A novel temperature-controlled media milling device to produce drug nanocrystals at the laboratory scale
Abstract
Introduction
Poor water solubility presents a significant challenge to the pharmaceutical industry, as 70 to 90 % of drugs in the development pipeline, and 40 % of drugs on the market exhibit poor water solubility and bioavailability (Ma et al., 2022, Lipinski, 2002). Pharmaceutical companies continue investing in research for new drug molecules with good affinity for the pharmacological target; however, unsatisfactory drug potence due to the low solubility of the compounds often leads to development discontinuation, translating in significant loss of resources and time (McGuckin et al., 2022, Dahan et al., 2016). Particle size reduction is the most universally used strategy to enhance the absorption of poorly soluble actives with micronisation, a technique traditionally achieved via milling, allowing the obtention of particles with sizes between 2–10 µm. Work from Liversidge and Cundy, in the early 1990′s, described the production of sub-micrometric drug particles using media milling techniques adapted from the pigments industry (Liversidge and Cundy, 1995). Nanocrystals (NCs) are particles of pure drug with a mean particle size below 1 µm and crystalline properties (Uwe et al., 2008). Unlike conventional polymer and lipid nanoparticles, which require the use of carrier materials, NCs are surrounded by a thin layer of stabiliser, such as surfactants or polymeric stabilisers, to prevent agglomeration. According to the Noyes and Whitney equation, a reduction of particle size increases the dissolution rate by means of increasing the specific surface area, which is critical for Class II drugs in the biopharmaceutical classification system (poor solubility, high permeability) (Noyes and Whitney, 1897, Dizaj et al., 2015, Junyaprasert and Morakul, 2015). NCs can be produced using bottom-up and top-down techniques, leading to NCs suspensions, also known as nanosuspensions (NSs), with further water removal forming powdered NCs. NCs have made a significant clinical impact, with > 20 products on the market, including the recently approved long-acting injectable antiretroviral Cabenuva®, which marked and important milestone for the field.
Top-down techniques are the most employed, both in academic and industrial laboratories, with the primary benefit of achieving high drug loadings, while using water as a dispersion media, thus avoiding the use of organic solvents, which are normally required to dissolve the drug before precipitation in bottom-up techniques (Castillo Henríquez et al., 2024). Top-down approaches, on the other hand, require the application of high energy inputs and include techniques such as media milling and high-pressure homogenisation, with the former being the most used approach for the production of the currently marketed NCs products (Malamatari et al., 2018). Media mills consist of a milling chamber where the crude drug is stirred together with an aqueous solution of a stabiliser and the milling media, typically beads of various materials, such as Yttria stabilised zirconia, metal, plastic or glass. Agitation generates collisions, attrition and shear forces which lead to particle breakage and size reduction (Malamatari et al., 2018). One of the major advantages of this process is the possibility to be easily scaled up using of-the-shelf machinery (Müller et al., 2011). Crucially, industrial media mills are equipped with an integrated cooling system enabling precise control of the process temperature via an external jacket surrounding the milling chamber through which a cooling fluid circulates (Uwe et al., 2008, Malamatari et al., 2018).
Commercially available mills have processing capacities that require significant amounts of the drug for effective milling, ranging from several grams at the lab scale, to kilograms at the industrial scale (Peltonen, 2018). However, these systems are inconvenient at early stages of drug development when the amount of active is limited, or when working with expensive compounds. Consequently, the production of NCs using simplified, small media milling devices that can be used with milligrams is an interesting target for exploration. Romero et al, described the use of a magnetically stirred device with a milling chamber of 2 mL (Romero et al., 2016), whereas work from this group reported the manufacture of NCs using 10 mL vials (Permana et al., 2021, Permana et al., 2020, Bianchi et al., 2022,
Zhang et al., 2023, Abbate et al., 2023, Wu et al., 2022). Production of NCs using small-scale wet bead milling within academia has been most beneficial, providing ease and flexibility in terms of formulation optimisation by enabling control over various milling parameters, such as volume of milling media, quantity of drugs and stabilizers, which play a crucial role in the physical properties of the resulting NCs, while producing NCs in a cost, material and energy efficient manner (Chen et al., 2011).
One key difference between the magnetically stirred devices previously described and commercially available mills is the possibility to regulate the temperature of the process, a critical parameter in the milling process, which can affect the rheology of the slurry (drug, surfactant solution and beads) as well as the milling efficiency. Additionally, the heat generated during milling may disrupt the colloidal stability and lead to thermal drug decomposition. Implementation of a cooling jacket may provide superiority in terms of formulation optimisation as this system would allow each parameter to be specifically fine-tuned, per the requirements of the specific API, with the additional benefit of temperature regulation during the milling process. Additionally, employment of a thermally regulated system could be crucial for the extraction of biomolecules from plants, cells and tissues whereby media milling is widely used, and temperature plays a key role with respect to material decomposition.
This work reports the use of an original milling device for the production of drug NCs at the laboratory scale, with the unique feature of permitting temperature control via water circulation through a cooling jacket. The manufacture of NCs of three model hydrophobic drugs, itraconazole (ITZ), ivermectin (IVM) and curcumin (CUR) was performed, and manufacturing parameters, such as amount of milling media, milling time and milling temperature is presented. A commercial laboratory scale mill was used to reproduce the milling conditions of the novel mills and demonstrate potential for scale-up.
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Materials
CUR (CAS RN 458–37-7, molecular weight 368.39), ITZ (CAS RN 84625–61-6 molecular weight 875.11), and IVM (CAS RN 70288–86-7 molecular weight 705.64) were obtained from Tokyo Chemical Industries (United Kingdom). Poloxamer 188 (POL 188) was purchased from BASF Chemical company (Ludwigshafen, Germany). Polyvinyl alcohol (PVA) (9–10 kDa) was purchased from Sigma-Aldrich (Dorset, UK). YTZP Yttria-stabilised zirconia beads with a diameter of 0.1–0.2 mm obtained from Chemco (Guangfu China) were used as the media in the wet media milling process. Ultrapure water was obtained from a water purification system, Elga Purelab DV25, Veolia Water systems (Ireland). All other chemicals were of analytical grade.
Elise J. Catlin, Octavio E. Fandiño, Lucía Lopez-Vidal, Martina Sangalli, Ryan F. Donnelly, Santiago D. Palma, Alejandro J. Paredes, A novel temperature-controlled media milling device to produce drug nanocrystals at the laboratory scale, International Journal of Pharmaceutics, Volume 666, 2024, 124780, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124780.
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