Formation of stable nanocarriers by in situ ion pairing during block-copolymer-directed rapid precipitation.

We present an in situ hydrophobic salt forming technique for the encapsulation of weakly hydrophobic, ionizable active pharmaceutical ingredients (API) into stable nanocarriers (NCs) formed via a rapid precipitation process. Traditionally, NC formation via 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 in situ, the API solubility and crystallinity can be tuned to allow for NC formation. Unlike covalent API modification, the hydrophobic salt formation modifies properties via 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 in situ nanoprecipitation of salt NCs. These rules include the pK(a)s 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.

Single-Step Assembly of Multimodal Imaging Nanocarriers: MRI and Long-Wavelength Fluorescence Imaging.

Magnetic resonance imaging (MRI)- and near-infrared (NIR)-active, multimodal composite nanocarriers (CNCs) are prepared using a simple one-step process, flash nanoprecipitation (FNP). The FNP process allows for the independent control of the hydrodynamic diameter, co-core excipient and NIR dye loading, and iron oxide-based nanocrystal (IONC) content of the CNCs. In the controlled precipitation process, 10 nm IONCs are encapsulated into poly(ethylene glycol) (PEG) stabilized CNCs to make biocompatible T2 contrast agents. By adjusting the formulation, CNC size is tuned between 80 and 360 nm. Holding the CNC size constant at an intensity weighted average diameter of 99 ± 3 nm (PDI width 28 nm), the particle relaxivity varies linearly with encapsulated IONC content ranging from 66 to 533 × 10(-3) m(-1) s(-1) for CNCs formulated with 4-16 wt% IONC. To demonstrate the use of CNCs as in vivo MRI contrast agents, CNCs are surface functionalized with liver-targeting hydroxyl groups. The CNCs enable the detection of 0.8 mm(3) non-small cell lung cancer metastases in mice livers via MRI. Incorporating the hydrophobic, NIR dye tris-(porphyrinato)zinc(II) into CNCs enables complementary visualization with long-wavelength fluorescence at 800 nm. In vivo imaging demonstrates the ability of CNCs to act both as MRI and fluorescent imaging agents.