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WO2010025988A1 - Method and apparatus for producing microparticles - Google Patents

Method and apparatus for producing microparticles 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
Authority
WO
WIPO (PCT)
Prior art keywords
liquid composition
junction
microfluidic conduit
liquid
downstream
Prior art date
Application number
PCT/EP2009/059232
Other languages
French (fr)
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/en

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Classifications

    • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Manufacturing Of Micro-Capsules (AREA)

Abstract

A method and apparatus for producing microparticles by micro-encapsulation is disclosed. A feature of particular note is the use of microfluidics in the method and apparatus of the invention. 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. Thus a method is provided of producing microparticles comprising the following steps in the given order of : (a) Introducing a first liquid composition into a microfluidic conduit; (b) Introducing a second liquid composition into the microfluidic conduit at a first junction thereby to produce droplets of the first liquid composition in the second liquid composition, the second liquid composition comprising a polymerisable or gelable species; (c) Introducing a third liquid composition into the microfluidic conduit at a second junction downstream from the first junction thereby to produce droplets of the first liquid composition with a coating of second liquid composition dispersed in the third liquid composition; (d) Introducing further third liquid composition into the microfluidic conduit at a third junction downstream from the second junction thereby to produce more stable droplets of the first liquid with a coating of second liquid dispersed in the third liquid composition; (e) Polymerising or gelling the polymerisable or gelable species downstream of the third junction; and wherein the ratio of the flow velocites of the liquid compositions within the microfluidic conduit upstream and downstream of the third junction is at least 1.0:0.9, preferably at least 1.0:0.8, most preferably at least 1.0:0.7.

Description

METHOD AND APPARATUS FOR PRODUCING MICROPARTICLES
A method and apparatus for producing microparticles by microencapsulation is disclosed. A feature of particular note is the use of microf luidics 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.
Summary of the Invention
In a first aspect of the invention, a method is provided of producing microparticles comprising the following steps of:
(a) Introducing a first liquid composition into a microfluidic conduit;
(b) Introducing a second liquid composition into the microfluidic conduit at a first junction thereby to produce droplets of the first liquid composition in the second liquid composition, the second liquid composition comprising a polymerisable or gellable species;
(c) Introducing a third liquid composition into the microfluidic conduit at a second junction downstream from the first junction thereby to produce droplets of the first liquid composition with a coating of second liquid composition dispersed in the third liquid composition;
(d) Introducing further third liquid composition into the microfluidic conduit at a third junction downstream from the second junction thereby to produce more stable droplets of the first liquid with a coating of second liquid dispersed in the third liquid composition;
(e) Polymerising or gelling the polymerisable or gelable species downstream of the third junction wherein the ratio of the flow velocites of the liquid compositions within the microfluidic conduit upstream and downstream of the third junction is at least 1.0:0.9, preferably at least 1.0:0.8, most preferably at least 1.0:0.7.
By the term "microfluidic conduit" is meant a conduit wherein at least one dimension is in the range 1-1000 microns.
By "polymerisable or gelable species" is meant 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.
It has been further observed that 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 (μ2Q2) / (Y12A) where μ2 is the viscosity of the second liquid composition, Q2 the flow rate of the second liquid composition, y12 the interfacial tension of the second liquid composition with the first liquid composition and A the cross- sectional area of the microfluidic conduit.
It has been observed that 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.
It has been noted that 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 (S2) is given by 713 - (γi2 + γ23) , where 713 is the interfacial tension of the first liquid composition with the third liquid composition and γ23 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 spreading coefficients for the two immiscible liquid drops suspended in a third immiscible liquid when brought together is described in detail in Torza, S. and Mason, S. G., J. Coll. Int. Sci., 33, 1, 67 (1970) .
By reducing the flow velocity of the liquid compositions downstream of the third junction relative to upstream of the third junction, the droplets of the first liquid composition with a coating of second liquid composition have the opportunity to - A -
find a spherical shape before the polymerisable species is polymerised.
It should be noted that 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. In this way, 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.
In a second aspect of the invention an element is provided for producing microparticles according to the inventive method, the element comprising: (a) A microfluidic conduit for carrying the liquid compositions;
(b) A first junction on the microfluidic conduit for introducing the second liquid composition;
(c) A second junction on the microfluidic conduit for introducing the third liquid composition;
(d) A third junction on the microfluidic conduit for introducing further third liquid composition;
(e) Optionally an energy source for polymerising the polymerisable species; wherein the diameter of the microfluidic conduit downstream of the third junction is at least twice that of the microfluidic conduit upstream of the third junction.
By doubling the diameter of the microfluidic conduit downstream of the third junction relative to upstream of the third junction, 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. Thus 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. Thus the second liquid composition may also comprise a photoinitiator .
In a third aspect of the invention, an apparatus is provided comprising at least 1000, preferably at least 10000 inventive elements . Thus manufacture of the microparticles may be up- scaled to commercial levels by simple parallelisation of the inventive elements.
Brief Description of the Drawings
The invention is now described in more detail below with reference to the drawings which show in:
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; and Figure 4 an image of droplets of 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) .
Detailed Description of the Invention
Contact Angle and Interfacial Tension
The contact angle and interfacial tension were measured using a Kruss DSAlOO tensiometer (available from Kruss) . For 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. For 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. At each step 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. To avoid evaporation 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.
Apparatus
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) . In addition 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/cm2 at 365nm.
The apparatus is fabricated according to standard soft- lithography techniques. In brief 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.
Then 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.
Method
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) .
Results
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.

Claims

Claims
1. A method of producing microparticles comprising the following steps of:
(a) Introducing a first liquid composition into a microfluidic conduit;
(b) Introducing a second liquid composition into the microfluidic conduit at a first junction thereby to produce droplets of the first liquid composition in the second liquid composition, the second liquid composition comprising a polymerisable or gelable species;
(c) Introducing a third liquid composition into the microfluidic conduit at a second junction downstream from the first junction thereby to produce droplets of the first liquid composition with a coating of second liquid composition dispersed in the third liquid composition;
(d) Introducing further third liquid composition into the microfluidic conduit at a third junction downstream from the second junction thereby to produce more stable droplets of the first liquid with a coating of second liquid dispersed in the third liquid composition;
(e) Polymerising or gelling the polymerisable or gelable species downstream of the third junction; and wherein the ratio of the flow velocites of the liquid compositions within the microfluidic conduit upstream and downstream of the third junction is at least 1.0:0.9, preferably at least 1.0:0.8, most preferably at least 1.0:0.7.
2. A method of producing microparticles according to claim 1, wherein the ratio of the viscosity of the second liquid composition to the viscosity of the first liquid composition is at least 5:1, preferably at least 10:1, most preferably at least 100:1.
3. A method of producing microparticles according to claim 1 or claim 2, wherein the ratio of introduction of the first liquid composition and introduction of the second liquid composition at the first junction is at least 1:2, preferably at least 1:1, most preferably at least 2:1.
4. A method of producing microparticles according to any one of the preceding claims, wherein the ratio of the flow velocites of the liquid compositions within the microfluidic conduit downstream and upstream of the second junction is at least 1.1:1.0, preferably 1.2:1.0, most preferably 1.3:1.0.
5. An element for producing microparticles according to the method of any one of the preceding claims, the element comprising:
(a) A microfluidic conduit for carrying the liquid compositions;
(b) A first junction on the microfluidic conduit for introducing the second liquid composition; (c) A second junction on the microfluidic conduit for introducing the third liquid composition;
(d) A third junction on the microfluidic conduit for introducing further third liquid composition;
(e) Optionally an energy source for polymerising the polymerisable species; wherein the diameter of the microfluidic conduit downstream of the third junction is at least twice that of the microfluidic conduit upstream of the third junction.
6. An element according to claim 5, wherein the third junction is in fluid communication with a vertically upper half of the microfluidic conduit downstream of the third junction.
7. An element according to claim 5 or claim 6, wherein the energy source is a source of heat or ultra-violet light, or it is an electron beam.
8. An apparatus comprising at least 1000, preferably at least 10000 elements according to any one of claims 5 to claim 7.
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