Mechanochemical Preparation of Active Pharmaceutical Ingredients Monitored by In Situ Raman Spectroscopy

Abstract

The mechanochemical preparation of silver sulfadiazine and dantrolene, two marketed active pharmaceutical ingredients, was investigated by in situ Raman spectroscopy. For the first time, the mechanochemical transformations involving highly fluorescent compounds could be studied in situ with a high-resolution Raman system combined with a unique suitable Raman probe. Moreover, the kinetic features of the mechanochemical process were examined by a mathematical model allowing to describe the chemical changes under mechanical stress. This approach is promising both to broaden the scope of Raman in situ investigations that would otherwise be impossible and for process optimization at any scale.

Sustainability Assessment of Mechanochemistry by Using the Twelve Principles of Green Chemistry

“…This long sought-after goal in chemistry has been partially addressed by mechanochemistry in the growing number of publications focused on the synthesis of active pharmaceutical ingredients (APIs) and pharmaceutical solid forms such as polymorphs, cocrystals, salts and salt cocrystals; an area often named as medicinal mechanochemistry. [62][63][64] Most of these studies have been focused on developing alternative synthetic routes to marketed APIs, for which the benefit-risk balance was already known, [9b, 65,66] and therefore the mechanochemical procedures were preordained to provide products previously regarded as safe. However, in some cases, newly mechanosynthesized molecules and pharmaceutical solid forms have been studied to determine their biological activity, [67][68][69][70][71][72] toxicity, [73,74] and stability.…”

“…Most of these studies have been focused on developing alternative synthetic routes to marketed APIs, for which the benefit‐risk balance was already known, [9b,65,66] and therefore the mechanochemical procedures were preordained to provide products previously regarded as safe. However, in some cases, newly mechanosynthesized molecules and pharmaceutical solid forms have been studied to determine their biological activity, [67–72] toxicity, [73,74] and stability [75–77] .…”

Liquid‐Assisted Grinding Mechanochemistry in the Synthesis of Pharmaceuticals

“…Complementary to the PXRD monitoring which is sensitive to bulk crystalline species and limited to the determination of the amount of the amorphous phase, Raman spectroscopy does not require a sample to be crystalline. Very recently, a mechanochemical preparation of silver sulfadiazine monitored by in situ Raman spectroscopy was reported by Colacino et.al (Scheme 8b) [66] . While addition of aqueous ammonia (LAGs) was necessary for preparation of metallodrug silver sulfadiazine, too much aqueous ammonia may stabilize the silver centre and slow down the transformation.…”

“…Very recently, a mechanochemical preparation of silver sulfadiazine monitored by in situ Raman spectroscopy was reported by Colacino et.al (Scheme 8b). [66] While addition of aqueous ammonia (LAGs) was necessary for preparation of metallodrug silver sulfadiazine, too much aqueous ammonia may stabilize the silver centre and slow down the transformation.…”

From operando Raman mechanochemistry to "NMR crystallography": understanding the structures and interconversion of Zn-terephthalate networks using selective 17O-labelling.

“…With the aim of directly probing the binding modes of the terephthalate ligands by using 17 O ssNMR, 17 O-labelled terephthalic acid was used as a starting material to prepare Zn-BDC phases enriched on the carboxylate groups. Concerning the bridging hydroxyls, a direct enrichment during the mechanochemical synthesis of the Zn-BDC phases was envisaged by using 17 O-enriched water as a starting reactant (instead of normal water).…”