Some examples of polymorphic transitions on filed pharmaceutical products are given below. There are probably many more events, most of which have not been reported in the public domain, in which crystal polymorphism has occurred and led to manufacturing troubleshooting, batch rework, and large delays in project or clinical timelines.
- The most well-know example is probably Ritonavir, a HIV protease inhibitor, where a polymorph transitions led to a large decrease in bioavailability: In 1998, a more stable, less soluble crystalline phase appeared in the formulation that resulted in dissolution failures. Ultimately, the pharmaceutical product was withdrawn from the market because the manufacturing process was no longer able to reliably produce the desired polymorph. Eventually the product was reformulated with the most stable polymorph and relaunched.
- Rotigotine, a Parkinson drug, was filed by Schwarz Pharma in 2003 as a substance that does not show polymorphism. It was administered as skin patches. However, in 2008 it turned out that a new form had crystallised in these patches which reduced the efficacy. The product had to be withdrawn, affecting the improved quality of life many patients had experienced from the sustained release patches. The new crystal form was described in a patent filed in November 2008 (US 20090143460 A1):“Surprisingly, a further crystalline form of rotigotine (polymorphic form (II)) has now been identified and found to show a greatly enhanced thermodynamic stability and an improved shelf-life as well as a cubic crystal shape that represents an advantage over the needle-like particles of polymorphic form (I) regarding its handling properties such as filtering properties, flowability, electrostatic behavior, etc.”
- In 2010 the blood pressure medication Avalide, a combination of two anti-hypertensives, hydrochlorothiazide and irbesartan experienced a drug product recall of 60 million tablets. Concerns were over possible variability in the amounts of the less soluble polymorph of irbesartan, which may result in slower dissolution.
Examples taken from:”Crystal Polymorphism in Chemical Process Development”: Alfred Y. Lee, Deniz Erdemir and Allan S. Myerson. Ann. Rev. Chem. Biomol. Eng. 2. 2011
Below: A microscope picture of a crystal phase transition.