WO2010025988A1 - Procédé et appareil pour la fabrication de microparticules - Google Patents

Procédé et appareil pour la fabrication de microparticules Download PDF

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Publication number
WO2010025988A1
WO2010025988A1 PCT/EP2009/059232 EP2009059232W WO2010025988A1 WO 2010025988 A1 WO2010025988 A1 WO 2010025988A1 EP 2009059232 W EP2009059232 W EP 2009059232W WO 2010025988 A1 WO2010025988 A1 WO 2010025988A1
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WO
WIPO (PCT)
Prior art keywords
liquid composition
junction
microfluidic conduit
liquid
downstream
Prior art date
Application number
PCT/EP2009/059232
Other languages
English (en)
Inventor
Yves Hennequin
Maria Concepcion Pulido De Torres
Georgios Tetradis-Mairis
Original Assignee
Unilever Plc
Unilever N.V.
Hindustan Unilever Limited
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 Unilever Plc, Unilever N.V., Hindustan Unilever Limited filed Critical Unilever Plc
Publication of WO2010025988A1 publication Critical patent/WO2010025988A1/fr

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    • 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
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
    • B01J13/046—Making microcapsules or microballoons by physical processes, e.g. drying, spraying combined with gelification or coagulation
    • 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
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/14—Polymerisation; cross-linking

Definitions

  • a method and apparatus for producing microparticles by microencapsulation is disclosed.
  • a feature of particular note is the use of microfizidics in the method and apparatus of the invention.
  • Micro-encapsulation is an important technology for a variety of industrial fields such as laundry, household care, personal care, foods, agrochemicals and pharmaceuticals. Micro-encapsulation involves the separation of a dispersed phase from a medium with a wall or barrier (termed a shell) to form microparticles. The microparticles can then operate to protect and convey an active to a desired location where it can be released by bursting or dissolving the shell.
  • One of the aims of the inventive method and apparatus is to provide a means for rapidly producing a large volume of monodisperse microparticles using the encapsulation technique with the ability to control the wall thickness of the shell.
  • An advantage of being able to control the wall thickness of the shell is that the rate of release of the active may be tailored to suit needs by, for example, adjusting the bursting strength of the wall.
  • a method is provided of producing microparticles comprising the following steps of:
  • microfluidic conduit is meant a conduit wherein at least one dimension is in the range 1-1000 microns.
  • polymerisable or gelable species any species which can form a polymer or gel whether by, for example, covalent or associative bonding.
  • examples of a polymerisable species are tripropylene glycol diacrylate (TPGDA) or pentaerythritol triacrylate (PETA) and examples of gelable species are agar, pectin and kappa carrageenan.
  • the capillary number for the combination of the first liquid composition and the second liquid composition must be less than 0.1, preferably less than 0.01, most preferably less than 0.001.
  • the capillary number (Ca) is given by ( ⁇ 2Q2) / (Y12A) where ⁇ 2 is the viscosity of the second liquid composition, Q 2 the flow rate of the second liquid composition, y 12 the interfacial tension of the second liquid composition with the first liquid composition and A the cross- sectional area of the microfluidic conduit.
  • the contact angles of the first liquid composition relative to the second liquid composition on the microfluidic conduit and that of the second liquid composition relative to the third liquid composition on the microfluidic conduit must be at least 90 degrees, preferably at least 100 degrees, most preferably at least 110 degrees.
  • the spreading coefficient of the first liquid must be less than zero, the spreading coefficient of the second liquid must be less than zero and the spreading coefficient of the third liquid must be greater than zero.
  • the spreading coefficient of the second liquid composition (S 2 ) is given by 7 1 3 - ( ⁇ i 2 + ⁇ 2 3) , where 7 1 3 is the interfacial tension of the first liquid composition with the third liquid composition and ⁇ 2 3 is the interfacial tension of the second liquid composition with the third liquid composition.
  • the spreading coefficients of the first liquid composition (Si) and the third liquid composition (S3) are given by suitable rearrangement of the above-mentioned equation.
  • the droplets of the first liquid composition with a coating of second liquid composition have the opportunity to - A -
  • this method affords a means for producing microparticles by the encapsulation technique in the absence of surfactants. Furthermore the thickness of the coating of second liquid composition on the droplet of first liquid composition may be increased simply by increasing the proportion of the second liquid composition relative to the first liquid composition.
  • the ratio of the viscosity of the second liquid composition to the viscosity of the first liquid composition may be at least 5:1, preferably at least 10:1, most preferably at least 100:1.
  • An advantage of having a higher ratio is that the droplet of first liquid composition is found to be more centrally placed within the coating of second liquid composition. This is thought to be due to damping of the of the natural forward motion of the droplet of first liquid composition within the coating of second liquid composition resulting from recirculation flow within the second liquid composition (before the polymerisable species are polymerised) when the droplets of the first liquid composition with a coating of second liquid composition are propelled along the microfluidic conduit whilst dispersed in the third liquid composition. The droplet of first liquid composition may then be fixed in position by polymerising the polymerisable species.
  • the ratio of introduction of the first liquid composition and introduction of the second liquid composition at the first junction may be at least 1:2, preferably at least 1:1, most preferably at least 2:1.
  • the spacing between droplets of the first liquid composition in the second liquid composition is preferably at least half a droplet diameter (for a ratio of 1:2), preferably at least one droplet diameter (for a ratio of 1:1) and most preferably at least two droplet diameters (for a ratio of 2:1), thus minimising droplet coalescence.
  • the ratio of the flow velocities of the liquid compositions within the microfluidic conduit downstream and upstream of the second junction may be at least 1.1:1.0, preferably 1.2:1.0, most preferably 1.3:1.0. In this way, any satellite droplets of only second liquid composition can be accelerated into existing droplets of first liquid composition with a coating of second liquid composition.
  • an element for producing microparticles according to the inventive method, the element comprising: (a) A microfluidic conduit for carrying the liquid compositions;
  • the droplets of first liquid composition with a coating of second liquid composition have more space in which to find a spherical shape before the polymerisable species is polymerised.
  • the third junction may be in fluid communication with a vertically upper half of the microfluidic conduit downstream of the third junction.
  • the droplets of first liquid composition with a coating of second liquid composition are less likely to impinge on the bottom of the microfluidic conduit downstream of the third junction through the action of gravity and become deformed before the polymerisable species is polymerised.
  • the energy source may be a source of heat or ultra-violet light, or it is an electron beam.
  • the second liquid composition may also comprise a photoinitiator .
  • an apparatus comprising at least 1000, preferably at least 10000 inventive elements .
  • manufacture of the microparticles may be up- scaled to commercial levels by simple parallelisation of the inventive elements.
  • Figure 1 a schematic of the inventive apparatus
  • Figure 2 an image of droplets of first liquid composition (65% w/w glycerol-in-water solution) with a coating of second liquid composition (TPGDA with 4.5% w/w 1-hydroxycyclohexyl phenyl ketone) dispersed in a 20 centistokes silicone oil emerging into the chamber (108)
  • Figure 3 a graph of a normalised off-centre parameter for droplets of first liquid composition (65% w/w glycerol-in-water solution) with a coating of second liquid composition (TPGDA/PETA with 4.5% w/w 1-hydroxycyclohexyl phenyl ketone) dispersed in a 20 centistokes silicone oil emerging into the chamber (108) against the ratio of the viscosity of the second liquid composition to the viscosity of the first liquid composition
  • Figure 4 an image of droplets of first liquid composition (65% w/w glycerol-in-water solution) with a coating of second liquid composition
  • the contact angle and interfacial tension were measured using a Kruss DSAlOO tensiometer (available from Kruss) .
  • a contact angle measurement an approximately 20 microlitre droplet was placed on a substrate located on a movable table. The droplet was illuminated from one side and a camera located opposite recorded an image of the droplet. The built-in software then calculated the contact angle.
  • an interfacial tension measurement an approximately 20 microlitre droplet was held at the tip of a blunt needle connected to a syringe. The droplet was held statically in position while the measurement was carried out using the built-in software which uses a routine based on the Young-Laplace equation for a liquid meniscus.
  • the software captures an image of the droplet, extracts its profile (based on the contrast between the droplet shape and the background) and then fits the Young-Laplace equation to the data which returns the interfacial tension.
  • the droplet was formed inside a cuvette containing a portion of the sample liquid in the bottom. The cuvette was sealed around the needle such that the liquid in the bottom of the cuvette saturated the volume around the droplet thus reducing evaporation. Measurements of contact angle and interfacial tension were conducted at 20 degrees centigrade. Viscosity
  • the viscosity was measured using a Brookfield cone and plate rheometer with a 5cm diameter 1 degree angle cone at 100s "1 at 20 degrees centigrade.
  • the inventive apparatus shown in figure 1 comprises a first liquid composition inlet (101) , a first junction (105) in fluid communication with a second liquid composition inlet (102) and a microfluidic conduit of 50x100 micron cross-section in fluid communication with the first liquid composition inlet (101) and the first junction (105) .
  • the apparatus further comprises a second junction (106) in fluid communication with a first third liquid composition inlet (103) and a microfluidic conduit of 50x100 micron cross-section in fluid communication with the first junction (105) and the second junction (106) .
  • the apparatus also comprises a third junction (107) in fluid communication with a second third liquid composition inlet (104) and a microfluidic conduit of 150x100 micron cross-section in fluid communication with the second junction (106) and the third junction (107) .
  • a chamber (108) of 300x300 micron cross-section is also in fluid communication with the third junction (107) and illustrated in figure 1.
  • the chamber (108) is illuminated by a 100 Watt ultra-violet lamp with can provide about 100 milliwatts/cm 2 at 365nm.
  • the apparatus is fabricated according to standard soft- lithography techniques.
  • an approximately 75 micron layer of the photoresist SU8 is spin-coated onto a silicon wafer and cured in accordance with the topography of the inventive element.
  • a second approximately 220 micron thick layer of SU8 is then spin-coated onto the existing layer of SU8 and the region of this second coating corresponding to the chamber (108) is cured thus producing an inventive element with a microfluidic conduits of two different depths.
  • the uncured SU8 is then washed away with the appropriate developer and the resulting partially coated silicon wafer mould cleaned with isopropanol and dried.
  • a mixture of polydimethylsiloxane (PDMS) elastomer and cyuring agent (Sylgard 184 available from Dow Corning) in a proportion of 10:1 is poured over the mould, degassed under vacuum and partially cured at 70 degrees centigrade for 45 minutes in order to produce a replica.
  • Inlets and outlets are then punched with a blunt needle and the replica closed with a glass slide having a spin-coated 100 micron layer of the aforementioned PDMS partially cured at 70 degrees centigrade for 25-30 minutes, PDMS layer in contact with the replica, thereby to produce a closed replica.
  • the closed replica is then left to stand at 75 degrees centigrade for two hours in order to strengthen the bond between the replica and the PDMS layer on the glass slide.
  • the first liquid composition comprised a 65% w/w glycerol-in- water solution.
  • the second liquid composition comprised TPGDA with 4.5% w/w 1-hydroxycyclohexyl phenyl ketone as photoinitiator or mixtures of TPGDA and PETA with 4.5% w/w 1-hydroxycyclohexyl phenyl ketone.
  • the third liquid composition comprised a silicone oil with a viscosity of 20 centistokes (available from CRC Industries) .
  • the inventive apparatus was operated by pumping the first liquid composition into the apparatus at 0.0005 millilitres/minute, the second liquid composition was also pumped into the apparatus at 0.0005 millilitres/minute.
  • the third liquid composition was pumped into the apparatus at the second junction (106) at a rate of 0.003 millilitres/minute and further third liquid composition was pumped into the apparatus at the third junction at a rate of 0.01 millilitres/minute.
  • the ultra-violet lamp was then operated to rapidly polymerise the polymerisable species in the droplets of first liquid composition with a coating of second liquid compositions as they entered the chamber (108) from the third junction (107) .
  • Figure 2 shows an image of droplets of first liquid composition (65% w/w glycerol-in-water solution) with a coating of second liquid composition (TPGDA with 4.5% w/w 1-hydroxycyclohexyl phenyl ketone) dispersed in a 20 centistokes silicone oil emerging into the chamber (108) . It was observed that the droplets are not perfectly centred.
  • Figure 3 shows the results of experiments where the composition of the second liquid composition (mixtures of TPGDA and PETA with 4.5% w/w 1-hydroxycyclohexyl phenyl ketone) was varied in order to adjust the viscosity of the second liquid composition. It was observed that as the ratio of the viscosity of the second liquid composition to the viscosity of the first liquid composition increased, the droplets of first liquid composition remained more on-centre rather than off-centre.
  • the y-axis provides a measure of the degree of off-centring normalised so that the maximum degree of off-centring has the value of 1.0.
  • Figure 4 shows droplets of the first liquid composition (65% w/w glycerol-in-water solution) with a coating of second liquid composition (PETA with 4.5% w/w 1-hydroxycyclohexyl phenyl ketone) dispersed in a 20 centistokes silicone oil emerging into the chamber (108) .
  • the viscosity of the second liquid composition is such that the droplets of first liquid composition remain on-centre for long enough for the monomer to be polymerised and hence fix the droplets of first liquid composition in position.

Abstract

L'invention concerne un procédé et un appareil pour la fabrication de microparticules par micro-encapsulation. Une caractéristique particulière est l'utilisation d'un système microfluidique dans le procédé et l'appareil de l'invention. Un des objectifs du procédé et de l'appareil de l'invention est de fournir un moyen de fabrication rapide d'un grand volume de microparticules monodispersées en utilisant la technique d'encapsulation avec une capacité à contrôler l'épaisseur de paroi de l'enveloppe. Un avantage de la capacité à contrôler l'épaisseur de paroi de l'enveloppe est que le taux de libération de la substance active peut être personnalisé pour s'adapter aux besoins, par exemple, en ajustant la résistance à l'éclatement de la paroi. L'invention concerne ainsi un procédé de fabrication de microparticules qui comprend les étapes suivantes dans l'ordre donné : (a) introduction d'une première composition liquide dans une conduite microfluidique; (b) introduction d'une deuxième composition liquide dans la conduite microfluidique à une première jonction pour produire des gouttelettes de la première composition liquide dans la deuxième composition liquide, la deuxième composition liquide comprenant une espèce polymérisable ou gélifiable; (c) introduction d'une troisième composition liquide dans la conduite microfluidique à une deuxième jonction en aval de la première jonction, pour produire des gouttelettes de la première composition liquide munies d'un revêtement de la deuxième composition liquide dispersées dans la troisième composition liquide; (d) introduction d'une troisième composition liquide supplémentaire dans la conduite microfluidique à une troisième jonction en aval de la deuxième jonction pour produire des gouttelettes plus stables du premier liquide munies d'un revêtement du deuxième liquide dispersées dans la troisième composition liquide; (e) polymérisation ou gélification de l'espèce polymérisable ou gélifiable en aval de la troisième jonction. Selon l'invention, le rapport entre les vitesses d'écoulement des compositions liquides dans la conduite microfluidique en amont et en aval de la troisième jonction est d'au moins 1,0:0,9, de préférence d'au moins 1,0:0,8, de manière préférée entre toutes d'au moins 1,0:0,7.
PCT/EP2009/059232 2008-09-04 2009-07-17 Procédé et appareil pour la fabrication de microparticules WO2010025988A1 (fr)

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EP08305528 2008-09-04

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WO2015068045A2 (fr) 2013-11-11 2015-05-14 King Abdullah University Of Science And Technology Dispositif microfluidique pour la production et le traitement à haut volume d'émulsions monodispersées
US9714897B2 (en) 2015-02-09 2017-07-25 Slingshot Biosciences, Inc. Hydrogel particles with tunable optical properties and methods for using the same
US9915598B2 (en) 2012-04-06 2018-03-13 Slingshot Biosciences Hydrogel particles with tunable optical properties
US10222391B2 (en) 2011-12-07 2019-03-05 The Johns Hopkins University System and method for screening a library of samples
US11313782B2 (en) 2020-01-24 2022-04-26 Slingshot Biosciences, Inc. Compositions and methods for cell-like calibration particles
US11598768B2 (en) 2020-05-04 2023-03-07 Slingshot Biosciences, Inc. Compositions and methods for passive optical barcoding for multiplexed assays

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10222391B2 (en) 2011-12-07 2019-03-05 The Johns Hopkins University System and method for screening a library of samples
US10739366B2 (en) 2011-12-07 2020-08-11 The Johns Hopkins University System and method for screening a library of samples
US10222392B2 (en) 2011-12-07 2019-03-05 The Johns Hopkins University System and method for screening a library of samples
US10942109B2 (en) 2012-04-06 2021-03-09 Slingshot Biosciences, Inc. Hydrogel particles with tunable optical properties
US9915598B2 (en) 2012-04-06 2018-03-13 Slingshot Biosciences Hydrogel particles with tunable optical properties
US10481068B2 (en) 2012-04-06 2019-11-19 Slingshot Biosciences Hydrogel particles with tunable optical properties
WO2015068045A2 (fr) 2013-11-11 2015-05-14 King Abdullah University Of Science And Technology Dispositif microfluidique pour la production et le traitement à haut volume d'émulsions monodispersées
US9714897B2 (en) 2015-02-09 2017-07-25 Slingshot Biosciences, Inc. Hydrogel particles with tunable optical properties and methods for using the same
US10753846B2 (en) 2015-02-09 2020-08-25 Slingshot Biosciences, Inc. Hydrogel particles with tunable optical properties and methods for using the same
US11686661B2 (en) 2015-02-09 2023-06-27 Slingshot Biosciences, Inc. Cytometric device hematology reference composition
US11747261B2 (en) 2015-02-09 2023-09-05 Slingshot Biosciences, Inc. Hydrogel particles with tunable optical properties and methods for using the same
US11761877B2 (en) 2015-02-09 2023-09-19 Slingshot Biosciences, Inc. Hydrogel particles with tunable optical properties and methods for using the same
US11927519B2 (en) 2015-02-09 2024-03-12 Slingshot Biosciences, Inc. Synthetic human cell mimic hydrogel particle for cytometric or coulter device
US11313782B2 (en) 2020-01-24 2022-04-26 Slingshot Biosciences, Inc. Compositions and methods for cell-like calibration particles
US11726023B2 (en) 2020-01-24 2023-08-15 Slingshot Biosciences, Inc. Compositions and methods for cell-like calibration particles
US11598768B2 (en) 2020-05-04 2023-03-07 Slingshot Biosciences, Inc. Compositions and methods for passive optical barcoding for multiplexed assays

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