Low-frequency shift dispersive Raman spectroscopy for the analysis of respirable dosage forms

A high performance Raman system equipped with a CCD (charged coupled device) sensor and recently developed optical filter technology is described. It provides high sensitivity, high resolution, and access to low-frequency vibrations enabling resolution of spectral features due to lattice vibrational modes and internal vibrational modes, greatly improving the ability to detect small changes due to variations in the three dimensional molecular arrangement, e.g., during loss of crystallinity. Applications to solid state analysis, such as solid phase identification and differentiation of glycopyrronium bromide and formoterol fumarate in pharmaceutical powders, and identification of active pharmaceutical ingredients, e.g., salmeterol xinafoate, fluticasone propionate, mometasone furoate, and salbutamol sulphate, as well as excipients, e.g., amino acids, in different formulations, are presented. For the first time, low-frequency shift Raman spectra of mannitol polymorphs were measured and used for solid phase identification. Unambiguous identification of two similar bronchodilator metered dose inhalers, Ventolin(®) HFA and Airomir(®), was accomplished. The low-frequency shift Raman signals can be used for the analysis of crystallinity of small samples (<5mg) of respiratory dosage forms in a multi-component formulation matrix containing less than 3% by weight of the component of interest.