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Treating complex medical conditions often requires the concurrent administration of multiple drugs, either taken simultaneously as separate dosage forms, or as a combination product. This study investigates the impact on the achievable supersaturation of the amorphous formulation when co-administered with a crystalline drug, and the consequences for membrane transport. Non-sink dissolution studies were conducted for a physical mixture of amorphous atazanavir and crystalline darunavir. Flux of atazanavir across a monolayer of Caco-2 cells and across an artificial membrane, was determined in the absence and presence of a pre-equilibrated suspension of darunavir crystals. Miscibility between the drugs was investigated using nano thermal analysis and differential scanning calorimetry. The maximum achievable concentration of atazanavir decreased with increasing darunavir concentration, even when the latter drug was not saturated in the solution. Furthermore, the membrane flux of atazanavir was reduced significantly in the presence of darunavir, indicating that liquid-liquid phase separation occurs at lower supersaturation for atazanavir when darunavir is present. Interestingly, the formation of this colloidal phase of atazanavir also reduced darunavir concentration. The drugs were found to remain phase separated in the dry state, whereas darunavir partitioned into the atazanavir drug-rich phase in aqueous media. This suggests that water facilitated mixing of the drugs in the colloidal phase, which affected the release and membrane transport properties of atazanavir. These findings further illustrate the complexity of formulating or co-administrating multicomponent drugs, even when present in different solid forms, and provide new insights into how amorphous drugs behave when co-administered with crystalline drugs.