Non-Invasive, Continuous, Quantitative Detection of Solvent Content in Vacuum Tray Drying.

A non-invasive capacitance instrument was embedded in the base of a vacuum-drying tray to monitor continuously the residual amount of solvent left in a pharmaceutical powder. Proof of concept was validated with Microcrystalline Cellulose laced with water, as well as water/acetone mixtures absorbed in a spray-dried Copovidone powder. To illustrate the role of impermeability of the base, we derive a model of vapor sorption that reveals the existence of a kinetic limit when solids are thinly spread, and a diffusion limit with greatly diminished effective diffusivity at large powder thickness. By monitoring the residual solvent content of powders, this new in situ technique offers advantages over indirect methods like mass spectrometry of vapor effluents, but without complications associated with probe fouling. To prescribe design guidelines and interpret signals, we model the electric field shed by the probe when a powder holds variable solvent mass fraction in the vertical direction.

Continuous Twin-Screw wet granulation process with In-Barrel drying and NIR setup for Real-Time Moisture Monitoring.

The purpose of this study was to evaluate if wet granule formation and drying could take place in a single operation by utilizing in-barrel drying. The drying kinetics of the formulation were studied in order to select appropriate processing parameters and assess feasibility with short residence times in the extruder. The 18-mm extruder was operated in a 40:1 L:D ratio with 8 zones. The first two zones were used for material feeding and wet granule formation and the remaining zones were used for drying at elevated temperature. The impact of screw configuration as well as screw speed, feed rate, and residence time were all studied to optimize the drying process. Due to limitations of temperature and residence time, vacuum was added to enable sufficient drying. In-line NIR spectroscopy was incorporated into the twin-screw wet granulation (TSWG) process to monitor the moisture content of wet granules in real-time. The set-up was optimized and a predictive model was developed for future experiments. This study demonstrated the success of this technique on a pilot-scale (18-mm) extruder for the first time. Granules were formed and dried to a target loss on drying (LOD) of less than 2 % at moderate temperatures (100 °C - 110 °C) with one single operation. Streamlining wet granulation and drying into one unit operation can have a profound impact on pharmaceutical manufacturing reducing time, footprint, and environmental exposure due to reduced product transfers.

Identification of ortho-Substituted Benzoic Acid/Ester Derivatives via the Gas-Phase Neighboring Group Participation Effect in (+)-ESI High Resolution Mass Spectrometry.

Benzoic acid/ester/amide derivatives are common moieties in pharmaceutical compounds and present a challenge in positional isomer identification by traditional tandem mass spectrometric analysis. A method is presented for exploiting the gas-phase neighboring group participation (NGP) effect to differentiate ortho-substituted benzoic acid/ester derivatives with high resolution mass spectrometry (HRMS1). Significant water/alcohol loss (>30% abundance in MS1 spectra) was observed for ortho-substituted nucleophilic groups; these fragment peaks are not observable for the corresponding para and meta-substituted analogs. Experiments were also extended to the analysis of two intermediates in the synthesis of suvorexant (Belsomra) with additional analysis conducted with nuclear magnetic resonance (NMR), density functional theory (DFT), and ion mobility spectrometry-mass spectrometry (IMS-MS) studies. Significant water/alcohol loss was also observed for 1-substituted 1, 2, 3-triazoles but not for the isomeric 2-substituted 1, 2, 3-triazole analogs. IMS-MS, NMR, and DFT studies were conducted to show that the preferred orientation of the 2-substituted triazole rotamer was away from the electrophilic center of the reaction, whereas the 1-subtituted triazole was oriented in close proximity to the center. Abundance of NGP product was determined to be a product of three factors: (1) proton affinity of the nucleophilic group; (2) steric impact of the nucleophile; and (3) proximity of the nucleophile to carboxylic acid/ester functional groups. Graphical Abstract ᅟ.

Mapping the dark space of chemical reactions with extended nanomole synthesis and MALDI-TOF MS.

Understanding the practical limitations of chemical reactions is critically important for efficiently planning the synthesis of compounds in pharmaceutical, agrochemical, and specialty chemical research and development. However, literature reports of the scope of new reactions are often cursory and biased toward successful results, severely limiting the ability to predict reaction outcomes for untested substrates. We herein illustrate strategies for carrying out large-scale surveys of chemical reactivity by using a material-sparing nanomole-scale automated synthesis platform with greatly expanded synthetic scope combined with ultrahigh-throughput matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS).

Iron(III)-Mediated Oxidative Degradation on the Benzylic Carbon of Drug Molecules in the Absence of Initiating Peroxides.

Metal ions play an important role in oxidative drug degradation. One of the most ubiquitous metal ion impurities in excipients and buffers is Fe(III). In the field of oxidative drug degradation chemistry, the role of Fe(III) has been primarily discussed in terms of its effect in reaction with trace hydroperoxide impurities. However, the role of Fe(III) acting as a direct oxidant of drug molecules, which could operate in the absence of any hydroperoxide impurities, is less common. This work focuses on Fe(III)-induced oxidation of some aromatic drug molecules/drug fragments containing benzylic C-H bonds in the absence of initiating peroxides. Alcohol and ketone degradates are formed at the benzylic carbon atom. The formation of a π-stabilized cation radical is postulated as the key intermediate for the downstream oxidation. Implications are briefly discussed.