Drug Phase Transformation and Water Redistribution during Continuous Tablet Manufacturing: A Case Study of Carbamazepine Dihydrate.

In recent years, continuous tablet manufacturing technology has been used to obtain regulatory approval of several new drug products. While a significant fraction of active pharmaceutical ingredients exists as hydrates (wherein water is incorporated stoichiometrically in the crystal lattice), the impact of processing conditions and formulation composition on the dehydration behavior of hydrates during continuous manufacturing has not been investigated. Using powder X-ray diffractometry, we monitored the dehydration kinetics of carbamazepine dihydrate in formulations containing dibasic calcium phosphate, anhydrous (DCPA), mannitol, or microcrystalline cellulose. The combined effect of nitrogen flow and vigorous mixing during the continuous mixing stage of tablet manufacture facilitated API dehydration. Dehydration was rapid and most pronounced in the presence of DCPA. The dehydration product, amorphous anhydrous carbamazepine, sorbed a significant fraction of the water released by dehydration. Thus, the dehydration process resulted in a redistribution of water in the powder blend. The unintended formation of an amorphous dehydrated phase, which tends to be much more reactive than its crystalline counterparts, is of concern and warrants further investigation.

Understanding the Synergic Mechanism of Weak Interactions between Graphene Oxide and Lipid Membrane Leading to the Extraction of Lipids.

Revealing how weak forces interact synergistically to induce differences in nanobio effects is critical to understanding the nature of the nanobio interface. Herein, graphene oxide (GO) and a lipid membrane are selected as a nanobio model, and interaction forces at the GO-biomembrane interface are modulated by varying the amounts and species of oxygenated functional groups on the surface of GO. A synergic mechanism of interfacial interaction forces is investigated by a combination of surface-enhanced infrared absorption (SEIRA) spectroscopy, confocal laser scanning microscopy (CLSM), and electrochemical impedance spectroscopy (EIS). The results reveal that after balancing with electrostatic repulsion, the moderate attraction between GO and lipid headgroups (such as electrostatic and/or hydrophobic interactions) is most favorable for lipid extraction, whereas lipid extraction is inhibited under an attraction that is too strong or too weak. Under moderate attraction between GO and the headgroups of lipids, the appropriate degree of rotation freedom is maintained for GO, which is beneficial to the hydrogen-bonding interaction between the C═O group in the phosphatide hydrophobic region and GO, thus triggering the insertion of GO into the lipid alkyl chain region, resulting in the rapid and significant extraction of lipids. Our results have important guiding significance for how to reveal the synergistic mechanism of weak interactions at the nanobio interface.

Specific Generation of Singlet Oxygen through the Russell Mechanism in Hypoxic Tumors and GSH Depletion by Cu-TCPP Nanosheets for Cancer Therapy.

The generation of singlet oxygen (1 O2 ) during photodynamic therapy is limited by the precise cooperation of light, photosensitizer, and oxygen, and the therapeutic efficiency is restricted by the elevated glutathione (GSH) levels in cancer cells. Herein, we report that an ultrathin two-dimensional metal-organic framework of Cu-TCPP nanosheets (TCPP=tetrakis(4-carboxyphenyl)porphyrin) can selectively generate 1 O2 in a tumor microenvironment. This process is based on the peroxidation of the TCPP ligand by acidic H2 O2 followed by reduction to peroxyl radicals under the action of the peroxidase-like nanosheets and Cu2+ , and their spontaneous recombination reaction by the Russell mechanism. In addition, the nanosheets can also deplete GSH. Consequently, the Cu-TCPP nanosheets can selectively destroy tumor cells with high efficiency, constituting an attractive way to overcome current limitations of photodynamic therapy.

In Situ Surface-Enhanced Infrared Absorption Spectroscopy of Aqueous Molecules with Facile-Prepared Large-Area Reduced Graphene Oxide Island Film.

Midinfrared plasmons in patterned graphene could advance the development of surface-enhanced infrared absorption spectroscopy (SEIRAS). However, limitation in measuring the extinction spectra with transmission and external reflection configurations greatly restricts the analyses of aqueous samples. In addition, complicated, time- and cost-consuming preparation of patterned graphene also limits its progress. Here we demonstrate a facile-prepared large-scale reduced graphene oxide island film on a total internal reflection silicon prism, which not only shows a prominent enhancement effect in mid-infrared region but also effectively eliminates the contribution of bulk solution by optical near-field effect. As a result, the entire vibrational fingerprints of methylene blue monolayer in aqueous solution can be acquired with high sensitivity in real time. Our work extends the application of graphene-based SEIRAS to aqueous environment, breaking through previously unattainable technology.

Mechanistic Analysis of Cocrystal Dissolution as a Function of pH and Micellar Solubilization.

The purpose of this work is to provide a mechanistic understanding of the dissolution behavior of cocrystals under the influence of ionization and micellar solubilization. Mass transport models were developed by applying Fick's law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving cocrystal surface to predict the pH at the dissolving solid-liquid interface (i.e., interfacial pH) and the flux of cocrystals. To evaluate the predictive power of these models, dissolution studies of carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) cocrystals were performed at varied pH and surfactant concentrations above the critical stabilization concentration (CSC), where the cocrystals were thermodynamically stable. The findings in this work demonstrate that the pH dependent dissolution behavior of cocrystals with ionizable components is dependent on interfacial pH. This mass transport analysis demonstrates the importance of pH, cocrystal solubility, diffusivity, and micellar solubilization on the dissolution rates of cocrystals.

[Exosome-Mediated Small RNA Delivery For Gene Therapy].

Small RNAs,including small interfering RNAand microRNA,are emerging as promising ther-apeutic drugs against a wide array of diseases.Current techniques for small RNA transfer use viruses or synthetic agents as delivery vehicles,however,these kinds of vehicles have a high toxicity and low target-specific.Exosomes ,natural nanocarriers derived from endogenous cells ,have the intrinsic ability to trav-erse biological barriers and to naturally transport functional small RNAs between cells.Exosome-based de-livery of small RNAs may provide an untapped source of effective delivery strategy to overcome impedi-ments such as inefficiency,unspecificity and immunogenic reactions,and exosomes potentially represent a novel and exciting delivery vehicle.In this review,we provide an update and overview of the new find-ings that reveal the potential applications of exosome-based small RNA delivery as therapeutics in clinical settings.

Mechanistic Analysis of Cocrystal Dissolution, Surface pH, and Dissolution Advantage as a Guide for Rational Selection.

The dissolution behavior of a dibasic drug ketoconazole under the influence of pH has been evaluated and compared to its three 1:1 cocrystals with diacidic coformers, fumaric acid, succinic acid (SUC), and adipic acid. Mass transport models were developed by applying Fick's law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving surface to predict the interfacial pH and flux of the parent drug and cocrystals. All 3 cocrystals have the ability to modulate the interfacial pH to different extents compared to the parent drug due to the acidity of the coformers. Dissolution pH dependence of ketoconazole is significantly reduced by the cocrystallization with acidic coformers. Due to the different dissolution pH dependence, there exists a transition pH where the flux of the cocrystal is the same as the parent drug. Below this transition pH, the drug flux is higher, but above it, the cocrystal flux is higher. The development of these mass transport models provide a mechanistic understanding of the dissolution behavior and help identify cocrystalline solids with optimal dissolution characteristics.

Dynamic surface properties of PEG-coated CuS nanoparticles alter their interaction with cells as revealed by surface-enhanced infrared spectroscopy.

Characterization of the dynamic changes of the basic surface properties of nanoparticles is of great significance to reveal the interaction mechanism between nanoparticles and cells; however, it is often neglected due to the limitations of existing analytical methods. This knowledge has been renewed by using surface enhanced infrared absorption spectroscopy (SEIRAS) to study the interaction between PEG-CuS nanoparticles and living cells attached to rGO-Au modified Au films. Based on the difference spectra of cell membranes and the associated water, we clearly revealed that Cu2+ ions produced by the degradation of PEG-CuS can coordinate with PEG, thus changing the interaction between nanoparticles and cells including how and how many nanoparticles enter the cells and the sequential photothermal effect, which breaks through the limitations of the present analytical methods.

Mechanistic Basis of Cocrystal Dissolution Advantage.

Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development.

Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5.

Besides enhancing aqueous solubilities, cocrystals have the ability to fine-tune solubility advantage over drug, supersaturation index, and bioavailability. This review presents important facts about cocrystals that set them apart from other solid-state forms of drugs, and a quantitative set of rules for the selection of additives and solution/formulation conditions that predict cocrystal solubility, supersaturation index, and transition points. Cocrystal eutectic constants are shown to be the most important cocrystal property that can be measured once a cocrystal is discovered, and simple relationships are presented that allow for prediction of cocrystal behavior as a function of pH and drug solubilizing agents. Cocrystal eutectic constant is a stability or supersatuation index that: (a) reflects how close or far from equilibrium a cocrystal is, (b) establishes transition points, and (c) provides a quantitative scale of cocrystal true solubility changes over drug. The benefit of this strategy is that a single measurement, that requires little material and time, provides a principled basis to tailor cocrystal supersaturation index by the rational selection of cocrystal formulation, dissolution, and processing conditions.