CN106432136B - A kind of Hydrochioro and atenolol are total to unformed system and preparation method thereof - Google Patents
A kind of Hydrochioro and atenolol are total to unformed system and preparation method thereof Download PDFInfo
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- CN106432136B CN106432136B CN201610512904.1A CN201610512904A CN106432136B CN 106432136 B CN106432136 B CN 106432136B CN 201610512904 A CN201610512904 A CN 201610512904A CN 106432136 B CN106432136 B CN 106432136B
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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
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- 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 kind of Hydrochioros and atenolol to be total to unformed system and preparation method thereof, there is not sharp diffraction maximum from the point of view of powder x-ray diffraction spectral results in the amorphous system, differential scanning calorimeter finds single glass transition temperature, infrared spectrometer finds the broadening of absorption peak and the variation of peak shift, can determine from above result and form a kind of unformed system altogether with very strong intermolecular interaction.And the experiment for carrying out solubility and intrinsic dissolution rate unformed altogether to obtaining, compared with crystalline pharmaceutical, solubility and dissolution rate are significantly improved.Also the physical stability of unformed system altogether is characterized simultaneously, the results showed that the system can stablize preservation 30 days under 4 DEG C and 25 DEG C of drying conditions.The invention further relates to two kinds of total unformed preparation methods, unformed system provides two kinds of approach altogether for preparation for freeze grinding method and solvent evaporated method.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to the unformed system altogether of a kind of Hydrochioro and atenolol with
And its two kinds of preparation methods.
Background technique
Suggest that the blood pressure standard used is according to the World Health Organization (WHO): all normal adult'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 not application decompression
The blood pressure of medicine person continues >=and 140/90mmHg can be diagnosed as hypertension.Hypertension is that one kind is higher than just with systemic arterial blood pressure
Normal range is the disease of main clinical manifestation.The pathogenesis of hypertension is not yet fully apparent from, generally believe now be related to it is a variety of
Factor includes neuromechanism disorder, and periphery itself adjustment mechanism weakens, and hormone or Topically active substance exception and electrolyte lose
Weighing apparatus etc..
Hypertension is high in China's disease incidence at present, and the death toll of the cardiovascular and cerebrovascular complication as caused by hypertension
It is rising year by year, hypertension has become the big killer for threatening human health.Chinese residents nutrition in 2004 and health are existing
Shape investigation result shows, China 18 years old and the above prevalence of hypertension rate are 18.8%, estimates that national number of patients is 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.
Currently, hypertension is a kind of disease that can not be eradicated, need patient by take drugs and be careful in one's diet come
Carry out the adjusting and control of blood pressure.Present clinically common drug for hypertension includes the following categories: diuretic antihypertensive medicine, sympathetic
Neuroleptic, calcium channel blocking agent, renin-angiotensin system depressant and blood vessel dilatation pipe.Anti-hypertension
Drug generallys use drug combination, i.e., the drug of different Hypotensive Mechanisms is taken together, so that blood pressure preferably is controlled, it is common
Scheme of combination drug therapy includes that thiazide diuretic and angiotensin receptor antagonist are combined；Thiazide diuretic and beta receptor hinder
Stagnant dose of combination；Phenothiazine drug and calcium antagonist are combined；And angiotensin receptor antagonist and calcium antagonist combination etc..
Therefore the combination of these drug combinations is usually also prepared into compound preparation in the market, to increase the convenient to take of patient.These are often
Compound preparation also plays the role of the blood pressure of control patient vital.
Hydrochioro (Hydrochlorothiazide) is a kind of diuretic antihypertensive medicine, and the basic medicine for the treatment of hypertension
Object, it is safely and effectively, inexpensive.The entitled chloro- 3,4- dihydro -2H-1,2,4- benzothiadiazine -7- sulfonamide-of 6- of Hydrochioro chemistry
1,1- dioxide.Molecular structure is as follows:
The precise mechanism that Hydrochioro reduces arterial pressure is unclear, compare approval saying be by natriuretic diuretic,
Cause the negative balance of internal sodium, water, the antihypertensive effect for reducing extracellular fluid and reduction peripheral vascular resistance to play.It can be applied alone
Or it is used in combination with other drugs for hypertension.It is applied alone and 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 drug in classification, drug water solubility is extremely low, about 0.7mg/ml.Due to its lower solubility, the medicine is also reduced
The oral administration biaavailability of object.Therefore the water solubility for how enhancing drug becomes particularly important to improve its bioavilability just.
Atenolol belongs to adrenoceptor blocking drug, in addition to being used to treat angina pectoris and arrhythmia cordis, and treatment
The fiest-tire medication of hypertension.The drug price is cheap, and treatment hypertension is safe and effective, can reduce the generation of cardiovascular complication
Rate and case fatality rate.The Hypotensive Mechanism of the medicine can mainly block heart β1receptor, inhibit myocardial contraction, and reducing heart rate reduces the heart
Discharge rate.The medicine is preferable for various antihypertensive effect.It is shared with other antihypertensives (diuretics, calcium channel blocker etc.)
Severe or resistant hypertension in can treating.
The treatment of hypertension is mainly based on drug combination, and today there is also many appearances of compound medicine preparation for treating hypertension.Hydrogen
The problem of chlorothiazide and atenolol drug combination poorly water-soluble, is also unresolved at present.
Summary of the invention
The purpose of the present invention is to provide it is a kind of can significantly increase Hydrochioro and atenolol drug combination water solubility with
And improve the unformed system altogether of the intrinsic dissolution rate of drug.
Another purpose of the invention is that providing the preparation method of the total unformed system.
It is yet a further object of the present invention to provide a kind of pharmaceutical compositions containing the total unformed system.
The purpose of the present invention is what is be accomplished by the following way:
A kind of Hydrochioro and atenolol are total to unformed system, this altogether unformed system with Hydrochioro and atenolol
For active pharmaceutical ingredient, it is prepared using solvent evaporated method or freeze grinding method；It is formed by hydrogen chlorine in unformed system altogether
The drug molecule of thiazine and atenolol exists with amorphous forms, and the molar ratio of the Hydrochioro and atenolol is
1:0.25~1.5, preferably 1:0.5~1.25, mole of further preferred 1:0.5~1, most preferably Hydrochioro and atenolol
Than for 1:1.
Hydrochioro is total to unformed system with atenolol mainly to be existed in powder form, and partial size is less than 150 μm.
The solvent evaporated method is after dissolving Hydrochioro and atenolol using organic solvent, to reheat decompression and steam
Dry solvent.The heating temperature is 35-60 DEG C, and organic solvent is methanol, ethyl alcohol, acetonitrile, normal propyl alcohol, n-butanol, tetrahydrofuran,
Any one in ethyl acetate, preferable organic solvent are methanol.
The Hydrochioro and atenolol of solvent evaporated method preparation are total to unformed system and are radiated using Cu-K α, to spend 2 θ tables
Show the not sharp peak that spreads out of X-ray powder diffraction spectrum；The infrared absorption spectrum measured with KBr tabletting 3367,1664,
1559、1522、1399、1327、1240、1156、1060、1027、605、539cm-1There is absorption 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, up to Hydrochioro and atenolol be total to unformed system after dry；It is preferred that grinding frequency
Rate 10Hz, milling time 45 minutes.
The Hydrochioro and atenolol of freeze grinding method preparation are total to unformed system and are radiated using Cu-K α, to spend 2 θ tables
Show the not sharp peak that spreads out of X-ray powder diffraction spectrum；The infrared absorption spectrum measured with KBr tabletting 3358,1664,
1559、1512、1399、1326、1243、1169、1058、1028、674、605、539cm-1There is absorption peak at place.
Above-mentioned Hydrochioro and atenolol be total to the preparation method of unformed system the following steps are included: by Hydrochioro and
After atenolol is using organic solvent dissolution, then heating under reduced pressure solvent evaporated.
Above-mentioned Hydrochioro and atenolol be total to the preparation method of unformed system the following steps are included: by Hydrochioro with
Atenolol is uniformly mixed, and is placed under liquid nitrogen environment, is ground 10-60 minutes with the frequency mechanical of 5-20Hz；It is preferred that grinding
Frequency 10Hz, milling time 45 minutes.
Unformed system altogether of the present invention is made of Hydrochioro and atenolol.Two kinds of drugs are all hypotensor
Object.Two kinds of drugs all exist with amorphous forms.There is stronger intermolecular force to each other.Pass through powder x-ray diffraction
Technology determines that two kinds of drugs all exist with amorphous forms.Single glass transition temperature is found by differential canning calorimetry
Degree, illustrates to form uniform unformed system.Find have between two kinds of drugs than stronger by infrared spectrum technology
Interaction.The amorphous article solves the problems, such as Hydrochioro and atenolol drug combination poorly water-soluble, not arbitrarily with
Two kinds of material mixings can effectively be combined into unformed system altogether.
The unformed measurement for carrying out solubility and intrinsic dissolution rate altogether to being prepared with two methods, discovery are fixed in total nothing
The solubility of Hydrochioro is 4.44~4.72 times of crystalline drug in type system, and dissolution rate also improve 6.5 times with
On.
Beneficial effects of the present invention compared with the prior art: the present invention solves existing Hydrochioro and combines with atenolol
The problem of medication poor solubility, to solve the problems, such as that drug combination provides new approaches later.
Detailed description of the invention
Fig. 1 is total to unformed system X-ray powder according to Hydrochioro-atenolol prepared by embodiment solvent evaporated method
Diffracting spectrum；
Fig. 2 is total to unformed system X-ray powder according to Hydrochioro-atenolol prepared by embodiment freeze grinding method
Diffracting spectrum；
Fig. 3 is total to unformed system differential scanning amount according to Hydrochioro-atenolol prepared by embodiment solvent evaporated method
Thermal map spectrum；
Fig. 4 is total to unformed system differential scanning amount according to Hydrochioro-atenolol prepared by embodiment freeze grinding method
Thermal map spectrum；
The infrared spectroscopy of the single Hydrochioro drug of Fig. 5；
The infrared spectroscopy of the single atenolol drug of Fig. 6；
Fig. 7 is total to unformed system infrared spectroscopy according to Hydrochioro-atenolol prepared by embodiment solvent evaporated method；
Fig. 8 is total to unformed system infrared spectroscopy according to Hydrochioro-atenolol prepared by 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；
Figure 11 is total to Hydrochioro in unformed system according to what embodiment freeze grinding method and solvent evaporated method were prepared
Intrinsic dissolution curve；
Figure 12 is total to atenolol in unformed system according to what embodiment freeze grinding method and solvent evaporated method were prepared
Intrinsic dissolution curve；
Figure 13 prepares the X-ray powder of sample according to atenolol described in comparative example and nifedipine with molar ratio 1:1 ratio
Last diffracting spectrum；
Figure 14 prepares the X-ray powder of sample according to atenolol described in comparative example and nifedipine with molar ratio 2:1 ratio
Last diffracting spectrum；
Specific embodiment
The present invention will be further explained with reference to the examples below, and the examples are merely illustrative, by no means implies that it
The protection scope limiting the invention in any way.
Embodiment
It is unformed altogether that following analysis method is used to characterize Hydrochioro-atenolol of the invention:
1.X ray powder diffraction:
Instrument: XTRA/3KW X-ray diffractometer (Arl Inc. of Switzerland), target: Cu-K α radiation, wavelength: 1.5406A, pipe
Pressure: 40KV, Guan Liu: 40mA, step-length: 0.02 °, scanning speed: 1.2 °/min, scanning range is 3 °~40 °.
2. differential scanning calorimeter:
Instrument: TA DSC2000 differential scanning calorimeter instrument (American), range: -20-280 DEG C, heating 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.3, infrared spectroscopy
Instrument: Nicolet IS10 type infrared spectrometer (Nicolet company of the U.S.)
Embodiment 1
Hydrochioro 0.299g is weighed, is added in 30ml methanol, stirs to obtain clear solution.Again by atenolol 0.2663g
It is added in above-mentioned clear solution, room temperature (20 ± 5 DEG C) stirs to obtain clear solution, this clear solution is depressurized to rotation at 55 DEG C and is steamed
Solvent is sent out, 25 DEG C of vacuum drying are total to unformed system to get Hydrochioro and atenolol in 24 hours.
Embodiment 2
Hydrochioro 0.4485g is weighed, is added in 50ml ethyl alcohol, stirs to obtain clear solution.Again by atenolol 0.3994g
It is added in above-mentioned clear solution, room temperature (20 ± 5 DEG C) stirs to obtain clear solution, this clear solution is depressurized to rotation at 50 DEG C and is steamed
Solvent is sent out, 25 DEG C of vacuum drying are total to unformed system to get Hydrochioro and atenolol in 24 hours.
Embodiment 3
Hydrochioro 0.299g is weighed, atenolol 0.2663g is weighed, two kinds of powder are mixed, and in vortex instrument
It is upper to be vortexed one minute, it is allowed to uniformly mixed.Mixture is placed in (Freezer Mill in the refrigeration grinding machine full of liquid nitrogen later
6770, USA) frequency, is adjusted to 10Hz, grinds 10 circulations, each circular grinding 2 minutes is 1 minute cooling.After grinding
It takes out sample to be placed in silica gel drier after placement 1 hour, Hydrochioro can be obtained and atenolol is total to unformed system.
Embodiment 4
Hydrochioro 0.299g is weighed, atenolol 0.2663g is weighed, two kinds of powder are mixed, and in vortex instrument
It is upper to be vortexed one minute, it is allowed to uniformly mixed.Mixture is placed in (Freezer in the refrigeration grinding machine full of liquid nitrogen later
Mill 6770, USA), frequency is adjusted to 10Hz, grinds 15 circulations, each circular grinding 2 minutes is 1 minute cooling.By grinding
Sample is taken out after mill to be placed in silica gel drier after placement 1 hour, and Hydrochioro can be obtained and atenolol is total to unformed system
System.
Comparative example
Nifedipine is also a kind of common drug for treating hypertension as Hydrochioro, however works as and utilize atenolol
When carrying out unformed preparation altogether with nifedipine with the molar ratio of 2:1, from the point of view of the result of X-ray powder diffraction, the system
In there are stronger crystal diffraction peak, illustrate to there are some drugs to be in system with existing for crystal form, and cannot be formed steady
Fixed unformed system altogether.
When atenolol and nifedipine are mixed with unformed altogether with the molar ratio of 1:1, from X-ray powder diffraction
Result from the point of view of, although it is available altogether unformed sample, this altogether unformed system physical stability it is very poor, one day with
Afterwards, unformed shape drug will recrystallize in system, thus lose altogether unformed system in solubility and dissolved corrosion
On advantage.
Above-mentioned two comparative run explanation is not that any two kinds of drugs are equal using the method for the present invention preparation with arbitrary proportion mixing
It can effectively combine and form stable unformed system altogether.
X-ray powder diffraction result
Do not occur sharp diffraction maximum in PXRD result using the unformed system altogether that the above method is prepared, says
It is bright in system and be not present crystalline drug.(see Fig. 1 and Fig. 2)
Differential scanning calorimetry result
The above method be prepared altogether it is unformed only occur single glass transition temperature in DSC result, say
It is bright to form uniform single_phase system.(see Fig. 3 and Fig. 4)
The results of FT-IR
Compared to the infrared spectroscopy (see Fig. 5 and Fig. 6) of single medicine, the infrared light spectral peak of unformed system occurs bright altogether
Aobvious broadening, and peak shift is deviated, this illustrates in system drug, and intermolecular there is strong interactions.Wherein utilize
Sample infrared absorption spectrum prepared by solvent evaporated method (embodiment 1 and embodiment 2) 3367,1664,1559,1522,
1399、1327、1240、1156、1060、1027、605、539cm-1There is absorption peak at place；Utilize freeze grinding method (embodiment 3 and reality
Apply example 4) sample of preparation 3358,1664,1559,1512,1399,1326,1243,1169,1058,1028,674,
605、539cm-1There is absorption peak at place.(see Fig. 7 and Fig. 8)
Physical stability experiment
The unformed sample altogether being prepared according to embodiment method is placed in the dry environment of 4 DEG C and 25 DEG C, point
Not at first day, seven days, fortnight, 30 days time points take out sample, carry out X-ray powder diffraction experiment, see whether
Sample recrystallizes.From result we have found that the unformed altogether of two methods preparation can be stabilized in the above conditions
30 days.(see Fig. 9 and attached drawing 10)
Solubility experiment
Hydrochioro-Ah the replacing for weighing excessive pure Hydrochioro bulk pharmaceutical chemicals and being prepared respectively with two methods of embodiment
Luo Er is total to unformed sample and is placed in 40ml pure water, and three individuals are measured under 37 DEG C of temperature condition and the speed conditions of 120rpm
The solubility of Hydrochioro in system.We are it can be found that compared to pure Hydrochioro bulk pharmaceutical chemicals, by freezing from the result of table one
The solubility for the Hydrochioro in unformed system altogether that polishing and solvent evaporated method are prepared 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 (Hydrochioro bulk pharmaceutical chemicals and be total to unformed sample with Hydrochioro-atenolol that two methods of embodiment are prepared respectively)
It is placed under the pressure condition of 100bar and is kept for 30 seconds, it is 0.0707cm that sample, which is pressed into surface area,2Small pieces, sample small pieces
It throws into the pure water solvent of 10ml and (guarantees that only one surface of sample small pieces is exposed in dissolution medium), and stirring in 300rpm
The measurement of drug concentration is carried out under the conditions of mixing using the UV detector in situ that instrument carries.From the intrinsic dissolution rate of table two
Experimental result can be seen that compared to bulk pharmaceutical chemicals, and the intrinsic dissolution rate of two kinds of drugs is all shown in unformed system altogether
The raising of work.(Figure 11, Figure 12 are respectively Hydrochioro and the intrinsic dissolution curve of atenolol)
Intrinsic dissolution rate of two: the two kinds of drugs of table in different systems
Claims (10)
1. a kind of Hydrochioro and atenolol are total to unformed system, which is characterized in that the total unformed system is with Hydrochioro
It is active pharmaceutical ingredient with atenolol, is prepared using solvent evaporated method or freeze grinding method；It is formed by unformed altogether
The drug molecule of Hydrochioro and atenolol exists with amorphous forms in system, the Hydrochioro and atenolol
Molar ratio be 1:1~1.25；Wherein, unformed system uses the Hydrochioro and atenolol of solvent evaporated method preparation altogether
Cu-K α radiation indicates the not sharp peak that spreads out of X-ray powder diffraction spectrum to spend 2 θ；It is measured with KBr tabletting infrared
Absorption spectrum is in 3367,1664,1559,1522,1399,1327,1240,1156,1060,1027,605,539cm-1There is suction at place
Receive peak；The Hydrochioro and atenolol of freeze grinding method preparation are total to unformed system and are radiated using Cu-K α, are indicated with spending 2 θ
The not sharp peak that spreads out of X-ray powder diffraction spectrum；The infrared absorption spectrum measured with KBr tabletting 3358,1664,
1559、1512、 1399、1326、1243、1169、1058、1028、674、605、539cm-1There is absorption peak at place.
2. Hydrochioro according to claim 1 and atenolol are total to unformed system, it is characterised in that Hydrochioro with
Atenolol is total to unformed system partial size less than 150 μm.
3. Hydrochioro according to claim 1 and atenolol are total to unformed system, which is characterized in that the solvent
Evaporation be by Hydrochioro and atenolol using organic solvent dissolution after, then heating under reduced pressure solvent evaporated.
4. Hydrochioro according to claim 3 and atenolol are total to unformed system, which is characterized in that the heating temperature
Degree is 35-60 DEG C, and organic solvent is methanol, ethyl alcohol, acetonitrile, normal propyl alcohol, n-butanol, tetrahydrofuran, any one in ethyl acetate
Kind.
5. Hydrochioro according to claim 4 and atenolol are total to unformed system, it is characterised in that organic solvent is
Methanol.
6. Hydrochioro according to claim 1 and atenolol are total to unformed system, which is characterized in that the 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 minutes.
7. Hydrochioro according to claim 6 and atenolol are total to unformed system, which is characterized in that the grinding
Frequency 10Hz, milling time 45 minutes.
8. the preparation method that a kind of Hydrochioro described in claim 1 and atenolol are total to unformed system, it is characterised in that
Method includes the following steps: after Hydrochioro and atenolol are dissolved using organic solvent, then heating under reduced pressure solvent evaporated.
9. the preparation method that a kind of Hydrochioro described in claim 1 and atenolol are total to unformed system, it is characterised in that
Method includes the following steps: Hydrochioro is uniformly mixed with atenolol, it is placed under liquid nitrogen environment, with 5-20Hz's
Frequency mechanical is ground 10-60 minutes.
10. the preparation method that Hydrochioro according to claim 9 and atenolol are total to unformed system, it is characterised in that
The grinding frequency 10Hz, milling time 45 minutes.
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