Co-crystals and APIs

Crystal formulations can be fundamental to the performance of medicines that have inherent barriers to drug delivery such as low solubility, slow dissolution rates, or potentially low permeability. This is particularly true for difficult-to-dissolve active pharmaceutical ingredients (APIs) that are administered orally in high doses.

API co-crystals – which consist of API molecules and co-formers – are growing in importance as a tool to overcome these challenges to pharmaceutical development, particularly a drug’s solubility. But API formulation can be daunting, with complex chemical synthesis, safety and stability issues to overcome. And co-crystal development requires a specific skillset, particularly when it comes to selecting the appropriate co-former.

Innovative Use of Co-Crystals to Produce New API

Teva API looked to co-crystals as a means to create a new generic alternative to Imbruvica® (Ibrutinib), a widely prescribed anticancer drug. Imbruvica is used to treat patients with Mantle cell lymphoma and chronic lymphocytic leukemia who have received at least one prior therapy, as well as four other indications. Pharmacyclics, AbbVie and Johnson & Johnson market the product, a selective and covalent inhibitor of Bruton’s tyrosine enzyme.

With guidance from the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) on the use and application of co-crystals, Teva API’s product development team arrived at a unique crystal form of Ibrutinib. This API (IBR HFCC) was produced by crystalizing two molecules of Ibrutinib with one molecule of fumaric acid. The use of fumaric acid allowed Teva API to develop a stable, effective product with similar solubility to Ibrutinib and a stability of at least 18 months.

IBR HFCC Patented In US and EU

IBR HFCC is now patented in the United States and European Union (EU) and Teva API has submitted its Drug Master File (DMF) to the FDA, an important milestone for the company.

If approved, IBR HFCC eventually will provide patients with an effective and more affordable alternative to Imbruvica. That’s important because the drug’s cost can place a significant financial burden on patients and their families that may cause some individuals to abandon their therapy.

Gaining a Competitive Advantage

In addition to achieving its vision to provide affordable, accessible and high quality drugs to more people worldwide, Teva API has added a new technical competency to its drug development arsenal. Through its innovative work with co-crystals, it has established a proficiency that gives Teva a distinctive competitive edge in the industry.