Nanomilling: Shaping the Solubility and Bioavailability of Today’s Therapeutics

Nanomilling: Shaping the Solubility and Bioavailability of Today’s Therapeutics

Nanomilling: Shaping the Solubility and Bioavailability of Today’s Therapeutics

Poor water solubility is an increasingly common issue in pharmaceutical development. Approximately 40% of marketed drugs and as many as 90% of active pharmaceutical ingredients (APIs) in the discovery pipeline are poorly water-soluble. Nanomilling is proving to offer drug developers great utility supporting the bioavailability, enhanced dissolution rate and solubility of these poorly water-soluble APIs. Since 2000, a growing number of BCS class II and IV APIs have been commercialized using this versatile technology, including both oral solid dose (OSD) and parenteral forms.¹ Currently, the FDA has approved 12 nanomilled drug products including Aristada® and Invega Sustenna® (see table).² In this article, Dr. Robert Lee, President of the CDMO Division of Lubrizol Life Science Health (LLS Health), explores nanomilling and how it is shaping the bioavailability of many therapeutics.

Nanomilling and New Pathways

With the continued development and advancement of nanomilling technologies, the challenges associated with formulating poorly water-soluble drugs for the best therapeutic effect are now less daunting. The technique offers great versatility and is supporting new drug discovery as well as the redevelopment and lifecycle management of existing pharmaceuticals.

Several drugs on the market have been reformulated to improve efficacy, safety, and patient compliance. According to the Regulatory Affairs Professional Society (RAPS), companies are increasingly adopting the Lesser known 505(b)(2) regulatory pathway, which allows new dosage forms, formulations or drug combinations to be approved by the FDA.³

Generally, new drugs are approved in one of three ways. One, a drug never approved by the FDA is approved using a new drug application (NDA) through the 505(b)(1) pathway. Two, a generic drug referencing an existing NDA is approved using an abbreviated new drug application (ANDA) through the 5050) pathway. And three, an over-the­ counter (OTC) drug is approved by referencing its current monograph.

These three pathways collectively account for most of the products on the market. There are, however, several other pathways by which a drug can obtain approval.

One of the more popular alternatives is the 505(b)(2) pathway, which guides the approval of drugs that are already on the market but have been changed in several meaningful aspects. As described in Applications Covered  by  Section  505(b)(2), FDA’s 1999 guidance document, a 505(b)(2) application is “one for which one or more of the investigations relied upon by the applicant for approval  were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.”

Revitalizing poorly soluble drugs by using new insoluble drug delivery technologies is proving to be a viable lifecycle management tactic that is adopted by pharma’s innovators seeking to gain marketing exclusivity or renew patent protection. This approach also benefits from reduced risk since the toxicology profile of the APIs is known.

Nanomilling: A Brief Overview

Milling is one of the most common pharmaceutical unit operations to reduce drug particle size and increase surface area. Nanomilling refers to the process of reducing particle size below 1000 nm by wet media milling. The conversion to nanocrystals increases the surface area-to-volume ratio of the API, allowing for greater interaction with water, which in turn increases the API dissolution rate. According to Research and Markets, nanocrystals will account for 60% of a $136 billion nanotechnology-enabled drug delivery market by 2021.⁴

The smaller API particles generated by nanomilling can dissolve more readily, with the rate of dissolution being inversely proportional to the diameter of the particle. This creates a high concentration gradient that facilitates the transfer of the API across biological barriers including membranes (i.e., gastro-intestinal tract and blood/brain barrier).

Nano-suspensions disperse nanometer-sized drug particles in an aqueous vehicle, which are useful for oral and inhaled drug products and especially beneficial for parenterals. High-energy media milling is a top­ down process increasing the exposed surface area of an API. This improves the rate of dissolution. Additionally, nanomilling improves the homogeneity of a drug product and therefore content and dose uniformity.

Notably, nanoparticulate suspensions behave in a similar fashion to a molecular solution, and from a manufacturing stand­ point, the process overall is efficient, reproducible and highly scalable (including at commercial scale).

Conventionally referred to as a nanoparticulate suspension, wet media milling is an organic, solvent-free process that also offers formulators several distinct advantages, including:

  • No harsh organic solvents or pH extremes: Most nanomilled suspensions are aqueous-based. High API concentrations: 5-40+% API (w/w).
  • Reliable scale-up: Commercial nanomilling equipment utilizes a recirculation process that allows batch sizes to increase without changing process variables.
  • Reproducibility: Once a nanomilling process is optimized, there is minimal variation in particle size distribution from batch to batch.

FDA-Approved Nanomillled Drug Products

Brand API Dosage Form Indication Innovator
Rapamune® Rapamycin, Sirolimus Oral Solution
Oral Tablet
Immunosuppressant Wyeth
Emend® Aprepitant Oral Suspension

Oral Capsule

Anti-emetic Merck & Co.
Tricor® Fenofibrate Oral Tablet Hypercholesterolemia Abbott Laboratories
Megace ES® Megestrol Oral Suspension Anti-anorexic Par Pharmaceuticals
Triglide® Fenofibrate Oral Tablet Hypercholesterolemia Sciele Pharma Inc.
Avinza®* Morphine Sulphate Oral Capsule Pain King Pharmaceuticals
Focalin XR® Dexmethylphenidate HCl Oral Capsule Attention Deficit Hyperactivity Disorder (ADHD) Novartis
Ritalin LA® Methylphenidate HCl Oral Capsule CNS Stimulant Novartis
Zanaflex® Tizanidine HCl Oral Capsule Muscle Relaxant Acorda
Invega Sustenna® Paliperidone Palmitate Intramuscular Injection Schizophrenia,

Schizoaffective Disorder

Janssen Pharma
Ryanodex® Dantrolene Sodium Intravenous Infusion Malignant Hyperthermia Eagle Pharmaceuticals
Aristada® Aripiprazole Lauroxil Intramuscular Injection Schizophrenia Alkermes

Nanomilling can be universally applied to most drug candidates with poor water-solubility. Nanoparticulate suspensions also offer the advantage of higher mass packing (and thus higher dose) per injection volume and improved physical stability via the use of stabilizers such as polymers and/or surfactants.

Shaping New Opportunities for API Delivery

Producing nanoparticulate suspensions via wet media milling is proving to be an effective way to meet the bioavailability challenges of most poorly water-soluble APIs. Pharmaceutically, it’s an elegantly simple solution and typically results in a benign and biocompatible formulation. Nanomilling offers a homogeneous formulation that behaves like a molecular solution, as well as the potential to diminish the number of overall excipients required to support the delivery of the API.

With so many poorly water-soluble drug candidates emerging from drug discovery, advanced formulation techniques Like nanomilling provide optimal routes to improved bio­availability and enhanced therapeutic effect.⁵

Nanomilling’s versatility continues to reveal itself in research and development and demonstrates its utility in commercial applications. Nanomilling is advertised by contract development and manufacturing organizations and many offer this as one of their services. However, acquiring a media mill does not make one an expert in this delivery approach.

For drug developers, it’s important to find partners with the right equipment and extensive experience in stabilizing nanoparticulate suspensions as well as the analytical capabilities to demonstrate the validity and efficacy of the product in the process.

Identifying the proper formulation composition and process are key to successful drug development projects.

A typical challenge is identifying formulations that maintain stability over time. For a formulation to be developed effectively, it requires experience and institutionalized approaches to understand and optimize the process as it relates to the API’s particular chemistry and solubility.

A More Stable Position for Stabilizers

Take the timely, optimal selection of stabilizers. Not only must this selection process consider the physicochemical and pre-formulation data on the API, but it must also factor in the primary properties of the stabilizers themselves.

In general, there is no “one-size­ fits-all” approach to selecting nanoparticulate suspension stabilizers. Often it becomes an iterative process of optimizing and selecting the stabilizer, then finding the concentrations necessary to achieve the final desired formulation. For example, in some cases, two nanoparticulate suspensions may have essentially identical particle size distributions and physical stability but vastly differ in oral bioavailability.

Despite the seemingly simple concept of suspending nanoparticulates in a formulation, development may not be as straightforward to all who approach the methods commercially. For instance, nanoparticulate suspensions tend to become unstable and agglomerate over time as a result of the high surface energy of the particles. They can also exhibit Ostwald Ripening, where small particles preferentially dissolve and then re-crystallize onto the larger particles.⁶

Many of contract pharma’s top nanomilling experts agree a top-down scalable approach carries minimal regulatory risks. A top-down approach, by which larger particles are made into finer ones, can have limitations during the process as the finer particles tend to agglomerate, but a bottom-up approach may require an even more careful selection of a solvent and maintaining it at the saturated level.⁷

The Near-Universal Potential of Nanomilling

Out of all the approaches to formulating insoluble APIs, nanomilling possibly holds the greatest potential.  Used in FDA-approved drug products for decades, the nanocrystal form can be delivered by virtually all routes of administration.

Nanomilling is also a particularly efficient, reproducible process that is very scalable. Once initial feasibility has been assessed and a nanomilling process is optimized, there is minimal variation in particle size from batch to batch. This formulation approach is easy to scale to production, as commercial nanomilling equipment typically uses a recirculation process that allows batch sizes to increase without changing the process variables.

Nanomilling Feasibility Program

LLS Health is a leader in nanomilling to improve the rate of dissolution and bioavailability of BCS Class II and IV compounds. In just 8 weeks, our Nanomilling Feasibility Program (NFP) allows us to:

  • Develop a target product profile and screen your API for nanomilling with GRAS excipients
  • Generate a particle size distribution and short-term stability data for each formulation
  • Identify promising formulation(s) and provide material for small animal pharmacokinetic (PK) studies.

Learn more about our Nanomilling Feasibility Program here!

Trends Advancing Nanomilling Technology’s Future

Targeted drug products are a key objective of pharmaceutical development, especially given the advent of monoclonal antibodies. These targeted pharmaceuticals, typically composed of monoclonal antibody­ drug conjugates (ADCs), are confronted with a number of challenges that have limited and slowed their development and commercial use until, perhaps, now.

New formulation technologies using nanoparticles circumvent these limitations. In fact, more than 100 different APIs can be encapsulated by solid lipid nanoparticles (SLNP). Physicochemical attributes, for example, can be tailored through the inclusion of surfactants into the formations. The resulting particles can interact with either the hydrophobic or electrostatically-charged domains of amphipathic and hydrophilic molecules.

These particles efficiently bind to and are coated by pharmaceuticals and biopharmaceutical molecules, and now are being developed for large-molecule therapeutics targeting tumor cells and other tissues.

Nanoparticle formulations effectively link biopharmaceutical and pharmaceutical molecules, Like ADCs, but without the need for, and limitations of, conjugation chemistries. This results in final products with unique and useful physicochemical and biological attributes – including enhanced immunogenicity and safety for vaccines, and improved pharmaceutical and biopharmaceutical drug targeting accuracy against specific disease targets.

LLS Health, for example, combines a lipid-based approach with nanoparticles using a reverse cubic­ phase matrix (LyoCells®), which helps assure the hydrophobic and hydrophilic domains are never more than a few nanometres apart, potentially leading to unique solubilization properties.⁸⋅⁹

Alternative lipid-based approaches such as emulsions (hydrophobic core) or liposomes (hydrophilic core) offer a  micro-environment that is either hydrophobic or hydrophilic, but not both. The reverse cubic-phase matrix offers both and may be better suited for typical drug-like molecules that are often amphiphilic (i.e., containing both a non-polar hydrophobic region and a polar hydrophilic region). The technology is intended for a range of applications, suitable for a wide variety of dosage forms, and employs generally recognized as safe (GRAS) ingredients.

Aseptic Nanomilling Entering New, Sterile Territory

Increasingly, more and more therapeutic compounds and molecules are parenterals with sterile API processing requirements. When it comes to sterile products, most of the nanocrystal formulations are not amenable to terminal sterilization and require specialized sterilization regimes to process efficiently. Although there are several technologies for formulating BCS class II APIs for oral administration, the true value of nanomilling is in the development of parenteral dosage forms.

LLS Health is one of the few nano-technology services providers to offer aseptic nanomilling commercially. Via a proprietary, high-energy milling system designed to better accommodate aseptic processing, the company is one of the first to provide this capability to drug owners and developers.

Nanomilling’s Efficacy is Well Established and Going Places

Today’s drug innovators are turning to specialized partners to help deliver their products more successfully to market. Many synthesized and large­ molecule therapeutics can gain from nanotechnologies and nano­ milling for effective API delivery that brings their benefits to patients. As the technique becomes better understood, it will continue to fuel innovation to improve its ability to deliver medicine’s top therapies to patients.

Click here to learn more about our Nanomilling Feasibility Program.

Click here to read this article as it appeared in Volume 11, Issue 3 of International Pharmaceutical Industry.


  2. Nanomilling: A Key Option for Formulating Water-Insoluble APIs
  3.­ companies-are-using-a-once-obscure­ fda-drug-approval-pathway
  9. David Anderson and Robert Lee, “LyoCell®Technology: a Lipidic Drug Delivery System Based on Reverse Cubic and Hexagonal Phase Lyotropic Liquid Crystalline Nanoparticles” in CRC Concise Encyclopedia of Nanotechnology, Jan 2016.