© 2019 American Chemical Society. Bile salts, phospholipids, and digestive proteins are amphipathic compounds found naturally in the human gastrointestinal system. Therefore, it is important to consider their effects on the crystallization kinetics and solution behavior of drugs intended for oral delivery. Supersaturating drug delivery systems that employ high energy solid forms and polymeric additives are often hailed as the gold standard for increasing drug concentration in the gastrointestinal system. However, the effects of amphiphilic compounds present in the gastrointestinal system on the crystallization behavior of these systems are often overlooked. In this study, the effects of bile salts, phospholipids, mixtures of phospholipids and bile salts as well as digestive proteins on the crystallization kinetics of the antimicrobial agent clofazimine were evaluated. The crystallization inhibitory properties of these gastrointestinal amphiphiles were compared with commonly used synthetic polymers, and several of these amphipathic gastrointestinal compounds showed promise as crystallization inhibitors of clofazimine hydrochloride during induction time experiments. The best crystallization inhibitors from this induction time screening were then compared as solid physical mixtures in modified-fasted state simulated gastric fluid. Here it was found that heterogeneous nucleation of clofazimine hydrochloride occurred onto the dissolving surface of the administered clofazimine solid forms, preventing the various gastrointestinal compounds from inhibiting crystallization in this biorelevant media. This heterogeneous nucleation of clofazimine hydrochloride was monitored in real time, using optical microscopy techniques.