Aggregated Solution Morphology of Poly(acrylic acid)-Poly(styrene) Block Copolymers Improves Drug Supersaturation Maintenance and Caco-2 Cell Membrane Permeation.

Amorphous solid dispersions of polymers and drugs have been shown to improve supersaturation maintenance of poorly water-soluble drugs. Herein, amorphous spray-dried dispersions (SDDs) of poly(acrylic acid)-polystyrene (PS-b-PAA) diblock copolymers with differing degrees of polymerization were prepared in aggregated and nonaggregated states with the Biopharmaceutical Classification System Class II drug, probucol (PBC). Specifically, PS90-b-PAA15, PS90-b-PAA80, PS38-b-PAA220, and PS38-b-PAA320 amphiphilic block polymers that covered a compositional range in the area of oral drug delivery were prepared to examine the role of molecular weight and controlled aggregation in promoting drug supersaturation and maintenance. In addition, hydrophilic homopolymers PAA20, PAA96, PAA226, and PAA392 were prepared as controls to evaluate the role of the block copolymer-based SDDs in PBC solubilization. Characterization such as powder X-ray diffraction, scanning electron microscopy, and dissolution tests under nonsink conditions were then performed to evaluate the SDDs. When comparing the block copolymer systems, polymers that were preaggregated into micellular structures prior to spray drying with the drug promoted higher drug solubility and maintenance than when the drug was formulated with molecularly dissolved PS-PAA block polymer. Interestingly, the aggregated PS90-b-PAA80 SDD with 25 wt % PBC achieved 100% burst release and maintained full supersaturation of PBC at pH 6.5 (physiological pH in the small intestine). Dissolution studies conducted at the pH of the stomach (pH = 1.2) show that a minimal amount of drug (∼10 µg/mL) was released, which could be used for protecting drugs from acidic environments (stomach) before reaching the small intestine. To evaluate drug bioavailability, in vitro Caco-2 cell assays were performed, which reveal that PAA-based excipients do not hinder drug permeation across the epithelial membrane and that PS90-b-PAA80 SDD with 25 wt % PBC achieved the highest membrane permeability coefficient. This work demonstrates that block copolymer-based SDDs capable of preaggregating into nanostructures may be a tunable drug-delivery platform that can improve solubility and supersaturation maintenance of Class II pharmaceutics while also not prohibiting bioavailability through model intestinal membranes. Indeed, this concept may be extended to accommodate a myriad of pharmaceutical and excipient structures.

Open-to-Air RAFT Polymerization in Complex Solvents: From Whisky to Fermentation Broth.

We investigate the use of in situ enzyme degassing to facilitate the open-to-air reversible addition-fragmentation chain transfer (RAFT) polymerization of hydroxyethyl acrylate (HEA) in a wide range of complex aqueous solvents, including, beer, wine, liquor, and fermentation broth. This enzyme-assisted polymerization procedure is impressively robust, and poly(HEA) was attained with good control over molecular weight and a narrow dispersity in nearly all of the solvents tested. Kinetics experiments on HEA polymerization in whisky and spectroscopic analysis of the purified polymers suggest high end-group fidelity, as does the successful chain extension of a poly(HEA) macro chain transfer agent with narrow dispersity. These results suggest enzyme-assisted RAFT may be a powerful and underutilized tool for high-throughput screening and materials discovery and may simplify the synthesis of well-defined polymers in complex conditions.

Diblock Terpolymers Are Tunable and pH Responsive Vehicles To Increase Hydrophobic Drug Solubility for Oral Administration.

Synthetic polymers offer tunable platforms to create new oral drug delivery vehicles (excipients) to increase solubility, supersaturation maintenance, and bioavailability of poorly aqueous soluble pharmaceutical candidates. Five well-defined diblock terpolymers were synthesized via reversible addition-fragmentation chain transfer polymerization (RAFT) and consist of a first block of either poly(ethylene-alt-propylene) (PEP), poly(N-isopropylacrylamide) (PNIPAm), or poly(N,N-diethylaminoethyl methacrylate) (PDEAEMA) and a second hydrophilic block consisting of a gradient copolymer of N,N-dimethylacrylamide (DMA) and 2-methacrylamidotrehalose (MAT). This family of diblock terpolymers offers hydrophobic, hydrophilic, or H-bonding functionalities to serve as noncovalent sites of drug binding. Drug-polymer spray dried dispersions (SDDs) were created with a model drug, probucol, and characterized by differential scanning calorimetry (DSC). These studies revealed that probucol crystallinity decreased with increasing H-bonding sites available in the polymer. The PNIPAm-b-P(DMA-grad-MAT) systems revealed the best performance at pH 6.5, where immediate probucol release and effective maintenance of 100% supersaturation was found, which is important for facilitating drug solubility in more neutral conditions (intestinal environment). However, the PDEAEMA-b-P(DMA-grad-MAT) system revealed poor probucol dissolution at pH 6.5 and 5.1. Alternatively, at an acidic pH of 3.1, a rapid and high dissolution profile and effective supersaturation maintenance of up to 90% of the drug was found, which could be useful for triggering drug release in acidic environments (stomach). The PEP-b-P(DMA-grad-MAT) system showed poor performance (only ∼20% of drug solubility at pH 6.5), which was attributed to the low solubility of the polymers in the dissolution media. This work demonstrates the utility of diblock terpolymers as a potential new excipient platform to optimize design parameters for triggered release and solubilizing hydrophobic drug candidates for oral delivery.

High-Throughput Excipient Discovery Enables Oral Delivery of Poorly Soluble Pharmaceuticals.

Polymeric excipients are crucial ingredients in modern pills, increasing the therapeutic bioavailability, safety, stability, and accessibility of lifesaving products to combat diseases in developed and developing countries worldwide. Because many early-pipeline drugs are clinically intractable due to hydrophobicity and crystallinity, new solubilizing excipients can reposition successful and even failed compounds to more effective and inexpensive oral formulations. With assistance from high-throughput controlled polymerization and screening tools, we employed a strategic, molecular evolution approach to systematically modulate designer excipients based on the cyclic imide chemical groups of an important (yet relatively insoluble) drug phenytoin. In these acrylamide- and methacrylate-containing polymers, a synthon approach was employed: one monomer served as a precipitation inhibitor for phenytoin recrystallization, while the comonomer provided hydrophilicity. Systems that maintained drug supersaturation in amorphous solid dispersions were identified with molecular-level understanding of noncovalent interactions using NOESY and DOSY NMR spectroscopy. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (poly(NIPAm-co-DMA)) at 70 mol % NIPAm exhibited the highest drug solubilization, in which phenytoin associated with inhibiting NIPAm units only with lowered diffusivity in solution. In vitro dissolution tests of select spray-dried dispersions corroborated the screening trends between polymer chemical composition and solubilization performance, where the best NIPAm/DMA polymer elevated the mean area-under-the-dissolution-curve by 21 times its crystalline state at 10 wt % drug loading. When administered to rats for pharmacokinetic evaluation, the same leading poly(NIPAm-co-DMA) formulation tripled the oral bioavailability compared to a leading commercial excipient, HPMCAS, and translated to a remarkable 23-fold improvement over crystalline phenytoin.

Tuning Electronic Structure, Redox, and Photophysical Properties in Asymmetric NIR-Absorbing Organometallic BODIPYs.

Stepwise modification of the methyl groups at the α positions of BODIPY 1 was used for preparation of a series of mono- (2, 4, and 6) and diferrocene (3) substituted donor-acceptor dyads in which the organometallic substituents are fully conjugated with the BODIPY π system. All donor-acceptor complexes have strong absorption in the NIR region and quenched steady-state fluorescence, which can be partially restored upon oxidation of organometallic group(s). X-ray crystallography of complexes 2-4 and 6 confirms the nearly coplanar arrangement of the ferrocene groups and the BODIPY π system. Redox properties of the target systems were studied using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). It was found that the first oxidation process in all dyads is ferrocene centered, while the separation between the first and the second ferrocene-centered oxidation potentials in diferrocenyl-containing dyad 3 is ∼150 mV. The density functional theory-polarized continuum model (DFT-PCM) and time-dependent (TD) DFT-PCM methods were used to investigate the electronic structure as well as explain the UV-vis and redox properties of organometallic compounds 2-4 and 6. TDDFT calculations allow for assignment of the charge-transfer and π → π* transitions in the target compounds. The excited state dynamics of the parent BODIPY 1 and dyads 2-4 and 6 were investigated using time-resolved transient spectroscopy. In all organometallic dyads 2-4 and 6 the initially excited state is rapidly quenched by electron transfer from the ferrocene ligand. The lifetime of the charge-separated state was found to be between 136 and 260 ps and demonstrates a systematic dependence on the electronic structure and geometry of BODIPYs 2-4 and 6.

Probing the electronic properties of a trinuclear molecular wire involving isocyanoferrocene and iron(II) phthalocyanine motifs.

A new trinuclear iron(II) complex involving two isocyanoferrocene ligands axially coordinated to iron(II) phthalocyanine, (FcNC)2FePc [Fc = ferrocenyl; Pc = phthalocyaninato(2-) anion], was isolated and characterized using a variety of spectroscopic methods as well as single-crystal X-ray diffraction. The redox behavior of the above molecular wire was investigated through electrochemical, spectroelectrochemical, and chemical oxidation approaches and compared to that of the bis(tert-butylisocyano)iron(II) phthalocyanine reference compound, (t-BuNC)2FePc. For both complexes, the first oxidation involves the phthalocyanine ligand and results in the formation of a red phthalocyanine cation-radical-centered [(RNC)2FePc](+) species, as evidenced by their UV-vis and electron paramagnetic resonance spectra. Despite the ~11.5 Šdistance between the isocyanoferrocene iron centers, the second and third oxidation potentials for (FcNC)2FePc are separated by ∼80 mV, which is indicative of a weak long-range metal-metal coupling in this system. Spectroscopic signatures of the mixed-valence [(FcNC)2FePc](2+) dication were obtained using spectroelectrochemical and chemical oxidation approaches. These experimentally assessed characteristics were also correlated with the electronic structure, redox properties, and spectroscopic signatures predicted by density functional theory (DFT) and time-dependent DFT analyses.