Wet Milling Particle Characterization

a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 2 5 5 e2 7 4
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Review
Overview of milling techniques for improving the

solubility of poorly water-soluble drugs
Zhi Hui Loh a, Asim Kumar Samanta b, Paul Wan Sia Heng a,*
a
GEANUS Pharmaceutical Processing Research Laboratory, Department of Pharmacy, National University of
Singapore, 18 Science Drive 4, Singapore 117543, Singapore
b
Janssen India, Department of PDMS-SMMD-AD, Johnson & Johnson Ltd., Higi House, Opp Ralli Wolf, LBS Marg,
Mulund (W), Mumbai 400080, India
article info abstract
Article history: Milling involves the application of mechanical energy to physically break down coarse
Received 10 August 2014 particles to finer ones and is regarded as a “topedown” approach in the production of fine
Received in revised form particles. Fine drug particulates are especially desired in formulations designed for
28 December 2014 parenteral, respiratory and transdermal use. Most drugs after crystallization may have to
Accepted 29 December 2014 be comminuted and this physical transformation is required to various extents, often to
Available online 17 February 2015 enhance processability or solubility especially for drugs with limited aqueous solubility.
The mechanisms by which milling enhances drug dissolution and solubility include al-
Keywords: terations in the size, specific surface area and shape of the drug particles as well as milling-
Drug solubility induced amorphization and/or structural disordering of the drug crystal (mechanochem-
Fluid energy milling ical activation). Technology advancements in milling now enable the production of drug
Ball milling micro- and nano-particles on a commercial scale with relative ease. This review will
Media milling provide a background on milling followed by the introduction of common milling tech-
High pressure homogenization niques employed for the micronization and nanonization of drugs. Salient information
Cryomilling contained in the cited examples are further extracted and summarized for ease of refer-
ence by researchers keen on employing these techniques for drug solubility and
bioavailability enhancement.
© 2015 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. This is
an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).
rate of dissolution of a drug is affected by factors embodied in

1. Introduction the NoyeseWhitney equation [1]. The extent to which drug
dissolution proceeds under prevailing physiological condi-
The process of drug dissolution is critical to the therapeutic tions is governed by its aqueous solubility. Drug solubility is
efficacy of a medicinal product regardless of its route of defined as the amount of drug that passes into solution when
administration. Dissolution involves the transfer of a solid an equilibrium is established between the drug solute in so-
drug into solution in the surrounding physiological fluid. The lution and any excess, un-dissolved drug to produce a
* Corresponding author. GEANUS Pharmaceutical Processing Research Laboratory, Department of Pharmacy, National University of
Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Tel.: þ65 6516 2930; fax: þ65 6779 1554.
E-mail address: [email protected] (P.W. Sia Heng).
Peer review under responsibility of Shenyang Pharmaceutical University.
http://dx.doi.org/10.1016/j.ajps.2014.12.006
1818-0876/© 2015 Shenyang Pharmaceutical University. Production and hosting by Elsevier B.V. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
256 a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 2 5 5 e2 7 4
saturated solution at a specified temperature [2]. The solubil- molecularly or as ultrafine crystals [9]. Alternatively, the drug
ity and dissolution rate of a drug are often positively corre- molecule may be modified chemically by the syntheses of
lated. The bioavailability of a drug is defined as the rate and suitable pro-drugs [10] or salt forms of the drug that often
extent to which a dissolved drug is absorbed and becomes exhibit greater aqueous solubility than the parent molecule.
available at its target site of action [3]. The bioavailability of a However, drug precipitation is a common threat faced by some
drug is thus dependent not just on its dissolution and solu- of these formulations [11]. Precipitation may arise from excess
bility characteristics, but also on its membrane permeability drug coming out of solution when a previously supersaturated
and associated absorption-related degradation. drug solution is diluted upon administration. For oral formu-
Currently, the pharmaceutical industry faces considerable lations, drug precipitation maybe triggered by the changing pH
challenges associated with the increasing number of poorly environment of the gastro-intestinal tract. To ensure that a
water-soluble drugs coming through the drug discovery pipe- drug stays in solution up till the point of absorption, lipids and
line [4,5]. Despite promising pharmacological activity, many of oils have been employed as drug carriers. Lipid formulations of
these drug candidates fall under class II of the Bio- drugs basically comprise drugs dispersed, but more often,
pharmaceutics Classification System (BCS), characterized by dissolved, in lipids or oils. These formulations improve drug
high membrane permeability but low aqueous solubility [6]. bioavailability by exploiting the innate lipid digestion and
These drugs exhibit erratic or incomplete absorption often absorption mechanisms in the body. Depending on the
leading to unsatisfactory drug exposure in vivo and poor chemical nature of the lipid, the formulation may also self-
bioavailability. Biopharmaceuticals and biotechnology- emulsify in the gastro-intestinal tract to facilitate lipid diges-
derived therapeutic agents face similar challenges [7]. For tion and maximize drug absorption. The advantage of lipid
BCS class II drugs, the dissolution step is the rate-determining formulations is that the drug is maintained in a solubilized
factor in drug absorption. Pharmaceutical scientists are state prior to absorption. A comprehensive reference on oral
constantly seeking new approaches to facilitate and enhance lipid-based formulations can be found in the book edited by
the solubility and thus dissolution rate of BCS class II drugs. David J. Hauss [12]. The key advantages and disadvantages of
Current strategies employed to improve the apparent solubi- the different strategies employed to improved drug dissolu-
lity of a drug include the use of: (i) co-solvents (e.g. low motion and bioavailability are highlighted in Table 1.
lecular weight polyethylene glycols and propylene glycol) in
combination with water to dissolve the drug; (ii) complexing
agents (e.g. cyclodextrins and its derivatives) to form water- 2. Milling
soluble inclusion complexes of the drug [8] or (iii) hydrophilic
excipients (e.g. polyvinylpyrrolidones and high molecular Apart from the techniques aforementioned, another strategy
weight polyethylene glycols) as drug carriers for the prepara- employed to improve solubility and ultimately, bioavailability
tion of solid dispersions in which the drug is dispersed of poorly water-soluble drugs is milling. The terms milling,
Table 1 e Key advantages and disadvantages of common strategies employed to improve drug dissolution and
bioavailability.
Technique Advantages Disadvantages
Use of co-solvents Simple technique Toxicity of solvents
Lower costs involved Risk of drug precipitation in-vivo
Applicable for a wide range of drugs Limited to liquid formulations
Complexation using Improves the chemical stability of the drug Successful complexation depends on both chemical
cyclodextrins May potentially enhance drug absorption by modifi- and geometrical properties of drug molecule
cation of lipid barrier Large amounts of cyclodextrins may be required due
to low complexation efficiencies
Higher costs involved
Solid dispersions Creates fine drug particles without excessive applica- Preparation method is difficult to scale up
tion of energy Amorphous drug forms created are physically unsta-
Fine particles are readily wetted with minimal risk of ble and may convert to crystalline forms during stor-
agglomeration age, accelerated by moisture absorption by the
Wide range of hydrophilic polymers are available as hydrophilic carrier
drug carriers
Chemical modification Prodrugs may enable drug targeting and improve drug Toxicity potential of prodrugs
(e.g. prodrugs) stability Fate of prodrugs is difficult to predict in-vivo due to
biological variations in the way they are handled in the
body
Lipid formulations Exploits the innate lipid digestion mechanisms of the Amount of lipids typically present in the formulation
body to enhance drug bioavailability may be insufficient to trigger an appropriate physio-
Emulsifiable lipid formulations further enhance lipid logical response to enhance drug bioavailability
digestion and drug bioavailability Quality control of lipid-based formulations is
Diversity of lipid excipients allow formulation challenging due to the complex and diverse
flexibilities physicochemical properties of lipids and the lack of
Lower risks of drug precipitation in-vivo standardized testing methods
a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 2 5 5 e2 7 4 257
size reduction, comminution, grinding and pulverization are counterparts. Based on the NoyeseWhitney equation, this is
often used interchangeably. Milling is a unit operation where likely to increase the dissolution rate of the milled drug parti-
mechanical energy is applied to physically break down coarse cles if the particles can also be adequately wetted. Milled par-
particles to finer ones and hence, is regarded as a “topedown” ticles possess higher surface free energies and this, coupled
approach in the production of fine particles [13]. As virtually with their thinner diffusion boundary layers [16] further
every drug can be comminuted to fine particles regardless of enhance the dissolution rate of the milled drug substance.
its solubility in aqueous or non-aqueous solvents, the “tope- Apart from size, milling also alters the surface roughness
down” approach has wider commercial and industrial appli- and shape of particles. This has been demonstrated in many
cations than the “bottom-up” approach (e.g. precipitation) studies on the development of inhalable dry powder formu-
where fine particles are constructed from their dissolved lations. It has been shown that the surface properties of milled
molecular state and suitable solvents/anti-solvents of the particles can affect wetting [17] and dissolution behavior [18].
drug need to be selected. Furthermore, milled particles are rarely isometric or spherical
Traditionally, milling is carried out to facilitate the extrac- in shape. Compared to particle size, considerably lesser
tion of crude drugs or to improve their bulk processing prop- attention has been devoted to the impact of particle shape
erties. Cutter mills, roller mills, pestle and mortars and runner [19e23] on drug dissolution, solubility and bioavailability
mills may be employed for this purpose. In these milling op- although early studies have demonstrated that when particles
erations, the dried crude drug may be cut by sharp blades are platelet-like or possess needle shapes, the shape factors of
(cutter mill), impacted by hammers or crushed/compressed by particles are closely related to their dissolution rates and
the application of pressure (roller mill, pestle and mortar). As a profiles [24e28]. Particle shape may be determined by image
limited amount of energy is imparted, the milled particles analysis techniques, laser diffraction [29], scanning electron
remain relatively coarse. Technological advancements in microscopy, transmission electron microscopy and atomic
milling equipment now enable the production of ultrafine drug force microscopy.
particles down to the micron or even sub-micron dimensions. In a milling operation, particle size reduction ceases at a
Griseofulvin, an anti-fungal drug, represents one of the pio- practical limit [30] beyond which the material becomes pro-
neering examples of drugs where solubility and absorption gressively difficult to comminute even when milling time is
were enhanced by milling. Milling of carbamazepine was found prolonged. When particle size reduction has reached a critical
to be more effective in enhancing drug dissolution than threshold, the continued transfer of mechanical energy from
formulating the drug as a solid dispersion due to polymorphic the mill to the drug substance leads to the accumulation of
transformation of the drug (from the b to a form) in the solid defects on the drug crystal and disordering of the crystal
dispersion system [14]. Other early examples of drugs where structure, eventually bringing about the disappearance of the
milling has resulted in enhanced dissolution include nitro- order in the positions of atoms or molecules in the crystal [31].
furantoin, nifedipine, ibuprofen and spironolactone [3]. These defects may manifest throughout the entire crystal
Milled drug particles are rarely used as it is and are in- resulting in complete amorphization of the drug or be
termediates in the production of pharmaceutical dosage restricted to the crystal surfaces in which case a thin, amor-
forms. Oftentimes, they are cohesive and exhibit poor flow phous (disordered) layer may be formed around a crystalline
properties, largely due to their higher surface energies (ordered) core [32,33]. Under these circumstances, the drug is
compared to their coarser counterparts. To alleviate this said to be “mechanochemically-transformed” or “activated” by
problem, inert pharmaceutical excipients or fillers, e.g. cal- the milling process. Drug amorphization as a result of milling
cium phosphate, lactose, mannitol and other sugars etc., are improves the aqueous solubility and dissolution characteristics
often added and mixed with the milled drug particles to of the drug. It may also confer additional benefits such as
improve powder flow. Alternatively, the drug particles may be improved compressibility [34]. Milling-induced amorphization
granulated with these fillers to form granules which typically of drug substances have been reported for piroxicam [35],
exhibit improved flow properties and content uniformities budesonide [36], naproxen [37] and indomethacin [38] amongst
than the corresponding physical mixtures. Apart from many others. However, the disadvantage of these solid state
improving flow during manufacturing, these fillers may also transformations is that amorphous regions or crystal defects
serve other functions e.g. modifying drug release, enhancing created may be thermodynamically unstable, leading to
drug stability and dissolution as well as taste-masking. amorphous-crystalline inter-conversions of the drug during
storage, alteration of particle size distribution, specific surface
area, chemical and physical reactivity, dissolution or overall
3. Mechanisms by which milling improves performance of the drug product [39].
drug dissolution and solubility An approximate measure of the extent of milling-induced
drug activation may be obtained experimentally by deter-
Milled products possess specific physical attributes that mining the amorphous content or residual crystallinity before
contribute to improved drug dissolution and solubility. Milling and after milling the drug substance using standard solid-
reduces the size and alters the size distribution of the drug state characterization tools such as x-ray powder diffraction
particles. These properties may be measured by light scattering (XRPD), Raman spectroscopy or differential scanning calo-
techniques such as photon correlation spectroscopy (5 mm rimetry. As the information obtained from these different
down to 0.001 mm) and laser diffraction (0.05 mme2000 mm), techniques complement each other, a combination of tech-
respectively [15]. By virtue of their smaller size, milled particles niques is often desired to fully elucidate the solid-state con-
possess larger specific surface area compared to their unmilled dition of the milled drug substance. The solubility of many
drugs e.g. griseofulvin [40], chloramphenicol palmitate, indo- cellulose, polyvinylpyrrolidone and poloxamer), singly or in
methacin and phenylbutazone have been enhanced by combination, helps to minimize the agglomeration of sus-
mechanochemical activation. Comprehensive information on pended particles via electrostatic and steric mechanisms. Steric
the mechanochemical activation of drugs can be obtained in stabilization is achieved when long chain polymers are adsor-
the review by Boldyrev [31]. bed onto the surfaces of the drug particles, forming a physical
barrier that prevents the close approach of the particles. The
chain length, molecular weight [45], hydrophobicity [46,47],
4. Milling adjuvants concentration, shape and surface energy [48] of the polymer
will influence the efficiency of adsorption. The method of
The micro or nanoparticles produced from milling possess a adding the polymer (periodic additions or addition at the start of
large surface/interfacial area, increased free energy and milling process) also affected its stabilizing properties [49].
decreased thermodynamic stability. These factors promote Electrostatic stabilization is achieved when charged polymers
particle agglomeration. Mechanochemically-activated parti- or ionic surfactants become Adsorbed on the surfaces of the
cle surfaces and amorphous regions generated during milling drug particles and lower their apparent charge. Apart from
also increase the surface free energy of the particles, favoring preventing agglomeration, these stabilizing molecules may also
agglomeration. In practice, it has been suggested that particle aid in preventing crystal growth (Ostwald ripening) that could
agglomeration arising from van der Waals' and other forces adversely alter the dissolution and bioavailability of the drug
(e.g. electrostatic forces) become significant at particles sizes suspension after storage. Hydroxypropylmethyl cellulose (3
of about 30 mm and below [41]. Fine, hydrophobic drug parti- cps) was found to stabilize and minimize crystal growth in a
cles less than 5 mm in size are known to be exceptionally prone nanosuspension of an unidentified drug compound NSV-102
to agglomeration and this is attributed to the inter-particulate (Novartis Pharma) produced by media milling, an example of
cohesive forces between them. Hence, when milling is pro- wet milling. This was attributed to improved surface coverage
longed, particle agglomeration may supersede particle frac- owing to its stronger interaction with the drug in comparison
ture and this severely reduces the efficiency of the mill over with other stabilizers, pluronic F-68, pluronic F-127, sodium
time. Agglomeration occurring during or after milling reduces lauryl sulfate and polyvinylpyrrolidone K-30, investigated [50].
the effective surface area of the drug particles, with their A screening study of polymers, copolymers, and surfactants
resultant dissolution rate and bioavailability, being compara- has revealed that the stabilizing performance of surfactants to
ble or even less than their untreated counterparts. It was be the best followed by linear synthetic polymers and semi-
observed that continued milling of ketoconazole in a cryo- synthetic polymers for the 9 drug compounds (cinnarizine,
genic impact mill led to apparent particle size growth by fine griseofulvin, indomethacin, mebendazole, naproxen, phenyl-
particle mechanofusion [42]. Aspirin, phenacetin and pheno- butazone, phenytoin, itraconazole and loviride) investigated
barbital are known to be prone to the effects of aggregation [51]. Common adjuvants employed in the dry and wet milling of
during particle size reduction. drugs are summarized in Tables 2e4.
In most cases, drugs are co-milled together with certain Achieving the desired size, shape and activation of drug
adjuvants to minimize the conditions promoting agglomera- particles in a milling process often requires extensive opti-
tion. These adjuvants are inert, non-toxic pharmaceutical mization of a multitude of process and material-related vari-
excipients that function as a carrier and/or stabilizer of the ables. In terms of processing, a prudent selection of the type of
drug in the milled product. There is considerable variation in milling equipment is required, followed by the adjustment of
the amount of excipient employed, with drug to excipient the conditions of milling such as the duration of milling,
ratios ranging from 1:3 to 50:1 w/w being reported in the material feed rate and other operational or equipment pa-
literature [43]. Typically, the excipient employed is hydro- rameters. Occasionally, a combination of milling techniques
philic in nature and notable examples are hydrophilic poly- may be necessary to achieve the desired outcomes. When
mers such as polyvinylpyrrolidone, cellulose ethers, such combination techniques are used, numerous process-
polyethylene glycol, polyvinyl alcohol or poloxamers; surfac- related variables need to be adjusted and fine-tuned as this
tants, ionic or non-ionic; inorganic materials like magnesium allows the unique advantages of each milling technique to be
aluminometasilicate [44] and cyclodextrins. By conferring synergistically combined for the desired outcome. Suitable
hydrophilicity to the hydrophobic drug particle surfaces, the and compatible adjuvants have to be selected to minimize
added excipient also enhances the wettability, solubility and agglomeration, improve wetting, stability and resultant solu-
bioavailability of the poorly water-soluble drug. bility of the milled drug particles. The following sections will
The efficiency of a particular stabilizer depends on its po- provide the background from literature on the common mill-
tential for interaction with the drug compound. Generally, ing techniques employed for size reduction.
milling may be conducted with the drug in its dry state (dry
milling) or suspended in a liquid medium (wet milling). In dry
milling, the mechanical energy imparted fosters drug-excipient 5. Milling techniques for the production of
interactions via van der Waals forces or hydrogen bonding. The microparticles
resultant drug-excipient composite particles are often stable,
exhibit low tendencies to agglomerate and retain the activated 5.1. Fluid energy milling
status of the drug [31,34]. In wet milling, the addition of sur-
factants (e.g. sodium lauryl sulfate and polysorbate 80) and Fluid energy milling, sometimes referred to as air jet milling,
polymers (e.g. hydroxypropylmethyl cellulose, hydroxypropyl effectively reduces the size of drug particles from the range of
Table 2 e Summary of examples obtained from scientific literature on the use of media milling for the production of drug
nanoparticles.
Drug Adjuvants Variables Mean particle size Equipment Authors
or particle size
range attained
Naproxen Vit E TPGS, Different <500 nm Planetary mill (Retsch PM 400 MA, [122]
pluronic F127, stabilizers Retsch, Haan, Germany)
SLS, DOSS, HPMC
3 cps
Griseofulvin HPC, SLS Concentration of 50-250 nm Wet-stirred media mill (Microcer, [123]
HPC Netzsch Fine Particle Technology,
PA, US)
Unidentified compound Vit E TPGS Concentration of <300 nm Planetary mill (PM400, Retsch, [124]
NVS-102 Vitamin E TPGS Newtown, PA, US)
Fenofibrate HPMC, DOSS Milling speed <700 nm Agitator ball mill (Dyno Mill [125]
Research Lab, WAB, Muttenz,
Switzerland)
Ibuprofen (transdermal) Pluronic F127, Vit Different 123 ± 4 nm Planetary mill (PM400, Retsch, [83]
E TPGS, PEG, PVP stabilizers Haan, Germany)
Paclitaxel Pluronic F68 and Different 307 ± 12 nm Roller-mill (Peira, Beerse, Belgium) [126]
(intraperitoneal) F127 stabilizers and
stabilizer ratios
Compound A (oral) Vit E TPGS, HPMC Stabilizer level 138.6 nm Media mill (Netzsch Labstar Mill, [127]
3cps and drug loading Exton, PA, USA) with a zeta agitator
in the recirculation mode
Griseofulvin, naproxen, HPMC (E15LV), Effect of different 163 nm Wet-stirred media mill (Microcer, [73]
fenofibrate (oral) SLS drugs on film (griseofulvin); Netzsch Fine Particle Technology,
properties 201 nm (fenofibrate); LLC, PA, US)
144 nm (naproxen)
Indomethacin Poloxamer 188 e 485 nm Planetary ball mill (Pulverisette 7 [86]
(inhalation) Premium, Fritsch, Germany)
Phenytoin (oral) PVP, SLS e ~300 nm Oscillating beads-milling [84]
apparatus (Multi-Beads Shocker,
Yasui Kikai, Osaka, Japan)
Itraconazole, HPMC (4000 Different drugs 8.72 ± 5.66 mm Wet milling machine (Micros- [49]
fenofibrate, e5600 cp), Tw80, and stabilizers (itraconazole); 0 Ring Mill, Nara Machinery, Tokyo,
griseofulvin, SLS, sodium 3.37 ± 2.48 mm Japan)
ibuprofen, alginate (fenofibrate);
azodicarbonamide, 2.65 ± 1.12 mm
sulfamethoxazole (griseofulvin)
3.30 ± 2.18 mm
(ibuprofen)
0.67 ± 0.52 mm
(azodicarbonamide)
0.63 ± 0.56 mm
(sulfamethoxazole)
Unidentified compound Vit E TPGS, Effect of different 230.2 ± 0.257 nm Media mill (Netzsch Labstar Mill, [50]
NVS 102 (oral) pluronic F68 and stabilizing agents Exton, PA, US) with a zeta agitator
F127, HPMC 3cps, on crystal growth in the recirculation mode
SLS, PVP K-30
Phenytoin, nifedipine, PVP, HPC, HPMC, Different scales 292 nm (phenytoin) Oscillating beads-milling [128]
pranlukast (oral) PVA, SLS, Tw80 of preparation 353 nm (nifedipine) apparatus (Multi-Beads Shocker,
334 nm (pranlukast) Yasui Kikai, Osaka, Japan)
Miconazole SLS, sodium Formulation 140 ± 1 nm Media mill (Netzsch Labstar Mill [129]
(ophthalmic) docusate, variables Selb, Germany)
benzalkonium
chloride, HPC-LF,
HPC-EF, PVP,
poloxamer,
HPMC
Candesartan cilexetil SLS, poloxamer Drug and 127 nm Heidolph mixer (RZR2051Control, [85]
(oral) 188, PVP K-30, stabilizer Rose Scientific, Alberta, Canada)
HPMC 6 cps concentrations
(continued on next page)
Table 2 e (continued )
Drug Adjuvants Variables Mean particle size Equipment Authors
or particle size
range attained
Cilostazol (oral) HPC, DOSS Different milling 260 nm Agitator ball mill (Dyno-Mill KDL [130]
processes Type-A, Willy A. Bachofen AG
Maschinenfabrik, Basel,
Switzerland)
Zn-insulin Sodium Different <150 nm Low energy wet media mill [131]
(subcutaneous and deoxycholate, stabilizers (Stoneware, East Palestine, OH, US)
intraduodenal) pluronic F68
Ethyl diatrizoate (radio- Poloxamine 908 Different 230 ± 10 nm Roller mill (Stoneware, East [132]
contrast medium) formulation Palestine, OH, US)
variables
Abbreviations: DOSS, dioctyl sulfosuccinate sodium; HPC, hydroxypropylcellulose; HPMC, hydroxypropylmethyl cellulose; PEG, polyethylene
glycol; PVA, polyvinyl alcohol; PVP, polyvinylpyrrolidone; SLS, sodium lauryl sulfate; TPGS, d-alpha tocopheryl polyethylene glycol 1000 suc-
cinate; Tw80, Tween 80 (polysorbate 80); Vit, vitamin.
20e100 mm to less than 10 mm. In this micronization method, excipient mixture [56]. This was attributed to the persistence
high velocity compressed air streams are injected into a of aggregates of pure, jet-milled fenofibrate which retarded
chamber where the starting raw materials are fed by a rate- drug dissolution. In an attempt to improve the bioavailability
controlled feeder (Fig. 1). As the particles enter the air of EMD 57033, a poorly water-soluble calcium sensitizing
stream, they are accelerated and caused to collide with each agent, Vogt et al. [57] found that co-grinding a mixture of EMD
other and the wall of the milling chamber with high velocities. 57033 with lactose and hydroxypropylmethyl cellulose using a
Particle size reduction is brought about by a combination of fluid energy mill was more effective than micronizing the drug
impact and attrition. Impacts arise from collisions between alone or spray drying a nanosuspension of the drug. Fluid
the rapidly moving particles and particles onto the wall of the energy milling of ibuprofen together with nanosilica was
milling chamber. Attrition occurs at surfaces of particles as carried out by Han and co-workers [58]. It was found that fluid
they move rapidly against each other, resulting in shear forces energy milling not only decreased the size of drug particles
that may break them up. A classifier may be integrated into from 102 to <10 mm but also facilitated the coating of nano-
the milling system such that only particles that are suffi- silica on the surfaces of the milled drug particles. This surface
ciently fine or have acquired dimensions below the pre- modification brought about by milling reduced particle
defined cut-off size are entrained in the exhausting air agglomeration and improved powder flow.
stream and removed from the milling chamber. Classification However, the popularity of fluid energy milling has some-
may be effected by a spinning wheel classifier where the what dipped following the development of other milling tech-
centrifugal force generated by the high spinning speed of the niques capable of effecting greater extents of size reduction,
fluted wheel limits the cut-off size of particles that can enabling the production of sub-micron or nanoparticles at
accompany the exhausting air through the wheel to the air commercial scale. The lowest mean particle diameters
exhaust outlet. Alternatively, a large tubular shaped milling achievable by fluid energy milling is 3e5 mm with size distri-
chamber, circular or oblong, may be used, with colliding air bution ranging from a few hundred nanometers to about 25 mm
jets at the periphery and the exhaust air leaving centrally, and a very low fractional content of nanoparticles [59]. None-
causing a centrifugal classification system for the milled theless, this milling technique remains as a benchmark for the
particles. Longer durations of milling are required when finer evaluation and development of new milling methods and
particles are desired. This process is suitable for meltable strategies. In the context of drug solubility enhancement, fluid
materials [52] and drugs that are heat-sensitive. It is also energy milling may be employed in combination with other
capable of manufacturing large quantities of powder particle design techniques (e.g. “bottom-up” approaches such
continuously. as precipitation, crystallization) to produce drug microparticles
Fluid energy milling has been successfully employed for with desirable morphological characteristics. Fluid energy
the micronization of many drugs for the purpose of improving milling of ibuprofen was investigated and found generally hard
their dissolution and solubility characteristics. Some exam- to mill in its dry state due to its ductility and low melting point
ples include ibuprofen [53], salbutamol sulfate [54] and feno- [53]. In the study, ibuprofen crystals of different sizes (<40 mm or
terol hydrobromide [55]. Drugs are commonly milled on their 50e250 mm) and morphologies (plate-like and needle-like crys-
own although occasionally, co-milling with suitable excipi- tals) were first produced by controlled crystallization. It was
ents is carried out. It was reported that fluid energy milling of reported that the drug could be milled down to less than 5 mm,
a blend of fenofibrate, a poorly water-soluble drug, together which is below the reported particle size for brittleeductile
with a mixture of hydrophilic excipients resulted in faster transition of the drug. Furthermore, it was observed that the
drug dissolution rates from a rapidly disintegrating dosage size and morphology of the starting drug crystals influenced the
form compared to a powder formulation of identical compo- milling outcome. Compared to plate-like crystals, needle-like
sition prepared by mixing pre-milled fenofibrate with the crystals were more susceptible to micronization. Milled
Table 3 e Summary of examples obtained from scientific literature on the use of high pressure homogenization for the
production of drug nanoparticles.
Drug Adjuvants Operating Minimum/avg Equipment Ref
parameters particle size
Telmisartan (oral) b-cyclodextrin, 15 cycles at 1200 bar 698 ± 23 nm High pressure homogenizer (Niro [133]
meglumine Soavi, Italy)
Nitrendipine (oral) PVA 20 cycles at 1000 bar 175 nm High pressure homogenizer [99]
(AH100D, ATS Engineering,
Shanghai, China)
Ketoprofen PLGA, CO2, PVA, ethyl Pressure drop of 1.34 mm High pressure piston pump [97]
acetate 900 bar & up to 150 (Haskel, Burbank, CA, US)
passes
Quercetin (topical) Tristearin, 1 or 2 cycles at 1000 bar 486 nm Hot and cold high pressure [134]
hydrogenated homogenizer (Panda 2K GEA; Niro
phosphatidylcholine Soavi, Parma, Italy)
Unidentified compound Pluronic F68, lipoid S75 15 cycles at 7250 psi, 5 187.6 ± 19.11 nm High pressure homogenizer [135]
PIK75 (intravenous) cycles at 15 000 psi and (Emulsiflex-C3, Avestin, Canada)
15 cycles at 18,000 psi
at 2e4 C.
Curcumin PVA, PVP, Vit E TPGS, 2 cycles each at 300, 500-700 nm High pressure homogenizer [136]
SLS, Na CMC 500 & 1000 bar (Micron LAB 40, APV Deutschland,
followed by 20 cycles Unna, Germany)
at 1500 bar
Fish oil (intravenous) Lecithin and glycerol 5 cycles at 500 150 nm High pressure homogenizer [137]
e1500 bar (Micron LAB 40, APV Deutschland,
Unna, Germany)
Tanshinone IIA Soybean lecithin, 3 cycles at 100 MPa 251.7 ± 16.6 nm High pressure homogenizer [138]
(intravenous) poloxamer 188, (Avestin, Ottawa, Canada)
glycerol, soybean oil,
medium-chain
triglyceride
Itraconazole (oral) Chitosan, N-trimethyl 2 cycles each at 150, 267.6 ± 15.8 nm High pressure homogenizer [139]
chitosan, 500, 1000 bar followed (AH100D, ATS Engineering,
polyethyleneimine by 15 cycles, 1350 bar Shanghai, China)
Emodin (oral) Poloxamer 188, Tw80, 500, 700, 900 bar with 28.6 ± 3.1 nm High pressure homogenizer [140]
compritol 888 ATO, 3, 4 and 5 cycles (NS1001L, Niro Soavi, Italy)
GMS, stearic acid,
lauric acid
Beclomethasone e 2 cycles each at 150 & 247 nm High pressure homogenizer [141]
dipropionate 300 bar followed by (AH110D, ATS Engineering, Italy)
(inhalation) 500 bar for different
homogenization
cycles
Baicalein (oral and Tw80, SLS, poloxamer 5 cycles at 200 bar 287 ± 5 nm High pressure homogenizer (NS [142]
parenteral) 188 followed by 5e35 1001L, Niro Soavi, Italy)
cycles at 1000 bar
Recombinant human Hydrogenated 2 cycles at 1000 bar 155.57 ± 2.59 nm High pressure homogenizer [143]
epidermal growth phospholipid, (Emulsiflex-C3, Avestin, Canada)
factor (topical) triglycerides,
diethylamine
cetylphosphate,
butylated hydroxyl
toluene in ethanol, Na
ascorbyl phosphate,
EDTA
Atorvastatin (oral) Chitosan 1e3 cycles at 20,000 214.8 ± 15.8 nm High pressure homogenizer (Nano [144]
e40,000 psi DeBEE, BEE International, MA, US)
Pranlukast (oral) Poloxamer 407, PEG 680 bar e 15 circles, 315.4 ± 4.2 nm High speed homogenizer (Ultra- [145]
200 1048 bar e next 9 Turrax T-18 Basic, IKA-Werk,
circles & 1500 bar e Staufen, Germany)
last 9 circles
Quercetin Tw80 2 cycles each at 300 & 338.3 nm High pressure homogenizer [146]
500 bar, 1 cycle at (Micron LAB 40, APV Deutschland,
1000 bar followed by 20 Unna, Germany)
cycles at 1500 bar
(continued on next page)
Table 3 e (continued )
Drug Adjuvants Operating Minimum/avg Equipment Ref
parameters particle size
Fenofibrate (oral) Soybean protein 1 to 10 cycles at100 to 200 to 250 nm High pressure homogenizer (ATS [147]
isolate, whey protein 800 bar Engineering, Ontario, Canada)
isolate, egg
phosphatidylcholine,
b-lactoglobulin,
cremophor EL and RH
40, poloxamer 188,
solutol HS15, Tw80
Astaxanthin (topical) Tween 60, glyceryl 1000 bar 160e190 nm High pressure homogenizer [148]
citrate/lactate/ (Panda, Niro Soavi, Italy)
linoleate/oleate, liquid
paraffin, ceramide, co-
anti oxidants,
cholesterol
Flurbiprofen (ocular) Glycerol behenate, 3 homogenization <199 nm High pressure homogenizer (APV- [149]
saturated fatty acid of cycles at 600 & 60 bar 2000, Invensys, Albertslund,
C18, Tw80 in first & second stage, Denmark)
respectively, at 85 C
Puerarin Lecithin and HPMC 6 cycles at 800 bar 448.9 ± 15.1 nm High pressure homogenizer [150]
followed by 15 cycles (Emulsiflex-C3 Avestin Inc.,
at 1500 bar Ottawa, Canada)
Camptothecin e 2 cycles each at 200 & 125.1 ± 8.6 nm High pressure homogenizer [151]
400 bar followed by 20 (NS1001L-Panda 2K, Niro Soavi,
cycles at 1300 bar Italy)
Co-enzyme Q10 (oral) Sucrose monolaurate, 20 homogenization 282 ± 15 nm Melt high pressure homogenizer [152]
mixture of mono, di & cycles at 800 bar (nanocrystals); (ATS Engineer, China)
triglycerides, medium- 143 ± 10 nm
chain triglycerides (lipid nanoparticles)
Quercetin Tw80 2 cycles each at 300 & 338 nm High pressure homogenizer [153]
500 bar, 1 cycle at (Micron LAB 40, APV Deutschland,
1000 bar & finally, 20 Unna, Germany)
cycles at 1500 bar
Lutein (oral and dermal) Decyl glycoside 2 cycles each at 200, 429 nm High pressure homogenizer [154]
500 & 1000 bar (Micron LAB 40, APV Deutschland,
followed by 25 cycles Unna, Germany)
at 1500 bar
Alkylpolyglycoside C8- Neutral oil, glycerol 3 cycles at 750 bar 150.40 ± 3.79 nm High pressure homogenizer [155]
10 (dermal) distearate, (EmulsiFlex-C3, Avestin, Germany)
Piroxicam (oral) Poloxamer 188 3 cycles at 500 bar and 414.3 ± 21.1 nm High pressure homogenizer [156]
30 cycles at 1500 bar (EmulsiFlex-C5 Avestin, Ottawa,
Canada)
Glibenclamide (oral) e 2 cycles at 500 bar 335 nm High pressure homogenizer [101]
followed by 20 cycles (Micron LAB 40, APV Deutschland,
at 1500 bar Unna, Germany)
Itraconazole (inhalation) Sodium taurocholate, 300 cycles at 20 000 psi 221 ± 10 nm High pressure homogenizer [157]
polyethylene 1000 (Emulsiflex-C5 Avestin, Ottawa,
succinate, poloxamer Canada)
407, Vit E
Abbreviations: CMC, carboxymethyl cellumose; EDTA, ethylenediamine tetraacetic acid; GMS, glycerol monostearate; HPMC, hydrox-
ypropylmethyl cellulose; PEG, polyethylene glycol; PLGA, poly(lactic-co-glycolic acid); PVA, polyvinyl alcohol; PVP, polyvinylpyrrolidone; Vit,
vitamin; SLS, sodium lauryl sulfate; Tw80, Tween 80 (polysorbate 80).
particles produced from smaller-sized starting materials also systems. Drug microparticles produced from fluid-energy
exhibited smaller volume mean diameters compared to their milling may be subjected to a subsequent milling process to
coarser counterparts for both morphologies of ibuprofen par- attain particles in nanoscale dimensions. In a study, horse-
ticles. The authors explained that with proper control of the radish peroxidase enzyme as a model drug was loaded in a
crystal attributes of the starting material, fluid energy milling suitable polymer matrix and pre-micronized using a fluid en-
might be equally, if not more effective than wet milling in ergy mill [60]. The protein-polymer microparticles were then
reducing the particle size of drugs. Despite it being a micron- subjected to a nanonization process (high pressure homogeni-
ization technique, fluid energy milling also plays a significant zation) to produce stable, protein-loaded nanoparticles with
role in the development of nanoparticulate drug delivery controlled drug release properties.
Table 4 e Summary of examples obtained from scientific literature on the use of cryomilling for the production of drug
nanoparticles.
Drug Adjuvants Variables Observations Equipment Ref.
Phenytoin PVP e Novel ultra cryomilling Wet milling machine (RMB- [102]
micronization technique using dry 04, Aimex, Tokyo, Japan)
ice beads and liquid nitrogen
Phenytoin PVP, Eudragit L100, e Enhancement of dissolution rate Wet milling machine (RMB- [105]
HPMC, HPMC with phenytoin nanoparticles 04, Aimex, Tokyo, Japan)
acetate-succinate,
MCC, HPC, CMC
Indomethacin e Milling time Dissolution rate depended on the Oscillatory ball mill (Mixer [38]
milling time Mill MM301, Retsch, Haan,
Germany)
Griseofulvin e Milling time Continued mode of attrition with Cryogenic impact mill (Spex [42]
milling time CertiPrep 6750 Metuchen,
Ketoconazole Continued milling caused apparent NJ, US)
particle growth
Furosemide PVP, inulin Milling time Solid state amorphization and Cryogenic impact mill (Spex [113]
chemical decomposition CertiPrep 6750 Metuchen,
NJ, US)
g-Indomethacin e e Atomic pair-wise distribution Oscillatory ball mill (Mixer [158]
functions was better than x-ray Mill MM301, Retsch, Haan,
diffractograms in assessing the Germany)
degree of disorder
Indomethacin e e Correlation between physical Oscillatory ball mill (Mixer [110]
stability and relaxation time was Mill MM301, Retsch, Haan,
established for the same Germany)
amorphous systems prepared by
different methods
Phenytoin, ibuprofen, e e No change in crystal form and Wet milling machine (RMB- [114]
salbutamol sulfate amorphization after milling 04, Aimex, Tokyo, Japan)
Glibenclamide e e Transformation from crystalline to Cryogenic freezer/mill [111]
amorphous state without chemical (Spex SamplePrep 6770,
decomposition Metuchen, NJ, US)
Griseofulvin e Milling time Reduction of crystallinity due to Cryogenic impact mill (Spex [115]
crystal defects rather than CertiPrep 6750 Metuchen,
amorphization of materials NJ, US)
Ranitidine hydrochloride e Milling time Ranitidine hydrochloride Oscillatory ball mill (Mixer [112]
polymorphs form 1 and 2 could be Mill MM301, Retsch, Haan,
fully converted to the amorphous Germany)
form
Carbamazepine Saccharin e Higher amorphization with Cryogenic impact mill (Spex [106]
cryogenic cogrinding than room CertiPrep 6750 Metuchen,
temperature cogrinding NJ, US)
Whole inactivated Chitosan, lactose, e Dry powder influenza vaccine Micro-ball mill (SPEX [159]
influenza virus trehalose successfully formulated CertiPrep 3117, Metuchen,
NJ, US)
Indomethacin polymorphs e e Amorphous materials obtained Cryogenic impact mill (Spex [109]
and solvates after milling possessed similar Tg CertiPrep 6750 Metuchen,
but significant differences in their NJ, US)
physical stability
Abbreviations: CMC, carboxymethyl cellulose; HPC, hydroxypropyl cellulose; HPMC, hydroxypropylmethyl cellulose; MCC, microcrystalline
cellulose; PVP, polyvinylpyrrolidone.
5.2. Ball milling frequency. The movement of the vessel causes the balls to
cascade or move in a particular pattern, colliding with each
Ball milling is another popular size reduction technique used for other and with the opposing inner wall of the vessel. Size
the production of microparticles, especially in research labo- reduction of the drug particles is effected from the impact they
ratories. Fundamentally, a ball mill comprises a vessel or vial receive from the balls as well as attritive forces arising from the
filled with balls, or rods, constructed from a variety of materials movement of the balls relative to each other [61,62].
such as ceramic, agate, silicon nitride, sintered corundum, zir- The quantities of the balls and starting material determine
conia, chrome steel, CreNi steel, tungsten carbide or plastic the extent of fill of the vessel and the intensity of the milling
polyamide (Fig. 2). The material to be milled is placed inside the process. Typically, the vessel is filled by the balls and starting
vessel, which is made to rotate or vibrate at a particular speed or material to 50% and 25% of the total volume of the vessel,
more dominant role in particle size reduction relative to

impaction and compression, yielding finer particles at the
expense of longer processing times. Apart from the speed of
rotation or vibration, the size, density and hardness of the
balls affect the rate and extent of particle size reduction.
Decreasing the size and/or increasing both the density and
hardness of the balls often increase the rate and extent of
particle size reduction.
The use of ball milling as a micronization technique for
enhancing drug solubility is well supported by literature
dating as far back as the 1970s. Apart from its comminution
function, ball milling also serves as an intensive mixing
technique capable of producing co-ground drug-excipient
mixtures comprising amorphous drug forms intimately mixed
with suitable hydrophilic excipients at the molecular level.
This interaction between the drug and hydrophilic excipient
enhances the wetting and dissolution of the drug. Studies on
the vibrational ball milling of griseofulvin and phenytoin have
demonstrated that milling these drugs in combination with
microcrystalline cellulose resulted in amorphization of the
drug, enhancing its dissolution and bioavailability [64,65]. Ball
milling of ibuprofen and aluminum hydroxide was carried out
to facilitate complex formation between ibuprofen and
aluminum hydroxide as well as drug amorphization which
Fig. 1 e Schematic diagram of a fluid energy mill. Air is
enhanced the dissolution of ibuprofen [66]. The incorporation
introduced through specially-designed fluid inlets creating
of excipients may, in some cases, mitigate milling-induced
sonic or supersonic air streams. Raw materials are
drug amorphization. It was demonstrated that the co-milling
introduced into the violent and turbulent air stream. High
of salbutamol sulfate with crystalline excipients (a-lactose
velocity collisions between the raw particles lead to
monohydrate, adipic acid, magnesium stearate) in a ball mill
effective pulverization of the feed into smaller particles.
was effective in reducing milling-induced amorphization or
structural disorder of salbutamol sulfate [67]. Ball milling of
pure drug mixtures have also been investigated. More
respectively, although variations exist in the literature. In the
recently, ball milling of a combination of two BCS Class II
case of a rotating vessel, rotation is usually carried out at
drugs, simvastatin and glipizide, resulted in the formation of
50e85 % of the critical speed, defined as the speed at which the
stable co-amorphous mixtures [68].
balls cease to cascade owing to the centrifugal force imparted
Despite the efficiency of ball milling for size reduction or
by the rotating vessel. The critical speed may be estimated
amorphization, it is less amendable to scale up. By a flow-
based on the following relationship [63]:
through method, with vibrating balls or discs in the milling
pffiffiffiffiffiffi chamber, milling efficiency can be improved. External jack-
Critical speed ðrpmÞ ¼ 54= Rft
eting for heat removal allows the mill to be used continuously
where Rft is the diameter of the vessel measured in feet. As and will limit the rise in temperature within the milling
the rotational speed of the vessel decreases, attrition plays a chamber.
Fig. 2 e Schematic diagram of a ball mill. The balls make up the grinding media and drive rollers help to rotate the milling
chamber.
[73] or layered on sugar beads [74]. It has been demonstrated in

6. Milling techniques for the production of many studies that these “solidification” processes retain the
nanoparticles mechanically-activated status and other desirable physical
attributes of the original, milled drug particles.
6.1. Wet milling Two common “topedown” approaches for the production
of drug nanoparticles are media milling and high pressure
Both fluid energy and ball milling techniques involve size (piston-gap) homogenization. These two milling techniques
reduction of drug particles in their dry state. The extent of size have been the focal point of research in the past decade due to
reduction achievable in these dry milling techniques is limited their ease of scale-up, robust processing, economic advan-
to a few micrometers [69]. It was reported that when the sol- tages and acceptance by regulatory authorities. Since 2000,
ubility of a drug is very low, down-sizing it to the micrometer the US Food and Drug Administration has approved numerous
range is insufficient to increase its dissolution rate and gastro- products e.g. Rapamune® (sirolimus, Wyeth), TriCor® (fenofi-
intestinal absorption [70]. In the last decade, significant ad- brate, Abbott) and Megace® ES (megestrol acetate, Par Phar-
vancements and evolutions in milling processes have enabled maceuticals) that have been produced by these techniques
the production of submicron-sized (<1 mm) or nanoparticles [75]. Tables 1 and 2 summarize the current research on the
[43]. This process may be termed as nanonization. Nano- application of media milling and high pressure homogeniza-
particles, sometimes termed as nanocrystals, are typically tion in particle size reduction and solubility enhancement of
200e500 nm in size [71], and are particularly suited for the specific drugs.
formulation of parenteral preparations. Nanoparticles
possess significant advantages over microparticles in 6.2. Media milling
enhancing drug solubility. Most notably, the process of
nanonization increases not only the surface area and disso- Media milling can be considered a modernized version of the
lution rate of the drug particles, but also the saturation solu- ball mill (Fig. 3). This technology, first developed by Liversidge
bility of the drug. Ordinarily, the saturation solubility of a drug and co-workers [76,77], is a classical wet milling technique
is dependent on the temperature and solvent used for disso- wherein a sufficiently concentrated dispersion of drug parti-
lution. When the size of drug particles falls below 1 mm, cles in an aqueous or non-aqueous liquid medium is subjected
dissolution pressure increases due to the strong curvature of to a traditional ball milling operation [77,78]. The liquid me-
the particle surface. This leads to an increase in saturation dium prevents adhesion and subsequent compaction of the
solubility in accordance to the Ostwald-Freundlich and Kelvin milled drug particles on the wall of the vessel and/or the
equations. Hence, at the nanoparticulate level, the saturation surfaces of the milling balls, which is a common occurrence
solubility of a drug becomes a function of particle size. The when the drug is milled in its dry state. This improves the
increase in saturation solubility of the drug will increase the yield of nanoparticles. The liquid may also serve additional
concentration gradient for drug diffusion and promote drug purposes such as lubrication and coating of the newly-formed
absorption. Additionally, it was reported that orally-delivered particle surfaces through various physicochemical in-
nanoparticles displayed strong adhesive properties to the teractions like electrostatic and hydrophobic interactions
mucosal surfaces of the gastro-intestinal tract, arising from [79,80].
the increased van der Waals forces of attraction between the In media milling, mechanical attrition and impaction of
nanoparticles and the gut wall. This would further contribute the suspended drug particles are brought about by grinding
to the increased absorption and bioavailability of drugs balls, often termed as the milling media, constructed out of a
administered as nanoparticles. variety of material such as glass (yttrium-stabilized), zirco-
Drug nanoparticles are most commonly produced by wet nium oxide, ceramics or highly cross-linked polystyrene
milling. As the name suggests, wet milling involves size resins [78]. Pearl balls and beads are commonly used as well in
reduction of drug particles suspended in a liquid medium that which case the techniques are termed pearl and bead milling,
may be aqueous or non-aqueous in nature. Wet milling is respectively. Unlike ball milling where the whole vessel ro-
particularly suited for potent drugs and drugs which possess tates or oscillate/vibrates whilst in operation, the vessel re-
high residual moisture contents (>50% moisture) because dry mains stationary in media milling. Movement of the balls is
milling may be problematic for drugs of this nature. In wet initiated by a stirring or agitating device, often represented by
milling, a drug nanosuspension is produced as the end prod- several discs mounted on a central shaft rotating at high ve-
uct although for improved product stability (minimization of locities, 20 000 rpm and above, within the vessel. For this
Ostwald ripening and possible hydrolytic degradation of reason, media milling is sometimes known as “stirred-ball
drug), patient convenience and the drive towards green or milling”. Media milling is a continuous process wherein the
sustainable manufacturing processes, the nanosuspension drug suspension is pumped through the milling chamber to
may subsequently be transformed into a solid dosage form effect size reduction of the suspended material. Prior to their
(e.g. tablets and capsules) by granulation, freeze drying and exit from the milling chamber, the milled particles pass
spray drying [43] using suitable excipients or “matrix formers” through a screen that serves to separate the suspended, mil-
like mannitol or lactose. The dissolution rate of ezetimibe, a led particles from the milling media. Media milling has been
lipid-lowering compound, was improved even after nano- employed for particle size reduction of loviride [81], ezetimibe
crystals of the drug were tableted without the inclusion of any [72], alpha-lipoic acid [82], ibuprofen [83], cinnarizine, nap-
solubilizing agents like sodium lauryl sulfate [72]. Drug roxen [74], ketoconazole, phenytoin [84] and candesartan cil-
nanoparticles may also be incorporated into polymer films exetil [85]. The majority of these cited studies involve the
Fig. 3 e Schematic representation of the media milling process. The milling chamber is charged with milling media. A crude
slurry consisting of drug, water and stabilizer is fed into the milling chamber and processed into a nanocrystalline
dispersion.
conversion of the resultant drug nanosuspension into a suit- such as erosion-resistant polymers and ceramics, used in the
able solid dosage form like dry powders and tablets. Less construct of the milling media as well as other key equipment
conventionally, stable nanoparticles of naproxen, fenofibrate components (e.g. inner walls of milling chamber and stirring
and griseofulvin produced from wet-stirred media milling device) in contact with the milled product. Optimization of
have also been incorporated into hydroxypropylmethyl cel- key process parameters like stirring speed and in particular,
lulose polymer films [73]. The dissolution rates of the drugs milling time also contributes to reducing the likelihood of
were improved by nanonization and based on x-ray diffrac- erosion. This is because milling durations of up to several days
tion and Raman spectroscopic analysis, the process of film are not uncommon in media milling [77] and such long milling
formation did not affect drug crystallinity. Another interesting durations are likely to promote erosion of the milling media.
example is the incorporation of crystalline nanoparticles of Commercially, media milling is exemplified by the Nano-
indomethacin, prepared by media milling, into coated Crystal® technology from Elan Pharmaceutical Technologies.
mannitol microparticles using an aerosol flow reactor To date, NanoCrystal®-based products have been approved by
method. The nanostructured microparticles produced worldwide regulatory agencies including the US, Canada, EU
exhibited rapid dissolution properties [86]. and Japan.
In recent years, there is a trend towards the use of milling
media of much smaller dimensions (<100 mm) to bring about 6.3. High pressure homogenization
the nanonization of drugs. As it is difficult to separate milling
media of this size from the milled products using the con- The production of nanosuspensions using high pressure or
ventional screen separator without choking or plugging the piston-gap homogenization was first developed by Muller
screen, centrifugal technology has been employed to effect et al. in 1994 [90]. It is a high energy process in which size
such separations. The Ultra Apex Mill (Kotobuki Industries) is reduction of drug particles is achieved by repeatedly cycling,
an example where centrifugal technology has been integrated to 200 plus cycles, with the aid of a piston, a drug suspension
into the design of the mill to effectively separate the milling through a very thin gap at high velocity, around 500 m/s, and
media, which can range from 15 to 100 mm, from the milled pressure, 1000e1500 bars (Fig. 4). The width of the gap, which
product. This mill has been successfully employed for the generally falls within the range of 5e20 mm, may be adjusted
production of nanoparticles of albendazole, danazol and according to the viscosity of the suspension and the applied
omeprazole as well as probucol [87] for the enhancement of pressure. Pre-micronization of the starting materials using a
their dissolution and absorption properties. process like fluid-energy milling may be necessary prior to
A major drawback of media milling is the erosion of the homogenization. This is to minimize clogging of the homog-
balls arising from the intensive mixing forces in the vessel. enization gap and to reduce milling time. When the suspen-
Residues of the milling media produced from erosion may sion is forced through the gap at a high flow rate, the static
result in product contamination [71,88,89], leading to chemi- pressure exerted on the liquid falls below the vapor pressure
cal destabilization of the newly-formed particle surfaces and of the liquid at the prevailing temperature (Bernoulli's equa-
possibly affecting critical product attributes such as particle tion). As a result, the liquid boils and gas bubbles are formed
size and size distribution. Monitoring impurity levels in the which collapse when the liquid exits from the gap and normal
final milled product is thus warranted. Contamination prob- pressure is resumed. The powerful cavitation forces arising
lems may be mitigated by a prudent choice of the materials from the formation and collapse of the gas bubbles, coupled
Dissocubes™ technology resulting in bioavailability

enhancement.
In 1999, a variant of the high pressure homogenization
process, known as the Nanopure® (pure nanocrystals) tech-
nology, was introduced. This technology is owned and
developed by Pharmasol GmbH, Berlin. Homogenization in
this case is conducted in a non-aqueous dispersion medium,
polyethylene glycols, propylene glycol, water-alcoholic mix-
tures or suitable oils [96], rendering the process suitable for
comminuting drugs susceptible to hydrolysis. This technique
is also suitable for drugs that are thermolabile. This stems
from the option of conducting homogenization under milder
conditions such as reduced temperature [97] and in the event
where the nanosuspension has to be converted into a solid
form, less heat will be required for solvent removal (compared
to homogenization using water) thereby preserving drug sta-
bility. Supercritical CO2 has also been employed as a disper-
Fig. 4 e Schematic diagram of the high pressure
sion medium. In two recent studies, high pressure
homogenization process. The microparticles are forced
homogenization of phenytoin [98] and ketoprofen [97]
through a minute gap in the micronizing zone. This creates
dispersed in supercritical CO2 was carried out. The use of su-
conditions of high turbulence and shear, combined with
percritical CO2 enhanced the efficiency of homogenization as
compression, acceleration, pressure drop and impact,
the liquid medium could be easily evaporated under ambient
leading to the formation of a nanosuspension.
conditions, allowing the milled product to be readily recov-
ered in the form of a dry powder.
High pressure homogenization has also been combined
with a shearing effect, bring about nanonization of the drug with precipitation and this is marketed as the Nanoedge™
microparticles [91e93]. The extent of subdivision of the technology. In this technique, the drug is first dissolved in a
nanoparticles depends on the pressure applied as well as the water-miscible alcoholic solvent (e.g. methanol, ethanol or
number of passes or homogenization cycles the drug sus- isopropanol), then added to water to cause it to precipitate.
pension is subjected to during the process. The mechanical The precipitated particles are subsequently homogenized.
properties (hardness) of the drug particles also affect the The homogenization step is purported to reduce the size and
milling outcome, with mechanically softer drug particles size distribution of the precipitated particles, thereby mini-
achieving a lower (200e300 nm) nanometer size range even- mizing the likelihood of crystal growth and improving the
tually [7]. High pressure homogenization is a high energy stability of the nanosuspension during storage. Precipitation,
process. In the course of milling, the drug particles are in tandem with high pressure homogenization, has been
exposed to a power density of up to 1013 W/m3 which is successfully applied for the preparation of nitrendipine
comparable to power densities observed in nuclear power nanocrystals to improve drug bioavailability. Chitosan, which
stations. The high energy imparted mechanically activates the was used subsequently to modify the surfaces of the nano-
drug particles potentially leading to partial or complete crystals, further enhanced drug bioavailability without
amorphization of the drug [94]. High pressure homogenizers bringing about any measurable increase in the size of the
are available in different capacities, ranging from few tens of original nanocrystals [99].
milliliters for laboratory use to a few thousand liters for large
scale production. The process is robust and may easily be 6.4. Cryogenic milling
adapted for aseptic production of parenteral drug nano-
suspensions. High pressure homogenization is employed for In principle, size reduction begins when the externally-
the production of parenteral nutrition emulsions (e.g. Lip- applied stress induces sufficient strain within the particles
ofundin® and Intralipid®). High pressure homogenization also and causes the formation of cracks. The cracks are then
enables continuous processing and unlike media milling, propagated through lines of weaknesses in the material, with
contamination problem from milling equipment is much less. new cracks being initiated and perpetuated along the way at
In the last decade or so, extensive research has been carried other discontinuities. A cascade effect occurs and material
out on the application of high pressure homogenization for fracture results. The mechanical property such as hardness or
particle size reduction and solubility enhancement of drugs. elasticity of a drug is likely to affect the ease of crack initiation
Table 2 summarizes the research reports in the area over the and propagation during milling. Logically, harder materials
recent years. Commercially, high pressure homogenization is require greater energy input to effect particle size reduction as
exemplified by the Dissocubes™ technology which has been they do not yield to the externally applied stress as readily as
owned by SkyePharma PLC since 1999. Nanosuspensions softer materials. However, the brittleness or plasticity of the
prepared using Dissocubes™ are water-based and are char- material also plays a critical role in rendering the ease of
acterized by well-defined particle sizes and narrow particle particle size reduction. It is easier to comminute hard and
size distributions, with few particles exceeding 5 mm in size brittle materials, such as chalk, than soft and viscoelastic
[95]. Many different drugs have been processed by the materials, such as rubber, waxes or natural gums. Instead of
brittle fracture, more plastic materials are capable of meltable material that may be used both as an excipient and
absorbing large amounts of energy through viscoelastic active ingredient in inhalable dry powder formulations [103],
deformation without crack initiation or propagation. At was subjected to a micro-ball milling technique using stain-
ambient conditions, these materials resist fracture or may less steel ball bearings as the grinding agent. Ball milling was
even melt (for waxy materials) when exposed to the heat carried out in the presence of liquid nitrogen vapor. Apart
generated during milling. Drug substances that exhibit such from chilling the chamber, the liquid nitrogen also prevented
characteristics are not likely to be amenable to the conven- plastic deformation of the material and improved the particle
tional dry or wet milling methods aforementioned. However, fracture process [52].
there had been few studies on the milling of soft and highly Cryomilling is advantageous in that it minimizes the
plastic pharmaceutical materials [52]. degradation of thermolabile drug substances and loss of vol-
Cryogenic milling or cryomilling in short, is a size reduc- atile drug compounds. It also reduces the risk of explosion,
tion method specially catered to soft, elastic/plastic, non- oxidation of formulation constituents and particle aggrega-
brittle and thermolabile materials. Cryomilling may be car- tion during the milling [104]. The latter stems from the low
ried out either by first freezing the materials in liquid nitrogen surface tension and viscosity of liquid nitrogen which allows it
(100 to 150 C) prior to milling or by milling the materials to penetrate into inter and intra-particulate void spaces and
under cryogenic conditions, i.e., in the presence of liquid ni- micropores of the particles, forming a physical barrier which
trogen (Fig. 5). Exposure to liquid nitrogen results in the prevents particle agglomeration [105]. Cryomilling decreases
“embrittlement” of the material which facilitates crack prop- the effect of temperature-induced changes during milling.
agation, reducing the specific energy required for milling [100] Jayasankar et al [106], in a study on co-crystal formation be-
and potentially shortening the milling duration. Although tween carbamazepine and saccharin, reported that co-
freeze drying performs a similar function and renders a ma- grinding the drug and excipient under cryogenic conditions
terial brittle and porous, by virtue of the fact that it is a drying was necessary to prevent the reaction from proceeding
process implies that it is more suitable for liquids or solid through the melt phase which commonly occurs when co-
materials containing higher residual moisture contents. Sal- grinding is carried out at ambient conditions. Cryogenic co-
azar et al. [101] studied media milling and high pressure ho- grinding also led to higher levels of amorphization than co-
mogenization of glibenclamide that was first pre-treated by grinding at room temperature. These results are echoed in
freeze-drying. Freeze-drying rendered the drug brittle and another study involving the ball milling of 3 different crys-
porous, facilitating the subsequent milling process. This talline forms of piroxicam [107]. Differing extents of drug
combination approach reduced milling time and improved amorphization was achieved by ball milling the drug under
milling efficiency. different temperature conditions (ambient and cryogenic
Cryomilling enables the production of both micron and conditions), with cryogenic ball milling being more effective in
nano-sized particles but it has not been widely adopted in the inducing drug amorphization. This is because milling at
pharmaceutical industry for the milling of drugs. Sugimoto cryogenic temperatures effectively ‘traps’ the milled material
et al. [102] studied the cryogenic co-milling of phenytoin and in its amorphous state by removing the thermal energy
polyvinylpyrrolidone as a means to improve the dissolution required for re-crystallization to occur [108]. In this regard,
rate of the drug. Phenytoin was dispersed in liquid nitrogen cryogenic milling is advantageous as it enables the production
and subjected to media milling using beads constructed out of amorphous material without the deleterious effects of
of zirconium or dry ice. Spontaneous sublimation of the dry solvents or heating [61]. Crowley and Zografi [109] studied the
ice beads together with liquid nitrogen at ambient condition cryogenic grinding of 5 crystal forms of indomethacin and
enabled the recovery of a high yield (85e90 %) of dry found that amorphization occurred for one of the solvates
phenytoin nanoparticles, since material loss arising from (indomethacin methanolate) and all the three polymorphs (g,
adhesion to the surfaces of the milling media was of no a, and d) studied. Recently, g-indomethacin was subjected to
consequence. In another study, pluronic F-68, a soft and cryomilling and it was reported that the amorphous
Fig. 5 e A) Cryogenic mill, B) Schematic diagram showing a cross-section of the cryogenic milling chamber. Cryogenic
atmosphere is supplied in the chamber.
indomethacin produced exhibited enhanced dissolution rates reproducible particle sizing [116]. It uses light-scattering
which was positively related to the duration of cryomilling measurements to calculate the volume-based particle size
[38]. The same group of researchers had also evaluated the distribution. In the last decade, alternative techniques to
physical stability of the cryomilled amorphous indomethacin characterize particle size distribution based on focused beam
samples by measuring the time required for the drug to re- reflectance measurement (FBRM), ultrasonic attenuation
crystallize on storage [110]. Cryogenic grinding was success- spectroscopy (UAS), phase Doppler method (PDA), spatial
fully used to convert crystalline glibenclamide to its amor- filtering technique (SFT) and shadow Doppler velocimetry
phous form, averting possible chemical degradation during (SDV) have surfaced. FBRM uses a focused beam of laser light
the process. The crystalline-amorphous conversion was that scans across a particle passing in front of the probe
shown to be connected with the amide-imidic acid tautom- window to measure a chord length distribution. UAS mea-
erism of glibenclamide [111]. Chieng and co-workers [112] sures the volume-based particle size distribution from
investigated the effect of cryomilling on 2 polymorphic extinction spectra using the fundamental equations of mass,
forms of ranitidine hydrochloride and evaluated the physical momentum and energy balance describing the interaction
stability of the milled amorphous drug under different storage between an ultrasonic wave and suspended particle. The PDA
conditions. is based upon the principles of light scattering interferometry
High impact cryomilling thus enables the production of and measurements are made using the same optical probe as
completely amorphous drugs that may otherwise be difficult for laser Doppler velocimetry (LDV). SFT uses the measuring
to obtain by milling at room temperature. However, drug principles of the fiber optical spatial filtering velocimetry (SFV)
amorphization may not always be advantageous from a sta- and the fiber optical spot scanning (FSS) in order to determine
bility point of view. In a recent study on the cryomilling of simultaneously the size and the velocity of particles. SFV is a
furosemide, it was reported that the duration of cryomilling method of the velocity determination of an object by
and resultant drug amorphization were factors responsible for observing the object through a spatial filter in front of a
the chemical decomposition of the drug [113]. Drug amorph- receiver. FSS is an addition to the SFV to observe the shadow
ization may not occur in all cases. In a study by Niwa et al. image of a moving particle through a single optical fiber with a
[114], the nanocrystals of phenytoin, ibuprofen and salbuta- small diameter. SDV is based on the imaging of a conventional
mol sulfate produced from an optimized cryomilling process LDV probe volume onto a linear photodiode array.
retained their crystalline character. This was explained by the Particle size measurements can be made in-line or on-line.
mild processing conditions that prevailed during cryomilling. In in-line particle sizing, a probe is directly inserted into the
Feng et al. [115] reported that cryogenic milling of griseofulvin process stream for measurements. However, the main process
led to a reduction in drug crystallinity due to the increase of stream often operates at high particle flow rates. It is therefore a
crystal defects, rather than the formation of amorphous drug. common method to measure in a side-stream that can be iso-
A body of research on the use of cryomilling to process mo- lated from the main process flow. Another option is the appli-
lecular materials, including model pharmaceutical com- cation of a dilution step between the particle stream and the
pounds, has been carried out by Willart and Descamps [108]. measuring device. In on-line particle sizing, a sample is diverted
Table 3 summarizes the latest research findings on the use from the manufacturing process stream for measurement, to
of cryomilling for particle size reduction and solubility circumvent the high particle flow rate in the main stream.
enhancement of drugs. As particle shape along with size are directly related to the
product quality and performance, the use of a single param-
eter to describe the physical dimension of particles is often
7. Process analytical technology (PAT) in insufficient, especially for non-spherical (rod or plate-like)
milling particles. Therefore, in-line or on-line particle sizing
together with shape measurement can play a crucial role in
In 2004, the Food and Drug Administration (FDA) initiated the controlling milling processes. However, little attention has
quality by design (QbD) concept, in which process analytics been given to real-time particle shape measurement due to
are embedded to monitor, in real time, critical process and the lack of available technologies. Laser Doppler methods
product attributes rapidly and non-destructively. The aim of have been employed to analyze particle shape, but only with
the PAT initiative is to diminish the reliance on end product limited success [29,117,118]. Dynamic image analysis (DIA) is
testing to ascertain product quality, improve process under- still the most commonly used technique for particle shape
standing as well as develop intelligent sensing and responsive characterization. However, manual operation was required
manufacturing processes. It represents the agency's move to a for sample preparation, measurement and data analysis due
science-based approach to pharmaceutical manufacturing. In to low level of automation. Recent advancements in technol-
line with this initiative, there is a need to implement process ogies of high speed cameras and computers have increased
analytical tools to achieve better understanding of the particle the level of automation which enabled the measurement of
phenomena during milling. As aforementioned, the size and two dimensional images of dynamic particles [119]. DIA was
shape of milled particles can affect the dissolution properties, specifically suitable in sizing non-spherical particles [119,120].
resultant bioavailability and storage stability of the formu- However, the use of the DIA systems have been mostly limited
lated product. Hence, it is critical to monitor and track the to wet analysis, where particles are suspended in a liquid
evolution of particle size and shape during milling. Laser medium to allow easy control of particle flow rate and
diffraction has become the method of choice for particle size thus reduction of motion blur during image acquisition.
measurement during milling due to its versatility, rapid and Recently, Sympatec Inc. (Clausthal-Zellerfeld, Germany)
Table 5 e Summary of different PAT approaches in milling.

Technique Mechanism Measurement parameters
Particle size analysis
Laser diffraction Light scattering Volume-based particle size distribution
FBRM (focused beam reflectance Focused beam laser light scan across a particle Particle chord length distribution
measurement)
UAS (ultrasonic attenuation Interaction between ultrasonic wave and suspended Volume-based particle size distribution
spectroscopy) particle
PDA (phase Doppler method) Light scattering interferometry Size, velocity and concentration of
spherical particles
SFT (spatial filtering technique) Combination of spatial filtering velocimetry (SFV) Particle chord length and velocity
and fiber optical spot scanning (FSS)
SDV (shadow Doppler velocimetry) Doppler shift in a laser beam Particle size and velocity
Particle size and shape analysis
DIA (dynamic image analysis) Image analysis Particle size and shape analysis in
wet environment
DIA (QICPIC) Image analysis Particle size and shape analysis in
dry environment
DIA (Eyecon™) Image analysis using illumination technique 3D particle characterization
commercialized a DIA system (QICPIC) that is capable of area of research wherein the function of milling extends
capturing images of dry powder particles in a rapidly-moving beyond size reduction and offers a more holistic and inte-
air stream. Another introduction of DIA system is the non- grated approach to particle design.
invasive, real-time 3D particle characterizer capable of giv-
ing live particle size and shape information for coarser parti-
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Wet Milling Particle Characterization

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a s i a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 1 0 ( 2 0 1 5 ) 2 5 5 e2 7 4

H O S T E D BY Available online at www.sciencedirect.com

journal homepage: http://ees.elsevier.com/ajps/default.asp

Overview of milling techniques for improving the

article info abstract

rate of dissolution of a drug is affected by factors embodied in

more dominant role in particle size reduction relative to

[73] or layered on sugar beads [74]. It has been demonstrated in

Dissocubes™ technology resulting in bioavailability

Table 5 e Summary of different PAT approaches in milling.

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