The Role of Particle Size Reduction in Early Drug Development

Introduction

The development of new drugs has become an increasingly complex process, with modern pharmaceutical compounds often exhibiting poor solubility, leading to limited bioavailability and growing challenges in drug formulation. In fact, poor solubility is, probably, the main reason why many promising investigational new drugs (INDs) fail to progress through clinical trials.

Thus, addressing solubility issues has become a critical part of early drug development. Several strategies are used to overcome this problem, including particle size reduction.

Growing Solubility Challenges in Drug Development

The rise in poorly soluble drugs could be attributed to advances in drug design and to the discovery of more complex molecules to target specific biological pathways. While these molecules can potentially deliver increased efficacy and specificity, they frequently present solubility issues that could prevent their clinical success.

Traditionally, the Biopharmaceutics Classification System (BCS) would categorize poorly soluble compounds as Class II, where solubility is the limiting factor for absorption, or Class IV, where both low solubility and low permeability are reducing drug exposure. To better address these solubility issues, the Refined Developability Classification System (rDCS) provides a more precise approach, dividing the former Class II into two categories, Class IIa, where the drug’s bioavailability is limited by its dissolution rate, or Class IIb, where solubility is the limiting factor.

A reduction of the particle size can lead to an increase in dissolution rate for drugs falling into the Class IIa category. By decreasing the size of the particles, we are increasing their surface area, allowing for faster dissolution and improved bioavailability. However, for Class IIb drugs, limited by their solubility, an increase in the dissolution rate will not necessarily lead to an improvement of their exposure, requiring additional strategies to successfully progress through development.  Understanding this distinction is essential to select the right development strategy.

Reducing particle size, as discussed, increases the surface area in contact with the dissolution media relative to the particle volume, promoting faster dissolution. However, excessively small particles can lead to challenges such as poor powder flow or stability issues. It is, therefore, important to establish the optimal particle size distribution and to strike the right balance between performance and processability, without introducing additional challenges.

Drus substance showing signs of agglomeration

Controlling Particle Size through Crystallization

Crystallization is one of the main strategies to optimize particle size during early development. It allows for precise control of particle characteristics, including size and morphology, by adjusting key process parameters such as solvent choice, cooling rates, agitation and supersaturation levels.

Controlling particle size during crystallization also offers several advantages. It reduces the need for post-crystallization particle size reduction methods like milling or micronization, and protects the crystal integrity of the material, helping to maintain its stability and preventing the formation of unwanted amorphous content, which can affect the drug’s behavior.

Despite these advantages, crystallization alone may not always be sufficient to achieve the desired particle size. In such cases, additional size reduction strategies can be implemented.

Downstream Processing

When crystallization methods are insufficient, mechanical particle size reduction techniques are used. These methods reduce particle size through processes like jet or wet milling, thus improving dissolution.

Mechanical processes, however, can introduce stresses that may affect the crystal structure of the drug. It is, therefore, important to monitor the particle properties closely throughout the process to prevent unwanted changes, such as amorphization, which can lead to variable dissolution profiles. Non-mechanical techniques, such as spray drying or supercritical fluid crystallization, provide alternatives that are often less aggressive. However, these techniques can lead to amorphization and may require more complex equipment and careful control of the drying conditions.

Micronization is one of the most used techniques in the pharmaceutical industry to reduce particle size. It involves the mechanical reduction of particles to the micron scale (typically 1–10 microns) through high-energy processes such as jet milling. By reducing the particle size to the micron range, the surface area increases substantially, and the dissolution rate can be significantly enhanced, leading to faster and more complete absorption in the body.

Jet milling works by propelling particles into each other at high speed using compressed air or gas. As the particles collide, they break into smaller particles. This technique is preferred for its ability to produce fine, uniform particles without the need for extreme temperatures, making it suitable for thermally sensitive compounds. It can provide high control over the particle size distribution by adjusting the pressure and flow rate of the gas, while there is minimal risk of contamination. However, jet milling can also have some problems. The process can be energy-intensive, which may impact scalability for large-volume manufacturing, and, in some cases, it can cause amorphization, affecting drug stability and dissolution profile.

Drub substance exhibiting a homogeneous particle size distribution

Wet milling is also a widely used technology to reduce particle size. It involves suspending the drug particles in a liquid medium, which acts as a lubricant, reducing friction and heat during the milling process. This process is particularly suitable for heat-sensitive drugs. Wet milling can achieve extremely small particle sizes, even down to the nanometer scale, making it an effective method for improving the bioavailability of poorly soluble drugs. Because the liquid medium helps dissipate energy, wet milling is less likely to cause amorphization of the crystal structure of the drug.

Another advantage of this technology is its scalability. While process optimization is necessary when transitioning from lab-scale to plant-scale, the fundamental principles of wet milling remain the same. This ensures that particle size distribution, product quality, and drug performance can be maintained throughout the drug development cycle, from preclinical batches to full commercial production.

However, a drying step is required. After wet milling, the suspension must be filtered and dried to remove the excess of solvent, which adds an extra step to the process, increasing the time and cost of production. Depending on the solvent used, there may also be issues related to solvent recovery, disposal, or residual solvent levels in the final product, which need to comply with regulatory requirements. The presence of a liquid medium increases the risk of contamination from the milling equipment or the liquid itself. Strict cleaning protocols are required to ensure product purity.

Nanoparticles in Drug Delivery

Nanoparticles, defined as particles with a size between 1 and 100 nanometers in diameter, represent an innovative approach to enhance the bioavailability of poorly soluble drugs. Nanoparticles exhibit a much higher surface-to-volume ratio than larger particles, resulting in significantly faster dissolution rates.

Beyond improving dissolution rates, nanoparticles have opened the door to new drug delivery strategies. Due to their small size, nanoparticles can be engineered to bypass biological barriers, making them particularly useful for drugs targeting the central nervous system or other targets typically with difficult access.

Despite their potential, nanoparticles also present some challenges, particularly in terms of stability and scalability. Additionally, regulatory hurdles for nanoparticle-based formulations are tough, as the safety and behavior of such small particles must be carefully evaluated.

There are several methods to produce nanoparticles, each with its own advantages depending on the drug’s characteristics and desired properties.

High pressure homogenization is a technique that uses high pressure to force a drug suspension through a narrow valve, creating nanoparticles by shearing and breaking down the particles. High pressure homogenization is particularly effective in delivering narrow particle size distributions and is commonly used for heat sensitive compounds since the process does not generate excessive heat.

Precipitation can sometimes provide another route to nanoparticles. In this case, the drug is dissolved in a solvent and then rapidly mixed with an anti-solvent where the drug has poor solubility, causing the drug to precipitate out as nanoparticles.  A variation of this method involves the creation of nanoparticles in an emulsion system, where the drug is dissolved in a solvent and then dispersed in an anti-solvent. This method enables the formation of uniform nanoparticles in a controlled environment, often leading to improved stability of the resulting particles.

Solid powder isolated in a manufacturing plant

Spray drying involves the atomization of a solution of the drug into droplets followed by the rapid evaporation of the sprayed droplets into solid powder by hot air at a certain temperature and pressure. It can also be used to create nano-sized particles with controlled surface properties by varying the parameters that control the process.

Supercritical fluid crystallization (SFC) is an advanced technique that allows for the generation of very small particles, often in the sub-micron range. In this process, the drug is dissolved in a supercritical fluid such as supercritical carbon dioxide (CO₂), which is then rapidly expanded, causing the precipitation of fine particles. The rate of expansion and other parameters can be controlled to fine-tune the particle size and shape. Supercritical fluid crystallization is particularly useful for heat-sensitive or fragile compounds, as it avoids the need for high temperatures or extreme mechanical stress. As well as providing an excellent control over particle size and morphology, the lack of organic solvents in the process makes this a green and clean technology option. However, supercritical fluid crystallization also comes with limitations, including scalability challenges and the need for specialized equipment.

Each of these technologies has its own set of advantages and challenges, often depending on the nature of the drug, the desired particle size, and the production scale. For instance, wet milling and high-pressure homogenization are ideal for scaling up, while techniques like spray drying and nanoprecipitation provide precise control over the particle characteristics at smaller scales.

Conclusions

As the pharmaceutical industry increasingly encounters poorly soluble drugs, particle size reduction has become a key strategy for enhancing bioavailability. Whether through traditional methods like milling or advanced techniques such as supercritical fluid crystallization and nanoparticle production, the common goal of these technologies is to increase surface area and to improve dissolution rates.

Selecting the right approach requires a deep understanding of both the drug’s properties and the specific formulation challenges. By controlling particle size, formulators can overcome solubility obstacles and bring more effective, life-saving therapies to market.

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