Pharmaceutics最新文献

{"title":"Exploring the Anticancer Potential of NO-Donor Oxadiazole Assemblies Against Malignant Pleural Mesothelioma.","authors":"Irina A Stebletsova, Alexander A Larin, Egor M Matnurov, Ivan V Ananyev, Maria V Babak, Leonid L Fershtat","doi":"10.3390/pharmaceutics17020230","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020230","url":null,"abstract":"<p><p><b>Background:</b> Nitric oxide (NO) has been linked to the pathogenesis of asbestos-related pleural diseases, including an extremely aggressive cancer called malignant pleural mesothelioma (MPM). Given that MPM cells are characterized by a higher expression of NO synthases and elevated NO production relative to normal cells, the use of NO-donor compounds could potentially saturate the cancerous cells with NO, triggering their death. <b>Methods</b>: We developed a novel class of NO prodrugs by merging two NO-releasing components, 1,2,5-oxadiazole 2-oxides (furoxans) and 1,2,4-oxadiazoles, and studied their NO-releasing characteristics in a time-dependent manner using the Griess assay. The cytotoxicity against two human MPM cell lines and non-cancerous lung fibroblasts was evaluated using a colorimetric MTT assay. <b>Results</b>: All compounds exhibited excellent NO-donating properties, surpassing the capacity of two reference NO donor compounds, 3-carbamoyl-4-(hydroxymethyl)furoxan (CAS-1609) and 4-ethoxy-3-phenylsulphonylfuroxan (CHF-2363), by at least 1.5-3 times. All oxadiazole hybrids demonstrated high cytotoxicity against MPM cell lines in a low micromolar range, comparable or higher than the cytotoxicity of the standard-of-care drug cisplatin. <b>Conclusions</b>: Notably, the novel compounds displayed a markedly greater selectivity towards cancerous cells than cisplatin when compared with non-cancerous lung fibroblasts, aligning with the intended design.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compartment Model and Neural Network-Based Analysis of Combination Medication Ratios.","authors":"Yuxin Zeng, Jieyu Yang, Yong Li","doi":"10.3390/pharmaceutics17020228","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020228","url":null,"abstract":"<p><p><b>Background:</b> Combination medication strategies often involve complex interactions, making determining the appropriate pharmacodynamic component ratios challenging. <b>Methods:</b> This study established a time-dose relationship model through the compartment model, deriving the in vivo drug quantity ratios corresponding to the blood concentrations of the pharmacodynamic components. A neural network was then employed to establish a dose-effect relationship model between the blood concentrations of the pharmacodynamic components and the overall body response. Utilizing the feedback adjustment mechanism of neural networks continuously adjusts the network to achieve the desired drug efficacy, thereby deriving the corresponding dose ratio of the pharmacodynamic components. Empirical studies were conducted on combining <i>Cynanchum otophyllum</i> saponins <i>M</i>₁ and <i>M</i>₂ with phenobarbital for epilepsy treatment, as well as the anti-ischemic stroke activity of the prototype and metabolites of <i>Erigeron breviscapus</i>. <b>Results:</b> After adjusting the efficacy, the model recalculated the new ratio proportions for each combination, validated by the reduced Combination Index (<i>CI</i>). <b>Conclusions:</b> This model provides a new approach to combination medication strategies.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating In Vitro Dissolution and Physiologically Based Pharmacokinetic Modeling for Generic Drug Development: Evaluation of Amorphous Solid Dispersion Formulations for Tacrolimus.","authors":"Evangelos Karakitsios, Maria-Faidra-Galini Angelerou, Iasonas Kapralos, Georgia Tsakiridou, Lida Kalantzi, Aristides Dokoumetzidis","doi":"10.3390/pharmaceutics17020227","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020227","url":null,"abstract":"<p><p><b>Objectives</b>: Tacrolimus, a Biopharmaceutics Classification System (BCS) class II drug, is widely used for transplant patients to prevent graft rejection. To enhance its bioavailability, amorphous solid dispersion (ASD) formulations were developed and evaluated. The release properties of several ASD-based tacrolimus formulations were studied using an in-house USP IV dissolution method. <b>Methods</b>: The pharmacokinetics of a promising test product were compared with the commercially available Advagraf^® in a pilot clinical bioequivalence study with 12 healthy subjects. A previously published PBPK model for tacrolimus was validated using in vivo data and then applied to predict the human pharmacokinetics of several ASD-based tacrolimus formulations. <b>Results</b>: This study compares the pharmacokinetic (PK) parameters-AUC, Cmax, and Tmax-of Advagraf^® and a test formulation using two methodologies: one incorporating the dissolution profile directly into the PBPK model and the other utilizing the DLM approach. The results show that both methods provided accurate predictions for Cmax and Tmax, with the dissolution profile approach underestimating AUC slightly, while the DLM method predicted AUC adequately. Sensitivity analysis refining the DLM scalars in the Ileum and Colon led to optimized predictions of PK parameters. Furthermore, this study explores the use of PBPK modeling to predict in vivo behavior for additional tacrolimus formulations, highlighting the influence of formulation composition, such as the inclusion of Eudragit-S100, on dissolution profiles and bioavailability. <b>Conclusions</b>: This study evaluates formulations with different compositions and manufacturing characteristics; key factors that could influence their performance in the body were identified. These insights-spanning qualitative, quantitative, and manufacturing aspects-can greatly simplify the development of generic drugs, offering strong evidence of the critical role that physiologically based pharmacokinetic (PBPK) modeling can play in the early phases of generic drug development, especially in designing and assessing biopredictive dissolution methods.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Co-Administration of Paclitaxel with Novel Pyridine and Benzofuran Derivatives that Inhibit Tubulin Polymerisation: A Promising Anticancer Strategy.","authors":"Magdalena Perużyńska, Radosław Birger, Patrycja Kłos, Halina Kwiecień, Łukasz Struk, Jacek G Sośnicki, Laurence Lafanechère, Marek Droździk","doi":"10.3390/pharmaceutics17020223","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020223","url":null,"abstract":"<p><p><b>Background</b>: Paclitaxel (PTX), a crucial microtubule-stabilising agent in cancer treatment, is limited by its adverse effects and hydrophobic nature, which necessitate the use of toxic solvents. This study proposes a novel approach combining PTX with new microtubule-destabilising compounds at low, safe doses that are ineffective when used individually. <b>Objective:</b> The aim was to evaluate the therapeutic efficacy of combining PTX with previously described pyridine (S1, S22) and benzofuran derivatives (13b, 14), which have demonstrated promising anticancer properties by inhibiting microtubule polymerisation. <b>Methods:</b> The PrestoBlue assay was used to determine the optimal concentrations of each compound, enabling synergistic interactions with a low dose of PTX in HeLa cervical cancer cells. The combined effects of the compounds and PTX on apoptosis, cell cycle distribution, and mitotic spindle formation were then evaluated. <b>Results:</b> The results showed that compounds 13b (1 µM), 14 (0.1 µM), S1 (2 µM), and S22 (2 µM) enhanced the proapoptotic and antimitotic effects of 1 nM PTX, which was ineffective alone. Notably, live-cell imaging revealed that the concurrent use of S1 and PTX produced effects similar to those of a higher PTX concentration (5 nM). <b>Conclusions:</b> These findings suggest that these compounds enhance the anticancer efficacy of low-dose PTX, potentially paving the way for more effective and safer cancer therapies.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyphenols from <i>Bacopa procumbens</i> Nanostructured with Gold Nanoparticles Stimulate Hair Growth Through Apoptosis Modulation in C57BL/6 Mice.","authors":"Salvador Pérez-Mora, Juan Ocampo-López, María Del Consuelo Gómez-García, Sandra Viridiana Salgado-Hernández, Yazmin Montserrat Flores-Martinez, David Guillermo Pérez-Ishiwara","doi":"10.3390/pharmaceutics17020222","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020222","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Alopecia is a hair disorder with a significant impact on quality of life, and its incidence has been increasing in recent years. Current therapeutic options are limited and may cause adverse side effects, highlighting the need to develop safer and more effective formulations. Therefore, the objective of this study was to evaluate the effect of a formulation based on the bioactive fraction of <i>Bacopa procumbens</i> (BFNB), conjugated with gold nanoparticles, on hair growth through the modulation of apoptosis in C57BL/6 mice. <b>Methods</b>: The potential biological activities of the secondary metabolites of <i>B. procumbens</i> present in BFNB were analyzed in silico. In vivo experiments evaluated the expression of pro-apoptotic markers p53, caspase 3-p11, caspase 9-p10, and Bax, as well as anti-apoptotic marker Bcl-2, through Western blotting. Immunohistochemistry further assessed the expression and localization of some of these markers. Additionally, molecular docking and interactomic analyses were performed, complemented by functional enrichment, to explore molecular pathways modulated by the evaluated proteins. <b>Results</b>: In silico analyses suggested that BFNB metabolites are involved in the modulation of hair growth, hair fragility, and apoptosis. This finding was supported by in vivo experiments in mice, where BFNB significantly decreased the expression of p53, caspase 3-p11, caspase 9-p10, and Bax while increasing Bcl-2 levels. Immunohistochemistry showcased a reduction in pro-apoptotic markers in dermal and follicular bulb cells. Furthermore, molecular docking studies identified BFNB metabolites as potential direct modulators of these key proteins, strengthening evidence of their role in apoptotic regulation. The interactomic analysis highlighted 50 proteins associated with apoptosis, and functional enrichment underscored key processes such as p53 signaling, regulation of the apoptosome, and mitochondrial membrane involvement in the intrinsic apoptosis mechanism, among other pathways. <b>Conclusions</b>: This study demonstrates that BFNB effectively modulates apoptosis through key molecular mechanisms, highlighting its potential as an innovative therapy for promoting hair growth.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3D-Printed Contact Lenses to Release Polyvinyl Alcohol as a Therapeutic Agent for the Treatment of Dry Eyes.","authors":"Piyush Garg, Parvin Shokrollahi, Haile Fentahun Darge, Chau-Minh Phan, Lyndon Jones","doi":"10.3390/pharmaceutics17020219","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020219","url":null,"abstract":"<p><p><b>Purpose:</b> Dry eye disease is highly prevalent, and the most common treatment, lubricating eye drops, only remains effective for a very short period of time. This project aims to 3D print a proof-of-concept, custom-fit, polyvinyl alcohol (PVA)-eluting contact lens (CL) for the treatment of dry eye disease. PVA is a commonly used viscosity enhancer in eye drops, with the capability of reducing symptoms of dry eye by stabilizing the tear film and reducing tear evaporation. The protective effects of PVA could be attributed to its water-retaining ability, which provides moisturization and prevents the loss of water. <b>Method:</b> In this work, a low-cost stereolithography-based 3D printer was retrofitted with a humidity and temperature control kit to 3D print a PVA-loaded custom-fit CL. To evaluate the print quality of the 3D-printed CL, circularity was used to evaluate the shape fidelity in 3D printing. The PVA release from these lenses was assessed, along with its role in acting as a viscosity enhancer. The effect of PVA was further analyzed by a dry eye disease (desiccation stress) cell model. <b>Results:</b> The shape fidelity evaluation of the 3D-printed CL displayed excellent circularity. The diameter, sagittal depth, and base curve of the 3D-printed lenses were measured to be 14.27 ± 0.06 mm, 3.77 ± 0.16 mm, and 6.4 ± 0.24 mm, respectively. The PVA release curves showed that approximately 1300 µg of PVA was released over the study duration of 24 h. <b>Conclusions:</b> Overall, this work demonstrates that a 3D-printed PVA-eluting CL is a promising candidate for the treatment of dry eye.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancements in the Application of Numerical Simulation During Tablet Compaction.","authors":"Zhe Li, Haolong Xiong, Qiong Li, Abid Naeem, Lingyu Yang, Weifeng Zhu, Yanni Wu, Zhengji Jin, Liangshan Ming","doi":"10.3390/pharmaceutics17020220","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020220","url":null,"abstract":"<p><p><b>Background:</b> Numerical simulation is a technique that utilizes electronic computers to combine concepts of the discrete element method (DEM), finite element method (FEM), computational fluid dynamics (CFD), etc., and express simulated behaviors utilizing numerical computations and images. Compaction is the main process of tablet manufacturing; most of the current studies have focused on macroscopic compaction and tablet characterization, while the internal stress state and microstructure changes as a result of the compaction process are not well understood. Therefore, an in-depth understanding of the flow and compaction behavior of pharmaceutical powders is essential for the analysis and control of the compaction process. <b>Methods:</b> Current research shows that compaction is shifting from macroscopic behavior toward internal microscopic behavior using numerical simulation technology. <b>Results:</b> This review focuses on the application of various numerical simulation technologies during compaction and the contact model, or the constitutive equation commonly used in numerical simulation. In addition, the difficulties of numerical simulation technology in calibrating powder parameters and the limitations of the current research are also discussed. <b>Conclusions:</b> Numerical simulation research in medicine and other fields will continue to flourish as numerical simulation technology advances, attracting more and more researchers using it effectively.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of Albuterol Delivery via Anesthesia Bag in Pediatric Critical Care.","authors":"Sébastien Tessier, Victoria K Ploszay, Christian Robitaille, Jigneshkumar Vaghasiya, Andrew J Halayko, Louise Chartrand","doi":"10.3390/pharmaceutics17020218","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020218","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Aerosolized medications are common practice for mechanically ventilated pediatric patients. Infants often receive nebulized medications via hand ventilation using an anesthesia bag, but evidence on optimal aerosol delivery with this method is limited. For this study, various configurations of the Mapleson breathing circuit were tested to optimize albuterol delivery to a simulated pediatric model. <b>Methods:</b> Using a simulated pediatric lung model (ASL 5000) with the semi-open Mapleson anesthesia circuit, 2.5 mg/3 mL of albuterol sulfate solution was nebulized to a viral/bacterial filter (Respiguard 202). Four models were compared with varying fresh gas flows (FGFs), small-volume nebulizer (SVN) placements, and adjusting dead space. Five Registered Respiratory Therapists (RRTs) bagged the aerosol into a collection filter following defined ventilation parameters. Each model was tested in random order to avoid fatigue bias. Albuterol concentrations eluted from in-line filters were measured by spectrophotometry (absorbance at 276 nm). <b>Results:</b> No inter-user variability was observed among the RRTs. Significant differences in albuterol recovered were noted between models (One Way ANOVA, Tukey's post hoc, n = 5). Model 4, with the nebulizer closest to the collecting filter, recovered 21.77 ± 1.89% of albuterol. The standard clinical model was the least effective, with only 0.10 ± 0.17% albuterol recovery. <b>Conclusions:</b> Modifying the anesthesia breathing circuit significantly improved aerosol drug delivery efficiency. Our findings suggest that current clinical practices for nebulized drug delivery are inefficient and can be markedly improved with simple adjustments in nebulizer positioning and gas flow within the circuit.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral Administration of Neratinib Maleate-Loaded Lipid-Polymer Hybrid Nanoparticles: Optimization, Physical Characterization, and In Vivo Evaluation.","authors":"Radhika Rajiv Mahajan, Punna Rao Ravi, Sakshi Jadhav, Prinsi Kishorbhai Pansuriya, Bhushan Gopalsing Naik, Shalaka Hanmant Anture, Łukasz Szeleszczuk","doi":"10.3390/pharmaceutics17020221","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020221","url":null,"abstract":"<p><p><b>Background</b>: Neratinib maleate (NM), a tyrosine kinase inhibitor, is used in the treatment of breast cancer. Current oral therapy of NM suffers from low and variable bioavailability due to the solubility and permeability-related issues of the drug. To overcome the low oral bioavailability, the drug is recommended to be administered at high doses, causing severe gastrointestinal side effects leading to discontinuation of the drug therapy. <b>Methods</b>: In this work, NM-loaded lipid-polymer hybrid nanoparticles (NM-LPNs) were designed and optimized to improve the oral bioavailability of the drug. A systematic approach involving a screening design followed by an optimization design based on the principles of design of experiments (DoE) was used to prepare NM-LPNs. Minimum particle size (PS) ranging between 200 and 300 nm and maximum drug loading (DL (%)) were set as the target physicochemical properties. The optimized NM-LPNs, with a mean PS of 278.57 ± 21.16 nm and a DL (%) of 25.77 ± 1.11%, were further characterized for physicochemical properties, thermal and diffractometric analysis, stability, in vitro drug release, and oral pharmacokinetic studies. <b>Results</b>: The nanoparticles exhibited a burst release followed by a prolonged release up to 12 h in the in vitro drug release studies in pH 6.8 media. <b>Conclusions</b>: The mean C_max and the AUC_last values were found to increase significantly for NM-LPNs by 1.72 times (<i>p</i> < 0.01) and 1.58 times (<i>p</i> < 0.01), respectively, when compared to plain NM in the oral pharmacokinetic studies. The optimized NM-LPN formulation can reduce the oral dose of NM and, thereby, its dose-dependent side effects.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multivariate Data Analysis to Assess Process Evolution and Systematic Root Causes Investigation in Tablet Manufacturing at an Industrial Scale-A Case Study Focused on Improving Tablet Hardness.","authors":"Rita Mathe, Tibor Casian, Ioan Tomuta","doi":"10.3390/pharmaceutics17020213","DOIUrl":"https://doi.org/10.3390/pharmaceutics17020213","url":null,"abstract":"<p><p><b>Background/Objectives</b>: Only a few studies performed at industrial scale in non-simulated conditions have investigated the effect of input variability from the product's lifecycle on product quality. The purpose of this work was to identify the root causes for the low and variable hardness of core tablets prepared using high-shear wet granulation through batch statistical modeling and to verify the short- and long-term effectiveness of the improvement actions. <b>Methods</b>: The novelty of this study is the use of multivariate methods for the complex assessment of a wide data set belonging to two proportional composition strengths, manufactured at an industrial scale, with different tablet shapes and sizes, with the aim of identifying inter-related active ingredient and process variables with the highest impact on hardness value and for defining optimal processing conditions leading to a robust product. <b>Results</b>: Four main variables affecting the output variable were identified: API particle size, nozzle type used for granulation, wet discharge, and drying intensity. These were included in an updated control strategy (3 out of 4 variables having to be within the desired ranges: API d0.5 < 45 microns; granulation nozzle that ensures liquid dispersion into droplets; gentle wet discharge and drying processes). In the case of the product studied, the newly defined process conditions could even accommodate d0.5 up to 70 microns and still ensure adequate core tablet hardness (at least 30% above the lower specification limit) for the successive film-coating step. <b>Conclusions</b>: Besides the beneficial impact of reducing the risk for out-of-specification hardness results, this study also offered the benefit of cost avoidance and yield improvement. The improvement was confirmed through the significant average hardness increase (15-20%) and between-batch variability decrease, leading to decent sigma quality levels (2.5) for the control phase batches.</p>","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":"17 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143503364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}