Advancing Approaches in Detecting Polymorphism - Pharmaceutical Technology

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Advancing Approaches in Detecting Polymorphism
Identifying polymorphs is a crucial part of the drug-development process as researchers forward select methods to improve detection.


Pharmaceutical Technology



Figure 3
The problem with acetaminophen was the repeated failures of research groups to isolate the orthorhombic form using the method of slow evaporation from ethanol as described by Haisa et al. (3), explains Frampton. Eventually, it was discovered that the orthorhombic form could be produced from solution by using seeds of the orthorhombic modification that were isolated from melt-crystallized acetaminophen (7).

"It is clear that in this case, conventional solvent-screening techniques of the time would fail to produce any evidence of the less-stable orthorhombic form since it was only possible to produce seeds of the orthorhombic form under somewhat extreme conditions," says Frampton. "Given that the crystal structures of the two modifications were available, it was reasonably straightforward to identify the pure forms from their X-ray powder diffraction (XRPD) patterns (see Figures 3a and 3b). The form assignment from XRPD was subsequently confirmed by single-crystal X-ray analysis.


Figure 4
Sodium diclofenac. Sodium diclofenac (see Figure 4) is a nonsteroidal anti-inflammatory drug that shows polymorphism. The sodium salt of the drug is manufactured by Novartis as "Voltaren." Frampton says there are three known anhydrous crystal modifications of the free base: two monoclinic forms (C2/c, P21/c), and an orthorhombic form (Pcan) (8–10).

"Sodium diclofenac has also been shown to readily form stable hydrate phases when crystallized from aqueous miscible solvents," explains Frampton (11). "Although these hydrated materials are not technically polymorphic phases since they are solvates, they do present interesting solid-form challenges."


A decision framework for on polymorphism for generic drug applications
He explains that the current literature reports a sodium diclofenac pentahydrate phase that was derived from the results of a single crystal X-ray diffraction study (11). The pentahydrate phase was based on the crystalline asymmetric unit of the structural model containing two molecules of sodium diclofenac and 10 molecules of water in the monoclinic space group P21/m. The results of the structural investigation, however, showed that the solved structure had a disordered sodium-water linkage and a high overall crystallographic R factor of 7.06%.


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