Indirect 1H-[13C] MRS of the human brain at 7 T using a 13C-birdcage coil and eight transmit-receive 1H-dipole antennas with a 32-channel 1H-receive array.

The neuronal tricarboxylic acid and glutamate/glutamine (Glu/Gln) cycles play important roles in brain function. These processes can be measured in vivo using dynamic 1H-[13C] MRS during administration of 13C-labeled glucose. Proton-observed carbon-edited (POCE) MRS enhances the signal-to-noise ratio (SNR) compared with direct 13C-MRS. Ultra-high field further boosts the SNR and increases spectral dispersion; however, even at 7 T, Glu and Gln 1H-resonances may overlap. Further gain can be obtained with selective POCE (selPOCE). Our aim was to create a setup for indirect dynamic 1H-[13C] MRS in the human brain at 7 T. A home-built non-shielded transmit-receive 13C-birdcage head coil with eight transmit-receive 1H-dipole antennas was used together with a 32-channel 1H-receive array. Electromagnetic simulations were carried out to ensure that acquisitions remained within local and global head SAR limits. POCE-MRS was performed using slice-selective excitation with semi-localization by adiabatic selective refocusing (sLASER) and stimulated echo acquisition mode (STEAM) localization, and selPOCE-MRS using STEAM. Sequences were tested in a phantom containing non-enriched Glu and Gln, and in three healthy volunteers during uniformly labeled 13C-glucose infusions. In one subject the voxel position was alternated between bi-frontal and bi-occipital placement within one session. [4-13C]Glu-H4 and [4-13C]Gln-H4 signals could be separately detected using both STEAM-POCE and STEAM-selPOCE in the phantom. In vivo, [4,5-13C]Glx could be detected using both sLASER-POCE and STEAM-POCE, with similar sensitivities, but [4,5-13C]Glu and [4,5-13C]Gln signals could not be completely resolved. STEAM-POCE was alternately performed bi-frontal and bi-occipital within a single session without repositioning of the subject, yielding similar results. With STEAM-selPOCE, [4,5-13C]Glu and [4,5-13C]Gln could be clearly separated. We have shown that with our setup indirect dynamic 1H-[13C] MRS at 7 T is feasible in different locations in the brain within one session, and by using STEAM-selPOCE it is possible to separate Glu from Gln in vivo while obtaining high quality spectra.

Effect of basket mesh size on the hydrodynamics of a partially filled (500 mL) USP rotating basket dissolution testing Apparatus 1.

The USP Rotating Basket Dissolution Testing Apparatus 1 is listed in the USP as one of the tools to assess dissolution of oral solid dosage forms. Baskets of different mesh sizes can be used to differentiate between dissolution profiles of different formulations. Here, we used Particle Image Velocimetry (PIV) to study the hydrodynamics of the USP Apparatus 1 using baskets with different mesh openings (10-, 20- and 40-mesh) revolving at 100 rpm, when the vessel was filled with 500 mL. The velocity profiles throughout the liquid were found to vary significantly using baskets of different mesh sizes, typically increasing with increased size of the opening of the basket mesh, especially for axial and radial velocities. This, in turn, resulted in a significantly different flow rate through the basket, which can be expected to significantly impact the dissolution rate of the drug product. A comparison between the results of this work with those of a previous study with a 900-mL fill volume (Sirasitthichoke et al., Intern. J. Pharmaceutics, 2021, 607: 120976), shows that although the hydrodynamics in the USP Apparatus 1 changed with fill level in the vessel, the flow rate through the basket was not significantly affected. This implies that tablets dissolving in the two systems would experience similar tablet-liquid medium mass transfer coefficients, and therefore similar initial dissolution rates, but different dissolution profiles because of the difference in volume.

Influence of basket mesh size on the hydrodynamics in the USP rotating basket dissolution testing Apparatus 1.

The USP Apparatus 1 (rotating basket), typically used to assess drug product reproducibility and evaluate oral solid dosage forms performance, consists of a cylindrical glass vessel with a hemispherical bottom and a wire basket rotating at constant speed. Baskets with different wire openings can be used in alternative to the standard mesh opening (40-mesh) in order to discriminate between drug formulations during early stage of drug product development. Any changes introduced by different basket geometries can potentially and significantly impact the system hydrodynamics and cause variability of results, thus affecting product quality. In this work, Particle Image Velocimetry (PIV) was used to experimentally quantify the velocity distribution in the USP rotating basket Apparatus 1 using baskets of different mesh sizes (10-, 20-, and 40-mesh size) under the typical operating conditions described in dissolution testing procedures. Similar flow patterns were observed in all cases. However, the radial and axial velocities in the USP Apparatus 1 generally increased with increasingly larger openings of the basket mesh. Increasing the basket agitation speed also resulted in an overall increase in the velocities, especially below in the innermost core region below the basket, where drug fragments typically reside. More importantly, the flow entering and leaving the baskets was quantified from the velocity profiles in the immediate vicinity of the baskets. It was found that the flow increased significantly with increasingly larger mesh openings, which can, in turn, promote faster dissolution of the oral solid dosage forms, thus affecting drug dissolution profiles. Hence, the selection of the basket mesh size must be carefully considered during drug product development.

Computational hydrodynamic comparison of a mini vessel and a USP 2 dissolution testing system to predict the dynamic operating conditions for similarity of dissolution performance.

The hydrodynamic characteristics of a mini vessel and a USP 2 dissolution testing system were obtained and compared to predict the tablet-liquid mass transfer coefficient from velocity distributions near the tablet and establish the dynamic operating conditions under which dissolution in mini vessels could be conducted to generate concentration profiles similar to those in the USP 2. Velocity profiles were obtained experimentally using Particle Image Velocimetry (PIV). Computational Fluid Dynamics (CFD) was used to predict the velocity distribution and strain rate around a model tablet. A CFD-based mass transfer model was also developed. When plotted against strain rate, the predicted tablet-liquid mass transfer coefficient was found to be independent of the system where it was obtained, implying that a tablet would dissolve at the same rate in both systems provided that the concentration gradient between the tablet surface and the bulk is the same, the tablet surface area per unit liquid volume is identical, and the two systems are operated at the appropriate agitation speeds specified in this work. The results of this work will help dissolution scientists operate mini vessels so as to predict the dissolution profiles in the USP 2, especially during the early stages of drug development.

In vitro-in vivo correlation strategy applied to an immediate-release solid oral dosage form with a biopharmaceutical classification system IV compound case study.

The ability to predict in vivo response of an oral dosage form based on an in vitro technique has been a sought after goal of the pharmaceutical scientist. Dissolution testing that demonstrates discrimination to various critical formulations or process attributes provides a sensitive quality check that may be representative or may be overpredictive of potential in vivo changes. Dissolution methodology with an established in vitro-in vivo relationship or correlation may provide the desired in vivo predictability. To establish this in vitro-in vivo link, a clinical study must be performed. In this article, recommendations are given in the selection of batches for the clinical study followed by potential outcome scenarios. The investigation of a Level C in vitro-in vivo correlation (IVIVC), which is the most common correlation for immediate-release oral dosage forms, is presented. Lastly, an IVIVC case study involving a biopharmaceutical classification system class IV compound is presented encompassing this strategy and techniques.

Dissolution of prednisone tablets in the presence of an arch-shaped fiber optic probe in a USP dissolution testing apparatus 2.

During dissolution testing of solid dosage forms in the United States Pharmacopoeia (USP) Apparatus 2, samples are manually withdrawn from the medium in the vessel prior to the analysis. Probes permanently inserted in the medium can automate the sampling process but can also alter the system's hydrodynamics, possibly resulting in different dissolution-testing results. In this work, dissolution tests were conducted in a USP Apparatus 2 with and without an arch-shaped fiber optic probe using prednisone tablets fixed at nine different locations on the vessel bottom. The resulting dissolution profiles were compared using statistical tools. Dissolution rates obtained with the probe were typically higher than those obtained without the probe. The magnitude of the difference between dissolution profiles depended on the tablet location: Larger differences were observed with tablets located immediately downstream of the probe. The differences in dissolution profiles were generally small enough to satisfy the US Food and Drug Administration criteria (f1 and f2 values), although a paired t-test [P(t-test)] indicated that most of the profiles were statistically different [P(t-test) <0.05]. The hydrodynamic effects generated by the arch-shaped fiber optic probe resulted in detectable differences in the dissolution profiles, which, although limited, were clearly measurable and could introduce variations in test results.