CN110386879A - The novel crystal forms of Propranolol free alkali - Google Patents
The novel crystal forms of Propranolol free alkali Download PDFInfo
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- CN110386879A CN110386879A CN201810364327.5A CN201810364327A CN110386879A CN 110386879 A CN110386879 A CN 110386879A CN 201810364327 A CN201810364327 A CN 201810364327A CN 110386879 A CN110386879 A CN 110386879A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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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
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Abstract
The present invention relates to a kind of crystal form of Propranolol free alkali, Propranolol free alkali has the structure of compound formula (I) as follows.The invention further relates to prepare the method for the crystal form, the therapeutical uses of the Pharmaceutical composition of the compound containing crystal form and the form.
Description
Technical field
The present invention relates to a kind of forms of compound, are specifically related to a kind of crystal form A of Propranolol free alkali.The present invention
Further to preparing the method for the crystal form, the purposes of the Pharmaceutical composition containing the crystal form and the crystal form.
Background technique
Propranolol Hydrochloride is commonly called as " inderal ", is a non-selective beta-receptor blockader, to myocardium β 1 and beta 2 receptor
There is antagonism, suitable for treatment sinus property and supraventricular arrhythmias, auricular fibrillation, angina pectoris, pheochromocytoma is preoperative controls
It treats, hemangioma, also has certain curative effect to treatment hypertension.British James W.Black took the lead in preparing general naphthalene in 1964
Luo Er.1976, the plurality of specifications tablet of the trade name INDERAL of WYETH went through to list in the U.S..Ground is difficult to understand within 1981
The Propranolol Hydrochloride 25mg specification tablet of group lists at home at first, and the domestic main listing dosage form of this product includes hydrochloric acid at present
Capsule, sustained release tablets, tablet, the injection equal-specification of Propranolol.But without free alkali correlation crystal form and its pharmaceutical composition report
Road.
Summary of the invention
The present invention is intended to provide a kind of Propranolol free alkali of crystalline state, i.e. compounds of Formula I:
There are a kind of sufficient crystal habits for formula (I) compound.Formula (I) compound is generally termed as 1- isopropyl ammonia
Base -3- (naphthalene -1- oxygroup) propan-2-ol.
In one aspect of the invention, the crystal form of formula (I) compound is crystal form A, which is actual anhydrous
Form exists.
Crystal form A can be identified by its melting starting point, powder x-ray diffraction figure.The melting of crystal form A is initially
In the range of 90~93 DEG C.
When crystal form A is substantial pure and substantially anhydrous form, it 7.5 (± 0.1), 10.9 (± 0.1),
There are the X ray powder diffraction pattern at special high-intensitive peak in 14.3 (± 0.1), 15.2 (± 0.1), 16.6 (± 0.1) 2 θ.More into
One step, 2 θ of the X-ray powder diffraction figure of crystal form A are in 7.5 (± 0.1), 10.9 (± 0.1), 14.3 (± 0.1), 15.2 (±
0.1), 16.6 (± 0.1), 17.7 (± 0.1), 18.5 (± 0.1), 22.8 (± 0.1) have feature at 25.0 (± 0.1)
Peak.
As a result, in one aspect of the invention, formula (I) crystal form A of compound is provided,
Formula (I) compound is generally termed as 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol.
According to another aspect of the present invention, the crystal form A of 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol is provided,
It is characterized in that, the X-ray powder diffraction indicated with 2 θ angles about 7.5 (± 0.1), 10.9 (± 0.1), 14.3 (±
0.1), there are diffraction maximum in 15.2 (± 0.1), 16.6 (± 0.1).
According to another aspect of the present invention, the crystal form A of 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol is provided,
It is characterized in that, the X-ray powder diffraction indicated with 2 θ angles is in about 7.5 (± 0.1), 10.9 (± 0.1), 14.3 (±
0.1), 15.2 (± 0.1), 16.6 (± 0.1), 17.7 (± 0.1), 18.5 (± 0.1), 22.8 (± 0.1) and 25.0 (±
0.1) there is diffraction maximum.
Another aspect of the present invention provides the preparation method of above-mentioned formula (I) compound crystal form A, is existed by formula (I) compound
It is completely dissolved in suitable solvent, then room temperature crystallization, the solvent is selected from: ethyl acetate, methanol, methyl tertiary butyl ether(MTBE), second
Nitrile, ethyl alcohol, tetrahydrofuran, the preferred solvent are selected from: ethyl acetate, methanol, methyl tertiary butyl ether(MTBE) or acetonitrile.
In specific embodiments of the present invention, a kind of method for crystallising of formula (I) compound is provided, by formula (I) compound
By being completely dissolved in methyl tertiary butyl ether(MTBE), room temperature crystallization then separates solid, and the formula (I) that crystal form A is obtained after dry is changed
Close object.
In specific embodiments of the present invention, the dissolution is carried out by heating.
In specific embodiments of the present invention, another method for crystallising of formula (I) compound is provided, by formula (I) chemical combination
It is completely dissolved in object ethyl acetate, room temperature crystallization then separates solid, obtains formula (I) compound of crystal form A after dry.
In specific embodiments of the present invention, another method for crystallising of formula (I) compound is provided, by formula (I) chemical combination
It is completely dissolved in object methanol, room temperature crystallization then separates solid, obtains formula (I) compound of crystal form A after dry.
Another aspect of the present invention provides another method for crystallising of formula (I) compound, by formula (I) compound acetonitrile
In be completely dissolved, room temperature crystallization then separates crystalline solid form, obtains formula (I) compound of crystal form A after dry.It will be of the invention
Crystal form A be used as pharmaceuticals in the case where, crystal form A of the invention is mixed with excipient appropriate usually, preparation is made, into
It exercises and uses.But this does not negate that crystal form A itself of the invention is directly used as pharmaceuticals.The medical composition, wherein general naphthalene
Luo Er free alkali can exist in the form of crystal form A, can also by crystal form A and the preparation of pharmaceutically acceptable excipient and
At such as various liquid preparations.
As above-mentioned excipient, can enumerate the filler commonly used in pharmaceuticals, adhesive, lubricant, disintegrating agent,
It is toner, corrigent, emulsifier, surfactant, cosolvent, suspension, isotonic agent, buffer, preservative, antioxidant, steady
Determine agent, sorbefacient etc., it as needed can also be by the appropriately combined use of above-mentioned additive.
As above-mentioned filler, for example, lactose, white sugar, glucose, cornstarch, mannitol, sorbose can be enumerated
Alcohol, starch, dextrin, microcrystalline cellulose, silica, calcium monohydrogen phosphate etc..
As above-mentioned adhesive, for example, can enumerate polyvinyl alcohol, methylcellulose, ethyl cellulose, Arabic gum,
Tragacanth gum, gelatin, shellac, hypromellose, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone,
Polyethylene glycol etc..
As above-mentioned lubricant, for example, magnesium stearate, calcium stearate, rich horse odium stearate, talcum, poly- second can be enumerated
Glycol, colloidal silicon dioxide etc..
As above-mentioned disintegrating agent, for example, microcrystalline cellulose, agar, gelatin, calcium carbonate, low substituted hydroxy-propyl can be enumerated
Cellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, carboxymethyl starch, sodium carboxymethyl starch
Deng.
As above-mentioned colorant, for example, di-iron trioxide, Yellow ferric oxide, famille rose, caramel, β-can be enumerated
Allow the colorant added in the pharmaceuticals such as carrotene, titanium oxide, talcum, Riboflavin Sodium Phosphate.
As above-mentioned corrigent, cocoa power, menthol, peppermint oil, borneol, cinnamomi cortex pulveratus etc. can be enumerated.
As mentioned emulsifier or surfactant, for example, octadecyl triethanolamine, dodecyl sulphate can be enumerated
Sodium, dodecyl alanine, lecithin, glyceryl monostearate, sucrose fatty ester, fatty acid glyceride etc..
As above-mentioned cosolvent, for example, can enumerate polyethylene glycol, propylene glycol, benzoic acid benzyl ester, ethyl alcohol, cholesterol,
Triethanolamine, sodium citrate, Tween 80, niacinamide, cyclodextrin and cyclodextrine derivatives and organic and or inorganic acids, such as
Tartaric acid, acetic acid, citric acid, malic acid, sulfuric acid, phosphoric acid etc..
As above-mentioned suspension, in addition to above-mentioned surfactant, for example, polyvinyl alcohol, polyvinyl pyrrole can be enumerated
The hydrophilic macromolecules such as pyrrolidone, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose.
As above-mentioned isotonic agent, for example, glucose, sodium chloride, mannitol, D-sorbite etc. can be enumerated.
As above-mentioned buffer, for example, the buffers such as phosphate, acetate, carbonate, citrate can be enumerated.
As foregoing preservatives, for example, can enumerate methyl p-hydroxybenzoate, propylparaben, methaform,
Benzylalcohol, benzyl carbinol, dehydroactic acid, sorbic acid etc..
As above-mentioned antioxidant, for example, sulphite, ascorbic acid, alpha-tocopherol etc. can be enumerated.
In addition, as above-mentioned preparation, can enumerate tablet, powder, granule, capsule, syrup, lozenge, sublingual tablet,
The preparations such as sublingual/buccal film, inhalant;Suppository, ointment, cream, gelling agent, Eye ointments, transdermal agent, eye drops, drop
The external preparations such as nose agent, auristilla, cataplasm, lotion or injection.
Above-mentioned oral preparation can be carried out formulation with appropriately combined above-mentioned additive.It should be noted that as needed also
Above-mentioned dosage surface can be coated.
Above-mentioned external preparation can with appropriately combined above-mentioned additive, excipient especially therein, adhesive, corrigent,
Emulsifier, surfactant, cosolvent, suspension, isotonic agent, preservative, antioxidant, stabilizer, sorbefacient, film forming
Agent etc. carries out formulation.
Above-mentioned injection can be with appropriately combined above-mentioned additive, emulsifier especially therein, surfactant, hydrotropy
Agent, suspension, isotonic agent, buffer, preservative, antioxidant, stabilizer, sorbefacient etc. carry out formulation.
It can also include in this field in addition to the ingredient referred to specifically above about the type of the composition discussed
Conventional other compositions.
Crystal form A of the invention can be also used for providing the combination of the controlled release containing carrier and inventive compound
Object, wherein the release of active constituent can be controlled and be adjusted to allow the lower dispensing of frequency or improve the drug of the ingredient
Dynamics or toxic characteristic.The composition of the controlled release can be prepared according to conventional methods.
Crystal form A or composition of the invention is as pharmaceuticals in use, its usage amount is according to symptom, age, administration mode
And it is different, usual adult is administered daily 5mg~200mg, divides 1 time or is administered for several times.Children's dosage can be reduced suitably.
Crystal form A and composition of the invention is as pharmaceuticals in use, can be used as following purposes: dropping as secondary prevention
The low myocardial infarction death rate;Hypertension (shares individually or with other antihypertensives);Exertional angina pectoris;It controls supraventricular fast
Fast arrhythmia cordis, ventricular arrhythmia, it is especially related with catecholamine or digitalis causes arrhythmia cordis, it can be used for digitalis
The room of unsatisfactory curative effect flutters, the control of atrial fibrillation ventricular rate, it can also be used to which intractable proiosystole improves the symptom of patient;Lower fertilizer
Thicker cardiomyopathy efferent tract pressure difference mitigates the symptoms such as angina pectoris, palpitaition and faintness;α receptor blocker is cooperated to be used for chromaffin cell
Tumor Patient controlled tachycardia;Heart rate for controlling hyperthyroidism is too fast, it can also be used to treat thyroid crisis;
For hemangioma;For melanoma;Portal hypertension Gastroesophageal Varices bleeding;Migraine;Cerebrovascular ischemic disease;
Familial essential tremor;Schizophrenia;Anxiety disorder;Fallot's disease (F4) anoxic blue spell;Hemorrhagic fever;Regeneration
Aplastic anemia;Contraception;Restless legs syndrome;Aortic dissection.
When composition of the invention is as pharmaceuticals, can difference, symptom, age according to disease etc. difference and contain
There is other therapeutic agent, to obtain more effect.
Detailed description of the invention
Fig. 1: formula (I) compound: 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in methyl tertiary butyl ether(MTBE)
Crystal A DSC spectrogram.
Fig. 2: formula (I) compound: 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in methyl tertiary butyl ether(MTBE)
Crystal A TGA spectrogram.
Fig. 3: formula (I) compound: 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in methyl tertiary butyl ether(MTBE)
Crystal A XRPD spectrogram.
Fig. 4: formula (I) compound: the crystalline substance that 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in ethyl acetate
The DSC spectrogram of body A.
Fig. 5: formula (I) compound: the crystalline substance that 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in ethyl acetate
The TGA spectrogram of body A.
Fig. 6: formula (I) compound: the crystalline substance that 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in ethyl acetate
The XRPD spectrogram of body A.
Fig. 7: formula (I) compound: the crystal A that 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in methyl alcohol
DSC spectrogram.
Fig. 8: formula (I) compound: the crystal A that 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in methyl alcohol
TGA spectrogram.
Fig. 9: formula (I) compound: the crystal A that 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in methyl alcohol
XRPD spectrogram.
Figure 10: formula (I) compound: the crystal A that 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in acetonitrile
DSC spectrogram.
Figure 11: formula (I) compound: the crystal A that 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in acetonitrile
TGA spectrogram.
Figure 12: formula (I) compound: the crystal A that 1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystallizes in acetonitrile
XRPD spectrogram.
Specific embodiment
In order to which further the present invention will be described, will be illustrated below by specific embodiment, but reality below
Example is applied to be not limited in any way protection scope of the present invention.
The synthesis of embodiment 1:1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol.
10.00ml purified water is added into the there-necked flask of 100.00ml, is added with stirring 1.00g Propranolol Hydrochloride
10.00ml saturated sodium bicarbonate is added in (offer of Adamas-beta Reagent Company), and stirring detects pH > 7, and methylene chloride is added
10.00ml stirs liquid separation, collects organic phase, and water phase uses methylene chloride 10.00ml extraction primary again, merges methylene chloride phase, add
It is dry to enter anhydrous sodium sulfate, then removes methylene chloride under reduced pressure, obtains off-white powder 0.58g, as 1- isopropylamino -3-
(naphthalene -1- oxygroup) propan-2-ol.
The preparation of the crystal form A of embodiment 2:1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol
1- isopropylamino-the 3- prepared in 0.58g embodiment 1 (naphthalene -1- oxygroup) propan-2-ol is added to 10.00ml
In methyl tertiary butyl ether(MTBE), 50 DEG C are warming up to, dissolves within stir about 10 minutes, is subsequently reduced to room temperature crystallization, filter, filter cake is in 40 DEG C of drums
Air-dry it is dry after 0.33g white solid, gained sample through DSC (attached drawing 1) determine its melt initiation temperature degree be 92.3 DEG C, heat absorption
Peak value: 95.7 DEG C, TGA (attached drawing 2), XRPD (attached drawing 3) data are detailed in attached drawing.
The preparation of embodiment 3:1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystal.
1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol prepared in 50.00mg embodiment 2 is weighed to be added to
In 1.00ml ethyl acetate, room temperature lower open mouth is placed, and the crystal of precipitation is taken out sample presentation detection after about 4 days, through DSC (attached drawing 4)
Determine that its melting starts to be 90.1 DEG C, endothermic peak: 95.0 DEG C, TGA (attached drawing 5) is detailed in attached drawing.XRPD (attached drawing 6) is detailed in attached
Figure.Formula (I) compound of crystallization, DSC show that it has almost the same fusing point with crystal A.
The preparation of embodiment 4:1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystal.
1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol prepared in 50.00mg embodiment 2 is weighed to be added to
In 1.00ml methanol, the crystal of precipitation is taken out into sample presentation detection after about 4 days, determines that its melting starts to be 91.1 through DSC (attached drawing 7)
DEG C, endothermic peak: 94.9 DEG C, TGA (attached drawing 8) is detailed in attached drawing.XRPD (attached drawing 9) is detailed in attached drawing.Formula (I) compound of crystallization,
DSC shows that it has almost the same fusing point with crystal A.
The preparation of embodiment 5:1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol crystal.
1- isopropylamino -3- (naphthalene -1- oxygroup) propan-2-ol prepared in 50.00mg embodiment 2 is weighed to be added to
In 1.00ml acetonitrile, the crystal of precipitation is taken out into sample presentation detection after about 4 days, through DSC (attached drawing 10) determine its melting start for
91.8 DEG C, endothermic peak: 95.5 DEG C, TGA (attached drawing 11) is detailed in attached drawing.XRPD (attached drawing 12) is detailed in attached drawing.The formula (I) of crystallization is changed
Object is closed, DSC shows that it has almost the same fusing point with crystal A.
It should be noted that all documents referred in the present invention are incorporated as referring in this application, just as each
Piece document is individually recited as with reference to such.In addition, it should also be understood that, above-described is that specific implementation of the invention is arranged and transported
Technical principle, after having read the contents of the present invention, those skilled in the art can do various changes or be repaired to the present invention
Change without departing from spirit and scope of the invention, such equivalent forms are also fallen in the scope of the present invention.
Remarks: XRPD:X- ray powder diffraction
DSC: differential scanning calorimetry
TGA: thermogravimetric analysis
Claims (10)
1. a kind of crystal form A of Propranolol free alkali, is characterized in that, 2 θ of characteristic peak of X-ray powder diffraction figure be 7.5 (±
0.1), 10.9 (± 0.1), 14.3 (± 0.1), 15.2 (± 0.1), 16.6 (± 0.1), the wherein structure of Propranolol free alkali
Formula is formula (I) shown,
2. the crystal form A of the Propranolol free alkali according to claim 1, it is characterized in that 2 θ of its X-ray powder diffraction figure characteristic peak
For 7.5 (± 0.1), 10.9 (± 0.1), 14.3 (± 0.1), 15.2 (± 0.1), 16.6 (± 0.1), 17.7 (± 0.1), 18.5
(±0.1)、22.8(±0.1)、25.0(±0.1)。
3. being characterized in that the melting of its differential scanning calorimetric curve according to formula (I) compound of any one of claims 1 or 2
It is initially at 90~93 DEG C.
4. a kind of method for the crystal form A for preparing Propranolol free alkali in claim 1, wherein the formula (I) compound is one
It is completely dissolved in solvent kind selected from the following: Lower alkyl acetates, lower alkyl alcohol, dialkyl ether or acetonitrile, then room temperature
Lower crystallization, and dry acquisition crystal form A.
5. according to method for claim 4, wherein the solvent is selected from: ethyl acetate, methanol, methyl tertiary butyl ether(MTBE) or acetonitrile.
6. method for claim 4, wherein the solvent is methyl tertiary butyl ether(MTBE), and it is described be completely dissolved be by heat into
Capable.
7. a kind of pharmaceutical composition, it includes the crystalline substances of Propranolol free alkali described in any claim in claim 1-3
Type A and pharmaceutically acceptable excipient.
8. pharmaceutical composition according to claim 7 further includes other therapeutic agent.
9. the described in any item pharmaceutical compositions of claim 7-8 for tablet, powder, granule, capsule, syrup, contain
The preparations such as piece, sublingual tablet, sublingual/buccal film, inhalant;Suppository, ointment, cream, gelling agent, Eye ointments, transdermal agent,
Eye drops, nasal drop, auristilla, cataplasm, lotion or injection.
10. the described in any item drugs of crystal form A or claim 7-9 of the Propranolol free alkali of any one of claim 1-3
Composition in preparation for treating sinus property and supraventricular arrhythmias, auricular fibrillation, angina pectoris, pheochromocytoma preoperative therapy,
Application in hypertension, angiomatous drug.
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US5290958A (en) * | 1993-03-18 | 1994-03-01 | Industrial Technology Research Institute | Phase transfer catalytic process for preparing intermediates of atenolol, propranolol, and their derivatives |
CN103030567A (en) * | 2012-07-25 | 2013-04-10 | 浙江工业大学 | Propranolol medicine enantiomer resolution method |
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