Size matters: Nanoparticles and their potential for the formulation of sparingly soluble active ingredients

Nanoparticles, nanocrystals, nano effect - the term "nano" seems to be omnipresent. Not only in the pharmaceutical natural science sector, but also in the context of paints, food, textiles or high-performance processors. All topics deal with particles that are smaller than a millionth of a meter in diameter. As tiny as they are, nanoparticles offer great potential for humans, nature and technology.

Nanoparticles in the pharmaceutical industry
In the pharmaceutical industry, the advantages of nanoparticles have been used for several years. Their chemical, biological and physical properties are fundamentally different from those of larger particles and can improve solubility, drug release, bioavailability and drug transport. Depot effects can also be achieved with nanoparticles so that the active ingredient is released over several hours, days or even weeks after a single application.

There are numerous subgroups of nanoparticulate systems - two groups are divided here:
Group 1:
Systems that act as carriers for an active substance. The active ingredient is transported through the body with the help of a nanoparticle. The active substance can, for example, be functionalized onto the surface or be bound inside the nanoparticle. This depends strongly on the shape, size and carrier material of which the nanoparticle is made. The structure of the active ingredient and the desired effect in the body also have an influence. The aim of such carrier systems is the targeted transport of the active substance to the site of action in the body.

Group 2:
Systems in which the active substance itself is the nanoparticle. This is often referred to as nanocrystals. Such nanocrystals consist exclusively of active ingredient and are not coupled to other carrier materials. This is intended to improve the solubility of sparingly soluble active substances. Because of the particle size in the nanometer range, nanocrystals have a higher specific surface area, which leads to a higher dissolution rate - compared to larger particles of the same drug.
A large number of chemical and biological active ingredients are sparingly soluble in water or physiological media and more than 70% of new active ingredients. Due to their properties, nanocrystals offer great potential, especially for drug formulations with sparingly soluble active ingredients. This applies not only to oral products, but especially to topical and parenteral dosage forms.

Manufacturing of active substance nanocrystals
The production of nanocrystals can be carried out by various methods: bottom-up and top-down. In bottom-up approaches, the active ingredient nanoparticles are successively built up from individual molecules, while in top-down approaches active ingredient particles are physically comminuted.
The two most frequently used methods for the physical comminution of active substance particles are high-pressure homogenization and grinding with the aid of milling beads in an aqueous medium (so-called wet grinding). In both processes, the active substance to be comminuted is dispersed in an aqueous medium with polymers and/or surfactants serving as excipients. Selection, combination and concentration of these excipients are carried out specifically for every active substance. They stabilize the dispersed active ingredient particles so that their agglomeration is prevented.
In high-pressure homogenization using a piston-gap homogenizer, the suspension is pumped through a gap of a few microns width at very high pressure (>2000 bar). The cavitation and shear forces generated in this process cause the active ingredient particles to be comminuted. In wet grinding using a ball/bead mill, the suspension consisting of active ingredients and excipients is comminuted in a grinding chamber with the aid of milling beads at high rotation speeds. The milling beads used for this purpose are made of very hard materials, such as zirconium oxide. The active ingredient is crushed under the influence of the rotating grinding chamber by physical impacts with the milling beads.

The nanosuspensions can already be the final dosage form and can be administered orally, dermally, intramuscularly or subcutaneously, for example. A lyophilization of the nanosuspension is also possible, which can increase the storage stability. For application, the lyophilizate can then be reconstituted using a suitable medium.

If you are interested in how the production and subsequent lyophilisation of a nanosuspension is carried out in our clean rooms, please watch the following video: media centre

The nanosuspensions can also be further processed: For oral administration by coating on pellets and filling into capsules or by granulation and further processing into tablets; in semi-solid dosage forms for dermal or nasal application. For this purpose, oleo- or hydrogels can be used for the formulation of the final dosage form.

Sterile nanosuspensions - a particular challenge
If nanosuspensions are to be administered in parenteral dosage forms, for example for subcutaneous or intramuscular application, the requirements for sterile products must be met. According to the European Pharmacopoeia, terminal sterilization in the final container is the preferred method of choice. Common methods are steam sterilization, sterilization with dry heat or by ionizing radiation.
As these processes involve a high energy input, they are usually not suitable for nanosuspensions. Even terminal sterile filtration is often not applicable. Active ingredient and excipient materials used for stabilization are present undissolved in the nanosuspension and often cannot pass the sterile filter. In order to reduce the microbial load in nanosuspensions, alternative methods must therefore be used. These consist of selecting different sterilization processes for individual starting materials and manufacturing the end product under aseptic conditions. Due to the high complexity, the production of nanosuspensions under aseptic conditions is not yet commercially available.

Where is the journey going?
The technologies for manufacturing suspensions with nanocrystals offer great opportunities, especially for improving the solubility and bioavailability of sparingly soluble active ingredients. They are already established for oral and dermal dosage forms from development to production scale. With the growing demand for parenteral dosage forms for sparingly soluble biological and chemical active ingredients, these technologies for the production of aseptic nanosuspensions need to be developed quickly to market maturity.
HWI has established the technologies known today for the production of nanosuspensions and can already draw on extensive experience in development projects. In addition, HWI is working intensively on processes for the flexible and cost-efficient development and production of aseptic nanosuspensions, with special emphasis on sparingly soluble active ingredients with low bioavailability.
For this project, a funding application has been submitted to the Innovation and Technology Support Program (InnoTop) of the ISB Rhineland-Palatinate. The project is supported by funding from the European Regional Development Fund (ERDF ).