Polymorphism in Drug Development and Manufacturing

Polymorphism describes the fact that some materials with the same composition can exist in more than one crystalline form, characterized by different molecular packing. The ability to identify, understand, and control the polymorphic form of a material is important to multiple technical fields but is of special relevance to the field of pharmaceuticals.

Most pharmaceutical products are administered as solids (e.g. tablets, capsules and inhalation materials) and the polymorphic form of the Active Pharmaceutical Ingredient (API) is of direct interest because it can influence the dissolution behaviour of the product in-vivo, and therefore the bioavailability.

In turn, the polymorphic form of the API can be affected by processing, formulation and storage conditions so it is often important to carry out checks during API synthesis route development, formulation development, storage and manufacture etc.

It is possible that an API can exist in multiple different polymorphic forms, and the determination of form or of the combination of forms, in a specific sample can be technologically challenging, especially when there are other important factors affecting the overall picture such as the existence of solvates, hydrates and also amorphous material. Thus, the analytical challenges can be difficult, and multiple methods are typically used across the industry. 

The three leading techniques (NMR spectroscopy, Raman spectroscopy and X-Ray Diffraction) are available from Bruker. These techniques are highly complementary and all have the advantages of being well-established, information rich, non-destructive in nature, and requiring only a small amount of sample (10s to 100s of mg) per assay.

High resolution solid-state NMR spectroscopy is performed to give clear and unambiguous information on the chemical structure of an unknown material. The technique is inherently quantitative and also has the advantage of being able to simultaneously measure amorphous materials within a mixed-phase sample. Time Domain NMR spectroscopy is a simplified variation of the NMR technique which analyses the relaxation behaviour of molecules, a property that is determined by their molecular structure. Different forms of the same molecule exhibit different relaxation characteristics and this technique is particularly useful for solid form quantification of different polymorphs, amorphous material and even excipients.

Raman spectroscopy enables the fast and reliable differentiation between polymorphs and is therefore widely used to measure bulk materials (such as a sample of an API). Product forms, including tablets, can also be analyzed by Raman microscopy and imaging, allowing the determination of the spatial distribution of a specific polymorph. When combined with a sample heating option, the technique can be used to study the conversion between different polymorphic forms.  Additionally, the instrumentation can be employed in applications where contaminant particles are present in a sample and their spectra can be compared with a spectral library of clearly defined substances.

Single crystal X-ray diffraction (SC-XRD, SCD) and powder diffraction (XRPD) allow ab initio determination of crystal structures. An important advantage of SC-XRD over XRPD is the fact that SC-XRD enables the determination of absolute structures thus making it the tool of choice to characterize enantiomers. XRPD however can also be used for structure analysis of disordered or amorphous materials to characterize short and long range order. Additionally, XRPD is used for phase identification and quantitative phase analysis of both crystalline and amorphous materials.