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Ingredients, Formulations & Finishing
Powder-mixing is a crucial process in the manufactureof tablets
and capsules, which make up 80 per cent ofpharmaceutical products.
The blending of powders is also crucial in the production of most
other types of pharmaceuticals including aerosols, suspensions and
topical products. However, little technologicalprogress has been
made in this important area ofpharmaceutical manufacturing.
The V-blender is the equipment most commonly usedto mix
pharmaceutical powders; this induces mixing bythe tumbling motion
of particles. Yet there is littlefundamental understanding of the
technology, and thereis no generally accepted method for altering
the different
operational parameters of themixer (see (1) for detail onscaling
of V-blenders). Due tothis poor understanding, currentmixing
technology is designedempirically. It is incapable ofmixing drugs
of differentformulations and concentrations
in bulk, leaving a reduced therapeutic dosage rangeavailable to
the physician (see (2) for detail on currentmixing technology).
A primary goal for the pharmaceutical industry is toproduce a
uniform product – and yet current mixingtechnology is capable of
enormous diversity of behaviour.Within a V-blender, entirely
unexpected and dramaticsegregation phenomena can occur under
relativelycommon processing conditions (see (2) for detail on
V-blender behaviour). The methods traditionally used tomanufacture
drugs are therefore in need of revision.
As drugs are becoming more potent and dosages arebecoming
smaller, it will become increasingly importantfor manufacturers to
be able to understand and controlblending and product properties.
In particular, they willneed to be able to mix smaller proportions
of minute
particles with otheringredients (see (2) for detailon future
pharmaceuticalmanufacturing) but availableinstruments are generally
tooover-sized to cope with thesesmall amounts of material.
A team of chemists from Imperial College London mayhave found a
solution to this problem. They havedeveloped a novel powder-mixing
device that couldpotentially provide a better-controlled system for
themixing of pharmaceutical powders in large-scaleproduction
processes.
It could offer significant benefits to the
pharmaceuticalindustry by providing opportunities for efficient,
reliableand rapid development of new products. A reduction inthe
time-to-market of products would maximiseprofitability for
companies and enable important therapiesto be made available
earlier to patients.
The innovative device is a micro-scale ‘powder-mixingchip’,
which can deliver specified amounts of powdersmore precisely and
therefore offer more accurate dosing. Itmixes powders by using
multiple streams of nitrogen gasand sonic transducers to manipulate
powder throughmicro-channels. A second-generation prototype chip
hasbeen built, and testing of the technology has been carriedout
with promising results – showing for the first time theapplication
of miniaturised powder mixing.
DESIGN OF THE ‘POWDER-MIXING CHIP’The unique design of the chip
(see Figure 1) was createdusing the microfabrication technique of
wet etching on aglass plate. The bottom plate of the chip was
etched withmicro-channels, each splitting into two channels of
asmaller width. This bifurcation was repeated eight times toproduce
eight rows of channels with an identical cross-section. In total,
256 gas channels were made leading to amain powder-moving
channel.
The etching was combined with the aligned placementof three
further glass plates that fit exactly on top of themicro-channels,
leaving the main powder-moving channelopen. Another square glass
plate the same size as the bottomone formed the top plate of the
chip. The powders to bemixed were gravity-fed into the chip via two
powder inlets,and the powder streams were conveyed through the chip
bya stream of nitrogen at approximately 1.5 bar (see Figure 2).
The gas microchannels prevent the powder fromsticking to the
walls or clogging. As the two powderstreams converge in the main
channel, mixing is caused by the pattern of opposing nitrogen
inlets, whichcreate turbulence.
A micro-scale ‘powder-mixing chip’ has been developed that could
offer potential advantages over existing mixing technologies in
terms of control of product properties and process attributes, and
acceleration of the mixing process.
74 Innovations in Pharmaceutical Technology
Powder-Mixing on a MicrochipBy Michelle Cotterill at Imperial
Innovations
Figure 1: The ‘powder-mixing chip’ design
Left: The chip designshows the gas channels(black) and the
T-shapedpowder-moving channel;the arrows illustrate theflow
direction. Right:Shown is a small part ofthe chip design, where the
different rows of gaschannels are recognisable.
Figure 2: A prototype‘powder-mixing chip’
The figure shows aprototype with two powderinlets (fitted
pipette tips)as well as three nitrogeninlets (plastic
tubesconnected to N2-bottle).
IPT 27 2008 4/12/08 11:09 Page 74
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TESTING AND DEVELOPMENTSix types of pharmaceutical powders were
successfullymoved through the first-generation chip, and the mixing
ofsamples of lactose powder was also achieved. The sampleswere dyed
orange and purple so that the degree of mixingcould be measured and
the mixed purple and orangeparticles were collected on adhesive
tape, which was placednear the outlet of the chip. The ratio of
purple to orangeparticles was evaluated in twelve different squares
of thesame dimensions and was found equal to 0.66±0.09.
The reason why a smaller number of purple particleswere counted
was due to the different particle sizedistribution of the lactose
sample that was used for thepurple colour. Taking this factor into
account, the resultsindicated that a uniform mixture was generated.
However,in order to achieve mixing ratios with a higher dilution
ofone component, a different strategy was necessary. Thiswas done
by employing a pulsed injection technique on asecond-generation
chip.
For the second device, the well-known process of‘fluidisation of
dry particles’ was used; this occurs when gasor liquid is passed up
through granular material so that thesolid particles take on a
dynamic fluid-like state.
The powder injection technique was based ongenerating and
collapsing a ‘fluidised’ bed of particles
in a cylindrical powder inlet, which was fitted with a gas inlet
and outlet to create single gas stream. Figure 3 is a picture
sequence of the injection and the process (see (3) for detail on
the ‘fluidised bedinjection’ technique).
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Figure 3: Sequence of a fluidised bed injectionof Dibasic
CalciumPhosphate particles in thesecond-generation chip
(A) Nitrogen gas fluidisesdry particles in the powderinlet. (B)
The gas pressurehas just been turned onand free-flowing
particlesare being introduced intothe main channel. (C-D) Aparticle
plug is introducedinto the channel; the gaspressure was turned on
for300ms in this experiment.(E-F) The gas flow has justbeen
re-applied and thepowder plug is transportedtowards the outlet.
Thepowder bed in the inletbecomes fluidised again for the next
injection.
A t=0ms B t=40ms C t=80ms
D t=280ms E t=320ms F t=360ms
Powder inlet
Gas inlet Outlet
1mm
IPT 27 2008 4/12/08 11:09 Page 75
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By innovatively employing several injection channels ona single
chip with a larger powder inlet in the middle, thesecond-generation
‘powder-mixing chip’ was capable ofdelivering high quality mixtures
with unlimited mixingratios. Tablets of different ratios of test
powders madeusing the second device are shown in Figure 4.
These initial findings suggest that the ‘powder-mixingchip’
could provide an effective and well-controlledsystem for the mixing
of powders to create drugs ofdifferent formulations. It could
potentially replacecurrent mixing technology in the
early-stagedevelopment phases of pharmaceutical production.
BENEFITS TO THE PHARMACEUTICAL INDUSTRYThe key benefits offered
by the ‘powder-mixing chip’ arecontrol of product properties and
process attributes, andacceleration of the mixing process:
Controlled MixingAs current pharmaceutical products and
processes aredeveloped empirically and uncertainties over
thetechnology exist, the pharmaceutical industry adoptsoverly
conservative dosages. However, the ‘powder-mixingchip’ enables
accurate regulation of drug dosages, therebyincreasing the range
that can be offered to physicians. Itsability to control mixing to
generate more complicatedand uniform mixtures of pharmaceutical
products goesfurther than the technology presently in use. This
small-
scale technology could enable small amounts of expensiveand
scarce drugs to be used without waste.
Accelerated MixingUsing a micro-application could accelerate the
mixing ofpharmaceutical powders, as slow mixing rates are
generallya feature of V-blenders (see (2) for detail on
V-blenderbehaviour). The particles are mixed randomly by
fallingthrough the V-blender, and so for a thoroughly mixedproduct
to be achieved, the falling action has to be inducedrepeatedly –
which can be time-consuming. The ‘powder-mixing chip’, however, is
able to produce quantities ofinstantly well-mixed product
relatively quickly incomparison, enabling the faster delivery of
products.
CONCLUSIONAccurate and effective powder mixing is
becomingincreasingly important in the pharmaceutical industry,with
manufacturers needing fast and precise methods toassist the
production of new therapies. The ‘powdermixing chip’ could
potentially improve the mixingtechnique, and is ideal for the full
range of powdermixing activities in pharmaceutical production.
The research team at Imperial is currently carryingout further
tests to explore generating different mixturesinside the chip, and
experiments with sound transducershave been conducted. A patent has
been filed on the chipand the powder mixing method.
References
1. Alexander A, Shinbrot T, Johnson B and Muzzio FJ, V-
blender segregation patterns for free-flowing materials:
effects of blender capacity and fill level, International
Journal of Pharmaceutics, 269, pp19-28, 2004
2. Muzzio FJ, Shinbrot T and Glaser BJ, Powder
technology in the pharmaceutical industry: the need to
catch up fast, Powder Technology, 124, pp1-7, 2002
3. Vilkner T, Shivji A and Manz A, Dry powder injection on
chip, Lab on a Chip, 5, pp140-145, 2005
76 Innovations in Pharmaceutical Technology
Figure 4: Tablets ofdifferent formulationsmade using the
second-generation device
(a) A tablet containing equalportions of white, orangeand blue
particles.
(b) Six tablets containingdifferent ratios of white and blue
particles. (The red particles were residuesfrom previous
experiments.)
Michelle Cotterill is Marketing Services Executive at Imperial
Innovations, the leading technologycommercialisation company based
at ImperialCollege London. She was educated at the Universityof
Sheffield where she completed an LLB in Law,including intellectual
property law and medical lawand ethics. Michelle has four years’
communications
experience in the areas of healthcare and technology, and
joinedImperial Innovations in 2007 to focus on new product
marketing. Email: [email protected]
IPT 27 2008 4/12/08 11:10 Page 76
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