Hot-melt extrusion
Hot-melt extrusion is used to disperse APIs in a matrix at the molecular level to form solid solutions and is used as a method
to improve solubility of poorly water-soluble drugs (3). Evonik has developed a system, Melt Extrusion Modeling and Formulation
Information System (MEMFIS), as a predictive modeling tool in developing hot-melt extrusion formulations. MEMFIS helps in
selecting initial formulations with no API consumption, using mathematical models and algorithms based on solubility parameter
theories (i.e., hydrogen bonding and polar and dispersive forces). MEMFIS uses chemical structures, solubility parameters,
physicochemical properties, and a myriad of processing conditions to suggest initial formulation components and process settings
for a hot-melt extrusion formulation (1).
In terms of miscibility estimation, for example, MEMFIS evaluates which excipients have higher potential to form a solid solution
by assessing the drug miscibility of a given excipient in comparison to other excipients. The qualitative method, (i.e., which
excludes hydrogen-bonding capability in the evaluation) considers the drug miscibility with an excipient in comparison to
other excipients to make the determination of whether one excipient is more or less miscible. Only dispersive interactions
are considered. Qualitative-only methods may lead to the exclusion of valuable excipients from the screening studies that
could potentially form strong hydrogen bonds with the APIs (1).
In the quantitative evaluation in the MEMFIS, which is a deeper analysis, in addition to polar and dispersive interactions,
the specific possible hydrogen-bonding interactions are investigated at a molecular level to derive a quantitative expectation
in terms of drug–excipient miscibility in a binary system. In this quantitative assessment, additional specific hydrogen-bonding
capability is considered. This involves considering polymers from a monomer perspective (i.e., meaning the composition of
the polymer) and specifying the type of hydrogen bonding that could be involved and its impact on the solubility parameters.
Solubility-parameter estimation and molecular-interaction considerations are important tools in estimating first formulations
in solid-dispersion product. High-throughput screening is accomplished based upon molecular structure, intra- and inter-molecular
bonding, and their impact on solubility parameters (1). In addition to MEMFIS, Evonik is positioned in solid-dispersions through
its methylacrylate polymers (Eudragit). Several late-stage products have been developed with these excipients in solid-solution
formulations. Evonik has both hot-melt extrusion and spray-drying capabilities.
Thin-film technology advances as a specialized oral dosage form
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Other companies are advancing their hot-melt extrusion capabilities. In October 2011, Ashland Specialty Ingredients, which
acquired International Specialty Products (ISP) in 2011, announced it was adding a GMP hot-melt extruder at its Columbia,
Maryland, R&D center to better serve pharmaceutical companies working with poorly soluble drug compounds. The 180-mm Leistritz
extruder allows companies that seek to commercialize drugs, which are made more soluble with dispersions from Ashland, to
scale up to GMP clinical and commercial quantities produced by hot-melt extrusion. Ashland planned to finish installing and
testing the equipment in the fourth quarter of 2011 and to begin a full-service offering early in 2012. The company has an
existing extruder at its Wilmington, Delaware Research Center. With the addition of the extruder, Ashland is able to conduct
kinetic-solubility and polymer-screening tests using both spray drying and hot-melt extrusion techniques to determine the
best solubility solution in clinical trials. In October 2009, ISP launched a drug-solubility initiative that focused on solubilization
technologies that involved excipients, formulation, and related processing services, which included solid-dispersion technology,
both hot-melt extrusion and spray drying. In 2009, ISP partnered with the equipment manufacturer Coperion for advancing hot-melt
extrusion technology.
In February 2012, the CDMO Bend Research formed a licensing agreement with Eli Lilly under which Lilly gains access to Bend's
proprietary spray-dried dispersion technology, which is designed to improve the bioavailability of compounds with low aqueous
solubility. In addition, as part of an already existing agreement with Lilly, Bend Research will continue to provide formulation,
development, analytical, engineering, and manufacturing services to Lilly to support its preclinical and clinical development
programs. In August 2011. Bend Research also formed a collaboration with the CDMO Xcelience for oral solid-solubilization
formulation solutions and clinical-supply manufacture.
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In July 2011, the CDMO Pharmaceutics International (Pii) added hot-melt extrusion to its formulation and process-development
solutions capabilites. The company purchased a 16-mm and an 18-mm Leistritz twin-screw extruders. This investment enables
Pii to carry out feasibility studies to pilot-scale cGMP productionfor Phase I and II clinical-trial materials using hot-melt
extrusion.
In 2009, BASF launched its polymeric solubilizer, Soluplus, which is used in hot-melt extrusion applications. In 2010, the
company partnered with GEA Niro to allow BASF to make cGMP spray-drying tests and pilot productions of APIs at GEA's test
station in Copenhagen. Dow Wolf Cellulosics offers several expicients for hot-melt extrusion applications, including poly
(ethylene) oxide resins (e.g., Polyox) and cellulosic derivatives [e.g., Ethocel (ethylcellulose ethers)] and Methocel (cellulose
ethers).
In April 2011, the CDMO Pharmatek Laboratories added spray drying to its drug formulation and manufacturing capabilities.
The company purchased a Buchi B-290 Mini Spray Dryer for formulation feasibility studies and small-scale clinical manufacture.
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