Targeted particle engineering for solid dosage drug formulations has become an imperative given the challenging compounds in the pharmaceutical pipeline, the growing interest in inhaled delivery, and the move to continuous manufacturing. Contract development and manufacturing organizations (CDMOs) with extensive knowledge and experience with optimization of crystallization and particle engineering processes provide customers with improved product quality, lower costs, and accelerated development and commercialization timelines.

Multiple Drivers for Enhanced Particle Engineering

A number of changes occurring in the pharmaceutical industry are creating a significant need for the development of advanced particle engineering technologies for solid dosage drugs, regardless of their route of administration.

The biggest driver is the growing percentage of drug candidates that suffer from poor water solubility and consequently poor bioavailability — various estimates range from 40%-70%. The use of high-throughput and combinatorial chemistry capabilities in drug discovery has led to the identification of novel compounds with attractive therapeutic benefits, but challenging pharmacokinetic properties. Different strategies, from the straightforward (particle size reduction) to the more complex (preparation of amorphous solid dispersions or incorporation in lipidic vehicles, complexation with cyclodextrins and salt, or cocrystal formation), have been developed to enhance water solubility and ultimately improve dissolution rates and bioavailability. Most of these approaches require expertise in particle engineering.

While oral delivery remains the preferred route of administration, interest in delivery via inhalation has recently attracted attention as an additional approach to overcoming poor water solubility/bioavailability. Delivery first to the lungs, followed by absorption into the bloodstream, provides an alternative mechanism for making the active pharmaceutical ingredient (API) available to the body. APIs for inhaled drug products require specific size, shape and surface properties, thus effective particle engineering is crucial to their successful development and manufacturing.

In addition to poor water solubility, many new drug candidates are classified as highly potent APIs (HPAPIs). These drug substances are effective at very low doses. In addition, formulated oral solid dosage (OSD) drugs based on HPAPIs typically contain very low concentrations of the active substance. Appropriate particle engineering is important to ensure that the HPAPI is evenly distributed throughout the formulated OSD and exhibits acceptable release profiles.

Finally, continuous manufacturing of OSD products has become a reality. FDA has approved the use of continuous processing for the manufacture of two different drug products in the last two years and actively encourages its adoption. Effective implementation of continuous processes for final product formation — such as grinding and tabletting — requires APIs with excellent flow properties. Application of particle engineering technology is therefore essential for developing solid APIs with appropriate particle characteristics.

A Little About Targeted Particle Engineering

Effective particle engineering depends on the successful achievement of three primary activities: target identification, knowledge gathering and process control. Appropriate target identification ensures a high yield of a high-quality product that is produced as the desired polymorph with the desired particle properties. Successful knowledge-gathering generates information about various particle characteristics, solubilities, the metastable zone, and the supersaturation properties of an API. Implementation of appropriate controls leads to the development of an optimal solvent system, crystallization and/or milling/micronization processes, and the establishment of appropriate physical analytics.

In all three cases, systematic development work is required. For target identi- fication, thorough polymorph screening and evaluation of crystallization habits and limitations are essential. Systematic studies are also required to fully characterize API particles, including crystal form and flowability; particle size, shape and habit; specific surface area, purity and stability; bulk and tapped densities; and processability. Intellectual property considerations can also be identified. To obtain this information, a range of analytical techniques are used, including in-line particle size measurement during crystallization, metastable zone determination, particle size distribution analysis, x-ray diffraction for polymorph determination, scanning electron microscopy, microcalorimetry and more.1, 2

Notable Advances

Advances in particle engineering tech- nologies in three particular areas are worth noting, because they have had significant impact on the development of solid dosage drugs.

First, micronization increases the dissolution rate of poorly soluble APIs due to the increase in surface area. Water solubility and dissolution rate of drugs are key drivers for their absorption in the GI tract. For a therapeutic effect, a sufficient amount of drug needs to be absorbed at a sufficient rate. As the majority of new drugs under development are poorly soluble, the challenge of low solubility occurs more and more often in drug development, as does the need for micronization.3, 4

Second, nanomilling results in the production of an intermediate that can also be considered a formulated product. API manufacturers that perform nanomilling are thus also producing formulated products in some cases, which impacts their regulatory status. Nanomilling aims to produce particles in the size range of a few nanometers to a few hundreds of nanometers. After production, a nanosuspension is obtained. For oral administration, the liquid of the nanosuspension needs to be removed to obtain a solid oral dosage form or formulate accordingly for an oral liquid nanosuspension. Therefore, nanomilled drug substances become formulated inter- mediates rather than API.5

Third, large porous particles have been shown to have aerodynamic properties comparable to those of small particles, but due to their larger size, they are not at- tacked by macrophages in the alveoli. The ability to engineer these types of large particles is facilitating the formulation of solid dosage drugs for inhalation delivery.6 In order to achieve a therapeutic effect, locally in the lungs or systemically, inhaled drug particles need to reach the site of absorption in the tiny alveoli. To make this journey, the particles need to possess a very narrow range of aerodynamic diameter (related to geometric diameter and density). The aerodynamic diameter window of 1-3µm is referred as ideal for inhalation drugs. Particles of this size range are targeted by phago- cytosis of macrophages, thus removing the drug particles from their absorption site. By engineering drug particles with large size and low mass, the absorption site in lungs can be reached and phagocytosis avoided.7

CDMOs Meet Technical Needs

Particle engineering is a specialized field that requires specialized knowledge and expertise as well as specialized analyti- cal and manufacturing equipment. Most (bio)pharmaceutical companies cannot justify the extensive investment required to establish the high level of capability required to achieve effective particle engineering. They therefore do not have the in-house know-how or resources needed to solve these types of problems. In other cases, sponsor firms may have the ability to perform particle engineering studies, but not for highly potent compounds, which require specialized containment solutions, or not for commercial manufacturing.

Effective particle engineering efforts that lead directly to products with the desired PSD can eliminate milling costs.

Measurable Impact

Effective particle engineering at Fermion has been achieved by gaining a thorough understanding of crystallization processes combined with implementation of full automation in production. Crystallization and particle engineering issues are also considered at the very earliest stages of each project. The extensive crystallization know-how and wide range of particle engineering technologies, combined with the use of detailed R&D studies and a variety of milling capabilities allows Fermion to rapdily develop processes that not only provide high yields, but also the desired product quality in terms of physicochemical properties.

One obvious advantage to this approach is a reduction in the variation of particle properties, which leads to a minimization of product quality variation. Low levels of variation have been achieved because our approach to particle engineering leads to the production of particles that consistently meet particle size distribution (PSD) specifications. One consequence: approximately 50% of products produced at Fermion do not require milling or micronization. Consistent PSDs are also highly beneficial to the milling process when milling is required because a smaller particle size is needed.

Skillfully designed crystallization processes are also very effective purification methods. In many cases at Fermion, well-designed crystallization processes have replaced laborious, multistep purification processes, including those that involve multiple but ineffective crystallization processes. Cost reductions are also achieved through effective particle engineering. Higher yields and the elimination of purification steps are both possible through optimization of crystallization processes. Effective particle engineering efforts that lead directly to products with the desired PSD can eliminate milling costs.


With careful particle engineering, products have consistent quality and fewer deviations. Ultimately, particle engineering supports security of supply. Fermion recognizes the valuable role that particle engineering plays today and its increasing importance in future drug development and manufacturing. The company is therefore continually investing in expanding capabilities.

Recent additions have included the installation of different types of milling equipment for medium-scale processes (tens of kilograms) — including pin, ham- mer and jet mills that are also designed for the micronization of HPAPIs — and HPAPI micronization capabilities for large-scale production (up to 1000 kg). Fermion will also invest in Raman analysis capabilities in R&D scale in 2017. In addition, an online particle size distribution analyzer will be installed in 2017 in the expanded commercial production facilities at our site in Hanko, Finland.

The added equipment and analytical capabilities further enable Fermion to support our customers with the rapid development of tailored particle-engineering solutionsfor their challenging intermediates and APIs.


  1. Hilfiker, Polymorphism in the Pharmaceutical Industry. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, FRG, 2006.
  2. Brittain, Harry G. Polymorphism in Pharmaceutical Solids – Drugs and the Pharmaceutical Sciences. New York: Marcel Dekker Inc.,
  3. Kawabata, Yohei, Koichi Wada, Manabu Nakatani, Shizuo Yamada, Satomi Onoue. “Formulation Design for Poorly Water-soluble Drugs based on Biopharmaceutics Classification System: Basic Approaches and Practical Applications.” International Journal of Pharmaceutics 1 (2011): 1-10. Web.
  4. Kalepu, Sandeep, Vijaykumar Nekkanti. “Insoluble Drug Delivery Strategies: Review of Recent Advances and Business Prospects.” Acta Pharmaceutica Sinica B 5.5 (2015): 442-453. Web.
  5. Müller, Rainer H., Sven Gohla, Cornelia M. Keck. “State of the Art of Nanocrystals – Special Features, Production, Nanotoxicology Aspects and Intracellular Delivery.” European Journal of Pharmaceutics and Biopharmaceutics 78.1 (2011):1-9. Web.
  6. Edwards, David A., Justin Hanes, Giovanni Caponetti, Jeffrey Hrkach, Abdelaziz Ben-Jebria. “Large Porous Particles for Pulmonary Drug ” Science 276.5320 (1997): 1868-1872. Web.
  7. Patel, Brijeshkumar, Nilesh Gupta, Fakhrul Ahsan. “Particle Engineering to Enhance or Lessen Particle Uptake by Alveolar Macrophages and to Influence the Therapeutic ” European Journal of Pharmaceutics and Biopharmaceutics 89 (2015): 163-174. Web.