Quality-by-Design Compounding of Semisolids Using an Electronic Mortar and Pestle Device for Compounding Pharmacies: Uniformity, Stability, and Cleaning

Background/Objectives: Manual preparation of semisolid formulations (creams, ointments, gels) is prone to variability in mixing energy and time, which may compromise uniform API distribution. This study aimed to evaluate an Electronic Mortar and Pestle (EMP; Unguator™) as a standardized compounding tool, with objectives to: (i) validate stability-indicating UHPLC methods; (ii) assess content uniformity across jar strata; (iii) quantify the impact of mixing time and rotation speed via design of experiments (DOE); and (iv) verify cleaning effectiveness and cross-contamination risk. Methods: Five representative formulations were compounded: urea 40%, clobetasol 0.05%, diclofenac 2.5% in hyaluronic acid 3% gel, urea 10% + salicylic acid 1%, and hydroquinone 5%. UHPLC methods were validated per ICH Q2(R2) and stress-tested under acid, base, oxidative, thermal, and UV conditions. Homogeneity was assessed by stratified sampling (top/middle/bottom). A 32 factorial DOE (time: 2/6/10 min; speed: 600/1500/2400 rpm) modeled effects on % label claim and RSD. Cleaning validation employed hydroquinone as a tracer, with swab sampling pre-/post-use and post-sanitization analyzed by HPLC. Results: All UHPLC methods met specificity, linearity, precision, accuracy, and sensitivity criteria and were stability-indicating (Rs ≥ 1.5). Formulations achieved 90–110% label claim with strata CV ≤ 5%. DOE revealed speed as the dominant factor for clobetasol, urea, and diclofenac, while time was more influential for salicylic acid; gels exhibited curvature, indicating diminishing returns at high rpm. Model-predicted optima were implementable on the Unguator™ with minor rounding of rpm/time. Cleaning validation confirmed post-sanitization residues below LOQ and