1,5-Asymmetric induction during nucleophilic additions to arene­tricarbonyl­chromium complexes: tri­carbonyl­(η6-1-methyl-4-{spiro­[(1R,2S)-1,7,7-trimethyl­bicyclo­[2.2.1]heptane-3,2′-1,3-dioxolan]-2-yl­oxy}benzene)­chromium

The tricarbonyl­chromium unit bound to the arene ring of the chiral title complex, [Cr(C19H26O3)(CO)3], is rotated by ca 25° in agreement with the proposed mechanism for 1,5-asymmetric induction of nucleophilic attack

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

Gelation Chemistries for the Encapsulation of Nanoparticles in Composite Gel Microparticles for Lung Imaging and Drug Delivery

The formation of 10–40 μm composite gel microparticles (CGMPs) comprised of ∼100 nm drug containing nanoparticles (NPs) in a poly­(ethylene glycol) (PEG) gel matrix is described. The CGMP particles enable targeting to the lung by filtration from the venous circulation. UV radical polymerization and Michael addition polymerization reactions are compared as approaches to form the PEG matrix. A fluorescent dye in the solid core of the NP was used to investigate the effect of reaction chemistry on the integrity of encapsulated species. When formed via UV radical polymerization, the fluorescence signal from the NPs indicated degradation of the encapsulated species by radical attack. The degradation decreased fluorescence by 90% over 15 min of UV exposure. When formed via Michael addition polymerization, the fluorescence was maintained. Emulsion processing using controlled shear stress enabled control of droplet size with narrow polydispersity. To allow for emulsion processing, the gelation rate was delayed by adjusting the solution pH. At a pH = 5.4, the gelation occurred at 3.5 h. The modulus of the gels was tuned over the range of 5 to 50 kPa by changing the polymer concentration between 20 and 70 vol %. NP aggregation during polymerization, driven by depletion forces, was controlled by the reaction kinetics. The ester bonds in the gel network enabled CGMP degradation. The gel modulus decreased by 50% over 27 days, followed by complete gel degradation after 55 days. This permits ultimate clearance of the CGMPs from the lungs. The demonstration of uniform delivery of 15.8 ± 2.6 μm CGMPs to the lungs of mice, with no deposition in other organs, is shown, and indicates the ability to concentrate therapeutics in the lung while avoiding off-target toxic exposure

Formation of Stable Nanocarriers by in Situ

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 re-approval. This technique greatly expands the types of APIs that can be successfully encapsulated in NC form. Three model API’s were investigated and successfully incorporated into NCs by forming salts with hydrophobic counter ions: 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 counter ion, 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