How does XRPD protect both patients and patents?
In this four-part blog series, we explore how one type of solid form analysis – X-ray powder diffraction (XRPD) – is helping drug developers optimize the solubility and performance of drugs. In this second part of the series, we discuss how using XRPD to identify different polymorphic forms can protect your patients and your patents. If you missed it, part one can be found here.
Why polymorph detection is important for the therapeutic and business success of drugs
In the last blog, we discussed how solubility is a major challenge in drug development. X-ray powder diffraction (XRPD) solid form analysis helps tackle this issue as it can be used to detect an API’s polymorphic forms, enabling developers to make more informed decisions on how to optimize the drug substance’s solubility and stability.
It’s well understood that different polymorphic forms of an API may exhibit different physical properties, such as crystal habit, friability and solubility. In turn, these properties can impact the processes used to make the drug, and can also impinge on the efficacy of the product administered to the patient. Hence, polymorphic composition can affect the real-world therapeutic and business success of a drug.
Polymorphs can also have a major impact on intellectual property (IP) rights. For example, it can have disastrous effects for the originator when a new polymorph is identified. This can lead to product recalls, such as this case concerning ritonavir, or a competitor commercializing the unprotected polymorph.
Missed polymorphs reduce market advantage of statin
In 2000, the drug Atorvastatin was released under patent as a cholesterol-lowering statin. In 2003, however, a generics company filed a patent for an effective polymorphic form that was not included in the originator’s patent. The generics company went on to manufacture and sell its polymorphic equivalent in 2011, with first-to-file revenue in the first six months amounting to around $600 million.
XRPD offers a way to discover and characterize polymorphs
So how is XRPD best suited to detect and characterize polymorphs? And how does the technique compare to other methods? Single crystal diffraction is one method that can be used to determine the absolute structure of a crystal and its atomic geometry. However, the technique is limited to measuring just one crystal at a time, and it cannot be used to measure powder samples, making it generally poorly suited to polymorph analysis for pharmaceuticals. It is also a time-intensive procedure since high-quality crystals must be of a certain size in order to be measured (ideally 150 µm -250 µm).
Electron diffraction is another technique capable of determining the crystalline structure and polymorphic forms of nano-crystals. However, this technology is still in its infancy, and far away from making it into the mainstream as an evaluation method for drug development.
Polymorphs can also be characterized using thermal analysis techniques such as differential scanning calorimetry (DSC) or thermogravimetric analysis (TGA). DSC works by recording the transition temperature when an API changes its state, meaning it can be useful in determining the stability of the solid form of API polymorphs. TGA, on the other hand, records changes in mass as a result of temperature change in a controlled environment. Each form of an API will generate a different thermogram, so the technique is able to identify the presence of different polymorphs and provide information on their relative stability.
The major benefit of XRPD, however, is its ability to provide information on the structure of the API in question when it is in powdered form, all with time- and cost-efficiency. XRPD allows bulk measurement of samples consisting of multiple smaller crystals, giving a more holistic understanding of the API. The resulting diffractogram is quickly obtained and gives a fast indication of the presence of single or multiple polymorphs. Analysis methods like thermal analysis still have their place, however, as they provide complementary insight alongside XRPD about aspects including thermal stability.
Conclusions
Detecting and characterizing polymorphs is critically important for the therapeutic and market success of drugs. XRPD offers an unrivaled ‘all-in-one’ technique to spot polymorphic forms in powdered drug formulations, allowing drug developers to improve the performance and safety profiles of drug products, as well as protecting their IP. In the next blog of this series, we discuss how XRPD can be used in combination with other techniques to take drug development even further.
Download the full guide here to find out more about how XRPD can help your drug development projects.
Further reading