyl cellulose
Sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, any or its group of PVP, Arabic gum, tragacanth or carbopol
It closes；The coating retarding agent is selected from ethyl cellulose (EC), hypromellose (HMPC), polyvinylpyrrolidone
(PVP), cellulose acetate-phthalate (CAP), acrylic resin it is any or combinations thereof.
Wherein, in the preferred technical solution of the present invention, the dosage form of described pharmaceutical composition be selected from tablet, suspension,
Capsule, granule, pill, powder, pill, syrup, mixture, distillate medicinal water, effervescent agent, paste, emulsion, medicinal tea, pulvis, note
Penetrate agent, infusion, gelling agent, emplastrum, plaster, creme, ointment, liniment, lotion, suppository, liniment, paste, solidifying paste or
Any or its sustained release preparation, positioning delivery formulations, quick releasing formulation, controlled release preparation, oral cavity disintegration preparation.
The present invention also provides above-mentioned Syprine Hydrochlorides in preparing the drug for treating Wilson disease
Purposes.
The present invention provides another Syprine Hydrochloride compounds, it is characterised in that it is existed in the form of crystal form II.
When the compounds of this invention carries out X-ray powder diffraction using Cu K α radiation source, in diffraction in X-ray powder diffraction
2 θ=16.5 ° ± 0.2 ° of angle, 18.7 ° ± 0.2 °, 21.2 ° ± 0.2 °, 21.9 ° ± 0.2 °, 22.6 ° ± 0.2 °, 23.8 ° ±
0.2°、24.1°±0.2°、25.0°±0.2°、25.7°±0.2°、26.3°±0.2°、28.6°±0.2°、29.8°±0.2°、
33.3 ° ± 0.2 °, 34.2 ° ± 0.2 °, 35.3 ° ± 0.2 °, 38.4 ° ± 0.2 °, 39.5 ° ± 0.2 ° has characteristic absorption peak, knot
Structure formula are as follows:
Further, in the X-ray powder diffraction collection of the compound, the relative intensity of 2 θ angle of diffraction characteristic peaks
Value are as follows:
The preparation method of Syprine Hydrochloride compound of the present invention, steps are as follows:
Suitable quantity of water is added into load weighted trientine, stirs, hydrochloric acid is added and adjusts pH value, appropriate organic solvent is added
It stirs and evenly mixs, crystallization, obtained Syprine Hydrochloride is dried under reduced pressure.
Wherein, the organic solvent is alcohols；
Further, the alcohol organic solvent is selected from: methanol, ethyl alcohol, ethylene glycol, isopropanol.
Further, the pH value is 7.5~10.0；Preferably 8.0~9.5.
Further, the temperature that is dried under reduced pressure is 30 DEG C~50 DEG C.
Further, the crystallization is to stir or stand crystallization.
Further, the crystallization temperature is 0 DEG C~room temperature.
The present invention also provides a kind of pharmaceutical composition, it is by above-mentioned Syprine Hydrochloride as active constituent, addition or
Pharmaceutically acceptable auxiliary material is not added to be prepared；
What pharmaceutically acceptable carrier of the present invention was well known in the art is used to prepare the common figuration of above-mentioned preparation
Agent or auxiliary material.Oral preparation or the common excipient of external preparation or auxiliary material include but are not limited to filler (diluent), profit
Lubrication prescription (glidant or antitack agent), dispersing agent, wetting agent, adhesive, regulator, solubilizer, antioxidant, bacteriostatic agent, emulsification
Agent, disintegrating agent etc..Adhesive, such as syrup, Arabic gum, gelatin, sorbierite, tragacanth, cellulose and its derivates are (such as micro-
Crystalline cellulose, sodium carboxymethylcellulose, ethyl cellulose or hypromellose etc.), gelatine size, syrup, starch slurry or poly-
Vinylpyrrolidone etc.；Filler, for example, it is lactose, Icing Sugar, dextrin, starch and its derivative, cellulose and its derivates, inorganic
Calcium salt (such as calcium sulfate, calcium phosphate, calcium monohydrogen phosphate, precipitated calcium carbonate), sorbierite or glycine；Lubricant, such as micro mist silicon
Glue, magnesium stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol；Disintegrating agent, such as starch and its derivative
Object (such as sodium carboxymethyl starch, Explotab, pregelatinized starch, modified starch, hydroxypropul starch, cornstarch) gathers
Vinylpyrrolidone or microcrystalline cellulose；Wetting agent, such as lauryl sodium sulfate, water or alcohol etc..
The common excipient of injection of the present invention or auxiliary material include but are not limited to: antioxidant, such as sodium sulfite,
Sodium hydrogensulfite, sodium pyrosulfite, dibutyl benzoic acid etc.；Bacteriostatic agent, such as 0.5% phenol, 0.3% cresols, 0.5% trichlorine uncle
Butanol；Regulator, such as hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate and buffer (including phosphoric acid dioxy sodium and phosphorus
Sour disodium hydrogen etc.)；Emulsifier, such as Tween-80, do not have that sour sorb is smooth, pluronic gram F-68, lecithin, Fabaceous Lecithin；Increase
Solvent, such as Tween-80, bile, glycerol etc..
It is subject in addition, also active constituent can be prepared requirement by it with pharmaceutically acceptable slow-released carrier or controlled release carrier
Retarding agent coating is such as added or by active principle microcapsules according still further to the preparation method of sustained-release preparation well known in the art in mixing
Pellet, including sustained release pellet or controlled release micro pill etc. is made after change again；The slow controlled release carrier includes but are not limited to oil
Dopant, hydrophilic colloid or coating retarding agent etc., the oil dopant is selected from glycerin monostearate, hydrogenated castor
Oil, dormant oil, polysiloxanes or dimethyl siloxane it is any or combinations thereof；The hydrophilic colloid is selected from carboxymethyl cellulose
Sodium, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, any or its group of PVP, Arabic gum, tragacanth or carbopol
It closes；The coating retarding agent is selected from ethyl cellulose (EC), hypromellose (HMPC), polyvinylpyrrolidone
(PVP), cellulose acetate-phthalate (CAP), acrylic resin it is any or combinations thereof.
Wherein, in the preferred technical solution of the present invention, the dosage form of described pharmaceutical composition be selected from tablet, suspension,
Capsule, granule, pill, powder, pill, syrup, mixture, distillate medicinal water, effervescent agent, paste, emulsion, medicinal tea, pulvis, note
Penetrate agent, infusion, gelling agent, emplastrum, plaster, creme, ointment, liniment, lotion, suppository, liniment, paste, solidifying paste or
Any or its sustained release preparation, positioning delivery formulations, quick releasing formulation, controlled release preparation, oral cavity disintegration preparation.
The present invention also provides above-mentioned Syprine Hydrochlorides in preparing the drug for treating Wilson disease
Purposes.
Syprine Hydrochloride compound described in description of the invention is each meant in the form of crystalline state crystal form I or crystal form II
Syprine Hydrochloride compound existing for form.Below by way of specific embodiment, the present invention is described in further detail, but
It is not intended to limit the present invention, various changes and modifications can be made by those skilled in the art in light of the present invention, without departing from this hair
Bright spirit should belong to scope of the appended claims of the present invention.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
Detailed description of the invention
I X-ray powder diffraction collection of crystal form that the method for Fig. 1 embodiment 1 is prepared；
The DSC map for the crystal form I that the method for Fig. 2 embodiment 1 is prepared；
The infared spectrum for the crystal form I that the method for Fig. 3 embodiment 1 is prepared；
I X-ray powder diffraction collection of crystal form that the method for Fig. 4 embodiment 2 is prepared；
I X-ray powder diffraction collection of crystal form that the method for Fig. 5 embodiment 3 is prepared；
I X-ray powder diffraction collection of crystal form that the method for Fig. 6 embodiment 4 is prepared；
I X-ray powder diffraction collection of crystal form that the method for Fig. 7 embodiment 9 is prepared；
II X-ray powder diffraction collection of crystal form that the method for Fig. 8 embodiment 10 is prepared；
II X-ray powder diffraction collection of crystal form that the method for Fig. 9 embodiment 11 is prepared；
Specific embodiment
In the following embodiments, the Syprine Hydrochloride sample source is in prior art CN201210442924.8；Institute
The trientine crude product stated is obtained or is obtained according to prior art preparation by commercially available.
Embodiment 1
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 25.0mL water is added, it is 8.0 that hydrochloric acid, which is added dropwise, and adjusts pH value, ethyl alcohol 50mL is added,
Stirring and crystallizing at room temperature takes precipitating, is placed in 80 DEG C of dryings to get the white powder of the crystal form I of Syprine Hydrochloride compound, receives
Rate is 80%.
The detection method of crystal of the present invention includes:
1, X powder diffraction is tested
1) it sample treatment: directly weighs sample and makees X diffraction experiment.
2) test apparatus: X ' Pert Pro MPD Philips X-ray powder diffraction instrument (penetrates source CuK α, graphite monochromatic
Device, measurement range: 5-50 ° of 2 θ).
3) experimental condition: CuK α radiation, graphite monochromator, pipe press 40KV, Guan Liu 35mA, 2 5-50 ° of θ scanning ranges, scanning
9 °/point of speed, 0.03 ° of step-length.Slit condition: transmite slit is 0.5 °, and receiving slit is 1mm.
2, differential scanning calorimetery (DSC) is tested
Using DSC Q100 analyzer, initial temperature is set as 40 DEG C, and final temperature is set as 260 DEG C, and heating rate is set
It is set to 10 DEG C/min (10K/min).
3, infrared spectrum measurement is tested
The use of instrument is 6700 Fourier transformation infrared spectrometer of ThermoFisher Nicolet, and uses paraffin oil
Paste the detection of legal system piece.
The Syprine Hydrochloride compound crystal form I that detection embodiment 1 is prepared, powder X-ray diffraction are shown according to the method described above
Fig. 1, DSC are shown in that Fig. 2, IR are shown in Fig. 3.
Embodiment 2
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 25.0mL water is added, it is 7.5 that hydrochloric acid, which is added dropwise, and adjusts pH value, methanol 250mL is added,
Stirring and crystallizing at room temperature takes precipitating, is placed in 80 DEG C of dryings to get the white powder of the crystal form I of Syprine Hydrochloride compound, receives
Rate is 78%.
The crystal form I that Syprine Hydrochloride compound obtained is detected according to 1 the method for embodiment, measures its powder X-ray diffraction
See Fig. 4.
Embodiment 3
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 100.0mL water is added, it is 9.5 that hydrochloric acid, which is added dropwise, and adjusts pH value, and ethyl alcohol is added
500.0mL stands crystallization at 0 DEG C, takes precipitating, is placed in 60 DEG C of dryings to get the white of the crystal form I of Syprine Hydrochloride compound
Powder, yield 75%.
The crystal form I that Syprine Hydrochloride compound obtained is detected according to 1 the method for embodiment, measures its powder X-ray diffraction
See Fig. 5.
Embodiment 4
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 50.0mL water is added, it is 10.0 that hydrochloric acid, which is added dropwise, and adjusts pH value, and methanol is added
500.0mL takes precipitating in 0 DEG C of standing crystallization, is placed in 60 DEG C of dryings to get the white powder of the crystal form I of Syprine Hydrochloride compound
End, yield 76%.
The crystal form I that Syprine Hydrochloride compound obtained is detected according to 1 the method for embodiment, measures its powder X-ray diffraction
See Fig. 6.
Embodiment 5
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 100.0mL water is added, it is 8.0 that hydrochloric acid, which is added dropwise, and adjusts pH value, and methanol is added
50.0mL takes precipitating in 0 DEG C of stirring and crystallizing, is placed in 80 DEG C of dryings to get the white powder of the crystal form I of Syprine Hydrochloride compound
End, yield 77%.
The crystal form I of Syprine Hydrochloride compound obtained, the structure point of products obtained therefrom are detected according to 1 the method for embodiment
Analyse result and X-ray powder diffraction pattern and 1 no significant difference of embodiment.
Embodiment 6
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 15.0mL water is added, it is 7.5 that hydrochloric acid, which is added dropwise, and adjusts pH value, ethyl alcohol 250mL is added,
In 0 DEG C of stirring and crystallizing, precipitating is taken, is placed in white powder of 80 DEG C of dryings to get the crystal form I of Syprine Hydrochloride compound, yield
It is 79%.
The crystal form I of Syprine Hydrochloride compound obtained, the structure point of products obtained therefrom are detected according to 1 the method for embodiment
Analyse result and X-ray powder diffraction pattern and 1 no significant difference of embodiment.
Embodiment 7
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 50.0mL water is added, it is 10.0 that hydrochloric acid, which is added dropwise, and adjusts pH value, ethyl alcohol 50mL is added,
Crystallization is stood at room temperature, takes precipitating, is placed in 60 DEG C of dryings to get the white powder of the crystal form I of Syprine Hydrochloride compound, is received
Rate is 75%.
The crystal form I of Syprine Hydrochloride compound obtained, the structure point of products obtained therefrom are detected according to 1 the method for embodiment
Analyse result and X-ray powder diffraction pattern and 1 no significant difference of embodiment.
Embodiment 8
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 15.0mL water is added, it is 9.5 that hydrochloric acid, which is added dropwise, and adjusts pH value, methanol 250mL is added,
Crystallization is stood at room temperature, takes precipitating, is placed in 60 DEG C of dryings to get the white powder of the crystal form I of Syprine Hydrochloride compound, is received
Rate is 75%.
The crystal form I of Syprine Hydrochloride compound obtained, the structure point of products obtained therefrom are detected according to 1 the method for embodiment
Analyse result and X-ray powder diffraction pattern and 1 no significant difference of embodiment.
Embodiment 9
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 50.0mL water is added, it is 9.5 that hydrochloric acid, which is added dropwise, and adjusts pH value, acetone 250mL is added,
Stirring and crystallizing at room temperature takes precipitating, is placed in 80 DEG C of dryings to get the white powder of the crystal form I of Syprine Hydrochloride compound, receives
Rate is 78%.
The crystal form I that Syprine Hydrochloride compound obtained is detected according to 1 the method for embodiment, measures its powder X-ray diffraction
See Fig. 7.
Embodiment 10
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 25.0mL water is added, it is 9.5 that hydrochloric acid, which is added dropwise, and adjusts pH value, methanol 50mL is added,
In 0 DEG C of standing crystallization, precipitating is taken, is placed in white powder of 30 DEG C of dryings to get the crystal form II of Syprine Hydrochloride compound, yield
It is 68%.
The crystal form II that Syprine Hydrochloride compound obtained is detected according to 1 the method for embodiment, measures its powder X-ray diffraction
See Fig. 8.
Embodiment 11
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 25.0mL water is added, it is 8.0 that hydrochloric acid, which is added dropwise, and adjusts pH value, ethyl alcohol 250mL is added,
Stirring and crystallizing at room temperature takes precipitating, is placed in 30 DEG C of dryings to get the white powder of the crystal form II of Syprine Hydrochloride compound,
Yield is 78%.
The crystal form II that Syprine Hydrochloride compound obtained is detected according to 1 the method for embodiment, measures its powder X-ray diffraction
See Fig. 9.
Embodiment 12
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 50.0mL water is added, it is 8.0 that hydrochloric acid, which is added dropwise, and adjusts pH value, methanol 250mL is added,
Stirring and crystallizing at room temperature takes precipitating, is placed in 50 DEG C of dryings to get the white powder of the crystal form II of Syprine Hydrochloride compound,
Yield is 70%.
The crystal form II of Syprine Hydrochloride compound obtained, the structure of products obtained therefrom are detected according to 1 the method for embodiment
Analyze result and X-ray powder diffraction pattern and 11 no significant difference of embodiment.
Embodiment 13
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 50.0mL water is added, it is 9.5 that hydrochloric acid, which is added dropwise, and adjusts pH value, ethyl alcohol 50mL is added,
In 0 DEG C of standing crystallization, precipitating is taken, is placed in white powder of 50 DEG C of dryings to get the crystal form II of Syprine Hydrochloride compound, yield
It is 71%.
The crystal form II of Syprine Hydrochloride compound obtained, the structure of products obtained therefrom are detected according to 1 the method for embodiment
Analyze result and X-ray powder diffraction pattern and 11 no significant difference of embodiment.
Embodiment 14
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 15.0mL water is added, it is 7.5 that hydrochloric acid, which is added dropwise, and adjusts pH value, and methanol is added
500.0mL takes precipitating in 0 DEG C of stirring and crystallizing, is placed in 45 DEG C of dryings to get the white of the crystal form II of Syprine Hydrochloride compound
Powder, yield 68%.
The crystal form II of Syprine Hydrochloride compound obtained, the structure of products obtained therefrom are detected according to 1 the method for embodiment
Analyze result and X-ray powder diffraction pattern and 11 no significant difference of embodiment.
Embodiment 15
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 15.0mL water is added, it is 10.0 that hydrochloric acid, which is added dropwise, and adjusts pH value, and ethyl alcohol is added
500.0mL takes precipitating in 0 DEG C of stirring and crystallizing, is placed in 50 DEG C of dryings to get the white of the crystal form II of Syprine Hydrochloride compound
Powder, yield 70%.
The crystal form II of Syprine Hydrochloride compound obtained, the structure of products obtained therefrom are detected according to 1 the method for embodiment
Analyze result and X-ray powder diffraction pattern and 11 no significant difference of embodiment.
Embodiment 16
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 100.0mL water is added, it is 7.5 that hydrochloric acid, which is added dropwise, and adjusts pH value, and ethyl alcohol is added
250mL stands crystallization at room temperature, takes precipitating, is placed in 50 DEG C of dryings to get the white of the crystal form II of Syprine Hydrochloride compound
Powder, yield 78%.
The crystal form II of Syprine Hydrochloride compound obtained, the structure of products obtained therefrom are detected according to 1 the method for embodiment
Analyze result and X-ray powder diffraction pattern and 11 no significant difference of embodiment.
Embodiment 17
Syprine Hydrochloride of the present invention is prepared according to following operating procedure:
50.0g trientine is weighed, the stirring of 100.0mL water is added, it is 10.0 that hydrochloric acid, which is added dropwise, and adjusts pH value, and methanol is added
250mL stands crystallization at room temperature, takes precipitating, is placed in 30 DEG C of dryings to get the white of the crystal form II of Syprine Hydrochloride compound
Powder, yield 70%.
The crystal form II of Syprine Hydrochloride compound obtained, the structure of products obtained therefrom are detected according to 1 the method for embodiment
Analyze result and X-ray powder diffraction pattern and 11 no significant difference of embodiment.
1 the compounds of this invention Syprine Hydrochloride of test example draws moist comparison
Product 1g is taken, carrying out draws moist test, (2010 editions second annex XIX J drugs of Pharmacopoeia of People's Republic of China draw
Moist test direction principle).
About the defining standard for drawing moist weight gain:
It deliquesces: absorbing enough moisture and form liquid
It is great draw it is moist: draw wet weight gain not less than 15%
Have draw it is moist: draw wet weight gain less than 15% but not less than 2%
Slightly draw moist: drawing wet weight gain less than 2% but not less than 0.2%
Nothing is moist almost without drawing: drawing wet weight gain less than 0.2%
The compounds of this invention Syprine Hydrochloride crystal form I and Syprine Hydrochloride crystal form II, respectively by the above embodiment of the present invention
It is prepared, Syprine Hydrochloride existing product is prepared referring to having method disclosed in document (CN201210442924.8).
1 the compounds of this invention of table draws moist comparison
Seen from table 1, moisture absorption weight gain of the Syprine Hydrochloride compound as made from the method for the present invention in 2 hours is less than
9%, less than the 1/3 of the prior art.It follows that Syprine Hydrochloride of the present invention significantly improves its hygroscopicity, and effect is obvious
Better than existing product.
The stability study of 2 the compounds of this invention Syprine Hydrochloride of test example
Study on the stability condition includes:
1. thermal degradation: taking test sample about 200mg, be placed in 40 DEG C of drying boxes and place；
2. light degradation: taking test sample about 200mg, be placed in the environment that illumination is 4500 ± 500lx and place；
3. high humidity is degraded: taking test sample 200mg, be placed in and be placed with KNO3In the vessel that saturated solution humidity is 75%, room temperature
It places.
Study on the stability the results are shown in Table 2.It is provided according to quality standard, the content of impurities of Syprine Hydrochloride must not exceed
2.0%.
Wherein, the compounds of this invention Syprine Hydrochloride crystal form I and Syprine Hydrochloride crystal form II, respectively by the above-mentioned reality of the present invention
It applies example to be prepared, Syprine Hydrochloride existing product is prepared into referring to having method disclosed in document (CN201210442924.8)
It arrives.
2 stability test result of table
In conclusion present invention significantly reduces the hygroscopicity of trientine (hygroscopicity be only existing product 1/3), this
Outside, the regulation that there is trientine of the invention outstanding stability, impurity content to be better than quality standard, better than existing production
Product.
Claims (9)
1. a kind of Syprine Hydrochloride compound, it is characterised in that: the X-ray powder diffraction of the compound is as shown in Figure 8.
2. the preparation method of Syprine Hydrochloride compound according to claim 1, steps are as follows:
Suitable quantity of water is added into load weighted trientine, stirs, hydrochloric acid is added and adjusts pH value, appropriate organic solvent stirring is added
It mixes, obtained Syprine Hydrochloride is dried under reduced pressure by crystallization；
Wherein, the organic solvent is alcohols；Alcohol organic solvent is selected from: methanol, ethyl alcohol, ethylene glycol, isopropanol；
Wherein, the temperature that is dried under reduced pressure is 30 DEG C~50 DEG C.
3. the preparation method of Syprine Hydrochloride compound according to claim 2, it is characterised in that: the pH value is 7.5
~10.0.
4. the preparation method of Syprine Hydrochloride compound according to claim 3, it is characterised in that: the pH value is 8.0
~9.5.
5. the preparation method of Syprine Hydrochloride compound according to claim 2, it is characterised in that: the crystallization is to stir
Mix or stand crystallization.
6. according to the preparation method of Syprine Hydrochloride compound described in claim 2 or 5 any one, it is characterised in that: institute
The crystallization temperature stated is 0 DEG C~room temperature.
7. a kind of pharmaceutical composition, it is characterised in that: it is by Syprine Hydrochloride described in claim 1 as active constituent,
It adds or does not add pharmaceutically acceptable auxiliary material and be prepared.
8. pharmaceutical composition according to claim 7, it is characterised in that: the dosage form of described pharmaceutical composition is selected from piece
Agent, suspension, capsule, granule, pill, powder, pill, syrup, mixture, distillate medicinal water, effervescent agent, paste, emulsion, tea
Any one of agent, pulvis, injection, infusion, gelling agent, creme, liniment, lotion, suppository, liniment, paste or its sustained release
Preparation, positioning delivery formulations, quick releasing formulation, controlled release preparation, oral cavity disintegration preparation.
9. Syprine Hydrochloride compound according to claim 1 is preparing the drug for treating Wilson disease
In purposes.
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| WO2017049529A1 (en) | 2015-09-24 | 2017-03-30 | Innolife Co., Ltd. | A pharmaceutical composition comprising a copper chelating tetramine and the use thereof |
| CN109239208A (en) * | 2017-07-11 | 2019-01-18 | 四川科瑞德凯华制药有限公司 | A kind of quality determining method of Syprine Hydrochloride |
| CN111479798A (en) | 2018-05-04 | 2020-07-31 | Gmp奥奋有限公司 | Crystalline forms of triethylenetetramine tetrahydrochloride and their pharmaceutical use |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006104400A1 (en) * | 2005-03-26 | 2006-10-05 | Protemix Corporation Limited | Copper antagonist compositions |
| CN102924289A (en) * | 2012-11-07 | 2013-02-13 | 广东奥尔诚药业有限公司 | Synthetic process of hydrochloric acid trientine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006104400A1 (en) * | 2005-03-26 | 2006-10-05 | Protemix Corporation Limited | Copper antagonist compositions |
| CN102924289A (en) * | 2012-11-07 | 2013-02-13 | 广东奥尔诚药业有限公司 | Synthetic process of hydrochloric acid trientine |
Non-Patent Citations (2)
| Title |
|---|
| A simple and convenient preparation of triethylene tetramine dihydrochloride (trien) for the treatment of Wilson"s disease and its stability;Suzuki, Toshio等;《Byoin Yakugaku》;19871231;第13卷(第6期);第335-339页 * |
| The purification of triethylenetetramine and its dihydrochloride for the treatment of Wilson’s disease;Purchase, Rupert;《Journal of Chemical Research》;20051231(第4期);第233页左栏第1-2段，第234页左栏第2段 * |
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