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Interest in oral delivery of biological drug products, commonly prepared through lyophilization, is surging. Typically, low solid content solutions are employed for lyophilization to enhance mass transfer and minimize drying time. Yet, this approach often results in lyophilized powders with low bulk density and poor flowability, challenging downstream processing steps that are required for oral product development. Increasing solid content in a starting solution can, in theory, increase the density of lyophilized cakes and powders post-milling. However, the effectiveness of improving powder density and flowability using a higher solid content has not been experimentally verified. In addition, the impact of using a higher solid content on other physicochemical properties of lyophilized materials remains uncertain. To address the knowledge gaps, we lyophilized three common bulk cryoprotectants at two different solid contents (5% and 10%) and systematically evaluated their solid-state properties, bulk density, flowability, compaction characteristics, and physical stability. We found that powders prepared at a higher solid content (10%) exhibited higher bulk density, but they still failed to meet the requirements for easy oral product development. A change in solid content also leads todistinct solid-state properties, compaction behaviors, and stability, highlighting the importance of thorough characterization of lyophilized materials when solid content is changed in the course of oral solid dosage formulation development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ketorolac, a nonsteroidal anti-inflammatory drug, exhibits moderate antipyretic and anti-inflammatory properties, as well as potent analgesic effects. It is widely used in clinical practice for pain relief in cases of mild and severe pain such as postoperative pain, fractures, sprains, toothaches and cancer pain. Due to its relatively short half-life, patients experiencing pain often need frequent injections or oral medications, leading to poor patient compliance. Thus, it is crucial to create long-acting sustained-release formulations of ketorolac. This paper provides an overview of the research, applications, and challenges associated with ketorolac sustained-release formulations over the past decade, based on a comprehensive review of the literature. The aim is to provide fresh insights for the research and development of long-acting, sustained-release, and controlled-release formulations of ketorolac., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

This study investigates the effect of silanol density on the surface of glass containers on the stability of monoclonal antibody (mAb) formulations subjected to mechanical stress. By calcining Type I glass containers at different temperatures, we altered the concentration of silanols on the glass surface and examined its impact on the stability of protein formulations under mechanical stress. Contact angle measurements and Fourier Transform Infrared (FTIR) spectroscopy indicated that silanol formation influences the hydrophilicity of the surface. Additionally, mAb solutions filled in Type I glass containers with varying silanol densities were repeatedly dropped from a height of 0.5 m to simulate mechanical stress during transport. The results demonstrated that increasing surface silanol density reduces protein monomer loss and the formation of protein aggregates and subvisible particles. Furthermore, protein aggregates and subvisible particles formed by dropping did not activate the complement in human serum in vitro. Adjusting the silanol density on the glass container surface offers an economical and environmentally friendly approach to improving the stability of mAb formulations during transportation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Conventional drug formulations release active pharmaceutical ingredients (APIs) immediately after administration, while long-acting (LA) drug products are designed for prolonged therapeutic effects, thereby reducing administration frequency and improving patient compliance. The development of LA therapeutics for chronic disease treatment has significantly helped patients adhere to their regimens, reducing the need for daily doses and easing the burden on healthcare systems. Advances in treatment have transformed Human Immunodeficiency Virus (HIV) into a manageable chronic disease, and efforts are underway to eliminate HIV in the future. Nowadays, antiretroviral therapies (ARTs) are widely available and accessible, daily oral pre-exposure prophylaxis (PrEP) has been highly effective and the new LA ARTs and LA PrEP are being actively pursued. The development of LA antiretrovirals for HIV has revolutionized the landscape of global implementation of HIV prevention and treatment. This article provides an overview of LA medicines (pills, injections, solid implants, and in situ forming depots) for the prevention and treatment of HIV from a pharmaceutics perspective, describing approved medicines, recognizing promising technologies, and discussing the pros and cons of poly (lactic-co-glycolic acid) (PLGA) particles, liposomes, hydrogels, and organogel formulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Enhancing the aqueous solubility via amorphization of crystalline poor glass-forming drugs represents a challenge, particularly when drug dosing is high. In such scenarios, there is often a need for high polymer loadings, leading to an increase in the dosage form mass and less patient acceptability. This work investigated the role that polymer type and after-melt cooling rate had upon the amorphicity of solid dispersions (SDs) containing high levels of naproxen and three commonly used polymeric excipients: Eudragit® EPO, Kollidon® VA64, and Soluplus®. Using a combination of thermogravimetry, conventional and fast-scan DSC, oscillatory rheology, in silico Hansen solubility parameter computation, FTIR, and PXRD, we have shown that amorphicity could be affected by the cooling rate with the specific polymer type and amount playing a significant role in the degree of this impact. The amorphous drug content, evident at higher cooling rates, was found to be dependent on drug-polymer interaction and polymer melt viscosity. Higher polymer concentration and faster cooling produced less melt crystallization upon cooling, which was attributed to a shift in nucleation to lower temperatures where it could be inhibited by polymer matrix viscosity. Amorphous drug content, which contained drug nuclei, was evidenced by cold crystallization upon reheating. After 4 weeks of 'gentle' storage, cold crystallization increased if nucleation was the dominant process, whereas cold crystallization decreased if crystal growth prevailed. Storage at elevated temperature and humidity resulted in the absence of cold crystallization, and increased melt crystallisation. Thus, faster cooling could serve as an additional tool to improve amorphous yield and stability of high drug-loaded SDs, however, intermolecular polymer-drug interaction, melt viscosity of the drug-polymer matrix, and storage conditions are of critical importance to achieve this goal., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In the realm of therapeutic antibodies, co-formulations comprising two or more monoclonal antibodies (mAbs) have emerged as a promising strategy, offering enhanced treatment efficacy, improved efficiency, and prolonged intellectual property protection. These advantages have sparked significant interest among both patients and pharmaceutical companies. However, the quantification and analysis of individual mAbs within such co-formulations pose a substantial challenge due to their similar physicochemical properties. To address this challenge, we introduce a pH gradient cation exchange chromatography (CEX) method designed to effectively separate three mAbs that share significant similarities in molecular weight, structure, and isoelectric points (pIs) etc. This versatile approach not only facilitates the accurate quantification of each mAb's concentration and their respective ratios within the co-formulation, but also allows for the comprehensive characterization of all charge variants present. In the case of a co-formulation containing three antibodies, the developed CEX method demonstrated superior performance compared to other techniques. The method's robustness was further underscored by its qualification parameters, including acceptable precision (RSD ≤ 3 %), accuracy (95 %-115 % recovery), and linearity (R 2  > 0.99) across a range of 10 to 30 μg load for each mAb. Moreover, the method has been successfully applied in stability studies to quantitatively analyze individual mAb concentrations within co-formulations, marking a significant advancement in the field. Through this work, we contribute a crucial analytical insight into mAb co-formulations, especially those comprising three or more molecules, underscoring its considerable potential to propel the field of biotherapeutic co-formulations forward., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Pharmaceutical tablets are routinely film-coated to improve appearance, reduce medication errors and enhance storage stability. Terahertz pulsed imaging (TPI) can be utilised to study the liquid penetration into the porous tablet matrix in real time. Using polymer-coated flat-faced tablets with anhydrous lactose or mannitol, we show that when the tablet matrix contains anhydrous material, the anhydrous form transforms to the solid-state hydrate form in the tablet core while the immediate release coating dissolves. The process starts at the interface between the coating and the core. It commences inward for more than 7min, resulting in a shell of hydrate form on the order of a few hundred microns thicknesses immediately underneath the dissolving coating. TPI is sensitive enough to detect and spatially resolve this process based on the subtle change in the refractive index of the two materials. TPI can further resolve tablets with different components using the time-domain waveforms in reflection and provide insights into the presence of hydrate material (lactose monohydrate) in altering the water mass transport mechanism. The kinetics data obtained from TPI fit the power law model (y=kt m ), whose constants enable us to infer the different mass transport mechanisms., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mingrui Ma reports financial support was provided by Cambridge Commonwealth European and International Trust. Mingrui Ma reports financial support was provided by CSC Chinese Scholarship Council. Member of the editorial board at IJParm - JAZ If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Favipiravir, a high dose antiviral drug effective for oral treatment for COVID-19, with poor water solubility is formulated using a simple, low-cost melt coating and granulation methodology. High-dose (82.5 % w/w API) tablets (600 mg and 800 mg) with desired release profiles are developed while minimizing excipient burden. First, twin-screw melt coating and granulation (MCG) of Favipiravir, using Poloxamer P188 as a binder as well as a surfactant, was utilized to create Favipiravir granules with high solubility and tabletability. These granules were then blended with a small amount of extra-granular ingredients (high molecular weight Hydroxypropylmethyl Cellulose and Magnesium Stearate) and compacted into tablets with desired controlled-release tablets. Results demonstrate that the application of MCG to coat and granulate a poorly soluble drug, using a low melting point surfactant as a binder and wetting agent, can be an effective approach to manufacture high-dose modified release formulations for low solubility drugs that are common in the treatment of infectious diseases, cancer, autoimmune diseases, and many other conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

In this study, lyophilizates with the second-class antipsychotic agent lurasidone hydrochloride were developed as orodispersible platforms to improve patients' adherence. The primary aim was to evaluate the effect of the amino acid additive (L-arginine, L-lysine, L-histidine) and the freeze-drying stage on the pharmaceutical performance of the designed formulations. The composition was initially optimized using an experimental design approach. The amino acids (in particular L-histidine) acted as dispersing agents, prevented drug aggregation and assured high drug content uniformity within the lyophilizate matrix. The freeze-drying stage reduced the particles dimensions which significantly increased solubility of lurasidone hydrochloride, and consequently, it's dissolution rate. The presence of L-arginine in lyophilizate composition balanced out sufficient compression strength with a rapid drug release. Despite the fact that L-lysine enhanced the mechanical strength, it also caused delayed drug release. Notably, L-histidine and L-arginine accelerated transport of lurasidone hydrochloride through the porcine buccal epithelium with approximately 100% and 50% increase in absorption, respectively, when compared to commercial reference drug. Overall, the designed lyophilizates containing L-histidine and L-arginine, hold promise as orodispersible platforms for improved performance of lurasidone hydrochloride., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Buffer exchange is a critical step in biologics development, playing a pivotal role in removing contaminants, adjusting sample conditions, and facilitating compatibility studies. The efficiency of centrifugal concentrators for polysorbate removal was compared to a two-step approach involving a surfactant removal column followed by buffer exchange. Trastuzumab-pkrb from Herzuma® was used. While a 30 kDa centrifugal concentrator was ineffective in polysorbate removal, a 50 kDa concentrator caused partial removal. Surfactant removal column proved more effective in removing polysorbates. Buffer exchange using polysorbate-containing formulation buffer, even with a 50 kDa concentrator, accumulated polysorbate, revealing the need for a different approach in small-scale formulation. Adding polysorbate in a separate step after buffer exchange appeared to be a good strategy to prevent this problem. The two approaches did not reveal any differences in the protein aggregation behavior., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The coamorphous formulations have attracted increasing interest due to enhanced solubility and bioavailability, together with synergistic pharmacological effects. In this study, a ternary coamorphous system of polyphenols was successfully prepared, wherein baicalein (Bai) and resveratrol (Res) were constructed into a single-phase coamorphous system mediated by piperine (Pip). FTIR and ss 13 C NMR spectra together with quantum chemical calculation and molecular dynamics simulation suggested Pip as a molecular bridge connected Bai and Res molecules through π-π stacking and hydrogen bonding interactions. The configuration of coamorphous Bai-Pip-Res could minimize the system energy to facilitate its formation and enhance the stability. The ternary system showed 3.2, 4.3 and 5.3-fold increase in apparent solubilities of Bai, Res and Pip, and maintained the peak concentrations for at least 24 h. Compared to binary coamorphous systems, the ternary system exhibited superior physical stability under temperature and humidity conditions. Furthermore, coamorphous Bai-Pip-Res exhibited enhanced antibacterial activity, significant antioxidant ability and synergistic anti-inflammatory effect. This work offers a promising strategy to construct a ternary coamorphous delivery system with enhanced pharmaceutical properties by incorporating a molecular bridge, especially for components with the lack of intermolecular interactions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Numerous commercially available biopharmaceuticals are frozen or freeze-dried in vials. The temperature at which ice nucleates and its distribution across vials in a batch is critical to the design of freezing and freeze-drying processes. Here we study experimentally how the level of particulate impurities - a key parameter in pharmaceutical manufacturing - affects the ice nucleation behavior. Samples prepared under particulate-free conditions were found to nucleate at significantly lower temperatures and with more variability than samples of the same composition that were prepared under standard laboratory conditions, i.e., without using any means of lowering particulate counts. In contrast, spiking solutions with silver iodide particles resulted in significantly higher and less variable nucleation temperatures. These findings confirm that the level of particulates has a relevant effect on the rate of ice nucleation under conditions of industrial relevance. We further assessed the nucleation behavior of two biopharmaceuticals, a vaccine based on a viral vector and a mAb, and observed major differences in their nucleation behavior. This emphasizes the importance of measuring the ice nucleation behavior of biopharmaceuticals during process design., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marco Mazzotti reports financial support was provided by The Janssen Pharmaceutical Companies of Johnson & Johnson. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Cosmetic inspection of freeze-dried products is an important part of the post-manufacturing quality control process. Traditionally done by human visual inspection, this method poses typical challenges and shortcomings that can be addressed with innovative techniques. While many cosmetic defects can occur, some are considered more critical than others as they can be harmful to the patient or affect the drug's efficacy. With the rise of artificial intelligence and computer vision technology, faster and more reproducible quality control is possible, allowing real-time monitoring on a continuous manufacturing line. In this study, several continuously freeze-dried samples were prepared using formulations and process settings that lead deliberately to specific defects faced in freeze-drying as well as defect-free samples. Two approaches (i.e. patch-based approach and multi-label classification) capable of handling high-resolution images based on Convolutional Neural Networks were developed and compared to select the optimal one. Additional visualization techniques were used to enhance model understanding further. The best approach achieved perfect precision and recall on critical defects, with a prediction time of less than 50 ms to make a decision on the acceptance or rejection of vials generated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

This study used Raman and near-infrared (NIR) spectroscopy to monitor small real-time changes in powder blends and tablets in low-dose pharmaceutical formulations. The research aims to enhance process analytical technology (PAT) in pharmaceutical manufacturing, ensuring high-quality and uniform products with applications to produce drugs with narrow therapeutic indices (NTI). The study utilizes Raman and NIR spatially resolved spectroscopy (SRS) techniques to monitor a moderate cohesive material's active pharmaceutical ingredient (API) concentrations during manufacturing. The sampling locations were a bin blender for the batch blending procedure where the powder heterogeneity plays a significant role in product homogeneity, a feed frame of a tablet press where powder blend dynamics is critical to final product quality, and the outlet port of the tablet press where tablets immediately after ejection can be monitored in real-time. The study used semifine acetaminophen (APAP) as the API. Results indicated that Raman and NIR SRS could detect small API concentration changes as low as 0.50 %w/w, demonstrating their sensitivity and utility in real-time monitoring. The findings support the feasibility of these techniques in ensuring tight process control and highlight the performance of reducing waste and optimizing manufacturing processes in line with quality by design principles. The results highlight the importance of residence time distribution (RTD) in understanding the flow of the materials and powder behavior within the tablet press feed frame. RTD analyses showed that both Raman and NIR SRS techniques could effectively track concentration changes and ensure uniformity in the powder blends and tablets with signal-to-noise ratios higher than 3, demonstrating the sensitivity of the methods to small API changes. The %RSD during a steady state of 250 s (corresponding to 1.04 kg of material at 15 kg/h) for the step changes presented values of 6.74 % at 0.50 %w/w, 5.39 % at 1.00 %w/w, and 2.99 % at 1.50 %w/w for Raman predictions in powder blends within the feed frame and 15.46 % at 0.50 %w/w, 9.64 % at 1.00 %w/w, and 5.68 % at 1.50 %w/w for NIR SRS predictions of tablets ejected at the outlet port of the tablet press. In conclusion, this research demonstrates the potential of advanced spectroscopic techniques and data analysis in pharmaceutical manufacturing. By enabling precise real-time monitoring and control, these techniques contribute to higher-quality drug products, particularly NTI drugs, aligning with modern regulatory expectations and advancing pharmaceutical production technology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Poly(DL-lactide-co-glycolide) (PLGA) and N-methyl-2-pyrrolidone (NMP)-based in situ forming implants are liquid formulations that solidify through phase separation following injection into the body. Drug is dissolved or suspended in the final formulation liquid prior to injection. Depending on the polymers used, the depots formed can deliver drug over different periods of time. Accordingly, it is important to understand the impact of PLGA properties on implant drug release. However, currently available publications only investigate such impacts based on a single drug, which is insufficient to determine the potential interplay between drug and PLGA properties affecting drug release, or to draw any solid conclusions concerning the general impact of PLGA on drug release. The current work explores in situ forming implants with different active pharmaceutical ingredients (APIs) to determine whether any interplay between the APIs and the polymer attributes might affect drug release. In particular, the drug state (solution or suspension form) may impact polymer interaction and drug release. Naproxen and meloxicam were chosen as model drugs and were loaded into in situ forming implants. The final implants of naproxen and meloxicam were solutions and suspensions, respectively. The impact of PLGA properties (slight changes in molecular weight (MW), slight/major changes in lactic/glycolic acid (L/G) ratio, as well as changes in polymer blockiness in end-cap (acid vs ester)) on drug release was investigated. The slight changes in PLGA MW (18-31 KDa), L/G ratio (75/15-85/15) and blockiness had similar impacts on the release of naproxen and meloxicam from the formulations. These impacts were consistent with a previous report on risperidone implants. However, the impact of end-cap and significant change in the L/G ratio (from 75/15-85/15 to 50/50) was determined to be drug dependent. For meloxicam and for risperidone (previous report), the ester end-cap (compared to the acid end-cap) and much higher L/G ratio (75/15-85/15 versus 50/50) resulted in significantly longer overall drug release durations. In contrast, the naproxen implants had shorter release durations when prepared with the ester end-caped polymer (compared to acid end-cap), and when prepared with significantly higher L/G ratio polymers (75/15-85/15 versus 50/50). In addition, using the same PLGA polymer, implants loading different APIs demonstrated different release durations. This work highlights the complexity of PLGA attributes in determining the performance of implant drug formulations and the critical role of the interplay with the API properties. This study provides valuable knowledge for the future development of in situ forming implant drug products., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Over the next decade, Precision Medicine (PM) is poised to become the standard of care in pharmaceutical therapy, necessitating a fundamental transformation in the design and development of innovative custom-made drug products. To date, a comprehensive review linking PM with practical personalized drug formulations is missing. This review attempts to provide an overview of state-of-the-art formulation approaches capable of translating PM evaluation and resulting recommendations (clinical research) into tailored drug products (non-clinical research) for real-world patients. Comprehensive literature searches in four scientific databases (Scopus, SciFinder, Web of Science, and PubMed) were performed. Current approaches to point-of-care PM formulations and needs-based locally distributed manufacturing presently under research & development (R&D) as alternatives to conventional large-scale manufacturing of one-size-fits-all drug products are discussed. The following methods were identified as the most promising PM formulation strategies: tablet splitting, liquid dispensing, compounding pharmacies, additive manufacturing, drug impregnation, drug extrusion, and orodispersible films (ODFs). The challenges and opportunities of current state-of-the-art formulation technologies that can enable making PM routinely accessible in practice settings will be discussed. Additionally, light will be shed on point-of-use manufacturing (Pharmacy on Demand) as an uncharted territory for PM and its pathway towards practical implementation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Atomization-based techniques are widely used in pharmaceutical industry for production of fine drug particles due to their versatility and adaptability. Key performance measure of such techniques is their ability to provide control over critical quality attributes (CQAs) of produced drug particles. CQAs of drug particles produced via atomization critically depend on fluid dynamics of sprays; resulting mixing, heat and mass transfer; distribution of supersaturation and subsequent nucleation and growth of particles. It is essential to develop and use computational fluid dynamics (CFD) models for adequate understanding of multi-scale transport processes ranging from molecular scale mixing and particle scale processes, and from atomizer nozzle to overall spray chamber scale establishing relationships between CQAs and design and operating parameters of spray nozzle and chamber. In this work, we critically review past and current research efforts on CFD modelling of pharmaceutical atomization-based processes with an objective to provide clear assessment of the state of the art and to provide recommendations. An overview of the key atomization-based methods for producing drug particles with desired CQAs is presented. Key underlying physical processes and relevant concepts are then outlined. This discussion is related to the demands on CFD models; and state of the art is then discussed with respect to the process needs. Recommendations are provided towards higher fidelity and more efficient models of atomized multiphase flow dynamics and turbulence, drying modelling for the produced particles, and validation approaches. We conclude by highlighting a perceived need for numerical atomization studies with a pharmaceutical context; then, we deliver an outlook on current promising active control and machine learning strategies to augment the shift towards quality-by-design approaches in pharmaceutical manufacturing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

The pharmaceutical industry has expressed a lot of interest in site specific drug delivery & oral controlled release to increase treatment efficiency. The idea of a unique drug delivery system was developed to address several concerns with the physicochemical characteristics of drug molecules and the associated formulations. The use of gastro retentive systems for drug delivery, which focus on site-specific drug release for either systemic or local effects in the stomach, is one of these cutting-edge strategies for lengthening gastric residency time. This approach is especially useful for drugs that have a small window of upper gastro intestinal tract absorption. This review has discussed various gastro-retentive techniques, including floating & non-floating systems. With a focus on the numerous gastro retentive approaches that have lately emerged as the most efficient methods for site specific oral controlled release drug administration, the aim of this study on gastro retentive drug delivery systems was to synthesise the most current findings. We have highlighted the major reasons affecting gastric retention so that you may comprehend the many physiological challenges involved. Next, we discussed the different gastro retentive strategies that have been developed and improved to date, including floating, high density, mucoadhesive, unfoldable, expandable, super porous hydrogel, & magnetic systems. The benefits of gastro retentive medication administration techniques were then thoroughly discussed., Competing Interests: Declarations. Conflict of Interest: The authors declare that they have no conflict of interest., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

This study examines the influence of crospovidone (CP) manufacturer variability on the dissolution profiles of hydrochlorothiazide (HCTZ) tablets. Four CP batches from different manufacturers were characterized using pharmacopeial and physicochemical tests, including infrared absorption, loss on drying, and scanning electron microscopy (SEM). Significant differences were observed in the particle size distribution, wetting time, and water absorption capacities of the CP batches. Tablets were formulated using both direct compression and wet granulation methods. For the latter, the superdisintegrant was either added to the binder solution or incorporated intra- or extra-granularly. Disintegration and dissolution tests revealed that both CP concentration and the method of incorporation significantly affected tablet performance. Poly Kovidone and Max-Povidon exhibited superior performance at lower concentrations, while differences between brands became less pronounced at higher concentrations. The extra-granular method notably enhanced drug release profiles. Statistical analyses, including f 2 similarity factors and MANOVA with Principal Component Analysis (PCA), highlighted significant differences in dissolution behavior among the formulations. These findings emphasize the importance of controlling excipient variability to ensure consistent product performance. The study concludes that a 2% CP concentration is optimal for mitigating source variability and that the extra-granular addition of CP in wet granulation is recommended for enhancing its functional properties., Competing Interests: Declarations. Conflict of Interest: The authors declare that they have no competing interests., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

In vitro methods for quality and equivalence assessment of semi-solid products applied to the skin have increasingly garnered attention because in vivo bioequivalence studies is high cost, complexity, and time-consuming. Regulatory authorities established draft guidelines that outline a modular framework demanding qualitative, quantitative, microstructure and product performance equivalence to support generic products. In line with these guidelines, our study aimed to evaluate the relationship between microstructure and performance attributes in both originator and generic semi-solid products applied to the skin. In this context, reference and three generics of ketoprofen gel were selected as models for semi-solid formulations. Microstructure of all products was assessed regarding pH, specific gravity, drying rate, formulation rheology and potential drug polymorphism. Additionally, performance attributes of products were evaluated using in vitro release testing and in vitro permeation testing. Polymorphism and drying rate data showed no significant difference in microstructure of ketoprofen gels. All tested products exhibited pseudo-plastic flow behavior with thixotropic characteristic. However, differences in pH, specific gravity and viscosity values at low shear stress were observed between reference product and generic products, according to EMA guidance. Although IVRT outcomes did not entirely align with Q3 attributes, IVRT results for reference product versus Generic Product-I and Generic Product-II met the acceptance limits according to FDA guidance, which differs from EMA's assessment. Furthermore, in vitro release rate results were consistent with IVPT data. Consequently, it can be concluded that microstructure of semi-solid products applied to the skin may not consistently correlate with performance attributes due to various alternations influenced by manufacturing process parameters and/or formulation components., Competing Interests: Declarations. Conflict of Interest: There is no conflict of interest with any commercial or other associations in this study., (© 2025. The Author(s).)

Agricultural waste, such as rice straw, has become increasingly valuable as biocomposites in various industries. For cosmetic and pharmaceutical sectors, these biocomposites have improved active substance incorporation and waste reduction, which is pivotal for mitigating environmental impact. This study reports the encapsulation of a protein derivative derived from rice straw within a nanoemulsion for skin care applications, emphasizing stability and efficacy. Protein hydrolysates were produced by extracting proteins in an alkaline medium, followed by precipitation at the isoelectric point. The hydrolysates were enzymatically treated with Alcalase® at 80 °C and pH 10 for 45 min to generate antioxidant-rich formulations. Utilizing Hydrophilic-Lipophilic Deviation (HLD) theory, oil-in-water (O/W) emulsions were formulated by adjusting variables to achieve an HLD near zero. Sunflower oil and surfactants were combined, stirred at 70 °C, and homogenized using a rotor-stator. The final formulation's stability and permeability were evaluated through fluorescence microscopy, particle size analysis, zeta potential measurements, and accelerated stability assays. Nanoemulsion ENE37 showed high stability with 47.25 nm size, PDI 0.21, and excellent dispersion, maintaining integrity without phase separation. Hydrolyzed protein into ENE37 (NE37-HP) improved stability, increasing zeta potential and preventing aggregation while maintaining structure without phase inversion. NE37-HP exhibited shear-thinning behavior and good diffusion capacity, achieving 20.14 μg/cm 2 .h. The HLD theory and ternary diagrams are valuable methodological tools for formulating stable nanoscale emulsions. Additionally, this dosage form, containing protein hydrolysates derived from rice straw, demonstrated potential for adequate dermal absorption in humans., Competing Interests: Declarations. Ethics Approval and Consent to Participate: This article does not contain any studies involving animals performed by any of the authors. This article does not contain any studies involving human participants performed by any of the authors. Consent for Publication: Not applicable. Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article., (© 2025. The Author(s).)

Lipid-based formulations are essential for enhancing drug solubility and bioavailability, yet selecting optimal lipid excipients for specific drugs remains challenging. This study introduces Sol_ME, a machine learning-based model designed to predict drug solubility in lipidic environments, thereby streamlining the formulation process. The Sol_ME model uses PubChem® fingerprints, focusing on solubility correlations with lipid excipients, minimizing reliance on traditional parameters like LogP and molecular weight. The model was trained on a dataset of 1,379 drug-solvent entries and applied to the formulation of Apalutamide, a BCS Class II drug. Experimental validation was performed with 35 drug-solvent combinations to assess the accuracy of predicted solubilities. Sol_ME achieved a high predictive accuracy with a correlation coefficient of 0.998. The model successfully identified Cinnamon oil as the optimal excipient for Apalutamide, further refining the formulation with Vanillin. This reduced formulation volume by 75%, enabling the development of a single-unit 240 mg soft gelatin capsule. Experimental validation showed 80% alignment between predicted and actual solubilities. The Sol_ME model demonstrates significant potential to optimize lipid-based drug formulation, offering a data-driven approach that enhances efficiency. The success of Apalutamide formulation highlights its practical utility. Future work will expand the dataset and extend the model to solid lipid systems, broadening its application in drug delivery technologies., Competing Interests: Declarations. Ethics Approval and Consent to Participate: Not Applicable. Consent for Publication: All authors are agreed to publish the manuscript. Conflicts of Interest: There is no conflict of interest or objection from the side of the authors., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Amorphous solid dispersions (ASDs) are a prevalent method for increasing the bioavailability and apparent solubility of poorly soluble drugs. Consequently, extensive research, encompassing both experimental and computational approaches, has been dedicated to developing methods for assessing the key factors influencing their stability, notably drug-polymer interactions. A common computational approach to rank the compatibility of a drug with a set of solvents or polymers is to compare thermodynamic observables, such as solvation free energies at infinite dilution. However, the impact of the molecular weight of the polymer excipient on these interactions remains underexplored. This study delves into this impact through atomistic simulations of Indomethacin in PVP(-VA) and HPMC, and through simulations using a coarse-grained model, emphasizing its critical importance. First, we demonstrate that the molecular weight of the polymer plays a pivotal role in determining the solvation free energy of the drug, at times exerting a more significant influence than the specific chemical identity of the polymer. Additionally, our simulations suggest that higher molecular weight polymers lead to lower solvation free energies and, thus, suggest better compatibility with the drug. Yet, the lower free energy of solvation of the drug in longer polymers does not translate into a higher solubility. This work highlights the subtle role polymer molecular weight plays when measuring thermodynamic observables in amorphous solid dispersions, a role which must be considered when optimizing pharmaceutical formulations.

Lyophilization remains a key method for preserving sensitive biopharmaceuticals such as monoclonal antibodies. Traditionally, stabilization mechanisms have been explained by vitrification, which minimizes molecular mobility in the lyophilized cake, and water replacement, which restores molecular interactions disrupted by water removal. This study proposes a novel design strategy that combines water activity and glass-transition temperature as the main indicators to predict long-term stability in lyophilized formulations. The water activity, calculated as the product of water activity coefficient and (residual) water content, serves as a mutual indicator of molecular interactions and influence of residual water content in the lyophilizate. By predicting beneficial excipient combinations through activity coefficient calculations using the perturbed-chain statistical association fluid theory model and calculating T g using the Gordon-Taylor equation, the study identifies favorable excipient systems, such as sucrose/ectoine mixtures, providing formulation windows that offer broad stability ranges. The approach was validated with stability studies, confirming that formulations within a water activity range of 0.025-0.25 exhibit high (long-term) stability. This work advances formulation development by integrating water-excipient interactions and residual moisture content into a predictive model, moving beyond traditional empirical methods and offering a robust pathway to the design of stable biopharmaceutical formulations. This makes it possible to achieve high/favorable water activities despite low residual moisture (thus, high glass-transition temperatures) with plausible excipient concentrations and combinations.

A new 3.2 mm 1 H- 19 F-X magic angle spinning dynamic nuclear polarization NMR (MAS DNP-NMR) probe was developed with a unique coil design with separate radiofrequency channels for 1 H excitation and 13 C or 19 F detection to enable acquisition of 1 H- 19 F cross-polarization (CP) MAS experiments, direct-detected 19 F spectra with proton decoupling, and acquisition on 13 C with simultaneous double decoupling on the 1 H and 19F channels as well as 1 H- 19 F- 13 C double-CP experiments under low temperature MAS DNP conditions. We use these sequences to study AZD2811, which is an active pharmaceutical ingredient (API), in its pure dry state as well as in its corresponding drug delivery formulation consisting of drug-loaded polymeric nanoparticles (PNPs). Included in this study are also small interfering RNAs (siRNAs) for therapeutic targeting of peptidyl-prolyl cis-trans isomerase B (Ppib) mRNA. We demonstrate that 1 H- 19 F CP MAS experiments performed on the new HFX probe represent a notable advantage over usually acquired direct-detected 19 F experiments. The indirect 19 F DNP enhancement ε on/off ( 19 F) = 26 was obtained via 1 H- 19 F CP for the pure API impregnated with DNP solution, with an overall 30-fold sensitivity gain compared to the direct-detected 19 F experiment under similar conditions. DNP enhancement value of ε on/off ( 19 F) = 42 was obtained via 1 H- 19 F CP for the polymeric nanoparticle suspension and ε on/off ( 19 F) ≈ 150 were obtained for two different siRNAs in frozen DNP solution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

(20 S)-Ginsenoside Rh2 is a natural saponin derived from Panax ginseng Meyer (P. ginseng), which showed significantly potent anticancer properties. However, its low water solubility and bioavailability strongly restrict its pharmaceutical applications. The aim of current research is to develop a modified (20 S)-Ginsenoside Rh2 formulation with high solubility, dissolution rate and bioavailability by combined computational and experimental methodology. The "PharmSD" model was employed to predict the optimal polymer for (20 S)-Ginsenoside Rh2 solid dispersion formulations. The solubility of (20 S)-Ginsenoside Rh2 in various polymers was assessed, and the optimal ternary solid dispersion was evaluated across different dissolution mediums. Characterization techniques included the Powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FTIR). Molecular dynamics simulations were employed to elucidate the formation mechanism of the solid dispersion and the interactions among active pharmaceutical ingredient (API) and excipient molecules. Cell and animal experiments were conducted to evaluate the in vivo performance of the modified formulation. The "PharmSD" solid dispersion model identified Gelucire 44/14 as the most effective polymer for enhancing the dissolution rate of Rh2. Subsequent experiment also confirmed that Gelucire 44/14 outperformed the other selected polymers. Moreover, the addition of the third component, sodium dodecyl sulfate (SDS), in the ternary solid dispersion formulation significantly amplified dissolution rates than the binary systems. Characterization experiments revealed that the API existed in an amorphous state and interacted via hydrogen bonding with SDS and Gelucire. Moreover, molecular modeling results provided additional evidence of hydrogen bonding interactions between the API and excipient molecules within the optimal ternary solid dispersion. Cell experiments demonstrated efflux ratio (EfR) of Rh2 ternary solid dispersion was lower than that of pure Rh2. In vivo experiments revealed that the modified formulation substantially improved the absorption of Rh2 in rats. Our research successfully developed an optimal ternary solid dispersion for Rh2 with high solubility, dissolution rate and bioavailability by integrated computational and experimental tools. The combination of Artificial Intelligence (AI) technology and molecular dynamics simulation is a wise way to support the future formulation development., Competing Interests: Declarations. Ethics approval and consent to participate: No ethical approval is required for this study. Consent to publish: All the authors read and approved the final version of the manuscript. Competing interests: The authors report no conflicts of interest., (© 2024. Controlled Release Society.)

Poloxamer 338 is used as versatile thermo-responsive gelling agent in topical and sub-cutaneous applications. Due to application specific needs a gel point below body or even below room temperature is required. The influence of inorganic salts and active pharmaceutical ingredients (APIs) on the gel point was investigated using oscillatory rheology to identify the driving forces and predictors for gel point alteration. While most inorganic salts decreased the gel point, API salts exhibited an increase. Consistent with previous findings, the extent of gel point alteration caused by inorganic salts could be empirically described by the Hofmeister series, primarily influenced by the anion. Notably, this study revealed a concentration-dependent increase in the gel point in the presence of API salts. Moreover, this increase could be accurately predicted in a linear manner by considering the respective logP value. By utilizing the proposed prediction model, the effect of API addition on the gel point can be estimated, facilitating formulation development to achieve the desired gelling behavior for specific applications., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are employees of BASF SE, 67,056 Ludwigshafen am Rhein, Germany., (Copyright © 2025. Published by Elsevier B.V.)

Objective: The present study aims to develop and evaluate the voriconazole-loaded thermoresponsive hydrogel using in silico tools., Methods: Poloxamer 407 and PEG 400 were selected as the components from in silico studies for thermoresponsive hydrogel of voriconazole. The cohesive energy density (CED) and solubility parameters (SP) were calculated using Biovia Material Studio 2022 software to predict the polymer-polymer miscibility and drug-polymer miscibility. Different evaluation techniques used to select the optimized formulation. The in vitro antimicrobial activity against Candida albicans was determined for the optimized formulation to illustrate the efficacy of the developed formulation., Results: Hydrogel containing 15% poloxamer exhibited gelation time of 92.67 ± 3.51 s, and gelation temperature of 36.67 °C with good spreadability of 13.00 ± 0.02 cm 2 . CED values for poloxamer 407, PEG 400, and Voriconazole individually were found to be 3.23 × 10 -8 , 3.21 × 10 -8 , 4.84 × 10 -8 , respectively, whereas in the combination of poloxamer 407 and PEG 400 was found to 3.85 × 10 -8 and in ratio 9:1 was found to be 3.81 × 10 -8 indicated the best miscibility between poloxamer 407 and PEG 400 in 9:1 ratio. Based on solvation-free energy of voriconazole (-48.343 kJ/mol) ethanol was selected as the solvent system. Optimized formulation showed the sustained release over the 36 h and good antimicrobial effect., Conclusion: A thermoresponsive hydrogel of voriconazole was developed using Biovia Material Studio 2022, integrating computational predictions and molecular dynamics simulations to streamline polymer and solvent selection. This approach minimized trial-and-error experiments, enabling efficient formulation while enhancing understanding of polymer-polymer and drug-polymer interactions.

Many attempts have been made to integrate medicinal chemistry knowledge into therapeutic decision-making in pharmacy programs across North America. Examples include the use of Structure-Based Therapeutic Evaluations, alignment of medicinal chemistry content with courses in pharmacology, pharmaceutics and pharmacotherapeutics, and team-based or problem-based learning methods. The majority of these approaches indicate that students have greater confidence or comfort with medicinal chemistry, but there remain few cases where an improvement in performance has been measured. This is especially challenging for assessing a student's ability to implement medicinal chemistry learning in pharmacotherapeutic decision-making. Building upon our national special interest group's recent environmental scan of medicinal chemistry instruction in Canadian Pharmacy programs, we are investigating strategies for integration of medicinal chemistry learning in therapeutic decision-making. This commentary will discuss methods and evidence to support medicinal chemistry integration, relevant assessment strategies, and potential paths forward., Competing Interests: Declaration of competing interest The authors listed above have no conflict of interest to declare and no affiliations with or involvement in any organization or entity with any financial interest in this submission., (Copyright © 2024. Published by Elsevier Inc.)

Albendazole, an anthelmintic recognized by the World Health Organization as an essential medicine, is known to have limitations in solubility and bioavailability. To improve these properties, binary and ternary multicomponent systems were designed employing different combinations of albendazole desmotropes with maltodextrin and aspartic acid. The impact of these systems in solution was evaluated through phase solubility analysis. Moreover, solid systems were produced using the kneading method and evaluated with a combination of techniques, including dissolution tests, Fourier-Transform infrared spectroscopy, X-ray powder diffraction, and scanning electron microscopy. These studies demonstrated that multicomponent systems had higher solubility than free desmotropes, with the system formulated using solid form II of albendazole exhibiting the most significant improvement. Additionally, the dissolution percentage of each solid system in simulated gastric fluid was significantly increased. It can therefore be concluded that these innovative systems offer promising alternatives for improving the oral bioavailability of albendazole, generating significant interest in the pharmaceutical field., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The fundamental idea underlying the use of amorphous solid dispersions (ASDs) is to make the most of the solubility advantage of the amorphous form of a drug. However, the drug stability becomes compromised due to the higher free energy and disorder of molecular packing in the amorphous phase, leading to crystallization. Polymers are used as a matrix to form a stable homogeneous amorphous system to overcome the stability concern. The present work aims to design ASD-based formulations under the umbrella of quality by design principles for improving oral drug bioavailability, using celecoxib (CXB) as a model drug. ASDs were prepared from selected polymers and tested both individually and in combinations, using various manufacturing techniques: high-shear homogenization, high-pressure homogenization, microfluidics-on-a-chip, and spray drying. The resulting dispersions were further optimized, resorting to a 3 2 full-factorial design, considering the drug:polymers ratio and the total solid content as variables. The formulated products were evaluated regarding analytical centrifugation and the influence of the different polymers on the intrinsic dissolution rate of the CXB-ASDs. Microfluidics-on-a-chip led to the amorphous status of the formulation. The in vitro evaluation demonstrated a remarkable 26-fold enhancement in the intrinsic dissolution rate, and the translation of this formulation into tablets as the final dosage form is consistent with the observed performance enhancement. These findings are supported by ex vivo assays, which exhibited a two-fold increase in permeability compared to pure CXB. This study tackles the bioavailability hurdles encountered with diverse active compounds, offering insights into the development of more effective drug delivery platforms., Competing Interests: Declarations. Ethics approval and consent to participate: This study included experimental procedures that were approved by international regulations of the European Union (European Directive 2010/63/EU regarding the protection of laboratory animals used for scientific purposes), were in accordance with the Portuguese law on animal welfare (Decreto-Lei 113/2013) and were thoroughly reviewed and approved by the Portuguese National Authority for Animal Health, Phytosanitation, and Food Safety (DGAV—Direção-Geral de Alimentação e Veterinária, Lisbon, Portugal). All animal housing and experiments were conducted in strict accordance with the institutional guidelines for care and use of laboratory animals. Consent for publication: The authors consent to publication. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

This paper presents an innovative approach that utilizes self-synthesized homopolymers of polyvinylpyrrolidone (PVP) with different architectures as effective matrices for inhibiting the crystallization of naproxen (NAP). We have thoroughly investigated amorphous solid dispersions containing NAP and (i) self-synthesized linear PVP, (ii) self-synthesized three-armed star-shaped PVP, and (iii) self-synthesized linear PVP with a mass (M n ) corresponding to the length of one arm of the star polymer, as well as (iv) commercial linear PVP K30 as a reference. Differential scanning calorimetry, X-ray diffraction, and infrared spectroscopy studies, as well as molecular dynamics simulations were conducted to gain comprehensive insights into the thermal and structural properties, as well as intermolecular interactions in the NAP-PVP systems. The main purpose of all experiments was to assess the impact of macromolecule structure (topology, molecular weight) on the kinetics of the crystallization of NAP - a drug that is very difficult to vitrify. Our studies clearly showed that the most effective matrix in inhibiting the NAP crystallization is linear, self-synthesized PVP with higher molecular weight (M n ) similar to that of the commercial PVP K30, but lower, strictly controlled dispersity. We also found that crystallization of API proceeds at a similar pace for the binary mixture composed of a star-shaped PVP and linear polymer with M n corresponding to M n of one arm of the star-shaped macromolecule in the vicinity of the T g . The obtained data highlight the key role of polymer structure in designing new pharmaceutical formulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Despite the potential benefits of nasal drug delivery, there is a need for a systematic evaluation of the efficacy of powder formulations adhering to the nasal mucosa. This study aims to establish a systematic evaluation method for nasal drug absorption from powder formulations. We selected three model compounds-antipyrine, griseofulvin, and acyclovir-and analyzed their pharmacokinetics following nasal administration of powder formulations under physiological conditions. Our experimental design incorporated assessments of the drug absorption patterns. Antipyrine demonstrated rapid absorption exclusively from the nasal cavity. In contrast, griseofulvin exhibited absorption from the nasal cavity and the gastrointestinal tract. This phenomenon could be attributed to the rapid nasal clearance of the drug with an initial half-life of 5 min. To further establish the physiological validity of our method, we conducted an experiment to investigate the impact of changing the mucociliary clearance (MC) on nasal absorption that resulted in a 1.2-fold increase in the bioavailability of acyclovir upon prolonged MC. Our findings support the utility of established methods in evaluating nasal absorption and their behavior in the nasal cavity. This study holds a promising advancement toward effective drug delivery via nasal administration, potentially leading to targeted delivery and improved therapeutic outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The adoption of pure component models, such as iterative optimization technology (IOT) algorithms, is gaining significant interest in the pharmaceutical industry, primarily because of their calibration-free/minimal calibration requirements for process analytical technology applications. The IOT methods have recently demonstrated great potential for monitoring the quality of continuous powder mixtures by near-infrared (NIR) spectroscopy. However, the dynamic conditions of continuous manufacturing processes may limit the effectiveness of such approaches. Density variations introduced to NIR spectra that are collected from dynamic powder mixtures at different process conditions is detrimental to the drug prediction accuracy and robustness of IOT methods. This work introduces a new method, called external variable augmented iterative optimization technology (EVA-IOT), which incorporates the shape of non-chemical external sources of variability into the pure component spectra matrix to improve the prediction accuracy and robustness of the base IOT algorithm. This approach derives the shape of non-chemical external variables from the latent structure of decomposition methods using NIR spectra acquired from a single mixture at known levels of the external variable. A density-augmented EVA-IOT method was developed and implemented to quantify the active pharmaceutical ingredient (API) in continuous powder mixtures flowing at varying process conditions in a simulated continuous process. The EVA-IOT method demonstrated a significantly enhanced API prediction accuracy and robustness against process variation compared to alternative IOT methods. The overall prediction performance of EVA-IOT was comparable to that of global partial least square (PLS) regression models while reducing the calibration burden up to 97%. This makes EVA-IOT a material-sparing alternative to calibration-intensive robust decomposition modeling approaches for monitoring the quality of continuous pharmaceutical powder streams., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Danlong oral liquid (DLOL) is a traditional Chinese proprietary medicine commonly used to treat chronic respiratory diseases, including bronchial asthma and chronic obstructive pulmonary disease. However, the therapeutic effects and pharmacological mechanisms of DLOL in improving airway remodeling remain unclear., Aims of the Study: This study utilizes in vivo and in vitro experiments, serum pharmacological analysis, and network-based pharmacology approaches to investigate the effects and mechanisms of DLOL on airway remodeling and epithelial-mesenchymal transition (EMT) in asthma., Methods: An asthma model was established through ovalbumins (OVA) sensitization and challenge in BALB/c mice to observe the effects of DLOL on airway hyperresponsiveness (AHR), inflammation, remodeling, and molecular markers of EMT. The absorbed chemical prototype constituents of DLOL were analyzed using Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS), and targets for asthma and airway remodeling were predicted using a network pharmacology approach. Key biological processes and signaling pathways were analyzed. Additionally, TGF-β1 was used to induce EMT in BEAS-2B cells. TGF-β1 and DLOL-containing serum were screened to determine the optimal time and concentration in BEAS-2B cells using CCK8 assays. The cell scratch assay was used to assess cell migration, while immunofluorescence and immunohistochemistry were employed to evaluate protein expression levels., Results: DLOL improved AHR in asthmatic mice, reduced inflammatory cell infiltration in lung tissue, decreased airway wall and smooth muscle thickness, and reduced collagen deposition. It also down-regulated mesenchymal markers (N-cadherin, vimentin, α-SMA) and key remodeling factors (TGF-β1, MMP9), while up-regulating the epithelial marker E-cadherin. A total of 17 absorbed chemical prototype constituents were identified, predicting 54 core targets involved in airway remodeling. Following Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, the key targets were found to be associated with the regulation of cell migration, cell-cell adhesion, and cell adhesion molecular processes, with the PI3K-Akt signaling pathway likely playing a critical role. Cellular experiments confirmed that DLOL-containing serum inhibited TGF-β1-induced EMT in BEAS-2B cells and suppressed the phosphorylation of Akt and GSK-3β., Conclusion: This study identifies, for the first time, the serum medicinal chemistry of DLOL using UPLC-MS. Combining network pharmacology, in vivo and in vitro experiments, it elucidates the effects and potential mechanisms of the drug on airway remodeling and EMT. DLOL may offer a novel therapeutic approach for asthma-related airway remodeling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metabolic syndrome (MS) has a high prevalence, with an estimated one-quarter of the world population affected by this pathological condition. Among the diseases of this syndrome are dysregulation of lipids, hypertension, and insulin resistance. Unfortunately, available drugs in the market used for treating MS, as almost 75% of all drugs, are highly insoluble, presenting a significant demand for strategies to increase their solubility. Taking advantage of the fact that drugs in the amorphous state can provide a solubility enhancement, a new drug-drug co-amorphous (CoA) formulation to potentially simultaneously treat two or more MS conditions was explored, combining the co-formers Bezafibrate (BZT) a lipid-regulating drug, and Gliclazide (GZD) a hypoglycemic agent. A phase diagram was constructed to characterize the binary system's thermal properties, including glass transition temperatures of all compositions studied. The formulations were characterized by FTIR; redshifts of IR bands from 1547 to 1538 cm -1 and 1717 to 1609 cm -1 were observed due to the formation of intermolecular interactions, such as hydrogen bonds. The co-amorphous binary systems lead to an increase in the solubility of both BZT and GZD; specifically, for the composition x BZT  = 0.5, the increase was 2.1× for BZT and 1.5 times for GZD while for x BZT  = 0.7 an increase of 4× of BZT was achieved. The structural stability of the samples was verified by XRD and DSC, showing long-term stability retention of the amorphous state for more than eight years. The enhanced solubility and stability of the co-amorphous systems make them potential formulations for regulating lipids and lowering glycemia., Competing Interests: Declarations. Conflict of Interest: All the authors confirm that this is original work and that there are no financial or other potential conflicts of interest., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Amorphous solid dispersion (ASD) is one of the most studied strategies for improving the dissolution performance of poorly water-soluble drugs, but ASDs often have low drug loadings, thereby necessitating larger dosage sizes. This study intended to create Soluplus® (SOL)-based microparticle ASDs with high drug loading (up to 60 w/w%) and long-term stability (at least 16 months) using electrospraying to enhance the dissolution of poorly water-soluble celecoxib (CEL). X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses showed that the electrosprayed SOL-CEL microparticles were amorphous, and Fourier transform infrared spectroscopy (FTIR) data indicated the presence of hydrogen bonding between SOL and CEL in the microparticles, which helped stabilize the ASDs. In vitro dissolution studies demonstrated that these ASDs improved the CEL dissolution rate by up to 8.2-fold compared to the crystalline form. Electrospraying presents a promising alternative to conventional methods like hot-melt extrusion (HME) and spraying drying (SD) for the production of ASDs, providing simplicity, high drug loading capability and long-term stability, thus catering to a variety of poorly water-soluble drugs., Competing Interests: Declarations. Conflicts of Interest: The authors declare no conflicts of interest., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The study of the flow properties of particles is crucial because it directly impacts the efficiency and product quality of various industrial particulate processes, such as continuous manufacturing of solid oral dosages. However, challenges arise due to the flow behavior of cohesive particles, which tend to adhere to surfaces or other particles, necessitating careful process design. The importance of selecting appropriate measurement pathways for accurate characterization has been overlooked. In response, an overview of measurement technologies for surface energy and cohesive/adhesive forces is provided in this work, aiming to establish a practical guide. Understanding these forces is crucial for optimizing continuous manufacturing processes to effectively mitigate flow-related issues such as obstructions, segregation, irregular flow, and flooding. Furthermore, various methods characterization experiments were conducted and compared to illuminate the methodological disparities. This analysis provides valuable insights into particle adhesion, cohesion, and powder flowability, potentially enhancing industrial particulate processes development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Real-time release testing (RTRt) of tablet dissolution can significantly improve manufacturing efficiency along with the adoption of continuous manufacturing in the pharmaceutical industry. To assure product quality without destructive testing, models for RTRt should be sufficiently reliable and robust. Whereas mechanistic models have merits of broader applicability and interpretability, data-driven models have been common approaches due to computational speed. This paper discusses challenges and opportunities in the application of mechanistic models for dissolution testing to enable RTRt of solid dosage. After a comprehensive literature review on mechanistic dissolution models and RTRt, the potential benefits and challenges of mechanistic models are presented. Compared to data-driven models, mechanistic models require less experimental data that can reduce time and cost for RTRt development. However, to enable the implementation of mechanistic models in RTRt, computational time should be short either by using a simple mechanistic model or by applying surrogate models., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Onivyde® is an intravenous irinotecan liposomal injection approved by the FDA for the treatment of gemcitabine-refractory metastatic adenocarcinoma of the pancreas in combination with fluorouracil and leucovorin. In the Onivyde® formulation, irinotecan is encapsulated in the inner compartment of the liposome using sucrose octasulfate as a trapping agent, and stabilized by a pegylated lipid membrane, resulting in prolonged circulation in the body. Due to its complex formulation design, there is limited information available regarding the critical quality attributes (CQAs) of Onivyde® and suitable methods for evaluating these attributes. In this study, we have developed a series of analytical methods to comprehensively characterize Onivyde®. These methods encompass particle size analysis, morphology and structure assessment, examination of physical and chemical properties, determination of drug and lipid contents, and evaluation of its release behavior in vitro., Competing Interests: Declaration of competing interest The authors declare the following financial interests/ personal relationships which may be considered as potential competing interests: Anna Schwendeman reports financial support was provided by US Food and Drug Administration. Anna Schwendeman reports a relationship with EVOQ Therapeutics and ASKO Holdings that includes: board membership, consulting or advisory, equity or stocks , and funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this decade, one of the major trends in the pharmaceutical industry is the adoption of continuous manufacturing. This requires the development of continuous equivalents of essential pharmaceutical processes such as film coating. The process of film coating is the last step of the processing of solid dosage forms and is critical because it determines the visual appearance of the end product, along with ensuring its stability and possibly even defining the rate of drug release. Several manufacturers advertise continuous solutions for film coating, these include semi-continuous and fully continuous appliances. State-of-the-art continuous coaters can match the throughput of continuous manufacturing lines, because largest appliances have a capacity of 1200-1500 kg/h. The paper also describes the main challenges related to continuous film coating including waste production at the beginning and end of the process and the problem caused by elastic recovery of the tablets when film coating is performed immediately after tablet compression. Lastly, we give an overview of the in-line sensors that can be used to monitor the quality of the film coated tablets, enabling real-time quality control of the process. Near-infrared and Raman spectroscopy can measure the mass gain of the tablets, while terahertz pulsed imaging and optical coherence tomography enable coating thickness measurement of individual tablets and even the characterization of intra-tablet coating thickness variability. UV imaging and machine vision can also measure coating thickness, and they are also excellent for detecting tablets with defective coating., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Polyoxylglycerides-based solid mixtures, commercially known as Gelucire®, are excipients commonly used for bioavailability improvement of poorly water-soluble drugs. However, their effect on solutions containing hydrophobic drugs above crystalline solubility has not yet been explored. The goal of this study was to investigate the impact of a mix of two commercial Gelucire® with high HLB values (Gelucire®50/13 and Gelucire®48/16) on the amorphous solubility and crystallization from supersaturated solutions of ketoprofen, used as model drug. The results evidenced a strong interaction between Gelucire® components and the drug-rich nanodroplets generated upon liquid-liquid phase separation. This led to two important consequences: on one hand, the drug amorphous solubility was decreased, together with the amorphous-to-crystalline solubility ratio; on the other hand, the enlargement and coalescence of the drug-rich droplets were prevented. This stabilizing effect towards the drug-rich phase was comparable to, or even stronger than, that obtained with traditional amorphous polymers (PVP or HPMC) and contributed to inhibiting drug crystallization. Notably, the impact of Gelucire® on drug crystallization from the supersaturated state depended on its micellar behaviour: the monomeric form (below 50 μg/mL) accelerated the formation of crystals, whereas pre-micellar aggregates (50-500 μg/mL) and solubilizing micelles (above 500 μg/mL) inhibited drug crystallization. These findings will contribute to a better understanding of the behaviour of supersaturated drug solutions in the presence of Gelucire® and will facilitate the rational design of supersaturating drug delivery systems containing these excipients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Kollidon® SR is one of the recent versatile coprocessed excipients in the formulation of modified-release dosage forms. It is prepared by co-spray drying aqueous dispersions of polyvinylacetate and polyvinylpyrrolidone. This article gives a critical review of the physicochemical attributes and technological properties of Kollidon® SR. The current review discusses various technological approaches used in the formulation with Kollidon® SR, from conventional ones like direct compaction and wet granulation to more advanced methodologies such as 3D printing, electrospinning and hot-melt extrusion. The review further elaborates on the influence of the major factors on drug release kinetics from Kollidon® SR-based formulations. Furthermore, this review unravels the potential of Kollidon® SR in the development of site-targeted oral drug delivery systems and focuses on its adaptability to other routes of administration. Further, the review deals with the considerations to be made regarding stability to make sure the formulations based on Kollidon® SR are reliable., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This Perspective summarizes successful fragment-to-lead (F2L) studies that were published in 2023 and is the ninth installment in an annual series. A tabulated summary of the relevant articles published in 2023 is provided (17 entries from 16 articles), and a comparison of the target classes, screening methods, and overall fragment or lead property trends for 2023 examples and for the combined entries over the years 2015-2023 is discussed. In addition, we identify several trends and innovations in the 2023 literature that promise to further increase the success of fragment-based drug discovery (FBDD), particularly in the areas of NMR and virtual screening, fragment library design, and fragment linking.

The current project was designed to develop piperine-loaded solid lipid microparticles (SLMs) to assess the anti-arthritic potential of piperine (PIP). Variable proportions of carnauba wax, beeswax, and tween 80 were employed for preparing SLMs by using the solvent evaporation technique. The developed formulations were subjected to particle size measurements, entrapment efficiency (EE), and zeta potential (ZP) determination. Microparticles were also investigated for piperine-lipid compatibility, thermal analysis, surface morphology, piperine (PIP) release trend, and anti-rheumatic activity in rats. The network's grafting was confirmed by FTIR and XRD results. The thermal stability of the constructed network was confirmed by the DSC and TGA results. SEM findings confirm porous surface morphology. The dissolution experiments on SLMs confirmed the sustained release profile, delivering 87.82% to 94.92% of piperine at 7.4 pH for 24 h. All developed formulations followed a zero-order kinetic model and the Korsmeyer-Peppas model. Furthermore, the anti-rheumatic potentials of piperine from SLMs were also investigated and compared with diclofenac sodium (the standard treatment) in a rat model. The analysis revealed that PIP significantly reduced the severity of arthritis, as confirmed by the findings of multiple arthritic assessment parameters., Competing Interests: Declarations. Conflict of Interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Dosage forms containing Ivermectin (IVER) and Praziquantel (PRAZ) are important combination drug products in animal health. Understanding the relationship between products with differing in vitro release characteristics and bioequivalence could facilitate generics. The goal of this study was to create granulations for each active ingredient, with similar release mechanisms, but substantially different in vitro release rates, and then compressing these granulations into tablets with differing release rates. Four granulation formulations were created: fast and modified release for PRAZ and IVER, respectively. The manufacturing process used high shear wet granulation and fluid bed drying, milling and sieving. Solid components, including the granulating agent, were blended in a high shear granulator and then water or a hydroalcoholic solution was added to activate the binder and initiate granule formation. Drying in a fluid bed with inlet air temperature set for 70°C and inlet air volume adjusted as required to maintain fluidization. Milling was performed in a cone mill and classification of final product was done using a vibratory sieve shaker with 18, 20, 40, and 60 mesh sieves. Formulations and processing approaches were successfully developed to produce a collection of PRAZ and IVER granules with differing particle size distributions and in vitro release characteristics. Differences in drug content in the classified granulations were observed and attributed to the low surface energy of PRAZ and the different approaches used to incorporate the active ingredients. The granulations were compressed via compaction simulator and the results show the monolithic tablets had four different release profiles., Competing Interests: Declarations. Disclaimer: The findings and conclusions in this research have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency endorsement, determination, or policy. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the FDA. Conflict of Interest: The authors have no conflict of interest to declare with respect to this research., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The transdermal route is one of the effective routes for delivering drugs. It also overcomes many limitations associated with oral delivery. One of the limitations of this route is the drug's poor skin permeability-stratum corneum, the skin's outermost layer that also acts as a barrier for the drug to penetrate. Traditional liposomal formulation is utilized to overcome these limitations. However, these liposomes also have certain difficulty in delivering drugs across the barriers. Ultra-deformable vesicles are novel vesicular structures that are flexible and stable, they can easily bypass the skin barriers more efficiently and thus enhance bioavailability. These vesicles consist of ethosomes, transethosomes, and transferosomes. Transethosomes are more advanced than other vesicular systems because they contain ethanol, phospholipids, and edge activators, making them more deformable and easier to penetrate deeper skin membranes. These vesicular systems can be prepared by various methods, such as cold, hot, and thin film hydration. Characterization of transethosomes includes vesicular size, zeta potential, polydispersity index and encapsulation efficiency, stability, and drug release studies. These vesicular systems can be utilized to deliver a variety of medications transdermally, including analgesics, antibiotics, and arthritis medications. Despite their promising potential, ethanol-based formulations present several problems requiring additional study. This review aims to describe various vesicular structures that have been used to overcome the barrier for the transdermal delivery of drugs and also describe brief composition, method of preparation, characterization, mechanism of penetration of transethosomes, as well as highlighted various applications of transethosomes in medicine, clinical trials and patents., Competing Interests: Declarations. Competing Interest: The authors of the manuscript have no conflict of interest to declare., (© 2025. The Author(s).)

Freeze drying is one of the common methods to extend the long-term stability of biologicals. Biological products in solid form have the advantages of convenient transportation and stable long-term storage. However, long reconstitution time and extensive visible bubbles are frequently generated during the reconstitution process for many freeze-dried protein formulations, which can potentially affect the management efficiency of staff, patient compliance, and product quality. The reconstitution time has been extensively studied, but the influence of the formulations on the formation of visible bubbles is often overlooked. This paper investigated the effect of freeze-drying formulation factors (i.e., protein concentrations, surfactant concentrations, and sucrose/mannitol compositions) on product stability and visible bubbles generated during reconstitution of freeze-dried etanercept formulations. The generating and breakup mechanisms of visible bubbles were detected via internal microstructure of cake, surface tension, and viscosity measurement. Under the same protein concentration, the formulation of mannitol mixed with sucrose in a weight ratio of 4:1 produces fewer visible bubbles during the reconstitution process compared to the formulation of sucrose with the same total mass. This has been proven to be due to the large number of smaller radius pores distributed in the pores of the freeze-dried cake of the former, while the average internal structure pores of the latter are much larger than those of the former. As an amorphous stabilizer, sucrose can ensure the long-term stability of protein and greatly reduce the generation and maintenance of foams in the reconstitution process, making it a more robust excipient for freeze-dried protein formulations., Competing Interests: Declarations. Conflicts of Interest: The authors have no conflicts of interest to declare., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The present work focuses on the production of sildenafil co-evaporates loaded emulgels as topical dosage forms for the treatment of premature ejaculation and erectile dysfunction. Topical administration of sildenafil citrate (SILD) co-evaporates is expected to improve the bioavailability profile of the drug and to avoid the severe side effects accompanying the traditional SILD dosage forms, especially for prohibited cardiovascular cases. Firstly, the solubility of SILD was improved via solid dispersion via co-evaporation technique using PEG-5KDa and PVP-K90 as hydrophilic carriers. The modified co-evaporates were characterized by DSC, XRD, and solubility studies. Different emulgels, loaded with SILD co-evaporates, were formulated and characterized by different analyses including the viscosity, stability, spreadability, and in vitro release studies. Finally, the clinical activity of the chosen formula was accomplished via the application of the emulgels on volunteers suffering from erectile dysfunction. The results showed that the prepared SILD/PVP K90 of 1:2 w/w ratio exhibited the highest solubility and dissolution rate. All formulated emulgels exhibited good physicochemical properties. Especially, the emulgel formula composed of 2%w/v HPMC, loaded with SILD /PVP- K90, revealed the highest release rate. The release mechanism of SILD from emulgels fits with the Korsmeyer Peppas mechanism. The results of in vivo studies indicated a significant improvement of both IVLT and IIEF-5 parameters in mild to moderate ED, accompanied by PE. The modified SILD emulgel is an alternative promising and safe transdermal drug delivery system for the management and treatment of mild to moderate ED with PE., Competing Interests: Declarations. Ethics Approval: The patients were recruited from the outpatient clinic of andrology, department of dermatology, Venereology, and Andrology, Assiut University Hospital, and Al Azhar University Hospital. The study was carried out according to the ethical approval number AZ-/PH/5/C/2022, approved by the College of Pharmacy, Al-Azhar University. Informed Consent: Not applicable. Consent to Participate: Not applicable. Consent to Publish: All authors have agreed to the publication of this manuscript. Competing Interests: There is no conflict of interest with any other authors or companies that may influence the work in the current paper., (© 2025. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)