Selective Crystallization of a Novel Polymorph
Managing the emergence of a new polymorph without interrupting clinical supply
Sarah Bethune, PhD, Associate Director, Pharmaceutics & Formulation Development, Avista Pharma Solutions, Inc.
Michael Bradley, Associate Director, Drug Substance Manufacturing, Avista Pharma Solutions, Inc.
Terry Harper, Associate Director, Material Characterization, Avista Pharma Solutions, Inc.
See what success looks like: Preventing polymorphs from sabotaging early clinical trials
When success in early trials creates a demand for new batches of API, the emergence of an unexpected polymorph can be a major setback to meeting critical clinical timelines.
Different polymorphs of the same API can exhibit different physical properties including stability, solubility, and bioavailability in the body. Isolating the stable polymorph reliably in each batch is vital to the success of API manufacturing and formulation. Ideally, the optimal polymorph is selected early in development to steer formulation strategies. However, it’s not uncommon for a new polymorph to arise after API manufacturing is underway.
Here’s a look at how Avista Pharma applied rigorous characterization standards and expert knowledge of critical water activity to isolate a previously undiscovered and uncharacterized polymorph. At the same time, they were challenged with supplying the original polymorph to maintain batch production in order to meet a critical need for an ongoing clinical trial.
Early indicators: Shifting peaks
After adopting the manufacture of an API from a CMO to produce new batches required for a clinical trial, the XRPD release test indicated shifting diffraction peaks. X-ray diffraction is a standard characterization tool to provide definitive fingerprinting in the identification of crystalline structures. On its own, the variation in diffraction peaks was not evidence of a polymorph, but the XRPD release test of a fourth manufacturing batch indicated distinctly new and not just shifted XRPD diffraction peaks. This was a sufficient deviation from the strict reproducibility standards at Avista Pharma to warrant further investigation.
With limited polymorph studies conducted before the previously manufactured batches, further testing was performed to determine whether there might be a mixture of multiple forms to explain the XRPD pattern.
“We were able to determine that the known monohydrate was in fact a variable hydrate and set out to characterize the new polymorph,” explained Sarah Bethune, PhD, Associate Director, Pharmaceutics & Formulation Development.
Finding the solution: Selective polymorph screen
When a starting material is suspected to be a mixture, the selective properties of solvents can be used to activate crystallization and separate the materials.
By designing a polymorph study to screen against a panel of various organic solvents, Sarah’s team confirmed the presence of a new anhydrous crystalline polymorph. Analysis of the data revealed two distinct polymorphs which were successfully isolated as single phases.
Sophisticated characterization techniques of the solid forms also included XRPD, DSC, TGA, PLM, DVS, KF, and NMR. Characterization data became part of the intellectual property package for the client.
Optimizing stability: Critical water activity
The thermodynamic stability of both anhydrous and hydrate polymorphs is dependent upon the critical water activity of the solvent system. Therefore, distinct phase boundaries can be identified by comparing stability across various water activity media, much like the approach to determining the critical transition temperature between a monotropic and enantiotropic polymorph.1
Avista Pharma exceeds current industry standards by applying this principle through the use of competitive slurries to definitively assign thermodynamic stability. Reliance upon thermal data alone can present an incomplete picture of a stability profile. In this case, examination of the critical water activity revealed larger thermodynamic stability space for the anhydrous form, which was later chosen to replace the original API for scale-up.
Parallel delivery: Meeting clinical demand
Polymorphism is typically viewed as a complication during API development, but it can also present opportunities. The profile of the newly isolated polymorph spearheaded a new scale-up effort with confidence in its favorable stability.
However, the clinical trial underway required timely manufacture of the original polymorph to continue delivery to patients. In parallel with scaling up production of the new anhydrous form, the manufacturing team applied the results of the polymorph study to optimize production of the original polymorph. Accounting for the critical water activity in the manufacturing process yielded the monohydrate exclusively, thus enabling critical clinical studies to continue without interruption.
Confronting and resolving challenges in the early stages of API development is part of Avista Pharma’s mission to improve the yield and purity of products. Rapid delivery of the original API while characterizing a new polymorph for optimal production is the kind of response to dual challenges that has built a strong record of client success.
Success beyond science.
- On the polymorphism of pharmaceuticals and other molecular crystals. II Applicability of Thermodynamic Rules. Burger, A. & Ramberger, R. Mikrochim Acta (1979) 72: 273-316.
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