TOMISLAV FRIŠČIĆ
Department of Chemistry, McGill University, Montreal, Canada

Abstract

Mechanochemistry by ball milling has opened new opportunities for the efficient discovery and synthesis of drug solid forms (e.g. cocrystals, salts, polymorphs), as well as the synthesis of active pharmaceutical ingredients (APIs) through cleaner and faster solventless routes. Such developments signal the emergence of medicinal mechanochemistry: a discipline dedicated to developing solid-state, cleaner and more efficient alternatives to solution-based processes of pharmaceutical and medicinal chemistry. This review provides a brief introduction to mechanochemical techniques, notably liquid-assisted grinding, and highlights the use of mechanochemistry in screening for API solid forms and for the clean synthesis of APIs (e.g. Leu-enkephalin, Glibenclamide, Ethotoin or bismuth subsalicylate) by rapid, often catalytic, solvent-free and room-temperature reactivity

INTRODUCTION

This review highlights the emerging potential of mechanochemical transformations,(1) i.e. chemical reactivity conducted by milling or grinding in the absence of bulk solvents, in the context of pharmaceutical sciences. The increased use of automated ball mills and creation of versatile techniques such as liquid-assisted grinding (LAG) have opened unexpected new opportunities of mechanochemistry, first in discovery of solid forms of active pharmaceutical ingredients (APIs)(2) and also for their clean, low-waste API synthesis without requiring high temperatures or bulk solvents (Figure 1) (3). Thus, mechanochemistry might be the answer to the demands of pharmaceutical industries for cleaner, more efficient and innovative chemical processes,(4) and the vigorous recent development of API mechanochemistry may signal the emergence of medicinal mechanochemistry: a sub-discipline of mechanochemistry dedicated to cleaner, solventless alternatives to solution-based drug and solid form manufacture (3).

MECHANOCHEMISTRY IN PHARMACEUTICAL FORM DISCOVERY

Chemical and materials transfo ...