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Size reduction
In recent 30 years, particle size reduction technologies turned from an exploratory
approach into a mature commercial drug delivery platform. Nanonization technologies have
gained a special importance due to a steadily increasing number of development compounds
showing poor aqueous solubility. Many drug delivery companies and academic research groups
have contributed to the currently existing large variety of different technologies to produce drug
nanoparticles. These particles consist of pure active pharmaceutical ingredient (API) and are
often stabilized with surfactants and/or polymeric stabilizers adsorbed onto their surface.
The theoretical strength of crystalline materials can be calculated from interatomic
attractive and repulsive forces. The strength of real materials, however, is found to be many
times smaller than the theoretical value. The discrepancy is explained in terms of flaws of
various kinds, such as minute fissures or irregularities of lattice structure known as dislocations.
These have the capacity to concentrate the stress in the vicinity of the flaw. Failure may occur at
a much lower overall stress than is predicted from the theoretical considerations. Failure occurs
with the development of a crack tip which propagates rapidly through the material, penetrating
other flaws which may, in turn, produce secondary cracks. The strength of the material depends
therefore on the random distribution of flaws and is a statistical quantity varying within fairly
side limits. This concept explains why a material becomes progressively more difficult to grind.
Since the probability of containing an effective flaw decreases as the particle size decreases, the
strength increases until, with the achievement of faultless domains, the strength of the material
equals the theoretical strength. This position is not realized in practice due to complicating
factors such as aggregation.
The strength of most materials is greater in compression than in tension. It is therefore
unfortunate that technical difficulties prevent the direct application of tensile stresses. The
compressive stresses commonly used in comminution equipment do not cause failure directly but
generate by distortion sufficient tensile or shear stress to form a crack tip in a region away from
the point of primary stress application. This is an inefficient but unavoidable mechanism. Impact
and attrition are the other basic modes of stress application. The distinction between impact and
compression is referred to later. Attrition, which is commonly employed, is difficult to classify
but is probably primarily a shear mechanism.
Stress application is further complicated by ‘‘free crushing’’ and ‘‘packed crushing’’
mechanisms. In free crushing, the stress is applied to an unconstrained particle and released
when failure occurs. In packedcrushing, the application of stress continues on the crushed bed of
particles. Although further size reduction occurs, the process is less efficient due to vitiation of
energy by the effects of interparticulate friction and stress transmission via particles which do
not themselves fracture. This is easily demonstrated when a crystalline material is ground in a
pestle and mortar. The fine powder initially produced protects coarser particles. If the material is
sieved and oversize particles are returned, the operation may be completed with far less effort.
Heywood has stated that any type of crushing or grinding machine exhibits optimal
comminution conditions for which the ratio of the energy to new surface is minimal. If finer
grinding is attempted in such a machine, the; ratio is increased. Mills may thus become grossly
inefficient if called upon to grind at a size for which they were not designed. A limited size
reduction ratio is imposed upon a single operation, larger ratios being obtained by the adoption
of several stages, each employing a suitable mill. The fluid energy mill, which presents a size
reduction ratio of up to 400, is exceptional.
A low retention time is inherent in free crushing machines. Little overgrinding takes
place and the production of excessive undersize material or fines is avoided. Protracted milling
times are found with many low-speed mills, with the result that considerable overgrinding takes
place. Accumulation of product particles within the mill reduces the effectiveness of breaking
stresses and the efficiency of milling progressively decreases.
Care must be exercised during the milling of temperature-sensitive materials, especially
for a very fine product; caking results if the softening point is exceeded.
Several examples of change of physical structure during very fine grinding have been
reported, for example, changes in the crystal form of calcium carbonate after ball milling,
distortion of the kaolinite lattice, and formation of various barbiturate polymorphs. Changes such
as these could affect solubility and other physical characteristics which, in turn, might influence
formulation and therapeutic value.
Hazards from dust may become acute during dry grinding. Extremely potent materials
require dust proofing of machines and dust-proof clothing and masks for operators. Danger may
also arise from the explosive nature of many dusts.
The mean particle size ranges normally from 100 nm up to 1000 nm. If these drug
particles are suspended in a dispersion medium and used as such, then these formulations are
regarded as nanosuspensions. In order to develop a solid dosage form, these nanosuspensions
have to be transformed via e.g. spray drying, freeze drying or granulation into a dry product.
Today four different principles to produce drug nanoparticles are distinguished (Figure
1).
Nanoparticles can be obtained by using bottom-up processes, i.e. precipitation starting
from molecular solutions. Furthermore, comminution of larger particles down to nanoparticles
(top-down) can be performed. Another way is the combination of both principles (combination
techniques). The last way leads via a chemical reaction step directly to nanoparticles (chemical
reaction approach).
It is very important to identify whether the use of particle size reduction can contribute to
an increased oral bioavailability of the drug substance. The key question to be answered is
whether the oral bioavailability of the compound is limited either by its low absolute solubility in
the gastrointestinal tract or by its low dissolution rate. To answer this question, a formulation
screening study in a predictive animal model should be performed. For this purpose, the plasma
concentration levels obtained after administration of at least three different formulations needs to
be compared: a solubilized system, a micronized system as well as a nanonized system. Two
different scenarios are possible. The oral bioavailability of the solubilized systems is far better
than the performance of both the micronized and the nanonized system, whereas there is almost
now difference of the performance of the micronized system and the nanonized system. In this
case the compound shows solubility limited bioavailability (Figure 3, upper left) and the use of
particle size reduction is less promising. The other scenario of a dissolution rate limited
compound is depicted in figure 3, lower right. It can be seen that particle size reduction leads to a
better oral bioavailability of the drug molecule. The oral bioavailability increases with
decreasing particle size. Once again the best result again is obtained, when the drug molecule is
in solution, i.e. it is molecularly dispersed. It can be stated that in case of dissolution rate limited
compounds particle size reduction technologies can be very helpful to increase the oral
bioavailability. In some cases, poor aqueous solubility of drug molecules does not necessarily
lead to a low bioavailability. For instance, some hormones are extremely poorly soluble but
become bioavailable by solubilization through body’s own surface actives, such as gall salts etc.
Through formulation screening studies, it is furthermore possible to identify whether a
sophisticated formulation approach is necessary or not. In some case, it is sufficient to use
micronized APIs to achieve the pharmacodynamic effect. Based on a cost-benefit analysis it
could be decided to develop a micronized formulation further, even though the use of a
nanonized system would result in a higher bioavailability.
Once particle size reduction techniques have been successfully tested in preclinical
programs and have been identified as suitable formulation approach they need to be tested in
clinical studies. The production of clinical trial material using drug nanoparticles is much more
complex than the production of standard formulations. Especially small and mid-size
pharmaceutical companies have not all the required equipment available in-house. The normal
way would be to approach a specialized partner to produce clinical trial material. However, it can
be also considered to implement a new technology in the in-house technology portfolio. In this
case, the gain of time resulting from a frontloading approach can be very helpful.