DCAT Value Chain Insights’ “5 Minutes With,” part of the DCAT Member Company Community section, features interviews with business and industry leaders on issues impacting the bio/pharmaceutical manufacturing value chain. 

This “5 Minutes With” features Christian Jones, Chief Commercial Officer, Nanoform, to discuss one of the key industry challenges in drug formulations: how to improve bioavailability of poorly water-soluble drugs. It is estimated that 40% of approved drugs are considered insoluble, and nearly 90% of developmental compounds are considered poorly soluble (see references 1–2). He discusses one approach to resolve that challenge: nanoparticle technology. 

Question: Poorly water-soluble compounds that limit bioavailability represent a technological challenge in formulation development. Nanoparticle technology is one approach that can be used to overcome this challenge. Can you outline how the technology is applied, and how it improves bioavailability?  

Jones (Nanoform): Nanoparticle technologies work by decreasing the size of active pharmaceutical ingredient (API) particles. This increases the specific surface area of the particles, thereby leading to an enhanced dissolution rate. I can speak about one specific nanoparticle technology, Controlled Expansion of Supercritical Solutions (CESS) (Nanoform). CESS is a scalable, bottom-up recrystallization method that involves dissolving API powder in supercritical carbon dioxide and then recrystallizes the API under controlled temperature and pressure to create reproducible nanoparticles that are tunable in size, shape, and polymorphic form.  

The CESS process begins by guiding supercritical carbon dioxide into a pressure vessel loaded with the API. The temperature and pressure within the vessel are then raised, dissolving the API powder in the supercritical carbon dioxide. Under controlled conditions, a stable nucleation phase is achieved, which leads to the formation of nanoparticles. Finally, the carbon dioxide is sublimated in the collection vessel, leaving behind the final API nanoparticles ready for collection and formulation. These nanoparticles consist of pure drug substance and can be formed to fall within a 10-100 nm size range. By reducing the size of the drug particles to this extent, the aqueous solubility, and thus the bioavailability, of the particles can be increased. This is the first step, but the best result is achieved when the API nanoparticles are then married to the right formulation using dry- or wet-formulation techniques. 

Question: What are the advantages/disadvantages of using nanoparticle-based technology relative to other strategies to address poorly water-soluble compounds, such as amorphous solid dispersions? Can nanoparticle technology be used in concert with other technologies to improve bioavailability? If so, can you explain?  

Jones (Nanoform): As with all decisions, it is important to look at the pros and cons before committing to an approach to address poor water solubility. Amorphous solid dispersions (ASDs) allow for control of particle properties, such as size and morphology, and can successfully address solubility challenges. However, many ASDs require at least 70% weight polymer to stabilize the material, which can make it challenging to form tablets or capsules. An additional drawback is using organic solvents, which can have environmental impact.  

A nanoparticle-based approach using supercritical carbon dioxide, for example, can help to lower carbon footprint as the supercritical carbon dioxide replaces the use of solvents. In addition, the CESS technology, earlier referenced, can create nanoparticle crystalline material without the use of excipients and can reduce the required API dose, thereby leading to simpler formulations and smaller pill sizes. However, because CESS can produce nanoparticles that are uniquely small (down to 10 nm), it is effectively pushing the boundaries of particle production. This means there is a need for analytical techniques to evolve in tandem to accurately measure and characterize particles at such a small size range.  

Question: Are there specialized considerations when handling and manufacturing nanoparticles, either in the manufacture of the API or in the drug product? 

Jones (Nanoform): In general, due to the small particle size in the nanoscale range, there are specific considerations to account for during handling and manufacturing. One of these factors is that the forces of attraction between particles are strong, and they, therefore, have a tendency to aggregate into micron-sized clusters. This means that from a handling perspective, they exhibit good flowability properties and are easier to handle than if the nanoparticles remained individual. Importantly, when it comes time to formulate with the nanoparticles, they then disaggregate very easily into the other constituents, thereby leading to an even distribution of nanoparticles in a suspension of wet media.  

Previous work has shown that nanoparticles also show good compressibility and dissolution in an oral fast-acting immediate-release (IR) tablet formulation, disintegrating and dissolving well in comparison with a standard reference IR tablet.  

Question: Nanoparticle technology can be applied to not only small-molecule APIs but also to biologics. Can you explain how and why direct nanoforming of biologics would be applied? Are there any limitations on the type of biologic that can be nanoformed (in terms of molecular weight, type of compound). What types or routes of administration would direct nanoforming of biologics enable? Any specialized consideration to take into account in the drug formulation/drug product when using a nanoformed biologic?  

Jones (Nanoform): Direct nanoforming of biologics has the potential to open up new delivery routes. Currently, most biologics are given via intravenous or subcutaneous administration. By reducing the size of biological particles, it may be possible to tap into new, localized delivery routes, such as pulmonary, oral, and nasal delivery. It may also be possible to optimize intravenous administration, for example, by increasing drug load per unit volume.  

In terms of how this is achieved, one approach is a bottom-up approach to the particle process. This can work with molecules from approximately 1–150 kD, and has been applied to molecules ranging from insulin to monoclonal antibodies, such as trastuzumab and rituximab.   

The process begins with a feed solution containing the biological drug substance. This is pumped into the nebulizer. The feed is then nebulized into a mist, which is transported into the drying chamber, and the mist is dried using a low-temperature drying gas. The dried particles are subsequently charged in an ionizer before being collected using electrostatic precipitation. The process has been specifically designed to maintain the integrity of highly sensitive biological molecules while reducing their particle size to a nanoscale range. By nanoforming larger, more complex biologics, it may be possible to increase stability and achieve other benefits, and this is an important area for the pharma industry to explore in the future.  

Question: What other applications do nanoformed APIs have? Is it relevant to all therapeutic compounds, or is it primarily relevant for specialized applications, such as to enable drug delivery across the brain–blood barrier?  

Jones (Nanoform); Nanoformed APIs are highly capable of addressing poor bioavailability, and that’s a core use. However, there is increasing interest in using nanoparticles to open up novel drug-delivery routes and create opportunities for novel intellectual property and formulations. The blood-brain barrier (BBB) is one of the most difficult areas to tackle, but it is possible that reducing the size of drug particles to the nanoscale range could facilitate transport through the BBB. This could open up new avenues to explore for treatment of central nervous system disorders. Previous studies have also yielded successful preliminary results from a nanoparticle hydrogel formulation developed as an adjunct to surgery to treat glioblastoma, the most common type of malignant primary brain tumor.  

However, using nanoparticles is not limited to the BBB, but opens access to a wide variety of delivery routes, including ophthalmic, respiratory, and topical and can be applied to both small molecules and biologics. 

References 

1. The US Food and Drug Administration: “Formulating Drug Products for Optimized Absorption: Elucidating Amorphous Solid Dispersions,” content as of August 30, 2022. 

2. T Loftsson and ME Brewster, “Pharmaceutical Applications of Cyclodextrins: Basic Science and Product development,” J Pharm Pharmacol, November 2020, 62 (11), Pages 1607-1621, doi: 10.1111/j.2042-7158.2010.01030.x.