Published Articles

How Aseptic Nanomilling Can Provide a Solution for Today’s Insoluble Compounds Including HPCs

High-energy media milling (nanomilling) has become an increasingly popular drug delivery technique and for good reason; it is suitable for oral, injectable, topical, and inhalable applications.

Appropriate for complex solid drug products of all kinds, nanomilling continues to prove its viability as an efficient, reliable, and validatable approach to enhancing the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs), as well as minimizing undesired side-effects.

Virtually agnostic and appropriate for most indications, nanomilling offers drug developers a number of flexible attributes, including organic solvent-free processing, relatively high drug loading, and tunability. Furthermore, its inherent compatibility with a broad variety of today’s insoluble APIs and highly potent APIs being developed to treat or cure chronic disease is another advantage.

Nanomilling’s applicability and utility are increasingly recognized by pharma and ongoing development of the methods and technologies behind it are providing new opportunities for more effective delivery of complex, insoluble, and increasingly potent APIs.

However, the key to commercializing an array of complex drug products being developed now or on the horizon may hinge on accomplishing high-energy nanomilling aseptically, with the ability to manage and control complex high-potency compounds (HPCs) in these drug products.

Offering an expert’s review of the method’s great potential, Dr. Robert Lee, president, CDMO Division of Lubrizol Life Science Health (LLS Health) explains how aseptic nanomilling (AN) can help to successfully develop and commercialize complex drug products.

Nanomilling: A Pathway for All Delivery Routes

For most small-molecule compounds and a growing number of large-molecule therapeutics, nanomilling is a popular, reliable methodology, with well- understood chemistries and physiologies to achieve bioavailability goals or desired delivery routes. It is also a proven means to provide parenteral administration routes for generally insoluble drug products in solution. As it stands, nanomilling, aseptic or non-aseptic,  is an ideal pathway for all delivery routes:

  • Parenteral
  • Ocular
  • Mucosal
  • Topical
  • Oral

Aseptic Nanomilling for Complex Drug Products

The majority of today’s nanomilled APIs are not amenable to terminal sterilization. While the preferred option is to terminally sterilize nanomilled drug products, there are fewer options for sterilizing insoluble and highly potent nanomilled formulations. Although sterile filtration is an alternative, it is tough to do at commercial scale and is estimated to be applicable to an even smaller minority of insoluble compounds in suspension.

In general, and depending on the indication, the vast majority of new chemical entity (NCE) APIs are BCS Class II & IV (water-insoluble). As little as 5–10% of nanoparticulate suspensions in these classes are amenable to terminal sterilization (gamma radiation) with only about another 5% amenable to sterile filtering. In these cases, AN is the only alternative.

The fact is, the majority of new APIs require nanomilled particulates in their formulations to function therapeutically but also require an aseptic process to assure sterility, especially for parenteral and ocular therapeutics.

For insoluble solid compounds and HPCs, nanomilling offers great advantages, but its broader application in the aseptic manufacture of these kinds of drugs may be stymied because there are few economically or technically feasible options to sterilize products after milling operations.

The Aseptic Nanomilling Method

Drug developers have been applying nanoparticulate technologies to their products for decades, and many of today’s most familiar therapeutics have employed the methodology. The efficacy of the method continues to deliver therapeutically effective drug products and the list is sure to grow with access to the aseptic, high-energy nanomilling required by today’s complex drug products.

Colloids, Nanoparticles, and Bioavailability

Colloidal particles are present in a broad variety of pharmaceuticals. Colloids can range in diameter from 1–1,000 nanometers and can be solid, liquid, or gaseous. For most pharmaceutical applications, however, colloids in the 1 to 100 nanometer range (nanoparticles) are used.

Particle size distribution (PSD) directly affects the bioavailability of APIs and the safety of intravenous lipid emulsions. As with suspensions, nanoparticle dispersions can contain a range of particle sizes that define the PSD.

When the particle size of an API is reduced, the surface area increases exponentially, and the particles exhibit a higher surface-area-to-volume ratio. More surface area allows smaller API particles to have greater interaction with the surrounding water and a higher dissolution rate in the human body.  The same logic applies to dissolving sugar cubes vs. powdered sugar. Because the powdered sugar has a significantly higher surface area, it dissolves much faster in tea or coffee.

Additionally, as material is broken down, the internal surface becomes exposed, bringing a change in the number or type of surface chemical sites and groups. Large increases in surface area can also affect the interaction between particles and system properties, including suspension rheology, coating, and adhesion. In general terms, smaller particles dissolve more quickly and, therefore, exhibit higher bioavailability. Overcoming poor bioavailability is one of the great formulation challenges facing the pharmaceutical industry. Poor bioavailability results in ineffective treatments, higher costs for patients (more medication required to treat the condition), and unpredictable dose delivery, which often leads to an increased risk of side-effects and poor patient compliance.

Fighting Insolubility

Pharmaceutical companies estimate that approximately 60% of the NCEs synthesized each year have an aqueous solubility of less than 0.1mg/mL. This low solubility is a significant cause of failure for discovery phase compounds. Poorly water-soluble compounds are both difficult to formulate and analyze in humans or animals and are often discarded.

Additionally, the synthesis of water-soluble analogs often results in decreased bioactivity when compared to their insoluble counterparts. A significant number of the “Top 200” drugs exhibit clinical or pharmacoeconomic limitations that arise from their poor water solubility.

Technical Innovation to Address Insolubility Challenges

High-energy milling is central to manufacturing nano-sized particles. LLS Health has decades of experience with the technology and has been a leading force advocating the methodology’s potential.

For example, to meet a significant market need for delivery of poorly water-soluble drugs, we were early developers of highly refined crystalline particles made by wet-milling APIs, water, and stabilizers to create a colloidal dispersion in the size range of 100 nanometers to 400 nanometers.

One benefit of the process is that, due to the non-covalent adsorption of stabilizing polymers onto the surface of the particle, they do not aggregate, which helps decrease the surface-free energy. Furthermore, the hydrophilic polymers used to stabilize colloidal dispersions are found in numerous marketed products and involve Generally Recognized as Safe2 (GRAS) materials.

These particles can be further processed into all dosage forms traditionally used to administer drugs via oral, parenteral, inhalation, or topical routes. The applicability of this technology is defined solely by the drug candidate’s aqueous solubility and is not constrained by the therapeutic category or chemical structure.

Opportunities for Oncology

One of the more useful aspects of nanoparticles is that they can be sized and shaped to support the permeation and retention of APIs in proximity to the preferred site of treatment; the location of a tumor, for example. For today’s chemotherapeutics, this is an especially important effect, because it allows pharmacologists more precise delivery control of cytotoxic ingredients and therefore better control of undesired side-effects that commonly accompany chemotherapy.

Aseptic Nanomilling Opens New Drug Development Opportunities

The most practical approach is to process sterile ingredients in sterile equipment in a sterile environment, but access to aseptic nanomilling capability is not widely available on a contract outsourced basis. In many cases, pharma has had to develop its own aseptic nanomilling expertise in-house, which may be providing a significant barrier to entry for certain drugs being considered for development.

With the intention of providing pharma’s innovators with the best tools to create more effective treatments, CDMOs need to continue investing in advancing nanoparticle processes and formulation development.

With access to high-energy aseptic mills and media, drug developers can leverage advanced milling methods and flexible scalable cGMP production capabilities to accommodate all phases of drug development. With aseptic nanomilling available on a contract manufacturing basis, pharma has the opportunity to forego the risk and investment required to bring this capability in-house to meet their development plans.

Ready for the Challenges Ahead

The challenge for traditional pharmaceutical companies is to deliver the right therapeutic to the right target at the right time. Nanoparticles help achieve this goal through improved bioavailability, controlled dosing, and precise targeting. Nanoparticle technology is versatile and can be applied to emerging routes of administration including drug-eluting devices (DEDs) and inhalants – the advent of aseptic nanomilling only extends its utility and versatility.

Enhanced drug delivery is a critical area of pharmaceutical research and one where nanoparticles have proven useful. When designing nanoparticulate systems, a formulator can consider specific particle properties and manipulate these to influence the overall system. With a clear understanding of the established science behind nanotechnology, developers and scientists will continue to use this versatile and now aseptic process to improve the therapeutic performance and value of today’s most advanced and complex drug products.

Click here to learn more about our Nanomilling Feasibility Program.

Click here to read this article as it appeared in Volume 12, Issue 2 of International Pharmaceutical Industry.