Templated Reactive Crystallization of Active Pharmaceutical Ingredient in Hydrogel Microparticles Enabling Robust Drug Product Processing.

Commercialization of most promising active pharmaceutical ingredients (APIs) is impeded either by poor bioavailability or challenging physical properties leading to costly manufacture. Bioavailability of ionizable hydrophobic APIs can be enhanced by its conversion to salt form. While salt form of the API presents higher solution concentration than the non-ionized form, poor physical properties resulting from particle anisotropy or non-ideal morphology (needles) and particle size distribution not meeting dissolution rate targets can still inhibit its commercial translation. In this regard, API physical properties can be improved through addition of non-active components (excipients or carriers) during API manufacture. In this work, a facile method to perform reactive crystallization of an API salt in presence of the microporous environment of a hydrogel microparticle is presented. Specifically, the reaction between acidic antiretroviral API, raltegravir and base potassium hydroxide is performed in the presence of polyethylene glycol diacrylamide hydrogel microparticles. In this bottom-up approach, the spherical template hydrogel microparticles for the reaction lead to monodisperse composites loaded with inherently micronized raltegravir-potassium crystals, thus improving API physical properties without hampering bioavailability. Overall, this technique provides a novel approach to reactive crystallization while maintaining the API polymorph and crystallinity.

Preparation of anisotropic multiscale micro-hydrogels via two-photon continuous flow lithography.

HYPOTHESIS: Polymeric anisotropic soft microparticles show interesting behavior in biological environments and hold promise for drug delivery and biomedical applications. However, self-assembly and substrate-based lithographic techniques are limited by low resolution, batch operation or specific particle geometry and deformability. Two-photon polymerization in microfluidic channels may offer the required resolution to continuously fabricate anisotropic micro-hydrogels in sub-10 µm size-range. EXPERIMENTS: Here, a pulsed laser source is used to perform two-photon polymerization under microfluidic flow of a poly(ethylene glycol) diacrylate (PEGDA) solution with the objective of realizing anisotropic micro-hydrogels carrying payloads of various nature, including small molecules and nanoparticles. The fabrication process is described via a reactive-convective-diffusion system of equations, whose solution under proper auxiliary conditions is used to corroborate the experimental observations and sample the configuration space. FINDINGS: By tuning the flow velocity, exposure time and pre-polymer composition, anisotropic PEGDA micro-hydrogels are obtained in the 1-10 µm size-range and exhibit an aspect ratio varying from 1 to 5. Furthermore, 200 nm curcumin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles and 100 nm ssRNA-encapsulating lipid nanoparticles were entrapped within square PEGDA micro-hydrogels. The proposed approach could support the fabrication of micro-hydrogels of well-defined morphology, stiffness, and surface properties for the sustained release of therapeutic agents.

Simultaneous Increase in Brightness and Singlet Oxygen Generation of an Organic Photosensitizer by Nanocrystallization.

Efficient organic photosensitizers are attractive for cancer cell ablation in photodynamic therapy. Bright fluorescent photosensitizers are highly desirable for simultaneous imaging and therapy. However, due to fundamental competition between emission and singlet oxygen generation, design attempts to increase singlet oxygen generation almost always leads to the loss of fluorescence. Herein, it is shown for the first time that nanocrystallization enables a simultaneous and significant increase in the brightness and singlet oxygen generation of an organic photosensitizer. Spectroscopic studies show simultaneous enhancement in the visible light absorption and fluorescence after nanocrystallization. The enhanced absorption of visible light in nanocrystals is found to translate directly to the enhanced singlet oxygen production, which shows a higher ability to kill HeLa cells as compared to their amorphous counterpart.

Nanocrystallization: A Unique Approach to Yield Bright Organic Nanocrystals for Biological Applications.

A new bottom-up nanocrystallization method is developed to fabricate highly fluorescent organic nanocrystals in aqueous media using an aggregation-induced emission fluorogen (AIEgen) as an example. The nanocrystallization strategy leads to the fabrication of uniform nanocrystals of 110 ± 10 nm size in aqueous media, which shows over 400% increase in brightness as compared to the amorphous nanoaggregates.