Multi-drug combination therapies are increasingly used for complex diseases but carry risks of harmful drug interactions. Effective drug–drug interaction prediction (DDIP) is essential for assessing risks among numerous drug pairs. Most DDIP methods involve two main steps: drug representation and drug pair interaction extraction, respectively challenged by the loss of personalized drug information and the need for differentiated interaction data, and are rarely studied. Specifically, personalized drug information refers to the distinct features of each drug. These properties can be easily confused by neighboring information during graph propagation. This issue is especially prominent in drug interaction graphs with long-tail distributions, which poses challenges for personalized drug information learning. Furthermore, it is crucial to learn interactions with differentiation in order to identify diverse drug relationships. Some methods simply concatenate drug features, often ignoring the differences of different drug relationships, while other methods based on substructures rely on professional pharmacological knowledge and are computationally complex. To address these issues, we propose a novel method, learning personalized Drug Features and differentiated Drug-Pair interaction information for drug–drug interaction prediction (DFPDDI). This approach employs a contrastive learning network with edge-aware augmentations and mutual information estimators to capture personalized drug features across various graph distributions. Furthermore, it applies a mutual information constraint to drug-pair representations, enhancing the accuracy of interaction predictions by better distinguishing between different types of drug relationships. The results evaluated on three public datasets demonstrate competitive performance compared to baselines. It also shows potential for accurate predictions, particularly in imbalanced-distribution graphs.