Predicting Polymorph Risk Before Formulation Locks in a Natural Product Candidate Through Crystal Landscape Reasoning and Solid-State Uncertainty Assessment

Polymorphism creates a development problem before it becomes a formulation problem. A natural product candidate may appear to have an acceptable solid form while its accessible crystal landscape remains incompletely sampled, its energetic ordering uncertain, or its crystallization behavior sensitive to solvent, temperature, and molecular conformation. This article develops a proposed decision framework for assessing polymorph risk before formulation choices become difficult to reverse. The analy