CN106432136A - Hydrochlorothiazide and atenolol co-amorphous system and preparation method thereof - Google Patents
Hydrochlorothiazide and atenolol co-amorphous system and preparation method thereof Download PDFInfo
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- CN106432136A CN106432136A CN201610512904.1A CN201610512904A CN106432136A CN 106432136 A CN106432136 A CN 106432136A CN 201610512904 A CN201610512904 A CN 201610512904A CN 106432136 A CN106432136 A CN 106432136A
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- atenolol
- hydrochioro
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- amorphous
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
- C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
- C07D285/28—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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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 hydrochlorothiazide and atenolol co-amorphous system and a preparation method thereof. From X-ray diffraction spectral results of powder, the amorphous system cannot find a sharp diffraction peak, a differential scanning calorimeter finds single glass transition temperature, an infrared spectrometer finds broadening of an absorption peak and change of peak displacement, and formation of the co-amorphous system with strong intermolecular interaction can be determined from the results. Solubility and intrinsic dissolution rate of obtained co-amorphous forms are experimented, the solubility and the intrinsic dissolution rate are obviously improved as compared with crystal drugs, and physical stability of the co-amorphous drug system is represented. Results indicate that the system can be stably preserved for 30 days under the drying temperature ranging from 4 DEG C to 25 DEG C. The invention further relates to two preparation methods of the co-amorphous drug system, and a refrigeration-rubbing method and a solvent evaporation method provide two ways for preparing the co-amorphous system.
Description
Technical field
The invention belongs to pharmaceutical technology field and in particular to a kind of Hydrochioro and atenolol common unformed system with
And its two kinds of preparation methods.
Background technology
According to the blood pressure standard that the World Health Organization (WHO) suggestion uses it is：All adult normal's systolic pressures should be less than or wait
In 140mmHg (18.6kPa), diastolic pressure is less than or equal to 90mmHg (12kPa).International hypertension association regulation does not apply step-down
The blood pressure of medicine person continues >=and 140/90mmHg can be diagnosed as hypertension.Hypertension is one kind is just higher than with systemic arterial blood pressure
Often scope is the disease of main clinical manifestation.The pathogenesis of hypertension is not yet fully apparent from, generally believe now be related to multiple
Factor includes neuromechanism disorder, and periphery itself regulation mechanism weakens, and hormone or Topically active material exception and electrolyte lose
Weighing apparatus etc..
Hypertension is high in China's incidence of disease at present, and the death toll of the cardiovascular and cerebrovascular complication being caused by hypertension
Rising year by year, hypertension has become as the big killer threatening human health.The Chinese residents nutrition of 2004 is existing with health
Shape investigation result shows, China 18 years old and above prevalence of hypertension rate are 18.8%, estimates national number of patients more than 1.6
Hundred million.Compared with 1991, illness rate rises 31%, number of patients increase by ten thousand people about more than 7000.
At present, hypertension is a kind of disease that can not effect a radical cure, and needs patient by drug administration and to be careful in one's diet
Carry out regulation and the control of blood pressure.The drug for hypertension clinically commonly used now includes following a few class：Diuretic antihypertensive medicine, sympathetic
Neuroleptic, calcium channel blocking agent, RAS depressant and blood vessel dilatation pipe.Anti-hypertension
Medicine generally adopts drug combination, and that is, the medicine of different Hypotensive Mechanisms is together taken, thus preferably to control blood pressure, common
Scheme of combination drug therapy is included thiazide diuretic and is combined with angiotensin receptor antagonist；Thiazide diuretic is hindered with beta receptor
Stagnant dose of combination；Phenothiazine drug is combined with calcium antagonist；And angiotensin receptor antagonist and calcium antagonist combination etc..
Also generally the combination of these drug combinations is prepared into compound preparation therefore on market, to increase the taking convenience of patient.These are normal
Compound preparation also plays vital effect to the blood pressure controlling patient.
Hydrochioro (Hydrochlorothiazide) is a kind of diuretic antihypertensive medicine, is also the basic medicine for the treatment of hypertension
Thing, safely and effectively, inexpensive.Hydrochioro chemistry entitled 6- chloro- 3,4- dihydro -2H-1,2,4- benzothiadiazine -7- sulfonamide -
1,1- dioxide.Molecular structure is as follows：
The precise mechanism that Hydrochioro reduces arterial pressure is unclear, and the saying comparing accreditation is by natriuretic diuretic,
Cause the negative balance of internal sodium, water, reduce extracellular fluid and reduce peripheral vascular resistance come the antihypertensive effect to play.Can be alone
Or be used in combination with other drugs for hypertension.Alone it is used in light, moderate hypertension.In aged patients with hypertension, because of kidney list
Position is reduced, and water sodium capacity increases, and plasma renin activity reduces, and this kind of curative effect of medication is more preferably.Hydrochioro belongs to biopharmacy
II class medicine in classification, medicine water solubility is extremely low, about 0.7mg/ml.Due to its relatively low solubility, also reduce this medicine
The oral administration biaavailability of thing.The water solubility therefore how strengthening medicine just becomes particularly important to improve its bioavilability.
Atenolol belongs to adrenoceptor blocking drug, except for treating in addition to angina pectoris and arrhythmia cordis, is also treatment
The fiest-tire medication of hypertension.This drug price is cheap, and treatment hypertension safely and effectively, can reduce the generation of cardiovascular complication
Rate and case fatality rate.The Hypotensive Mechanism of this medicine mainly can block heart β1receptor, suppress myocardial contraction, reducing heart rate, reduce the heart
Discharge rate.This medicine is preferable for various antihypertensive effect.Share with other antihypertensives (diuretics, calcium channel blocker etc.)
Severe or intractable hypertension in can treating.
The treatment of hypertension, mainly based on drug combination, today there is also many appearance of compound medicine preparation for treating hypertension.Hydrogen
Chlorothiazide is also unresolved at present with the problem of atenolol drug combination poorly water-soluble.
Content of the invention
It is an object of the invention to provide one kind can significantly increase Hydrochioro and atenolol drug combination water-soluble with
And improve the common unformed system of the intrinsic dissolution rate of medicine.
The present invention further an object is that the preparation method providing this common unformed system.
It is yet a further object of the present invention to provide a kind of pharmaceutical composition containing this unformed system altogether.
The purpose of the present invention is achieved in the following ways：
A kind of Hydrochioro and atenolol unformed system altogether, this common unformed system is with Hydrochioro and atenolol
For active constituents of medicine, prepared using solvent evaporated method or freeze grinding method；Hydrogen chlorine in the common unformed system being formed
The drug molecule of thiazine and atenolol is all existed with amorphous forms, and described Hydrochioro with the mol ratio of atenolol is
1:0.25～1.5, preferably 1:0.5～1.25, further preferred 1:0.5～1, most preferably Hydrochioro and atenolol mole
Than for 1:1.
Unformed system mainly exists in powder form altogether for Hydrochioro and atenolol, and particle diameter is less than 150 μm.
Described solvent evaporated method is to adopt Hydrochioro and atenolol after organic solvent dissolving, then heats decompression steaming
Dry solvent.Described heating-up temperature is 35-60 DEG C, and organic solvent is methyl alcohol, ethanol, acetonitrile, normal propyl alcohol, n-butanol, oxolane,
In ethyl acetate any one, preferable organic solvent be methyl alcohol.
Unformed system uses Cu-K α to radiate, to spend 2 θ tables altogether for the Hydrochioro of solvent evaporated method preparation and atenolol
Show that X-ray powder diffraction spectrum does not have the sharp peak that spreads out；With KBr compressing tablet measure the infrared absorption spectroscopy that obtains 3367,1664,
1559、1522、1399、1327、1240、1156、1060、1027、605、539cm-1There is absworption peak at place.
Freeze grinding method is uniformly to be mixed Hydrochioro with atenolol, is placed under liquid nitrogen environment, with 5-20Hz
Frequency mechanical grind 10-60 minute, obtain final product the common unformed system of Hydrochioro and atenolol after being dried；Preferably grind frequency
Rate 10Hz, milling time 45 minutes.
Unformed system uses Cu-K α to radiate, to spend 2 θ tables altogether for the Hydrochioro of freeze grinding method preparation and atenolol
Show that X-ray powder diffraction spectrum does not have the sharp peak that spreads out；With KBr compressing tablet measure the infrared absorption spectroscopy that obtains 3358,1664,
1559、1512、1399、1326、1243、1169、1058、1028、674、605、539cm-1There is absworption peak at place.
The preparation method of above-mentioned Hydrochioro and the common unformed system of atenolol comprises the following steps：By Hydrochioro and
After atenolol adopts organic solvent dissolving, then heating under reduced pressure solvent evaporated.
The preparation method of above-mentioned Hydrochioro and the common unformed system of atenolol comprises the following steps：By Hydrochioro with
Atenolol is uniformly mixed, and is placed under liquid nitrogen environment, grinds 10-60 minute with the frequency mechanical of 5-20Hz；Preferably grind
Frequency 10Hz, milling time 45 minutes.
Unformed system altogether of the present invention is made up of Hydrochioro and atenolol.Two kinds of medicines are all hypotensor
Thing.Two kinds of medicines are all existed with amorphous forms.There is stronger intermolecular force to each other.By powder x-ray diffraction
Technology determines that two kinds of medicines are all existed with amorphous forms.Single glass transition temperature is found by differential canning calorimetry
Degree, illustrates to define homogeneous unformed system.Find have than stronger between two kinds of medicines by infrared spectrum technology
Interact.This amorphous article solves the problems, such as Hydrochioro and atenolol drug combination poorly water-soluble, not arbitrarily with
Two kinds of material mixings all can effectively be combined into unformed system altogether.
To the common unformed mensure carrying out solubility and intrinsic dissolution rate prepared with two methods, it is fixed in common nothing to find
In type system, the solubility of Hydrochioro is 4.44～4.72 times of crystalline drug, and dissolution rate also improve 6.5 times with
On.
Beneficial effects of the present invention compared with the prior art：The present invention is solved existing Hydrochioro and is combined with atenolol
The problem of medication poor solubility, for solving the problems, such as that drug combination provides new approaches later.
Brief description
Hydrochioro-atenolol unformed system X-ray powder altogether that Fig. 1 is prepared according to embodiment solvent evaporated method
Diffracting spectrum；
Hydrochioro-atenolol unformed system X-ray powder altogether that Fig. 2 is prepared according to embodiment freeze grinding method
Diffracting spectrum；
Hydrochioro-atenolol unformed system differential scanning amount altogether that Fig. 3 is prepared according to embodiment solvent evaporated method
Thermal map is composed；
Hydrochioro-atenolol unformed system differential scanning amount altogether that Fig. 4 is prepared according to embodiment freeze grinding method
Thermal map is composed；
The infrared spectrum of Fig. 5 single Hydrochioro medicine；
The infrared spectrum of Fig. 6 single atenolol medicine；
Hydrochioro-atenolol unformed system infrared spectrum altogether that Fig. 7 is prepared according to embodiment solvent evaporated method；
Hydrochioro-atenolol unformed system infrared spectrum altogether that Fig. 8 is prepared according to embodiment freeze grinding method；
After Fig. 9 is total to unformed system 30 days according to Hydrochioro-atenolol prepared by embodiment solvent evaporated method
Stability result；
After Figure 10 is total to unformed system 30 days according to Hydrochioro-atenolol prepared by embodiment freeze grinding method
Stability result；
Hydrochioro in the common unformed system that Figure 11 prepares according to embodiment freeze grinding method and solvent evaporated method
Intrinsic stripping curve；
Atenolol in the common unformed system that Figure 12 prepares according to embodiment freeze grinding method and solvent evaporated method
Intrinsic stripping curve；
Figure 13 is according to atenolol described in comparative example and nifedipine with mol ratio 1:1 ratio prepares the X-ray powder of sample
Last diffracting spectrum；
Figure 14 is according to atenolol described in comparative example and nifedipine with mol ratio 2:1 ratio prepares the X-ray powder of sample
Last diffracting spectrum；
Specific embodiment
With reference to embodiment, the present invention is described further, and embodiment is only explanatory, by no means implies that it
Limit the scope of the invention by any way.
Embodiment
Will be unformed altogether for Hydrochioro-atenolol that following analysis method is used for characterizing the present invention：
1.X ray powder diffraction:
Instrument:XTRA/3KW X-ray diffractometer (Arl Inc. of Switzerland), target:Cu-K α radiates, wavelength:1.5406A, pipe
Pressure:40KV, Guan Liu:40mA, step-length:0.02 °, sweep speed:1.2 °/min, sweep limits is 3 °～40 °.
2. differential scanning calorimeter：
Instrument：TA DSC2000 differential scanning calorimeter instrument (American), scope：- 20-280 DEG C, programming rate： 10
DEG C/min, the endothermic transition of Hydrochioro is at 266.06 DEG C.The endothermic transition of atenolol is at 153.12 DEG C.3rd, infrared spectrum
Instrument：Nicolet IS10 type infrared spectrometer (Nicolet company of the U.S.)
Embodiment 1
Weigh Hydrochioro 0.299g, add in 30ml methyl alcohol, stir to obtain settled solution.Again by atenolol 0.2663g
Add in above-mentioned settled solution, room temperature (20 ± 5 DEG C) stirs to obtain settled solution, rotation that this settled solution is reduced pressure at 55 DEG C is steamed
Send out solvent, 25 DEG C are vacuum dried 24 hours, obtain final product Hydrochioro and atenolol unformed system altogether.
Embodiment 2
Weigh Hydrochioro 0.4485g, add in 50ml ethanol, stir to obtain settled solution.Again by atenolol 0.3994g
Add in above-mentioned settled solution, room temperature (20 ± 5 DEG C) stirs to obtain settled solution, rotation that this settled solution is reduced pressure at 50 DEG C is steamed
Send out solvent, 25 DEG C are vacuum dried 24 hours, obtain final product Hydrochioro and atenolol unformed system altogether.
Embodiment 3
Weigh Hydrochioro 0.299g, weigh atenolol 0.2663g, two kinds of powder are mixed, and in vortex instrument
Upper vortex one minute, is allowed to mix.Afterwards mixture is placed in full of (Freezer Mill in the refrigeration grinding machine of liquid nitrogen
6770, USA), frequency is adjusted to 10Hz, grinds 10 circulations, each circular grinding 2 minutes, cool down 1 minute.After grinding
Taking-up sample is placed in after placing 1 hour in silica gel drier, you can obtain Hydrochioro and atenolol unformed system altogether.
Embodiment 4
Weigh Hydrochioro 0.299g, weigh atenolol 0.2663g, two kinds of powder are mixed, and in vortex instrument
Upper vortex one minute, is allowed to mix.Afterwards mixture is placed in full of (Freezer in the refrigeration grinding machine of liquid nitrogen
Mill 6770, USA), frequency is adjusted to 10Hz, grinds 15 circulations, each circular grinding 2 minutes, cool down 1 minute.Through grinding
After after mill, taking-up sample is placed in and places 1 hour in silica gel drier, you can obtain Hydrochioro and atenolol unformed system altogether
System.
Comparative example
Nifedipine is also a kind of common drug treating hypertension as Hydrochioro, but works as and utilize atenolol
With nifedipine with 2:When 1 mol ratio carries out unformed preparation altogether, from the point of view of the result of X-ray powder diffraction, this system
Middle have stronger crystal diffraction peak, illustrate in system with the presence of some drugs it is with crystal form, and can not be formed surely
Fixed common unformed system.
When atenolol and nifedipine are with 1:When 1 mixed in molar ratio preparation is common unformed, from X-ray powder diffraction
Result from the point of view of although unformed sample altogether can be obtained, but the physical stability extreme difference of this altogether unformed system, one day with
Afterwards, in system, unformed shape medicine will recrystallize, thus lose altogether unformed system in solubility and dissolved corrosion
On advantage.
Above-mentioned two comparative run illustrates not any two kinds of medicines with arbitrary proportion mixing using the inventive method preparation all
Stable common unformed system can effectively be combined to form.
X-ray powder diffraction result
In PXRD result, sharp diffraction maximum does not all occur using the common unformed system that said method prepares, say
Bright do not have crystalline drug in system.(see Fig. 1 and Fig. 2)
Means of differential scanning calorimetry result
All single glass transition temperature only occurs in the common unformed result in DSC that said method prepares, say
Bright define homogeneous single_phase system.(see Fig. 3 and Fig. 4)
The results of FT-IR
Compared to the infrared spectrum (see Fig. 5 and Fig. 6) of single medicine, the infrared light spectral peak generation of unformed system is bright altogether
Aobvious broadening, and peak shift there occurs skew, in this explanation system, medicine is intermolecular has strong interaction.Wherein utilize
Sample infrared absorption spectroscopy prepared by solvent evaporated method (embodiment 1 and embodiment 2) is 3367,1664,1559,1522,
1399、1327、1240、1156、1060、1027、605、539cm-1There is absworption peak at place；Using freeze grinding method (embodiment 3 and reality
Apply example 4) sample prepared 3358,1664,1559,1512,1399,1326,1243,1169,1058,1028,674,
605、539cm-1There is absworption peak at place.(see Fig. 7 and Fig. 8)
Physical stability is tested
The common unformed sample preparing according to embodiment method is positioned over the dry environment of 4 DEG C and 25 DEG C, point
Not at first day, seven days, fortnight, the time point of 30 days takes out sample, carries out X-ray powder diffraction experiment, sees whether
Sample recrystallizes.We have found that the common unformed of two methods preparation all can stable existence in the above conditions from result
30 days.(see Fig. 9 and accompanying drawing 10)
Solubility experiment
Weigh two methods of excessive pure Hydrochioro bulk drug and Hydrochioro-Ah the replacing being prepared respectively with embodiment
Unformed sample is placed in 40ml pure water Luo Er altogether, measures three individual under 37 DEG C of temperature conditionss and the speed conditions of 120rpm
The solubility of Hydrochioro in system.From the result of table one we it is found that compared to pure Hydrochioro bulk drug, by freezing
The solubility of the Hydrochioro in the common unformed system that polishing and solvent evaporated method prepare has significant raising.
Table one：Hydrochioro solubility
Intrinsic dissolution rate experiment
The micro digestion instrument of this experimental applications PION μ Diss profiler carries out the detection of intrinsic dissolution.Take the sample of 10mg
Product (two methods of Hydrochioro bulk drug and the Hydrochioro-atenolol unformed sample altogether prepared respectively with embodiment)
It is placed in and keeps 30 seconds under the pressure condition of 100bar, it is 0.0707cm that sample is pressed into surface area2Small pieces, sample small pieces
Throw to the pure water solvent of 10ml (ensureing that sample small pieces only one of which surface is exposed in dissolution medium), and stirring in 300rpm
Carry out the mensure of drug concentration using the original position UV-detector that instrument carries under the conditions of mixing.From the intrinsic dissolution rate of table two
Experimental result can be seen that compared to bulk drug, altogether in unformed system the intrinsic dissolution rate of two kinds of medicines be obtained for aobvious
The raising writing.(Figure 11, Figure 12 are respectively Hydrochioro and the intrinsic stripping curve of atenolol)
Table two：Two kinds of medicines intrinsic dissolution rate in different systems
Claims (10)
1. a kind of Hydrochioro and the common unformed system of atenolol are it is characterised in that this common unformed system is with Hydrochioro
It is active constituents of medicine with atenolol, prepared using solvent evaporated method or freeze grinding method；Formed is common unformed
In system, the drug molecule of Hydrochioro and atenolol is all with amorphous forms presence, described Hydrochioro and atenolol
Mol ratio be 1:0.25～1.5.
2. Hydrochioro according to claim 1 and atenolol altogether unformed system it is characterised in that described hydrogen chlorine
Thiazine is 1 with the mol ratio of atenolol:0.5～1.25.
3. Hydrochioro according to claim 2 and atenolol altogether unformed system it is characterised in that Hydrochioro with
Unformed system particle diameter is less than 150 μm to atenolol altogether.
4. Hydrochioro according to claim 1 and atenolol altogether unformed system it is characterised in that described solvent
Evaporation is to adopt Hydrochioro and atenolol after organic solvent dissolving, then heating under reduced pressure solvent evaporated.
5. Hydrochioro according to claim 4 and atenolol altogether unformed system it is characterised in that described heating temperature
Spend for 35-60 DEG C, organic solvent is methyl alcohol, ethanol, acetonitrile, normal propyl alcohol, n-butanol, oxolane are any one in ethyl acetate
Kind, preferable organic solvent is methyl alcohol.
6. Hydrochioro according to claim 1 and atenolol altogether unformed system it is characterised in that solvent evaporated method
Unformed system uses Cu-K α to radiate altogether for the Hydrochioro of preparation and atenolol, represents X-ray powder diffraction spectrum to spend 2 θ
There is no the sharp peak that spreads out；With KBr compressing tablet measure the infrared absorption spectroscopy that obtains 3367,1664,1559,1522,1399,
1327、1240、1156、1060、1027、605、539cm-1There is absworption peak at place.
7. Hydrochioro according to claim 1 and atenolol altogether unformed system it is characterised in that described freezing
Polishing is uniformly to be mixed Hydrochioro with atenolol, is placed under liquid nitrogen environment, is ground with the frequency mechanical of 5-20Hz
Mill 10-60 minute；Preferably grind frequency 10Hz, milling time 45 minutes.
8. Hydrochioro according to claim 1 and atenolol altogether unformed system it is characterised in that freeze grinding method
Unformed system uses Cu-K α to radiate altogether for the Hydrochioro of preparation and atenolol, represents X-ray powder diffraction spectrum to spend 2 θ
There is no the sharp peak that spreads out；With KBr compressing tablet measure the infrared absorption spectroscopy that obtains 3358,1664,1559,1512,1399,
1326、1243、1169、1058、1028、674、605、539cm-1There is absworption peak at place.
9. the Hydrochioro described in a kind of claim 1 and atenolol altogether unformed system preparation method it is characterised in that
The method comprises the following steps：Hydrochioro and atenolol are adopted after organic solvent dissolving, then heating under reduced pressure solvent evaporated.
10. the Hydrochioro described in a kind of claim 1 and atenolol altogether unformed system preparation method it is characterised in that
The method comprises the following steps：Hydrochioro is uniformly mixed with atenolol, is placed under liquid nitrogen environment, with 5-20Hz's
Frequency mechanical grinds 10-60 minute；Preferably grind frequency 10Hz, milling time 45 minutes.
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| CN107308181A (en) * | 2017-07-18 | 2017-11-03 | 卢广荣 | Treat the compound medicinal formulation of refractory hypertension |
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