Nanotech - a bead of hope for big pharma?

One of the greatest challenges for those working in the research and development of pharmaceutical products is the step from laboratory to full-scale production. Nanotechnology has provided a real step forward in the small but perfectly formed shape of nanoparticles - but the accurate creation of these particles is proving to be a key factor in this success

Nanoparticles offer exciting advantages and enormous potential for the pharmaceutical industry, both in terms of reduced development times – and hence reduced costs – and in improved drug efficacy. The level of interest and importance placed on nanotechnology by the industry is reflected in the increasing amount of investment that is being committed to this area, investment which some sources suggest is set to show continuous annual growth of more than 25% over the next five years.

The challenge for developers and manufacturers of pharmaceutical products is to create the right size and type of nanoparticles in a consistent, repeatable fashion. Nanoparticles can offer advantages in the development of new drugs, the resurrection of drugs that have been withdrawn from market or for which patents have expired and the efficacy of drugs, as well as proposing a solution for creating nanoparticles that can exploit these advantages and deliver real benefits to developers, manufacturers and end-users.

Drug development averages 12 to 15 years and just one in 5,000 new compounds make it to the consumer market. Naturally, pharmaceutical companies are searching for ways to improve these odds.

There are countless reasons why compounds don't make it past the trial stage: poor bioavailability; poor solubility (almost half of new chemical entities (NCEs) are impaired by poor water solubility); poor permeability; insufficient shelf life; insufficient half life; strong side effects; and poor targeting. These can result in poor performance characteristics, such as slow or variable onset, increased side effects and poor compliance, as well as the need for higher dosing.

Nanoparticles can, theoretically, improve all common drug administration techniques: oral; injection; trans¬dermal; transmucosal; ocular; pulmonary; and implant. Numerous studies show that particles less than 100nm in size have greater absorption and delivery efficiency in the gastrointestinal, pulmonary and vascular systems, and similar dermal penetration charac¬teristics. This could prove particularly beneficial to active pharmaceutical ingredients (APIs) which typically have low solubility (less than 0.Img/L) and/or low permeability.

Specific nanoparticle shapes can be used to encapsulate or bind drug compounds to improve the solubility, permeability, stability or absorption rates. This allows drug manufacturers to overcome numerous obstacles that have, in the past, been research dead-ends.

In some cases, the problem has been tissue or cellular damage, or irritation associated with comparatively large doses of drugs. Examples include drugs dosed via inhalers, which can cause coughing and throat irritation. Nano-sized doses, however, impart significantly less irritation or dam¬age, which the body is able to heal without adverse affect.

Additionally, nanotechnologies may allow producers to shorten the production cycle and save money by revisiting and reformulating compounds that never made it through trial phase, as well as older drugs that are no longer available or for which patents have expired, allowing them to be re-introduced. Companies can also change the method of drug delivery to improve customer acceptance or reduce manufacturing costs.

Creating repeatable distributions of submicron particles is essential to using them effectively. Traditional plasma gas processes deliver superior particle uniformity, but do not of¬fer the ability to disperse particles in a solution at their pri¬mary size. That's because the tremendous surface area and surface energy, which delivers the beneficial effects of nano¬materials, also prevents their easy dispersion into liquids.

Intermolecular forces increase as particles become smaller, causing cohesive forces –agglomerates, aggre¬gates or primary particles – in the product. Agglomerates are formed by point-focal or linear cohesive primary par¬ticles, while aggregates form by laminar binding. Primary particles are crystalline or amorphous particles that are separated against each other. The goal is to disperse these particles to their primary particle size as discrete entities.

Traditional methods of creating nanoparticles result in a single strong contact which can cause particles to break or be destroyed, increasing the risk of particle cohesion within the product (Figure 1).

Creating stable suspensions or dispersions of nanoparticles requires a comminution process such as a small-media mill provides. Using 75 to 125um grinding beads produces multiple mild contacts instead of one strong contact, helping to maintain the surface condition and crystal structure of the particles and yielding excellent product with outstanding process efficiency (Figure 2).

Decreasing the diameter of the bead delivers four pri¬mary results: the number of beads in the mill is increased; contact of the beads with the product is increased dramatically; bead weight is reduced; and the energy of one bead is significantly decreased (mean energy of one bead is equal to the specific energy input divided by the number of grinding beads).

The smaller the bead size, the more beads there are per unit volume. For example, if 1mm beads are loaded into a 1 litre vessel, there are around 1.1 mil¬lion beads. But with 0.05mm beads there are 9.4 billion beads. So the probability of contacts be¬tween particles and beads is significantly enhanced.

As the bead size decreases the space between the beads decreases, too. A rough calculation indicates the stand-off distance between the beads would be 44um for 1mm beads and 2um for 0.05mm beads. Mild dispersion holds back particle agglomerates larger than the stand-off distance, shearing them apart to their primary size. These changes create uniformity and reduce particle damage while maintaining productive work speeds.

Media milling – commonly called grinding – uses force shearing to reduce particles into the nano scale. When combined with new dispersion techniques, nanogrinding offers many benefits: excellent particle size control; ideal particle surface condition; comparative cost effectiveness; equipment scalability, from bench-top to production; limited or zero contamination of APIs; repeatability of process and it meets cGMP production requirements.

Popular because of their simplicity and scalability, fine¬-bead mills also offer lower costs compared to plasma gas and precipitation process techniques, as well as other al¬ternative technologies. Fine-bead mills provide an efficient way to disperse the output in primary particle size, assum¬ing the proper stabilizing agents are used.

In bead milling, kinetic energy is transmitted to the grinding media by the agitator shaft in the stator housing. Particle fineness is primarily defined by two basic parame¬ters: the stress intensity and the number of contact points. Stress intensity is a function of the kinetic energy in the grinding beads. The number of contact points determines how often the media interacts in the grinding chamber. Fine-particle distribution requires a high number of contact points, achieved by using smaller grinding media in the range of 50-200 pm. The rule of thumb is that particle size is equal to 1/1000 the size of the grinding media.

Selecting appropriate equipment is essential to developing a repeatable process and creating efficient workflow from the laboratory right through to full-scale production. New mills offer adequate product throughput at low-energy motor speeds, which prevents nanoparticle damage, while providing practical methods for handling and removing the grind¬ing media at the end of the process.

The ideal mill will have ‘plug flow’ to ensure that no product can by-pass the grinding process. Plug flow also ensures that the entire product passes through the machine at the same velocity, producing a uniform grind and residence time distribution.

Selecting appropriate materials of construc¬tion for the grinding media and mill chamber is also critical. The right material will prevent unwanted reactions and transfer contamination, which wastes time, money and materials. This last point is particularly important in lab-sized batches where there may be a limited inventory of target compound available for testing.

With the right milling equipment and grinding media researchers can cost-effectively create nanoparticles for drug delivery that are uniform and readily available. Selecting these from a reputable manufacturer who possesses the appropriate skills, knowledge, experience and resources will assure success in application and efficiency of process.

Author: Andy James, Applications Engineer at NETZSCH Mastermix

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