#1 Solid Support: PEG over Polystyrene for Difficult Sequences
**Resin benchmarking conflicts of interest.** OctaGel rankings come from Albericio/AAPPTEC. DEG-PS rankings come from Serban/Sunresin. Seplife claims come from Sunresin. TentaGel data often comes from Rapp Polymere conference posters. Truly independent head-to-head data comparing modern resins on the same peptides is scarce.
**Thermal equalisation.** One study showed microwave at 86°C eliminated resin-dependent purity differences entirely. If confirmed broadly, this would undermine the case for expensive PEG resins — but the study used only 3 test peptides (9, 15, 24-mer).
**No systematic loading-density dose-response.** Every published comparison tests 2 loading levels. A proper dose-response (e.g., 0.05, 0.1, 0.15, 0.2, 0.3, 0.5 mmol/g on the same resin and peptide) has never been published for Fmoc-SPPS.
**Mass recovery vs purity trade-off** is under-reported. DEG-PS gave 2.2× better mass recovery than ChemMatrix at comparable purity. Most studies report only crude purity, not recovery yield — this matters enormously for manufacturing economics.
#2 Loading Density: Target ≤0.2 mmol/g
**Loading density × backbone interaction** is the largest gap. Kassem 2009 found higher loading won on PEG resin (0.81 > 0.48 mmol/g), but the comparison was confounded by linker choice. Biotage 2023 found lower loading won on PS (0.33 > 0.70 mmol/g). The 'lower is always better' rule is probably wrong — it likely depends on backbone, linker, and solvent simultaneously, but no study has tested this.
**Thermal equalisation.** One study showed microwave at 86°C eliminated resin-dependent purity differences entirely. If confirmed broadly, this would undermine the case for expensive PEG resins — but the study used only 3 test peptides (9, 15, 24-mer).
**No systematic loading-density dose-response.** Every published comparison tests 2 loading levels. A proper dose-response (e.g., 0.05, 0.1, 0.15, 0.2, 0.3, 0.5 mmol/g on the same resin and peptide) has never been published for Fmoc-SPPS.
#3 Flexible Crosslinkers (DEG, BDDMA) as PS-Based Alternatives
**Thermal equalisation.** One study showed microwave at 86°C eliminated resin-dependent purity differences entirely. If confirmed broadly, this would undermine the case for expensive PEG resins — but the study used only 3 test peptides (9, 15, 24-mer).
**No systematic loading-density dose-response.** Every published comparison tests 2 loading levels. A proper dose-response (e.g., 0.05, 0.1, 0.15, 0.2, 0.3, 0.5 mmol/g on the same resin and peptide) has never been published for Fmoc-SPPS.
#4 PEG-Grafted Hybrid Resins: Best of Both Worlds
**Thermal equalisation.** One study showed microwave at 86°C eliminated resin-dependent purity differences entirely. If confirmed broadly, this would undermine the case for expensive PEG resins — but the study used only 3 test peptides (9, 15, 24-mer).
**No systematic loading-density dose-response.** Every published comparison tests 2 loading levels. A proper dose-response (e.g., 0.05, 0.1, 0.15, 0.2, 0.3, 0.5 mmol/g on the same resin and peptide) has never been published for Fmoc-SPPS.
#5 Match Resin to Solvent: Green Solvent Compatibility
**Thermal equalisation.** One study showed microwave at 86°C eliminated resin-dependent purity differences entirely. If confirmed broadly, this would undermine the case for expensive PEG resins — but the study used only 3 test peptides (9, 15, 24-mer).
**No systematic loading-density dose-response.** Every published comparison tests 2 loading levels. A proper dose-response (e.g., 0.05, 0.1, 0.15, 0.2, 0.3, 0.5 mmol/g on the same resin and peptide) has never been published for Fmoc-SPPS.
#6 On-Resin Macrocyclisation at Ultra-Low Substitution
**GVL solvent inconsistency.** Al Musaimi 2018 reported GVL comparable to DMF with microwave; Wegner/Ipsen 2021 found 18% purity vs 60% for DMF. Almost certainly a resin effect, but uncharacterised.
**Thermal equalisation.** One study showed microwave at 86°C eliminated resin-dependent purity differences entirely. If confirmed broadly, this would undermine the case for expensive PEG resins — but the study used only 3 test peptides (9, 15, 24-mer).
**No systematic loading-density dose-response.** Every published comparison tests 2 loading levels. A proper dose-response (e.g., 0.05, 0.1, 0.15, 0.2, 0.3, 0.5 mmol/g on the same resin and peptide) has never been published for Fmoc-SPPS.
#7 Supply Chain Risk and Dual-Resin Qualification
**Thermal equalisation.** One study showed microwave at 86°C eliminated resin-dependent purity differences entirely. If confirmed broadly, this would undermine the case for expensive PEG resins — but the study used only 3 test peptides (9, 15, 24-mer).
**No systematic loading-density dose-response.** Every published comparison tests 2 loading levels. A proper dose-response (e.g., 0.05, 0.1, 0.15, 0.2, 0.3, 0.5 mmol/g on the same resin and peptide) has never been published for Fmoc-SPPS.