CN109010348A - A kind of lacidipine-spirolactone is total to amorphous solid dispersion and its preparation - Google Patents
A kind of lacidipine-spirolactone is total to amorphous solid dispersion and its preparation Download PDFInfo
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- CN109010348A CN109010348A CN201811252352.0A CN201811252352A CN109010348A CN 109010348 A CN109010348 A CN 109010348A CN 201811252352 A CN201811252352 A CN 201811252352A CN 109010348 A CN109010348 A CN 109010348A
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- spirolactone
- lacidipine
- amorphous solid
- solid dispersion
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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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
Abstract
The invention belongs to pharmaceutical technology field, it is related to a kind of lacidipine-spirolactone and is total to amorphous solid dispersion and preparation method thereof.The invention prepares amorphous solid dispersion altogether with lacidipine and spirolactone carrier each other with Synergistic Hypotensive Effects, using solvent evaporation method.Lacidipine is formed in conjunction with spirolactone in molar ratio 1:1-9, is radiated using Cu-K α, composes not sharp diffraction maximum with the powder x-ray diffraction that 2 angles θ indicate；Significant change has occurred in the peak position of amorphous solid dispersion, peak intensity altogether in FTIR spectrum.With lacidipine crystal and spirolactone crystal phase ratio, the dissolution rate and dissolution rate of lacidipine and spirolactone are significantly improved in amorphous solid dispersion altogether.Preparation method is simple for solid dispersions in the present invention, favorable reproducibility, is easy to amplify production, carries out commercial conversion, has good potential applicability in clinical practice.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of lacidipine-spirolactone is total to amorphous solid dispersion
And preparation method thereof.
Background technique
The chemical name of lacidipine (Lacidipine) are as follows: (E) -4- [2- [3- (1,1- dimethylethyloxy) -3- oxygen
Generation -1- acrylic] phenyl]-Isosorbide-5-Nitrae-dihydro -2,6- dimethyl-3,5-dipicolinic acid diethylester, being that one kind is special, potent holds
Long dihydropyridine calcium channel blocker, the calcium channel of the retardance vascular smooth muscle of substantial selectivity, expands peripheral arterial, subtracts
Low peripheral vascular resistance lowers cardiac afterload, reduces blood pressure.The clinically first-line drug as treatment hypertension.Physics
Properties, lacidipine are white or off-white color crystalline powder, meet photo-labile, readily soluble in ethyl acetate, in acetone
It dissolves, it is slightly molten in methanol/ethanol, it is almost insoluble in water.175~179 DEG C of fusing point.Molecular formula and molal weight are respectively
C26H33NO6And 455.54g/mol.Structural formula is as follows:
Spirolactone (Spironolactone) chemical name are as follows: -7 α of 17 beta-hydroxy-3-oxy-(acetylthio) -17 α-is pregnant
Steroid -4- alkene -21- carboxylic acid-gamma lactone；Pregnant steroid -4- alkene -21- the carboxylic acid of (7 α, 17 α) -7- (acetyl mercapto) -17- hydroxyl -3- oxo
Gamma lactone is artificial synthesized steroidal compounds, and structure is similar to aldosterone, is the competitive inhibitor of aldosterone, has
Diuresis and antihypertensive effect are combined frequently as the ancillary drug for the treatment of hypertension with other depressor.In terms of physical property, in spiral shell
Ester is the grain powder of white or off-white color, has slight mercaptan smelly.It is easily dissolved in chloroform, in benzene or acetic acid
It is readily soluble in ethyl ester, it dissolves in ethanol, it is insoluble in water.Molecular formula and molal weight are respectively C24H32O5S and 416.57g/
mol.Fusing point is 203~209 DEG C, melts while decomposing.Structural formula is as follows:
Lacidipine and spirolactone are two kinds of insoluble drugs with pharmacology synergistic effect, pass through different effects respectively
Mechanism reduces blood pressure, and the antihypertensive drugs of both different role mechanism is used in combination, and is more advantageous to and reduces adverse reaction and enhancing
Drug effect realizes individualized treatment clinically.
Long-term treatment for hypertension chronic diseases takes orally the administration high as a kind of simplicity, safety, patient's compliance
Mode is particularly important.For II class drug of BCS, the solubility of drug is to limit the principal element of its dissolution rate, in turn
Limit its oral administration biaavailability.Therefore, the solubility for improving insoluble drug, for improving the oral life of insoluble drug
Object availability is of great significance.
Amorphous (Co-amorphous) is that active pharmaceutical ingredient and other small-molecule substances (drug or auxiliary material) combine altogether
The single phase amorphous binary system with single glass transition temperature formed.It is amorphous altogether to be in a kind of thermodynamics high energy
State can improve the physicochemical properties such as solubility, dissolution rate, the stability of drug, and stability is higher than amorphous monomer, be a kind of
The new way of medicament research and development.
We are had found by numerous studies, and two kinds of medicine preparations of lacidipine and spirolactone are dispersed at total amorphous solid
After body, the dissolution rate of lacidipine and spirolactone is significantly improved in this amorphous solid dispersion altogether, and has
Good high wet stability.
Summary of the invention
The purpose of the present invention is a kind of lacidipine-spirolactone is prepared to be total to amorphous solid dispersion.This is altogether without fixed
Shape solid dispersions drugloading rate is high, can significantly improve the solubility and dissolution rate in vitro of two kinds of insoluble drugs, and have
Good high wet stability.Meanwhile the combination of both different role mechanism drugs can generate collaboration pharmacological action, and then improve
Curative effect is conducive to individualized treatment clinically.
The present invention provides a kind of lacidipine-spirolactones to be total in amorphous solid dispersion, including lacidipine, spiral shell
Ester, wherein the molar ratio of lacidipine and spirolactone are as follows: 3:1-1:9, preferably are as follows: 1:1-1:9, more preferably 1:6-1:9.
Further, the molar ratio of lacidipine and spirolactone can be 3:1,1:1,1:3,1:6,1:9.
When the molar ratio of lacidipine and spirolactone are as follows: when 3:1,1:1 and 1:3, at 120 minutes, the dissolution of lacidipine
Respectively 5.1%, 21% and 56%, the dissolution of spirolactone is respectively 46.2%, 57% and 60.4%；And work as lacidipine and spiral shell
The molar ratio of lactone are as follows: when 1:6 and 1:9, the dissolution of lacidipine is respectively 69% and 63.7%, and the dissolution of spirolactone is respectively
68.4% and 58.3%.
At 120 minutes, lacidipine-spirolactone is total to amorphous solid dispersion within the scope of 1:3-1:9, and lacidipine is molten
Out 50% or more, while spirolactone dissolution, up to 50% or more, and within this range, lacidipine realizes synchronous with spirolactone
Release, can achieve preferable synergistic effect between lacidipine and spirolactone.
And when lacidipine-spirolactone is total to amorphous solid dispersion within the scope of 1:6-1:9, lacidipine dissolution exists
60% or more, while spirolactone dissolution, up to 55% or more, lacidipine and spirolactone realize optimal dissolution, collaboration effect
Fruit is best.
Meanwhile the present invention is total to amorphous solid dispersion to lacidipine-spirolactone and carries out high humidity stability test, as a result
Show: the molar ratio of lacidipine and spirolactone are as follows: when 1:6 and 1:9, after being placed 10 days under super-humid conditions (RH 92.5%), draw
The dissolution of western Horizon is 67.1% and 64.9%, and the dissolution of spirolactone is respectively 60.9% and 64.7%.It proves under super-humid conditions,
1:6 and 1:9 amorphous solid dispersion has good stability.
Lacidipine-spirolactone of the invention is total to amorphous solid dispersion and has the feature that
1, powder x-ray diffraction (PXRD)
The PXRD diffracting spectrum that lacidipine-spirolactone is total to amorphous solid dispersion is amorphous diffraction ring, without point
Sharp diffraction maximum.
2, differential scanning calorimetry (DSC)
The endothermic fusion peak of lacidipine is at 185.56 DEG C, and the endothermic fusion peak of spirolactone is at 207.32 DEG C, lacidipine-
Spirolactone is total to the glass transition temperature of amorphous solid dispersion at 92.87 DEG C.
3, FTIR spectrum method (FT-IR)
Lacidipine infrared spectroscopy characteristic waves are as follows: 3348.3cm-1, spirolactone infrared spectroscopy characteristic waves are as follows:
1691.1cm-1；1768.1cm-1；1674.1cm-1。
Altogether in unformed solid dispersions, spirolactone 1691cm-1The peak C=O of the ethanethioyl at place broadens and to low wave
Number movement, lacidipine is in 3348.3cm-1The peak-NH at place disappears.Show the thioacetyl in the-NH and spirolactone of lacidipine
The O=C of base forms intermolecular hydrogen bonding.
It is a further object of the present invention to provide the preparation sides that a kind of lacidipine-spirolactone is total to amorphous solid dispersion
Method.
Lacidipine-the spirolactone is total to the preparation method of amorphous solid dispersion, it includes by lacidipine and spiral shell
Lactone is dissolved in organic solvent, obtains supernatant liquid, depressurizes rotary evaporation of solvent at 20~60 DEG C, and by residue vacuum
Dry 24 hours to get total amorphous solid dispersion.
The organic solvent is one or more of ethyl alcohol, methanol, chloroform or ethyl acetate, preferred alcohol, first
Alcohol or both mixed solvent.
Preferably 30~40 DEG C of temperature of the decompression rotary evaporation of solvent.
PXRD, DSC and FT-IR map of amorphous solid dispersion altogether disclosed by the invention and existing patent report
Lacidipine crystal and spirolactone crystal are different.Therefore, the solid forms are that one kind is totally different from the prior art and obtains
Lacidipine and spirolactone form.
It is an advantage of the present invention that using lacidipine and spirolactone as effective component being not required to that any other carrier is added
Total amorphous solid dispersion can be prepared, drugloading rate is up to 100%, evaded addition polymer support bring it is at high cost,
The problems such as easy to moisture absorption, volumes of formulation is big, biological safety.By being total to amorphous solid to lacidipine-spirolactone obtained
Dispersion carries out In Vitro Dissolution experiment, and compared with physical mixture, prepared total amorphous solid dispersion can be significantly improved
The dissolution in vitro of lacidipine and spirolactone.Lacidipine-spirolactone (1:6,1:9) is total to amorphous solid dispersion in high humidity
Under the conditions of have good stability.Therefore, amorphous solid dispersion can be further prepared into the peroral dosage forms such as tablet, hard capsule altogether,
With preferable potential applicability in clinical practice.Preparation method is simple, easy to operate in the present invention, low in cost, good economy performance, is easy to industry
Metaplasia produces, and is total to amorphous solid dispersion with directive significance to the insoluble drug for preparing other pharmacological actions collaboration.
Detailed description of the invention
Fig. 1 is the x-ray diffractogram of powder spectrum of lacidipine bulk pharmaceutical chemicals；
Fig. 2 is the x-ray diffractogram of powder spectrum of spirolactone bulk pharmaceutical chemicals；
Fig. 3 is the x-ray diffractogram of powder spectrum that different proportion lacidipine-spirolactone is total to amorphous solid dispersion；
Fig. 4 is the DSC figure of lacidipine bulk pharmaceutical chemicals；
Fig. 5 is the DSC figure of spirolactone bulk pharmaceutical chemicals；
Fig. 6 is the DSC figure that different proportion lacidipine-spirolactone is total to amorphous solid dispersion；
Fig. 7 is the FT-IR map of lacidipine bulk pharmaceutical chemicals；
Fig. 8 is the FT-IR map of spirolactone bulk pharmaceutical chemicals；
Fig. 9 is the FT-IR map that different proportion lacidipine-spirolactone is total to amorphous solid dispersion；
Figure 10 is dissolution curve.It respectively represents lacidipine bulk pharmaceutical chemicals, physical mixture and different proportion and draws west ground
Flat-spirolactone is total to the dissolution curve of lacidipine in amorphous solid dispersion；
Figure 11 is dissolution curve.Respectively represent spirolactone bulk pharmaceutical chemicals, physical mixture and different proportion lacidipine-
Spirolactone is total to the dissolution curve of spirolactone in amorphous solid dispersion；
Figure 12 dissolution curve.It respectively represents different proportion lacidipine-spirolactone after super-humid conditions are placed 10 days and is total to nothing
The dissolution curve of lacidipine in white amorphous solid dispersion.
Figure 13 dissolution curve.It respectively represents different proportion lacidipine-spirolactone after super-humid conditions are placed 10 days and is total to nothing
The dissolution curve of spirolactone in white amorphous solid dispersion.
Specific embodiment
By example in detail below, above content of the invention is described in further detail, it is not intended that implementing
Example limitation of the present invention.
The solid-state of amorphous solid dispersion is characterized as below altogether in the present invention:
1, powder x-ray diffraction
Instrument: powder x-ray diffraction (Japanese Rigaku company)
Target: Cu-K α radiation
Wavelength:
X-ray light pipe voltage: 40kV
X-ray light pipe fulgurite stream: 30mA
Step-length: 0.02 °
Scanning speed: 6 °/min
The result shows that: lacidipine-spirolactone is total to amorphous solid dispersion system, observes in diffraction pattern amorphous
Diffraction ring, not sharp diffraction maximum.
2, differential scanning calorimetry (DSC)
Instrument: 1 thermal analyzer of DSC (Mettler-Toledo company of Switzerland)
Range: 25~230 DEG C
Heating rate: 10 DEG C/min
The result shows that: the endothermic fusion peak of lacidipine is at 185.56 DEG C；The endothermic fusion peak of spirolactone is at 207.32 DEG C；
Lacidipine-spirolactone is total to the glass transition temperature of amorphous solid dispersion at 92.87 DEG C.
3, FTIR spectrum method (FT-IR)
Instrument: Fourier infrared spectrograph (Bruker company of Switzerland)
Absorbing wavelength: 400-4000cm-1
The result shows that: the result shows that: lacidipine infrared spectroscopy characteristic waves are as follows: 3348.3cm-1
Spirolactone infrared spectroscopy characteristic waves are as follows: 1691.1cm-1；1768.1cm-1；1674.1cm-1
Altogether in unformed solid dispersions, spirolactone 1691cm-1The peak C=O of the ethanethioyl at place broadens and to low wave
Number movement, lacidipine is in 3348.3cm-1The peak-NH at place disappears.Show the thioacetyl in the-NH and spirolactone of lacidipine
The O=C of base forms intermolecular hydrogen bonding.
The influence that different lacidipines and spirolactone ratio dissolve out lacidipine and spirolactone:
Embodiment 1:
Lacidipine and spirolactone molar ratio are 3:1.Weigh 0.5g lacidipine bulk pharmaceutical chemicals and 0.15g spirolactone raw material
Medicine is added ethanol in proper amount and is dissolved to clarification.Rotary evaporation of solvent is depressurized at 20~60 DEG C, and residue vacuum dry 24 is small
When to get.Dissolution rate by dissolution determination method as described below measurement lacidipine is 5.1%, the dissolution rate of spirolactone are as follows:
46.2%.
Embodiment 2:
Lacidipine and spirolactone molar ratio are 1:1.Weigh 0.5g lacidipine bulk pharmaceutical chemicals and 0.46g spirolactone raw material
Medicine is added ethanol in proper amount and is dissolved to clarification.Preparation process is the same as embodiment 1.It is measured by dissolution determination method as described below and draws west
The dissolution rate of Horizon is 21%, the dissolution rate of spirolactone are as follows: 57%.
Embodiment 3:
Lacidipine and spirolactone molar ratio are 1:3.Weigh 0.5g lacidipine bulk pharmaceutical chemicals and 1.37g spirolactone raw material
Medicine is added ethanol in proper amount and is dissolved to clarification.Preparation process is the same as embodiment 1.Drug is measured by dissolution determination method as described below
Dissolution rate be 56%, the dissolution rate of spirolactone are as follows: 60.4%.
Embodiment 4:
Lacidipine and spirolactone molar ratio are 1:6.Weigh 0.5g lacidipine bulk pharmaceutical chemicals and 2.74g spirolactone raw material
Medicine is added ethanol in proper amount and is dissolved to clarification.Preparation process is the same as embodiment 1.Drug is measured by dissolution determination method as described below
Dissolution rate be 69%, the dissolution rate of spirolactone are as follows: 68.4%.
Embodiment 5:
Lacidipine and spirolactone molar ratio are 1:9.0.5g lacidipine bulk pharmaceutical chemicals and 4.1g spirolactone bulk pharmaceutical chemicals are weighed,
Ethanol in proper amount is added and is dissolved to clarification.Preparation process is the same as embodiment 1.By the molten of dissolution determination method as described below measurement drug
Out-degree is 63.7%, the dissolution rate of spirolactone are as follows: 58.3%.
Embodiment 6:
High wet stability: prepared total amorphous solid dispersion is placed in surface plate, opening is placed in 92.5%
Under relative humidity conditions, dissolved corrosion variation is investigated in sampling in the 10th day.
Dissolution determination method:
Precision weighs lacidipine bulk pharmaceutical chemicals, spirolactone bulk pharmaceutical chemicals respectively, and lacidipine-spirolactone physical mixture (rubs
You are than 1:6) and prepared lacidipine-spirolactone be total to amorphous solid dispersion (being equivalent to containing lacidipine about 4mg) and fill
Enter in hard capsule case, referring to 2015 editions Chinese Pharmacopoeia dissolution methods (the second method of annex X C), using 0.07% Tween 80
Aqueous solution is dissolution medium, and revolving speed is 50 turns per minute, operates according to methods, when through 5,10,20,30,45,60,120min, takes continuous filter
Liquid measurement calculates it by external standard method and accumulates dissolution rate.
High performance liquid chromatography testing conditions:
Instrument: high performance liquid chromatograph (Hitachi, Ltd)
Chromatographic column: Thermo Hypersil C18 chromatographic column (250 × 4.6mm, 5 μm)
Mobile phase: methanol: water=80:20 (v/v)
Flow velocity: 1.0ml/min
Detection wavelength: 284nm；238nm
By attached drawing 10, Figure 11 is it is found that lacidipine bulk pharmaceutical chemicals and spirolactone bulk pharmaceutical chemicals 120min dissolution rate are respectively 1.2%
With 43%, lacidipine and spirolactone 120min dissolution rate are respectively 6% and 37.6% in physical mixture (1:6), draw west ground
Flat-spirolactone (3:1,1:1,1:3,1:6,1:9) is total to lacidipine 120min dissolution rate in amorphous solid dispersion and is respectively
5.1%, 21%, 56%, 69% and 63.7%；The dissolution rate of spirolactone is respectively 46.2%, 57%, 60.4%, 68.4% He
58.3%.As seen from the figure, amorphous solid dispersion system altogether set forth in the present invention, it is molten with the increase of spirolactone amount
Out-degree and dissolution rate significantly improve, and up to balance when 1:6, therefore 1:6-1:9 is optimal prescription.And it is total to prepared by this law
Amorphous solid dispersion dissolution rate is fast and is above two kinds of bulk pharmaceutical chemicals and its physical mixture.
By attached drawing 12, Figure 13 is it is found that lacidipine-spirolactone (1:1,1:3) is total to amorphous solid dispersion super-humid conditions
Lower dissolution rate is decreased obviously, and lacidipine-spirolactone (1:6,1:9) is total to amorphous solid dispersion super-humid conditions stability inferior
Well.
Claims (8)
1. lacidipine-spirolactone is total to amorphous solid dispersion, which is characterized in that including lacidipine, spirolactone, wherein
The molar ratio of lacidipine and spirolactone are as follows: 3:1-1:9, preferably 1:1-1:9, more preferably: 1:6-1:9.
2. lacidipine-spirolactone as described in claim 1 is total to amorphous solid dispersion, which is characterized in that lacidipine
Molar ratio with spirolactone is 1:6 or 1:9.
3. lacidipine-spirolactone as claimed in claim 1 or 2 is total to the preparation method of amorphous solid dispersion, feature
It is, lacidipine and spirolactone is dissolved in organic solvent in proportion, depressurize rotary evaporation of solvent, residue vacuum is dry
It is dry to be total to amorphous solid dispersion to get this.
4. lacidipine-spirolactone as claimed in claim 3 is total to the preparation method of amorphous solid dispersion, feature exists
In, the organic solvent be one or more of ethyl alcohol, methanol, chloroform or ethyl acetate organic solvent, preferred alcohol,
Methanol or both mixed solvent.
5. lacidipine-spirolactone as described in claim 3 is total to the preparation method of amorphous solid dispersion, feature exists
In the temperature for depressurizing rotary evaporation is 20~60 DEG C, preferably 30~40 DEG C.
6. a kind of pharmaceutical composition is total to amorphous solid dispersion comprising lacidipine-spirolactone of any of claims 1 or 2.
7. lacidipine-spirolactone of any of claims 1 or 2 is total to amorphous solid dispersion or medicine as claimed in claim 6
Compositions are preparing the application in antihypertensive drugs.
8. lacidipine-spirolactone of any of claims 1 or 2 is total to amorphous solid dispersion or medicine as claimed in claim 6
Compositions improve the application in oral administration biaavailability drug in preparation.
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Cited By (2)
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| CN114736177A (en) * | 2022-03-23 | 2022-07-12 | 化学与精细化工广东省实验室 | Furosemide/spironolactone/L-phenylalanine ternary co-amorphous form and preparation method and application thereof |
| CN114736263A (en) * | 2022-03-08 | 2022-07-12 | 天津大学 | Binary co-amorphous substance and application thereof |
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| CN108498508A (en) * | 2018-03-23 | 2018-09-07 | 朱军星 | A kind of subdermal implantation line for long-acting decompression |
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| CN108498508A (en) * | 2018-03-23 | 2018-09-07 | 朱军星 | A kind of subdermal implantation line for long-acting decompression |
Non-Patent Citations (1)
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| 郭慧慧 等: "共无定形药物——新型单相无定形二元体系", 《化学进展》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114736263A (en) * | 2022-03-08 | 2022-07-12 | 天津大学 | Binary co-amorphous substance and application thereof |
| CN114736263B (en) * | 2022-03-08 | 2023-12-26 | 天津大学 | Binary co-amorphous material and application thereof |
| CN114736177A (en) * | 2022-03-23 | 2022-07-12 | 化学与精细化工广东省实验室 | Furosemide/spironolactone/L-phenylalanine ternary co-amorphous form and preparation method and application thereof |
| CN114736177B (en) * | 2022-03-23 | 2023-12-01 | 化学与精细化工广东省实验室 | Furosemide/spirolactone/L-phenylalanine ternary co-amorphous form and preparation method and application thereof |
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