Resonant ion-dip infrared spectra of C 6 H 6-H 2 O and C 6 H 6-HOD have been recorded in the OH stretch fundamental region. The spectra provide further evidence for the unique, large-amplitude motions present in these hydrogen-bonded complexes. In C 6 H 6-H 2 O, transitions out of the lowest ortho ͑⌸͒ and para ͑⌺͒ ground state levels are observed. A transition at 3634 cm Ϫ1 is assigned as an unresolved pair of parallel transitions ͑⌺→⌺ and ⌸→⌸͒ involving the symmetric stretch fundamental ͑at 3657 cm Ϫ1 in free H 2 O͒. In the antisymmetric stretch region, transitions at 3713, 3748, and 3774 cm Ϫ1 are assigned as ⌸→⌺, ⌺→⌸, and ⌸→⌬ transitions, respectively. The spacing of the transitions is consistent with nearly free internal rotation of H 2 O about benzene's sixfold axis in both ground and vibrationally excited states. The intensities of combination bands depends critically on the mixing of some local mode character into the symmetric and antisymmetric stretches at asymmetric positions of H 2 O on benzene. Surprisingly, in C 6 H 6-HOD, five transitions are observed in the OH stretch region, all arising from the ground state zero point level. Even more unusual, the higher-energy combination bands are many times stronger than the OH stretch fundamental. The local mode OH stretch has components both parallel and perpendicular to benzene's sixfold axis, leading to strong parallel and perpendicular transitions in the spectrum. A two-dimensional model involving free internal rotation and torsion of HOD in its plane is used to account for the qualitative appearance of the spectrum. The form of the OH(vϭ0) and OH(vϭ1) torsional potentials which reproduce the qualitative features of the spectrum are slightly asymmetric, double-minimum potentials with large-amplitude excursions for HOD over nearly 180°.
A near-infrared (NIR) calibration was developed using an efficient offline approach to enable a quantitative partial least-squares (PLS) chemometric model to measure and monitor the concentration of active pharmaceutical ingredients (API) in powder blends in the feed frame (FF) of a tablet press. The approach leveraged an offline "feed frame table," which was designed to mimic the full process from a NIR measurement perspective, thereby facilitating a more robust model by allowing more sources of variability to be included in the calibration by minimizing the consumption of API and other raw materials. The design of experiment (DOE) for the calibration was established by an initial risk assessment and included anticipated variability from factors related to formulation, process, environment, and instrumentation. A test set collected on the feed frame table was used to refine the PLS model. Additional fully independent test sets collected from the continuous drug product manufacturing process not only demonstrated the accuracy and precision of the model but also illustrated its robustness to material variability and process variability including mass flow rate and feed frame paddle speed. Further, it demonstrated that a calibration can be generated on the offline feed frame table and then successfully implemented on the full process equipment in a robust manner. Additional benefits of using the feed frame table include streamline model monitoring and maintenance activities in a manufacturing setting. The real-time monitoring enabled by this offline calibration approach can be useful as a key component of the control strategy for continuous manufacturing processes for drug products, including detecting special cause variations such as transient disturbances and enabling product collection/rejection based upon predetermined concentration limits, and may play an important role in enabling real-time release testing (RTRt) for manufactured pharmaceutical products.
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