Combined decoction selectively modifies chemical composition of traditional Asian medicine: a systematic analysis on Palmijihwang-tang using theoretical additive model

Combined decoction (CD)—boiling multiple herbs together—is a fundamental preparation method in Traditional Asian Medicine. While biological synergies are well documented, chemical interactions during the decoction process itself remain largely unexplored. Understanding these preparation-dependent chemical modifications is crucial for standardizing and modernizing traditional herbal medicines. We developed a systematic analytical framework combining theoretical additive modeling with structural similarity analysis to investigate structure-dependent extraction in CD. Using Palmijihwang-tang as a proof-of-concept model, we used liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) to compare chemical profiles of CD with predicted profiles from individual decoctions (ID). We then predicted drug-likeness and bioactivity in silico and validated our findings with cell-based assays. CD systematically modified compound extraction based on structural features, selectively enhancing certain structural groups while suppressing others. These distinct extraction patterns correlated with the compounds' physicochemical properties, structural complexity, and predicted therapeutic properties—suggesting an empirically optimized process. Cell-based assays confirmed these chemical alterations lead to measurable biological differences between CD and ID preparations. Our findings suggest that CD selectively modifies the chemical composition of herbal formulations through structure-dependent extraction, providing a preliminary chemical basis for better understanding traditional decoction practices. This highlights the critical importance of considering preparation methodology in herbal medicine standardization. Our analytical framework opens new avenues for investigating these CD effects across a wider range of traditional prescriptions. We believe this approach may ultimately contribute to the improved understanding and standardization of this fundamental method in Traditional Asian Medicine.