ABSTRACT
Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.
Subject(s)
Atropine/chemistry , Diazepam/chemistry , Atropine/chemical synthesis , Diazepam/chemical synthesis , Green Chemistry Technology , Hydrogen-Ion Concentration , Solvents/chemistryABSTRACT
The overall study goal was to produce a microparticle formulation containing atropine sulfate for ocular administration with improved efficacy and lower side effects, compared with that of the standard marketed atropine solution. The objective was to prepare an atropine sulfate-loaded bovine serum albumin-chitosan microparticle that would have longer contact time on the eyes as well as better mydriatic and cycloplegic effect using a rabbit model. The microparticle formulation was prepared by method of spray-drying technique. The percent drug loading and encapsulation efficiency were assessed using a USP (I) dissolution apparatus. The particle sizes and zeta potential were determined using laser scattering technique and the surface morphology of the microparticles was determined using a scanning electron microscope. The product yield was calculated from relative amount of material used. In vitro cytotoxicity and uptake by human corneal epithelial cells were examined using AlamarBlue and confocal microscopy. The effects of the microparticle formulation on mydriasis in comparison with the marketed atropine sulfate solution were evaluated in rabbit eyes. The prepared microparticle formulation had ideal physicochemical characteristics for delivery into the eyes. The in vivo studies showed that the microparticles had superior effects on mydriasis in rabbits than the marketed solutions
Subject(s)
Atropine/chemical synthesis , Chitosan/chemical synthesis , Cornea , Drug Delivery Systems/methods , Microspheres , Serum Albumin, Bovine/chemical synthesis , Animals , Atropine/administration & dosage , Atropine/metabolism , Cattle , Cells, Cultured , Chemistry, Pharmaceutical , Chitosan/administration & dosage , Chitosan/metabolism , Cornea/drug effects , Cornea/metabolism , Eye/drug effects , Eye/metabolism , Humans , Mydriasis/drug therapy , Mydriasis/metabolism , Rabbits , Serum Albumin, Bovine/administration & dosage , Serum Albumin, Bovine/metabolismSubject(s)
Alkaloids/analysis , Tropanes/analysis , Alkaloids/chemical synthesis , Alkaloids/pharmacology , Atropine/analysis , Atropine/chemical synthesis , Atropine/pharmacology , Chemical Phenomena , Chemistry , Cocaine/analysis , Cocaine/chemical synthesis , Cocaine/pharmacology , Scopolamine/analysis , Scopolamine/chemical synthesis , Scopolamine/pharmacology , Stereoisomerism , Tropanes/chemical synthesis , Tropanes/pharmacologyABSTRACT
A new technically feasible method for synthesizing atropine is described. This method can also be applied to N-substituted nortropan- and granatan-3-oles. The quaternization of these basic tropic acid ester yields new substances which have a pharmacological profile different from that of atropine. The stereoselectivity of the quanternization reaction is discussed.
