Formulating drugs for hot-melt extrusion (HME) was one of the topics at the Pharmaceutical Extrusion Seminar organized by Leistritz near the company’s US headquarters in New Jersey in June. Several of the speakers noted the growing problem of poorly soluble drugs in the drug development pipeline and the need for efficient production methods for improving solubility. While other options, such as spray drying, are available, HME is attractive because it does not require solvents and is a continuous process, which brings advantages of efficiency, flexibility, and process control.
HME has been used in the pharmaceutical industry since the late 1980s, but because of its growing acceptance and use, the past five years have seen increasing application of fundamental research and understanding of HME to pharmaceutical formulations, notes Charlie Martin, president of Leistritz. This year’s Pharmaceutical Extrusion Seminar (PES) was the 8th annual, and the experience of attendees has significantly increased in the past five years, says Martin. In the first few years of the PES, only 10–20% of attendees had any extrusion experience, but now 80–90% do. In addition, many companies now have research to present.
One area of research is the use of supercritical carbon dioxide (CO2) in HME for foaming and as a fugitive plasticizer (i.e., a material that acts as a plasticizer or processing aid during the process but does not remain in the final product). Supercritical CO2 reduces the glass transition temperature of polymeric excipients and acts as a molecular lubricant to reduce melt viscosity. Processing temperatures can be reduced by as much as 20 °C, which can be important if the API has low thermal stability, noted Graciela Terife, senior scientist for Pharmaceutical Sciences at Merck, in a presentation.
Identifying an appropriate polymer to use as an excipient in HME was also discussed at the seminar. Requirements for polymers include high thermal stability, appropriate glass transition temperature and melt viscosity, no toxicity, and, perhaps most challenging, solubility with the target drug, explained Shaukat Ali, technical sales manager at BASF. He explained that a screening test in which the API and polymer are mixed in a solvent and dried onto a film can be used to evaluate compatibility. Suppliers have done this work with many excipient-API combinations; BASF, for example, has published an HME compendium with this data.
In the HME process, high temperatures and shear combined with intermolecular interactions (e.g., ionic, hydrogen bonds, and polar forces) between API and polymers breaks up a crystal lattice of poorly soluble actives; the amorphous active is then stabilized within the polymer matrix, explained Firouz Asagarzadeh, director of technical services at Evonik, in a presentation. Miscibility of drug substances in polymers plays a crucial role in formation of solid solutions and stabilization of the amorphous structures. Polymer selection should be based upon structure of the active and polymers. To select appropriate polymers, Evonik has developed a miscibility and process estimation package called MemFis (Melt Extrusion Modeling and Formulation Information System). MemFis calculations do not require use of any active, and using MemFis minimizes screening experiments.
HME also lends itself to direct production of combination products, in which a drug is loaded into a device that can be shaped or molded as part of the extrusion process. HME is being used, for example, to produce fibers loaded with drugs that are injected for local delivery (e.g., ocular drugs), sutures containing drugs for dental applications, and catheters containing drugs or antimicrobials, explained Tony Listro, managing director of Foster Delivery Science.
Although HME is still a cutting-edge technology, experience and understanding are growing and development continues, as evidenced by the presentations at the seminar.