Detect and control polymorphism: pro tips for pharmaceutical scientists

How to detect and control polymorphism in drug development: Pro tips from our webinar 

Polymorphism presents an ongoing challenge for pharmaceutical manufacturers. It is difficult to predict whether a crystalline drug will form multiple polymorphs, or which structure will take shape. At the same time, controlling polymorphs is a crucial part of the drug scale-up process to ensure that drug substances retain their intended structure and remain efficacious.

Indeed, the consequences can be disastrous if drugs don’t retain their stability in storage. Take the example of ritonavir, which was initially prescribed in liquid form but pulled from shelves when, upon storage, another polymorph started to crystallize. The withdrawal cost the manufacturer an estimated US$250 million and set back production significantly.

The best way to prevent this kind of setback is through comprehensive polymorph detection and control using X-ray diffraction (XRD). In this webinar, XRD expert Natalia DadivanyanI explained how Malvern Panalytical’s Aeris XRD system can help detect even the slightest changes that could pose a risk to your drug substance’s performance. Here’s our summary of the highlights from the session.

Key takeaways 

• X-ray diffraction (XRD) is one of the best solutions for polymorph detection because it enables fast and accurate analysis of crystal structure. The Aeris Compact XRD system enables high-quality data without the complexity, expense, or physical footprint demanded by a floor-standing instrument.
• Integrating Aeris into drug development workflow, particularly in the Scale-up stage allows to run efficient solid form validation without the need for a crystallographic background.

Why polymorphism matters in drug development

Polymorphism refers to the phenomenon by which molecules crystallize in different structures, e.g. different crystalline or amorphous forms. Despite having the same chemistry, these different structures have different properties, which influence their pharmaceutical and biopharmaceutical performance.

For example, different polymorphs may display different solubility, compaction properties, stability, and bioavailability – all key factors to control during drug development.

Although it is impossible to predict which polymorphs will form under which conditions, manufacturers can and should be on the lookout for polymorph formation during clinical development and scale-up. That’s where XRD comes in.

Key quote  

"X-ray diffraction (XRD) allows us to benchmark solid form, but also better understand the pre-formulation process and perform solid form optimization."

XRD offers a wide range of analysis options

X-ray diffraction works by “bouncing” X-rays off the atoms in a sample and measuring the angles at which they diffract. Such an experiment provides the distances between atoms to determine the structures in which they are arranged. Different crystal forms will have different XRD patterns, making it an effective way of spotting different polymorphic structures.

The particular advantage of using XRD for polymorph detection is that it can be applied at many stages throughout the drug development workflow. For example, it can be applied to APIs and formulations, as well as for polymorph risk assessment, in salt and polymorph screenings, and even for crystallinity determination.

However, several factors can get in the way of effective polymorph detection with XRD; chiefly, a lack of user-friendliness in the instruments. Without a specialist on hand, it can be challenging to run and XRD experiment and interpret its result. But this doesn’t have to be the case.

Key quote  

"The main advantages of Aeris are its plug-and-play simplicity in combination with high data quality. This is particularly helpful if you have limited experience with XRD - you don't need to be an expert to run an experiment, and you also don't have to be one to analyze the data."

High-quality XRD results without unnecessary complexity

Aeris offers simple, reproducible sample loading with an external sample changer, giving you fast, accurate results in a flexible manner. What’s more, its touchscreen interface offers plug-and-play simplicity for users of all levels of experience, from beginner onwards.

Further simplification of XRD analysis can be supported by the analytical SW package HighScore Suite. It allows you to run various types of analysis starting from pattern matching to limit testing, quantification of multiple amorphous and crystalline phases, and cluster analysis to identify similar XRD patterns and hence predict which polymorphs are likely to have

comparable physical properties (solubility, bioavailability, etc.) and crystallinity/amorphicity assessment. Due to the Smart Batches feature most of this information can be extracted in an automated or semi-automated way, providing push-button solutions for a quick, yet reliable analysis to anyone from chemists to crystallographers – independent of the depth of XRD knowledge and experience.

Finally, OmniTrust solution makes working in regulated environments easy and time-efficient...How so? OmniTrust allows you to restrict access according to user profiles and it provides a reliable and comprehensive way of accessing and reviewing system audit trail data.