Fingerprinting the structure of pharmaceuticals

By Dr Matt Wilkinson

- Last updated on GMT

Related tags: Nuclear magnetic resonance

A new solid-state proton NMR (nuclear magnetic resonance) technique
has been developed that can quickly determine polymorphism of
active pharmaceuticals within tablet formulations.

The efficacy of a solid drug formulation often relies on the crystalline form (polymorph) that the active pharmaceutical ingredient (API) is in, as different polymorphs can have very different physical properties that affect how quickly the crystal dissolves. This can lead to significant variation in the bioavailability of a compound and has led to pharmaceutical firms not only patenting the chemical structure of a drug, but also the polymorph type. In an article published in the latest issue of the journal Angewandte Chemie​, researchers from the UK's University of Warwick and AstraZeneca have shown that a new solid-state NMR technique can be used to distinguish between different API polymorphs, even after they have been mixed with filler compounds (excipients). The technique, known as proton double-quantum combined rotation and multi-pulse spectroscopy, 1​H DQ CRAMPS for short, enables well-resolved 2D (two dimensional) spectra to be obtained that can fingerprint an API polymorph, even when mixed with excipients. While other techniques do exist that can identify different polymorphs, such as x-ray diffraction (XRD), x-ray powder diffraction (XRPD) and Raman spectroscopy, they produce results that can be difficult to interpret especially when the API is in the presence of excipients. "The advantage of NMR over other techniques such as XRPD or Raman is that you are focussing in on individual atomic sites,"​ said lead author of the report, Dr Steven Brown of the University of Warwick. He continued by explaining that pharmaceutical companies currently use 13​C solid state NMR for these studies, but that studying the carbon nuclei was not as efficient as studying the protons attached to them as they are less sensitive and less abundant. In addition, because the 13​C nuclei are generally not directly involved in the intermolecular interactions that vary from polymorph to polymorph, they are not as sensitive to the changes. However, until recently, solid-state proton NMR has been difficult as the magic angle spinning (MAS) technique used in 13​C solid-state NMR does not decouple the 1​H nuclei leading to significant line broadening that makes individual peaks hard to separate. The 1​H DQ CRAMPS removes these confusing couplings such that sharp lines are observed in the spectra. "Solid state NMR is the method of choice for studying polymorphs and big pharma has started to invest in high-field solid state NMR instruments,"​ said Dr Brown. "These 2D 1​H experiments can be conducted in less than 2 hours, while the corresponding 13​C experiment would take nearly four days of instrument time to collect as much information." ​ Nevertheless, the researchers emphasise that a 2D spectra is still needed to distinguish the signals that relate to the API from those that correspond to excipients. These 2D spectra provide a very useful 'fingerprint' for the API within a formulation in less than two hours - making it ideal for studying formulations during the development process as well as in a routine quality control (QC) setting. This is particularly important as compounds can be subjected to high temperatures and pressures during the formulation process and these, can in theory, cause the API to switch from one polymorph to another. "We believe that this new approach should be adopted as a routine tool in the characterisation of pharmaceutical products,"​ said Dr Brown. "The fact that we can use this method to see which polymorph is in a tablet enables us to answer one of the key questions asked during the regulatory process: whether the API in the tablet is still in the same form that was used to generate efficacy and safety data."

Related topics: Contract Manufacturing & Logistics

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