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Polymorph screening is a critical step in developing an active pharmaceutical ingredient for a pharmaceutical formulation.
The solid-state properties of an active pharmaceutical ingredient (API) play a crucial role in a finished drug product. Screening strategies for polymorphism is an important aspect of solid-state chemistry and a critical part of formulation development. Jan-Olav Henck, senior director of APIs and director of the West Lafayette site for Aptuit (Greenwich, CT) discusses screening strategies and applications with Patricia Van Arnum, senior editor of Pharmaceutical Technology.
PharmTech » Can you outline the major issues involved in solid-state chemistry and strategies for polymorph screening?
» Henck: Solid-state chemistry contributes to the development of safe and effective drugs by enabling reproducible and predictable performance at critical interfaces in the drug-development process. These interfaces, between the discovery/development and development/production stages of drug-development programs, are the most consuming time intervals in the pharmaceutical industry.
There is typically a lack of robust data on a compound at the discovery/development interface. Mechanical stress applied during scale-up can therefore introduce disorder in the crystal. At the development/production interface, energy values, and various forces and mechanical pressures, can also introduce problems to the integrity and stability of the drug. Setbacks at both of these interfaces are extremely costly—in both time and resources—to drug development programs.
Theoretical developments in solid-state chemistry, applied practically to the drug-development process, help pharma and biotech innovators shorten their development timelines and gain valuable information early in the product lifecycle to avoid problems and strengthen the data available on a molecule or compound. In addition, these early insights ultimately lead to better understanding of the solid-state material, strengthen patents and intellectual property protection, inform discussions with the FDA with regard to quality by design (QbD), for example, and increase knowledge about bioavailability issues.
Our solid-state chemistry experts at Aptuit have developed a proprietary production screen specifically designed to characterize the proclivity to change that exists within a drug product, whether it be the API, the excipients, or the excipient/API form. The approach involves using mathematical models applied to solid-state chemistry data to develop predictions which inform the understanding of API and drug formulations, and expedite the scale-up processes for molecules and compounds.
Our approach, which involves the practical application of advanced theoretical developments to increase our understanding of APIs and drug formulations, can be tailored to small molecules, large molecules, and biologicals. It helps drug developers understand the properties of their compounds early on with limited material and data, and ultimately guides the development of the drug. It is useful not only to drug innovators who have some capability in polymorphisms, but may not have full solid-state analytical capabilities, but also to law firms involve in patent protection cases.
The production screen consists of two main components that investigate the influence of temperature, humidity, and physical stress on a solid form in varying levels of detail. The prescreen broadly plots scenarios based upon general dynamic measurements. Data and models from the prescreen inform follow-on measurements and analysis via pointscreens intended to characterize the nature of any kinetic and/or thermodynamic changes that might be occurring.
A more extensive production screen will use multiple point screens to determine specific risk with respect to changes in material properties as a function of the primary external stressors. The results of the extensive production screen can be used to optimize an existing production process or inform the development of and ideal production platform for a candidate drug product. Read more on this topic in Patricia Van Arnum's Solid-State Chemistry: A Technical Forum.