Sonocrystallization Assisted Particle Engineeringfor Improved
Delivery of Inhalable Medicines
Graham Ruecroft *, Dipesh Parikh, David HipkissProsonix Ltd, The
Magdalen Centre, Robert Robinson Avenue, Oxford Science Park,
Oxford, OX4 4GA, UK, www.prosonix.co.uk
Power ultrasound assisted particle engineering technologies such
as Solution Atomization andCrystallization with Ultrasound (SAXTM)
and now UMAX®, along with Dispersive Crystallizationwith Ultrasound
(DISCUS® - an ultrasound assisted antisolvent method used to
promoteefficient solute / solvent diffusion into the antisolvent
and the formation of micro-crystals), canbe used for the
manufacture of optimal particles designed and formulated as
inhalable drugproducts for respiratory disorders. These particle
engineering technologies require the use ofindustrial ultrasonic
equipment operating at 20 -100 kHz. UMAX® facilitates the
manufacture ofboth spheroidal and more regular shaped particles for
Dry Powder Inhalation (DPI) orpressurized Metered Dose Inhalation
(pMDI). UMAX® microcrystalline fluticasone propionatecan be
formulated for pMDI whereby impactor performance can be matched or
improved whencompared to Flixotide® 50.
Particles for inhaled medicines can be manufactured with the
optimal performance attributes ofsize, shape, surface rugosity, low
surface free energy, crystallinity and stability. In all
casesrespiratory doses and fine particle fraction (FPF) can be
improved significantly and often byover 100 % when compared with
mechanically micronized material. Inhalable pharmaceuticalmaterials
can now be manufactured with superior clinical performance and
improved patientcompliance, regardless of the device used to
deliver the actual drug substance. UMAX® can beused to manufacture
inhaled combination particles whereby two or more
pharmaceuticalingredients can be processed into highly crystalline
particles. This is particularly beneficial whenthere is a
synergistic action between the multiple drugs, requiring them to be
delivered together.
Micronization and milling techniques can have a detrimental
effect on the material properties ofthe particles required for
inhalation. They may be highly charged and also
undergomorphological alterations, undesirable surface
transformation, and formation of amorphousstructure.
Molecule-to-particle techniques involving sonocrystallization (1,
2) offer superiorproduction methods that embrace the FDA quality by
design (QbD) initiative. The therapeuticareas of interest include
asthma and Chronic Obstructive Pulmonary Disease (COPD). Themethods
of preparation of corticosteroid particulate pharmaceutical
substances are discussed,along with rationale as to why such
particles have superior performance when subject to in vitrolung
deposition studies.
Introduction
Abstract The UMAX® ProcessUMAX® is being developed for
thepreparation of microcrystallineparticles for inhaled drug
delivery(asthma and COPD), (3, 4).
The process comprises the steps of (i)forming a solution of a
desiredsubstance in a suitable solvent, (ii)generating a fine
aerosol, (iii)collecting the concentrated droplets ina non-solvent,
and (iv) applying powerultrasound to the viscous dropletsdispersed
in the non-solvent to effectcrystallization of the substance.
The product slurry is then transferredto solid isolation,
preferably by spray-drying or supercritical carbon dioxidedrying.
Optimal performance attributesfor inhalation (5) can be
achievedalongside unprecedented morphologycontrol. Quite often the
technique willproduce spheroidal particles. Thisprocessing
technique also provides theplatform for a novel particleengineering
solution whereby a singledroplet containing the two APIs in anexact
ratio can be converted to acombination particle containing
bothmaterials as separate crystallineentities.
Sonocrystallization and Microcrystals
In combination therapies for asthma and COPD, the APIs often
have synergistic action atmolecular and cellular level and need to
be delivered in an exact ratio (11). Indeed, tripletherapy using an
anticholinergic as the third component can become possible with
thiscombination particle technology (12). Atomization based
sonocrystallization approaches helpengineer spherical particles
that have excellent dispersion characteristics. in either DPI
orpMDI, by operating careful control of the evaporation
process.
Process Parameters for DISCUS® , SAXTM / UMAX®• Solvent and
antisolvent choices• Solubility• Temperatures of solvents and
anti-
solvents• Ultrasonic power
Figure 3: UMAX® processFigure 4: SEM images and AFM contour
plots forFluticasone propionate used for asthma products
• Concentration of feed solution• Feed rates of API solution•
Atomizer and atomization (for SAX / UMAX)• Productivity
1. Ruecroft, G.; Hipkiss, D.; Tuan Ly, T.; Maxted, N.; Cains,
P.W. Org. Process Res. Dev. 2005, 9, 923.2. Ruecroft. G, chimica
oggi, Chemistry Today, 2007, 25 (3), 12.3. Price, R.; Kaerger, J.
S. World Patent WO 05/073827, 2005.4. Price, R.; Kaerger, S. J.
Pharm. Res. 2004, 21 (2), 372.5. Ruecroft, G.; Parikh, D.
Pharmaceutical Technology, Pharmaceutical Ingredients, 2008,
s28-s356. Ruecroft, G.; Robinson, J. WO 08/114052, 2008
The crystalline corticosteroid particles are designed for
formulation with appropriate excipientsinto structured inhalable
drug products using Dry Powder (DPI) and pressurized Metered
DoseInhalers (pMDI). In vitro lung deposition and stability trials
reveal that these particles haveoutstanding performance when
compared with conventionally manufactured API particles. ForDPI the
micronized drug particles are usually admixed with coarser
excipient particles ofmaterials such as lactose monohydrate,
whereas pMDI comprises of a suspension ofmicronized drug particles
in a liquefied HFA propellant.
The structured pharmaceutical products can be single or
multi-dose devices. Importantly, theprocess of aerosolization from
such devices and deposition of particles in the lung isdependent on
the particle surface interfacial properties, which will ultimately
govern theperformance and efficacy of the structured drug
product.
Inhaled Formulation
DISCUS® (6, 7) is an antisolventmethod whereby powerful
cavitationeffects promote efficient solute /solvent diffusion into
the antisolventand the formation of microcrystals.
An antisolvent stream is recirculatedrapidly through the
flow-cell whilst thesubstrate feed solution is fed slowlyinto the
flow cell. This leads to rapiddispersion and crystallization of
micronand sub-micron sized particles, oftypically regular
morphology, whichcan then be isolated by, for example,spray drying.
With DISCUS® theresulting particles are governed moreby solvent
diffusion characteristicsyielding particles of more
regularmorphology with smooth surfacetopology.
Figure 1: DISCUS® processFigure 2: SEM images and AFMcontour
plots of DISCUS® sample 4.
The DISCUS® Process
Cavitation bubbles derived from the application of power
ultrasound are micro-reactors wheresynthetic reaction and crystal
nucleation take place (1, 8). The sononucleation of
metastablesolutions in classical crystallization can lead to
improvements in crystal size distribution,morphology, impurities,
polymorph selection and solid-liquid separation.
For SAXTM, UMAX® and DISCUS® the process conditions must be
chosen to maximize crystalnucleation at the expense of growth, via
the generation of high supersaturation either in theatomized
droplets or liquid dispersion. Acoustic cavitation improves
crystallization via improvedmixing, increased molecular diffusivity
and clustering (9), and dramatic temperature / pressurechanges
(10). In the methods discussed a number of parameters influence the
particlecharacteristics and require optimization.
Both spheroidal and more regular shaped particles can now be
prepared so as to have optimumperformance attributes for DPI and
pMDI. It not only helps to generate the targeted particle sizebut
in fact one can engineer them to the requirements of their ultimate
end use (5).
Sonocrystallization and Microcrystals
7. Ruecroft, G.; Robinson, J ; Parikh, D. WO 08/155570, 20088.
Luche, L. Synthetic Organic Sonochemistry, Plenum Press, New York
1998.9. Guo, Z.; Kougoulos, E.; Jones, A. J. Cryst. Growth, 2005,
273, 555.10. Virone, C.; Kramer, H.J.M.; van Rosmalen. G,M.; Stoop,
A.H.; Bakker, T.W. J. Cryst. Growth, 2006, 294, 9.11. Hannay, M.;
Govind, N.; Ludzik, A.; Jansen, R.; Fletcher, I. Respiratory Drug
Del. 2008, 1, 319.12. Singh, D.; Brooks, J.; Hagan, G.; Cahn, A.;
O’Connor, B.J. Thorax, 2008, 63, 592.
The drug particles of the API (0.1 – 5 microns) in the blended
powder formulation or HFAsuspension must aerosolize appropriately
so that they can be transported to the lung.Spheroidal crystalline
particles with significant surface rugosity are considered best for
drypowder pulmonary drug delivery due to their small contact area
and potential large separationdistance between particles, leading
to decreased attachment forces and improved powder
re-dispersion.
Measuring performance
• Solvent and antisolvent choices• Solubility• Temperatures of
solvents and anti-
solvents• Ultrasonic power
• Concentration of feed solution• Feed rates of API solution•
Atomizer and atomization (for SAX / UMAX)• Productivity
Figure 5: CAB balance for Fluticasone propionate
Sonocrystallization Assisted Particle Engineeringfor Improved
Delivery of Inhalable Medicines
Graham Ruecroft *, Dipesh Parikh, David HipkissProsonix Ltd, The
Magdalen Centre, Robert Robinson Avenue, Oxford Science Park,
Oxford, OX4 4GA, UK, www.prosonix.co.uk
Drug Delivery to the LungDDL20Edinburgh 2009
The UMAX® ProcessA CAB value of 1 means that the adhesive and
cohesive forces are equal. However the actualforces should be
proportionate for optimal aerosolization. AFM can also be used to
measurethe surface corrugation, as defined by the height of the
peaks and troughs of the nano-surface (14).
The Next Generation Impactor (NGI), (15) is a well established
technique to measure the sizedistribution of an aerosol, the fine
particle fraction (FPF) and the mass median aerodynamicdiameter
(MMAD), (16). The FPF refers to the amount of active ingredient
collected in thelower chamber in the NGI, expressed as a percentage
of the total amount of active ingredientdelivered per actuation.
Typical DPI formulations using respiratory grade lactose
andmicronized or milled API will normally give FPF of around 10-16%
amounting to less than 1%of the formulated mass of drug and lactose
reaching the lung.
Aerosolization efficiency is dependent upon various properties
including particle size and sizedistribution, surface properties,
crystallinity, hygroscopicity, electrostatic charge, and
relativehumidity. In addition there is direct relationship between
the FPF and particle size, powdercohesion and air shear force.
Although size is an important design criterion, UMAX®
particlesgenerally have superior dispersion characteristics. This
is attributed to irregular surfacemorphology. UMAX® and DISCUS®
particles, whilst having similar size distribution profiles,have
very different surface morphology as shown in Figure 2 and 4.
The particles defined by increased surface rugosity yielded
different aerosol performance andhigher FPF. From a particle
engineering perspective, a single API can be engineered for bothDPI
and pMDI delivery platform, and, more specifically, be tuned to
achieve superiorperformance in comparison to marketed commercial
products.
Figure 7 shows in vitro deposition profiles for Fluticasone
propionate (FP) samples of UMAX®particles alongside commercially
available Flixotide® 50 containing micronized materialformulated
for pMDI. Stages 3 to 8, and more specifically 4 and 5, relate to
the Fine ParticleFraction (FPF) that would, under human respiratory
forces, be deposited in the deep lung.Flixotide® has been available
for generic substitution since 2004, yet to date no
genericequivalent exists. This is likely due to GSK’s proprietary
Flixotide® inhaler which has patentprotection through 2014.
This work clearly demonstrated that the particle characteristics
could be modified in order toreach a desired lung deposition
profile. Importantly, the use of UMAX technology thereforemay offer
a potential route to an attractive and currently well protected
market.
Discussion
The particles were assessed forperformance benefits incomparison
to UMAX® andmicronized particles. Theaerosolization efficiency
ofUMAX® particles (sample 3) wassignificantly greater than that
ofmicronized steroid. This data isshown in Figure 6. The
steroidparticles prepared by theDISCUS® approach (sample 4)produced
significantly lower %FPF than micronized steroid. Theoptimal UMAX®
particles showexcellent stability over a 3 monthperiod compared to
over 60%loss in FPF for micronizedmaterial.
In combination therapies for asthma and COPD, the APIs often
have synergistic action atmolecular and cellular level and need to
be delivered in an exact ratio (11). Indeed, tripletherapy using an
anticholinergic as the third component can become possible with
thiscombination particle technology (12). Atomization based
sonocrystallization approaches helpengineer spherical particles
that have excellent dispersion characteristics. in either DPI
orpMDI, by operating careful control of the evaporation
process.
Process Parameters for DISCUS® , SAXTM / UMAX®
Figure 3: UMAX® processFigure 4: SEM images and AFM contour
plots forFluticasone propionate used for asthma products
• Concentration of feed solution• Feed rates of API solution•
Atomizer and atomization (for SAX / UMAX)• Productivity
Figure 6: Fine Particle Fraction (FPF) data forvarious
crystalline samples formulated as DPIover a 3 month period
The crystalline corticosteroid particles are designed for
formulation with appropriate excipientsinto structured inhalable
drug products using Dry Powder (DPI) and pressurized Metered
DoseInhalers (pMDI). In vitro lung deposition and stability trials
reveal that these particles haveoutstanding performance when
compared with conventionally manufactured API particles. ForDPI the
micronized drug particles are usually admixed with coarser
excipient particles ofmaterials such as lactose monohydrate,
whereas pMDI comprises of a suspension ofmicronized drug particles
in a liquefied HFA propellant.
The structured pharmaceutical products can be single or
multi-dose devices. Importantly, theprocess of aerosolization from
such devices and deposition of particles in the lung isdependent on
the particle surface interfacial properties, which will ultimately
govern theperformance and efficacy of the structured drug
product.
Inhaled Formulation
A CAB value of 1 means that the adhesive and cohesive forces are
equal. However the actualforces should be proportionate for optimal
aerosolization. AFM can also be used to measurethe surface
corrugation, as defined by the height of the peaks and troughs of
the nano-surface (14).
The Next Generation Impactor (NGI), (15) is a well established
technique to measure the sizedistribution of an aerosol, the fine
particle fraction (FPF) and the mass median aerodynamicdiameter
(MMAD), (16). The FPF refers to the amount of active ingredient
collected in thelower chamber in the NGI, expressed as a percentage
of the total amount of active ingredientdelivered per actuation.
Typical DPI formulations using respiratory grade lactose
andmicronized or milled API will normally give FPF of around 10-16%
amounting to less than 1%of the formulated mass of drug and lactose
reaching the lung.
Aerosolization efficiency is dependent upon various properties
including particle size and sizedistribution, surface properties,
crystallinity, hygroscopicity, electrostatic charge, and
relativehumidity. In addition there is direct relationship between
the FPF and particle size, powdercohesion and air shear force.
Although size is an important design criterion, UMAX®
particlesgenerally have superior dispersion characteristics. This
is attributed to irregular surfacemorphology. UMAX® and DISCUS®
particles, whilst having similar size distribution profiles,have
very different surface morphology as shown in Figure 2 and 4.
The particles defined by increased surface rugosity yielded
different aerosol performance andhigher FPF. From a particle
engineering perspective, a single API can be engineered for bothDPI
and pMDI delivery platform, and, more specifically, be tuned to
achieve superiorperformance in comparison to marketed commercial
products.
Figure 7 shows in vitro deposition profiles for Fluticasone
propionate (FP) samples of UMAX®particles alongside commercially
available Flixotide® 50 containing micronized materialformulated
for pMDI. Stages 3 to 8, and more specifically 4 and 5, relate to
the Fine ParticleFraction (FPF) that would, under human respiratory
forces, be deposited in the deep lung.Flixotide® has been available
for generic substitution since 2004, yet to date no
genericequivalent exists. This is likely due to GSK’s proprietary
Flixotide® inhaler which has patentprotection through 2014.
This work clearly demonstrated that the particle characteristics
could be modified in order toreach a desired lung deposition
profile. Importantly, the use of UMAX technology thereforemay offer
a potential route to an attractive and currently well protected
market.
13. Price, R.; Jones, M.D.; Harris, H.; Hooton, J.C.; Shur, J.;
King, G.S.; Mathoulion, C.A.; Nichol, K.; Smith, T.L.;Dawson, M.L.;
Ferrie, A.R. Eur. J. Pharma. Biopharma. 2008, 69, 496.
14. Young, P.; Adi, S.; Adi, H.; Tang, P.; Traini, D.; Chan,
H-K. Eur. J. Pharma. Sci. 2008, 35, 12.15. Marple. V.A.; Olson,
B.A.; Santhanakrishnan, K.; Robert, D.L.; Mitchell, J.P.;
Hudson-Curtis, B.L. J. of Aerosol
Medicine 2004, 17 (4), 335.16. Chow, A.H.L.; Tong, H.H.Y.;
Chattopadhyay, P.; Shekunov, B.Y. Pharmaceutical Res. 2007, 24 (3),
411.
7. Ruecroft, G.; Robinson, J ; Parikh, D. WO 08/155570, 20088.
Luche, L. Synthetic Organic Sonochemistry, Plenum Press, New York
1998.9. Guo, Z.; Kougoulos, E.; Jones, A. J. Cryst. Growth, 2005,
273, 555.10. Virone, C.; Kramer, H.J.M.; van Rosmalen. G,M.; Stoop,
A.H.; Bakker, T.W. J. Cryst. Growth, 2006, 294, 9.11. Hannay, M.;
Govind, N.; Ludzik, A.; Jansen, R.; Fletcher, I. Respiratory Drug
Del. 2008, 1, 319.12. Singh, D.; Brooks, J.; Hagan, G.; Cahn, A.;
O’Connor, B.J. Thorax, 2008, 63, 592.
The drug particles of the API (0.1 – 5 microns) in the blended
powder formulation or HFAsuspension must aerosolize appropriately
so that they can be transported to the lung.Spheroidal crystalline
particles with significant surface rugosity are considered best for
drypowder pulmonary drug delivery due to their small contact area
and potential large separationdistance between particles, leading
to decreased attachment forces and improved powder
re-dispersion.
Measuring performance
The cohesive-adhesivebalance (CAB), as determinedby Atomic force
microscopy(AFM), has been used tounderstand the interaction ofdrug
particles with largerexcipient carrier particles(lactose) for DPI
and thepropensity for the drugparticles to be released fromthe
carrier and therebytransported to the lung byinspiratory forces
(13). Ideallya CAB value of 1 is required foroptimal fine particle
fraction(FPF).
• Concentration of feed solution• Feed rates of API solution•
Atomizer and atomization (for SAX / UMAX)• Productivity
Figure 5: CAB balance for Fluticasone propionate
Particle engineering techniques involving the use of ultrasound
can be used to engineermicrocrystalline particles for both DPI and
pMDI, in turn yielding structured drug products thatcan out-perform
quite significantly the existing commercial products. In addition
to superiorperformance, in terms of in vitro lung deposition and
FPF, the products and particles showgreater medium to long term
stability over micronized material.
Conclusions
By modifying the UMAX®conditions, FP particles could beprepared
and then formulated forpMDI. When assessed byImpactor (Anderson
Cascade)studies the distribution profilecould be matched to that
ofFlixotide® 50 (using a proprietarypMDI device).
Figure 7 illustrates theoptimization process, in whichpowders
were generated thatover-perform (UMAX® 3) andunder-perform (UMAX®
2) thestandard micronized andcommercially formulated testsample
(Flix 50 -in grey), untiloptimal conditions were found(UMAX® 1 and
4).
Figure 7: In vitro ACI deposition profiles forvarious UMAX®
samples of Fluticasonepropionate
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