CN108567744A - The preparation method of Hydrochioro spherical particle and its single compound vertical compression tablet - Google Patents
The preparation method of Hydrochioro spherical particle and its single compound vertical compression tablet Download PDFInfo
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- CN108567744A CN108567744A CN201710149785.2A CN201710149785A CN108567744A CN 108567744 A CN108567744 A CN 108567744A CN 201710149785 A CN201710149785 A CN 201710149785A CN 108567744 A CN108567744 A CN 108567744A
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- 0 *=S(c(cc(c(NCN1)c2)S1(=O)=O)c2Cl)(N)=O Chemical compound *=S(c(cc(c(NCN1)c2)S1(=O)=O)c2Cl)(N)=O 0.000 description 1
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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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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Abstract
The present invention provides the preparation methods of a kind of Hydrochioro spherical particle and its folk prescription or compound vertical compression tablet.The Hydrochioro spherical particle is prepared by alkali-soluble acid analysis method and ball-type aggregation method, average grain diameter is between 50 200 μm, and between Hausner ratios 1.1 1.8, karr coefficient is between 10% 50%, 5 minutes dissolution rates are between 10% 80%, and 20 minutes dissolution rates are between 40% 100%.The dissolution rate of Hydrochioro is improved, while improving dry jet mixing pile, is suitable for direct tablet compressing, improves the bioavilability and stability of its tablet.
Description
Technical field：
The invention belongs to field of medicine preparing technology, it particularly relates to arrive a kind of Hydrochioro spherical particle and its list
The preparation method of compound vertical compression tablet.
Background technology：
Hydrochioro (Hydrochlorothiazide, HCTZ), molecular formula：C7H8ClN3O4S2, molecular weight：297.74,
Structural formula is：
Hydrochioro is clinically used diuretics and antihypertensive, is primarily adapted for use in cariacedema, liver originality water
Oedema caused by swollen, renal edema and cortex hormone of aadrenaline and hyperestrogenism；It can also be used for hypertension, diabetes insipidus.Hydrogen
The solubility of chlorothiazide in water is small, and dissolution rate is slow, influences the bioavilability of drug.
Invention content
Hydrochioro spherical particle, which is characterized in that average grain diameter is between 50-200 μm, Hausner ratios 1.1-1.8
Between, karr coefficient is between 10%-50%, and 5 minutes dissolution rates are between 10%-80%, and dissolution rate is in 40%- within 20 minutes
Between 100%.
Hydrochioro spherical particle of the present invention is prepared using the alkali-soluble acid analysis method, and the preparation method includes such as
Lower step：
(1) Hydrochioro is dissolved in alkaline solution by；
(2) under the solution stirring that obtains step (1), a certain proportion of polymer is added, dissolves, solution is made；
(3) solution that obtains step (2) is under appropriate mixing speed, at moderate temperatures；A certain amount of bridge formation is added
Agent and acid reagent；
(4) it is complete to wait for that Hydrochioro particle is precipitated by, makes its solidification, and continues stirring a period of time；
(5) is filtered, massive laundering, drying；Obtain the Hydrochioro spherical particle.
Step (3) forms drug microparticles using ball-type aggregation method.
Hydrochioro spherical particle of the present invention is prepared using alkali-soluble acid analysis method and ball-type aggregation method.
The preparation method of Hydrochioro spherical particle of the present invention, the aqueous slkali described in step (1) are alkali metal
Hydroxide solution, alkali metal hydroxide are selected from sodium hydroxide, potassium hydroxide, magnesium hydroxide or barium hydroxide；Preferably hydrogen
Sodium oxide molybdena or potassium hydroxide, more preferable sodium hydroxide.
The preparation method of Hydrochioro spherical particle of the present invention, polymer used in step (2) are selected from poly- second
Alkene pyrrolidone, hydroxypropyl methylcellulose, Utech L100, Eudragit L100-55, hydroxypropylmethylcellulose acetate methyl cellulose succinate acid
One or more combinations in ester, F68.
Hydrochioro spherical particle of the present invention, which is characterized in that proper temperature is 0-50 degrees Celsius in step (3)
Between, mixing speed was linear velocity between 5-1000m/ minutes.
The preparation method of Hydrochioro spherical particle of the present invention, acid reagent is selected from hydrochloric acid, lemon in step (3)
Acid, acetic acid, citric acid, maleic acid, palmitic acid or lactic acid；It is preferably selected from hydrochloric acid, citric acid, acetic acid.
The preparation method of Hydrochioro spherical particle of the present invention, it is molten to be selected from esters for bridging agent used in step (3)
Agent, alcohols solvent, ketones solvent, halogenated hydrocarbon solvent, alkane solvents, ether solvent or its mixed solvent.
The preparation method of Hydrochioro spherical particle of the present invention, wherein bridging agent used is by acetic acid in step (3)
One or more compositions in the esters such as methyl esters, ethyl acetate, propyl acetate.
The preparation method of Hydrochioro spherical particle of the present invention, wherein bridging agent used is by positive fourth in step (3)
One or more compositions in the alcohols such as alcohol, normal propyl alcohol, isopropanol.
The preparation method of Hydrochioro spherical particle of the present invention, wherein bridging agent used is by third in step (3)
One or more compositions in the ketones such as ketone, espeleton, methylisobutylketone.
The preparation method of Hydrochioro spherical particle of the present invention, wherein bridging agent used is by dichloro in step (3)
One or more compositions in the halogenated hydrocarbons such as methane, chloroform.
The preparation method of Hydrochioro spherical particle of the present invention, wherein bridging agent used is by penta in step (3)
One or more compositions in the alkanes such as alkane, pentamethylene, hexane, hexamethylene, octane.
The preparation method of Hydrochioro spherical particle of the present invention, wherein bridging agent used is by methyl in step (3)
One or more compositions in the ethers such as tertbutyl ether.
The preparation method of Hydrochioro spherical particle of the present invention, wherein the bridging agent used in the step (3)
Ethyl acetate or n-butanol.
Include the vertical compression tablet of above-mentioned Hydrochioro spherical particle, the specially folk prescription or compound of Hydrochioro spherical particle
Vertical compression tablet.
Include the folk prescription or compound vertical compression tablet of above-mentioned Hydrochioro spherical particle, wherein the tablet is in parts by mass
It calculates, composition includes：0.1-50 parts of Hydrochioro spherical particles, 1-100 parts of fillers, 1-50 portions of disintegrants, 1-25 parts of bondings
Agent, 0.05-2 parts of lubricants.
Include the folk prescription vertical compression tablet of above-mentioned Hydrochioro spherical particle, wherein the tablet is calculated in parts by mass, group
At including：0.1-50 parts of Hydrochioro spherical particles, 1-100 parts of fillers, 1-50 portions of disintegrants, 1-25 parts of adhesives, 0.05-
2 parts of lubricants.
Include the compound vertical compression tablet of above-mentioned Hydrochioro spherical particle, wherein the tablet is calculated in parts by mass, group
At including：0.1-50 parts of Hydrochioro spherical particles, 0.1-50 parts of compound medicines, 1-100 parts of fillers, 1-50 portions of disintegrants,
1-25 parts of adhesives, 0.05-2 parts of lubricants.
The compound vertical compression tablet of Hydrochioro spherical particle of the present invention, wherein the compound medicine be selected from shellfish that
Puli, Losartan Potassium, Olmesartan, reserpine, Irbesartan, Telmisartan, Valsartan, Telmisartan ester, candesartan Cilexetil,
Benzene sulfonic acid enalapril, Cilazapril, quinapril, Ramipril, Benazepril, Perindopril, Spirapril, fosinopril or
Captopril；Preferably benazepil, Losartan Potassium, Olmesartan, reserpine, Irbesartan, Telmisartan；More preferably shellfish
That Puli or Losartan Potassium.
The folk prescription or compound vertical compression tablet of Hydrochioro spherical particle of the present invention, wherein the filler is by breast
It is one or more in sugar, microcrystalline cellulose, starch, pregelatinized starch, calcium bicarbonate, calcium carbonate, mannitol, Icing Sugar, dextrin
Composition.
The folk prescription or compound vertical compression tablet of Hydrochioro spherical particle of the present invention, wherein the disintegrant is by handing over
Join one or more during povidone, croscarmellose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, mountain chinaberry are determined
Composition.
The folk prescription or compound vertical compression tablet of Hydrochioro spherical particle of the present invention, wherein described adhesive is by hydroxyl
One or more compositions in third methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, pregelatinized starch.
The folk prescription or compound vertical compression tablet of Hydrochioro spherical particle of the present invention, wherein the lubricant is by hard
One or more compositions in fatty acid magnesium, talcum powder.
The folk prescription of Hydrochioro spherical particle of the present invention or the preparation method of compound vertical compression tablet, including step：
(1) sieves with 100 mesh sieve filler, disintegrant, adhesive spare；
(2) main ingredient of recipe quantity, filler, disintegrant, adhesive are uniformly mixed by；
(3) mix lubricant of additions recipe quantity is uniform；
(4) measures the content of main ingredient in hybrid fine particles, and piece weight is determined according to content, tabletted.
It is an advantage of the present invention that providing a kind of Hydrochioro spherical particle, and it is applied to comprising Hydrochioro
Folk prescription or compound vertical compression tablet preparation in.The Hydrochioro spherical particle assembles legal system by alkali-soluble acid analysis method and ball-type
Standby, average grain diameter controls between 50-200 μm, the dissolution rate of Hydrochioro can be improved, while improving its dry jet mixing pile, fits
For direct tablet compressing, the bioavilability and stability of its tablet are improved.
Definition
Unless otherwise defined, all technical terms used herein or proprietary vocabulary have the common of technical field
The meaning that technical staff is generally understood.
Term " pharmaceutically acceptable carrier " is pharmaceutically acceptable ingredient or medium, including but not limited to molten
Agent, excipient, diluent, adjuvant, filler etc..Common pharmaceutically acceptable carrier includes physiological saline, buffer,
Carbohydrate, gelatin, starch, Ringer's solution, cellulose etc..The pH of the carrier is usually 3-11, preferably 5-9, more preferable 7-
8。
All patents, patent application and the bibliography quoted in the application are incorporated by this Shen by reference
Please, incorporated extent is individually recited as reference just as each document.If between the application and document provided herein
There are conflict, the content that should be subject in the application.
In the folk prescription of Hydrochioro spherical particle of the present invention or the preparation method of compound vertical compression tablet, main ingredient refers to
Active constituents of medicine in pharmaceutical preparation.
Description of the drawings
The collection of illustrative plates shape of Hydrochioro spherical particle prepared by the present invention is illustratively shown in the attached drawing of the present patent application
State, and for illustrating the principle of the present invention together with specification so that those skilled in the relevant art can easily use this
Invention.
Fig. 1 shows the electron microscopic picture for the spherical particle that bulk pharmaceutical chemicals are prepared with example 1,2,3,5 and 8；
Fig. 2 shows powder diffraction (being abbreviated as XRD) collection of illustrative plates of bulk pharmaceutical chemicals and the example 1-9 spherical particles prepared；
Fig. 3 shows differential scanning calorimetry (being abbreviated as DSC) collection of illustrative plates of bulk pharmaceutical chemicals and the example 1-9 shape particles prepared；
Fig. 4 shows infrared (the being abbreviated as IR) collection of illustrative plates of bulk pharmaceutical chemicals and the example 1-9 shape particles prepared；
Fig. 5 shows the dissolution curve of bulk pharmaceutical chemicals and the example 1-9 spherical particles prepared.
Specific implementation mode
This application describes preferred embodiment and example, those skilled in the art on the basis of reading the application,
Change appropriate can be carried out to embodiment described herein and example.Therefore, the claimed content of the application includes
To all equivalent modifications and variations of theme in the application claims in law allowable range.
With reference to specific example to Hydrochioro particle of the present invention and its folk prescription or compound vertical compression tablet
Preparation method is described further, but protection scope of the present invention is not limited to this.
Example 1
Hydrochioro 4.0g is dispersed in about 18 times of amount deionized waters, and 10% sodium hydroxide (NaOH), which is added, makes it completely
Dissolving.Under linear velocity stirring in 125m/ minutes, solution is poured into constant temperature in crystallizer and after 14ml ethyl acetate is added, is added to 10 DEG C
Entering 9.5ml 10%HCl makes its precipitation, persistently stirs 45 minutes, adds 60ml deionized waters, be stirred for 30 minutes, filters, with
Deionized water elutes, and drying obtains Hydrochioro spherical particle.
Example 2
Hydrochioro 4.0g is dispersed in about 20 times of amount deionized waters, 10%NaOH is added and makes it completely dissolved.Linear velocity
Under stirring in 125m/ minutes, solution is poured into constant temperature in crystallizer, after addition 16ml n-butanols, 9.5ml 10% is added to 10 DEG C
HCl makes its precipitation, persistently stirs 45 minutes, adds 60ml deionized waters, be stirred for 30 minutes, filters, is eluted with deionized water,
Drying；Obtain Hydrochioro spherical particle.
Example 3
Hydrochioro 4.0g is dispersed in about 20 times of amount deionized waters, 10%NaOH is added and makes it completely dissolved.It is added 1:
0.01 polymer Polyvinylpyrrolidone (PVP K30).Under linear velocity stirring in 125m/ minutes, solution is poured into crystallizer
10ml ethyl acetate is added to 20 DEG C in constant temperature, and 9.5ml 10%HCl, which are added, makes its precipitation, persistently stirs 45 minutes, adds 60ml
Deionized water is stirred for 30 minutes, and filtering is eluted with deionized water, is dried；Obtain Hydrochioro spherical particle.
Example 4
Hydrochioro 4.0g is dispersed in about 20 times of amount deionized waters, 10%NaOH is added and makes it completely dissolved.It is added 1:
0.01 polymer hydroxypropyl methylcellulose (HPMC).Under linear velocity stirring in 125m/ minutes, solution is poured into constant temperature in crystallizer and is arrived
20 DEG C, 10ml ethyl acetate is added, 9.5ml 10%HCl, which are added, makes its precipitation, persistently stirs 45 minutes, adds 60ml deionizations
Water is stirred for 30 minutes, and filtering is eluted with deionized water, is dried；Obtain Hydrochioro spherical particle.
Example 5
Hydrochioro 4.0g is dispersed in about 20 times of amount deionized waters, 10%NaOH is added and makes it completely dissolved.It is added 1:
0.01 polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS).Under linear velocity stirring in 125m/ minutes, by solution
It pours into constant temperature in crystallizer and 10ml ethyl acetate is added to 20 DEG C, 9.5ml 10%HCl, which are added, makes its precipitation, persistently stirs 45
Minute, 60ml deionized waters are added, are stirred for 30 minutes, filters, is eluted with deionized water, are dried；Obtain Hydrochioro spherical shape
Particle.
Example 6
Hydrochioro 4.0g is dispersed in about 20 times of amount deionized waters, 10%NaOH is added and makes it completely dissolved.It is added 1:
0.01 polymer poloxamer (F68).Under the stirring of linear velocity 125m/ minutes, solution is poured into crystallizer constant temperature to 20 DEG C,
10ml ethyl acetate is added, 9.5ml 10%HCl, which are added, makes its precipitation, persistently stirs 45 minutes, adds 60ml deionized waters, then
Stirring 30 minutes, filtering, is eluted with deionized water, is dried；Obtain Hydrochioro spherical particle.
Example 7
Hydrochioro 4.0g is dispersed in about 20 times of amount deionized waters, 10%NaOH is added and makes it completely dissolved.It is added 1:
0.01 polymer Utech L100.Under linear velocity stirring in 125m/ minutes, solution is poured into constant temperature in crystallizer and is added to 20 DEG C
Enter 10ml ethyl acetate, 9.5ml 10%HCl, which are added, makes its precipitation, persistently stirs 45 minutes, adds 60ml deionized waters, then stir
It mixes 30 minutes, filters, eluted with deionized water, dry；Obtain Hydrochioro spherical particle.
Example 8
Hydrochioro 4.0g is dispersed in about 20 times of amount deionized waters, 10%NaOH is added and makes it completely dissolved.It is added 1:
0.01 polymer Eudragit L100-55.Under the stirring of linear velocity 125m/ minutes, solution is poured into crystallizer constant temperature to 20 DEG C,
10ml ethyl acetate is added, 9.5ml 10%HCl, which are added, makes its precipitation, persistently stirs 45 minutes, adds 60ml deionized waters, then
Stirring 30 minutes, filtering, is eluted with deionized water, is dried；Obtain Hydrochioro spherical particle.
Example 9 (particle)
Hydrochioro 4.0g is dispersed in about 18 times of amount deionized waters, 10%NaOH is added and makes it completely dissolved.It is added 1:
0.01 polymer Polyvinylpyrrolidone (PVP K30).Under linear velocity stirring in 125m/ minutes, solution is poured into crystallizer
12ml n-butanols are added to 20 DEG C in constant temperature, and 9.5ml 10%HCl, which are added, makes its precipitation, persistently stirs 45 minutes, adds 60ml and go
Ionized water is stirred for 30 minutes, and filtering is eluted with deionized water, is dried；Obtain Hydrochioro spherical particle.
Example 10 (folk prescription)
Prescription：Hydrochioro spherical particle 5g, MCC 8g, lactose 4g, amylum pregelatinisatum 10g prepared by example 3, stearic acid
Magnesium 0.135g.
Technique：Hydrochioro spherical particle prepared by example 3, MCC, lactose, amylum pregelatinisatum are weighed by recipe quantity, mixing
Uniformly, it sieves with 100 mesh sieve, the magnesium stearate of recipe quantity is added, be uniformly mixed, measure Hydrochioro content in hybrid fine particles, according to
Content determines piece weight, tabletted.
Example 11 (folk prescription)
Prescription：Hydrochioro spherical particle 5g, crospovidone 8g, lactose 4g, amylum pregelatinisatum 10g prepared by example 3,
Magnesium stearate 0.135g.
Technique：Hydrochioro spherical particle prepared by example 3, crospovidone, lactose, amylum pregelatinisatum are claimed by recipe quantity
Amount is uniformly mixed, sieves with 100 mesh sieve, the magnesium stearate of recipe quantity is added, and is uniformly mixed, and measures Hydrochioro in hybrid fine particles and contains
Amount, piece weight is determined according to content, tabletted.
Example 12 (compound, benazepil)
Prescription：Hydrochioro spherical particle 2.5g, benazepril hydrochloride 2g, MCC 4g, lactose 6g prepared by example 3, can
Pressure property starch 14g, magnesium stearate 0.1425g.
Technique：Hydrochioro, benazepril hydrochloride, MCC, lactose, amylum pregelatinisatum are weighed by recipe quantity, are uniformly mixed,
It sieves with 100 mesh sieve, the magnesium stearate of recipe quantity is added, be uniformly mixed, measure Hydrochioro content in hybrid fine particles, it is true according to content
Stator weight, it is tabletted.
Example 13 (compound, Losartan Potassium)
Prescription：Hydrochioro spherical particle 2.5g prepared by example 2, Losartan Potassium 10g, MCC 4g, lactose 6g, compressibility
Starch 14g, magnesium stearate 0.1825g.
Technique：Hydrochioro, Losartan Potassium, MCC, lactose, amylum pregelatinisatum are weighed by recipe quantity, are uniformly mixed, and cross 100
Mesh sieves, and the magnesium stearate of recipe quantity is added, and is uniformly mixed, and measures Hydrochioro content in hybrid fine particles, piece is determined according to content
Weight, it is tabletted.
Scanning electron microscope (SEM).To Hydrochioro bulk pharmaceutical chemicals (being referred to as API in below table and attached drawing) and in fact
Particle prepared by example 1,2,3,5 and 8 carries out electron-microscope scanning, records collection of illustrative plates, the result is shown in Figure 1.In each figure of electron-microscope scanning of Fig. 1 respectively
Designate amplification factor.
X-ray powder diffraction (XRD).The Hydrochioro particle that Hydrochioro bulk pharmaceutical chemicals and example 1 are prepared to example 9
Carry out XRD determining.Experiment condition：Detector：D-tex, Cu-K α targets, Guan Liu：40mA, pipe pressure：40kV, divergent slit：It 1 °, connects
Receive slit 2mm, scanning range：5-45 °, continous way, sweep speed：20 °/minute, are as a result shown in Fig. 2.
Differential scanning calorimeter (DSC).The Hydrochioro prepared to example 9 to Hydrochioro bulk pharmaceutical chemicals and example 1 is micro-
Grain carries out DSC measurement.Experiment condition：Nitrogen flow rate：50ml/ minutes, temperature range：30-300 DEG C, heating rate：10 DEG C/minute
As a result clock is shown in Fig. 3.
Granulometry (MS2000).To Hydrochioro bulk pharmaceutical chemicals, micronizing bulk pharmaceutical chemicals (API-micronised) and reality
Hydrochioro particle prepared by example 1 to example 9 carries out granulometry.Experiment condition：Refractive index:1.632 vibration rate:65%,
Testing time:10s, air pressure:1.5bar the results are shown in Table 1.
Table 1.
For the data result of table 1 it is found that the grain size of prepared spherical particle is significantly less than bulk pharmaceutical chemicals, grain size minimum is former
Expect 1/10th of medicine.Grain size is smaller, and specific surface area is bigger, then dissolves out faster.
Fourier Transform Infrared Spectrometer analyzes (FTIR)：Hydrochioro bulk pharmaceutical chemicals and example 1 are prepared to example 9
Hydrochioro particle carries out infrared IR detections, as a result sees Fig. 4.
Using funnel method, prepared by Hydrochioro bulk pharmaceutical chemicals, micronizing Hydrochioro bulk pharmaceutical chemicals and example 1 to example 9
The angle of repose of particle, bulk density, heap density is measured, and calculates Hausner ratios and karr coefficient %.Experimental result
It is shown in Table 2.
Table 2.
As known from Table 2, the mobility of the spherical agglomerated particle of preparation is blocked compared to bulk pharmaceutical chemicals, example 2, example 3 and example 4
That index, Hausner's ratios and angle of repose numerical value are substantially close, and example 1,8 mobile performance of example 6, example 7 and example
It is significantly improved compared with bulk pharmaceutical chemicals.The reason is that the agglomerated particle added prepared by these polymer has preferable roundness, appearance shape
Looks are more regular, and these batch narrower particle size distributions.Example 9 is ball top shape since its grain size is smaller (table), between particle
There is a little adhesion, therefore its mobile performance is poor compared with raw material, is equivalent to the mobility value by the bulk pharmaceutical chemicals of micronizing.
Hydrochioro bulk pharmaceutical chemicals, micronizing Hydrochioro bulk pharmaceutical chemicals and example 1 are prepared to example 9 using funnel method
The Packing character of particle is measured, and calculates river north equation parameter.Experimental result is shown in Table 3.
Table 3.
The mobility parameter (a, b) and coefficient R 2 of the spherical agglomerated particle of preparation are as shown in table 3, wherein a indicates stream
Dynamic property, then the smaller mobility of a values is better, and from interpretation of result, in addition to example 9, the mobility of prepared ball coalescing particle is all excellent
In bulk pharmaceutical chemicals.Example 9 is then suitable with micronizing bulk pharmaceutical chemicals.1/b can indicate required tapping when powder reaches minimum volume
Number, then b values are bigger, and the number needed is fewer, and the fillibility of powder is also better.From the results of view, example 1, example 4, example 5
Bulk pharmaceutical chemicals are substantially better than with the fillibility of example 6, the fillibility of other each batches is suitable with bulk pharmaceutical chemicals, and example 9 is then slightly worse.
Using dissolution method (Japanese stripping curve database), weigh to Hydrochioro bulk pharmaceutical chemicals (micronizing hydrogen chlorine
The Hydrochioro particle that thiazine bulk pharmaceutical chemicals or example 1 are prepared to example 9) 25mg, according to dissolution method (paddle board method), with
PH4.0 hac buffers 900ml is solvent, and rotating speed is 100 turns per minute, is operated in accordance with the law, through 5,10,20,30,45,60 points
Zhong Shi takes solution appropriate, discards primary filtrate, and precision measurement subsequent filtrate is appropriate, and solubilization goes out medium and is made in every 1ml containing 2-10
The solution of μ g, as test solution.According to containing the UV-VIS spectrophotometry under quantifier, measures and inhale at the wavelength of 272nm
Luminosity calculates dissolution rate.The dissolution rate of particle is shown in Fig. 5.
Claims (20)
1. Hydrochioro spherical particle, which is characterized in that average grain diameter between 50-200 μm, Hausner ratios 1.1-1.8 it
Between, karr coefficient is between 10%-50%, and 5 minutes dissolution rates are between 10%-80%, and dissolution rate is in 40%- within 20 minutes
Between 100%.
2. Hydrochioro spherical particle according to claim 1, preparation method include the following steps：
(1) Hydrochioro is dissolved in aqueous slkali by；
(2) under the solution stirring that obtains step (1), polymer appropriate is added, dissolves, solution is made；
(3) solution that obtains step (2) is under appropriate mixing speed, at moderate temperatures；It is added with speed appropriate certain
The bridging agent and acid reagent of amount；
(4) it is complete to wait for that Hydrochioro particle is precipitated by, makes its solidification, and continues stirring a period of time；
(5) is filtered, massive laundering, drying；Obtain the Hydrochioro spherical particle.
3. Hydrochioro spherical particle according to claim 1, which is characterized in that omit the step (2) in operation.
4. the preparation method of Hydrochioro spherical particle according to claim 2 or 3, which is characterized in that institute in step (1)
The aqueous slkali stated be alkali hydroxide soln, alkali metal hydroxide be selected from sodium hydroxide, potassium hydroxide, magnesium hydroxide or
Barium hydroxide；Preferably sodium hydroxide or potassium hydroxide, more preferable sodium hydroxide.
5. the preparation method of Hydrochioro spherical particle according to claim 2 or 3, which is characterized in that institute in step (2)
Polymer is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, Utech L100, Eudragit L100-55, hydroxypropylmethylcellulose acetate
One or more combinations in methyl cellulose succinate, F68.
6. the preparation method of Hydrochioro spherical particle according to claim 2 or 3, which is characterized in that the step (3)
The middle proper temperature used is between 0-50 degrees Celsius, mixing speed was linear velocity between 5-1000m/ minutes.
7. the preparation method of Hydrochioro spherical particle according to claim 2 or 3, which is characterized in that the step (3)
The acid reagent of middle use is selected from hydrochloric acid, citric acid, acetic acid, citric acid, maleic acid, palmitic acid or lactic acid；It is preferably selected from hydrochloric acid, lemon
Lemon acid, acetic acid.
8. the preparation method of Hydrochioro spherical particle according to claim 2 or 3, which is characterized in that the step (3)
In bridging agent used be selected from esters solvent, alcohols solvent, ketones solvent, halogenated hydrocarbon solvent, alkane solvents, ether solvent or
Its mixed solvent.
9. the preparation method of Hydrochioro spherical particle according to claim 7, which is characterized in that the esters solvent choosing
It is selected from n-butanol, normal propyl alcohol, isopropyl from one or more, the described esters solvent in methyl acetate, ethyl acetate, propyl acetate
One or more, the described esters solvent in alcohol is one or more, described in acetone, espeleton, methylisobutylketone
One or more, described esters solvent of the esters solvent in dichloromethane, chloroform is selected from pentane, pentamethylene, hexane, hexamethylene
The one kind of one or more, the described esters solvent in methyl tertiary butyl ether(MTBE), propyl ether, isopropyl ether or butyl ether in alkane, octane
Or it is a variety of.
10. the preparation method of Hydrochioro spherical particle according to claim 9, which is characterized in that in the step (3)
The preferred methyl acetate of bridging agent or n-butanol of use.
11. Hydrochioro spherical particle described in claim 1 is used to prepare folk prescription or compound vertical compression tablet, feature exist
In the tablet is calculated in parts by mass, and composition includes 0.1-50 parts of Hydrochioro spherical particles, 0-50 parts of compound medicines, 1-
100 parts of fillers, 1-50 portions of disintegrants, 1-25 parts of adhesives, 0.05-2 parts of lubricants.
12. Hydrochioro spherical particle described in claim 1 is used to prepare folk prescription vertical compression tablet, which is characterized in that described
Tablet is calculated in parts by mass, and composition includes：0.1-50 parts of Hydrochioro spherical particles, 1-100 parts of fillers, 1-50 parts of disintegrations
Agent, 1-25 parts of adhesives, 0.05-2 parts of lubricants.
13. Hydrochioro spherical particle described in claim 1 is used to prepare compound vertical compression tablet, which is characterized in that described
Tablet is calculated in parts by mass, and composition includes：0.1-50 parts of Hydrochioro spherical particles, 1-50 parts of compound medicines, 1-100 parts fill out
Fill agent, 1-50 portions of disintegrants, 1-25 parts of adhesives, 0.05-2 parts of lubricants.
14. the compound vertical compression tablet of Hydrochioro spherical particle according to claim 13, which is characterized in that the compound
Drug is selected from benazepil, Losartan Potassium, Olmesartan, reserpine, Irbesartan, Telmisartan ester, Valsartan, replaces meter Sha
It is smooth, candesartan Cilexetil, benzene sulfonic acid enalapril, Cilazapril, quinapril, Ramipril, Benazepril, Perindopril, spiral shell
Puli, fosinopril or captopril.
15. the compound vertical compression tablet of Hydrochioro spherical particle according to claim 13, which is characterized in that the compound
Drug is selected from benazepil, Losartan Potassium, Olmesartan, reserpine, Irbesartan or Telmisartan.
16. the folk prescription or compound vertical compression tablet of Hydrochioro spherical particle according to claim 11, which is characterized in that institute
Filler is stated by lactose, microcrystalline cellulose, starch, pregelatinized starch, calcium bicarbonate, calcium carbonate, mannitol, Icing Sugar, dextrin
One or more compositions.
17. the folk prescription or compound vertical compression tablet of Hydrochioro spherical particle according to claim 11, which is characterized in that institute
State disintegrant by crospovidone, croscarmellose sodium, sodium carboxymethylcellulose, sodium carboxymethyl starch, mountain chinaberry it is fixed in
One or more compositions.
18. the folk prescription or compound vertical compression tablet of Hydrochioro spherical particle according to claim 11, which is characterized in that institute
Adhesive is stated by one or more groups in hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, pregelatinized starch
At.
19. the folk prescription or compound vertical compression tablet of Hydrochioro spherical particle according to claim 11, which is characterized in that institute
Lubricant is stated to be made of one or more in magnesium stearate, talcum powder.
20. the folk prescription of Hydrochioro spherical particle according to claim 11 or the preparation method of compound vertical compression tablet,
It is characterized in that, including step：
(1) sieves with 100 mesh sieve filler, disintegrant, adhesive spare；
(2) main ingredient of recipe quantity, filler, disintegrant, adhesive are uniformly mixed by；
(3) mix lubricant of additions recipe quantity is uniform；
(4) measures the content of main ingredient in hybrid fine particles, and piece weight is determined according to content, tabletted.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114773251A (en) * | 2022-03-24 | 2022-07-22 | 天津大学 | L-tryptophan spherical crystal and preparation method and application thereof |
| CN115300476A (en) * | 2022-09-01 | 2022-11-08 | 华润双鹤药业股份有限公司 | Pharmaceutical composition and preparation method thereof |
| EP4233845A1 (en) * | 2022-02-28 | 2023-08-30 | Zaklady Farmaceutyczne Polpharma S.A. | A process for manufacturing hydrochlorothiazide having fine particle size distribution |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010082705A1 (en) * | 2009-01-19 | 2010-07-22 | 뉴모텍(주) | Axial motor |
-
2017
- 2017-03-14 CN CN201710149785.2A patent/CN108567744A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010082705A1 (en) * | 2009-01-19 | 2010-07-22 | 뉴모텍(주) | Axial motor |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4233845A1 (en) * | 2022-02-28 | 2023-08-30 | Zaklady Farmaceutyczne Polpharma S.A. | A process for manufacturing hydrochlorothiazide having fine particle size distribution |
| WO2023161493A1 (en) * | 2022-02-28 | 2023-08-31 | Zaklady Farmaceutyczne Polpharma S.A. | A process for manufacturing hydrochlorothiazide having fine particle size distribution |
| CN114773251A (en) * | 2022-03-24 | 2022-07-22 | 天津大学 | L-tryptophan spherical crystal and preparation method and application thereof |
| CN114773251B (en) * | 2022-03-24 | 2024-05-24 | 天津大学 | L-tryptophan spherical crystal and preparation method and application thereof |
| CN115300476A (en) * | 2022-09-01 | 2022-11-08 | 华润双鹤药业股份有限公司 | Pharmaceutical composition and preparation method thereof |
| CN115300476B (en) * | 2022-09-01 | 2024-04-16 | 华润双鹤药业股份有限公司 | Pharmaceutical composition and preparation method thereof |
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