[go: up one dir, main page]

WO2010060876A1 - Procédé de dispersion permettant de déterminer l'adhérence de particules - Google Patents

Procédé de dispersion permettant de déterminer l'adhérence de particules Download PDF

Info

Publication number
WO2010060876A1
WO2010060876A1 PCT/EP2009/065622 EP2009065622W WO2010060876A1 WO 2010060876 A1 WO2010060876 A1 WO 2010060876A1 EP 2009065622 W EP2009065622 W EP 2009065622W WO 2010060876 A1 WO2010060876 A1 WO 2010060876A1
Authority
WO
WIPO (PCT)
Prior art keywords
tube
flow
particle size
average particle
gas
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.)
Ceased
Application number
PCT/EP2009/065622
Other languages
German (de)
English (en)
Inventor
Claudius Weiler
Marc Egen
Peter Langguth
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.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
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 Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of WO2010060876A1 publication Critical patent/WO2010060876A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/02—Investigating particle size or size distribution
    • G01N15/0205—Investigating particle size or size distribution by optical means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N2015/0096—Investigating consistence of powders, dustability, dustiness
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/02—Investigating particle size or size distribution
    • G01N2015/0277—Average size only

Definitions

  • the present invention relates to a process for the dispersion of powders which form agglomerates due to their small particle size ( ⁇ 10 ⁇ m).
  • the method makes it possible to determine the average particle size as a function of the volumetric flow of a defined atomizing gas stream and, in addition, by means of calibration with reference particles, the determination of an average adhesion force which prevails between the individual particles.
  • Powders which consist of particles which have a geometric particle size of less than 10 ⁇ m are present in agglomerated form.
  • the adhesive forces between the particles lead to the formation of agglomerates (A. Zahradnicek, F. Löffler:
  • a dispersion which means the decomposition of the agglomerates into primary particles in the gas atmosphere by commercially available Venturi nozzles instead. Due to the pressure drop of an expanded gas flow while powder agglomerates are sucked (Venturi principle) and passed into an injector. Due to a strong acceleration, the dispersion occurs due to particle-particle collision, particle-wall collision and due to centrifugal forces. The aim of this dispersing is to ensure by a high energy input (in excess) complete decomposition of powder agglomerates, which can not be concluded by reaching the complete dispersion on the particle adhesion.
  • Atomic force microscopy AFM makes it possible to directly measure the particle adhesion between individual particles. However, this technique does not allow a direct measurement to be used to determine a mean particle strength of a particle collective.
  • Powders find many uses in technology. Especially in the field of pharmaceutical technology, powders are used in order to develop dosage forms on the basis of which it is possible to administer active substances.
  • powder inhalants for example Inhalation powder, which are filled, for example, in suitable capsules (inhalettes), applied by means of powder inhalers in the lung.
  • suitable capsules inhalettes
  • powder inhalers in the lung.
  • other systems in which the amount of powder to be applied is pre-dosed (eg blisters), as well as multi-dose powder systems are known.
  • inhalative application may also be effected by administration of suitable powdered inhalation aerosols, for example as described in U.S. Pat
  • HFA 134a, HFA227 or their mixture are suspended as propellant carried out.
  • powder inhalation the microparticles of a pure drug are transported through the airways on the lung surface, e.g. in the alveoli, by means of the inhalation process applied. These particles sediment on the surface and can be absorbed by the active and passive transport processes in the body only after the dissolution process.
  • An important aspect of powder inhalation is that only particles of a certain aerodynamic size reach the target organ lung during the inhalative application of the active ingredient.
  • the average particle size of these respirable particles (inhalable fraction) is in the range of a few micrometers, typically between 0.1 and 10 .mu.m, preferably below 6 .mu.m.
  • Such particles are usually produced by micronization (air jet milling) or by spray drying. It follows that the particles of these inhalable powders are in agglomerated form, and must be dispersed during inhalation. Such dispersion is achieved by the patient as part of the inhalation process with the aid of an inhaler. For the correct technical interpretation of the dispersing power as well as for examining the extent to which a powder formulation (inhalable powder) can be deagglomerated and thus used by the patient, it is necessary in the development of such products to know which average particle adhesion force comprises a powder.
  • the object of the invention is to provide measuring methods for the powder characterization of powders with an average particle size of less than 10 ⁇ m.
  • a further object of the invention is to provide a measuring apparatus (current tube) for the powder characterization of powders with an average particle size of less than 10 ⁇ m.
  • Another object of the invention is to provide a method for the characterization of poorly flowing powders (primary particle size in the range of 1 to 10 microns) and bulk materials, in particular for inhalation powder available.
  • Another object of the present invention is to provide an analytical measuring method for determining the average particle adhesion of pharmaceutical preparations for inhalation application.
  • the above objects can be achieved by a method of measuring the average particle size as a function of the mass flow of the atomizing gas by means of a flow tube.
  • a method of measuring the average particle size as a function of the mass flow of the atomizing gas by means of a flow tube.
  • Atomizing gas by means of a flow tube the powder is introduced via a funnel in a flow tube, through which an air stream, which acts as a Zerstäubungsgasstrom on the powder, is passed.
  • the average particle size is measured by means of a particle measuring system (eg Helos laser diffractometer, Sympatec company).
  • the average particle size of the sample is measured while maintaining various mass flows of the atomizing gas with the help of the flow tube.
  • This size is called Xso Deagg in the following.
  • the parameter of the mean particle size as a function of the deagglomeration current represents a technically important quantity for the characterization of an aerosol which is generated from a powder pulp. This characteristic value is accessible by a method using the inventive flow tube. Including further experimentally accessible parameters, an average particle adhesion force can be determined.
  • Hull and Raasch [Rumpf, H .; Raasch, J .: Deagglomeration in Currents. 1st European Symposium Mincing, Frankfurt (1962) 151-159] hereby distinguish the stress of a body due to the resistance force during acceleration and the stress due to shear stress and particle rotation in shear flows. In gas flows, the stress from particle rotation clearly predominates, so that the shear stress can be neglected in order to estimate the deagglomeration in a shear flow.
  • the resistance force acting on the body is referred to its surface and receives the so-called comparative stress ⁇ y [Niedballa, S .: Dispersion of Fine Particle Fractions in Gas Flows - Influence of
  • the inventive flow tube allows the powder to be analyzed to be subjected to a deagglomeration process that allows the measured average particle size Xso Deagg to be directly related to the applied mass flow of the atomizing gas . This means that a specific mean particle size Xso Deagg can be measured for each atomizing gas flow .
  • the determination of the average particle size Xso Deagg as a function of the applied mass flow of the atomizing gas is carried out by feeding the sample (powder) to be measured to the flow tube (the following numbering refers to the information in FIGS. 1, 2 and 3).
  • the dimensions and tolerances derivable by the figures are to be regarded as examples of particularly preferred embodiments and should not be construed as limiting the scope of protection. It shows
  • Figure 1 is a schematic drawing as a 3D model of a flow tube for determining the average particle size Xso Deagg in direct relation to the applied mass flow of the atomizing gas .
  • Figure 2 is a schematic drawing of a power tube indicating the characteristic geometric dimensions of the components.
  • the current tube represents a tube which has a total length of L E + L A. In a preferred manner, this pipe is characterized by a continuous, uniform, concentric pipe opening. Through this tube, a sputtering gas is passed through as part of the measurement for determining the average particle size Xso Deagg .
  • the amount of atomizing gas is characterized by the mass flow of the gas M g , which is expressed in kg per second.
  • the open cross section of the flow tube is given by the parameter A (flow cross section area of the flow tube in m 2 ).
  • the parameter A flow cross section area of the flow tube in m 2 .
  • L E distance measured from the supply port of the atomizing gas
  • this feed for the sample is formed as a uniform feed tube.
  • the open internal diameter for feeding the sample (powder) is characterized by Di (T) , where Di (T) represents the internal diameter of the opening of the feed tube within the flow tube at which the powder is exposed to the atomizing gas flow.
  • the feed for the sample (powder) is preferably designed such that the feed tube with the inner diameter Di (T) at least 20% and a maximum of 50% - based on the inner diameter of the flow tube Di (R) - extends into the flow tube ,
  • the wall thickness of the feed tube for the sample (powder) is characterized by a wall thickness of 0.5 mm.
  • the flow tube according to the invention for determining the average particle size Xso Deagg as a function of the applied mass flow of the atomizing gas is characterized by the information listed in Table 1 about the dimensions and the mass flows of the atomizing gas:
  • the flow tube is characterized by the dimensions listed in Table 2 and the mass flows of the atomizing gas:
  • Another object of the invention is a measuring structure for determining the average particle size X 50 Deagg as a function of the applied mass flow of the atomizing gas by the invention comprises (see sketch in Fig. 3, this structure is to be regarded as a preferred embodiment and not as limiting the scope may be interpreted).
  • a sputtering gas By means of compressed air (numeral 3 in Fig. 3), a sputtering gas is provided.
  • the flow rate can be varied over a control valve (numeral 4 in FIG. 3) in the range of 0.00054 - 0.0043 kg / s and via a mass flow flow meter (Kobold DMS-614C3FD23L) (numeral 5 in FIG. 3) with an accuracy of ⁇ 2,15- 10 "5 kg / s
  • the sample (powder) is fed via a vibrating dosing trough (Sympatec Vibri HDD200 with V-profile trough) (number 6 in Fig.
  • a particle size analysis is carried out with the aid of a particle measuring system, preferably by means of laser diffraction.
  • a particle size analysis by means of the particle measuring system "Laser Diffractometer Helos", Fa. Sympatec using the following measurement parameters has proven to be useful:
  • At least 3 samples are measured according to these criteria and the average particle size X50 is determined as a geometric mean of these measured values as a function of the respective mass flow of the atomizing gas.
  • the median value X 50 is understood to mean the particle size below which 50% of the particles (volume-related) is located.
  • Number 9 in Fig. 3 represents a suction system by means of which the analyzed aerosol can be collected and disposed of.
  • Mg Deag g (0.95) ⁇ 6n z ers täubungsgasstrom in which a powder is nearly complete, ie broken down to approximately 95% in the primary particles. This value is available through that
  • This assigned value is referred to as the deagglomeration current Mg e e a a g g 8 g [ (0 ', 95').
  • the measured value X 50 totally corresponds to the mean geometric particle size known to the person skilled in the art, which is accessible by means of laser diffraction.
  • the determination of the measured value X 50 can be determined totally according to the following method:
  • Dispersing unit Dry disperser RODOS with suction funnel, Sympatec
  • Focal length 100 mm (measuring range: 0.9 - 175 ⁇ m)
  • Measuring time / waiting time approx. 15 s (in the case of 200 mg)
  • Map sheet will crush all larger agglomerates.
  • the powder is then spread on the front half of the vibrating trough (from about 1 cm from the front edge) dispersed.
  • the frequency of the vibrating trough is varied so that the supply of the
  • the method for determining the deagglomeration current Mg Deag8 (0'95 > is characterized in that, according to equation 1, for a degree of dispersion of 0.95 the parameter X '5 ⁇ n 0 eags ' is determined, the parameter X 50 being the total geometric mean
  • the invention provides a method for determining the average particle adhesion force F H and the analytical method for determining this physical quantity.
  • average particle adhesion force F 11 is meant the adhesive force between two equal sized particles of average particle size X 50 totai of a particle collective
  • the method for determining the average particle adhesion force F n is characterized in that this physical quantity is determined using the measured value X 50 total , the mean geometric geometry known to the person skilled in the art
  • a current tube which has the dimensions according to Table 3.
  • the characteristic particle size is the median value X 50 Deagg at a deagglomerating flow Mg Deagg of 0.00054 kg / s, 0.00108 kg / s, 0.00215 kg / s, 0.00323 kg / s and 0.00431 kg / s of the sample (powder) according to Measuring structure Fig. 3 determined using a current tube according to the diagram of Fig. 2, is used.
  • the current tube is characterized by the dimensions according to Table 1, preferably according to Table 2 and more preferably according to Table 3.
  • the mean geometric particle size X50 is determined.
  • X50 is the total known to the expert average particle size, which is accessible by laser diffraction (for more details, see under “detailed description”: Laser diffraction method for determining the mean geometric particle size).
  • the value of Mg Dea88 (0 can be EAGs determined 95> by extrapolation to the mathematically determined value X 50 '".
  • the average particle adhesion force F H is accessible.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Analysing Materials By The Use Of Radiation (AREA)

Abstract

L'invention concerne un procédé de dispersion de poudres formant des agglomérats du fait de leur faible taille de particules (<10 µm). Le procédé permet de déterminer la taille moyenne des particules en fonction du débit volumétrique d'un flux de gaz de pulvérisation défini.
PCT/EP2009/065622 2008-11-28 2009-11-23 Procédé de dispersion permettant de déterminer l'adhérence de particules Ceased WO2010060876A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102008059513 2008-11-28
DE102008059513.6 2008-11-28

Publications (1)

Publication Number Publication Date
WO2010060876A1 true WO2010060876A1 (fr) 2010-06-03

Family

ID=41665290

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/065622 Ceased WO2010060876A1 (fr) 2008-11-28 2009-11-23 Procédé de dispersion permettant de déterminer l'adhérence de particules

Country Status (1)

Country Link
WO (1) WO2010060876A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103630471A (zh) * 2013-11-20 2014-03-12 江苏大学 一种柴油机排气中颗粒中值粒径的测量方法
US9786944B2 (en) 2008-06-12 2017-10-10 Massachusetts Institute Of Technology High energy density redox flow device

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1129705A1 (fr) * 2000-02-17 2001-09-05 Rijksuniversiteit te Groningen Formulation en poudre pour inhalation
US20030015195A1 (en) * 2001-06-22 2003-01-23 Haaije De Boer Anne Powder formulation disintegrating system and method for dry powder inhalers
US20030147074A1 (en) * 2001-12-19 2003-08-07 Tetsuji Yamaguchi Sample supplying device for a dry particle-size distribution measuring apparatus and method
US20070122349A1 (en) * 2001-07-27 2007-05-31 Herbert Wachtel Measuring Particle Size Distribution in Pharmaceutical Aerosols

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1129705A1 (fr) * 2000-02-17 2001-09-05 Rijksuniversiteit te Groningen Formulation en poudre pour inhalation
US20030015195A1 (en) * 2001-06-22 2003-01-23 Haaije De Boer Anne Powder formulation disintegrating system and method for dry powder inhalers
US20070122349A1 (en) * 2001-07-27 2007-05-31 Herbert Wachtel Measuring Particle Size Distribution in Pharmaceutical Aerosols
US20030147074A1 (en) * 2001-12-19 2003-08-07 Tetsuji Yamaguchi Sample supplying device for a dry particle-size distribution measuring apparatus and method

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9786944B2 (en) 2008-06-12 2017-10-10 Massachusetts Institute Of Technology High energy density redox flow device
CN103630471A (zh) * 2013-11-20 2014-03-12 江苏大学 一种柴油机排气中颗粒中值粒径的测量方法
CN103630471B (zh) * 2013-11-20 2015-10-28 江苏大学 一种柴油机排气中颗粒中值粒径的测量方法

Similar Documents

Publication Publication Date Title
DE69631119T2 (de) Pulver zur verwendung in trockenpulverinhalatoren
EP1419373B1 (fr) Dispositif de determination de la repartition granulometrique d&#39;aerosols
DE69907951T2 (de) Verbesserungen in bezug auf pulver
DE69631159T2 (de) Pulver und deren verwendung in trockenpulverinhalatoren
DE60003162T2 (de) Modifizierte trägerpartikel zur verwendung in trockenpulverinhalatoren
DE60030721T2 (de) Pulverpartikel mit glatter oberfläche zur verwendung in der inhalationstherapie
DE60131265T2 (de) Pharmazeutische formulierungen für trockenpulverinhalatoren
DE4140689B4 (de) Inhalationspulver und Verfahren zu ihrer Herstellung
Zeng et al. The influence of lactose carrier on the content homogeneity and dispersibility of beclomethasone dipropionate from dry powder aerosols
DE60120936T2 (de) Behandlung von atemerkrankungen
DE60104399T2 (de) Pulverformulierung zur inhalation
DE60128902T2 (de) Formulierungen zur verwendung in inhalationsvorrichtungen
Cordts et al. Capabilities and limitations of using powder rheology and permeability to predict dry powder inhaler performance
DE69908650T2 (de) Mahlverfahren zur herstellung feingemahlener medizinischer substanzen
DE2239091A1 (de) Pharmazeutische pulverzusammensetzung
DE1792207B2 (de) Pulverpraeparat zur inhalation
DE69906147T2 (de) Zerkleinerungsverfahren zur herstellung von feingemahlenen medizinischen substanzen
DE69817774T2 (de) Trägerstoff für trockenpulverinhalator, verfahren zu dessen herstellung und diesen enthaltende arzneimittel
EP2288898A1 (fr) Dispositif et procédé de détermination des propriétés de formulations d&#39;aéorols
WO2010060876A1 (fr) Procédé de dispersion permettant de déterminer l&#39;adhérence de particules
DE102008060614B4 (de) Verfahren zur Herstellung einer Inhalationsatmosphäre für die Allergenprovokation
CN105658334B (zh) 制备包含高剂量强度活性成分的吸入用药物制剂的方法
DE10136554A1 (de) Verfahren zur Bestimmung der Aerosol-Partikelgrößenverteilung und Vorrichtung zur Durchführung eines derartigen Verfahrens
DE102007049931A1 (de) Vorrichtung und Verfahren zur kontinuierlichen Herstellung von sphärischen Pulveragglomeraten
DE60018395T2 (de) Methacoline oder histamine formulierungen zur feststellung von asthma

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09756739

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09756739

Country of ref document: EP

Kind code of ref document: A1