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 5
"We were prompted to reinterpret the single-crystal X-ray data after repeated thermogravimetric analysis (TGA) and Karl Fischer (KF) measurements indicated that the water content was reproducibly always slightly less (e.g., 21.48% and 21.0% from TGA and KF, respectively) than the theoretical content of 22.07% based a fully hydrated pentahydrate structure," says Frampton. These values equate to 4.83 and 4.69 moles of water respectively. Figure 5 shows an example TGA.

"Redetermination of the single-crystal X-ray structure reveals that the structure contains only a pseudomirror plane, and as such, the true space group of the structure is P21 and not P21/m. The asymmetric unit of the structure now contains four molecules of sodium diclofenac and 19 molecules of water, yielding an overall stoichiometry of a 4.75 hydrate," says Frampton.

All the atoms in the crystalline asymmetric unit are now fully ordered, and all hydrogen atoms, including those on the 19 water molecules, were located in the Fourier difference maps and were included within the refinement. The theoretical water content for a fully hydrated 4.75 hydrate is 21.19%, which is in accord with the other analytical data, Frampton explains. The structure now has a much-improved crystallographic R factor of 3.04%.

"It is important to stress in this case that the correct result was only obtained after the consideration of all the analytical data and that we should not be surprised by the noninteger value of the water content," he says. A further hydrated species, a triclinic 3.50 hydrate, was also identified in the study.

Andolast. Andolast, an NCE being developed by Rottapharm S.P.A. (Monza, Italy) for certain respiratory disorders, shows the challenge in polymorph screening and the potential opportunities for discovering and patenting a polymorph.

Andolast is administered as a dry powder for inhalation. "When a product is used in the form of micronized powder for the treatment of respiratory tract disease, the particle-size distribution (PSD) of the inhaled drug is crucial to its performance," explains Markus von Raumer, product manager of the solid-state development unit at Solvias AG (Basel, Switzerland). "Physical chemical characteristics play a fundamental role in the case of inhaled drugs not only for the solubility issues shared with oral drugs but also due to the aggregation phenomena, which can impact negatively the performance of the powder, ultimately affecting its pharmacological activity," he says (12).

During the early pharmaceutical development of andolast, deviations in the consistency of the API's physical chemical characteristics were observed, and a review of the solid-state issues was required, explains von Raumer. These deviations related to: batch-to-batch PSD variability (which affected released fraction and therefore drug efficacy); batch-to-batch variability in hygroscopicity (which affected released fraction and hence manufacturability); and batch-to-batch variability in chemical–physical characteristics that reflected in flow and blend properties (which affected manufacturability and therefore product cost).

Analysis of the complete batch history, combined with fresh physicochemical analysis of key samples, revealed several issues. Deviations occurred independently upon the supplier, upon the batch scale, and upon the batch purity. For all batches, the same chemistry and the same isolation procedure was used.

"Sequential to compilation of historic data, the crystallization conditions and a crystallization process investigation was carried out," says von Raumer. The screening was based upon product precipitation from several water-miscible solvents changing concentration, water content, and temperature. Phase-equilibration experiments were carried out as well. In these experiments, material from the previous batches was slurried in different solvents, at different water concentrations, different temperatures, and for different times. Crystallization from different media gave different solids, in terms of XRPD, Fourier transform (FT)-Raman spectra, and hygroscopicity.


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