Hydroxypropyl methylcellulose (HPMC) in sustainable pharmaceutical synthesis – Mechanistic insights, green metrics and outlook

The transition toward greener pharmaceutical manufacturing has heightened interest in water as a sustainable reaction medium. Hydroxypropyl methylcellulose (HPMC), a cost-effective and widely available cellulose derivative, has recently emerged as a micelle-mimicking additive capable of creating hydrophobic pockets that enhance solubility, reactivity and selectivity in aqueous systems. This review critically evaluates the role of HPMC in the synthesis of Active Pharmaceutical Ingredients (APIs), integrating mechanistic insights with sustainability metrics such as process mass intensity (PMI), E-factor and atom economy. Whereas previous reviews have largely cataloged applications, the present review highlights the advantages of HPMC, as a cost-effective and sustainable medium, contrasting it with designer surfactants such as TPGS-750-M and Savie, which – despite enabling notable progress – remain relatively costly and may still require co-solvents under certain conditions. Representative case studies in metal-catalyzed (Pd, Cu, Ni), metal-free (amide couplings, SNAr), and photoredox reactions are discussed, with emphasis on reaction efficiency at extremely short times, promising scalability, and environmental benefits. We further identify key limitations: restricted reaction scope and barriers to regulatory acceptance. By outlining critical research gaps and industrial opportunities, this work provides a forward-looking perspective on how HPMC can advance sustainable synthetic chemistry and accelerate the adoption of water-based technologies in pharmaceutical manufacturing.