Amorphous Drug-Polymer Salts: Maximizing Proton Transfer to Enhance Stability and Release.

An amorphous drug-polymer salt (ADPS) can be remarkably stable against crystallization at high temperature and humidity (e.g., 40°C/75% RH) and provide fast release. Here, we report that process conditions strongly influence the degree of proton transfer (salt formation) between a drug and a polymer and in turn the product's stability and release. For lumefantrine (LMF) formulated with poly(acrylic acid) (PAA), we first show that the amorphous materials prepared by slurry conversion and antisolvent precipitation produce a single trend in which the degree of drug protonation increases with PAA concentration from 0% for pure LMF to ∼100% above 70 wt % PAA, independent of PAA's molecular weight (1.8, 450, and 4000 kg/mol). This profile describes the equilibrium for salt formation and can be modeled as a chemical equilibrium in which the basic molecules compete for the acidic groups on the polymer chain. Relative to this equilibrium, the literature methods of hot-melt extrusion (HME) and rotary evaporation (RE) reached much lower degrees of salt formation. For example, at 40 wt % drug loading, HME reached 5% salt formation and RE 15%, both well below the equilibrium value of 85%. This is noteworthy given the common use of HME and RE in manufacturing amorphous formulations, indicating a need for careful control of process conditions to ensure the full interaction between the drug and the polymer. This need arises due to the low mobility of macromolecules and the mutual hindrance of adjacent reaction sites. We find that a high degree of salt formation enhances drug stability and release. For example, at 50% drug loading, an HME-like formulation with 19% salt formation crystallized faster and released only 20% of the drug relative to a slurry-prepared formulation with 70% salt formation. Based on this work, we recommend slurry conversion as the method for preparing ADPS for its ability to enhance salt formation and continuously adjust drug loading. While this work focused on salt formation, the impact of process conditions on the molecular-level interactions between a drug and a polymer is likely a general issue for amorphous solid dispersions, with consequences on product stability and drug release.

Kinetics of Surface Enrichment of a Polymer in a Glass-Forming Molecular Liquid.

X-ray photoelectron spectroscopy has been used to measure the surface concentration and the surface enrichment kinetics of a polymer in a glass-forming molecular liquid. As a model, the bulk-miscible system of maltitol-polyvinylpyrrolidone (PVP) was studied. The PVP concentration is significantly higher at the liquid/vapor interface than in the bulk by up to a factor of 170, and the effect increases with its molecular weight. At a freshly created liquid/vapor interface, the concentration of PVP gradually increases from the bulk value at a rate controlled by bulk diffusion. The polymer diffusion coefficient obtained from the kinetics of surface enrichment agrees with that calculated from viscosity and the Stokes-Einstein equation. Our finding allows prediction of the rate at which the surface composition equilibrates in an amorphous material after milling, fracture, and a change in ambient temperature.

Surface Enrichment of Surfactants in Amorphous Drugs: An X-ray Photoelectron Spectroscopy Study.

Surfactants are commonly incorporated into amorphous formulations to improve the wetting and dissolution of hydrophobic drugs. Using X-ray photoelectron spectroscopy, we find that a surfactant can significantly enrich at the surface of an amorphous drug, up to 100% coverage, wihout phase separation in the bulk. We compared four different surfactants (Span 80, Span 20, Tween 80, and Tween 20) in the same host acetaminophen and the same surfactant Span 80 in four different hosts (acetaminophen, lumefantrine, posaconazole, and itraconazole). For each system, the bulk concentrations of the surfactants were 0, 1, 2, 5, and 10 wt %, which cover the typical concentrations in amorphous formulations, and component miscibility in the bulk was confirmed by differential scanning calorimetry. For all systems investigated, we observed significant surface enrichment of the surfactants. For acetaminophen containing different surfactants, the strongest surface enrichment occurred for the most lipophilic Span 80 (lowest HLB), with nearly full surface coverage. For the same surfactant Span 80 doped in different drugs, the surface enrichment effect increases with the hydrophilicity of the drug (decreasing log P). These effects arise because low-surface-energy molecules (or molecular fragments) tend to enrich at a liquid/vapor interface. This study highlights the potentially large difference between the surface and bulk compositions of an amorphous formulation. Given their high mobility and low glass transition temperature, the surface enrichment of surfactants in an amorphous drug can impact its stability, wetting, and dissolution.

Impact of Drug-Polymer Intermolecular Interactions on Dissolution Performance of Copovidone-Based Amorphous Solid Dispersions.

For poorly soluble drugs formulated as amorphous solid dispersions (ASDs), fast and complete release with the generation of drug-rich colloidal particles is beneficial for optimizing drug absorption. However, this ideal dissolution profile can only be achieved when the drug releases at the same normalized rate as the polymer, also known as congruent release. This phenomenon only occurs when the drug loading (DL) is below a certain value. The maximal DL at which congruent release occurs is defined as the limit of congruency (LoC). The purpose of this study was to investigate the relationship between drug chemical structure and LoC for PVPVA-based ASDs. The compounds investigated shared a common scaffold substituted with different functional groups, capable of forming hydrogen bonds only, halogen bonds only, both hydrogen and halogen bonds, or nonspecific interactions only with the polymer. Intermolecular interactions were studied and confirmed by X-ray photoelectron spectroscopy and infrared spectroscopy. The release rates of ASDs with different DLs were investigated using surface area normalized dissolution. ASDs with hydrogen bond formation between the drug and polymer had lower LoCs, while compounds that were only able to form halogen bonds or nonspecific interactions with the polymer achieved considerably higher LoCs. This study highlights the impact of different types of drug-polymer interactions on ASD dissolution performance, providing insights into the role of drug and polymer chemical structures on the LoC and ASD performance in general.

Inhalable Nanocomposite Microparticles with Enhanced Dissolution and Superior Aerosol Performance.

Previous studies have shown that combining colistin (Col), a cationic polypeptide antibiotic, with ivacaftor (Iva), a cystic fibrosis (CF) drug, could achieve synergistic antibacterial effects against Pseudomonas aeruginosa. The purpose of this study was to develop dry powder inhaler formulations for co-delivery of Col and Iva, aiming to treat CF and lung infection simultaneously. In order to improve solubility and dissolution for the water-insoluble Iva, Iva was encapsulated into bovine serum albumin (BSA) nanoparticles (Iva-BSA-NPs). Inhalable composite microparticles of Iva-BSA-NPs were produced by spray-freeze-drying using water-soluble Col as the matrix material and l-leucine as an aerosol enhancer. The optimal formulation showed an irregularly shaped morphology with fine particle fraction (FPF) values of 73.8 ± 5.2% for Col and 80.9 ± 4.1% for Iva. Correlations between "D×ρtapped" and FPF were established for both Iva and Col. The amorphous solubility of Iva is 66 times higher than the crystalline solubility in the buffer. Iva-BSA-NPs were amorphous and remained in the amorphous state after spray-freeze-drying, as examined by powder X-ray diffraction. In vitro dissolution profiles of the selected DPI formulation indicated that Col and Iva were almost completely released within 3 h, which was substantially faster regarding Iva release than the jet-milled physical mixture of the two drugs. In summary, this study developed a novel inhalable nanocomposite microparticle using a synergistic water-soluble drug as the matrix material, which achieved reduced use of excipients for high-dose medications, improved dissolution rate for the water-insoluble drug, and superior aerosol performance.

Insights into the Dissolution Behavior of Ledipasvir-Copovidone Amorphous Solid Dispersions: Role of Drug Loading and Intermolecular Interactions.

The generation of a colloidal drug-rich phase by dissolving an amorphous solid dispersion (ASD) is thought to have a positive impact on oral absorption and bioavailability. Thus, understanding which formulations generate these species is important. In this study, ledipasvir-copovidone ASDs, with and without surfactants, were prepared, and their release performance was examined at different drug loadings. An intrinsic dissolution rate assembly was used to limit potential surface area variations among formulations, and the release of both polymer and drug was monitored as a function of time. Drug-rich colloids only formed when the drug loading (DL) was at or below 5%; at a DL of 7.5% or above, drug release became negligible. The drug and polymer released congruently at and below 5% DL and incongruently at higher DLs. Thus, the limit of congruency (LoC) is between 5 and 7.5% DL. X-ray photoelectron spectroscopy (XPS) of partially dissolved tablet surfaces revealed that a drug-rich layer formed on the surface of the tablet. This was most evident for the higher DL ASDs and led to amorphous drug-controlled dissolution. Consequently, the surface drug-enriched layer physically hindered the polymer from further release. Evidence is provided that the extent of drug-polymer interactions as a function of DL plays a central role in dictating the observed release behavior. Some surfactants were found to promote the formation of drug-rich colloids at considerably higher DLs, providing a formulation strategy to increase the LoC.

Multifunctional superparamagnetic nanocarriers with folate-mediated and pH-responsive targeting properties for anticancer drug delivery.

Multifunctional nanocarriers with multilayer core-shell architecture were prepared by coating superparamagnetic Fe(3)O(4) nanoparticle cores with a mixture of the triblock copolymer methoxy poly(ethylene glycol)-b-poly(methacrylic acid-co-n-butyl methacrylate)-b-poly(glycerol monomethacrylate) and the folate-conjugated block copolymer folate-poly(ethylene glycol)-b-poly(glycerol monomethacrylate). The model anticancer agent adriamycin (ADR), containing an amine group and a hydrophobic moiety, was loaded into the nanocarrier at pH 7.4 by ionic bonding and hydrophobic interactions. The release rate of the loaded drug molecules was slow at pH 7.4 (i.e. mimicking the blood environment) but increased significantly at acidic pH (i.e. mimicking endosome/lysosome conditions). Acid-triggered drug release resulted from the polycarboxylate protonation of poly(methacrylic acid), which broke the ionic bond between the carrier and ADR. Cellular uptake by folate receptor-overexpressing HeLa cells of the folate-conjugated ADR-loaded nanoparticles was higher than that of non-folated-conjugated nanoparticles. Thus, folate conjugation significantly increased nanoparticle cytotoxicity. These findings show the potential viability of a folate-targeting, pH-responsive nanocarrier for amine-containing anticancer drugs.