The basic principle of ball milling is to reduce the size of particles which may have a variety of chemical,
physical and mechanical characteristics. Planetary ball mills operate with a rotating disk which spins
in the opposite direction to the vials, as illustrated in Figure 1.5, generating high levels of
energy/centrifugal force within the vial/balls, allowing grinding to take place. Ball mills reduce the size
Figure 1.4: A schematic diagram highlighting the three main compression methods
for excipients undergoing direct compression, with plastic deformation showing particle shape retention, elastic deformation indicating particle shape rebound and fragmentation deformation profile highlighting resulting in particle fracture and production of pores within the dosage form.
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of particles through transfer of energy from the balls to the powder causing comminution, as well as
mixing/blending/dispersing the powder. Particle size can depend on various parameters, including 1)
Characteristics of the ball, including; mass, density, ball size distribution; 2) Characteristics of the
powder, including; mass, volume, density, hardness, size, distribution of charge; and 3) The speed and
time of rotation. The size reduction of particles also falls under three mechanisms; the first is abrasion
where very fine particles are broken off the main particle due to low intensity stress. The second
mechanism is cleavage where particles about 50-80% the size of the original are formed due to slow
high intensity stresses and the final mechanism is fracture where rapid high intensity stress causes
small size fragments to form with a high particle size distribution (Monov et al., 2012).
The particle size is reduced due to the breakage of bonds within the particle which alters the shape
(Castricum et al., 1997). Milling can also result in a loss of energy in the particles due to the weaker
Figure 1.5: A diagram showing the motion of balls and powder through
a planetary ball mill. Centrifugal force is produced through the opposite acceleration and velocity of the vial and supporting disk, causing high levels of energy within the moving balls, which come into contact with the powder, causing particle breakdown upon collision.
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bonds, caused by repeated impact of the balls (Shabir et al., 2011). The breakage of bonds can also
uncover parts of the particles exposing them to free radicals, and also allowing the formation of new
chains and bonds, which could in some cases increase the molecular weight of the particles (Castricum
et al., 1997), disputing the general principle of particle size reduction and reduction of molecular mass.
The surface characteristics of materials that have undergone ball milling are also altered. There is a
larger surface area produced compared to the original powder as the particles are finer. Some studies
have shown that the particles display nanoporous surface caused by the impact of the balls that have
high energy, and the generation of heat due to friction between the particle and ball upon contact
(Shabir et al., 2011). In the study by Shabir et al. (2011) the surface charge and hydrophobicity of the
material had altered. The surface charge had become less negative due to a smaller particle size and
increased drug loading, as the drug was positively charged, and the decrease in hydrophobicity was
due to the increased surface area of the particles allowing more interaction with water. This increased
hydrophilicity was also shown in another study by Jones et al. (2011), which was attributed to the
increased surface area available to interact with water.
Ball milling can also alter the crystal form of certain powders, and change them to a more amorphous
material. The loss of crystal structure is caused by the reduction in particle size, as a result of fracturing
of the crystals along their slip planes. Milling can therefore result in a partial or total loss of crystal
form as more amorphous domains are formed. Crystals with a more needle like morphology are more
prone to loss of crystal structure than crystals with a plate like morphology (Ho et al., 2012). This loss
of crystal form can in turn lead to changes in the hydrophilicity of a material as well as affecting the
solubility and bioavailability of drugs (Jones et al., 2011).
1.7.1.1 Ball Milling in ODTs
Ball milling can be a method of modifying excipients to optimise them for use in ODTs. Excipients such
as mannitol can be individually ground to improve its compressibility/compactability, or excipients can
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ODTs. The co-milling method has been used in several studies to improve ODT properties, mainly
employing a co-milled combination of mannitol with crospovidone.
A study by Katsuno et al. (2013) co-milled a mixture, of micronized crospovidone (m-cpvp) and
mannitol to improve the stability of the powder blend. An SEM study to assess particle size and shape
showed that the mannitol crystals within the co-ground mix had significantly reduced in size and
changed shape to a more block like structure, with no large mannitol crystals contained in the co-
ground mix. M-cpvp had a popcorn like shape with lots of cavities, which wasn’t significantly different
after milling. Post-compression, SEM also showed a significant difference between the surface of the
tablet between co-milled and a physical mixture of the excipients, with the co-milled tablet having a
surface that was a lot smoother than the tablet containing the physical mixture of the two. It was
suggested that co-milling promoted inter particle bonding and fusion during compression. The study
showed that a co-ground mix absorbed a lot less moisture than just the m-cpvp on its own and the
physical mix of the two excipients, which meant that co-milling had led to a reduction in hygroscopicity
of the m-cpvp. This was as a result of milling which had led to an aggregation between mannitol and
m-cpvp, which prevented water absorption into the m-cpvp as mannitol is a non-hygroscopic
excipient. This was confirmed by stability studies, which showed that a co-ground mix was much more
stable in accelerated conditions (40˚C and 75% relative humidity) for 1 day/1 week, with strength
remaining at 1.5MPa and disintegration below 30s. Storage of the co-milled powder for one month
under accelerated conditions showed a slight decrease in strength, with disintegration remaining
below 30s. In comparison the physical mixture and individual excipients displayed a worsening in
tablet properties. Overall this study showed that co-milling was advantageous for preparing ODT
formulations as it produced stable, mechanically robust and suitably disintegrating tablets compared
to unmilled formulations.
A study by Shu et al. (2002) used a vibrational rod mill to produce a co-milled mix of regular
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mix showed an overall increase in hardness of the tablets as the amount of the co-ground mix within
the formulation increased up to 30%, with the disintegration time remaining at around 60s for all of
the formulations. Particle size reduction of crospovidone was evident in both co-grinding and
individual grinding, whilst mannitol particle size also reduced in both cases. However co-grinding was
found to decrease particle size more than individually ground material, which showed that
crospovidone could act as a grinding assistant for mannitol. This study also looked at different
excipients utilised in the co-ground mix, with the mannitol being substituted for other saccharides
(erythritol, xylitol, lactose, glucose), and crospovidone substituted for other disintegrants
(crosscarmellose sodium, L-HPC, sodium carboxymethyl starch, partially pre-gelatinzed starch). The
relevant tests conducted showed that mannitol couldn’t be substituted within the co-ground mix as
tablets took too long to disintegrate, however they all had good mechanical hardness. The substitution
of the crospovidone however produced tablets that were mechanically robust and disintegrated
relatively quickly, with all formulations disintegrating within 30-45s.
Other studies have used milling to asses other properties surrounding ODTs. A study by Jones et al.
(2011) looked at the impact of ball milling parameters on ODTs manufactured by freeze drying.
Mixtures of gelatin and mannitol were milled in the frozen state before freeze drying. The milling
parameters that were altered were milling time, rotation speed and ball to powder weight ratio (BPR).
It showed that post milled powders had increased wettability due to the increased surface area of
particles, and also porosity of the powders varied significantly depending on milling conditions.
From the above studies it can be deduced that milling can have a direct impact on the improvement
in ODT properties, particularly those manufactured through direct compression. The one study by
Jones et al. (2011) showed no improvement in ODT performance using freeze drying technology,
whereas the other studies using direct compression all showed an improvement in the properties of
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around 20mins to produce ODTs that had a fast disintegration time as well as a good mechanical
strength, and that co-milling of mannitol and crospovidone was a very popular combination.