Validated Stability-Indicating Method for Alendronate Sodium Employing Zwitterionic Hydrophilic Interaction Chromatography Coupled with Charged Aerosol Detection

Alendronate sodium is widely used in the treatment of osteoporosis and Paget’s disease. The HPLC method development for alendronate sodium, in particular, is challenging owing to the absence of chromophoric group and its high polarity. In the present study, a short and simple isocratic method was developed involving hydrophilic interaction liquid chromatography, coupled with a charged aerosol detector. The developed method was validated according to the ICH Q2(R1) guideline and was successfully applied for the analysis of a marketed formulation containing the drug.

     

Formal synthesis of (+)-didemniserinolipid B

The formal synthesis of (+)-didemniserinolipid B is achieved using Weinreb reaction, Yadav’s chiral propargyl alcohol protocol and hydrolytic ketal formation as the key steps.     

Quantitation of memantine hydrochloride bulk drug and its tablet formulation using proton nuclear magnetic resonance spectrometry

The use of quantitative nuclear magnetic resonance spectrometry for the determination of non‐UV active memantine hydrochloride with relative simplicity and precision has been demonstrated in this study. The method was developed on a 500 MHz NMR instrument and was applied to determination of the drug in a tablet formulation. The analysis was performed by taking caffeine as an internal standard and D₂O as the NMR solvent. The signal of methyl protons of memantine hydrochloride appeared at 0.75 ppm (singlet) relative to the signal of caffeine (internal standard) at 3.13 ppm (singlet). The method was found to be linear (r² = 0.9989) in the drug concentration range of 0.025 to 0.80 mg/ml. The maximum relative standard deviation for accuracy and precision was <2. The limits of detection and quantification were 0.04 and 0.11 mg/ml, respectively. The robustness of the method was revealed by changing nine different parameters. The deviation for each parameter was also within the acceptable limits. The study highlighted possibility of direct determination of memantine hydrochloride in pure form and in its marketed tablet formulation by the use of quantitative NMR, without the need of derivatization, as is the requirement in HPLC studies. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis of New 2,4‐Diaryl‐6‐methyl‐5‐nitropyrimidines as Antibacterial and Antioxidant Agents

A new series of 2,4‐diaryl‐6‐methyl‐5‐nitropyrimidines ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i ) were synthesized in good yields by Suzuki–Miyaura coupling of 2,4‐dichloro‐6‐methyl‐5‐nitropyrimidine ( 3 ) with various aryl boronic esters ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i ) in the presence of 1,1′‐ bis(diphenylphosphino)ferrocene dichloropalladium(II) (Pd(dppf)₂Cl₂). Further, antibacterial and antioxidant properties were screened for the title compounds 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i . Most of the compounds possessed significant activity against Gram‐positive bacteria Staphylococcus aureus and Bacillus subtilis and Gram‐negative bacteria Escherichia coli and Klebsiella pneumoniae. The antioxidant activity of the title compounds showed significant antioxidant activity when compared with vitamin C.     

Kinetics and mechanistic details of bulk ZnO dissolution using a thiol–imidazole system

Oxide dissolution is important for metal extraction from ores and has become an attractive route for the preparation of inks for thin film solution deposition; however, oxide dissolution is often kinetically challenging. While binary “alkahest” systems comprised of thiols and N-donor species, such as amines, are known to dissolve a wide range of oxides, the mechanism of dissolution and identity of the resulting solute(s) remain unstudied. Here, we demonstrate facile dissolution of both bulk synthetic and natural mineral ZnO samples using an “alkahest” that operates via reaction with thiophenol and 1-methylimidazole (MeIm) to give a single, pseudotetrahedral Zn(SPh)₂(MeIm)₂ molecular solute identified by X-ray crystallography. The kinetics of ZnO dissolution were measured using solution ¹H NMR, and the reaction was found to be zero-order in the presence of excess ligands, with more electron withdrawing para-substituted thiophenols resulting in faster dissolution. A negative entropy of activation was measured by Eyring analysis, indicating associative ligand binding in, or prior to, the rate determining step. Combined experimental and computational surface binding studies on ZnO reveal stronger, irreversible thiophenol binding compared to MeIm, leading to a proposed dissolution mechanism initiated by thiol binding to the ZnO surface with the liberation of water, followed by alternating MeIm and thiolate ligand additions, and ultimately cleavage of the ligated zinc complex from the ZnO surface. Design rules garnered from the mechanistic insight provided by this study should inform the dissolution of other bulk oxides into inks for solution processed thin films.

Oxide dissolution is important for metal extraction from ores and has become an attractive route for the preparation of inks for thin film solution deposition; however, oxide dissolution is often kinetically challenging.     

Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening

Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3 + 2) cycloadditions with N-phenyl sydnone with the rate constant of up to 1.46 M^–1 s^–1. Most significantly, the sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions were predicted to be mutually orthogonal. This was validated experimentally and used for highly selective fluorescence labeling of two proteins simultaneously.     

Study of the forced degradation behavior of prasugrel hydrochloride by liquid chromatography with mass spectrometry and liquid chromatography with NMR detection and prediction of the toxicity of the characterized degradation products

Prasugrel was subjected to forced degradation studies under conditions of hydrolysis (acid, base, and neutral), photolysis, oxidation, and thermal stress. The drug showed liability in hydrolytic as well as oxidative conditions, resulting in a total of four degradation products. In order to characterize the latter, initially mass fragmentation pathway of the drug was established with the help of mass spectrometry/time‐of‐flight, multiple stage mass spectrometry and hydrogen/deuterium exchange data. The degradation products were then separated on a C₁₈ column using a stability‐indicating volatile buffer method, which was later extended to liquid chromatography‐mass spectrometry studies. The latter highlighted that three degradation products had the same molecular mass, while one was different. To characterize all, their mass fragmentation pathways were established in the same manner as the drug. Subsequently, liquid chromatography‐nuclear magnetic resonance (NMR) spectroscopy data were collected. Proton and correlation liquid chromatography with NMR spectroscopy studies highlighted existence of diastereomeric behavior in one pair of degradation products. Lastly, toxicity prediction by computer‐assisted technology (TOPKAT) and deductive estimation of risk from existing knowledge (DEREK) software were employed to assess in silico toxicity of the characterized degradation products.