Statistical data treatment for residence time distribution studies in pharmaceutical manufacturing.

Residence time distribution (RTD) method has been widely used in the pharmaceutical manufacturing for understanding powder dynamics within unit operations and continuous integrated manufacturing lines. The dynamics thus captured is then used to develop predictive models for unit operations and important RTD-based applications ensuring product quality assurance. Despite thorough efforts in tracer selection, data acquisition, and calibration model development to obtain tracer concentration profiles for RTD studies, there can exist significant noise in these profiles. This noise can make it challenging to identify the underlying signal and get a representative RTD of the system under study. Such concerns have previously indicated the importance of noise handling for RTD measurements in literature. However, the literature does not provide sufficient information on noise handling or data treatment strategies for RTD studies. To this end, we investigate the impact of varying levels of noise using different tracers on measurement of RTD profile and its applications. We quantify the impact of different denoising methods (time and frequency averaging methods). Through this investigation, we see that Savitsky Golay filtering turns out to a good method for denoising RTD profiles despite varying noise levels. The investigation is performed such that the key features of the RTD profile (which are important for RTD based applications) are preserved. Subsequently, we also investigate the impact of denoising on RTD-based applications such as out-of-specification (OOS) analysis and RTD modeling. The results show that the degree of noise levels considered in this work do not significantly impact the RTD-based applications.

Palladium-Catalyzed Direct C-H Glycosylation of Free (N-H) Indole and Tryptophan by Norbornene-Mediated Regioselective C-H Activation.

We describe the palladium-catalyzed direct C-H glycosylation of free N-H indole or tryptophan for the stereoselective synthesis of 2-glycosylindoles and tryptophan-C-glycosides. This reaction relies on the ortho-directing transient mediator norbornene, which underwent regioselective C-H functionalization at the indole or tryptophan ring, providing high chemoselectivity. This method offers a more straightforward, step-economical, and cost-effective route to construct C-glycosides. The gram-scale amenable building blocks can be further functionalized at C3 and N-H, displaying the robustness of present method.

Homogeneous distribution of phosphor particles inside resin using a vertical vibration method for efficient laser-based white light illumination.

We report what we believe to be an innovative method for the homogeneous distribution of phosphor particles inside the optical resin-based layer using a vertical vibrational technique for efficient laser-based white light illumination. In this method, single-stage vibration energy was efficiently used against phosphor sedimentation with the help of a mechanical vibrator system. The vertical vibrational energy was transferred to negate the downward gravitational effect acting on each phosphor particle. Therefore, the phosphor particles inside the layer were stable and uniformly distributed from the initial to final drying stages, creating approximate refractive index homogeneity inside the medium. The sedimentation problem was resolved, and all the optical parameters to support this method were properly analyzed and found to be stable and suitable for laser-based illumination applications.

Tris(pentafluorophenyl)borane-Catalyzed Stereoselective C-Glycosylation of Indoles with Glycosyl Trichloroacetimidates: Access to 3-Indolyl-C-glycosides.

An efficient and highly regioselective method for the synthesis of 3-indolyl-C-glycosides has been developed through coupling of glycosyl trichloroacetimidates with a wide range of substituted indoles in the presence of catalytic amounts of B(C6F5)3 within a few minutes. This methodology has a wide scope of substrates under mild reaction conditions and provides exclusively ß-stereoselective 3-indolyl-C-glycosides in 64-87% yields.

Intramolecular 6-exo-dig Post-Ugi Cyclization of N-Substituted 2-Alkynamides: Direct Access to Functionalized Morpholinone Glycoconjugates.

We herein report a chemo- and regioselective 6-exo-dig catalytic cyclization of Ugi adducts N-substituted 2-alkynamides to access functionalized morpholinone glycoconjugates in the presence of triphenylphosphine. This array allows an interesting multicomponent access to a library of functionalized morpholinone glycoconjugates under mild reaction conditions with regeneration of catalyst triphenylphosphine, supported by 31P nuclear magnetic resonance studies. Density functional theory shows the 6-exo-dig oxocyclization pathway is preferred, which supports our experimental observation.

The strategic use of para-quinone methides to access synthetically challenging and chemoselective α,α'-diarylmethyl N-glycosides from unprotected carbohydrate amines.

Reported herein is a practical route to access synthetically challenging and chemoselective α,α'-diarylmethyl N-glycosides via Sc(OTf)3-catalyzed 1,6-conjugate addition of amino sugars with para-quinone methides (p-QMs). The reactions proceed smoothly without a base and under mild reaction conditions with a broad substrate scope and moderate to good yields.

An eco-friendly N-benzoylglycine/thiourea cooperative catalyzed stereoselective synthesis of ß-L-rhamnopyranosides.

A new practical utility for ß-stereoselective L-rhamnopyranosylations are conducted using rhamnosyl trichloroacetimidate donors in the presence of N-benzoylglycine/thiourea cooperative catalysis. This method represents the first instance where amino acid derivative N-benzoylglycine is used as a catalyst for ß-L-rhamnopyranosylations. This method represents the first instance where environmentally benign amino acid derivative, such as N-benzoylglycine which is reported as less toxic and can be used as efficient catalyst for smooth transformation under eco friendly conditions. On the other hand ß-stereoselectivity of rhamnosyl trichloroacetimidate donors protected with O-picoloyl groups at remote positions (C-2 and C-3) has been investigated while the glycosylation reactions of 2-O-picoloyl group substituted l-rhamnosyl donor displays predominant ß-stereoselectivity. Reaction proceeded smoothly with moderate to high yield under mild reaction conditions at room temperature with 10 mol% catalyst loadings and tolerant of a wide range of glycoside acceptors.

Laser-line-driven phosphor-converted extended white light source with uniform illumination.

We report the development of laser-driven extended white light source designed as a light sheet for general illumination. This light sheet is made of two large diffused glass plates. A Ce:YAG phosphor layer was coated and sandwiched between the two diffusing sheets. The blue laser beam was first converted into a uniform laser line using a cylindrical lens, and a laser line was made incident parallel to the edges of the designed light sheet. The blue photons are waveguided inside the glass sheet via total internal reflection and scattered from the diffused surface. Some of the blue photons are absorbed by the Ce:YAG phosphor and down-converted into yellow light of longer wavelength. The white light emanating from the diffuse surface is the combined effect of yellow light with original blue light. The developed light sheet with the combination of laser line generation and total internal reflection is a unique and low-cost method for generating white light with uniform illumination. The details of the development of the light sheet and laser line generation are described. The experimental parameters, such as correlated color temperature and color coordinates, are reported.

Synthesis of Structurally Diverse Substituted Aziridinyl Glycoconjugates via Base-Mediated One-Pot Post-Ugi Cyclization.

The base-promoted intramolecular cyclization of Ugi-azide adduct has been demonstrated for the synthesis of highly substituted aziridinyl glycoconjugates in one pot. The reactions are scalable and efficient and have an operationally simple broad substrate scope. To gain insight into the mechanism of aziridine formation, DFT and control experiments show that the cyclization of the aziridine glycoconjugate pathway was preferred, as it proceeds with a low activation energy barrier (0.57 kcal mol-1), which supports our experimental observation.

Improvement of tablet coating uniformity using a quality by design approach.

A combination of analytical and statistical methods is used to improve a tablet coating process guided by quality by design (QbD) principles. A solid dosage form product was found to intermittently exhibit bad taste. A suspected cause was the variability in coating thickness which could lead to the subject tasting the active ingredient in some tablets. A number of samples were analyzed using a laser-induced breakdown spectroscopy (LIBS)-based analytical method, and it was found that the main variability component was the tablet-to-tablet variability within a lot. Hence, it was inferred that the coating process (performed in a perforated rotating pan) required optimization. A set of designed experiments along with response surface modeling and kriging method were used to arrive at an optimal set of operating conditions. Effects of the amount of coating imparted, spray rate, pan rotation speed, and spray temperature were characterized. The results were quantified in terms of the relative standard deviation of tablet-averaged LIBS score and a coating variability index which was the ratio of the standard deviation of the tablet-averaged LIBS score and the weight gain of the tablets. The data-driven models developed based on the designed experiments predicted that the minimum value of this index would be obtained for a 6% weight gain for a pan operating at the highest speed at the maximum fill level while using the lowest spraying rate and temperature from the chosen parametric space. This systematic application of the QbD-based method resulted in an enhanced process understanding and reducing the coating variability by more than half.