Particle Engineering for Improved Bioavailability in Oral Solid Dose Medications

Oral solid dose (OSD) form medications remain the industry juggernaut. Though biopharmaceuticals continue to grow and evolve, offering new and unique treatment options, small-molecule drugs maintain their dominance with OSD medications leading the charge.

Considering OSD drugs date back to 1,500 B.C., the industry has had time to perfect the form factor, improve manufacturability and enhance the efficacy of one of the most portable and easily ‘packageable’ dosage forms.1

Despite this long-held dominance, however, challenges in the manufacture of effective OSDs remain — in particular, the gradual decline in aqueous solubility of small molecules coming out of discovery. Hence, there continues to be a strong focus on enhancing the bioavailability of these substances.

Solubility issues are typically the most common hurdles to achieving ideal bio- availability, and these can be divided into molecules that are poorly soluble and those that are just too slow to dissolve. Approximately 80% of the drug candidates in the R&D pipeline exhibit poor solubility in water.2 Drugs with solubility/dissolution-related issues and those falling into class II and IV of the Biopharmaceutical Classification System (BCS)2 and class IIa, IIb, and IV of the Developability Classification System (DCS)3 typically exhibit  poor  or  varying   bioavailability, effectively canceling out some of the convenience offered by OSD. For molecules falling in class IIb and IV of the DCS, oral absorption is limited by solubility in the gastrointestinal tract. The molecules will not be completely dissolved in the three- hour transit time of the small intestine (where most drugs are absorbed). For molecules falling into DCS class IIa, complete solubility of the drug is feasible, but the OSD needs to ensure that the drug is freely able to disperse and dissolve. In these cases it may be critical to control particle size, surface area, wettability or all three of these factors.

As manufacturers of OSDs look for ways to successfully provide poorly soluble molecules within the dosage form, there is a growing demand for the application of so-called enabling  technologies, i.e., those that can mitigate the poor solubility of the API. Particle engineering approaches, such as micronization and comicronization, remain as simpler, lower-cost options that could be utilized for DCS IIa drugs, and while not likely to solve all the challenges of a DCS IIb drug, could be a cost-effective option for those that are close to being a DCS IIa. Particle-size engineering and analysis require specialized equipment and expertise, leading many pharmaceutical companies to turn to a reliable contract development and manufacturing organization (CDMO) partner.

With more than 25 years of experience handling particle engineering and analysis, Catalent is one such CDMO. After the company made the decision to acquire Micron Technologies in 2014, Catalent has become a leader in particle engineering and analytical services. With a thorough understanding of which approach is needed for each specific API, Catalent can help manufacturers avoid costly trial and error and better direct efforts to produce bioavailability-enhanced products that ultimately offer an improved patient experience. 

As manufacturers of osds look for ways to successfully provide poorly soluble molecules within the dosage form, there is a growing demand for the application of socalled enabling technologies, i.e., those that can mitigate the poor solubility of the API.

Understanding Particle Engineering

The goal of particle engineering is to first gather quantitative data that can help guide improvement efforts for the drug. More specifically, particle characterization should, at a minimum, not only con- sider the mean particle size, particle-size distribution and shape of the particles (both API and nonactive ingredients) in the formulation, but may also consider other factors.4

Due to the complexities involved in selecting and conducting the best analytical method for this type of research, it is not surprising that the 2017 Nice Insight Contract Development and Manufacturing Survey found access to specialized technologies to be the number one rea- son for engaging with a CDMO partner.5 With particle analysis in particular being a costly field, a CDMO partner with experience in characterization can help select the most accurate method(s) while also offering analytical guidance throughout the process. Catalent has over 350 analytical scientists and over 25 years’ handling hundreds of APIs, allowing them to pro- vide numerous particle-size testing options for both stand-alone particle analysis and more complete processes.

Several different methodologies and technologies may be used for characterization. As with any analysis, it  can be helpful to use more than one method, especially when a test is not specific. In addition, more specific, complex methods may provide more information, but a simpler method may be more cost-effective for fast access to data over a large number of samples. For example, while scanning electron microscopy provides more information about particle form, optical microscopy and laser diffraction are still more commonly used for run-of- the-mill samples. 

The goal of particle engineering is to first gather quantitative data that can help guide improvement efforts for the drug.

The Path to Improved Bioavailability

The solubility and oral absorption of DCS Class IIa drugs is limited by their dissolution rate. Based on the Noyes-Whitney equation, dissolution rate is directly proportional to surface area of the drug particles. In micronization, an increase in particle surface area is achieved by reducing particle size. DCS includes a proposed equation to calculate target particle size (D90). If the D90 is below this value, oral absorption of the drug is not limited by the dissolution rate, even in sink conditions.

The micronization process is a simple and well-established method that offers a consistent particle-size distribution with- out the use of solvents and without producing excessive heat.6 Traditional mechanical techniques such as hammer, pin and conical milling may not produce the de- sired particle-size distribution suitable for specialized applications, such as those intended for pulmonary delivery. Jet mills rely on impact and attrition of the API particles themselves to reduce particle size and, for solid-dose medications, are one of the most common and effective forms of micronization.6 High-velocity particle collisions cause larger particles to break down, and by careful design, centrifugal forces separate larger particles and ensure they linger in the mill, while the newly created small particles are able to escape into the collection system. This self-regulating process helps ensure a consistent result.

Additionally, when improved control is desired, or when working with highly potent compounds, there are more enhanced micronization options; for example, cryogenic micronization, which is similar in principal to jet milling but performed at temperatures as low as -50°C. This is becoming increasingly popular for micronization of compounds that have low brittleness or are tacky at ambient temperature. The colder temperatures help increase brittleness and friability of the compounds resulting in a finer particle size. Another option is to use a multiprocessing classifier mill, like that housed in Catalent’s Dartford, U.K. facility, which simultaneously micronizes and classifies powder substances and can be especially valuable when a narrow particle size range is required. Catalent has a range of different air jet mills at various scales including those that can micronize 250 mg or less of API, which may be suitable for companies looking at micronization during early development. Further, Catalent has achieved full containment in order to handle potent compounds. Micronization of potent drugs is difficult due to dust, which is a part of the milling process and has historically made the process inside containment impossible at larger scales.

Co-micronization, in which a small percentage of an excipient is blended with API prior to micronization, is an advancement on the traditional process. Compared with micronization followed by blending, the comicronization process promotes enhanced interactions between API and excipients. The potential advantages include decreased agglomeration, avoidance of dry blending, enhanced hydrophilic character and solubility, enhanced dissolution rate, and better flow properties. By increasing rate of dissolution and/or solubility, co-micronization can improve bioavailability of poorly soluble molecules, where particle size reduction alone may not be sufficient.

Though equipment considerations remain important, however, equipment alone cannot satisfy cGMP guidelines and deliver consistent results. When scientists are looking into particle engineering services it is best to seek existing expertise from a company that not only uses specialized equipment, but also offers support for any custom protocol development that may be required depending on the potency of the API, validation, execution and, of course, reporting.


OSD medication, being the preferred dosage form for in-house manufacturing, continues to be the dosage form of choice. Enabling technologies such  as particle   engineering will continue to have a place in drug product development for poorly soluble APIs. Particle characterization and engineering can identify optimal particle size, provide a more thorough understanding of the drug, and point to bioavailability enhancement options through particle reduction processes — a simple, elegant solution to a modern-day dissolution-rate issue.

Ultimately, if the goal is to ensure robust and consistent bioavailability with the most cost-effective OSD, then micronization and co-micronization have a case for being the ideal solution. Catalent has many other enabling technologies in their portfolio, and are ideally placed to advise companies about which data need to be collected to make an in- formed decision about whether particle engineering is right for a given molecule. In addition, Catalent has capability all the way from preclinical development to commercial supply. Catalent now integrates particle engineering capabilities with its existing expertise in characterization, giving customers options for molecule to phase 1 OSD materials with a fast turnaround.


  1. Mestel, Rosie. “The Colorful History of Pills Can Fill Many a Tablet.” Los Angeles Times. 25 Mar. 2002. Web.
  2. Löbenberg, Raimar, Gordon L. Amidon. “Modern Bioavailability, Bioequivalence and Biopharmaceutics Classification System. New Scientific Approaches to International Regulatory Standards.” European Journal of Pharmaceutics and Biopharmaceutics 50.1 (2000): 3-12. Web.
  3. Butler, James M., Jennifer B. Dressman. “The Developability Classification System: Application of Biopharmaceutics Concepts to Formulation Development.” Journal of Pharmaceutical Sciences 99.12 (2010): 4940-54. Web.
  4. Tong, Henry, Albert Chow. “Particle Size Analysis in Pharmaceutics: Principles, Methods and Applications.” Pharmaceutical Research 24.2 (2007). Web.
  5. The 2017 Nice Insight Contract Development and Manufacturing Survey.
  6. Markarian, Jennifer. “Need for Particle Engineering Increases.” Pharmaceutical Technology. 17 Sep. 2004. Web.


Ronak Savla, Ph.D.

Dr. Ronak Savla is a Scientific Affairs Manager with Catalent Pharma Solutions and the Catalent Applied Drug Delivery Institute. Previously, he was the Applied Drug Delivery Fellow at Catalent. He received his Pharm.D. and Ph.D. from Rutgers University. His current research interests are the application of in silico models and simulations to aid in drug formulation design, integration of novel formulation technologies into the industry, and patient-centric research. Dr. Savla is an author and co-author on over 35 publications.