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Solid Form Changes During Drug Development: Good, Bad, And Ugly Case Studies

The relevance of solid form in drug development has been well established over time. In order to fully understand drug properties, attention has been paid to solid state structure of drug molecules and their relationship to the drug formulation. While each drug developer has had their own strategies and workflows for screening and choosing solid forms of drug molecules, the industry is aware of instances where “the best laid plans” often go awry. This manuscript has summarized several case studies in development programs that display the “good, bad, and ugly” of solid form changes.

It has been reported that the solid form of active pharmaceutical ingredients (APIs) has significantly impacted quality and consistency of the final dosage form for drug development compounds (Newman and Byrn 2003), especially for solid oral dosage formulations.

Therefore, monitoring and controlling the API solid form in both drug substance and drug product has been recommended in order to ensure consistent biopharmaceutical properties throughout a drug development program. Every innovator drug developer has approached API solid form decisions with a unique paradigm; however, identifying and maintaining the optimal API solid form in early pharmacokinetic studies, as well as maintaining this form through product launch, has been recognized as an ideal situation. This utopian scenario, however, has often been noted to be far removed from reality, especially if the API solid form has been ignored or assumed to be trivial for a particular program. This has often led to significant program delays and cost as bioequivalence studies, new crystallization studies, or formulation development may have been needed.

This manuscript presents the “good, bad, and ugly” aspects of API solid form changes in the pharmaceutical industry. It has explored and elaborated upon specific case studies that outline the impact of API solid form changes brought about by choosing a non-ideal salt form for early preclinical development, relaxed due-diligence for a “fast-tracked” compound, a serendipitous late stage form change, lack of attention to solid form for an in-licensed compound, and a less than bullet-proof intellectual property (IP) landscape surrounding an innovator molecule.

The goal of these examples was to show that adequate attention to API solid form during development will aid in managing risk for a program. Whether an innovator company was looking to out-license a gold molecule as a platinum package, an innovator company was looking to bring a drug to market with a strong patent landscape, or a generic company was looking to enter the market with IP for their molecule, the case studies presented in this manuscript clearly show that API solid form is an important aspect of any development program.

 

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