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Nano-Particle formation using Solution Enhanced Dispersion by Supercritical Fluid (SEDS)


Nano-Particle formation using Solution Enhanced Dispersion by Supercritical Fluid (SEDS) By Nitin Aggarwal ChE-702 Modules in Nano Pharmaceuticals – PowerPoint PPT presentation

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Title: Nano-Particle formation using Solution Enhanced Dispersion by Supercritical Fluid (SEDS)

Nano-Particle formation using Solution Enhanced
Dispersion by Supercritical Fluid (SEDS)
  • By
  • Nitin Aggarwal
  • ChE-702
  • Modules in Nano Pharmaceuticals
  • Dr. Rajesh Dave

Different Concepts used to Manufacture Particles
  • RESS Rapid Expansion of Supercritical Solutions.
  • GAS or SAS Gas (or Supercritical fluid)
  • - One specific implementation being
  • SEDS (Solution Enhanced Dispersion by
    Supercritical Fluids)
  • PGSS Particles from Gas-Saturated Solutions (or
  • ASES Aerosol Solvent Extraction System.
  • SEDS A specific implementation of ASES consists
    in co- pulverizing the substrate(s)
    solution and a stream of
    supercritical carbon dioxide through
    appropriate nozzles.

SEDS The specific implementation of
GAS/SAS Concept
  • The process is devised to recrystallize solid
    compounds that are not soluble in supercritical
  • The polymer is first dissolved in a liquid
    organic solvent and a gas is employed as an
    antisolvent for the polymer.
  • The gas is injected into the solution in a closed
    chamber and the particle precipitation occurs as
    the gas concentration in solution increases with

The Governing Principle GAS/SAS/SEDS (Solvent-Ind
uced phase Separation)
  • Upon introduction of the antisolvent, the
    fluidsolid and the liquidliquid phase
    boundaries are shifted to higher temperatures or
    higher pressures, respectively.
  • As a result, the system which was initially in
    the one-phase homogeneous region finds itself in
    the two-phase region upon which undergoes phase
    separation leading to particle formation.

Supercritical Antisolvent Process (SAS)
  • A supercritical fluid acts as an antisolvent for
    polymer solutions as in the GAS process, but the
    contacting mechanism is different than that
    employed in the GAS process.
  • Polymer is dissolved in a liquid solvent and the
    solution is sprayed into a chamber where a
    supercritical fluid already exists, causing rapid
    contact between the two media.
  • This generates higher supersaturation ratio of
    the solution, resulting in fast nucleation and
    growth, and consequently creates smaller

Solution Enhanced Dispersion by Supercritical
Fluids (SEDS) A modified version of the SAS
  • In this process, the liquid solution and
    supercritical fluid are sprayed together using a
    specially designed coaxial nozzle.
  • The supercritical fluid serves a multiple purpose
    in that it is used both as an anti-solvent and as
    a dispersion medium.
  • The spontaneous contact of high-speed streams of
    a liquid solution and a supercritical fluid
    generates the finely dispersed mixture and a
    prompt particle precipitation.

  • The governing principle for the systems is the
    solvent-induced phase separation, or
    compositional quench.

Solution Enhanced Dispersion by Supercritical
Fluids (SEDS) The Process
  • SEDS was developed by the Bradford University.
  • The conditions are set up so that the
    supercritical fluid can extract the solvent from
    the solution at the solution at the same time as
    it meets and disperses the solution.

Some of the Advantages of the Process (SEDS)
  • The technique is especially suitable for polymers
    because majority of polymers are not soluble in
    supercritical fluids or gases.
  • A special advantage of this technique is its
    adaptability for continuous operations, which is
    important for large-scale mass production of
  • Addition of a carrier (often a polymer) to the
    active solution can lead to the formation of
    active substance-loaded micro-/nano-spheres.

A Need for Modification for formation of some
particles SEDS
  • Preparation of particles having very low
    solubility in conventional organic solvents was
    problematic, eg. Proteins, sugars.
  • Lactose, for example, has very low solubility in
    conventional organic solvents. But it dissolves
    readily in water, which is not soluble in
    supercritical fluid.
  • Although solutions of such proteins in organic
    solvents can be prepared, it is generally
    undesirable to do so because of the risk of the
    protein unfolding and denaturing.

The Modification SEDS
  • Co-introduction of two solvents and a
    supercritical fluid through a nozzle with three
    coaxial passages into a particle formation
  • At the point where the active substance solution
    and solvent 2 are introduced, hydrogen-bonding
    and/or similar interactions are formed between
    both solvents.
  • The dispersion of the active substance solution
    (in solvent 1) and solvent 2, and the extraction
    of these two solvents occur simultaneously.

Preparation of Budesonide/?-Cyclodextrin
Complexes in Supercritical Fluids with a Novel
SEDS Method
  • Cyclodextrins (CDs) are a group of cyclic
    oligosaccharides which are widely used as
    excipients in pharmaceutical formulations.
  • Drug/CD complexes have traditionally been
    prepared in solution (evaporation, freeze drying,
    spray drying and precipitation methods), in
    suspension or in solid state.
  • The complexes usually need to be dried and/or
    micronised before further processing.
  • The produced powders may contain excess empty CD
    molecules which increases the bulk volume of the

Why SEDS for the preparation of
Budesonide/?-Cyclodextrin Complexes?
  • It has been observed that there exists a static
    equilibration of a drug and CD in supercritical
    carbon dioxide (SC-CO2) to form solid drug/CD
    complexes with high complexation efficiencies.
  • The nature of the process is such that during the
    depressurization of the system in other processes
    the particle size distribution of the final
    product cannot be controlled.
  • Therefore a process which involves a continuous
    spraying of a drug and/or excipient solution has
    to be used to control the particle size of the
    end product.

Preparation of Budesonide/?-Cyclodextrin
Complexes with SEDS
  • Liquid-state carbon dioxide (CO2) was conducted
    from the cylinder through a cooler (-10oC).
  • The flow rate of the liquid CO2 was controlled by
    a high-pressure pump.
  • CO2 was pressurised and heated to a temperature
    above its critical point to achieve supercritical

Preparation of Budesonide/?-Cyclodextrin
Complexes with SEDS
  • SC-CO2 was pumped continuously through a coaxial
    nozzle together with budesonide and CD solutions
    (dissolved in same (conventional method) or
    separate (modified method) solvents) into a
    highpressure particle formation chamber.
  • At the end of the experiment, the produced powder
    was rinsed with SC-CO2 for 10 min.
  • The yield () of the powder was calculated as the
    percentage ratio of collected powder (mg) to the
    initial amount of budesonide and CD (mg) in the
    pumped solution(s).

Conventional and Modified SEDS methods
  • Conventional Method
  • Solution 1 (3.3 mg/mL budesonide and 10
    mg/mL g-CD in 50 V/V ethanol)
  • Solution 2 (3.3 mg/mL budesonide in 50 V/V
  • During the experiment, solution 1 or solution 2
    was mixed with supercritical carbon dioxide in
    the coaxial nozzle.

Conventional and Modified SEDS methods
  • Modified Method
  • Solution 3 (3.3 mg/mL budesonide in 99.5
  • Solution 4 (10 mg/mL g-CD in 50V/V ethanol)
  • During the experiment solution 3 (through pump
    B) was mixed with SC-CO2 and then pumped together
    with solution 4 (pump A) into the coaxial nozzle.

Results and Discussion
  • The yield of the budesonide/?-CD complex powders
    varied from 28 to 81 (conventional method) and
    from 56 to 68 (modified method) according to
    the processing conditions.
  • The formation of drug/?-CD complexes typically
    resulted in a markedly higher dissolution rate of
    the drug.
  • The SEDS-processed budesonide/? -CD powders
    showed more reproducible dissolution behaviour as
    compared to unprocessed budesonide.
  • The conventional SEDS method (100150 bar ,
    4060oC) and modified SEDS method (100 bar, 80oC)
    produced budesonide/? -CD complex powders with
    drug/CD molar ratios of 0.460.05 and 0.45,

Particle Morphology of the SEDS-Processed
  • SEM images of unprocessed, micronised budesonide.
  • b) SEDS-processed budesonide/g-cyclodextrin
  • complexes conventional method 100 bar,
  • c) Modified method 100 bar, 60oC.

Effect of Processing Conditions
  • Conventional method
  • - The increase in pressure from 100 to 200
    bar (at 60oC) reduced the amount of budesonide
    from 0.14 to 0.09 mg/mg powder.
  • - The increase in temperature from 60oC to
    80oC led to precipitation of uncomplexed
    budesonide in the powder before the complexation
    took place.
  • Modified method- The decrease in temperature from
    80oC to 60oC reduced the amount of budesonide
    from 0.13 to 0.09 mg/mg powder.
  • The precipitation of uncomplexed budesonide was
    also observed when the initial budesonide/?-CD
    molar ratio in solution 1 was increased from 11
    to 21 (processing conditions of 100 bar and
    60oC, conventional method).

Effect of Processing Conditions
Effect of SEDSprocessing conditions on the
complexation efficiency between budesonide and
Influence of the Processing Method
  • Compared with the conventional method, the use of
    the modified method reduced the amount of
    budesonide from 0.14 to 0.09 mg/mg powder (100
    bar, 60oC) and from 0.22 to 0.13 mg/mg powder
    (100 bar, 80oC), respectively.
  • The reduction of budesonide content can be
    explained by-
  • - The shorter contact time between
    budesonide and ?-CD
    during the modified SEDS process, and
  • - The increased solvating power of
    SC-CO2 due to the increase in the ethanol
    concentration in SC-CO2 (from 0.2 V/V
    (conventional method) to 0.6 V/V (modified

  • SEDS is a novel, single-step method which can
    produce solid drug/CD complexes.
  • Compared to the drug/CD complexation methods
    described earlier in the literature (e.g.
    precipitation, freeze drying, spray drying etc.
    in supercritical fluids), the present SEDS method
    provides several advantages
  • The preparation of solid drug/CD complexes in a
    single-step process.
  • The achievement of high complexation efficiency
    (avoidance of excess CD in powder).
  • The possibility to minimize the contact of the
    drug with water during the process.
  • The achievement of an enhanced dissolution rate
    of the drug (which is comparable to the
    dissolution behaviour of micronised drug/CD

Formation of Salbutamol Sulphate Microparticles
using SEDS
  • Salbutamol sulphate (SS) is a well known drug in
    treatment of asthma.
  • Experimental Set-up
  • Schematic diagram of apparatus A Carbon
    dioxide cylinder, B Dryer, C Cooling device, D
    CO2 pump, E High-pressure precipitator, F
    Co-centric nozzle, G Oven, H Solution pump.

Comparison of the formation of SS from SAS and
  • SAS processed salbutamolMeOH mixtures in
    supercritical CO2 formed tightly networked

Comparison of the formation of SS from SAS and
  • Seperated particles were found when the mixture
    was treated with SEDS process.
  • Scanning electron micrographs of salbutamol
    sulphate (SS) a) unprocessed, b) processed at
    140 bar, c) processed at 180 bar.

The Reason
  • This is attributed to the co-centric nozzle in
    the system, in which the external passage serves
    to carry a flow of SC-CO2 and the internal one
    serves passage of drug solution.
  • Because of this, in the tip of nozzle, better
    dispersion of droplets are attained and mass
    transfer between solvent and SC-CO2 is possible
    and particles will be formed and dried without

  • The precipitated particles were uniformly
    distributed on the wall of the bottom of the
    precipitation vessel.
  • The occupied volume by the processed drug was
    larger than unprocessed material.
  • The processed particles presented completely
    different morphology depending on the operation
  • - The SS sample precipitated at 140 bar
    showed needle-like particles.
  • - Precipitation at 180 bar resulted in the
    production of flake- like particles.
  • For both samples there was no network between

  • Particle formation by SCF through SEDS was
    successful in precipitation of SS from methanolic
  • In future the effect of process parameters such
  • - Pressure
  • - Temperature
  • - Flow rate of drug solution
  • - Flow rate of SCF
  • - Nozzle diameter
  • should be investigated in order to obtain
    appropriate SS microparticles for pharmaceutical

Finally SEDS as a platform technology in
Particle Engineering
  • Processing of a range of products including
    organics, biologicals, polymers, carbohydrates.
  • Highly crystalline solid state.
  • Preparation of polymorphic forms of drugs.
  • Low residual solvent levels in products.
  • Composite particles such as drug polymer matrix
    may be obtained.
  • Fine particle coating, for example in modified
    drug release and taste masking.

  • Tarja T.,Velega S., Heikkila T., Matilainen L.,
    Pekka J., Carlfors J., Lehto V., Rvinen T.,
    Rvinen K. Preparation of Budesonide/g-Cyclodextri
    n Complexes in Supercritical Fluids with a Novel
    SEDS Method, Wiley Inter Science, 2006.
  • Palakodaty S, York P. 1999. Phase behavioral
    effects on particle formation processes using
    supercritical fluids. Pharm Res 16976985.
  • York P. 1999. Strategies for particle design
    using supercritical fluid technologies. Pharm Sci
    Technol Today 2430440.
  • Najafabdi A., Vatanara A., Gilani K., Tehrani M.
    Formation Salbutamol sulphate microparticles
    using Solution Enhanced Dispersion by
    supercritical carbon dioxide, DARU Volume 13, No.
    1, 2005.

  • Reverchon E, Della Porta G, Pallado P.
    Supercritical antisolvent precipitation of
    salbutamol microparticles. Powder Technol 2001
  • Jung J, Perrut M. Particle design using
    supercritical fluids Literature and patent
    survey. J Supercritical Fluids 2001 20179219.
  • B.Yu. Shekunov, M.H. Hanna and P. York, J.Crystal
    Growth 1999, 198/199, 1345.
  • Hanna MH, York P, Rudd D, Beach S. 1995. A novel
    apparatus for controlled particle formation using
    supercritical fluids. Pharm Res 12S141.

Thank You