Every month thousands of patients are treated with ocular ciprofloxacin, yet crystalline deposits form on the surface of the cornea in one in ten patients. This occurs due to a pH shift when the formulation is instilled onto the eye, since ciprofloxacin formulations are buffered to pH 4.5 to keep the drug in solution, whereas the tear pH is around 7. We deconstruct the formulation and the chemical pathophysiology of this condition to enable the selection of inhibitors that can derisk corneal toxicity. Through in vitro and ex vivo models we show that some structurally similar fluoroquinolones (levofloxacin and ofloxacin) can successfully inhibit the nucleation of ciprofloxacin. In contrast, other fluoroquinolones like norfloxacin can promote the formation of a less soluble ciprofloxacin–norfloxacin complex, increasing the risk of corneal deposition. We further identify that mannitol, a common excipient in marketed ophthalmic formulations, accelerates nucleation and could promote the risk of crystallisation. These findings identify both beneficial and counterproductive formulation components and define a practical anticrystal engineering strategy to prevent ciprofloxacin-induced ocular precipitation. We anticipate that this study may inspire further work designing nucleation inhibitors for transient, high supersaturation conditions such as those seen regularly during drug delivery.