CN1056974C - Drug material suitable for micronisation - Google Patents
Drug material suitable for micronisation Download PDFInfo
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- CN1056974C CN1056974C CN92104115A CN92104115A CN1056974C CN 1056974 C CN1056974 C CN 1056974C CN 92104115 A CN92104115 A CN 92104115A CN 92104115 A CN92104115 A CN 92104115A CN 1056974 C CN1056974 C CN 1056974C
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Abstract
The present invention relates to a 1-hydroxy-2-naphthalene carboxylate (hydroxy naphthaleneformate) of 4-hydroxy-alpha'-[[[6-(4-phenylbutoxy) hexyl] amino] methyl]-1, 3-phenyldicarbinol existing in a microcrystalline globular deposit form. The globular deposit freely flows, is easily pulverized and micronized and has average particle sizes of 70 to 300 micrometers and average surface area of 4 to 12 meters <2>/ gram. The hydroxy naphthaleneformate (in the form of the claim) can be prepared by immediately cooling hot organic / aqueous organic solution containing the hydroxy naphthaleneformate by cold organic /aqueous organic solution.
Description
The present invention is suitable for micronized drug material relevant for a kind of.Specifically; the present invention is relevant for 4-hydroxyl-α '-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1; the a kind of new of the 1-hydroxyl-2-naphthoate (hereinafter referred is a Hydroxynaphthoate) of 3-benzene dimethanol (hereinafter referred is a compd A) can easy micronized form, and the method for preparing this new model.
British patent specification No.2140800A (GB2140800A) is relevant for a kind of Phenethanolamine derivative that has selective excitement agent effect on β-2-adrenoceptor.Except that other use, this chemical compound can be used for treating the respiratory tract disease relevant with the reversibility airway obstruction, such as asthma and chronic bronchitis.Specifically, BG2140800A has narrated compd A and its physiologically acceptable salt, particularly (in example 20) its Hydroxynaphthoate.Compd A and its Hydroxynaphthoate have been found in this class respiratory tract disease of treatment special advantage.
When subject patient suffered respiratory symptom painful, the way of having found most convenient was to throw suitable β-2-analeptic by sucking or being blown into directly on site of action.For through these administrations, at first must make fine powder to active ingredient with suitable granular size scope.The material that satisfies required granular size specification generally can be by obtaining drug microparticlesization, but this application examples such as a kind of grinding machine, such as injector-type mill.
The inventor has been found that the Hydroxynaphthoate of working as compd A by GB2140800A, and when the method that example 20 is narrated prepared, the crystallization that obtains was that extremely difficult microgranule changes into required granular size scope.These crystalline solid be it seems to stick in the feed system (in injector-type mill) and cause and are assembled and finally cause blocking.This (crystalline) assembles and obstruction has hindered effective micronize.
An object of the present invention is to provide Hydroxynaphthoate a kind of new of compd A, easy micronized form, it has overcome the shortcoming (micronize aspect) relevant with above-mentioned the sort of concrete crystal form.
According to the present invention, provide the crystallite sphere of the Hydroxynaphthoate of compd A to accumulate thing here, it is free-pouring that this sphere is accumulated thing, easily pulverize and can be micronized.
Inventor's fantacy is found less than ground; the form of the Hydroxynaphthoate of the compd A of applying for a patent now; it is a kind of new spherical shapes that is combined with; the form of free mobility and the character easily pulverized, micronize becomes and is suitable for as by sucking or be blown into the material of the medicine type of administration easily.
The sphere that the invention provides crystallite is accumulated the Hydroxynaphthoate of the compd A of thing form.This form comprises the thin wafer of radially arranging around central atom reality or space.This form has unlimited structure, and wherein the polymorph of compd A Hydroxynaphthoate is resulting identical with GB2140800A example 20.This form that the inventor provides also comprises two or more (crystallite) spheries that fuse together and accumulates thing.In this manual, term " spheric " had both referred to spherical shapes, also referred to the profile of spheroidal (being spheroid).Should comprise ellipse garden shape (egg type) and the ellipse garden shape of distorting (pyriform) like sphere.
The compd A Hydroxynaphthoate of this new model that provides now must be free-pouring.This means the sure flour mill that freely flows into of this form, injector-type mill for example is so that it can be on commercial scale reduces its effective granular size by micronize.Determine the physical property of material of its flow behavior to comprise its bulk density, cementability, granular size, profile and the uniformity relevant with granular size.
Ideally, be energy free-flow, a kind of material should have high bulk density, low cementability and homogeneous granules size distribution.For satisfying this desirable properties, each granule of material internal also should have spherical shapes.The new model that provides now satisfies this standard.With R.L.Carr in Chemical Engineering (Chemical Emgineering) 1965, the measuring method that the 163-168 page or leaf is narrated, new model of the present invention presents high inflation bulk density, mainly between 0.2 to 0.5 grams per milliliter, particularly between 0.3 to 0.4 grams per milliliter, low cementability, mainly between 0 to 20%, particularly between 0 to 5%, granule profile and homogeneous granules size distribution with sphere (or being close to spherical), between 1 to 20, mainly between 1 to 5, typical value is about 3 by the measurement result uniformity coefficient.
The compd A Hydroxynaphthoate of this new model that provides now must be easily to pulverize, and this means that this form is easy to be fractured into certainly to be suitable for as by sucking or be blown into the required granular size of medicine type of administration.
The compd A Hydroxynaphthoate of this new model that provides now must be can be micronized; this means that this form is sure easily under the micronize condition; for example in injector-type mill, be fractured into to being suitable for as by sucking or be blown into the required granular size of medicine type of administration.
The compd A Hydroxynaphthoate of this new model that provides now preferably has 70 to 300 microns, be more preferably 100 to 200 microns mean particle size, measurement is to carry out in the laser diffraction method that " granular size measurement " (" Particle Size Measurement ") narrated in the book third edition in 1981 according to T.Allen, particle size distribution (measuring by screen analysis) is 10 to 2,000 micron, preferably 100 to 1, in 000 micrometer range, about the discussion of screen analysis, can be referring to the handbook of above-mentioned Allen.
The compd A Hydroxynaphthoate of this new model that provides now preferably has 4 to 12 meters
2/ gram is more preferably 6 to 10 meters
2The average surface area of/gram, measurement is to show " the long-pending and porous of powder surface " (Powder Surface Area andPorosity) 1984 by S.Lowell and J.E.Shields, Brunnauer described in the second edition, Emmett and Teller nitrogen absorption process (BET) carries out.
General general knowledge in powder grinding technique field is thought, for obtaining best flowability, should contain the bulky grain of low surface area in the material.Inventor's fantacy is found less than ground, under the situation of the form of preferred compd A Hydroxynaphthoate, the oarse-grained new model that contains high surface flows freelyr more than comprising the oarse-grained form known (pressing GB2140800A, example 20) with low surface area.This discovery is inconsistent with general general knowledge.For seeking to overcome the those of skill in the art of the mobile aspect difficulty relevant, can not remove to expect to produce a kind of material with this new-type preferred granular size/surface nature of process with the compd A Hydroxynaphthoate.
Other favourable physical property of the compd A Hydroxynaphthoate performance of this new model that provides now has low compressibility and relative low angle of repose.These terms and their measuring method can be referring to R.L.Carr at Chemical Engineering, and 1965, the narration that the 163-168 page or leaf is done.Preferably the angle of repose of present this new model is between 25-50 °, and particularly between 40-50 °, compressibility is between 5 to 25%, particularly between 8 to 20%.
The supply of the compd A Hydroxynaphthoate of present this new model allows it to carry out micronize with commercial scale.Like this; according to the further content of the present invention; be that it provides a kind of the compd A Hydroxynaphthoate is carried out micronized method; it comprises accumulates thing to this sphere with crystallite (this thing that accumulates is free-pouring; that easily pulverize and can be micronized) the compd A Hydroxynaphthoate that exists of form is fed in the pulverizer; Hydroxynaphthoate is ground into micronized material, and collects this micronized material.
Preferably the compd A Hydroxynaphthoate of present this form is adapted to pass through the needs that suck or be blown into the medicine type of administration by micronize up to the granular size scope that material had of collecting.The suitable granular size scope of making this purposes is 1 to 10 micron, preferably 1 to 5 micron.
The compd A Hydroxynaphthoate of present this form can prepare by suitable method.The present invention further content is, it provides a kind of preparation method of accumulating the compd A Hydroxynaphthoate that the thing form exists with the crystallite sphere, and it is free-pouring that this sphere is accumulated thing, easily pulverize and can be micronized.Said method comprises with a kind of organic solvent or aqueous organic solvent, the organic solution or the aqueous organic solution of compd A Hydroxynaphthoate are cooled off suddenly, thereby the crystallite sphere that provides the compd A Hydroxynaphthoate is accumulated thing (product), and collects this product.The temperature of solvent for use should be lower than the temperature of said solution.
For the sake of simplicity, hereinafter organic solution or aqueous organic solution are stated as " heat ", and organic solvent or water-containing organic solvent with lower temperature then is stated as " cold ".These terms are interpreted as relative, and nisi.
The crystalline material that is produced big spherical shapes by above-mentioned crystallization process is extremely unusual and unexpected, crystallization process Once you begin after, be than faster, the crystallization process of this " soon " generally can cause producing and has the very thin material of powder of small particle size.
In the above methods, " aqueous organic " solution or solvent can comprise up to about the water of 10% (v/v), preferably use the organic solution of heat and cold organic solvent in the above methods.
Preferably, the organic solvent of aqueous organic solution that is used for the organic solution of heat or heat has 40 ℃ to 150 ℃ boiling point (when 760 millimetress of mercury), particularly 60 ℃ to 120 ℃ boiling point.The compd A Hydroxynaphthoate should be slightly soluble in or be insoluble in this solvent when cold, then should be dissolved in this solvent when hot.The solvent that is suitable as the aqueous organic solution of hot organic solution or heat comprises more rudimentary alkyl (C
1-4) pure such as methanol, ethanol and isopropyl alcohol, more rudimentary alkyl (C
1-4) ether such as methyl tertiary butyl ether(MTBE) and more rudimentary alkyl (C
1-4) ester is such as ethyl acetate.In the methods of the invention one concrete in embodiment preferred, used organic solvent is a kind of more rudimentary alkylol, particularly methanol in the aqueous organic solution of hot organic solution or heat, ethanol or isopropyl alcohol, especially methanol.
In all above-mentioned situations, the aqueous organic solution of the organic solution of heat or heat can comprise a kind of single solvent, or the mixture of solvent.
Should be miscible mutually as the organic solvent in cold organic solvent or the cold water-containing organic solvent system with the solvent of the aqueous organic solution of organic solution that is used for heat or heat, preferably its freezing point is between-150 ° to-20 ℃, particularly between-130 ° to-50 ℃.The Hydroxynaphthoate of compd A is answered slightly soluble or is insoluble to this solvent when cold.The solvent that is suitable as in cold organic solvent or the cold water-containing organic solvent system comprises more rudimentary alkyl (C
1-4) pure such as methanol, ethanol and isopropyl alcohol, more rudimentary alkyl (C
1-4) ether such as methyl tertiary butyl ether(MTBE) and more rudimentary alkyl (C
1-4) ester is such as ethyl acetate, in the methods of the invention one concrete in embodiment preferred, be a kind of more rudimentary alkylol, particularly methanol as the organic solvent in cold organic solvent or the cold water-containing organic solvent system, ethanol and isopropyl alcohol, especially isopropyl alcohol.
In all above-mentioned situations, cold organic solvent or cold aqueous solvent can comprise a kind of single solvent, or the mixture of solvent.
Should be miscible mutually as the organic solvent in cold organic solvent or the cold water-containing organic solvent system with the solvent of the aqueous organic solution of organic solution that is used for heat or heat, preferably its freezing point is between-150 ° to-20 ℃, particularly between-130 ° to-50 ℃.The Hydroxynaphthoate of compd A is answered slightly soluble or is insoluble to this solvent when cold.The solvent that is suitable as in cold organic solvent or the cold water-containing organic solvent system comprises more rudimentary alkyl (C
1-4) pure such as methanol, ethanol and isopropyl alcohol, more rudimentary alkyl (C
1-4) ether such as methyl tertiary butyl ether(MTBE) and more rudimentary alkyl (C
1-4) ester is such as ethyl acetate, in the methods of the invention one concrete in embodiment preferred, be a kind of more rudimentary alkylol, particularly methanol as the organic solvent in cold organic solvent or the cold water-containing organic solvent system, ethanol and isopropyl alcohol, especially isopropyl alcohol.
In all above-mentioned situations, cold organic solvent or cold aqueous solvent can comprise a kind of single solvent, or the mixture of solvent.
The selected temperature that is used for making " heat " solution He " cold " solvent of compd A Hydroxynaphthoate generation rapid crystallization process, should make the sphere of crystallite accumulate thing can form.Used temperature will depend on selected solvent or dicyandiamide solution to a great extent.Easily, the temperature of the aqueous organic solution of hot organic solution or heat can be between 30 ℃ to 80 ℃, particularly between 40 to 70 ℃.Equally easily, the temperature of cold organic solvent or cold water-containing organic solvent can be between-35 ° to 15 ℃, particularly between-25 ° to 10 ℃.
Suddenly the cooling of aqueous organic solution of the organic solution of heat or heat both be added to it in cold organic solvent or the cold water-containing organic solvent so long and go, and also can be added to cold solvent in the solution of heat conversely.Preferably the aqueous organic solution of the organic solution of heat or heat is added in cold organic solvent or the cold water-containing organic solvent and goes.
In rapid refrigerative process, the temperature of preferably keeping mixture (" heat " solution and " cold " solvent) is about below 20 ℃, particularly-10 ℃ between 20 ℃, especially between 0 ℃ to 20 ℃.Mixture is maintained at the form of accumulating thing up to all (or most) Hydroxynaphthoates of compd A with the sphere of crystallite in this temperature range and crystallizes out.This crystallization process for example may need, and 10 to 120 minutes, particularly 20 to 90 minutes.
The Hydroxynaphthoate of compd A can be dissolved as in the aqueous organic solution of the organic solution of heat or heat, and in addition, this salt also can form on the spot by respectively compd A and 1-hydroxyl-2-naphthoic acid being dissolved in " heat " solution.
The raw material (Hydroxynaphthoate of compd A or compd A) that is used for said method can prepare by the method described in the GB2140800A.
The sphere of crystallite is accumulated thing in case form with method of the present invention, and promptly available any suitable method such as filtration, is collected.
Above-mentioned reference material, promptly GB2140800A:R.L.Carr is at Chemical Engineering magazine (Chemical Engineering) 1965, the article that the 163-168 page or leaf is delivered; " granular size measurement " (Particle Size Measurement) third edition in 1981 that T.Allen showed; S.Lowell and J.E.Shields shows " powder surface long-pending and porous " (Powder Surface Area and Porosity) 1984, and second edition etc. are all listed reference content in and are herein incorporated.
The compd A Hydroxynaphthoate of the new model that provides now, its preparation method and its micronized method will only be described by example.
In the accompanying drawings, Fig. 1 is that Fig. 2 is the scanning electron micrograph according to the new model of the compd A Hydroxynaphthoate of the example 8 prepared present patent application of stating below according to the scanning electron micrograph of the known crystal form that supplies the prepared compd A Hydroxynaphthoate of example relatively of stating below.Also more close in this picture with one, show that the sphere that the method narrated by example 8 makes accumulates the illustration on thing surface.
(A) preparation of the Hydroxynaphthoate of compd A
Comparison example
4-hydroxyl-α '-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1,3-benzene dimethanol (compd A) is dissolved in (＞60 ℃) isopropyl alcohol of heat, toward wherein adding the solution of 1-hydroxyl-2-naphthoic acid (1 equivalent) in (70 ℃) isopropyl alcohol of heat.In mixture, add crystal seed, allow to be cooled to 40 ℃ (about 2 hours), and then be cooled to 5 ℃ (about 2 hours).The filtration solid product of isolating out is washed and at vacuum drying with cold isopropyl alcohol.The product that obtains provides scanning electron micrograph shown in Figure 1.
Example 1
The Hydroxynaphthoate that cold (-15 ℃ approximately) isopropyl alcohol is added to compd A apace is in (about 65 ℃) isopropyl alcohol of heat in the formed solution.The suspension that produces allows to place 1 hour at about 5 ℃, filters then and collects product, wash with cold isopropyl alcohol, and dry under 50 ℃ vacuum.
Example 2
The Hydroxynaphthoate that cold (-15 ℃ approximately) isopropyl alcohol is added to compd A apace is in (about 40 ℃) methanol of heat in the formed solution.The suspension that produces allows to place 1 hour at about 5 ℃, filters then and collects product, wash with cold isopropyl alcohol, and dry under 50 ℃ vacuum.
Example 3
Compd A (4.63 kilograms) and 1-hydroxyl-2-naphthoic acid (2.10 kilograms) are dissolved in (about 60 ℃) methanol of heat.This solution is added in cold (about 5 ℃) isopropyl alcohol, and the temperature of " blended " solution is allowed to increase up to reaching 15 ℃, so mixture was kept 30 minutes at 15 ℃ (± 2 ℃) in the process that adds.Filter the product of isolating out then, wash with cold isopropyl alcohol, and dry under 40 ℃ vacuum.
Example 4
The mixture that compd A (12.4 kilograms) and 1-hydroxyl-2-naphthoic acid (5.6 kilograms) are formed in (57 ℃ ± 3 ℃) methanol of heat is added in cold (being lower than 15 ℃) isopropyl alcohol (isopropyl alcohol that also can select to contain the water of as many as 6% (v/v)).The temperature of mixture is no more than 15-20 ℃ in adition process.The suspension that obtains stirred about 1 hour at about 20 ℃, and solid collected by filtration is washed with cold isopropyl alcohol then, and dry under about 40 ℃ vacuum.
Example 5
The solution that the Hydroxynaphthoate of compd A forms in (the about 70 ℃) isopropyl alcohols (9.5 volume) of heat is added under nitrogen protection and stirring condition in cold (5-10 ℃) t-butyl methyl ether (25 volume) in 8 fens clock times.(at about 5 ℃) filter the solid matter of isolating out after 30 minutes, and with cold washed with isopropyl alcohol and dry, the fusing point of resulting product is 121.5-137.5 ℃.
Example 6
Hydroxynaphthoate at the following compd A of nitrogen protection is dissolved in hot (75 ℃) isopropyl alcohol (9.5 volume), allows solution under agitation slowly to be cooled to 57 ℃.Toward wherein adding cold (30 ℃) isopropyl alcohol (14 volume), and make the temperature of the mixture that obtains be about 17 ℃.After about 4 hours, leach solid product, with cold washed with isopropyl alcohol and dry under vacuum.
Example 7
The hot solution (about 60 ℃) that compd A and 1-hydroxyl-2-naphthoic acid (1 equivalent) are formed in methanol (5.8 volume) under agitation was added in about 1 minute in cold (10 ℃) isopropyl alcohol (11.6 volume), and the mixture that obtains stirred 1.5 hours at 0-5 ℃.The solid collected by filtration product is with cold washed with isopropyl alcohol and dry under vacuum.
Example 8
The hot solution (60 ℃) that compd A and 1-hydroxyl-2-naphthoic acid (1 equivalent) are formed in methanol (5.6 volume) was added in the cold isopropyl alcohol in about 0.5 hour.In whole mixed process, the temperature of keeping mixture is in 12 °-17 ℃ scope.Mixture stirred 1 hour at 15 ℃, the solid collected by filtration product, filter cake with cold washed with isopropyl alcohol and under 40 ℃ vacuum drying.
The product that obtains provides scanning electron micrograph shown in Figure 2.The crystallite character of this new model can find out from the appended illustration of Fig. 2 that the latter closely demonstrates the surperficial situation that a resulting sphere is accumulated thing.
(B) physical property of the compd A Hydroxynaphthoate of two kinds of forms
The table of listing has below compared the Hydroxynaphthoate (by the preparation of the method for top comparison example) of form known and some same physical propertys of the Hydroxynaphthoate (pressing example 8 described methods prepares) of the new model that provides now.
Table
Physical property comparison example example 8
Bulk density (grams per milliliter) 0.16 0.30
Coefficient of compressibility (%) 40 9.0
Caking property (%) 82 1.3
Angle of repose (degree) 65 41
Mean particle size (micron) 26 156
(laser analysis)
Average surface area (rice
2/ gram) 1.9 9.6
(BET analysis)
(C) micronize of the compd A Hydroxynaphthoate of two kinds of forms
Micronize is to carry out in the injector-type mill of known models." pharmaceutical science " (Pharmaceutical Sciences) that Remington showed 1985 the 17th editions, 1588 pages of suitable examples of usefulness carried out describing and explaining.Wherein disclosed content is herein incorporated by reference material.In atomization process, crude drug is brought in the cyclone separator by air-spray by feed hopper and Venturi tube, and the shear action of air-spray and the collision between drug particles are broken crystallization there.Fall into a container through micronized medicine by cyclone separator, " dust " then stayed in the tail gas and by big " vacuum scale removal " bag and captured.
(i) carry out micronize with the resulting material of comparison example
In the atomization process of this material, on the wall of Venturi tube, can form the cured shape deposit of medicine, thereby only just make process be forced to stop after a few minutes.
(ii) the material with example 6 gained carries out micronize
In the atomization process of this material, material is successfully flowed through Venturi tube and is entered cyclone separator by feed hopper.In about 20 minutes operating time, there is not cured shape material to be bonded in the Venturi tube.
Claims (26)
1. one kind makes 4-hydroxyl-α
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1, the 1-hydroxyl of the 3-benzene dimethanol-micronized method of 2-naphthoate, this method comprises accumulates 4-hydroxyl-α that the thing form exists to this sphere with crystallite
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1; 1-hydroxyl-2-the naphthoate of 3-benzene dimethanol is fed in the pulverizer; and wherein this sphere to accumulate thing be free-pouring, easy pulverizing and can be micronized; 1-hydroxyl-2-naphthoate is ground into micronized material, and collects this micronized material.
2. one kind prepares with the sphere of crystallite and accumulates 4-hydroxyl-α that the thing form exists
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1; the method of the 1-hydroxyl-2-naphthoate of 3-benzene dimethanol; it is free-pouring, easy pulverizing and can be micronized that this sphere is accumulated thing; said method comprises with a kind of organic solvent or aqueous organic solvent cools off the organic solution or the aqueous organic solution of 1-hydroxyl-2-naphthoate suddenly, and the crystallite sphere that the temperature of solvent for use should be lower than said 1-hydroxyl-2-naphthoate is accumulated the temperature of the solution that thing produces therein.
3. accumulate 4-hydroxyl-α that the thing form exists according to the said preparation of claim 2 with the sphere of crystallite
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1; the method of the 1-hydroxyl-2-naphthoate of 3-benzene dimethanol; it is free-pouring that this sphere is accumulated thing; that easily pulverize and can be micronized; said method comprises with cold organic solvent or cold water-containing organic solvent cools off the hot organic solution of 1-hydroxyl-2-naphthoate or the aqueous organic solution of heat suddenly; accumulate thing with the crystallite sphere that provides 1-hydroxyl-2-naphthoate, and collect said crystallite sphere and accumulate thing.
4. the said method of claim 3 it is characterized in that with cold organic solvent the organic solution of the heat of 1-hydroxyl-2-naphthoate being cooled off suddenly, thereby the crystallite sphere that obtains 1-hydroxyl-2-naphthoate is accumulated thing.
5. said method of claim 3, the organic solvent that it is characterized in that being used for the aqueous organic solution of the organic solution of heat or heat has 40 to 150 ℃ boiling point when 760mmHg.
6. the said method of claim 5 is characterized in that organic solvent comprises rudimentary alkylol.
7. said method of claim 6, wherein said alkylol is methanol, ethanol or isopropyl alcohol.
8. said method of claim 3 is characterized in that in cold organic solvent or cold water-containing organic solvent used organic solvent has-150 ° to-20 ℃ freezing point.
9. the said method of claim 8 is characterized in that this organic solvent comprises rudimentary (C
1-4) alkylol, rudimentary (C
1-4) alkyl ether or rudimentary (C
1-4) Arrcostab.
10. the said method of claim 9 is characterized in that this organic solvent comprises rudimentary alkylol.
11. the said method of claim 10, wherein said alkylol is a methanol, ethanol or isopropyl alcohol.
12. any said method of claim in the claim 3 to 11 is characterized in that the temperature of the aqueous organic solution of hot organic solution or heat is 30 ° to 80 ℃.
13. any said method of claim in the claim 3 to 11 is characterized in that the temperature of cold organic solvent or cold water-containing organic solvent is-35 ° to+15 ℃.
14. the method for a claim 12 is characterized in that the temperature of organic solvent that this is cold or cold water-containing organic solvent is-35 ° to+15 ℃.
15. the method for any claim in the claim 3 to 11, it is characterized in that in the process that turns cold suddenly of aqueous organic solution of hot organic solution that makes 1-hydroxyl-2-naphthoate with cold organic solvent or cold water-containing organic solvent or heat, the temperature of mixture is maintained at+below 20 ℃.
16. the method for a claim 12, it is characterized in that in the process that turns cold suddenly of aqueous organic solution of hot organic solution that makes 1-hydroxyl-2-naphthoate with cold organic solvent or cold water-containing organic solvent or heat, the temperature of mixture is maintained at+below 20 ℃.
17. the method for a claim 13, it is characterized in that in the process that turns cold suddenly of aqueous organic solution of hot organic solution that makes 1-hydroxyl-2-naphthoate with cold organic solvent or cold water-containing organic solvent or heat, the temperature of mixture is maintained at+below 20 ℃.
18. the method for a claim 14, it is characterized in that in the process that turns cold suddenly of aqueous organic solution of hot organic solution that makes 1-hydroxyl-2-naphthoate with cold organic solvent or cold water-containing organic solvent or heat, the temperature of mixture is maintained at+below 20 ℃.
19. the method for any claim in the claim 3 to 11, the aqueous organic solution that it is characterized in that the hot organic solution of 1-hydroxyl-2-naphthoate or heat are by 1-hydroxyl-2-naphthoic acid and 4-hydroxyl-α
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1,3-benzene dimethanol mix in the water-containing organic solvent of the organic solvent of heat or heat and are prepared into.
20. the method for a claim 12 is characterized in that the hot organic solution of 1-hydroxyl-2-naphthoate or the aqueous organic solution of heat are by 1-hydroxyl-2-naphthoic acid and 4-hydroxyl-α
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1,3-benzene dimethanol mix in the water-containing organic solvent of the organic solvent of heat or heat and are prepared into.
21. the method for a claim 13 is characterized in that the hot organic solution of 1-hydroxyl-2-naphthoate or the aqueous organic solution of heat are by 1-hydroxyl-2-naphthoic acid and 4-hydroxyl-α
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1,3-benzene dimethanol mix in the water-containing organic solvent of the organic solvent of heat or heat and are prepared into.
22. the method for a claim 14 is characterized in that the hot organic solution of 1-hydroxyl-2-naphthoate or the aqueous organic solution of heat are by 1-hydroxyl-2-naphthoic acid and 4-hydroxyl-α
1-[[[6-(4-phenyl butoxy] amino] methyl]-1, the 3-benzene dimethanol mixes in the water-containing organic solvent of the organic solvent of heat or heat and is prepared into.
23. the method for a claim 15 is characterized in that the hot organic solution of 1-hydroxyl-2-naphthoate or the aqueous organic solution of heat are by 1-hydroxyl-2-naphthoic acid and 4-hydroxyl-α
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1,3-benzene dimethanol mix in the water-containing organic solvent of the organic solvent of heat or heat and are prepared into.
24. the method for a claim 16 is characterized in that the hot organic solution of 1-hydroxyl-2-naphthoate or the aqueous organic solution of heat are by 1-hydroxyl-2-naphthoic acid and 4-hydroxyl-α
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1,3-benzene dimethanol mix in the water-containing organic solvent of the organic solvent of heat or heat and are prepared into.
25. the method for a claim 17 is characterized in that the hot organic solution of 1-hydroxyl-2-naphthoate or the aqueous organic solution of heat are by 1-hydroxyl-2-naphthoic acid and 40 hydroxyls-α
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl] 1,3-benzene dimethanol mix in the water-containing organic solvent of the organic solvent of heat or heat and are prepared into.
26. the method for a claim 18 is characterized in that the hot organic solution of 1-hydroxyl-2-naphthoate or the aqueous organic solution of heat are by 1-hydroxyl-2-naphthoic acid and 4-hydroxyl-α
1-[[[6-(4-phenyl butoxy) hexyl] amino] methyl]-1,3-benzene dimethanol mix in the water-containing organic solvent of the organic solvent of heat or heat and are prepared into.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/GB1992/000245 WO1993016031A1 (en) | 1992-02-11 | 1992-02-11 | Benzenedimethanol derivative suitable for micronisation |
| AU12298/92A AU1229892A (en) | 1992-02-11 | 1992-02-11 | Benzenedimethanol derivative suitable for micronisation |
| CN92104115A CN1056974C (en) | 1992-02-11 | 1992-05-29 | Drug material suitable for micronisation |
| NO933622A NO180676C (en) | 1992-02-11 | 1993-10-08 | 1-Hydroxy-2-naphthalene carboxylate (hydroxynaphthoate) salt of 4-hydroxy <alpha> 1 £££ 6- (4-phenylbutoxy) hexyl | amino | methyl | -1,3-benzenedimethanol and process for the preparation thereof |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/GB1992/000245 WO1993016031A1 (en) | 1992-02-11 | 1992-02-11 | Benzenedimethanol derivative suitable for micronisation |
| CN92104115A CN1056974C (en) | 1992-02-11 | 1992-05-29 | Drug material suitable for micronisation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1079146A CN1079146A (en) | 1993-12-08 |
| CN1056974C true CN1056974C (en) | 2000-10-04 |
Family
ID=4940625
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92104115A Expired - Lifetime CN1056974C (en) | 1992-02-11 | 1992-05-29 | Drug material suitable for micronisation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1056974C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10351663A1 (en) * | 2002-12-20 | 2004-07-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Stable, accurately dosable inhalable powder medicament for treating asthma or chronic obstructive pulmonary disease, containing tiotropium, specific form of salmeterol xinafoate and auxiliary |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2140800A (en) * | 1983-04-18 | 1984-12-05 | Glaxo Group Ltd | Phenethanolamine derivatives |
-
1992
- 1992-05-29 CN CN92104115A patent/CN1056974C/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2140800A (en) * | 1983-04-18 | 1984-12-05 | Glaxo Group Ltd | Phenethanolamine derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1079146A (en) | 1993-12-08 |
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| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
| OR01 | Other related matters | ||
| C17 | Cessation of patent right | ||
| CX01 | Expiry of patent term |
Expiration termination date: 20120529 Granted publication date: 20001004 |