Purpose: There is a significant interest in quantification of low levels of crystalline content in amorphous formulations. The presence of crystalline phase in any amount has the potential to affect drug’s efficacy. Traditional analytical tools such as differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) fail to detect crystalline content when present below 5%. Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is shown to be a useful probe to quantitate low levels of crystalline content in amorphous dosage forms. Fluorine atom is present in a large range of pharmaceutical compounds and it makes an interesting NMR probe owing to its high gyromagnetic ratio and 100% isotopic abundance. In this contribution we describe the capability of 19F SSNMR spectroscopy to study low levels (<1%) of crystalline content in amorphous solid dispersions (ASDs) of pharmaceutical fluorinated compounds.
Methods: The dispersions along with pure active pharmaceutical ingredients (APIs) will be characterized exhaustively by SSNMR to get information on 19F spectra. Small amounts of crystalline materials will be doped into the dispersions for probing through 19F SSNMR spectroscopy. The proton relaxation time in the rotating frame (1HT1rho) filtering experiments will be done to filter out the amorphous signal and quantify the crystalline content. Phase behavior of dispersions will be studied from proton relaxation times detected via 19F nucleus to assess miscibility.
Results: The study is currently in progress. Hence, the preliminary results acquired with triamcinolone are discussed here. The dispersion of triamcinolone was formulated with hypromellose acetate succinate (HPMCAS) at 50% w/w drug loading via spray drying. The dispersion was doped with low levels of crystalline API. The 1HT1rho filtering experiments revealed the presence of polymorph B and extracted the crystalline phase at less than 0.3%.
Conclusion: The preliminary results strongly support the suitability of 19F SSNMR spectroscopy for characterizations of amorphous forms for crystalline content. Through these case studies, the intent is to highlight the versatility of 19F SSNMR spectroscopy for complex dosage forms as ASDs.