Byrn offers several examples of techniques used to find polymorphs. In a study at Aptuit/SSCI, nabumetone was recrystallized
from a wide range of solvents under different conditions. About 250 experiments were performed, yielding Form I. When nabumetone
was recrystallized in capillaries, a procedure known to produce very high supersaturations, a new form was discovered in about
70 of 400 crystallizations. Analysis of these crystallization conditions shows that the appearance of the new form depends
on superaturation and quiescence and not on solvent content, Bryn explains.
In another study, SSCI/Aptuit compared the polymorphs formed in a common high-throughput technology with those from capillaries
and traditional crystallizations under a broad range of conditions. "It was clear that the plate crystallization technology,
which is commonly used in high-throughput polymorph screens, tends to overproduce one form relative to other methods," says
Byrn.
Other methods at work
Although XRPD is the most common technique used in the overall solid-state characterization of pharmaceutical materials, other
techniques are needed to understand the form, determine how it behaves under stress conditions, discern the relationship between
forms, and decide which form is suitable for development.
"The powder pattern will tell you if it is crystalline but will not provide critical information such as solvation state,
melting point, water uptake, solubility, and physical stability, for example," explains Byrn. "Thermal data such as differential
scanning calorimetry, thermogravimetry, and hot-stage microscopy are used to determine melting temperature, solvation state,
desolvation, and form changes upon drying. This information can be directly related to processing such as drying."
Gravimetric vapor sorption is used to measure water sorption and desorption, which can lead to environmental handling guidelines
to prevent hydrate formation or dehydration upon exposure to various relative humidity conditions. Other methods such as infrared,
Raman, and nuclear magnetic resonance (NMR) spectroscopies can often show specificity between forms that may be more difficult
to see with XRPD.
"These techniques, along with XRPD and others, are commonly used for quantitative solid-state method development to quantitate
the amount of different forms present in API or drug product or confirm that only one form is present. It is usually desired
to have only one form produced, but processing such as drying, milling, and granulation, can commonly lead to multiple forms,
indicating that an understanding of form changes during the process and better control of the process is needed,"explains
Byrn.
He points to recent advances in screening methodology using Raman microscopy to determine the presence of multiple forms in
the same crystallization vessel. "Additionally, NIR is finding some use as a tool for differentiating polymorphs during screening.
Finally, the developments of X-ray microscopy at Argonne National Laboratories [Argonne, IL] and other synchrotron sources
promises to increase our ability to detect solid forms in small samples."
Other spectroscopic methods may be used in detecting polymorphs. "Like infrared spectroscopy, where the absorption of infrared
energy is characteristic of a particular molecular vibration, the absorption of the radio-frequency radiation is characteristic
of the magnetic environment of the nuclei, explains SAFC-Pharmorphix's Frampton. When applied to solids, cross-polarization
magic-angle spinning solid-state nuclear magnetic resonance spectroscopy (CPMAS SS NMR) can give useful information regarding
the crystal structure and polymorphic form of the compound. It also can also reveal the degree of crystallinity of the sample
under investigation, he says. "Crystalline samples yield narrow lines as equivalent nuclei are in a constant magnetic environment
dictated by the crystal structure, whereas amorphous solids usually yield broader lines reflecting the range of environments
found in the solid. CPMAS SS NMR spectroscopy can also give valuable information on the crystalline asymmetric unit of the
crystal structure."
References
1. J. Bauer et al., "Ritonavir: An Extraordinary Example of Conformational Polymorphism," Pharm. Res. 18 (6), 859–866 (2001).
2. U. Griesser, "Relevance and Analysis of Polymorphism in Drug Development," presented at British Association of Crystal Growth Spring Meeting. Lancaster, UK, Apr. 4–6, 2006.
3. M. Haisa, S. Kashino, and H. Maeda, "The Orthorhombic Form of p-Hydroxyacetanilide," Acta Cryst. B30, 2510–2512 (1974).
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