Meeting Solubility Challenges - Pharmaceutical Technology

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Meeting Solubility Challenges
Pharmaceutical companies, equipment providers, contract-service providers, and excipient manufacturers apply various approaches for improving solubility. The article examines some recent developments. This article is part of a special issue on solid dosage and excipients.

Pharmaceutical Technology
Volume 36, Issue 3, pp. s6-s8

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
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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