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Nowadays, biodegradable polymers such as poly(lactic acid) (PLA), poly(D,L-lactic-co-glycolic acid) (PLGA) and poly(ε-caprolactone) (PCL) remain the most common biomaterials to produce drug-loaded nanoparticles (NPs). Pipemidic acid (PIP) is a poorly soluble antibiotic with a strong tendency to crystallize. PIP incorporation in PLA/PLGA NPs was challenging because of PIP crystals formation and burst release. As PIP had a poor affinity for the NPs, an alternative approach to encapsulation was used, consisting in coupling PIP to PCL. Thus, a PCL–PIP conjugate was successfully synthesized by an original drug-initiated polymerization in a single step without the need of catalyst. PCL–PIP was characterized by NMR, IR, SEC and mass spectrometry. PCL–PIP was used to prepare self-assembled NPs with PIP contents as high as 27% (w/w). The NPs were characterized by microscopy, DLS, NTA and TRPS. This study paves the way towards the production of NPs with high antibiotic payloads by drug-initiated polymerization. Further studies will deal with the synthesis of novel polymer–PIP conjugates with ester bonds between the drug and PCL. PIP can be considered as a model drug and the strategy developed here could be extended to other challenging antibiotics or anticancer drugs and employed to efficiently incorporate them in NPs. KEY WORDS: Pipemidic acid, Nanoparticle, Antibiotic, Nanoprecipitation, Crystalline drug, Drug-initiated   polymerization