The advantages of solid form analysis with XRPD

In this four-part blog series, we explore how one type of solid form analysis – X-ray powder diffraction (XRPD) – is helping developers improve the solubility and efficacy of drug products. In this fourth and final part of the series, we summarize the topics of the previous blogs, and discuss how XRPD can bring business value during drug development.

The solubility challenge

In the last few blogs in this series, we discussed how X-ray powder diffraction (XRPD) is a powerful technique which allows the detection and characterization of polymorphic forms of active pharmaceutical ingredients (APIs). Amongst other applications, XRPD is helping drug developers tackle one of their foremost challenges: poor drug solubility. Approximately 40% of current APIs are poorly soluble, and 90% of drugs in development contain poorly soluble APIs. Poor API solubility can have a major impact on the bioavailability and therefore the safety and efficacy of a drug. As such, pharmaceutical organizations are investing significant resources in finding new ways of improving drug substance solubility.

Establishing critical material attributes with XRPD

Here’s where solid form analysis with XRPD comes in. XRPD can assess the amorphous or crystalline nature of the API, helping to control properties like the physical stability and manufacturability of a drug, as well as its solubility in a biological system. Under these circumstances, solid state may be found to impact the Quality Target Product Profile (QTPP) and is therefore designated as a Critical Material Attribute (CMA). This can be measured and hence controlled by XRPD.

The latest XRPD techniques enable researchers to:

• Screen and select lead candidates based on their solid form
• Link the solid form to solubility and therefore bioavailability
• Identify polymorphs that may impact a drug’s processability, efficacy or safety
• Identify stable forms with enhanced manufacturability and storage profiles
• Investigate solid form alternatives, such as salts and co-crystals, that may increase efficacy
• Ensure that all relevant polymorphs are included in a patent

The importance of detecting polymorphic forms

From a drug development perspective, identifying and quantifying polymorphs is a key capability of XRPD. Polymorphic forms can dramatically affect the performance of an API, both in terms of bioavailability and manufacturability. And because over 50% of APIs are estimated to have more than one polymorphic form, integrating XRPD into solid form analysis is crucial for controlling polymorph composition.

However, polymorphs can have further impact on an API, beyond production processes, efficacy and safety. The business success of an innovative drug product is dependent on the strength of its intellectual property (IP) rights, which covers the solid state of the API. Failure to declare all known polymorphs in a patent, will leave the door open to competitors to identify a polymorph with a performance advantage, such as solubility, stability and manufacturability. This, of course, is a double-edged sword as innovators can extend patent lifetimes in much the same way. As such, XRPD can be essential for commercial exploitation.

Achieving the full potential of solid form analysis with XRPD

As described above, XRPD is a powerful technique for characterizing the solid state of drug substances. This provides valuable insight into the performance of the material for processing, the performance of the product to the end user, and helps to protect IP. However, XRPD is not without its challenges, though. For example, crystal orientation is a common issue that can cause deviations in measurements, reducing the analytical potential of the technique. There are ways to overcome this challenge, such as switching to transmission modes of measurement.

XRPD can also be used in combination with other techniques to provide a more comprehensive set of data on API structure. For example, measuring under non-ambient conditions can provide additional data on the stability of an API’s solid form at elevated temperature and humidity. Additionally, X-ray scattering techniques can be used alongside XRPD to gain further structural insights into nanomaterial particle size using small-angle X-rays (SAXS) and variability in amorphous materials using Pair Distribution Function (PDF).

The inclusion of techniques like these enables pharmaceutical scientists to make well-informed decisions for their API during multiple phases of the development pipeline, from research to manufacturing. Less reliable lead candidates can then be eliminated early in the development process, which saves time and cost, and ensures that subsequent development is built on a concrete understanding of the API’s solid form.

XRPD helps build therapeutic and business value during drug development

There is no question that XRPD can provide a clear understanding of an API (and all its forms) through solid form analysis, delivering a powerful route to potential safety and efficacy advantages. Moreover, XRPD helps fill in gaps in polymorph profiling, reducing ambiguity in patent applications.

Download the full guide here to discover how XPRD can fast-track stable solid forms in your drug development projects