[go: up one dir, main page]

US20040197275A1 - Process for the manufacture of powders of inhalable medicaments - Google Patents

Process for the manufacture of powders of inhalable medicaments Download PDF

Info

Publication number
US20040197275A1
US20040197275A1 US10/685,254 US68525403A US2004197275A1 US 20040197275 A1 US20040197275 A1 US 20040197275A1 US 68525403 A US68525403 A US 68525403A US 2004197275 A1 US2004197275 A1 US 2004197275A1
Authority
US
United States
Prior art keywords
ultrasound
segment
tubular reactor
micro
medicament
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/685,254
Inventor
Nathalie Jongen
Jacques LeMaitre
Paul Bowen
Marcel Donnet
Joerg Schiewe
Bernd Zierenberg
Cristina Soare
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ecole Polytechnique Federale de Lausanne EPFL
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Ecole Polytechnique Federale de Lausanne EPFL
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ecole Polytechnique Federale de Lausanne EPFL, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Ecole Polytechnique Federale de Lausanne EPFL
Priority to US10/685,254 priority Critical patent/US20040197275A1/en
Publication of US20040197275A1 publication Critical patent/US20040197275A1/en
Priority to US12/263,818 priority patent/US8496944B2/en
Assigned to BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG, ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE reassignment BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BOWEN, PAUL, DONNET, MARCEL, LEMAITRE, JACQUES, SOARE, CRISTINA LUCICA, JONGEN, NATHALIE, ZIERENBERG, BERND, SCHWIEWE, JOERGE
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0004—Crystallisation cooling by heat exchange
    • B01D9/0013—Crystallisation cooling by heat exchange by indirect heat exchange
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
    • B01D9/0054—Use of anti-solvent
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/0081—Use of vibrations, e.g. ultrasound
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F33/00—Other mixers; Mixing plants; Combinations of mixers
    • B01F33/30—Micromixers
    • B01F33/302—Micromixers the materials to be mixed flowing in the form of droplets
    • B01F33/3021—Micromixers the materials to be mixed flowing in the form of droplets the components to be mixed being combined in a single independent droplet, e.g. these droplets being divided by a non-miscible fluid or consisting of independent droplets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/18—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic using a vibrating apparatus
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2215/00—Auxiliary or complementary information in relation with mixing
    • B01F2215/04—Technical information in relation with mixing
    • B01F2215/0413—Numerical information
    • B01F2215/0418—Geometrical information
    • B01F2215/0431—Numerical size values, e.g. diameter of a hole or conduit, area, volume, length, width, or ratios thereof
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00788—Three-dimensional assemblies, i.e. the reactor comprising a form other than a stack of plates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00851—Additional features
    • B01J2219/00858—Aspects relating to the size of the reactor
    • B01J2219/0086—Dimensions of the flow channels
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00873—Heat exchange
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00889—Mixing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00925—Irradiation
    • B01J2219/00932—Sonic or ultrasonic vibrations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/0095—Control aspects
    • B01J2219/00984—Residence time

Definitions

  • the invention relates to an improved process for the production of powders of organic compounds by precipitation from liquid mixtures.
  • the international patent application WO 98/2237 discloses a process for the production of inorganic powders by precipitation from a liquid reaction mixture, the method comprising passing along a tubular reactor a segmented reaction flow comprised of discrete volumes of the reaction mixture separated by discrete volumes of a separating fluid which is substantially immiscible with said reaction mixture, the residence time of said discrete volumes of reaction mixture in the reactor being sufficient for the precipitation reaction to be effected.
  • inhalable medicaments For inhalable medicaments, a well-defined size and shape of the crystals is a pre-requisite.
  • the powder In order for a powdered compound or composition to be used in an inhaled medicament, the powder must have certain characteristics. For example, micronised medicaments or active ingredients generally come in solid form.
  • high requirements are placed on the particle size, the particle size distribution, the morphology, the stability and the flow performance of the powder holding the medicament.
  • the entire administered dose of the medicament does not reach the lungs. Rather, only a part of the dose does.
  • the particle size has a substantial influence on the proportion of the medicament which actually reaches the lungs. For this reason, particles are preferred which have a diameter of less than 20 ⁇ m, preferably less than 5 ⁇ m and greater than 0.3 ⁇ m.
  • the diameter of the particle should be within the given window and furthermore should have the narrowest possible size distribution. Larger particles are separated off during respiration in the upper airways whilst smaller particles are not deposited in the lungs and these leave again when exhaling.
  • the invention relates to an improved process for the production of powders of inhalable medicaments by crystallization from a supersaturated fluid containing said medicament, the method comprising passing along a tubular reactor
  • a second embodiment of the present invention is a micro-reactor for implementing the process according to this invention comprising a micro-mixer, a segmenter and a tubular reactor, wherein
  • the dimensions of the micro-mixer for dividing the added fluids which are to be mixed is in the range of 10 ⁇ m to 1 mm, preferably between 25 ⁇ m to 200 ⁇ m,
  • the dimensions of the channels of the segmenter lie in the range of 0.1 to 5 mm, preferably in the range of between 0.2 mm and 5 mm, and
  • the tubular reactor is configured to be tube-, pipe- or channel-shaped with diameters of the channels in the range of 0.5 to 10 mm, preferably 1 mm to 2 mm, and with a length of between 10 cm and 200 m, preferably between 1 m and 25 m and is equipped with an external ultrasound source.
  • the invention relates to an inhalable medicament with an aerodynamic diameter of less than 20 ⁇ m, preferably less than 5 ⁇ m and greater than 0.3 ⁇ m, characterized in that it is produced by means of the inventive process.
  • FIG. 1 shows a schematic flow chart of fenoterol crystallization.
  • FIG. 2 shows the X-Ray diffractogram of dried sample of fenoterol (SFTR-13.06.02) TWEENTM surface active agent and the reference powder.
  • FIG. 3 shows the SEM image of dried material of fenoterol (SFTR-13.06.02) and TWEENTM surface active agent.
  • FIG. 4 shows a schematic flow chart of Budesonide (11.07.02-SFTR) crystallization
  • FIG. 5 shows the X-rays diffractogram of budesonide powder crystallised and reference material.
  • the invention preferably relates to a process wherein the segmented flow passes along the tubular reactor as a plug flow.
  • tubular reactor consists of the following segments:
  • the particle size distribution of the organic compounds can be fine-tuned depending on the ratio of t R , t US and t A . Smaller particle size distributions can be obtained if longer t US are applied.
  • an ultrasound with a frequency of 20 to 60 kHz and/or an energy density from 10 to 80 WL ⁇ 1 is applied.
  • Another preferred embodiment is a process wherein the segmented flow or a precursor segmented flow from which the segmented flow is subsequently generated is produced by passing the fluid containing the organic compound or a component thereof and the separating fluid to a chamber having a restricted outlet from which the segmented flow issues, in particular wherein the segmented flow is produced in a segmentation arrangement comprised of two concentric tubes, said chamber being provided at the outlet of the inner of the tubes and said chamber has an internal diameter of 2 mm to 10 mm.
  • the innermost tube has an internal diameter of 0.1 to 2 mm and/or the distance between the outlet of the innermost tube and the inlet of the restriction is in the range 0.1 to 5 mm.
  • the separating fluid is passed to said chamber along the innermost tube.
  • segmented flow is prepared by passing the fluid containing the organic compound and the separating fluid to said chamber thereby producing the segmented reaction flow, in particular wherein discrete volumes of said component of the fluid comprising the organic compound are separated by discrete volumes of the separating fluid and the segmented reaction flow is produced by admixing said discrete volumes of the fluid containing said organic compound with the remaining component(s) of the mixture.
  • Another preferred embodiment is a process wherein the segmented reaction flow is prepared from said precursor flow by injecting said latter flow and the further component(s) of the fluid containing the medicament to a chamber having a restricted outlet under conditions such that said further component(s) of the reaction mixture become admixed with the discrete volumes of said first component of the reaction mixture whereby the segmented reaction flow is produced, in particular wherein the segmented reaction flow is produced in a mixing arrangement, in particular wherein the chamber of the mixing arrangement has a diameter of 9 mm to 10 mm, having preferably an internal diameter of 0.1 to 2 mm, comprised of two concentric tubes said chamber being provided at the outlet of the inner of the two tubes; and/or wherein the distance between the outlet of the innermost tube of the mixing arrangement and the inlet of the restriction is in the range 0.1 to 5 mm.
  • a fluid mixture containing the medicament is prepared in a micro-mixer before the segmentation, in particular wherein the fluid mixture is a mixture of a solution of the medicament with a suitable precipitant to create a meta-stable supersaturated fluid.
  • Another preferred embodiment is a process wherein the fluid mixture is a mixture of a solution of the medicament with a suitable detergent in order to influence particle size and shape during the subsequent crystallization process.
  • the separating fluid is
  • a hydrocarbon in the event that the organic compound is water-soluble, in particular a C 6-18 hydrocarbon; or
  • anticholinergics ipratropium bromide, oxitropium, tiotropium bromide, tiotroprium bromide-monohydrate,
  • betasympathomimetics bambuterol, biolterol, carbuterol, formoterol, clenbuterol, fenoterol, hexoprenalin, procaterol, ibuterol, pirbuterol, tulobuterol, reproterol, salbutamol, salmeterol, sulfonterol, terbutalin, orciprenalin, 1-(2-fluoro-4-hydroxy-phenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, erythro-5′-hydroxy-8′-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.-butyl-amino)ethanol, 1-(4-ethoxycarbonylamin
  • steroids flunisolide, dexamethasone-21-isonicotinate, seratrodast, mycophenolate mofetil, pranlukast, zileuton, butixocort, budesonide, deflazacort, fluticasone, proedrol, mometasin furoate, tipredan, beclometasone (or the 16,21-dipropionate), beclomethasone, Douglas, icomethasone enbutate, cyclometasone, cloprednol, fluocortin butyl, halometasone, deflazacort, alclometasone, cyclometasone, alisactide, prednicarbate, hydrocortisone-butyratepropionate, tixocortolpivalate, alclometaszone-dipropionate, lotrisone, canesten-HC, deprodone, flutica
  • adjuvants for inhalatives especially lactose, glucose, sucrose, mannitol and/or trehalose are used.
  • Active Ingredient Solvent Precipitating Agents Salt forms Water, methanol Alcohols (ethanol, propanol, iso-propanol), ketones (acetone, butanone) Free bases Alcohols (ethanol, Water, methanol propanol, iso-propanol, tert.-butanol), ketones (acetone, butanone)
  • Active Ingredient Solvent Precipitating Agents Polars Ketones (acetone, Alcohols (methanol, butanone) ethanol) Alcohols (ethanol, Water, methanol propanol, iso-propanol, tert.-butanol), ketones (acetone, butanone) Aromatics (toluene, Alcohols (ethanol, ethylbenzene) propanol, iso-propanol) Unpolar Halogen hydrocarbons Alcohols (ethanol, (dichloromethane, propanol, iso-propanol), trichloromethane) ether (dimethylether, dioxane)
  • Transport media are shown in the following tables, dependent on the active ingredients which are to be produced and the solvents which are used, wherein solvents and transport media are not miscible.
  • Active Ingredients Solvents Transport Media Polar Water, alcohols (methanol, Fluids: hydrocarbons ethanol iso-propanol, tert.- (benzene, butanol), ketones (acetone,, petrolether, cyclohexane, propanol, butanone) decaline, dodecane, benzene, toluene, xylene) Gases: air, nitrogen, carbon dioxide, helium, argon Unpolar Halogen hydrocarbons Fluids water, (dichloromethane, alcohols (methanol), trichloromethane), ether amides (formamide) (diethylether, dibutylether), Gases: air, aromatics (toluene, nitrogen, carbon ethylbenzene) dioxide, helium, argon
  • the starting material must be a solution with a high concentration of fenoterol in water (695 mg/ml, prepared at 90° C.), which in fact represents a liquid two phase mixture
  • the suspension formed is stabilized by addition of water containing a detergent (0.1 w.-% TWEEN surface active agent.
  • TWEEN is a trademark of ICI Americas Inc. for surface active agents, and emulsifying, dispersing, solubilizing and melting agents).
  • the solution is pumped through the reactor and enters the segmenter were small droplets are formed by segmentation with a transport fluid, dodecane at 18° C.
  • the droplets travel for 22 minutes through the tube before being treated for to 14 minutes with ultrasound.
  • ultrasound treatment Upon ultrasound treatment a highly concentrated suspension is formed inside the water phase which leaves the reactor together with the transport medium.
  • the separation between the slurry and the transport medium was made in an open beaker to which pure water or an aqueous solution of 0.1 w.-% of TWEEN 80 surface active agent was added (with a (dodecane+slurry)/water ratio of about one) (see FIG. 1).
  • Table 1 presents the particle size distribution measured in aqueous suspension.
  • TABLE 1 Particle size distribution data determined in suspension measured with the Malvern Mastersizer Sample d v10 ( ⁇ m) d v50 ( ⁇ m) d v90 ( ⁇ m) Span Medium SFTR- 1.21 2.51 5.20 1.59 aqueous 14.05.02 suspension SFTR- 0.77 1.70 5.92 3.03 (using TWEEN 13.06.02 surface active agent) stabilized aqueous suspension
  • the sample was also characterized by X-ray diffraction and thermoanalysis.
  • the powder produced by filtration and drying of the suspension was fully crystalline and conform to the starting material (FIG. 2).
  • FIG. 3 shows a SEM image of the powder.
  • Budesonide was crystallized from ethanol by a combined antisolvent and cooling crystallization using the segmented flow tubular reactor.
  • the starting material must be a solution with a high concentration of budesonide in ethanol (60 mg/ml, prepared at 60° C.)
  • the dodecane was saturated with ethanol prior to the experiment to avoid a diffusion of the ethanol into the dodecane phase.
  • the dodecane was injected at the temperature of 11° C. and the thermostatic bath around the tubular section of the segmented flow tubular reactor was also maintained at 11° C.
  • the warm ethanolic solution of budesonide was mixed with cold antisolvent using a 2-jet mixer at a volume ratio ethanol/water of 1:1.
  • the droplets were allowed to travel through the tube for 30 seconds before they undergo an ultrasonic treatment of 12 minutes where the tube is placed in an ultrasonic bath (FIG. 4).
  • the budesonide suspension together with the transport medium were collected in a beaker maintained at 10° C. This suspension was filtered and dried over silica gel at room temperature.
  • the powder yield is 60%.
  • the sample was also characterized by X-ray diffraction.
  • the powder produced by filtration and drying of the suspension was fully crystalline and conform to the starting material (FIG. 5).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Thermal Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Pulmonology (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to an improved process for the production of powders of an inhalable medicament by crystallization from a supersaturated fluid containing said medicament, the method comprising passing along a tubular reactor
(a) a segmented flow of that fluid comprised of discrete volumes; or
(b) a fluid mixture being separated by discrete volumes of a separating fluid which is substantially immiscible with said fluid,
characterized in that the crystallization is initiated by application of ultrasound

Description

    BACKGROUND OF THE INVENTION
  • 1. Technical Field [0001]
  • The invention relates to an improved process for the production of powders of organic compounds by precipitation from liquid mixtures. [0002]
  • 2. Background Information [0003]
  • The international patent application WO 98/2237 discloses a process for the production of inorganic powders by precipitation from a liquid reaction mixture, the method comprising passing along a tubular reactor a segmented reaction flow comprised of discrete volumes of the reaction mixture separated by discrete volumes of a separating fluid which is substantially immiscible with said reaction mixture, the residence time of said discrete volumes of reaction mixture in the reactor being sufficient for the precipitation reaction to be effected. [0004]
  • Unfortunately, this process is not applicable for inhalable medicaments. [0005]
  • For inhalable medicaments, a well-defined size and shape of the crystals is a pre-requisite. In order for a powdered compound or composition to be used in an inhaled medicament, the powder must have certain characteristics. For example, micronised medicaments or active ingredients generally come in solid form. In order to guarantee the inhalability of a powdered medicament, high requirements are placed on the particle size, the particle size distribution, the morphology, the stability and the flow performance of the powder holding the medicament. [0006]
  • In general, the entire administered dose of the medicament does not reach the lungs. Rather, only a part of the dose does. The particle size has a substantial influence on the proportion of the medicament which actually reaches the lungs. For this reason, particles are preferred which have a diameter of less than 20 μm, preferably less than 5 μm and greater than 0.3 μm. The diameter of the particle should be within the given window and furthermore should have the narrowest possible size distribution. Larger particles are separated off during respiration in the upper airways whilst smaller particles are not deposited in the lungs and these leave again when exhaling. [0007]
  • Therefore, there is a great requirement for processes which achieve powders of inhalable medicaments with uniform shape, small size and narrow size distribution. [0008]
  • It is known that crystallization of drug actives can be ultrasonically promoted, e.g. Causland and Cains in Drug Delivery Systems & Sciences, [0009] Volume 2 No. 2, June/July 2002, pp. 47-51.
  • However, there is no hint that the application of ultrasound to a tubular reactor with a segmented reaction flow would yield such a desired crystal formation. [0010]
    • BRIEF SUMMARY OF THE INVENTION
  • It has now been found surprisingly, that the application of ultrasound to a tubular reactor with a segmented reaction flow achieves crystals of inhalable medicaments with the desired shape and size. [0011]
  • Therefore, the invention relates to an improved process for the production of powders of inhalable medicaments by crystallization from a supersaturated fluid containing said medicament, the method comprising passing along a tubular reactor [0012]
  • (a) a segmented flow of that fluid comprised of discrete volumes; or [0013]
  • (b) a fluid mixture being separated by discrete volumes of a separating fluid which is substantially immiscible with said fluid, [0014]
  • characterized in that the crystallization is initiated by application of ultrasound. [0015]
  • A second embodiment of the present invention is a micro-reactor for implementing the process according to this invention comprising a micro-mixer, a segmenter and a tubular reactor, wherein [0016]
  • the dimensions of the micro-mixer for dividing the added fluids which are to be mixed is in the range of 10 μm to 1 mm, preferably between 25 μm to 200 μm, [0017]
  • the dimensions of the channels of the segmenter lie in the range of 0.1 to 5 mm, preferably in the range of between 0.2 mm and 5 mm, and [0018]
  • the tubular reactor is configured to be tube-, pipe- or channel-shaped with diameters of the channels in the range of 0.5 to 10 mm, preferably 1 mm to 2 mm, and with a length of between 10 cm and 200 m, preferably between 1 m and 25 m and is equipped with an external ultrasound source. [0019]
  • Furthermore the invention relates to an inhalable medicament with an aerodynamic diameter of less than 20 μm, preferably less than 5 μm and greater than 0.3 μm, characterized in that it is produced by means of the inventive process.[0020]
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 shows a schematic flow chart of fenoterol crystallization. [0021]
  • FIG. 2 shows the X-Ray diffractogram of dried sample of fenoterol (SFTR-13.06.02) TWEEN™ surface active agent and the reference powder. [0022]
  • FIG. 3 shows the SEM image of dried material of fenoterol (SFTR-13.06.02) and TWEEN™ surface active agent. [0023]
  • FIG. 4 shows a schematic flow chart of Budesonide (11.07.02-SFTR) crystallization [0024]
  • FIG. 5 shows the X-rays diffractogram of budesonide powder crystallised and reference material.[0025]
    • DETAILED DESCRIPTION OF THE INVENTION
  • The invention preferably relates to a process wherein the segmented flow passes along the tubular reactor as a plug flow. [0026]
  • Furthermore preferred is a process wherein the tubular reactor consists of the following segments: [0027]
  • (i) a residence time (t[0028] R) segment;
  • (ii) an ultrasound time (t[0029] US) segment, in particular wherein tUS is 1 to 30 s or wherein tUS is 0.5 to 15 min and tA is 0 to 30 s; and
  • (iii) optionally an aging time (t[0030] A) segment.
  • The particle size distribution of the organic compounds can be fine-tuned depending on the ratio of t[0031] R, tUS and tA. Smaller particle size distributions can be obtained if longer tUS are applied.
  • Preferably an ultrasound with a frequency of 20 to 60 kHz and/or an energy density from 10 to 80 WL[0032] −1 is applied.
  • Another preferred embodiment is a process wherein the segmented flow or a precursor segmented flow from which the segmented flow is subsequently generated is produced by passing the fluid containing the organic compound or a component thereof and the separating fluid to a chamber having a restricted outlet from which the segmented flow issues, in particular wherein the segmented flow is produced in a segmentation arrangement comprised of two concentric tubes, said chamber being provided at the outlet of the inner of the tubes and said chamber has an internal diameter of 2 mm to 10 mm. [0033]
  • Preferably, the innermost tube has an internal diameter of 0.1 to 2 mm and/or the distance between the outlet of the innermost tube and the inlet of the restriction is in the range 0.1 to 5 mm. [0034]
  • Preferably the separating fluid is passed to said chamber along the innermost tube. [0035]
  • Furthermore preferred is a process wherein the segmented flow is prepared by passing the fluid containing the organic compound and the separating fluid to said chamber thereby producing the segmented reaction flow, in particular wherein discrete volumes of said component of the fluid comprising the organic compound are separated by discrete volumes of the separating fluid and the segmented reaction flow is produced by admixing said discrete volumes of the fluid containing said organic compound with the remaining component(s) of the mixture. [0036]
  • Another preferred embodiment is a process wherein the segmented reaction flow is prepared from said precursor flow by injecting said latter flow and the further component(s) of the fluid containing the medicament to a chamber having a restricted outlet under conditions such that said further component(s) of the reaction mixture become admixed with the discrete volumes of said first component of the reaction mixture whereby the segmented reaction flow is produced, in particular wherein the segmented reaction flow is produced in a mixing arrangement, in particular wherein the chamber of the mixing arrangement has a diameter of 9 mm to 10 mm, having preferably an internal diameter of 0.1 to 2 mm, comprised of two concentric tubes said chamber being provided at the outlet of the inner of the two tubes; and/or wherein the distance between the outlet of the innermost tube of the mixing arrangement and the inlet of the restriction is in the range 0.1 to 5 mm. [0037]
  • Furthermore preferred is a process wherein a fluid mixture containing the medicament is prepared in a micro-mixer before the segmentation, in particular wherein the fluid mixture is a mixture of a solution of the medicament with a suitable precipitant to create a meta-stable supersaturated fluid. [0038]
  • Another preferred embodiment is a process wherein the fluid mixture is a mixture of a solution of the medicament with a suitable detergent in order to influence particle size and shape during the subsequent crystallization process. [0039]
  • Preferably the separating fluid is [0040]
  • a hydrocarbon, in the event that the organic compound is water-soluble, in particular a C[0041] 6-18 hydrocarbon; or
  • a lower alcohol or water, in the event that the organic compound is insoluble in water. [0042]
  • In the following text, examples are listed for the active ingredients, the adjuvants, the solvent and the precipitation agent. [0043]
  • The following are used as medicaments or active ingredients: [0044]
  • as anticholinergics; ipratropium bromide, oxitropium, tiotropium bromide, tiotroprium bromide-monohydrate, [0045]
  • as betasympathomimetics: bambuterol, biolterol, carbuterol, formoterol, clenbuterol, fenoterol, hexoprenalin, procaterol, ibuterol, pirbuterol, tulobuterol, reproterol, salbutamol, salmeterol, sulfonterol, terbutalin, orciprenalin, 1-(2-fluoro-4-hydroxy-phenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, erythro-5′-hydroxy-8′-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.-butyl-amino)ethanol, 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, [0046]
  • as antiallergics: disodiumchromeglicate, nedocromil, epinastin, and [0047]
  • as steroids: flunisolide, dexamethasone-21-isonicotinate, seratrodast, mycophenolate mofetil, pranlukast, zileuton, butixocort, budesonide, deflazacort, fluticasone, proedrol, mometasin furoate, tipredan, beclometasone (or the 16,21-dipropionate), beclomethasone, Douglas, icomethasone enbutate, cyclometasone, cloprednol, fluocortin butyl, halometasone, deflazacort, alclometasone, cyclometasone, alisactide, prednicarbate, hydrocortisone-butyratepropionate, tixocortolpivalate, alclometaszone-dipropionate, lotrisone, canesten-HC, deprodone, fluticasone-propionate, methylprednisolone-aceponate, halopredone-acetate, mometasone, mometasone-furoate, hydrocortisone-aceponate, mometasone, ulobetasol-propionate, aminogluethimide, triamciolone, hydrocortisone, meprednisone, fluorometholone, dexamethasone, betamethasone, medrysone fluclorolone acetonide, fluocinolone acetonide, paramethasone-acetate, deprodon propionate, aristocort-diacetate, fluocinonide, mazipredone, difluprednate, betamethasone valerate, dexamethasoneisonicotinate, beclomethasone-dipropionate, fluocortoloncapronate, formocortal, triamcinolon-hexacetonide, cloprednol, formebolone, clobetasone, endrisone, flunisolide, halcinonide, fluazacort, clobetasol, hydrocortisone-17-butyrate, diflorasone, fluocortin, amcinonide, netamethasone dipropionate, cortivazole, betamethasoneadamantoate, fluodexane, trilostan, budesonide, clobetasone, demetex, trimacinolone benetonide, 9.alpha.-chloro-6.alpha.-fluoro-11.beta. 17.alpha.-dihydroxy-16.-alpha.-methyl-3-oxo-1,4-androstadiene-17.beta.-carboxy acid methylester-17-propionate, ST-126. [0048]
  • Other medicaments produced with the process according to the invention are montelukast and pramipexole. [0049]
  • As adjuvants for inhalatives, especially lactose, glucose, sucrose, mannitol and/or trehalose are used. [0050]
  • Examples of solvent and precipitation agents, depending on the medicaments which are to be produced, are shown in the following tables, wherein solvents and precipitation agents must be miscible. [0051]
  • For anticholinergics/betasympathomimetics/antiallergics: [0052]
    Active Ingredient Solvent Precipitating Agents
    Salt forms Water, methanol Alcohols (ethanol,
    propanol, iso-propanol),
    ketones (acetone,
    butanone)
    Free bases Alcohols (ethanol, Water, methanol
    propanol, iso-propanol,
    tert.-butanol), ketones
    (acetone, butanone)
  • For steroids: [0053]
    Active Ingredient Solvent Precipitating Agents
    Polars Ketones (acetone, Alcohols (methanol,
    butanone) ethanol)
    Alcohols (ethanol, Water, methanol
    propanol, iso-propanol,
    tert.-butanol), ketones
    (acetone, butanone)
    Aromatics (toluene, Alcohols (ethanol,
    ethylbenzene) propanol, iso-propanol)
    Unpolar Halogen hydrocarbons Alcohols (ethanol,
    (dichloromethane, propanol, iso-propanol),
    trichloromethane) ether (dimethylether,
    dioxane)
  • Examples of transport media are shown in the following tables, dependent on the active ingredients which are to be produced and the solvents which are used, wherein solvents and transport media are not miscible. [0054]
    Active
    Ingredients Solvents Transport Media
    Polar Water, alcohols (methanol, Fluids: hydrocarbons
    ethanol iso-propanol, tert.- (benzene,
    butanol), ketones (acetone,, petrolether, cyclohexane,
    propanol, butanone) decaline, dodecane,
    benzene, toluene, xylene)
    Gases: air, nitrogen, carbon
    dioxide, helium, argon
    Unpolar Halogen hydrocarbons Fluids water,
    (dichloromethane, alcohols (methanol),
    trichloromethane), ether amides (formamide)
    (diethylether, dibutylether), Gases: air,
    aromatics (toluene, nitrogen, carbon
    ethylbenzene) dioxide, helium, argon
  • Procedures by way of examples and drawings carrying out the process according to the invention will be described in more detail hereinafter. The Examples which follow serve solely as a detailed illustration without restricting the subject matter of the invention. [0055]
    • EXAMPLE 1
  • Continuous Crystallization of Inhalable Fenoterol HBr Using a Microreactor [0056]
  • In order to crystallize fenoterol HBr with a particle size suitable for inhalation (90% of all crystals are smaller than 5.8 μm) a segmented flow tubular reactor was used. Fenoterol was crystallized from water by cooling, dodecane has been used as transport medium for segmentation and formation of small water bubbles. [0057]
  • The following parameters must be employed in order to achieve a crystal size small enough to be suitable for inhalation: [0058]
  • the starting material must be a solution with a high concentration of fenoterol in water (695 mg/ml, prepared at 90° C.), which in fact represents a liquid two phase mixture [0059]
  • an additive (dodecane, 6% v./v.) needs to be added to the hot solution [0060]
  • from this solution a very high supersaturation is created by rapid cooling down to 18° C. [0061]
  • the cooled homogeneous supersaturated solution is then allowed to rest for 22 minutes [0062]
  • crystallization is induced inside small bubbles of solution by ultrasonication, the ultrasound is applied for 14 minutes [0063]
  • the suspension formed is stabilized by addition of water containing a detergent (0.1 w.-% TWEEN surface active agent. TWEEN is a trademark of ICI Americas Inc. for surface active agents, and emulsifying, dispersing, solubilizing and melting agents). [0064]
  • Experimental: [0065]
  • The experiments were performed by dissolving 34.5 g fenoterol HBr in 50 ml of water. The solution was heated up to 90° C. in a thermostatic bath under nitrogen gas flow to dissolve the fenoterol. 3 ml of dodecane are added to the solution before the start of the experiment. [0066]
  • The solution is pumped through the reactor and enters the segmenter were small droplets are formed by segmentation with a transport fluid, dodecane at 18° C. The droplets travel for 22 minutes through the tube before being treated for to 14 minutes with ultrasound. Upon ultrasound treatment a highly concentrated suspension is formed inside the water phase which leaves the reactor together with the transport medium. The separation between the slurry and the transport medium was made in an open beaker to which pure water or an aqueous solution of 0.1 w.-% of TWEEN 80 surface active agent was added (with a (dodecane+slurry)/water ratio of about one) (see FIG. 1). [0067]
  • Results: [0068]
  • Table 1 presents the particle size distribution measured in aqueous suspension. [0069]
    TABLE 1
    Particle size distribution data determined
    in suspension measured with the
    Malvern Mastersizer
    Sample dv10(μm) dv50(μm) dv90(μm) Span Medium
    SFTR- 1.21 2.51 5.20 1.59 aqueous
    14.05.02 suspension
    SFTR- 0.77 1.70 5.92 3.03 (using TWEEN
    13.06.02 surface active
    agent) stabilized
    aqueous
    suspension
  • The sample was also characterized by X-ray diffraction and thermoanalysis. The powder produced by filtration and drying of the suspension was fully crystalline and conform to the starting material (FIG. 2). [0070]
  • Furthermore, DSC and TGA show equivalence between starting material and crystallization product. FIG. 3 shows a SEM image of the powder. [0071]
    • EXAMPLE 2
  • Continuous Crystallization of Inhalable Budesonide Using a Microreactor [0072]
  • Budesonide was crystallized from ethanol by a combined antisolvent and cooling crystallization using the segmented flow tubular reactor. [0073]
  • The following parameters must be employed in order to achieve a small crystal size: [0074]
  • the starting material must be a solution with a high concentration of budesonide in ethanol (60 mg/ml, prepared at 60° C.) [0075]
  • an additive (hydroxy-propyl cellulose, 1 w.-%) needs to be added to the hot solution [0076]
  • from this solution a very high supersaturation is created by mixing with water (1:1) as antisolvent and simultaneous cooling down to 11° C. [0077]
  • the cooled homogeneous supersaturated solution is then allowed to rest only for 30 seconds [0078]
  • crystallization is induced inside small bubbles of solution by ultrasonication, the ultrasound is applied for 12 minutes [0079]
  • Experimental: [0080]
  • 3 g budesonide were dissolved in 50 ml of ethanol at 60° C. and allowed to cool to 40° C. 50 ml water containing 1 w.-% of hydroxy-propyl cellulose were used as antisolvent and cooled down to 10° C. [0081]
  • The dodecane was saturated with ethanol prior to the experiment to avoid a diffusion of the ethanol into the dodecane phase. The dodecane was injected at the temperature of 11° C. and the thermostatic bath around the tubular section of the segmented flow tubular reactor was also maintained at 11° C. The warm ethanolic solution of budesonide was mixed with cold antisolvent using a 2-jet mixer at a volume ratio ethanol/water of 1:1. The droplets were allowed to travel through the tube for 30 seconds before they undergo an ultrasonic treatment of 12 minutes where the tube is placed in an ultrasonic bath (FIG. 4). The budesonide suspension together with the transport medium were collected in a beaker maintained at 10° C. This suspension was filtered and dried over silica gel at room temperature. The powder yield is 60%. [0082]
  • Results: [0083]
  • The particle size distribution in the suspension produced has not been measured. Table 2 shows the particle size distribution of the dry powder re-dispersed in water containing 0.1 w.-% TWEEN surface active agent. The size distribution may be different compared to the crystals in suspension due to agglomeration during drying. [0084]
    TABLE 2
    Particles size distribution data of budesonide powder.
    Sample dv10 (μm) dv50 (μm) dv90 (μm) Span
    Budesonide 1.32 7.59 12.86 1.52
  • The sample was also characterized by X-ray diffraction. The powder produced by filtration and drying of the suspension was fully crystalline and conform to the starting material (FIG. 5). [0085]

Claims (11)

What is claimed is:
1. An improved process for the production of powders of inhalable medicaments by crystallization from a supersaturated fluid containing said medicament, the improved process comprising passing along a tubular reactor
(a) a segmented flow of a supersaturated fluid containing medicament comprised of discrete volumes; or
(b) a fluid mixture being separated by discrete volumes of a separating fluid which is substantially immiscible with the supersaturated fluid containing medicament,
and initiating crystallization by application of ultrasound.
2. The process as claimed in claim 1 wherein the segmented flow passes along the tubular reactor as a plug flow.
3. The process as claimed in claim 1 wherein the tubular reactor consists of the following segments:
(i) a residence time (tR) segment;
(ii) an ultrasound time (tUS) segment; and
(iii) optionally an aging time (tA) segment.
4. The process as claimed in claim 3 wherein tUS is 1 to 30 s and tA is 0.5 to 15 min.
5. The process as claimed in claim 3 wherein tUS is 0.5 to 15 min and tA is 0 to 30 s.
6. The process as claimed in claim 1 wherein ultrasound with a frequency of 20 to 60 kHz is applied.
7. The process as claimed in claim 6 wherein the energy density of the ultrasound applied is from 10 to 80 WL−1.
8. A micro-reactor for implementing the process according to claim 1 comprising a micro-mixer, a segmenter and a tubular reactor, wherein
the dimensions of the micro-mixer for dividing the added fluids which are to be mixed is in the range of 10 μm to 1 mm, preferably between 25 μm to 200 μm,
the dimensions of the channels of the segmenter lie in the range of 0.1 to 5 mm, preferably in the range of between 0.2 mm and 5 mm, and
the tubular reactor is configured to be tube-, pipe- or channel-shaped with diameters of the channels in the range of 0.5 to 10 mm, preferably 1 mm to 2 mm, and with a length of between 10 cm and 200 m, preferably between 1 m and 25 m and is equipped with an external ultrasound source.
9. The micro-reactor according to claim 8, wherein the tubular reactor consists of the following segments:
(i) a residence time (tR) segment;
(ii) an ultrasound time (tUS) segment; and
(iii) optionally an aging time (tA) segment.
10. The micro-reactor according to claim 9, wherein the ultrasound time (tUS) segment is inserted into an ultrasound bath.
11. An inhalable medicament with an aerodynamic diameter of less than 20 μm, preferably less than 5 μm and greater than 0.3 μm, characterized in that it is produced by means of a process according to claim 1.
US10/685,254 2002-10-17 2003-10-14 Process for the manufacture of powders of inhalable medicaments Abandoned US20040197275A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/685,254 US20040197275A1 (en) 2002-10-17 2003-10-14 Process for the manufacture of powders of inhalable medicaments
US12/263,818 US8496944B2 (en) 2002-10-17 2008-11-03 Process for the manufacture of powders of inhalable medicaments

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP02/023273 2002-10-17
EP02023273 2002-10-17
US42541502P 2002-11-12 2002-11-12
US10/685,254 US20040197275A1 (en) 2002-10-17 2003-10-14 Process for the manufacture of powders of inhalable medicaments

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/263,818 Division US8496944B2 (en) 2002-10-17 2008-11-03 Process for the manufacture of powders of inhalable medicaments

Publications (1)

Publication Number Publication Date
US20040197275A1 true US20040197275A1 (en) 2004-10-07

Family

ID=33101761

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/685,254 Abandoned US20040197275A1 (en) 2002-10-17 2003-10-14 Process for the manufacture of powders of inhalable medicaments
US12/263,818 Expired - Fee Related US8496944B2 (en) 2002-10-17 2008-11-03 Process for the manufacture of powders of inhalable medicaments

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/263,818 Expired - Fee Related US8496944B2 (en) 2002-10-17 2008-11-03 Process for the manufacture of powders of inhalable medicaments

Country Status (1)

Country Link
US (2) US20040197275A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007135409A1 (en) * 2006-05-20 2007-11-29 Robert Price Particulate drug and drug compositions and their uses
US20100018853A1 (en) * 2007-03-19 2010-01-28 Prosonix Limited Process for Making Crystals
US20100190760A1 (en) * 2007-06-18 2010-07-29 Prosonix Limited Process for Making Crystals
WO2010112222A1 (en) * 2009-03-31 2010-10-07 Krka, D.D., Novo Mesto Progressive emulsion crystallization
WO2012040229A1 (en) * 2010-09-22 2012-03-29 Map Pharmaceuticals, Inc. Corticosteroid particles and method of production
US20140133262A1 (en) * 2011-06-22 2014-05-15 Kabushiki Kaisha Kobe Seiko Sho (Kobe Steel, Ltd.) Liquid mixing method and device

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2587412C (en) * 2004-11-17 2013-03-26 Velocys Inc. Emulsion process using microchannel process technology

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458335B1 (en) * 1996-07-15 2002-10-01 Calcitech Ltd. Production of powders
US20030180283A1 (en) * 2002-03-20 2003-09-25 Batycky Richard P. Method and apparatus for producing dry particles

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1262240B (en) 1964-11-14 1968-03-07 Helmut Pelzer Dipl Chem Dr Process for the production of very fine particles of crystallizable compounds
GB9828721D0 (en) 1998-12-24 1999-02-17 Glaxo Group Ltd Novel apparatus and process
GB0016002D0 (en) 2000-06-29 2000-08-23 Glaxo Group Ltd Novel process for preparing crystalline particles
WO2002089942A1 (en) 2001-05-05 2002-11-14 Accentus Plc Formation of small crystals

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6458335B1 (en) * 1996-07-15 2002-10-01 Calcitech Ltd. Production of powders
US20030180283A1 (en) * 2002-03-20 2003-09-25 Batycky Richard P. Method and apparatus for producing dry particles

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007135409A1 (en) * 2006-05-20 2007-11-29 Robert Price Particulate drug and drug compositions and their uses
US20100018853A1 (en) * 2007-03-19 2010-01-28 Prosonix Limited Process for Making Crystals
US9162160B2 (en) * 2007-03-19 2015-10-20 Prosonix Limited Process for making crystals
US10143991B2 (en) 2007-03-19 2018-12-04 Circassia Limited Process for making crystals
US20100190760A1 (en) * 2007-06-18 2010-07-29 Prosonix Limited Process for Making Crystals
US9278323B2 (en) * 2007-06-18 2016-03-08 Prosonix Limited Process for making crystals
WO2010112222A1 (en) * 2009-03-31 2010-10-07 Krka, D.D., Novo Mesto Progressive emulsion crystallization
WO2012040229A1 (en) * 2010-09-22 2012-03-29 Map Pharmaceuticals, Inc. Corticosteroid particles and method of production
US8574630B2 (en) 2010-09-22 2013-11-05 Map Pharmaceuticals, Inc. Corticosteroid particles and method of production
US20140133262A1 (en) * 2011-06-22 2014-05-15 Kabushiki Kaisha Kobe Seiko Sho (Kobe Steel, Ltd.) Liquid mixing method and device
US9776145B2 (en) * 2011-06-22 2017-10-03 Kobe Steel, Ltd. Liquid mixing method and device

Also Published As

Publication number Publication date
US8496944B2 (en) 2013-07-30
US20090068275A1 (en) 2009-03-12

Similar Documents

Publication Publication Date Title
US8496944B2 (en) Process for the manufacture of powders of inhalable medicaments
JP2004528899A (en) Continuous production of inhalable drugs
US6221398B1 (en) Process for the preparation of respirable particles
ES2260236T3 (en) PROCEDURE FOR PREPARATION AND COLLECTION OF CRYSTAL PARTICLES.
ES2702643T3 (en) Assisted procedure of particle size reduction
EP1357901B1 (en) Process for preparing particles
JP2004510731A (en) Inhalable particles incorporating a combination of two or more active ingredients
CZ20012331A3 (en) Process for preparing crystalline particles and apparatus for making the same
WO2000030614A1 (en) A process for producing particles with a converted amorphous and/or meta-stable crystalline region into crystalline state
PT2490779E (en) Process for improving crystallinity
PL199420B1 (en) Medicinal aerosol formulations
JP4768212B2 (en) Combined particles for asthma treatment
EP1585585B1 (en) Process and reactor for the manufacture of powders of inhalable medicaments
Saboti et al. Novel budesonide particles for dry powder inhalation prepared using a microfluidic reactor coupled with ultrasonic spray freeze drying
US20060188579A1 (en) Novel process
AU2018283777B2 (en) Amorphous nanostructured pharmaceutical materials
CN101312713A (en) Inhalable drug
WO2024121032A1 (en) Process for producing lactose crystals, inhalable formulation
WO2017053409A1 (en) Pulmonary delivery of progestogen
US20160045396A1 (en) Pulmonary Delivery of Progestogen

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SCHWIEWE, JOERGE;ZIERENBERG, BERND;JONGEN, NATHALIE;AND OTHERS;SIGNING DATES FROM 20040109 TO 20040526;REEL/FRAME:025943/0753

Owner name: ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE, SWITZERL

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SCHWIEWE, JOERGE;ZIERENBERG, BERND;JONGEN, NATHALIE;AND OTHERS;SIGNING DATES FROM 20040109 TO 20040526;REEL/FRAME:025943/0753