Poorly soluble molecules comprise more than 70 percent¹ of active pharmaceutical ingredients (API) entering the drug development pipeline. As the solubility of active APIs in new drug molecules continues to trend lower, pharmaceutical companies face increasing pressure to produce smaller API particles to overcome the slow dissolution rate problem.
There are multiple techniques available to increase the solubility and oral bioavailability of poorly soluble APIs, and improve their delivery. The common technique of micronization is insufficient for APIs exhibiting low solubility – leading to the adoption of other techniques such as nanomilling.
The Nanomilling Process
Nanomilling is a well-established and proven formulation process that enhances the bioavailability of poorly water-soluble drugs. It is a versatile approach capable of resolving issues associated with developing and commercializing drug products with low aqueous solubility, in a wide range of injectable, oral, and solid dosage forms.
The technology behind nanomilling was developed in the 1980s, and the first FDA-approved nanocrystal drug came to market in 2000.² It is an effective and scalable process by which mechanical energy is applied to physically break down coarse particles, reducing their size to less than 1,000 nm (usually in the 100 to 200 nm range, sometimes even smaller) by wet media milling. By decreasing their size into nanocrystals, the specific surface area increases, which allows for greater contact with water, thus increasing the active ingredient’s dissolution rate and bioavailability. This trend continues until the dissolution rate is faster than the absorption rate.
The main technique used for the nanomilling of APIs is high-energy media milling. Stirred media mills, sometimes referred to as bead mills, are highly effective for producing pharmaceutically active nanosuspensions. The process and equipment are amongst the easiest processes to scale and, being within a closed system, allow for control of the milling environment as well as protection of the operators from exposure to potent drugs.
The suspending medium for the initial drug slurry is water containing a surface-active agent, which then becomes a colloid suspension during the milling process. The surface active agents can be polymers, or either ionic or non-ionic surfactants, which serve to stabilize the particle size of the drug as it is reduced during milling. The stabilization occurs by the agent coating the surface and inhibiting particle aggregation, agglomeration, and a natural process called Ostwald ripening.
A typical media mill in recirculation mode is depicted in Figure 1 (components not shown to scale).
Nanomilling is a universal technique that can be applied to almost any API with water solubility below 200 µg/mL. It is a very adaptable drug delivery platform suitable for oral, injectable, inhalable, and buccal applications, for which fine drug particulates are especially desired in formulations. Benefits of particle size reduction for the parenteral route include small dose volumes (resulting from high drug loading) and avoidance of harsh solvents and/or extreme pH conditions. Advantages for the pulmonary route include the ability to use inhalers intended for solutions, as well as the ability to produce spray-dried powders whose particle sizes are optimized for deep lung delivery.
Other advantages include reduced fed/fasted variability in both liquid and solid dosage forms, faster onset of therapeutic action, low excipient side effects, and the ability to run continuously.
Several products using nano-sized active ingredients and wet media milling have entered the market, while more than 20 additional products are currently in the clinical trial phase. Examples of marketed products include:
- Rapamune® (Pfizer (Wyeth) Pharmaceuticals)
- Emend® (Merck & Co.)
- TriCor® Lipanthyl® (Abbot Laboratories, Fournier Pharma)
- Megace-ES (PAR Pharmaceuticals)
- Invega® Sustenna® Xeplion® (Janssen Pharmaceuticals)
- Triglide™ (Skye Pharmaceuticals)
Numerous BCS class II and IV APIs have benefitted from nanomilling and gained FDA approvals. It is BCS class II compounds that primarily benefit from a small particle size, since their dissolution step is the rate-determining factor in drug absorption. The BCS classes are depicted in Figure 2.
Experience You Can Trust
Nanomilling is a highly complex process requiring a unique level of CDMO expertise that can only be gained through extensive experience with developing a broad range of APIs.
The experts at Altasciences take your API from formulation to commercialization. We have the necessary procedures, equipment, and experience to work with any formulation. Our highly skilled teams work with the latest equipment, including the Netzsch DeltaVita 15-300 mill, that can reduce particles to nanometer size with our wet milling options, fill vials in a range of sizes (from 0.3 ml to 500 ml) and package them.
Learn more about Altasciences’ complete range of formulation development, manufacturing, and analytical services, or contact us to learn how nanomilling can help resolve your API formulation issues.
Speak with one of our experts.
Resources
1. Poor Solubility – Where Do We Stand 25 Years after the ‘Rule of Five’? https://www.americanpharmaceuticalreview.com/Featured-Articles/573402-Poor-Solubility-Where-Do-We-Stand-25-Years-after-the-Rule-of-Five/. Published February 18, 2021. Accessed October 2021.
2. Nanomilling of water-insoluble APIs. https://www.medicaldesignandoutsourcing.com/creating-water-insoluble-