Triboelectrification of Active Pharmaceutical Ingredients: Amines and Their Hydrochloride Salts.

The triboelectric properties of active pharmaceutical ingredients (APIs) contribute to problems during the manufacturing of pharmaceuticals. However, the triboelectric properties of APIs have not been comprehensively characterized. In this study, the effect of salt formulation on the triboelectric properties of APIs was investigated. The triboelectric properties of three groups of amines, namely tertiary amines, purine bases, and amino acids, and their hydrochlorides were evaluated using a suction-type Faraday cage meter. Most of the hydrochloride salts exhibited more negative charges than the corresponding free bases, and the degree by which the triboelectric property changed upon hydrochlorination depended on the structural groups of the compounds. In the case of tertiary amines, the change in the zero-charge margin upon hydrochlorination was negatively correlated with the zero-charge margin of the free base. In contrast, hydrochlorination of the amino acids led to a significant change in the zero-charge margin. In most cases, salt formation also affected the triboelectric properties of API powders. Controlling the triboelectric properties of APIs solves various problems caused by the electrification of raw material powders and granules during the production of pharmaceuticals, thereby increasing the quality of produced pharmaceuticals.

Nebivolol Polymeric Nanoparticles-Loaded In Situ Gel for Effective Treatment of Glaucoma: Optimization, Physicochemical Characterization, and Pharmacokinetic and Pharmacodynamic Evaluation.

Nebivolol hydrochloride (NEB), a 3rd-generation beta-blocker, was recently explored in managing open-angle glaucoma due to its mechanism of action involving nitric oxide release for the vasodilation. To overcome the issue of low ocular bioavailability and the systemic side effects associated with conventional ocular formulation (aqueous suspension), we designed and optimized polycaprolactone polymeric nanoparticles (NEB-PNPs) by applying design of experiments (DoE). The particle size and drug loading of the optimized NEB-PNPs were 270.9 ± 6.3 nm and 28.8 ± 2.4%, respectively. The optimized NEB-PNPs were suspended in a dual-sensitive in situ gel prepared using a mixture of P407 + P188 (as a thermo-sensitive polymer) and κCRG (as an ion-sensitive polymer), reported previously by our group. The NEB-PNPs-loaded in situ gel (NEB-PNPs-ISG) formulation was characterized for its rheological behavior, physical and chemical stability, in vitro drug release, and in vivo efficacy. The NEB-PNPs-loaded in situ gel, in ocular pharmacokinetic studies, achieved higher aqueous humor exposure (AUC0-t = 329.2 ng × h/mL) and for longer duration (mean residence time = 9.7 h) than compared to the aqueous suspension of plain NEB (AUC0-t = 189 ng × h/mL and mean residence time = 6.1 h) reported from our previous work. The pharmacokinetic performance of NEB-PNPs-loaded in situ gel translated into a pharmacodynamic response with 5-fold increase in the overall percent reduction in intraocular pressure by the formulation compared to the aqueous suspension of plain NEB reported from our previous work. Further, the mean response time of NEB-PNPs-loaded in situ gel (12.4 ± 0.6 h) was three times higher than aqueous suspension of plain NEB (4.06 ± 0.3 h).

Simultaneous Protein Adsorption and Viscosity Measurement using Micropillar-Enhanced Acoustic Wave (µPAW) Device for Pharmaceutical Applications.

At the early stages of drug development, the amount of drug materials is rather limited. In this case, viscosity measurement is often postponed to the later stages, where grams of proteins can be produced. Therefore, it is necessary to develop a viscometer capable of measuring the viscosity with high accuracy while requiring low sample volume. This study presents a novel viscosity measurement technique based on measuring the resonance frequency and motional resistance of a micropillar-enhanced acoustic wave (µPAW) device. The µPAW was developed by fabricating micropillars on the quartz crystal microbalance substrate in order to achieve ultra-high sensitivity, thanks to a unique coupling between the micropillar and the resonator. The experimental measurements demonstrated a nonlinear relationship between the density and viscosity of the fluid and the response of µPAW. A calibration correlation was developed using the response of µPAW in aqueous glycerol and sucrose solutions. The measurements were then extended using high-concentration BSA solutions as the model of protein solution. The main advantage of the µPAW device in this work over other viscometers is the ability to simultaneously measure solution viscosity and protein adsorption on the surface. This is a huge step forward in the development of sensing systems for the pharmaceutical industry, where real-time sensing of target biological proteins and measuring the viscosity of a solution is required.

Structural Features of the Glassy State and Their Impact on the Solid-State Properties of Organic Molecules in Pharmaceutical Systems.

This paper reviews the structure and properties of amorphous active pharmaceutical ingredients (APIs), including small molecules and proteins, in the glassy state (below the glass transition temperature, Tg). Amorphous materials in the neat state and formulated with excipients as miscible amorphous mixtures are included, and the role of absorbed water in affecting glass structure and stability has also been considered. We defined the term "structure" to indicate the way the various molecules in a glass interact with each other and form distinctive molecular arrangements as regions or domains of varying number of molecules, molecular packing, and density. Evidence is presented to suggest that such systems generally exist as heterogeneous structures made up of high-density domains surrounded by a lower density arrangement of molecules, termed the microstructure. It has been shown that the method of preparation and the time frame for handling and storage can give rise to variable glass structures and varying physical properties. Throughout this paper, examples are given of theoretical, computer simulation, and experimental studies which focus on the nature of intermolecular interactions, the size of heterogeneous higher density domains, and the impact of such systems on the relative physical and chemical stability of pharmaceutical systems.

Impact of formulation parameters on self-assembled liposomes (LeciPlex® III): A detailed investigation.

The present study investigated the feasibility of fabricating self-assembled liposomes, LeciPlex®, a phospholipid-based vesicular nanocarrier using cationic, anionic, and nonionic stabilizers. The phospholipid investigated was soy phosphatidylcholine and the nano-precipitation method based on solvent diffusion was applied as the fabrication technique of liposomes in this study. The effects of various formulation variables, such as lipid and stabilizer concentration, total solid concentration, and solvent type on the self-assembly of vesicles were studied for physical characterization including particle size analysis, differential scanning calorimetry, viscosity, optical transmittance, transmission electron microscopy, and small angle neutron scattering. All three LeciPlex® systems exhibited a direct relationship between particle size and phospholipid concentration. The two categoric variables, solvent, and stabilizer used to prepare LeciPlex® demonstrated a significant effect on particle size for all three LeciPlex® systems. Small angle neutron scattering, and optical transmittance confirmed the formation of micellar systems at a phospholipid: stabilizer ratio of 1:2 and vesicular systems at a ratio of 2:1 for the systems stabilized with anionic and nonionic surfactants. In contrast to this, the LeciPlex® formed with the cationic stabilizer Dioctadecyldimethylammonium bromide (DODAB), formed vesicles at both ratios. From these investigations, it was clear that the formulation space for LeciPlex® was diversified by the addition of cationic, anionic, and non-ionic stabilizers.

Nanometals incorporation into active and biodegradable chitosan films.

This study investigates the effects of incorporating ZnO, TiO2, and colloidal Ag nanoparticles on the antioxidant, antimicrobial, and physical properties of biodegradable chitosan films. The research focuses on addressing the growing demand for sustainable packaging solutions that offer efficient food preservation while mitigating environmental concerns. In this investigation, the physical properties including thickness, water content, solubility, swelling degree, tensile strength, and elasticity of the chitosan films were examined. Additionally, the samples were analyzed for total polyphenol content, antimicrobial activity, and antioxidant capacity. Notably, the incorporation of ZnO nanoparticles led to the lowest water content and highest strength values among the tested films. Conversely, the addition of colloidal Ag nanoparticles resulted in films with the highest antioxidant capacities (DPPH: 32.202 ± 1.631 %). Remarkably, antimicrobial tests revealed enhanced activity with the inclusion of colloidal silver nanoparticles, yet the most potent antimicrobial properties were observed in films containing ZnO (E.coli: 2.0 ± 0.0 mm; MRSA: 2.0 ± 0.5 mm). The findings of this study hold significant implications for the advancement of edible biodegradable films, offering potential for more efficient food packaging solutions that address environmental sustainability concerns. By elucidating the effects of nanoparticle incorporation on film properties, this research contributes to the ongoing discourse surrounding sustainable packaging solutions in the food industry.

Construction of a soybean protein isolate/polysaccharide-based whole muscle meat analog: Physical properties and freeze-thawing stability study.

A growing interest has arisen in recreating real meat by mimicking its texture characteristics and muscle fiber structure. Our previous work successfully created meat analog fiber based on soybean protein isolate (SPI) and sodium alginate (SA) with the wet-spinning method. In this work, we analyzed the microstructure, texture profile, and water retainability of the assembled plant-based whole muscle meat analog (PMA) made of SPI/SA-based meat analog fiber and systematically studied the effect of different combinations and contents of transglutaminase (TG), salt, and soybean oil on the rheological behavior of the formulated adhesive. The estimated optimal condition that has the most similar texture characteristic with real chicken breast meat is: for every 1:1 mass ratio of simulated plant meat fibers to the adhesive, add 0.1 % TG enzyme addition in the adhesive and 100 mM NaCl addition. The physical behavior of PMA during cryopreservation was investigated through freeze-thaw cycles and freezing times. The addition of a small amount of oil and salt can efficiently prevent the PMA through freezing conditions which is comparable with the addition of D-Trehalose (TD). Overall, this study not only created a plant-based whole muscle meat analog product that is similar in texture to real chicken breast meat but also provided a new direction for constructing fiber-rich structure protein-based muscle meat analogs and their further commercialization.

Control of the Iron State in Pharmaceuticals Used for Treatment and Prevention of Iron Deficiency Using Mössbauer Spectroscopy.

Various iron-containing medicaments, vitamins and dietary supplements are used or developed for treatment and prevention of the iron deficiency anemia which is very dangerous for human and may cause various disorders. From the other hand, blood losses, iron poor diet, microelements (co-factors) deficiency, metabolic failures, absorption problems, etc. can change the iron status and affect the health. These pharmaceuticals contain iron compounds in the ferrous and ferric states. It is known that ferrous salts are more suitable for the intestinal intake than ferric ones. On the other hand, pharmaceutically important ferritin analogues contain ferric hydrous oxides and appear to be effective for both injections and peroral administration. 57Fe Mössbauer spectroscopy is a unique physical technique which allows one to study various iron-containing materials including pharmaceuticals. Therefore, this technique was applied to study iron-containing pharmaceuticals for the analysis of the iron state, identification of ferric and ferrous compounds, revealing some structural peculiarities and for detection of aging processes in relation to the iron compounds. This review considers the main results of a long experience in the study of iron-containing pharmaceuticals by Mössbauer spectroscopy with critical analysis that may be useful for pharmacists, biochemists, biophysicists, and physicians.

A Rational Hierarchy to Capture Raw Material Attribute Variability in the Pharmaceutical Drug Product Development and Manufacturing Lifecycle.

Assessing the robustness of a drug product formulation and manufacturing process to variations in raw material (RM) properties is an essential aspect of pharmaceutical product development. Motivated by the need to demonstrate understanding of attribute-performance relationships at the time of new product registration and for subsequent process maintenance, we review practices to explore RM variations. We describe limitations that can arise when active ingredients and excipients invariably undergo changes during a drug product lifecycle. Historical approaches, such as Quality-by-Design (QbD) experiments, are useful for initial evaluations but can be inefficient and cumbersome to maintain once commercial manufacturing commences. The relatively miniscule data sets accessible in product development - used to predict response to a hypothetical risk of variation - become less relevant as real-world experience of actual variability in the commercial landscape grows. Based on our observations of development and manufacturing, we instead propose a holistic framework exploiting a hierarchy of RM variability, and challenge this with common failure modes. By explicitly incorporating higher ranking RM variations as perturbations, material-conserving experiments are shown to provide powerful and enduring robustness data. Case studies illustrate how correctly contextualizing such data in formulation and process development can avoid the traps of historical QbD approaches and become valuable for evaluating changes occurring later in the drug product lifecycle.

Comprehensive evaluation of polymer types and ratios in Spray-Dried Dispersions: Compaction, Dissolution, and physical stability.

Amorphous solid dispersion (ASD) is a well-established strategy for enhancing the solubility and bioavailability of poorly soluble drugs. A significant portion of ASD products are in tablet form. However, the influence of common polymers and drug loading on the manufacturability of ASD tablets remains underexplored. This study focuses on investigating spray-dried ASDs from a tableting perspective by evaluating their physiochemical and mechanical properties. Itraconazole (ITZ) and indomethacin (IND), at the drug loadings ranging from 10% to 50%, were prepared with two polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone (PVP), serving as representative systems. Our findings revealed that increasing the drug loading resulted in a decreased surface area in ITZ-HPMCAS, IND-HPMCAS, and IND-PVP ASDs. However, this trend was not observed in ITZ-PVP dispersions, possibly due to the morphological disparities. Compaction results demonstrated that tabletability improved with decreasing drug loadings, except for ITZ-PVP dispersions. A partial least square analysis underscored particle surface area as the key factor influencing the tensile strength of ASD tablets. Additionally, our study disclosed that ITZ-PVP ASDs exhibited the worst release profiles and stability performance. The comprehensive journey from characterizing ASD particles to analyzing their compaction behavior and investigating drug release and physical stability offered profound insights into the attributes crucial for the downstream processing of amorphous pharmaceuticals.