Elanor Pinto-Cocozza was previously technical project manager, Catalent Pharma Solutions.

Elanor Pinto-Cocozza

Advances in micronization for handling batch sizes of less than five grams make it easier to determine the feasibility and benefits of particle size reduction for new chemical entities (NCEs). At the initial discovery phase, screening of investigational new drugs is challenging, often because of the limited quantities of active pharmaceutical ingredients (APIs) available for analytical and performance testing. With typically 5000-10,000 compounds at the drug-discovery phase, reliable screening technologies are crucial for selecting which compounds should move on to the preclinical phase. Quite often, a mortar and pestle is used for particle size reduction when screening an NCE for 

 testing using animal studies. While a mortar and pestle is convenient and usually readily available, it is a mechanical process that can generate heat, and it cannot reliably achieve the uniform particle size distribution that is possible with other methods, such as air jet milling.

	Drug development times have increased significantly, and the time taken to bring new drugs to market has increased from approximately three years 50 years ago, to 12 years at the start of the new millennium. FDA approved 45 novel drugs in 2015 and 22 novel drugs in 2016 (1). From 2006 to 2014, the average number of novel drug approvals was approximately 28 per year.

	Creating new drugs is no easy process, it usually takes years, and some estimates of the cost per drug are more than two billion US dollars (2). With the number of NCEs entering company development pipelines, there is an increasing pressure for a more thorough, earlier review of an NCE’s potential and how to address pitfalls without further expenditure on the ongoing development of a drug. For example, not using the right technology for the preformulation development of the compound could result in failure during preclinical or even clinical testing due to poor bioavailability of the compound and not seeing the desired therapeutic effect during the preclinical or clinical study. One challenge right now, especially at the R&D and preclinical stages, is that a lot of money and time are invested to find compounds that are efficacious and have a positive therapeutic effect, but further development of these compounds is often unexpectedly challenging. The size of a drug particulate may be crucial to its bioavailability; smaller particles have larger surface area and consequently, a higher dissolution rate. Particle size engineering (i.e., increasing surface area by creating micro- or nano-crystals using techniques such as jet or ball milling) may be an attractive approach because of its simplicity.

	Particle size reduction for oral-dosage forms

	More than 90% of small-molecule NCEs designed to be taken orally display solubility issues (3). Poor solubility makes absorption of the drug from the gastrointestinal tract into the bloodstream a challenge, and the resulting low bioavailability may require enabling technologies to achieve a therapeutic effect. Today, pharmaceutical scientists working to create new drugs need to have a good working knowledge of the technologies available to develop oral formulations that can be used to improve the bioavailability of novel compounds. Along with salt form, lipid drug-delivery systems, and solid dispersions, particle size reduction is a standard platform technology for enhancing the bioavailability and optimizing the formulation of poorly soluble APIs--especially those falling into the Developability Classification System (DCS) category IIa, where rate of dissolution may be the biggest challenge.

	Most APIs in current development fall into DCS quadrant II, in that they have poor solubility but adequate permeability. Quadrant II may be further subdivided into sub-categories for which molecules are either dissolution rate-limited in the gastrointestinal tract (DCS IIa), or solubility-limited (DCS IIb), as delineated by the Solubility-Limited Absorbable Dose (SLAD) rule (see diagonal line in 

). For molecules falling in the DCS IIa category, the dose is expected to dissolve completely during the approximately three-hour transit through the small intestine, provided that more of the undissolved molecule is available in a form to quickly replace it.

	Particle size reduction does not affect a drug’s equilibrium solubility. Instead, it helps by increasing the surface area of drug that is exposed to fluids in the gastrointestinal tract, hence increasing the dissolution rate of the drug. Drugs that dissolve slowly may miss their “window of absorption.” The oral bioavailability of numerous poorly soluble compounds has been improved by micronizing or wet-milling (nanosizing). These compounds include DCS category IIa drugs (nitrendipine, carvedilol) and category IIb drugs that lie close to the SLAD line, where presumably the final bioavailability was satisfactory (perhaps due to having good permeability beyond the small intestine).

	Tricor (a brand name of AbbVie) is an example for which particle size engineering provided product differentiation and follow-on approvals. Tricor-1, the non-micronized form of the drug fenofibrate, was approved in 2001 for lowering triglycerides, but had a substantial food effect. This was followed by the FDA’s approval in 2003 of Tricor-2, a micronized, lower-dose formulation also with a food effect, for the broader indication of lowering low-density lipoprotein. The third iteration of this drug, the nano-milled Tricor-3, which was approved by the FDA in 2004, did not show a food effect. Its label was expanded as well, to include raising high-density lipoprotein. In general, micronization may be considered a more robust technology because nano-sized formulations may be harder to stabilize in the finished product.

	Particle size reduction for inhalation formulations

	Formulation development, particularly particle size engineering through sizing and size distribution, is often crucial in tailoring a drug product to treat specific diseases. Inhalation formulations have long been available to treat lung diseases, for example asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis.

	Drugs delivered orally must undergo absorption before they enter the bloodstream, but unfavorable systemic side effects are common. Dosage forms targeting localized diseases have the advantage of delivering drug to the precise disease location, thereby allowing lower doses and reducing systemic exposure (4). Inhaled drugs must be produced within precise size regimes in order to reach specific regions of the lung, for example, the bronchial tract (5). Moreover, particle sizes must be relatively uniform, typically within 2-5 µm in diameter to ensure that they consistently reach the right target region. Particles of greater than 5 µm are absorbed in the larynx and pharynx and into systemic circulation; particles smaller than 1 µm are exhaled from the lung. Micronization using air jet milling is the most common technology of particle size reduction for inhalation drugs.

	Lab-scale case study: Particle size reduction of less than 5 g

	Preformulation development and testing can be challenging due to the resources available. Quite often, the quantity of API available is limited during the early drug discovery phase--at times, as little as 400 mg. Most commercial mills available are limited to processing sublot sizes greater than 5 g. However, there are specialized lab-scale air jet mills available now that can process sublot batch sizes as small as 50-200 mg.

	Lab-scale air jet milling of small samples was tested using a free-flowing material (lactose) and a model drug (fenofibrate), which is not as flowable as lactose. With lactose, a wider range of air pressure was achievable within the mill. The mill was able to greatly reduce the particle size of fenofibrate from a D90 of 431 microns to less than 30 microns. With lactose, it was possible to overcome flow problems and mill material at different air pressures and sublot sizes as shown in 

	The optimal yield of 68% was observed at an air pressure of 4 barg. The maximum sublot size of 200 mg was able to achieve optimal yield of 70%. There were challenges in processing fenofibrate at lower mill pressures as shown in 

. The material could not fluidize and flow at pressures below 4 barg. Based on these results, the processing conditions to use with the lab-scale air jet mill are expected to be API dependent. The scanning electron microscope images (see 

) showed that the particle size reduction of the fenofibrate did not have a tight and uniform distribution as observed with large particulates in the micronized product. Despite some limitations, the lab-scale mill is useful for feasibility testing of APIs with small batch sizes of less than 5 g.

	The lab-scale air jet mill opens up the preformulation market in particle size reduction with less than 5 g of API. Currently, mechanical approaches using a mortar and pestle cannot achieve the particle size distribution and the crystallinity stability that is possible with micronization. While the design of the lab-scale air jet mill is not the same as the design of larger commercial air jet mill used in the pharmaceutical industry, the lab-scale mill would be a better choice for feasibility testing with API batch sizes of less than 5 g.

New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products

Tufts Center for the Study of Drug Development

, accessed Apr. 25, 2016.
	3. D. Hauss, “

Oral Lipid-based Formulations: Addressing an Urgent Industrial Need

,” New Jersey Centre for Biomaterials.
	4. Catalent, “

The Medicine Maker-Deep Breaths and Dry Powder

Formulation Considerations for Inhaled Products

	When referring to this article, please cite it as E. Pinto-Cocozza “Particle Size Reduction for Investigational New Drugs,” 

Articles

Modern air jet milling can be used to investigate the feasibility of micronization as a solubilization approach in formulation development.