Diffuse Reflectance Infrared Fourier Transform Spectroscopy in Pharmaceutical Analysis: Applications, Constraints and Regulatory Readiness—A Critical Review

Diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) offers organic solvent-free powder analysis with high solid-state sensitivity. This positions the technique at the intersection of green analytical chemistry, solid form control, and ICH Q14-aligned, science- and risk-based method development. Despite these advantages, it remains marginal in regulated quality control. This review assesses the DRIFTS literature from Kubelka–Munk theory to current uses in pharmaceutical assays, solid-form quantification, drug-excipient interactions and medicines quality control, and asks why these favourable ergonomics have not been translated into regulatory acceptance. Seven of the nine univariate DRIFTS assays identified operate within a window of about 0.1–3.5% w/w analyte in KBr; two exceed it, with one reaching 30% w/w. Contrary to the common characterisation of the field as univariate, eighteen multivariate DRIFTS assay methods were identified together with a further nine multivariate solid-form methods, published continuously since 1988; what has remained univariate is the single-analyte tablet assay built on peak-area integration. This range is best read as an empirically observed working window for the systems reviewed rather than as a universal limit. Robustness evidence is dominated by single-laboratory, single-instrument, single-lot studies; where multi-lot performance was tested for polymorphic impurities, calibration models transferred poorly and standard outlier diagnostics disagreed. Reports are systematically silent on particle size distribution, packing protocol, diluent water content and ambient humidity. DRIFTS is well-suited to bounded roles: identity confirmation, solid-form screening, compatibility studies and in-house assay of formulations with a known, stable matrix. To advance the field, future efforts must prioritise rigorous evidentiary discipline over the development of new instrumentation.