## Alternative Organic Solvents in RP-HPLC
### Propylene Carbonate  
Propylene carbonate (PC)--a carbonate ester derived from propylene glycol--was reported as a possible ACN substitution in RP-HPLC [57; 58]. It is a polar aprotic solvent mainly used as a reactive intermediate or as an inert solvent in various industries. It is used in degreasing, paint stripping, and cleaning applications, and as a carrier solvent for topically applied medications and cosmetics.  
Propylene carbonate presents several advantages over can, such as a higher biodegradability, a lower toxicity, and a lower capacity to bio-accumulate, leading to a relatively easy disposal of PC waste [57]. Also, PC has a higher boiling point and flashpoint temperature, reducing the risk of accidental fires in laboratories. In addition, PC is commercially available as an HPLC-grade solvent at reasonable prices. However, PC has two major drawbacks which obviously limit the possibility of a direct transposition from ACN to PC in RP-HPLC [59; 60]. The first drawback refers to the low miscibility of PC with water, which is why a third solvent is often added, such as MeOH or EtOH. The latter is the best candidate due to its green characteristics. The second problem comes from the high density and viscosity of PC, causing high-pressure drops in the chromatographic system. The backpressure will increase even more if EtOH is used as the ternary solvent.  
Some applications of PC in RP-HPLC have been reported for the determination of active substances in pharmaceutical formulations, but most of them used MeOH as a ternary solvent [57; 58; 61; 62; 63]. Nevertheless, [PERSON] et al. [59] studied the possibility of substituting ACN with PC and EtOH mixtures in RP-HPLC. Three series of compounds have been analyzed, including acidic (fenofibric, lovastatin, and simvastatin acids), neutral (toluene, fluorene, and fluoranthene), and basic (carbamazepine, diltiazem, and nicerogline) compounds. Through a systematic study, they showed that such an approach could be greener for pharmaceutical applications without any major impact in terms of elution order, chromatographic separation, efficiency, and peak symmetry. Moreover, the study of thermodynamic parameters showed that partition of analytes between the mobile and stationary phases was similar for both solvent systems. However, the most important difference is a lower mass transfer of analytes using PC-based mobile phases, so that optimal flow rates were found to be lower compared to acetonitrile-based mobile phases, increasing analysis time. Also, the limited miscibility of PC and pressure drop should be taken into account.  
Acetonitrile replacement by PC/EtOH mixtures has also been applied to bioanalytical applications by [PERSON] et al. [60]. A LC/MS-MS assay of enalapril and enalaprilat in human plasma was developed, and similar chromatographic performance was achieved using this green approach compared to the reference one. In addition, [PERSON] et al. [64] developed and validated green bioanalytical HPLC methods for voriconazole and tadalafil analysis using a mobile phase composed of a mixture of PC and EtOH as organic modifiers.  
Finally, PC appears to have the same advantages as EtOH, with the additional disadvantage coming from its limited miscibility with water. Indeed, the use of PC implies a ternary mobile phase leading to more difficult developments. It may explain the lower number of applications found with PC compared to EtOH.