Going micro to improve solubility in drugs
Peter Nelson, technical operations director at Catalent Micron Technologies examines why micronisation may be the answer to poor water solubility in drugs.
Over the past few everyday items such as computer chips and mobile phone batteries have been shrinking. Size reduction technology is also commonplace in drug development, where reducing the particle size of a promising active pharmaceutical ingredient (API) can help to overcome a hurdle facing 70% of drugs in the pipeline: poor water solubility.
Traditional oral dosage drugs are delivered into the circulatory system through absorption in the gastrointestinal tract (GIT). However, a challenge arises if drugs cannot permeate through the GIT into the bloodstream. Another potential issue is when slow rates of dissolution result in drugs not fully dissolving before completing their transit time in the small intestine, missing the ‘window of absorption’. Particle size reduction counters this by relying on the simple mathematic principle that reducing an object’s size will increase its relative surface area. This can consequently improve the particle’s rate of dissolution, ensuring that sufficient quantities of the active ingredient reach the bloodstream.
Micronisation is particularly effective at improving the efficacy of drugs that are dissolution rate limited. This is an extremely versatile and straightforward process for improving the solubility of drug candidates. Micronisation typically uses fluid energy jet mills to break down an API to produce micron-sized particles.
But how small do we want our micronised particles to be? If we apply the basic theory of micronisation, one may logically assume that a smaller particle size will produce an accelerated dissolution rate. However, micronisation is a multifaceted process. While it may directly alter particle size, it could also have secondary effects on other characteristics that influence API performance.
Particle size matters
It’s critical to understand exactly how micronisation can impact a drug’s performance. One important characteristic affected by micronisation is agglomeration between particles. The increased surface and amorphous area created by micronisation can cause a sticky situation for drug developers. Agglomeration is where particles stick either to each other or to a surface, adversely affecting powder flowability, making the micronised drug difficult to handle. It can also reduce the effective surface area of the micronised particles, cancelling the benefits provided by size reduction.
Smaller particle size may also negatively impact a drug’s performance through influencing wettability. Micronisation can often lead to particles having a high energy state, making particles hydrophobic and reduces the wettability of a drug; an important precursor to dissolution.
Changes in particle agglomeration and wettability are two examples highlighting how it is possible to overmicronise a material. This can increase the risk of delays, or even failure, when commercialising a promising drug compound. Drug developers can mitigate these issues by determining the optimum micronised particle size of a compound as early in the pipeline as possible.
If possible, all drug powders should undergo rigorous characterisation to determine the optimal particle size and their respective characteristics. While the amount of API material a drug developer has available could limit this, up to 10 trials can be performed with as little as 100g of an API.
How to deduce the best particle size
It is crucial to quantify the physical characteristics of an API to enable drug developers to identify the optimal particle size for optimal performance. A perhaps obvious but important tool used to achieve this is particle size analysis. A widely used technique to accomplish this is laser diffraction, which is often preferred for its repeatability, rapid measurements and high sample throughput.
However, laser diffraction cannot deduce all physical traits that can impact a drug’s performance, such as agglomeration. Microscopy is a simple technique that can accurately deduce the physical appearance of a chosen sample. It also creates limited disruption of agglomerates during sample preparation analysis. Surface area analysis is another useful analytical tool, and like microscopy, the sample preparation is not disruptive to agglomerates.
Although the impact of micronisation on the amorphous content and crystallinity of a sample is often negligible, it may be a concern for drug developers. As changes in these characteristics may negatively affect a drug’s performance, it is important to allay these fears. Crystallinity and amorphous content can be quantified through powder X-ray diffraction if the sample has a high amorphous content or through vapour sorption if the amorphous content is predicted to be below 5%.
The short-term stability of an API must also be considered when selecting an optimal particle size. All of the characteristics detailed above may not be static properties. Quantifying these variables at intervals of days, weeks, and even months, ensures that the optimal particle size remains stable in the short term.
Techniques such as co-micronisation with a surfactant like sodium lauryl sulphate (SLS) can also improve the solubility and intrinsic dissolution rate of an API, since SLS is a surface active agent. Another tool used to improve these characteristics is cryogenic micronisation, where the drug is stored overnight at room temperature before being processed at -50°C.
Smaller is not always better when micronising a drug. However, the optimal particle size can be determined through micronising an API to varying degrees, and subsequent rigorous physical characterisation and formulation development. By undertaking this during early phase and scale-up, a working particle size specification can be established early on for subsequent R&D and early phase batches.
[3] Effect of surfactants on the solubility and intrinsic dissolution rate of sparfloxacin. Mbah, CJ and Ozuo, CO. 3, Mar 2011, Pharmazie, Vol. 66, pp. 192-4.