Raman vibrational spectroscopy in the 300-3500 cm-1 range has long been a powerful tool in the pharmaceutical industry for characterizing solid-state drug formulations. The sub-300 cm-1 range is less well known due to past experimental limitations for reliably measuring the Raman scattered light at wavelengths very close to the Rayleigh peak. Another obstacle for the general use of Raman spectroscopy in the low-frequency region is that the interpretation of the spectral patterns is complicated due to their origins being tied to external lattice vibrations such as translations and rotations or to internal large-amplitude torsional motions, all of which are unique to the molecule and its solid form. There are no standardized characteristic group frequencies for low-frequency vibrational experimental spectra to be compared to for straightforward peak assignments. In this work, we focus on vibrations appearing in the 10 to 300 cm-1 range for crystalline diphenhydramine hydrochloride (the active ingredient in Benadryl®) and show that this region is rich with distinct features. The Raman spectrum is fully assigned using solid-state density functional theory to rigorously simulate the molecular structure, the crystal packing, the vibrational dynamics, and Raman scattering intensities of solid diphenhydramine hydrochloride. The quantum mechanical simulations show that the peaks in this region are primarily torsional vibrations with various phase relationships in the Z = 4 crystallographic unit cell, with the most intense features near 110 cm-1 being phenyl ring torsions. Raman data is presented of pure diphenhydramine hydrochloride, but also for commercial tablets showing that the low-frequency spectrum yields a strong spectral signature even in formulated products. The low-frequency Raman data is also compared to that acquired at high frequency and highlights the utility of the sub-300 cm-1 spectral range. Low-frequency Raman spectroscopy offers a compelling solution for profiling pure and formulated solid-state drugs.

Low-frequency Raman spectroscopy of pure and formulated diphenhydramine hydrochloride

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