A Great Manipulation: The Value of Engineering Particle Properties

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-08-02-2020, Volume 44, Issue 8
Pages: 25-30

Particle engineering is a useful tool to manipulate API particles into a form that is manufacturable and deliverable to the patient.

Particle engineering has inevitably grown in popularity over the years within the bio/pharma industry, not only because the number of challenging molecules entering development is swelling but also as a result of the control of processability or critical quality attributes (CQAs) of a drug that can be achieved. Whether ‘bottom up’ or ‘top down’, particle engineering can optimize drug development and broaden the range of suitable drug candidates effectively.

“The main goal of particle engineering is to manipulate the properties of the API particles so that they are suitable for delivery to the target site of the patient,” says Fergus Manford, patent attorney, Vectura. “The importance of particle engineering is that immediately following synthesis, the API particles are rarely in a physical form that is suitable for formulating with excipient into a final dose form. The API particles often require size reduction to either the micro- or nanoscale and might also need physical stabilization.”

The small matter of size

“Particle or crystal engineering is not a new science in pharma, but something that has been done for a very long time,” asserts Christian Jones, chief commercial officer, Nanoform. “When an API is crystallized in a well-controlled manner, it is engineered to a defined specification.”

The requirement for particle engineering in drug development can be attributed to a need to improve the dissolution and solubility of a molecule, addressing processability issues in downstream manufacturing, reducing attrition in clinical trials, and controlling a drug’s CQAs through particle size specification. “Engineering API particles below 100 nm provides a dramatic uplift in specific surface area directly correlated with dissolution behavior, and engineering particles in the 50 nm range and below increases the intrinsic solubility of the molecule,” Jones confirms.

“For bioavailability improvement, reducing the particle size of an API classified as type 2a (good permeability but poorly soluble and dissolution rate limited) under the Developability Classification System (DCS) will increase its surface area and eventually increase the dissolution rate of the API, as described by the Noyes–Whitney equation,” concurs William Wei Lim Chin, manager, Global Scientific Affairs, Catalent. “In terms of manufacturability of drug product, the particle size of either the API or excipient may have an impact on bulk density, flowability, blend uniformity, and compactibility of the solid dosage form. From a regulatory perspective, establishing particle size specification is of paramount importance if it is critical to a drug product’s performance by affecting dissolution, solubility, content uniformity, stability, or the product’s appearance.”

Manford also confirms the impact of particle size reduction on surface area, which leads to improvements in solubility and hence dissolution rates and bioavailability. “Smaller particle sizes also broaden both the route of administration and dosage forms available for the candidate molecule,” he notes. “For example, whereas larger particles are available for oral administration only, a smaller particle permits the drug candidate to be considered for pulmonary delivery.”

Important considerations

“The particle characteristics required will be determined by the challenge the particle engineering solution needs to address,” says Jones. As previously noted, particle size reduction is key for improvement of a dissolution-rate-limited compound’s bioavailability; however, the particle size which the API needs to be will, to some degree, be molecule dependent, he adds.

“Engineering API particles for respiratory drug delivery will require particles with a median in the 1–5-micron range and typically between 1–2 microns, with a narrow particle size distribution to ensure more targeted delivery where the particles flow to the target area of the lungs,” Jones continues. “To go deeper into the lungs towards the alveoli, particles in the sub-micron and nano range could be advantageous. But for lung delivery, size isn’t everything, as smaller particles may be exhaled out before depositing effectively in the lung. The ability to engineer particles with optimal shape, morphology, and rugosity can help them to be aerodynamic, exhibit less agglomeration, and perform better when administered to the patient.”

For Manford, although the most important considerations for particle engineering are particle size, size distribution, particle shape, and particle surface energy, he agrees that there are secondary factors to consider also. “Secondary considerations include the nature of the APIs and excipients, in particular the morphology and surface properties of the starting particles, as well as their ability to dissipate electrostatic charge and ability to control adhesiveness and cohesiveness,” he asserts. “The plasticity, hardness, brittleness, and friability should also be taken into consideration when selecting the particle engineering approach. Finally, the hygroscopicity of the API will also dictate which techniques are available to the user.”

Particle engineering has evolved over the years to respond to technological advancements in milling, crystallization, and particle formation, explains Chin. “The shape and surface properties of both the API and excipient can affect how they are attached to each other and dictate the desired delivery of the drug,” he says. “This is especially important for dry powder inhalers where the API is often micronized and mixed with a larger carrier/excipient particle.”

However, when micronizing particles to reduce their size, there is the potential issue of producing regions of surface disorder in the freshly micronized material, warns Manford.

“When an API is micronized or milled, mechanical energy is used to break up the crystals into smaller ones, and this energy has to go somewhere,” Jones explains. “The energy often remains on the surface of the particles, raising the surface free energy of those particles and creating amorphous domains on the crystalline material. This means that the API may be challenging to process further and formulate because of the inherent instability caused by the increased surface free energy.”

As a result of this surface energy, the API may adhere more strongly to other API particles and be more cohesive with other excipients in the formulation when energy levels are elevated, Jones notes. “This issue can cause significant challenges in formulation, batch-to-batch reproducibility, and stability,” he says. “To reduce surface free energy of API particles, they may need to be left undisturbed for up to six months before they can be processed post-micronization. This is a huge inventory cost for any pharma company.”

Additionally, the degree of wetting of a powder system by a liquid is determined by the surface energy, confirms Chin. “The good interaction between the liquid and the surface of the particle will ensure the wettability of the powder, and hence, its ability to dissolve,” he says.

When considering particle size distribution, it is better for it to be as narrow and as consistent as possible, continues Manford. “Conventional milling techniques are relatively uncontrolled, randomized processes, limited in their ability to produce a product with a uniform particle size distribution,” he notes. “Spray drying and high-pressure homogenization are better suited to producing narrow particle size distributions, but these are both wet processes and some candidate molecules might not be amenable to this formulation approach.”


In working with spray drying techniques, formulators need to be concerned with controlling the particle morphology through altering the atomization process, spray solution properties, and drying kinetics to modify the surface properties of the spray-dried particles, asserts Chin. “Such modification will also impact the density, flow, and mechanical properties of the spray dried particles,” he says.

Highlighting specific challenges pertaining to nanometer-sized particles, Manford states that there is a tendency for particles to agglomerate to a less energetic state. “In so doing, the agglomeration reduces the surface energy, but causes an increase in measured particle size,” he adds. “To combat the high surface energy produced whilst preparing the nanometer-sized particles, stabilizers are used to prevent agglomeration. There is, therefore, a tension between the desire to reduce the particle size with the need to use surface-energy reducing additives.”

“Whilst the reversion of energetic amorphous regions back to the crystalline state can dramatically increase the size of milled particles, the amorphous form actually improves the dissolution profile of drugs because the amorphous state is more readily soluble than the crystalline form,” Manford asserts.

Selecting the best technique

“The selection of particle engineering technique is largely driven by the API’s properties,” says Chin. “For example, if the API is sensitive to impact, shear, or high temperature at the point of collision, attrition milling is probably not a suitable technique. And if the API is inherently thermodynamically instable, any technique that induces amorphous regions on the particle surface will also not be suitable.”

The type and severity of the challenge facing the developer is critical when considering which technique should be employed, states Jones. “If the developer is using a very poorly soluble molecule, then spray drying and nanomilling may not be ideal and another technique, such as Controlled Expansion of Supercritical Solutions (CESS), may be required,” he states. “However, if it is only incremental solubility improvement that is required, then spray drying and nanomilling may suffice.”

For neutral compounds, or those having weakly ionizable groups, crystal engineering is an approach to produce drug particles as an alternative to salt formations, notes Manford. “And the desired route of administration would certainly influence the selected technique,” he adds. “Pulmonary drug delivery requires a small and consistent particle size distribution, which is best achieved using a fluid energy mill (jet mill).”

“For respiratory drug delivery, the appropriate technique will depend on whether the API is stable with respect to mechanical attrition, and whether it is the delivery device that is going to be the driver for improving drug product performance or the particles,” continues Jones. “There are many complex and over-engineered inhalers on the market that are designed to compensate for the poor properties of the API particles in the formulation and become a strong barrier to entry for any generic competitor. If drug developers in this space used perfectly engineered particles from a solution-to-particle approach where the right characteristics were built into the particles, it may be possible, in theory, to have very simple devices delivering these drugs, because the particles would have superior formulation performance. Alternatively, by coupling high performing particles with high performance devices, it could be possible to have super-performing products for patients.”

As some APIs are very expensive and are only available in limited quantities during the early stages of development, there needs to be awareness of how much material will be lost with the particle engineering technique, Manford explains. “Jet milling in particular is not well suited to milling small amounts of expensive material due to a combination of internal surface loss and inefficiencies in the collection vessels,” he says.

However, Chin continues, choosing a specific particle engineering technique over another generally relates to how a predictive correlation can be achieved between process parameters, individual particle properties, and bulk particle behavior. “This correlation is critical as it will help the formulators to optimally design processes and formulations,” he says. “If the technology is already well deployed internally at the outsourcing partner’s/developer’s site, then the choice is relatively easy. Beyond that, the choice will then boil down to expertise, the level of understanding, and the availability of capacity at commercial scale of that particular technology.”

The value of outsourced services

“Incorporating new drug candidates into a specific dosage form presents numerous technical challenges,” asserts Manford. “It is essential that the potential of these candidates be adequately assessed as quickly as possible; there is no benefit in spending money on a candidate that will fail during clinical development.”

However, to adequately assess each candidate, there is a requirement to develop a unique formulation that can effectively reflect any therapeutic potential that the candidate may offer, Manford notes. Therefore, there is the potential for companies to waste a significant amount of time and money in trying to micronize and formulate problematic candidates, or for companies to disregard promising candidates due to limited formulating experience, he adds.

“This assessment is precisely where [contract development and manufacturing organizations (CDMOs)] can add value,” Manford says. “CDMOs offer their clients immediate access to years of expertise and know-how acquired by working with a range of molecules. Many CDMOs also provide access to proprietary technologies and niche equipment necessary for achieving these optimal formulations, thereby providing a further competitive advantage at a time-critical stage in product development.”

In concurrence, Chin specifies that the role of the outsourcing partner is to ensure enhanced productivity and cost efficiency while also improving quality so that program milestones can be met. “Drug innovators expect outsourcing partnerships to offer advanced expertise that will help provide a de-risked and accelerated path to clinic and market. For this to happen, it is important for outsourcing partners to have integrated capabilities, from formulation development to commercial manufacturing, including analytical and packaging services,” he asserts.

Jones notes the differences between providing top-down or bottom-up services. “When outsourcing drug development that requires a top-down particle engineering solution, the developer should always consider whether the outsourcing partner has both drug substance and drug product manufacturing in house,” he says. “This capability will enable them to have a better control of the input material for the micronization process and the output material from the same process.”

If the API crystallization process is not very well controlled and the API is obtained from a single source, there is the potential for variability in drug product quality, Jones explains. Further along the process, at the micronization stage and then mixing stages, any potential variability will then be amplified exponentially, leaving the formulator with a highly variable drug product and potential batch failures.

“When outsourcing drug development that utilizes a ‘solution to particle’ [bottom up] engineering process, the developer does not need to be concerned about drug product variability due to quality of input material,” Jones continues. “The API can come from multiple sources providing it has a similar purity and quality specification, and the end crystallization process is less of a concern as the API material will be dissolved and recrystallized. This provides the drug developer with more certainty of a controlled formulation strategy and reduces the risk of batch failures, which can be highly expensive.”

Article Details

Pharmaceutical Technology
Vol. 44, No. 8
August 2020
Pages: 25–30


When referring to this article, please cite it as F. Thomas, “A Great Manipulation: The Value of Engineering Particle Properties,” Pharmaceutical Technology 44 (8) 2020.