Abstract. The objective of this article is to compare and contrast the international expectations associated with the model-independent similarity factor approach to comparing dissolution profiles. This comparison highlights globally divergent regulatory requirements to meet local dissolution similarity requirements. In effect, experiments customized to meet the current international regulatory expectations for dissolution and drug release unnecessarily increase manufacturing costs, hinder science and risk-based approaches, increase collective regulatory burden, reduce continuous improvement and innovation, and potentially delay patient access to urgently needed medication. Comparative assessment of regulatory differences in applying dissolution to demonstrate product similarity is crucial to reduce non-scientifically justified experiments and foster collaborative harmonization among global regulatory health authorities and the pharmaceutical industry.

Vibrationally mediated photodissociation is a two-photon technique for studying the spectroscopy and photodissociation dynamics of highly vibrationally excited molecules. In these experiments, a highly vibrationally excited t-butyl hydroperoxide (t-BuOOH) molecule, prepared by excitation in the region of the third overtone of the O–H stretching vibration (4νOH), absorbs a second photon to dissociate to OH and t-butoxy fragments, and laser induced fluorescence determines the quantum state populations of the OH fragment. Vibrational overtone excitation spectra, obtained by varying the vibrational overtone excitation wavelength while monitoring a single OH rotational state, are nearly identical to photoacoustic spectra. We fit the coarse structure in the vibrational overtone excitation spectrum in the region of the 4νOH transition and the photoacoustic spectra in the regions of the 5νOH and 6νOH transitions using a spectroscopic model of the interaction of the O–H bond stretching vibration with the torsional vibration about the O–O bond. This analysis determines the barrier to internal rotation of the O–H and t-butoxy groups through the trans configuration and its variation with vibrational excitation. The trans barrier in the ground vibrational state is 275 cm−1 and increases with vibrational excitation to 425, 575, and 680 cm−1 for t-BuOOH molecules with four, five, and six quanta of O–H stretching excitation, respectively. Comparison of the energy disposal in the vibrationally mediated photodissociation with that for direct photolysis at 376 nm, which adds the same amount of energy to the molecule, illustrates the unique dynamics that can occur when vibrational excitation precedes photodissociation. Single-photon photolysis produces fragments with large recoil velocities, while vibrationally mediated photodissociation produces slowly recoiling fragments having substantially more energy in internal excitation.

Vibrationally mediated photodissociation is a means of studying the spectroscopy of bound vibrational overtone states and of probing the electronic photodissociation dynamics of highly vibrationally excited molecules. In these experiments, a highly vibrationally excited hydrogen peroxide molecule prepared by initial excitation in the region of the third (4νOH) or fourth (5νOH) overtone of the OH stretching vibration absorbs an additional photon to dissociate to OH fragments whose individual quantum state populations are measured by laser induced fluorescence. This technique is a means of obtaining excitation spectra for bound highly vibrationally excited states and confirms the accuracy of a model that incorporates the role of the torsional vibration in the vibrational overtone spectroscopy. The photodissociation dynamics of highly vibrationally excited molecules are substantially different from those observed for dissociation by single photons of comparable or greater energy. Approximately 11% of the OH fragments formed in the vibrationally mediated photodissociation through 4νOH are vibrationally excited as compared to an unobservable amount (≤2%) in the single photon ultraviolet dissociation.

No abstract

No abstract