RESUMO
Two routes of the dehydration process of theophylline monohydrate have been proposed in this work from mid-frequency Raman difference spectra (MFRDS) results and experiments. MFRDS can establish short-range order correlations among various theophylline crystal forms. MFRDS results indicate that the short-range order of metastable Form III is most similar to that of monohydrate, which explains that Form III is the main dehydration products in the mild dehydration process. The phenomenon that unstable amorphous theophylline intermediate phase would appear during the dehydration process of theophylline monohydrate was confirmed indirectly by Powder X-ray Diffraction (PXRD) and optical microscope and reported in the previous reports, which could cause the nucleation of Form II, as MFRDS results indicate short-range order of amorphous solid dispersion of theophylline is most similar to that of Form II. MFRDS analysis shows the advantages in studying the phase transformation of small organic molecule crystals.
