Pharmaceutical Development Using XRPD Blog Series Part 2: How Does XRPD Protect Patients and Patents?

This four-part blog series introduces how powder X-ray diffraction (XRPD), a type of solid form analysis, assists pharmaceutical developers in optimizing the solubility and performance of drugs.

Part 2 of this series explains how using XRPD to identify various polymorphs helps protect patients and patents.
For other parts, see Part 1, Part 3, and Final Part.

Why the Detection of Polymorphs is Crucial for Therapeutic and Business Success of Pharmaceuticals

The previous blog explained how solubility is a major challenge in drug development. XRPD solid form analysis can be used for the detection of API polymorphs, allowing developers to make more informed decisions on optimizing the solubility and stability of active ingredients.

It is well known that different polymorphs of an active ingredient exhibit varying physical properties, such as crystal habit, friability, and solubility. These properties can affect the manufacturing process of pharmaceuticals and the effectiveness of drugs administered to patients, potentially impacting the real therapeutic and business success of a drug.

Moreover, polymorphs can have a significant impact on intellectual property (IP) rights. For example, if a new polymorph is discovered, it may lead to disastrous outcomes for the originator. As seen with ritonavir, it can lead to product recalls or commercialization by competitors using a non-protected polymorph.

Ignoring Polymorphs Can Damage Market Advantage for Statins

In 2000, atorvastatin was patented as a cholesterol-lowering statin drug. However, in 2003 a generic pharmaceutical company filed a patent for a novel, efficacious polymorph not included in the original patentee’s patent. This generic drug company manufactured and marketed its polymorphic formulation in 2011, achieving sales of around $600 million in the first six months.

XRPD as a Method for Detection and Characterization of Polymorphs

So, why is XRPD ideal for detecting and characterizing polymorphs, and how does it compare to other methods? Single-crystal X-ray diffraction is one method that can determine the absolute structure and atomic arrangement of crystals. However, it is generally unsuitable for drug polymorph analysis as it can only measure one crystal at a time and cannot measure powder samples. It also requires high-quality crystals of a certain size (ideally 150μm to 250μm), which can be time-consuming.

Electron diffraction is another technology capable of determining the crystal structure and polymorphs of nanocrystals. However, this technology is still in development and far from becoming a mainstream evaluation method in pharmaceutical development.

Polymorphs can also be characterized using thermal analysis techniques like differential scanning calorimetry (DSC) or thermogravimetric analysis (TGA). DSC can obtain the transition temperature when an API changes its state, helping determine the stability of solid forms of API polymorphs. Meanwhile, TGA records the mass changes due to temperature variation in a controlled environment, producing different thermograms for each form of API, allowing identification of different polymorphs and providing information about their relative stability. However, a major advantage of XRPD is its ability to provide structural information in a time- and cost-efficient manner when the target API is in powder form. XRPD can measure samples consisting of multiple small crystals all together, providing a more holistic understanding of the API. Diffraction patterns are promptly obtained, allowing quick confirmation of the presence of single or multiple polymorphs. Still, analytical methods like thermal analysis continue to play a role by providing complementary insights with XRPD on aspects like thermal stability.

Conclusion

The detection and characterization of polymorphs are critical for the therapeutic and market success of drugs. XRPD is an unmatched “all-in-one” technology for detecting polymorphs in powder drug formulations, enabling pharmaceutical developers to improve the performance and safety profiles of drugs and protect their IP. The next blog will discuss how combining XRPD with other technologies can further develop pharmaceutical development.

If you would like to learn more about how XRPD assists in drug development, download and view the FULL guide.

Click here for the FULL guide