Drug nanocrystals in the commercial pharmaceutical development process
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J.P. Möschwitzer / International Journal of Pharmaceutics 453 (2013) 142–156 143
1998). Due to the difficulty in controlling the process, bottom-up
techniques could not gain enough interest to become a standard
approach in thepharmaceutical industry at that time.
Aroundthe 1990sGary Liversidge andhiscolleagues from Ster-
ling Drug Inc./Eastman Kodak have applied a wet media-based
milling technique (wet ball milling, WBM), adapted from the
paint and photographic industry, to reduce the particle size of
poorlywater-soluble drugs (Liversidge et al., 1992; Liversidge and
Conzentino, 1995). This process has evolved since and eventually
became well known as NanoCrystal® technology in the pharma-
ceutical industry and is to date the most successful nanosizing
approach with currently 5 products on the market (see Table 1)
(Merisko-Liversidge and Liversidge, 2011).
In 1994 Müller and his colleagues have developed an alterna-
tivetechnologybasedonpiston gaphighpressurehomogenization
(HPH) to produce nanosuspensions (Müller). This technology was
named as DissoCubesTM, according to the cubic shape of the drug
nanocrystalsproducedwiththisprocess (Mülleret al., 2003). Later
this technologywas acquired by SkyePharma PLC and is currently
offered in addition to other size reduction technologies such as
the insoluble drug delivery microparticle technology (IDD-PTM)
(Keck and Müller, 2006; Shegokar and Müller, 2010). This tech-
nology, also referred to as Microfluidizer technology, is a typical
top-down process which is based on jet-stream homogenization.The drug is pumpedunder highpressure of up to1700bar through
a microfluidizer system ( Junghanns and Müller, 2008). In the col-
lision chamber of either Z-type or Y-type it comes to particle
collision, shear forces and cavitation forces leading to the desired
particle size reduction. The resulting particle size is preserved by
the use of various phospholipids or other surfactants and stabi-
lizers. Due to the relatively low power density of the standard
equipment, upto50 ormorepassesof thesuspensionarenecessary
for a sufficient particle size reduction (Mishra et al., 2003).
In1999theNanopure® technologywasdeveloped, anothervari-
ant of a piston-gap homogenization process, which is conducted
withwater-reducedor evenwater-free liquids as dispersionmedia
(Müller; Radtke, 2001).
By reducing the particle size to the nanometer range, thebioavailability of many poorly soluble compounds could be
improved significantly, which eventually led to a broader accep-
tance of the WBM and HPH techniques as enabling technology.
Today, the two techniques are by far the most industrial relevant
technologies to produce drug nanocrystals. Six different commer-
cialpharmaceuticalproductsbasedon nanosizing approaches have
already been approved (Table 1).
Following the success of these two technologies, this has trig-
gered the development of completely new or slightly different
technologies. During the first ten years after the invention of
the NanoCrystal® technology various groups, mainly specialized
drug delivery companies but also academic research groups, have
embarkedon the “Nano” approach. They have developedtheirown
technology to provide alternative solutions to their customers.Alternative technologies have mainlybeen developedbased on
bottom-up approaches,mainly because ofmore freedom to gener-
atenewintellectualproperty (IP) (ChanandKwok,2011; deWaard
et al., 2011). Basically, these approaches have the common goal to
providebetter processcontrol forproducingnanoparticulatestruc-
tures with enhanced dissolution characteristics. Precipitation in
the presence of special polymers to prevent crystal growth was
successfully applied for some APIs, such as ibuprofen, itraconazole
and ketoconazole (Rasenack and Müller, 2002a,b). The precipita-
tion can also be performed at elevated temperatures (Evaporative
Precipitation into Aqueous Solution, EPAS) (Chen et al., 2002). Fur-
thermore, organic drug solutions can be sprayed into cryogenic
liquids using the SFL technology (SFL: spray freezing into liquid
technology) (Hu et al., 2003). Upon contact with the cryogenic T
a b l e
1
M
a r k e t e d p r o d u c t s c o n t a i n i n g d r u g n a n o c r y s t a l s .
T r a d e n a m e
I N N n a m e
F D A a p p r o v a l
N a n o s i z i n g t e c h n o l o g y
C o m p a n y
A d m i n s t r a t i o n r o u t e
T h e r a p e u t i c b e n e fi t
R a p a m u n e ®
S i r o l i m u s
2 0 0 0
N a n o C r y s t a l ®
( W B M )
P fi z e r ( W y e t h )
O r a l
R e f o r m u l a t i o n , P a t i e n t f r i e n d l y
t a b l e t i n s t e a d o f s o l u t i o n
E m e n d ®
A p r e p i t a n t
2 0 0 3
N a n o C r y s t a l ®
( W B M )
M e r c k
O r a l
N C E
, H i g h b i o a v a i l a b i l i t y , n o
f o o d e f f e c t s
T r i c o r ®
L y p h a n t y l ®
F e n o fi b r a t e
2 0 0 4
N a n o C r y s t a l ®
( W B M )
F o u r n i e r P h a r m a , A b b o t t L a b o r a t o r i e s
O r a l
R e f o r m u l a t i o n , N o f o o d e f f e c t s
T r i g l i d e ®
F e n o fi b r a t e
2 0 0 5
I D D - P
®
( H P H )
S c i e l e , S h i o n o g i P h a r m a I n c .
O r a l
R e f o r m u l a t i o n , N o f o o d e f f e c t s
M e g a c e ®
E S
M e g e s t r o l e a c e t a t e
2 0 0 5
N a n o C r y s t a l ®
( W B M )
P A R P h a r m a c e u t i c a l s
O r a l
R e f o r m u l a t i o n , N o f o o d e f f e c t s ,
m o r e p a t i e n t f r i e n d l y
I n v e g a ®
S u s t e n n a ®
X e p l i o n ®
P a l i p e r i d o n e
p a l m i t a t e
2 0 0 9
N a n o C r y s t a l ®
( W B M )
J a n s s e n
P a r e n t e r a l , I n t r a m u s c u l a r
R e f o r m u l a t i o n
M
o d i fi e d a f t e r M ö s c h w i t z e r a n d R a i n e r ( 2 0 1 1 ) .
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144 J.P.Möschwitzer / International Journal of Pharmaceutics 453 (2013) 142–156
liquid (e.g. liquid nitrogen) the droplets are frozen. A subsequent
lyophilization step removes the organic solvent. Due to the mild
process conditions this technology is suitable for temperature sen-
sitive molecules, such as biological molecules (Yu et al., 2004).
Alternatively, precipitation can be performed in conjunction with
centrifugation techniques (High gravityprecipitation) (Chiouet al.,
2007).
In recent years many drug delivery companies have started to
developproductionmethodsfordrugnanocrystals basedon super-
critical fluid technologies (Fages et al., 2004; York, 1999). In cases
where the drug is soluble in supercritical fluids, such as supercrit-
ical carbon dioxide, the RESS technology (RESS: Rapid Expansion
from Supercritical Solutions) can be applied (Maston et al., 1987).
Incontrast,inmanycasesthesupercriticalgas isusedas antisolvent
for the drug.Mixingof an organic drug solutionwith the supercrit-
ical antisolvent leads to a precipitation of nanometer-sized drug
particles,whicharecollectedin variousways. Thegeneralprinciple
is referred to as gas antisolvent technology. Dependingon process
conditions and mixing types, various process variants exist (e.g.
GAS: gas antisolvent process, SAS: supercritical antisolvent pro-
cess, SEDS: solution enhanced dispersion of solids) (Byrappa et al.,
2008).
Althoughthe resultsobtainedwiththesealternativeapproaches
are very promising, they are currently not as widely used in thepharmaceutical industry to produce drug nanocrystals. Most of
these approachesrequire custom-madeproductionequipmentand
specialprocessingexpertise,which limits theirapplicabilitymainly
to dedicated research groups.
It is important tomention in this context that the development
of drug nanocrystals requires suitable analytical techniques such
as microscopic techniques or particle size analysis. These tech-
nologies have also evolved over time. Nowadays, the equipment
is much more user-friendly than some years ago. Particle charac-
terization canbe easily performedon routine basis and the results
are available withinminutes (Levoguer, 2012).
This review will focus mainly on drug nanocrystals produced
by applyingthe industrial relevant andwell-established top-down
technologies wet ball milling as well as high pressure homoge-nization. Obviously likemanyother newly developed technologies
the top-down approaches had initially also some drawbacks. The
discussion will focus on how the top-down particle size reduction
technologies have evolved over theyears tomature as established
techniqueswhicharenowwidely accepted andfrequently applied
by the pharmaceutical industry. In addition, this review will dis-
cuss how drug nanocrystals in general can be successfully used as
enabling technology for poorly water-soluble drugs.
2. Technological aspects for the production of drug
nanocrystals
2.1. Wet ball milling
Wetballmilling(alsoreferredtoaspearlmillingor beadmilling)
is by far the most frequently used production method for drug
nanocrystals in the pharmaceutical industry. The milling proce-
dure itself is rather simple; therefore this process can be basically
performed in almost every lab. The easiest way of doing WBM is
through low energy ball milling (LE-WBM) using a jar filled with
milling media (often just very simple glass beads). This system is
chargedwithcoarsedrugsubstance,preferablyinmicronizedform,
which is suspended in dispersion medium containing at least one
stabilizing agent. By moving thebeads eitherwith an electric stir-
rer (Fig. 1a), e.g. a magnetic stirrer, or bymoving the whole jar, e.g.
witha rollerplateor amixer (Fig.1b), themilling beadscaninteract
withthedrugparticles.At thebeginningof thenineties, verysimilar
set-upswereused inorder toestablish this technology forpharma-
ceuticalpurposes. Therelatively lowenergyinput leadsto verylong
milling timesof several days (Liversidge et al.,1992; Liversidge and
Conzentino, 1995; Merisko-Liversidge et al., 1996). The comminu-
tion process itself is caused by abrasion, cleavage and fracturing
(Hennart et al., 2012). For LE-WBM a combination of cleavage and
abrasioncanbe assumed as the main mechanism of size reduction
principles, as theprocess generallyyieldsvery fine particleswith a
narrow size distributionwhen it is performed long enough.
Alternativemilling procedures based on high energy processes
had to be developed in order to make this process more desir-
ablefor industrial pharmaceutical applications. TheNanoCrystalTM
process in its current form is based on such a high energy wet
ballmillingprocess(HE-WBM)(Merisko-LiversidgeandLiversidge,
2008). A necessary prerequisite for HE-WBM is the availability of
suitable equipment. Themanufacturers formilling equipmenthadtodevelopequipmentwith sufficientlyhighpowerdensitiesfor the
improvedprocesses. Today,HE-WBMcanbe regardedas a standard
procedure to produce nanosuspensions. Due to the much higher
powerdensity, theproduction times aresignificantlyreduced.Nor-
mally, the drug needs to be exposed to the high energy for about
Fig. 1. Setup forlow energywet ball milling. (A)Vial filledwith milling beads,suspension anda magnetic barplacedon a magnetic stirrer plate,the beads aremovedby the
rotatingmagnetic bar inside the vial. (B)Plastic bottle (small picture lower right) filled with milling beads and suspension moved by a standardmixer, thewhole system is
moved.
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J.P. Möschwitzer / International Journal of Pharmaceutics 453 (2013) 142–156 145
30–120min in order to achieve a nanosuspension of good qual-
ity (Merisko-Liversidge and Liversidge, 2011). Agitated ball mills
have the advantage that they can be operated in discontinuous
mode (often referred to as batch mode) or in continuous mode
(often referred to as re-circulation mode). Typically, the current
standard forlargescale production is oftenusingagitatedballmills
in re-circulation mode. These mills have media separators, either
as separating gap system or as filter cartridge, to hold the milling
medium back in the milling chamber, when the nanosuspension
is circulating (Kwade, 1999b). The suspension is pumped from the
holdtankwith a certainvelocity throughthemillingchamber.Only
within the relatively short passage period (i.e. the residence time
in the chamber) the drug particles are exposed to the energy input
and reduced in size. The comminution is a result of shear stresses
andcompressionforces inside themillingchamber (Kwade,1999a).
The drug particles are reduced in size by abrasion and cleavage
mechanisms (Hennart et al., 2012).
It isobvious that high energymills require specialmillingmedia
whichhas tobeproperly selectedbasedonthematerialof theinner
surfaces of themill, the agitator types andother factors. Using just
glassbeadsor zirconiumoxidemilling beads can lead to significant
contaminationof thenanosuspensioncausedbytheabrasioneither
of themilling beads orparts of themilling chamber (Hennart et al.,
2010; Juhnke et al., 2012). Initially, impurities caused by abrasionwere one of the major obstacles for a broader acceptance ofWBM.
Therefore,a majormilestonefor thebroadacceptanceof themilling
process was the introduction of highly crosslinked polystyrene
beads as milling media (Bruno, 1992; Kesisoglou et al., 2007;
Merisko-Liversidge et al., 2003). This milling media shows elastic
deformation, thereby the formation of cracks and abrasion from
beads is reduced. Nowadays, the commercial NanoCrystal® pro-
cess is performed with special PolyMillTM media, i.e. polysterene
beads with a diameter of about 0.5mm (Kesisoglou et al., 2007).
This leads to product qualities which allow the usage of nanosus-
pensions even for parenteral administration (Merisko-Liversidge
and Liversidge, 2011).
In the early nineties, there was no equipment available to pro-
duce nanosuspensions at very small scale. Hence, it was difficultto use this formulation approach for discovery purposes. Initially
several grams of API were needed to produce prototype formula-
tions (Liversidge et al., 1992). Today, even high energy mills are
available for small scale production of nanosuspensions. Several
research groups have reported ways to use existing planetary ball
mills with modified sample holders which can be used to process
several nanosuspensionsat thesame time ( Juhnkeet al., 2010;Van
Eerdenbrugh et al., 2009a). Alternatively, agitated ball mills are
used for drug quantities starting from 10mg (Merisko-Liversidge
and Liversidge, 2011). Using these mills it is now possible to pro-
duce nanosuspensions during the early discovery phase of the
formulationdevelopmentortoperformstabilizerscreeningstudies
with a minimal API consumption.
Withthecommercialavailabilityof suitableequipmentfor smallscale production up to the commercial scale production, wet ball
milling can be regarded as scalable approach. This aspect has
definitely helped for broader acceptance of this rather complex
technology (Merisko-Liversidge and Liversidge, 2011).
The versatility ofwet ballmilling is certainly another, if not the
most important aspect for the success of this technology. Almost
any API can be processed with wet media milling (Cooper, 2010).
Additionally, in most cases aqueous solutions of electrostatic sur-
factants in combination with cellulosic polymers can be used as
stabilizing vehicles (Cerdeira et al., 2010; Van Eerdenbrugh et al.,
2009b; Wu et al., 2011). Interestingly, most particle sizes reported
for nanosuspensions prepared bywet ball milling are in the range
between 100 and 300nm, irrespectively whether LE-WBM or HE-
WBMwas used. Table 2 gives a snapshot of some examples found
in the literature. Overall, the reported particle sizes of the various
APIs illustrate again the universal applicability of this particle size
reduction method. Based on the reported results it can be stated
that wet ball milling is in general superior over standardhigh pres-
sure homogenization in terms of the achievable particle sizes. All
these aspects have opened the possibility to usewetball milling as
a platform technology for formulating poorly soluble compounds.
2.2. High pressure homogenization
HPHcanberegardedas the secondmostimportant technique to
produce drug nanocrystals. Thebroad acceptance of this approach
is supportedbymany examples from the literature (e.g. references
of Table 2).
The application of HPH as particle size reduction method
requires the availability of special equipment; it cannot be tested
with a system as simple as “beads in a beaker”. Interestingly, high
pressure homogenizerswere already widely available in thephar-
maceutical industry aswell as in the food industry at the time the
first nanosuspensions based onHPHhave been developed. Theuse
of homogenizerswas already described for theproduction of lipo-
somesandemulsionsystems(Brandlet al.,1990;Collins-Goldetal.,
1990). Today, high pressure homogenizers canalso be used for the
production of solid lipid nanoparticles or nanostructured lipid car-riers (Mülleret al., 2000,2002,2011). Thepossibility to employthe
production equipment for various formulation approaches (multi-
purpose production lines) is an important advantage, as it is rather
costly to establish production lines in-house.
The steps involved in producing nanosuspensions by means
of HPH are similar and as simple as for WBM. Normally, a pre-
mix of the coarse drug and the dispersion medium is prepared
using high speed stirrers. The dispersion medium contains nor-
mally similarsurfactantand/orstabilizer systemsusedfor theWBM
approach (Wu et al., 2011). Subsequently, this coarse suspension
(theso called “macro-suspension”) is passed several times through
the high pressure homogenizer. Typically, the applied pressure is
increased step-wise from 10% to 100% in order to avoid clogging
of thenarrow homogenization gap. At production pressure,whichspans between 1000 and 2000bar, the gap has an opening of only
a fewmicrometer. This explains the importance of thepre-mixing
procedure for de-agglomeration and wetting purposes, especially
when relatively coarsematerial is processed.
The particle size reduction itself is caused by cavitation forces,
shear forces and collision. In general, several homogenization
cycles are needed to reach the minimal particle size. The number
of passes (i.e. homogenization cycles) depends onmany factors.
Thereby, the employed drug delivery technology defines the
type of homogenizer as well as the process conditions (e.g. IDD-
PTM technology, Dissocubes® or the Nanopure® technology, see
Section 1) (Keck and Müller, 2006; Shegokar and Müller, 2010).
Additional factors determining the process efficiency include size
of the startingmaterial, hardness of the drug and maximum pres-sure thatcanbereachedbythemachine.In general,higherpressure
leads to faster particle size reduction (Dumay et al., 2012; Fichera
et al., 2004; Kluge et al., 2012). The size of the impaction zone and
thecorrespondingvolumeareimportant factors,as theydetermine
proportionally the power density of the equipment. Thedifference
in power density of the Microfluidizer technology compared to
piston-gap processes is one reason for the different particle size
reductioneffectiveness of the two types of high pressure homoge-
nizers (Xiong et al., 2008).
HPH is less prone in generating process impurities as conse-
quence of abrasion and wearing of the equipment compared to
WBM.Althoughhighpressurehomogenizersconsistmainlyof steel
parts, the impurity levels found in nanosuspensions prepared via
HPHprocessesare considerably low.A comparative studyrevealed
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that a typical nanosuspensionafter 20cyclesat 1500bar contained
less than 1ppm iron (Krause et al., 2000). Abrasion and wearing
of HPH equipment can occur when extremely hard material is
processed in piston-gap homogenizers. In this case, the tip of the
homogenization valve posses a relatively small surface compared
to thevolume of suspension passing through it.Wear andtear tend
to happen when only stainless steel parts are used, leading to a
reduction in process efficiency. Therefore, modern homogenizers
havehomogenizationvalvesequippedwithceramic tips,whichcan
withstand harsh process conditions (Innings et al., 2011).
HPH is a scalable process,which is applied not only in the phar-
maceutical but also in the cosmetics and food industry (Dumay
et al., 2012). Today high pressure homogenizers areavailable from
ml-scale to large production scale (Keck and Müller, 2006).
Some references report an enzyme inactivation and a reduced
microorganism load as a result of HPH processes (Diels and
Michiels, 2006; Dumay et al., 2012). This can be seen as advan-
tage for large scale production, as the reducedmicroorganism load
increases the shelf life of the nanosuspension intermediate with-
out the need of additional filtration steps, at least if the intended
product is administered orally.
There arenumerous examples in the literature whereHPHwas
applied successfully to produce nanosuspensions. As opposed to
WBM, it seems that the particle size reduction effectiveness of the standard processes depends more on the physico-chemical
properties of the processed drug. Table 2 shows an overview of
mean particle sizes generated by HPH. The results are more scat-
tered than for WBM. There is no general rule, but it seems that
HPH is the method of choice for relatively soft materials with
tendency to smear when processed with others methods, such
as WBM. Table 2 shows that for the lipidic compound PX-18 (2-
N,N-Bis(oleoyloxyethyl)amino-1-ethanesulfonic acid) the smallest
particle size reported in the literature (41nm) could be obtained
by standardHPH.
2.3. Combinative technologies for the production of drug
nanocrystals
Although the standard technologies WBM and HPH are in the
meantime widely accepted and applied, there were still some
disadvantageswhich havebeenaddressedbycontinuous improve-
ment of these processes.
For both, WBM as well as HPH it is suggested to start with
micronized startingmaterial. Cloggingof the equipment can occur
when the process is conducted with too coarse drug particles.
In case of agitated ball mills in re-circulation mode this clogging
can occur at themedia separator; for high pressure homogenizers
clogging can occur within the feeding system of the homogenizer
or at the narrow homogenization gap as well as the interactionchamber.
Table 2
Literatureexamples for drugnanocrystals prepared by high pressure homogenization or wet ball milling, respectively.
No Drug Top-down method Smallest reported particle size (nm) Delivery route Reference
1 PX-18 HPH 41 Pardeike andMüller (2010)
2 Asulacrine HPH 133 Ganta et al. (2009)
3 Ubc-35440-3 HPH 182 Hecq et al. (2006)
4 Indometacin HPH 200 Sharmaet al. (2009)
5 Prednisolone HPH 211 Kassemet al. (2007)
6 Resveratrol HPH 244 Topical Kobierski et al. (2009)
7 Danazol HPH 300 Crisp et al. (2007)
8 Hesperitin HPH 300 Mishraet al. (2009)
9 Celecoxib HPH 320 Oral Dolencet al. (2009)10 Ascorbyl palmitate HPH 348 Teeranachaideekul et al. (2008)
11 Azithromycin HPH 400 Oral Zhang et al. (2007)
12 Tarazepide HPH 400 I.v. injection Jacobs et al. (2000)
13 Spironolactone HPH 400 I.v. injection Langguth et al. (2005)
14 Omeprazole HPH 500 I.v. injection Möschwitzer et al. (2004)
15 RMKP22 HPH 502 Grau et al. (2000)
16 Amphotericin B HPH 528 Kayseret al. (2003)
17 Hydrocortisone HPH 539 Kassemet al. (2007)
18 Budenoside HPH 599 Jacobs andMüller (2002)
19 Bupravaquone HPH 600 Oral Jacobs et al. (2001)
20 Clofazimine HPH 601 I.v. injection Peterset al. (2000)
21 Nimodipine HPH 650 I.v. injection Xiong et al. (2008)
22 Rutin HPH 750 Oral Mauludin et al. (2009)
23 RMKK98 HPH 800 Krause et al. (2000)
24 Oridonin HPH 913 Zhang et al. (2010)
25 Dexamethasone HPH 930 Kassemet al. (2007)
32 Diclofenac HPH <800 Lai et al. (2009)33 Itraconazole WBM 128 I.v. injection Beirowski et al. (2011)
34 Candesartan cilexetil WBM 128 Oral Nekkanti et al. (2009)
35 Crystalline API WBM 150 Lee (2003)
36 Loviride WBM 156 VanEerdenbrugh et al. (2007)
37 Ketoconazole WBM 164 Oral Basa etal. (2008)
38 Cyclosporine WBM 199 Nakarani et al. (2010)
39 Camptothecin WBM 202 I.v. injection Merisko-Liversidge et al. (1996)
40 Piposulfan WBM 210 I.v. injection Merisko-Liversidge et al. (1996)
41 Piposulfan WBM 210 Merisko-Liversidge et al. (1996)
42 Cilostazol WBM 220 Oral Jinno et al. (2006)
44 Etoposide WBM 256 I.v. injection Merisko-Liversidge et al. (1996)
45 Griseofulvin WBM 256 VanEerdenbrugh et al. (2008)
46 Naproxen WBM 270 Oral/I.v. injection Liversidge and Conzentino (1995)
47 Paclitaxel WBM 279 I.v. injection Merisko-Liversidge et al. (1996)
48 Hydrocortisone WBM 300 Ophthalmic Ali et al. (2011)
49 Cinnarizine WBM 366 VanEerdenbrugh et al. (2008)
50 1,3-Dicyclohexylurea WBM 800 Subcutaneous Chianget al. (2011)
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Relatively long process times are another disadvantage of
the standard approaches. This stands in contrast to the above-
mentioned 30–120min to produce nanosuspensions by WBM.
However, this time is the minimum contact time of a drug inside
themilling chamber.Whena largescalemill is runin re-circulation
mode, the suspension is only exposed to high energy at the time it
passes themilling chamber. Therefore, the total production time is
significantly longer, depending on the ratio between total batch
volume and volume of the milling chamber. A similar situation
applies for HPH. Commercially available high pressure homoge-
nizers can process 1000l of nanosuspension or more within 1h.
However, when 20 homogenization cycles are required to achieve
a certain particle size, the total process time can easily go up to
20h for batch sizes of 1000l, unless more homogenizers are used
in series.
In order to address the above-mentioned disadvantages, alter-
native processes have been developed. Significant reduction of
process times canbe achievedwhen the drug is pre-treated before
the top-down process step is performed. These relatively recently
developed techniques are referred to as combinative particle size
reduction methods. The company Baxter developed the first com-
binativemethod, the so called NanoedgeTM technology. It consists
of a bottom-up step (micro-precipitation) followed by a top-down
step (high-pressure homogenization). The drug is dissolved, e.g.in a water-miscible, non-aqueous media and precipitated in form
of a suspension consisting of brittle drug particles. This suspen-
sion is then further processed to a nanosuspension by means of
HPH (Kipp et al., 2003; Kipp, 2004; Rabinow, 2004). An alternative
method, which is alsoknown asH 69process,was developedmore
recently by Müller and colleagues. Ideally, the time between the
precipitation and the high pressure homogenization step should
beminimized, in order to obtain smaller drug nanocrystals. In this
regard it is optimal to conduct the precipitation directly within
the dissipation zone of the homogenizer. First results have shown
that this method can lead to very small particles (Müller and
Möschwitzer, 2005), butmore systematical research is needed for
a betterunderstanding of all critical process parameters.
Obviously, nomicronized startingmaterialis needed toperformthetwoabove-mentioned technologies.However,a remainingdis-
advantage is the presence of the non-aqueous solvent in the final
nanosuspension. The non-aqueous solvent can act as a co-solvent
which increases the solubility of the drug to an extentwhichcould
potentially compromise itsphysicalandchemicalstability. Inmost
cases, the non-aqueous solvent has to be removed in order to
reduce the risk of Ostwald ripening. To avoid this problem, alter-
native combinativemethodshave beendevelopedbyMöschwitzer
and colleagues, which are referred to as H 42 and H 96 technolo-
gies (Shegokar and Müller, 2010). The H 42 technology uses spray
drying of organic drug solutions as bottom-up step to produce a
modifiedstartingmaterial fora subsequentprocessstep,where the
modified drug is very efficiently processed by standard top-down
processes, e.g. HPH into nanosuspensions with small particle sizesand narrow size distributions (Möschwitzer, 2005; Möschwitzer
and Müller, 2006a). The spray drying process results in a pre-
treated, fine-dispersed starting material which can be directly
used for the subsequent high-pressure homogenization step. The
spray drying process yields basically solvent-free material. Thus,
the second size reduction step can be performed in solvent-free,
aqueousmedia.The risk forparticlegrowth is significantly reduced
compared to the combination of precipitation and HPH. The H
96 technology combines freeze-drying as bottom-up step with
standard top-down processes (Möschwitzer and Lemke, 2005;
Shegokar andMüller, 2010). Pre-treatmentwith freeze-drying can
beusedwhen temperaturesensitivematerial hasto beprocessedor
when ultra-small drugnanocrystalsof expensivedrugs areneeded.
The freeze-drying process can be controlled to produce extremely
0
500
1000
1500
2000
2500
3000
3500
I II III IV V VI
Process time
M e
a n p a r t i c l e s i z e [ n m ]
Standard HPH
Standard WBM
H 96 (FD-HPH)
H 42 (SD-HPH)
H 96 (FD-WBM)
Fig. 2. Mean particle size (PCS z -average) as function of the process time and the
particle size reduction technique.All discontinuous linesrepresent novelcombina-
tive methods with modified starting materials; the continuous lines represent the
standardmethods with unmodified starting material. Point I: after the pre-mixing
step (high-speed mixer), points II–VI represent: 1, 5, 10, 15, 20 homogenization
cyclesforHPHresults, orresultsafter 1,2, 4,8, 24h ofmilling forWBM (usinga low
energy ball mill).
Modified afterSalazar (2012).
brittle startingmaterial. Therefore, the subsequent top-down step
yields nanosuspensions with a very small particle size. The H 96
technology was used for the production of ultrasmall nanocrys-
tals of amphotericine B by combining freeze-drying with HPH.
The resulting nanosuspensions had a particle size clearly below
100nm, which enabled their use in specialized red-blood-cell
carriers (Staedtke et al., 2010). Since this approach is still relatively
new, the factors leading to the improved particle size reduction
efficiency are not fully understood yet. It seems that solid state
modifications play a significant role. A study using glibenclamide
as model compound has shown that smallest particle sizes were
obtained with amorphous starting material (Salazar et al., 2012).
However, in another study similar improvementof theparticlesizereduction effectiveness was also seen for modified glibenclamide
which was predominantly crystalline (Salazar et al., 2011). The
combination technologies nicely illustrate howstandardtechnolo-
giesarecontinuously improvedin orderto extend their application
areas.
Fig. 2 compares the particle size evolution of the model com-
pound glibenclamide as a function of process time for standard
top-downprocesses in comparison to the novel combinative tech-
niques. It can be seen that the pre-treatment leads to a significant
improvement of the particle size reduction effectiveness. Much
smaller particles were obtained already at the second time point,
which means after 1 homogenization cycle at 1500bar or 1h
milling time. Although standard WBM results eventually in the
same final particle size, process time for the conventional processis much longer. All combinative technologies perform distinctly
better than the standard HPH process. Pre-treatment of the API
material before HPH,makes it possible to obtain the sameparticle
size as with the standard WBM method. In this regard, the com-
binative methods allow the application of HPH processes also for
harder APIs which aremore difficult to nanosize.
It should be mentioned in this context that any pre-treatment
stepincreases thecomplexityof theoverallprocessandcan addsig-
nificant costs.Therefore it is obvious that combinative particle size
reduction methods will be only used, in case the more established
methods, like wet ball milling or standard high pressure homoge-
nizationcannotbe used tocometo thedesired results.Oneexample
is the production of nanosuspensions from amorphous APIs with
particle sizes smaller than 100nmusing thecombinativemethods.
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148 J.P.Möschwitzer / International Journal of Pharmaceutics 453 (2013) 142–156
Itis very challengingto achievethis ina reasonable time framewith
establishedmethods, such aswet ball milling.
3. The formulation selection process for poorly
water-soluble compounds
Theselectionof therightformulationapproach isoneof thekey
activities of formulators in the pharmaceutical industry. Key fac-
tors are the physico-chemical properties of APIs, such as aqueous
solubility,meltingpoint andtemperature andchemicalstability. In
addition, theformulatorneeds informationabout thepotencyof the
compound and the desired route of administration, as this deter-
mines the typeof the finaldosage formaswell as the requireddrug
load.Allthesefactorscanbeconsidered indecisiontrees,which are
often used in the industry to guide the formulator. However, there
are some biopharmaceutical relevant aspects which need more
attention, inordertoavoidfalsenegative results. Like anyother for-
mulationtechnology,drugnanocrystalsas enablingtechnologycan
only be successfulwhen all of these factors are taken into account.
It would not be sufficient to assume that the oral bioavailability of
any poorly soluble drug can be increased just by formulating it as
drugnanocrystal.
The well-known BCS system (Biopharmaceutics ClassificationSystem) is used very frequently to categorize compounds (Amidon
et al., 1995). According to the BCS system poorly soluble com-
pounds can belong to class 2 (low solubility, high permeability)
or class 4 (low solubility, low permeability). Therefore, BCS class
2 and 4 compounds would be theoretically good candidates for
nanosizing approaches. This is a widely used and well accepted
perceptionwithin thepharmaceutical industry.However, usingthe
BCSsystemas guidance for formulation selectionmight sometimes
oversimplify the complex nature of drug dissolution, solubility
and permeability. Poorly water-soluble compounds can possess
such a low aqueous solubility that the dissolution rate even from
ultra-small drug nanocrystals (e.g. sub 100nm) is too slow. In this
case it is not possible to reach sufficiently high drug concentra-
tions in the gastro-intestinal tract for an effective flux across theepithelialmembrane. Inaddition,other factors suchas effluxtrans-
port or pre-systemicmetabolism cannegatively influence the oral
bioavailability.
Therefore it was recommended to classify compounds into
slightly different categories, as they can show dissolution rate
limited, solubility or permeability limited oral bioavailability. The
result isknownasthe“DevelopabilityClassificationSystem”,which
is another way to categorize compounds in a more biorelevant
manner (Butler and Dressman, 2010). This system distinguishes
between dissolution rate limited compounds (DCS class IIa) and
solubility limited compounds (DCS class IIb) (see Fig. 3).
In order to select theright formulation approachandto address
the compound specific issues with a suitable formulation type it
is imperative to first understand the bioavailability limiting fac-tors. It is important to note that there is no one-fits-all formulation
approach. Each technology has its own advantages and disadvan-
tages. The main approaches to address poor water-solubility are
summarized in Table 3.
The better the formulator understands the interplay of the
physico-chemical properties of thedrug, the special aspects of the
various formulation options and the required in vivo performance,
the higher the chance that the optimal formulation approachwill
be chosen. This minimizestherisk of late failures inhumanclinical
trials, e.g. due to insufficient or highly variable drug exposures.
Compoundsshowingdissolution ratelimitedbioavailability can
bereferredtoasDCSclass IIacompounds.Obviously, theyrepresent
only one part of the BCS class 2 compounds. The extent of the oral
bioavailability of such compounds is directly correlatedwith their T
a b l e
3
F
o r m u a l t i o n a p p r o a c h e s f o r p o o r l y s o l u b l e d r u g s .
F o r m u l a t i o n a p p r o a c h
P o t e n t i a l d r u g l o a d
l o w , m e d i u m , h
i g h
S u i t a b l e f o r t e m p e r a t u r e
l a b i l e s u b s t a n c e s
S u i t a b l e
f o r c o m p o u n d s
w i t h h i g h m e l t i n g p o i n t
F o r m u l a t i o n fl e x i b i l i t y
l i q u i d , s o l i d
A d m i n i s t r a t i o n
r o u t e O r a l o r I V
C o m p l e x i t y o f
t h e p r o c e s s
F o
r s o l u b i l i t y o r d i s s o l u t i o n
r a
t e l i m i t e d c o m p o u n d s
M i c r o n i z a t i o n
H i g h
Y e s , c r y o g e n i c
Y e s
l + s ,
O r a l
S i m p l e
d
N a n o s i z i n g
H i g h
Y e s
Y e s
l + s
B o t h
C o m p l e x
d
C y c l o d e x t r i n f o r m u l a t i o n s
L o w
Y e s
Y e s
l + s
B o t h a
s + d
S a l t f o r m a t i o n
H i g h
Y e s
Y e s
s ( l : l i m i t e d )
O r a l
S i m p l e
( s ) + d
p H a d j u s t m e n t
L o w
Y e s
Y e s
l
B o t h
S i m p l e
( s ) + d
S o l i d s t a t e m a n i p u l a t i o n
– H M E
M e d i u m
N o
N o
s
C o m p l e x
s + d
– S D D
M e d i u m t o h i g h
L i m i t e d
Y e s
s
C o m p l e x
s + d
C o - c r y s t a l s
H i g h
Y e s
Y e s
s
M e d i u m
( s ) + d
L i p i d b a s e d s y s t e m s b
L o w
L i m i t e d
L i m i t e d
l + s
S i m p l e
s + d
a N o t a l l c y c l o d e x t r i n e t y p e s a r e s u i t a b l e f o r I V a d m i n i s t r a t i o n .
b E . g . , l i q u i d o r s e m i - s o l i d fi l l e d h a r d o r s o f t g e l a t i n e c a p s u l e s .
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J.P. Möschwitzer / International Journal of Pharmaceutics 453 (2013) 142–156 149
250 500 10000
Class IV
P r e d i c t e d P e f f i n h u m a n s c m / s e c x 1 0 - 4
10
1
0.1
Class I
Class III
Dose/solubility ratio
Class IIb
Solid-state manipulation (ASD)
Lipid-based systems
Complexation
Class IIa
Nanosizing
Salt formation
Co-crystals
Standard approaches
Permeation enhancer
Mucoadhesion
Permeation enhancer + solubilization
Lead optimization
Lead optimization
Class IV
-
10
1
0.1
Class I
Class III
Class IIb
Solid-state manipulation (ASD)
Lipid-based systems
Complexation
Class IIa
Nanosizing
Salt formation
Co-crystals
Permeation enhancer + solubilization
Lead optimization
Fig. 3. DCS classification systemand relevant formulation approachesfor the vari-
ous compound classes.
Modified afterButler and Dressman (2010).
dissolutionrate invivo.Thefractionof thedosethatdissolves in the
lumenis readilyabsorbedthroughthe intestinalmembrane. Conse-
quently, the bioavailabilityof such compounds canbe improvedby
any techniquewhich increasesprimarily thedissolution rate.Vari-
ous formulation approaches areknownwhich lead to an increased
dissolution rate, including salt formation, the use of co-crystals or
particlesizereduction. Theformulator hastoselect theoptimal for-
mulation approach according to theproperties of the specific drug
molecule.
Salt formationis oftenpreferredbypharmaceutical chemists,as
crystallization of salts can be used to produce very pure material.
However, it can only be applied when the compound is ionizable.
Salt formation can be regarded as conventional way to increase
the dissolution rate of APIs (Li et al., 2005; Serajuddin, 2007). The
increased dissolution rate of a salt can have a positive effect on
the bioavailability of poorly soluble compounds. Sometimes, it is
difficult to identify pharmaceutical acceptable salts, which can be
produced on a large scale.
APIs can also be crystallized together with guest molecules, inorder to create fast-dissolving co-crystals. Although this approach
seems to be very promising it is not frequently used as standard
formulation approach for poorly soluble compounds (Schultheiss
andNewman, 2009).
Particle size reduction is by far the most important approach
to address dissolution rate limited bioavailability. According to the
well-knownNoyes–Whitney equation (Eq. (1)) thedissolution rate
depends directly on the surface area ( A) of thedissolving particles.
Particlesizereduction leadsto anincreaseinsurfaceareaandhence
to an accelerated dissolution rate.
dc x
dt =
D · A
h (c s − c x) (1)
where dc x/dt is thedissolution rate;D is thediffusioncoefficient; Ais thesurfaceofdrug particle;h is the thicknessofdiffusional layer;
c s is the saturation solubility of the drug; c x is the concentration in
surrounding liquid at time x.
Two particle size reduction approaches can be distinguished,
namely micronization and nanosizing, often also referred to as
nanonization. Micronization can be regarded as standard tech-
nique, which is used on a routine basis to produce standardized
APIstartingmaterialhavinga certainparticle sizedistribution.This
unit operation is often carried out under the responsibility of the
chemical department, whichdelivers API with a standardized size
distribution. Micronization techniques include hammer milling,
pinmillingor air jetmilling.Dependingon thetechniqueemployed,
the meanparticle size generally ranges between 1 and 50m. The
fraction of fine particles below 1m is comparatively low. The
dissolution rate of poorly soluble drugs is increased compared to
non-micronizedmaterial.However, theeffectonthebioavailability
improvement is limited.
Nanosizing is particle size reduction to another dimension.
The term nanosizing subsumes the various formulation tech-
niqueswhichgenerate drug nanocrystalswith amean particle size
between 1 and 1000nm.Due to their small particle size these par-
ticles can vary distinctly in their properties from micronized drug
particles. Similarly to other colloidal systems drug nanocrystals
tend to reduce their energy state by forming larger agglomerates
or crystal growth. Thus, they are often stabilized with surfactants,
stabilizers or combinations thereof. Reduction of the particle size
to the nanometer range results in a substantial increase in surface
area ( A), thus this factoralonewill resultin a fasterdissolutionrate.
Inaddition, the Prandtl equation showsthat drug nanocrystals also
have a decreased diffusional distance h. This further enhances the
dissolution rate. Finally, the concentration gradient (c s− c x) is also
of high importance. There are reports that drug nanocrystals show
an increased saturation solubility c s. This can be explained by the
Ostwald–Freundlich equation (Kipp, 2004) and by the Kelvinequa-
tion (Müller and Böhm, 1998). It is still not clear to what extend
the saturation solubility can be increased solely as a function of
smaller particle size.Mostprobablythe increasedsolubilityof drug
nanocrystals is a combined effect of nanosized drug particles andsolid state effects caused by the particle fractionation during the
process. Authors have reported effects of 10% increase in satura-
tion solubility up to several folds (Dai et al., 2007; Hecqet al., 2005;
Müller and Peters, 1998). In a detailed studya marginal increase of
the solubility has been found for four drug molecules which were
processed to drug nanocrystals (Van Eerdenbrugh et al., 2010). It
can be stated that the increase of the dissolution rate remains the
main effect of nanosizing.
For compounds belonging to DCS class IIb and IV the intrinsic
solubility and the related achievable intraluminal drug concen-
tration are too low in order to achieve sufficient flux over the
epithelialmembrane. These compounds possess solubility limited
oral bioavailability. In order to achieve sufficient exposure levels
they have to be formulatedwith techniques that increase substan-tially the apparent solubility of the drug in the lumen. Basically,
this can be achieved by solubilization, complexation or solid state
manipulation. When formulations based on these principles are
ingested orally, drug concentration levels above the thermody-
namic equilibrium are reached in the gastrointestinal lumen. This
leads to an increased concentration gradient and a higher flux
across the membrane (Brouwers et al., 2009).
Solubilizationusing lipidbasedsystemsorco-solvent systems is
a simple and elegant way to formulate poorlywater-soluble com-
pounds (Pouton,2006; Strickley,2004). Veryoften, theyare applied
as first-choice option to formulatepoorly soluble compounds. Sol-
ubilized systems can theoretically also be used as formulation
approach for dissolution rate limited compounds (DCS class IIa).
Lipidbased systems canbe administeredvery flexible as liquid for-mulations in pre-diluted form, or as water-free concentrate filled
inhard or soft gelatinecapsules. Theycanbe used for oralas wellas
parenteral applications (Strickley, 2004). Nevertheless, these sys-
tems are of limited use when very high drug doses are needed.
Often the API is not sufficiently soluble in the available excipi-
ents. Another limitation is the quantity of certain solubilizers that
can be used, especially for chronic indications, as they can lead to
undesired side-effect, e.g. increase in plasma-lipid levels.
Alternatively, cyclodextrines, a class of functional excipients,
canbe used as solubilizers to increase the bioavailability of poorly
water-soluble drug molecules (Brewster and Loftsson, 2007). The
formationof inclusion andnon-inclusion complexes can lead to an
increase in the apparent solubility of compounds. Therefore these
excipients can be used when a certain degree of supersaturation is
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150 J.P.Möschwitzer / International Journal of Pharmaceutics 453 (2013) 142–156
required to achieve higher bioavailability. Commercially available
cyclodextrin formulations are available for many administration
routes. Dependingon themolecular type thesesystemscanbeused
inliquid aswell assolidformfororalandwithsomeexceptions also
for parenteral use. Similarly to lipid based systems, cyclodextrine
formulations require relatively high excipients to drug ratios.
Another way to address solubility limited bioavailability is the
manipulationof thedrug’s solid state. In general, these techniques
result in formulations which carry the drug molecules in a higher
energy state, e.g. in form of amorphous solid dispersions (ASDs)
(Leuner and Dressman, 2000). Various ways including hot-melt
extrusion(HME) (Breitenbach,2002) andspray-drying(spraydried
dispersions, SDD) (Friesen et al., 2008) are applied to produce
ASDs. These techniques are an elegant way to produce oral dosage
forms ofpoorly soluble compounds at industrial scale. Severalmar-
keted products have proven the suitability of this approach as
commercial oral dosage forms. However, ASDs are not as flexi-
ble as other formulation approaches, e.g. they cannot be easily
used in liquid form for parenteral administration of poorly solu-
ble drugs. Ideally, the poorly soluble drug needs to bewell soluble
in the polymer(–surfactant) systems, which are used as matrix
to keep the drug in amorphous form. The required drug-polymer
ratio is often a limiting factor in achieving high drug loads in
the final solid dosage form. In addition, this method is less suit-able for thermolabile compounds, as they are exposed to elevated
temperatures during the processing, if HME is used for manufac-
turing.
For the sake of completeness it should bementioned here that
recently a novel technology called NanOsmotic® (Alkermes) has
been developed which aims to combine the principles of parti-
cle size reduction, solubilization and osmotic controlled-release
(Liversidge, 2011).
4. Special biopharmaceutical aspects of drug nanocrystals
4.1. Drug nanocrystals for oral dosage forms
The previous section discussed the application for drug
nanocrystals as compared to other formulation approaches. As a
consequenceof the very fast dissolution rate andotherspecific fac-
tors drug nanocrystals possess some unique features with regard
tobiopharmaceuticalperformancewhichwillbediscussedinmore
detail in the following section.
When particle size reduction is used to formulate dissolution
rate limited compounds (DCS class IIa), the extend of the oral
bioavailability can be described as a function of the particles size.
A smaller particle size leads to higher c max values and propor-
tionally also an increased AUC. Jinno et al. (2006) have reported
the relationshipbetween particle size, dissolution velocity in vitro
and the in vivo effects for the poorly water-soluble drug cilosta-
zol in a very clear und understandable manner. The particle sizeof the drug was reduced by using different techniques. Hammer-
milling resulted in a mean particle size of 13m, jet-milling in
2.4m and wet ball milling using the NanoCrystal® technology
to a particle size of 0.22m. The effect of the particle size on
the dissolution velocity was first demonstrated with in vitro dis-
solution tests. The cilostazol nanocrystals dissolved immediately,
independently of the dissolution medium. In a study in beagle
dogs, this fast dissolution led to a superior performance of the
nanocrystalline cilostazol. The exposure was almost a function of
the particle size of the drug, with the best performance obtained
from cilostazol nanocrystals. In addition, the differences between
fed and fasted state were significantly reduced compared to the
suspensionpreparedwithjet-milledorhammermilleddrug.Mean-
while, the direct relationship between the particle size of the
drug and the achievable extend of drug absorption have been
reportedformanyotherdrugs.All thesedrugs havebenefitted from
the nanosizing approach in terms of bioavailability improvement
(Kesisoglou and Wu, 2008; Lenhardt et al., 2008; Li et al., 2011;
Quan et al., 2011; Shono et al., 2010; Willmann et al., 2010; Xia
et al., 2010).
Compoundswitha pronouncedabsorptionwindowin theupper
intestinal tract do also benefit from fast dissolving formulations.
The accelerated dissolution of drug nanocrystals leads to suffi-
ciently high drug concentrations at the absorption site. The drug
aprepitant, which is marketed as Emend® by Merck and Co., is
an example for a compound with an absorption window in the
upper intestinal tract (Wu et al., 2004). Similar results were found
for fenofibrate in a regional absorption study. The bioavailablity
of fenofibrate formulated as nanosuspension and administered
directly into the proximal and distal bowel was approximately
100% relative to the bioavailability when the nanosuspensionwas
administered orally. In contrast, the relative bioavailability was
only 32%when the fenofibrate nanosuspension was administered
directly into the colon (Zhu et al., 2010). Nanosized fenofibrate
dissolves quickly and is already dissolved at the site of preferred
absorption, i.e. the upper intestinal tract. In contrast, micronized
fenofibratemight notgetsufficiently absorbed,becauseitdissolves
too slowly and misses therefore the absorption window in theupper intestinal tract.
Furthermore, an increased dissolution rate of poorly water-
soluble drugs can lead to faster onset of action. This can be
beneficial for compounds, where the pharmacodynamic effect is
directly linked with the achievable plasma concentration, e.g.
pain treatments like naproxen (Liversidge and Conzentino, 1995;
Merisko-Liversidgeet al.,2003). Inthis case the short t max and high
c max levels resulting fromusing fast-dissolving nano-formulations
can lead to a faster pain relief.
As briefly mentioned above, the use of nano-formulations can
lead to reduced variation between the drug absorption in fasted
and fed state. This is another important reason for choosing
drug nanocrystals as formulation approach. Many studies have
reported reduced food effects when poorly water-soluble drugswereadministered as drugnanocrystal formulation. Poorly water-
solublecompounds administeredasstandardformulationbasedon
micronized API show often an enhanced absorption when admin-
istered together with food. One potential explanation is that bile
salts and food components can have a positive effect on the solu-
bilityandconsequentlyonthedissolution rateofmicronizeddrugs.
In addition, the dissolution is also prolonged by a reduced gastric
emptying rate; this can further enhance the oral absorption. In
contrast, nano-formulations show maximum dissolution already
in fasted state. Therefore the extent of absorption cannot be fur-
ther increased for those compounds when administered together
with food ( Jinno et al., 2006; Sauron et al., 2006; Shono et al.,
2010).
Special attention is neededwhen ionizable compounds are for-mulated as drug nanocrystals. The particle size reduction itself
is a rather versatile approach which works for all compounds
irrespectivelyof theirchemicalnature.Whenneutralor acidiccom-
pounds are administered orally in nanosized form the pH shift
from acidic to alkaline conditions works in favor for an increased
extend of dissolution in the intestine. An opposite situation exists
for basic compounds. When they are formulated as nanosized
product, sometimes a decreased bioavailability is found in in vivo
studies. The pH shift from acidic to neutral or alkaline conditions
can cause a decrease in solubility of these compounds, which can
result in uncontrolled precipitation of already dissolved material
(Sigfridsson et al., 2011b). The in vivo effect of such a pH shift has
to be examined for each compound, before excluding the nano-
approach. There are also examples for basic compounds which
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J.P. Möschwitzer / International Journal of Pharmaceutics 453 (2013) 142–156 151
havebeendevelopedas nano-formulations and tested successfully
invivo (Hecq et al., 2006; Jia et al., 2003).
4.2. Drug nanocrystals for non-oral applications
Nanosizing is a versatile formulation approach which can be
potentially used for all routes of administration (Cooper, 2010). In
the beginning drug nanocrystals were developed as oral dosage
forms,nowadaystheyarealsoconsidered fornon-oralapplications.
Literature examples are available for basically all administration
routes, including dermal (Al Shaal et al., 2010; Mishra et al., 2009),
ophthalmic (Kassem et al., 2007), pulmonary (Shrewsbury et al.,
2009; Steckel et al., 2003) or buccal (Rao et al., 2011).
Injectable formulations are the most important non-oral
application area for drug nanocrystals. The various aspects of
nanosuspensions for parenteral administration have already been
discussed extensively. For detailed information, the reader is
referred to these references (Kipp, 2004; Shi et al., 2009; Wong
et al., 2008). In the context of this review only the most impor-
tant aspects regarding the use of drug nanocrystals for non-oral
administration will be discussed below.
Nanosuspensions show some advantages over other formula-
tion types which contain the drug in solubilized form. Solutionsof poorly water-soluble compounds bear always the risk of pre-
cipitation upon administration. This can be avoided when stable
nanosuspensions are administered. Furthermore, the injection of
large amounts of solubilizers can be associated with side effects,
such as pain on the injection site. Therefore, stable nanosuspen-
sions, producedwitha minimumamountof safeandwell-tolerated
stabilizers, can be advantageous. Moreover, in contrast to other
injectable formulations, nanosuspensions are highly concentrated
systems, with a relatively low viscosity. Since the viscosity of
nanosuspensionsmainly depends on drugconcentrationandvehi-
cle composition, it can be to some extent adjusted.
Sterility is an important requirement of injectable products.
It could be shown, that sterile nanosuspensions can be obtained
eitherby aseptic production (Baert et al., 2009; Peters et al., 2000),by sterile filtration (Zheng and Bosch, 1997), heat treatment (Na
et al., 1999) or gammaradiation (Wong et al., 2008). In this regard
nanosuspensions are compatible with industrial available filling
lines and as flexible as other parenteral products.
The same holds for thevarious presentations of drug nanocrys-
tals. Thefinal drug product canbe provided either as ready-to-use
suspension or as lyophilized powder.
In 2009 a first parenteral product was successfully launched
on the market. Paliperidone palmitate is marketed as ready-to-
use pre-filled syringe containing a nanosuspension prepared by
theNanoCrystal® technology.The patient-friendlynanosuspension
has a low viscosity and a high drug load which results in a low
injection volumeand lowpain levels upon injection.
Thecorrect use of nanosuspensions for injectable dosage formsrequires some considerations. Depending on the particle size and
the aqueous solubility of the drug, nanosuspensions can perform
comparable to solutions types (Gao et al., 2008). In this case it
can be assumed, that the drug nanocrystals dissolve immediately.
However, when a drug is administered as nanosuspension its PK
characteristics and the biodistribution profile might be altered
compared to a solution (Du et al., 2012; Ganta et al., 2009; Wang
et al., 2011). In this case it can beassumed that the particles donot
dissolve fast enough. Consequently, they areaccumulatedas parti-
cles inMPS(mononuclearphagocytic system) richorgans, like liver
and spleen. This can leadto a prolonged actionof the drug. Inmany
cases intravenously administered nanosuspensions showed a bet-
ter tolerability in patients compared to drug solutions (Kipp, 2004;
Merisko-Liversidge et al., 2003; Rabinow et al., 2007).
5. Special aspects of drug nanocrystals as formulation
approach for commercial drug product development
The value to use drug nanocrystals as enabling technology to
improve the performance of poorly water-soluble new chemical
entities has been recognized bymany companies. They haveadded
this approach to their formulation toolbox and have included it
to their formulation decision trees (Branchu et al., 2007; Chaubal,
2004; Ku, 2008; Li and Zhao, 2007; Maas et al., 2007; Möschwitzer
and Op’t Land, 2008).
Over the years many companies have recognized the need
for adopting their development strategies in order to address
the increased complexity of their pipeline candidates. Some have
even shifted their development efforts to the very early stages, an
approachwhichis oftenreferredto asfrontloading.Thisapproachis
used to increase the success rate of the drug discovery byenabling
a robust and reliable testing of poorly water-soluble compounds
very early on (Ku and Dulin, 2012). It has been estimated that the
improvement rate of the screeningprocess canbe increasedsignif-
icantly when the appropriate techniques for poorly soluble drugs
are available (Merisko-Liversidge and Liversidge, 2011).
Their scalability is one important factorwhy drug nanocrystals
are included in the formulation decision trees of so many com-
panies. As mentioned earlier, drug nanocrystals can be used at alldevelopment stages, since nanometer-sized drug particles can be
producedfromextremelysmall scale uptocommercial production.
Thefirst formulations for animal studies are neededwhen var-
ious lead compounds are tested in early pharmacokinetic studies
(PK) as well as in efficacy studies using pharmacological animal
models (PD). Such tests are normally performed at relatively low
dose levels. However, already at this stage nano-formulations can
offer some advantages: (1) due to the versatility of the nano-
approach almost any substance can be formulated in this way
provided it is poorly soluble enough so that a nanosuspension
can be made. The only strict prerequisite, like for any other top-
down method, is that the drug has to be poorly soluble in the
dispersion medium (e.g. an aqueous medium). The solubility limit
differs dependingon the employed nanosizing technique between10g/mland100g/ml(Merisko-Liversidgeand Liversidge,2008).
(2)FormulationsforveryearlyPKstudies shouldnot require exten-
sivedevelopment.Theyaremostlyperformedinrodents,inorderto
limittheAPIrequirements. InitialPK formulationshaveto berather
straight-forward and can be either solutions or suspension-based
systems (Li and Zhao, 2007). The purpose is primarily to estab-
lish important pharmacokineticparameters, suchas rate/extend of
absorption, clearance, and distribution volume. Many approaches,
suchas cyclodextrinformulations, lipidor surfactantbasedsystems
as well as nano-formulations are used (Chaubal, 2004). Nanosus-
pensions can be seen in this regardas universalplatformapproach
which isthepreferredoptionat thisstage.(3) A furtheradvantageof
usingnanosuspensionsalreadyat thatstageistheuniversal routeof
administration. Properly chosen, nanosuspensions can be admin-istered orally as well as parenterally without the need to adopt
the formulation. This allows establishing meaningful data for the
absolute oral bioavailability very early on.
In contrast to the simple PK formulations, the requirements for
pharmacologicalmodels aremorecomplex.Dependingon theindi-
cation and the pharmacologicalmodel the selection of a universal
formulation can be sometimes very challenging, especially when
some frequently used systems areexcluded because of their inter-
ference with the model read-out (Ghosh et al., 2008). In this case
nanosizing is an elegant approach; sometimes it might be even
the only technique that can be easily applied to develop the first
formulations for pharmacological tests. At this stage of develop-
ment the available drug amounts are normally extremely limited,
therefore only some standard formulations are tested. With an
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increased understanding on how to develop robust nanosuspen-
sions it is nowadays possible to obtain acceptable formulations in
a very short development time without using a lot of scarce drug
material (Chaubal, 2004).
When the efficacy of the new chemical entities (NCEs) is suffi-
ciently high, one needs to demonstrate andestablish thesufficient
safety margin for the selected lead compounds. Nanosuspensions
are ideal formulations for toxicological studies as they can be rel-
atively easily formulated with safe vehicle compositions that are
already established as standard excipients for toxicological test-
ing. In manycases standard cellulose/poloxamernanosuspensions
can be produced which differ only in their distinctly smaller par-
ticle size from NCEs formulated into standard suspensions for
toxicological studies (Kesisoglou et al., 2007; Maas et al., 2007).
Nanosuspensions are superior tox-formulations as their drug load
can be very high compared to other systems like surfactant solu-
tionsor amorphoussoliddispersions.The higherdrug load reduces
the effects which are potentially associated with excipients of the
formulation.
The use of nanosuspensions for toxicological studies has been
intensively discussed in the literature (Chaubal, 2004; Maas et al.,
2007; Sharma et al., 2011; Sigfridsson et al., 2011c). One publica-
tion provides a very comprehensive overview about preparation
andmanufacturing logisticsof nanosuspensions for sucha purpose(Kesisoglou et al., 2007). Another literatureexample demonstrated
that the safety margin could be raised from 5× to 85× by using
a nanosuspension instead of a suspension based on micronized
drug. The nanosuspension was prepared in a very simple way
by low energy WBM using a simple Eppendorf tube and zir-
conium beads (Kwong et al., 2011). For the acidic compound
UG558 the same positive trend was found. The nanosuspension
performed about 4.6 times better than the microsupension. In
addition, thenanosuspension could be administered intravenously
allowing the determination of the absolute bioavailability of the
compound (Sigfridsson et al., 2009). When compounds have dis-
solution rate limited oral bioavailability they should normally
show a linear dose/AUC relationship. However, in some toxico-
logical studies a non-linear absorption is seen at very high doselevels. In this case particle size reduction is not sufficient to
increase the exposure further as the systems turns from a disso-
lution rate limited to a solubility limited system (Sigfridsson et al.,
2011a).
Thenext stageofdevelopmentbeginswhena seriesofNCEs has
been successfully tested in pre-clinical programs and at least one
compound could be qualified as clinical candidate. Many compa-
nieshave implementedformulationrankingorspecialPKscreening
studies with the aim to identify the most appropriate formulation
approach for the first-in-human (FIH) studies. Several factors do
play a role in theselectionof theoptimal formulation approach for
human clinical trials.
In most of the cases the desired drug product will be an oral
solid dosage form. Nanosuspensions can be transferred into soliddosage form by applying various conventional drying techniques.
Spray drying is a straight-forward method for drying of nanosus-
pensions(Chaubal andPopescu,2008;Gaoet al., 2010;Lee, 2003). It
has the advantage of being as scalable as nanosizing itself. Often, it
is thefirst choiceatthebeginningof thedrugproductdevelopment,
because it can be easily performed at bench as well as pilot scale.
Thespraydried intermediatecanbe compressed to tablet formula-
tions ( Jinno et al., 2008). The tablet compositionhas to be selected
carefully, in order to obtain a fast and complete reconversion to a
nanosuspensionwitha particle sizedistribution comparable to the
non-dried formulation (Heng et al., 2009). In general, spray drying
yieldspowderswithratherlowdensities,whichcould requireaddi-
tional process steps, suchas roller compaction toobtain tablettable
intermediates.
Fluidizedbedgranulation is an alternativemethod to produce a
dryintermediate.Dueto theavailable equipmentit requires some-
what larger quantities of nanosuspension and is therefore used
at a later stage. During fluidized bed granulation the nanosus-
pension is normally layered onto a core material, e.g. lactose or
microcrystalline cellulose (Wang et al., 2012). This method results
in a free-flowing granulate which can be easily compressed into
tabletsina subsequentprocessstep.Spray-layeringofnanosuspen-
sions onto beads is an alternative approach (Kayaert et al., 2011;
Möschwitzer and Müller, 2006b). After an optional overcoating-
step the drug nanocrystal-loaded cores can be either filled into
capsules or transferred into tablets. Another interesting approach
is used for the commercial manufacturing of Rapamune® tablets.
Thenanosuspension is coatedonto inert tablet coreswhichconsist
basically of lactose monohydrate, macrogol and talc (EMA, 2004).
Energetically nanosuspensions can be regarded as high energy
systems, because surface area is significantly increased when the
particle size is reduced. Consequently, nanosuspensions tend to
reducetheir freeenergybyeitheraggregationorcrystalgrowth.For
a long time this ledto theperception that nanosuspensions as such
would have a limited shelf life and would not be suitable as ready-
to-use formulations. The physical stability of a nanosuspension
depends on many aspects, e.g. the selection of the right stabilizer
principle, thesolubility of theAPI in the liquidphaseof the suspen-sion and last butnot leastalso onthe employednanosizingmethod.
Butwithall parameters selectedcarefully, nanosuspensions canbe
physically aswell as chemically very stable systems. For both top-
downmethods, examples have been reported, where the particle
sizesof physically stablenanosuspensionsremainedunchanged for
years ( JacobsandMüller, 2002;Merisko-Liversidgeand Liversidge,
2011). These data indicate that nanosuspensions can indeed be
used as ready-to-use suspensions.This is also demonstratednicely
by the example of megestrole acetate; a formulation that was
developed with a shelf-life of two years (Merisko-Liversidge and
Liversidge, 2011).
In view of the flexibility of this approach it is to some extent
surprising why notmore formulationsbased on drug nanocrystals
have reached themarket yet. Many pharmaceutical companies donot have sufficient in-house capabilities both in terms of equip-
ment and know-how to develop drug nanocrystals for clinical
studies. Even if all necessaryprerequisites would be fulfilled, com-
panies may not have all IP rights to use the different approaches
for late-stage development programs (Müller and Keck, 2012). At
the time when the different technologies for drug nanocrystals
production have been developedmost pharmaceutical companies
did not put enough effort in developing their own IP portfolio
in the nano-area. One of the potential reasons might be that in
the nineties of the last century major pharmaceutical companies
had not fully realized the potential of this approach (Cooper,
2010). Although poor aqueous solubility was already at that time
recognized as an issue for drug product development, it was
still possible to select alternative molecules with better devel-opability. The perception was that the risk of developing poorly
soluble compoundswould be toohighandthereforewater-soluble
alternatives were chosen (Merisko-Liversidge and Liversidge,
2011). Obviously, the situation has changed dramatically. No
major pharmaceutical company can afford anymore to exclude
molecules with difficult physico-chemical properties from fur-
ther development. Nowadays, as result of extensive formulation
screening during pre-clinical programs, compounds with more
challenging properties are frequently selected as clinical candi-
dates. Consequently, enabling technologies are needed to support
human clinical studies. However, the selection of an optimal
formulation approach with regard to a potential bioavailability
enhancement is only one aspect. Other criteria are the availability
of suitable equipment for lab scale and pilot scale aswell as access
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