Development and Validation of an In‐Line API Quantification Method Using AQbD Principles Based on UV‐Vis Spectroscopy to Monitor and Optimise Continuous Hot Melt Extrusion Process

open access journalA key principle of developing a new medicine is that quality should be built in, with a thorough understanding of the product and the manufacturing process supported by appropriate process controls. Quality by design principles that have been established for the development of drug products/substances can equally be applied to the development of analytical procedures. This paper presents the development and validation of a quantitative method to predict the concentration of piroxicam in Kollidon® VA 64 during hot melt extrusion using analytical quality by design principles. An analytical target profile was established for the piroxicam content and a novel in‐line analytical procedure was developed using predictive models based on UV‐Vis absorbance spectra collected during hot melt extrusion. Risks that impact the ability of the analytical procedure to measure piroxicam consistently were assessed using failure mode and effect analysis. The critical analytical attributes measured were colour (L* lightness, b* yellow to blue colour parameters—in‐process critical quality attributes) that are linked to the ability to measure the API content and transmittance. The method validation was based on the accuracy profile strategy and ICH Q2(R1) validation criteria. The accuracy profile obtained with two validation sets showed that the 95% β‐expectation tolerance limits for all piroxicam concentration levels analysed were within the combined trueness and precision acceptance limits set at ±5%. The method robustness was tested by evaluating the effects of screw speed (150–250 rpm) and feed rate (5–9 g/min) on piroxicam content around 15% w/w. In‐line UV‐Vis spectroscopy was shown to be a robust and practical PAT tool for monitoring the piroxicam content, a critical quality attribute in a pharmaceutical HME process

Space telescope and optical reverberation mapping project. IV. Anomalous behavior of the broad ultraviolet emission lines in NGC 5548

During an intensive Hubble Space Telescope (HST) Cosmic Origins Spectrograph (COS) UV monitoring campaign of the Seyfert 1 galaxy NGC 5548 performed from 2014 February to July, the normally highly correlated far UV continuum and broad emission line variations decorrelated for 60–70 days, starting 75 days after the first HST/ COS observation. Following this anomalous state, the flux and variability of the broad emission lines returned to a more normal state. This transient behavior, characterized by significant deficits in flux and equivalent width of the strong broad UV emission lines, is the first of its kind to be unambiguously identified in an active galactic nucleus reverberation mapping campaign. The largest corresponding emission line flux deficits occurred for the high ionization, collisionally excited lines C IV and Si IV(+O IV]), and also He II(+O III]), while the anomaly in Lyα was substantially smaller. This pattern of behavior indicates a depletion in the flux of photons with Eph > 54 eV relative to those near 13.6 eV. We suggest two plausible mechanisms for the observed behavior: (i) temporary obscuration of the ionizing continuum incident upon broad line region (BLR) clouds by a moving veil of material lying between the inner accretion disk and inner (BLR), perhaps resulting from an episodic ejection of material from the disk, or (ii) a temporary change in the intrinsic ionizing continuum spectral energy distribution resulting in a deficit of ionizing photons with energies >54 eV, possibly due to a transient restructuring of the Comptonizing atmosphere above the disk. Current evidence appears to favor the latter explanation

Space telescope and optical reverberation mapping project : III. optical continuum emission and broadband time delays in NGC 5548

We present ground-based optical photometric monitoring data for NGC 5548, part of an extended multiwavelength reverberation mapping campaign. The light curves have nearly daily cadence from 2014 January to July in nine filters (BVRI and ugriz). Combined with ultraviolet data from the Hubble Space Telescope and Swift, we confirm significant time delays between the continuum bands as a function of wavelength, extending the wavelength coverage from 1158 Å to the z band (~9160 Å). We find that the lags at wavelengths longer than the V band are equal to or greater than the lags of high-ionization-state emission lines (such as He II l1640 and l4686), suggesting that the continuum-emitting source is of a physical size comparable to the inner broad-line region (BLR). The trend of lag with wavelength is broadly consistent with the prediction for continuum reprocessing by an accretion disk with t μ l4 3. However, the lags also imply a disk radius that is 3 times larger than the prediction from standard thin-disk theory, assuming that the bolometric luminosity is 10% of the Eddington luminosity (L = 0.1LEdd). Using optical spectra from the Large Binocular Telescope, we estimate the bias of the interband continuum lags due to BLR emission observed in the filters. We find that the bias for filters with high levels of BLR contamination (~20%) can be important for the shortest continuum lagsand likely has a significant impact on the u and U bands owing to Balmer continuum emission

Space telescope and optical reverberation mapping project : III. optical continuum emission and broadband time delays in NGC 5548

We present ground-based optical photometric monitoring data for NGC 5548, part of an extended multiwavelength reverberation mapping campaign. The light curves have nearly daily cadence from 2014 January to July in nine filters (BVRI and ugriz). Combined with ultraviolet data from the Hubble Space Telescope and Swift, we confirm significant time delays between the continuum bands as a function of wavelength, extending the wavelength coverage from 1158 Å to the z band (~9160 Å). We find that the lags at wavelengths longer than the V band are equal to or greater than the lags of high-ionization-state emission lines (such as He II l1640 and l4686), suggesting that the continuum-emitting source is of a physical size comparable to the inner broad-line region (BLR). The trend of lag with wavelength is broadly consistent with the prediction for continuum reprocessing by an accretion disk with t μ l4 3. However, the lags also imply a disk radius that is 3 times larger than the prediction from standard thin-disk theory, assuming that the bolometric luminosity is 10% of the Eddington luminosity (L = 0.1LEdd). Using optical spectra from the Large Binocular Telescope, we estimate the bias of the interband continuum lags due to BLR emission observed in the filters. We find that the bias for filters with high levels of BLR contamination (~20%) can be important for the shortest continuum lagsand likely has a significant impact on the u and U bands owing to Balmer continuum emission

Space telescope and optical reverberation mapping project. IV. Anomalous behavior of the broad ultraviolet emission lines in NGC 5548

During an intensive Hubble Space Telescope (HST) Cosmic Origins Spectrograph (COS) UV monitoring campaign of the Seyfert 1 galaxy NGC 5548 performed from 2014 February to July, the normally highly correlated far UV continuum and broad emission line variations decorrelated for 60–70 days, starting 75 days after the first HST/ COS observation. Following this anomalous state, the flux and variability of the broad emission lines returned to a more normal state. This transient behavior, characterized by significant deficits in flux and equivalent width of the strong broad UV emission lines, is the first of its kind to be unambiguously identified in an active galactic nucleus reverberation mapping campaign. The largest corresponding emission line flux deficits occurred for the high ionization, collisionally excited lines C IV and Si IV(+O IV]), and also He II(+O III]), while the anomaly in Lyα was substantially smaller. This pattern of behavior indicates a depletion in the flux of photons with Eph > 54 eV relative to those near 13.6 eV. We suggest two plausible mechanisms for the observed behavior: (i) temporary obscuration of the ionizing continuum incident upon broad line region (BLR) clouds by a moving veil of material lying between the inner accretion disk and inner (BLR), perhaps resulting from an episodic ejection of material from the disk, or (ii) a temporary change in the intrinsic ionizing continuum spectral energy distribution resulting in a deficit of ionizing photons with energies >54 eV, possibly due to a transient restructuring of the Comptonizing atmosphere above the disk. Current evidence appears to favor the latter explanation