Formation of Stable Nanocarriers by <i>in Situ</i> Ion Pairing during Block-Copolymer-Directed Rapid Precipitation

We present an <i>in situ</i> hydrophobic salt forming technique for the encapsulation of weakly hydrophobic, ionizable active pharmaceutical ingredients (API) into stable nanocarriers (NCs) formed <i>via</i> a rapid precipitation process. Traditionally, NC formation <i>via</i> rapid precipitation has been difficult with APIs in this class because their intermediate solubility makes achieving high supersaturation difficult during the precipitation process and the intermediate solubility causes rapid Ostwald ripening or recrystallization after precipitation. By forming a hydrophobic salt <i>in situ</i>, the API solubility and crystallinity can be tuned to allow for NC formation. Unlike covalent API modification, the hydrophobic salt formation modifies properties <i>via</i> ionic interactions, thus circumventing the need for full FDA reapproval. This technique greatly expands the types of APIs that can be successfully encapsulated in NC form. Three model APIs were investigated and successfully incorporated into NCs by forming salts with hydrophobic counterions: cinnarizine, an antihistamine, clozapine, an antipsychotic, and α-lipoic acid, a common food supplement. We focus on cinnarizine to develop the rules for the <i>in situ</i> nanoprecipitation of salt NCs. These rules include the p<i>K</i>_as and solubilities of the API and counterion, the effect of the salt former-to-API ratio on particle stability and encapsulation efficiency, and the control of NC size. Finally, we present results on the release rates of these ion pair APIs from the NCs