Moving Beyond Particle Size Control

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology, June 2021 Issue, Volume 45, Issue 6
Pages: 22–25

Particle engineering is a vital tool in overcoming many formulation challenges, and technological advances are enabling developers to achieve the full potential of pipeline molecules.

Particle engineering plays a vital role in optimizing a drug’s effectiveness. The size of a particle will have an effect on the delivery of a drug, the route of administration—particularly in cases where an inhaled formulation is being developed—and will impact the rate at which a drug is metabolized in the body.

“In formulation and development, both active and excipient particles can be engineered to tailor the performance/efficacy of the drug product,” confirms Jamie Clayton, operations director, Freeman Technology (a Micromeritics company). “A relatively simple example would be controlling the particle size of an active to influence dissolution rate and by extension bioavailability.”

Additionally, particle size, along with other properties, influences bulk powder properties, Clayton continues. “Therefore, particle engineering is equally important for achieving desirable bulk powder properties, properties associated with the consistent manufacture of a drug product of acceptable quality, for example, a tablet with the required hardness,” he says.

“With drug particles or particle assemblies being the crucial component of solid dosage forms, which represent the vast majority of all medicines, it has become clear that ‘drug particles are of the essence’ when designing quality, safe, and efficacious medicines,” agrees Peter York, chief scientist at CrystecPharma.

Critical attributes, such as a drug’s solid state, particle size, and morphology, all impact a drug’s bioavailability, remarks João Henriques, group leader—Drug Product Development, Hovione. As a vast proportion of the development pipeline is now incorporating compounds with low aqueous solubility and permeability, addressing bioavailability is forming a significant part of development approaches.

“Particle engineering plays a pivotal role in addressing bioavailability issues,” says Henriques. “By modulating the solid state, particle size, or morphology, one can increase both the solubility and dissolution rate of a drug. The former is generally required when dealing with solubility-limited compounds and can be achieved by particle engineering techniques, such as spray drying and nano-milling.”

Furthermore, for downstream operations, particle engineering will dictate the processability of a drug, adds Henriques. “Even in the absence of bioavailability challenges, particle engineering can be used to mitigate processing problems, from avoiding segregation to improving flow and compactability,” he reveals. “Particle engineering is therefore an essential tool for formulators to enable successful pharmaceutical development programs of challenging drugs.”

“The importance of particle engineering and particle size analysis take on an even stronger role in the development of therapeutics with more novel routes of delivery, such as inhalation,” York notes. “Here, the particle properties not only dictate the pharmacokinetic performance of the drug, but also the amount of drug that reaches the targeted site of administration.”

Common challenges

A major challenge with particle engineering is access to the information needed to guide the process, Clayton explains. “The goal is to determine robust correlations between manipulable particle properties, process variables, and critical quality attributes of the drug product,” he adds. “Bulk powder properties are often vital in elucidating such correlations, but with a wide range of analytical techniques to choose from, it can be difficult to identify those of most value.”

Recently published collaborative studies have demonstrated the drive for industry to refine analytical strategies (1–3), Clayton continues. “These [studies] focus on the potential of material property databases to accelerate the identification of critical material attributes, support process optimization, and improve supply chain management. Such work is equally helpful for those learning how to efficiently gather information to support particle engineering,” he confirms.

“A particle engineering technology should ideally be built upon an understanding of the mechanical, physical, and/or chemical events taking place during particle formation,” adds York. “For drug substances, the requirements of good manufacturing practice (GMP) and regulatory specifications must be embedded into the engineering and operation of the process.”

Traditionally, particle size reduction methods are approached in a ‘top-down’ way, so, reducing the size of larger crystalline drug particles uses high-energy impact mills, York explains. “This method continues to be widely used as a ‘first approach’ in solving the dissolution challenge; however, the high energy applied, and uncontrolled fracture and breakage of particles frequently imparts negative features to the milled drug particles such as changes in the solid state and causing highly charged, static particles, which are difficult to process downstream,” he says. “These factors, as well as the need for particle engineering tools that address not only the issue of low drug dissolution, but also potential physicochemical and biopharmaceutical challenges, have provided the basis for innovation in drug particle engineering and new concepts and approaches in drug particle design and delivery.”

To ensure the desired characteristics have been achieved through particle engineering, it is necessary to employ analytical tools, highlights York. “Whilst particle size and size distributions are a key property to be measured, the wide range of effects of particle size reduction methods on drug substance structural chemistry necessitates additional analytics to determine whether the process has led to any detrimental changes in solid state, physicochemical properties and, in the case of biotechnology substances, the biochemical and potency characteristics,” he states.

Other common challenges encountered with particle engineering and size analysis are related to process scale-up, asserts Mafalda Paiva, group leader—Analytical Development, Hovione. “Particle size methods are product and size specific, and method development should be performed with lead process candidates,” she says. “A change in process scale is often accompanied by an increase in size that can translate to challenges in measuring the desirable primary particles. Attention is required when analyzing this data, for instance, employing an orthogonal technique such as scanning electron microscopy (SEM) to ensure the employed method is still fit for purpose.”

Further challenges can arise with particle engineering as a result of solid-state changes, emphasizes Paiva. “The use of particle engineering can often lead to changes in the solid form,” she reveals. “These [changes] may be as simple as residual amorphization upon high energy milling operations and the emergence of different polymorphs after spray drying.”


The hurdles associated with new drug candidates are numerous and varied, particularly when accommodating different routes of delivery, York continues. “By far the major current challenge is the low aqueous solubility of drugs, which constrains the dissolution and thereby subsequent bioabsorption of drug particles when administered to patients,” he notes. “Incorporating micron sized drug particles in the medicine provides a high surface area and drives up the rate of solution of the drug, which in some cases is sufficient to provide an efficacious product.”

Henriques concurs that low aqueous solubility of new chemical entities represents the most common challenge facing formulators that requires the use of particle engineering. “The increasing number of BCS [biopharmaceutical classification system] class II compounds means that the interest and demand for such technologies is also increasing,” he says.

BCS class IV actives, which have both low solubility and low permeability, represent one of the toughest formulation challenges, remarks Clayton. “Gastroretentive (GR) oral solid dosage forms can be the answer, with floating, sustained release tablets the most common approach,” he adds. “Engineering such tablets is a complex task and calls for an array of analytical insight, with particle morphology, blend flowability, and porosity information all of proven value (4).”

Another trend of note, highlights York, is the increasing prevalence of biotherapeutics entering the development pipeline. These compounds are typically more sensitive to high energy processing techniques that are used in conventional particle engineering, he explains.

“Emerging technologies enable particle engineering to be conducted in low temperature and chemically benign environments, providing opportunities to engineer particles of biological substances with high levels of retained biological activity and targeted particle properties to enable specific target product profiles to be achieved,” York stresses.

Novel and alternative approaches

There are many established particle engineering techniques that are being used for commercial supply of API programs, Henriques specifies. Techniques such as spray drying, hot-melt extrusion, and co-precipitation are commonly encountered, but there are also new methodologies emerging within academic and industrial initiatives, he comments.

“One [such technique] is the use of mesoporous silica for the impregnation of APIs,” says Henriques. “[This technique is providing formulators with the opportunity to overcome] some of the limitations of amorphous solid dispersions and is providing opportunities for the formulation of challenging compounds.”

A lot of interest over the past 20 years has been given to alternative approaches to ‘top down’ particle formation technologies, such as hot-melt extrusion and nano-milling, emphasizes York. “However, the converse strategy of ‘bottom-up’ particle formation techniques has proved a particularly fruitful area for particle engineering. In this approach, a solution of drug substance is subjected to a drying or solvent extraction process to yield drug particles, ideally in a single step operation,” he notes. “Manipulation of targeted particle characteristics, such as particle size, by means of varying process conditions delivers the ambition of particle engineering.”

An example of an innovative approach that is finding success in terms of drug particle engineering includes supercritical fluid (SCF) based technologies, which are available through specialist service providers, such as CrystecPharma, York states. “In supercritical anti-solvent (SAS) configurations, where the supercritical fluid (typically carbon dioxide due to its low critical point) acts as a powerful antisolvent, the solvent from a feed of drug solution is rapidly extracted in a pressure vessel, and dry drug particles precipitate almost instantaneously,” he notes. “The versatility of this technology is impressive in terms of excellent intra- and inter-batch reproducibility, as well as the ability to ‘tune’ the characteristics of the engineered drug particles, for example size, solid state and surface properties. Also, the low processing temperatures possible using supercritical carbon dioxide enable particles of delicate biotech drugs, from peptides to monoclonal antibodies, to be produced.”

Additionally, SCF is being used for wider process and formulation simplification, beyond ‘pure’ drug particle engineering, York continues. “Composite dry particles containing a second drug and/or functional additives can readily be manufactured in a single step—a feature termed in-particle design. Here, solution feed lines containing drug and/or excipients, in addition to the primary drug solution, feed into the pressure vessel to form dry composite particles upon contact with the SCF,” he explains. “Each particle contains a final composition equivalent to that of the sum of the solutes in the feed solutions. The scope and options provided by this feature are vast, and excipient inclusions can be diverse with tunable composition ratios. Added excipients could, for example, be for aiding drug stability, dissolution, absorption, or for modulating drug release profiles.”

The quantification of particle morphology—both particle size and shape—provides more in-depth information than just measuring size alone, a fact that is highlighted when developing a GR tablet, asserts Clayton. “Flowability data adds value here because the agents used to impart buoyancy tend to compromise flow properties,” he says. “Dynamic flow properties measured with a powder rheometer were helpful in identifying optimal formulations. This application also highlights the value of mercury porosimetry, which provides detailed information about pore size, pore size distributions, pore volume, and other metrics, thereby elucidating buoyancy behavior (4).”

“In modern pharmaceutical product development, particle engineering has moved beyond the simple concept of particle size control. Innovative technologies and approaches to particle design and engineering allow molecules to meet their full therapeutic potential, while streamlining development processes, simplifying formulations, and building novelty into products,” York concludes. “In addition to providing opportunities for enhanced intellectual property, cost of goods savings and added process efficiencies, a thoughtful approach to particle engineering can enable the development of therapeutics that better serve the needs of patients and healthcare providers.”


1. B. Van Snick, et al., Int. J. Pharm., 549 (1–2) 415–435 (2018).
2. M.S. Escotet-Espinoza, et al., Powder Technol., 339, 659–676 (November 2018).
3. F. Tahir, et al., Powder Technol., 364, 1025–1038 (March 2020).
4. T.T. Nguyen, et al., Int. J. Pharm., 574, 118865 (January 2020).

About the Author

Felicity Thomas is the European editor for Pharmaceutical Technology Group.

Article Details

Pharmaceutical Technology
Vol. 45, No. 6
June 2021
Pages: 22–25


When referring to this article, please cite it as F. Thomas, “Moving Beyond Particle Size Control,” Pharmaceutical Technology 45 (6) 2021.