Solid form changes during drug development: good, bad, and ugly case studies

Ann Newman,Robert Wenslow

doi:10.1186/s41120-016-0003-4

Abstract

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.

Highlights

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
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
* Correspondence: ann.newman@seventhstreetdev.com 1Seventh Street Development Group, Kure Beach, NC 28449, USA 2Crystal Pharmatech, New Brunswick, NJ, USA. 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 inlicensed compound, and a less than bullet-proof intellectual property (IP) landscape surrounding an innovator molecule

Summary

Background

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. Every innovator drug developer has approached API solid form decisions with a unique paradigm; 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, 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 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 inlicensed compound, and a less than bullet-proof intellectual property (IP) landscape surrounding an innovator molecule. Any material from the crystalline API categories that lacks long range order as characterized by x-ray powder diffraction (XRPD) has been referred to as amorphous API

Case studies

Conclusions