Organic Salts of Pharmaceutical Impurity p-Aminophenol.

The presence of impurities can drastically affect the efficacy and safety of pharmaceutical entities. p-Aminophenol (PAP) is one of the main impurities of paracetamol (PA) that can potentially show toxic effects such as maternal toxicity and nephrotoxicity. The removal of PAP from PA is challenging and difficult to achieve through regular crystallization approaches. In this regard, we report four new salts of PAP with salicylic acid (SA), oxalic acid (OX), l-tartaric acid (TA), and (1S)-(+)-10-camphorsulfonic acid (CSA). All the PAP salts were analyzed using single-crystal X-ray diffraction, powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. The presence of minute amounts of PAP in paracetamol solids gives a dark color to the product that was difficult to remove through crystallization. In our study, we found that the addition of small quantities of the aforementioned acids helps to remove PAP from PA during the filtration and washings. This shows that salt formation could be used to efficiently remove challenging impurities.

Plasticity in zwitterionic drugs: the bending properties of Pregabalin and Gabapentin and their hydrates.

The investigation of mechanical properties in molecular crystals is emerging as a novel area of interest in crystal engineering. Indeed, good mechanical properties are required to manufacture pharmaceutical and technologically relevant substances into usable products. In such endeavour, bendable single crystals help to correlate microscopic structure to macroscopic properties for potential design. The hydrate forms of two anticonvulsant zwitterionic drugs, Pregabalin and Gabapentin, are two examples of crystalline materials that show macroscopic plasticity. The direct comparison of these structures with those of their anhydrous counterparts, which are brittle, suggests that the presence of water is critical for plasticity. In contrast, structural features such as molecular packing and anisotropic distribution of strong and weak interactions seem less important.

Desymmetrization by Asymmetric Copper-Catalyzed Intramolecular C-H Insertion Reactions of α-Diazo-ß-oxosulfones.

Effective desymmetrization in copper-catalyzed intramolecular C-H insertion reactions of α-diazo-ß-oxosulfones in the formation of fused thiopyran dioxides is described for the first time. The use of a copper-bis(oxazoline)-NaBARF catalyst complex system leads to formation of the major thiopyran dioxide stereoisomer with up to 98:2 dr and up to 98% ee. The effect of varying the bis(oxazoline) ligand, copper salt, and site of C-H insertion on both diastereo- and enantioselectivities of these intramolecular C-H insertion reactions has been investigated. Similarly, desymmetrization in the formation of a fused cyclopentanone proceeds with up to 64% ee. These results represent the highest enantioselectivity reported to date in a copper-mediated desymmetrization through C-H insertion.

Synthesis of 1,2,5-oxathiazole-S-oxides by 1,3-dipolar cycloadditions of nitrile oxides to α-oxo sulfines.

Synthetic methodology for the generation of novel 1,2,5-oxathiazole-S-oxides from cycloaddition of nitrile oxide dipoles with α-oxo sulfines generated in situ via the α-sulfinyl carbenes derived from α-diazosulfoxides is described. Experimental evidence and mechanistic rationale for the unanticipated interconversion of the diastereomeric 1,2,5-oxathiazole-S-oxide cycloadducts are discussed. Notably, using rhodium acetate as a catalyst at 0 °C under traditional batch conditions led to the selective formation and isolation of the kinetic isomers, while, in contrast, using continuous flow thermolysis, optimal conditions for the synthesis and isolation of the thermodynamic isomers were established.

Exploring the Scope of Asymmetric Synthesis of ß-Hydroxy-γ-lactams via Noyori-type Reductions.

Enantio- and diastereoselective hydrogenation of ß-keto-γ-lactams with a ruthenium-BINAP catalyst, involving dynamic kinetic resolution, has been employed to provide a general, asymmetric approach to ß-hydroxy-γ-lactams, a structural motif common to several bioactive compounds. Full conversion to the desired ß-hydroxy-γ-lactams was achieved with high diastereoselectivity (up to >98% de) by addition of catalytic HCl and LiCl, while ß-branching of the ketone substituent demonstrated a pronounced effect on the modest to excellent enantioselectivity (up to 97% ee) obtained.

New polymorphs of curcumin.

Two new crystalline polymorphs and an amorphous phase of the active curcuminoid ingredient in turmeric are reported. Curcumin polymorph 2 has higher dissolution rate and better solubility than the known polymorph 1.