Pub Date : 2026-02-26DOI: 10.1208/s12249-026-03350-5
Aya A. Refaat, Sarah Yahia, Ibrahim M. El-Sherbiny
Dry eye disease (DED) is a rampant and multifactorial ocular disorder. Conventional ocular drug delivery faces significant challenges due to the complex ocular pathophysiology, inadequate bioavailability, rapid elimination, high viscosity, and the need for frequent administration. The present study involves the development of a fortified long-acting ocular gel laden with nano-formulated dexamethasone (DEX) for DED treatment by modifying the current artificial tears formulation, Systane® liquid eye gel drops. This modification was divided into two steps: mixing the commercial gel with ocular demulcents, hyaluronic acid (HA) (HA@in-situ gel), then loading it with a combination of free anti-inflammatory DEX and DEX-loaded chitosan (CS)/Pluronic (PL) nanoparticles (DEX-NPs), DEX-NPs-in-HA@in-situ gel. The 31. 22 factorial experimental designs were employed to optimize formulation for DEX-NPs. Morphology and size of optimum DEX-NPs were obtained using DLS and TEM. DEX-NPs showed a particle size of 250 ± 3 nm. DEX-NPs presented sustained release of DEX for about 5 days. The kinetic release profile of the DEX-NPs-in-HA@in-situ gel showed that the loaded gel follows the Korsmeyer Peppas model with R2 = 0.936. In-vivo evaluation involved the examination of histological micrographs of the cornea structure of the dry eye rat model after application of DEX-NPs-in-HA@in-situ gel. The results confirmed discernible improvement of corneal structure compared to the commercial unmodified eye gel.
{"title":"Fortified Long-acting Ocular Gel Laden with Nanoformulated Dexamethasone for Dry Eye Therapy","authors":"Aya A. Refaat, Sarah Yahia, Ibrahim M. El-Sherbiny","doi":"10.1208/s12249-026-03350-5","DOIUrl":"10.1208/s12249-026-03350-5","url":null,"abstract":"<div><p>Dry eye disease (DED) is a rampant and multifactorial ocular disorder. Conventional ocular drug delivery faces significant challenges due to the complex ocular pathophysiology, inadequate bioavailability, rapid elimination, high viscosity, and the need for frequent administration. The present study involves the development of a fortified long-acting ocular gel laden with nano-formulated dexamethasone (DEX) for DED treatment by modifying the current artificial tears formulation, Systane® liquid eye gel drops. This modification was divided into two steps: mixing the commercial gel with ocular demulcents, hyaluronic acid (HA) (HA@<i>in-situ</i> gel), then loading it with a combination of free anti-inflammatory DEX and DEX-loaded chitosan (CS)/Pluronic (PL) nanoparticles (DEX-NPs), DEX-NPs-in-HA@<i>in-situ</i> gel. The 3<sup>1</sup>. 2<sup>2</sup> factorial experimental designs were employed to optimize formulation for DEX-NPs. Morphology and size of optimum DEX-NPs were obtained using DLS and TEM. DEX-NPs showed a particle size of 250 ± 3 nm. DEX-NPs presented sustained release of DEX for about 5 days. The kinetic release profile of the DEX-NPs-in-HA@<i>in-situ</i> gel showed that the loaded gel follows the Korsmeyer Peppas model with R<sup>2</sup> = 0.936. <i>In-vivo</i> evaluation involved the examination of histological micrographs of the cornea structure of the dry eye rat model after application of DEX-NPs-in-HA@<i>in-situ</i> gel. The results confirmed discernible improvement of corneal structure compared to the commercial unmodified eye gel.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-026-03350-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Radiopharmaceuticals are biologically active molecules labeled with radionuclides that have advanced the possibility of the nuclear medicine. They support non-invasive, high-resolution diagnostic imaging of molecular and physiological processes in vivo. The techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) utilize short-lived β⁺ and γ-emitting isotopes to generate highly sensitive, three-dimensional assessments of biological function. In therapeutic applications, radionuclides that emit β⁻ particles, α particles, or Auger electrons enable targeted delivery of cytotoxic radiation to diseased tissues, while limiting off-target exposure to the healthy cells. The choice of radionuclide is guided by decay characteristics, half-life, production feasibility, and cost, and is coupled to a small molecule, peptide, antibody, or nanoparticle via bifunctional chelators that ensure in-vivo stability and precise biodistribution. Recent approvals highlight this clinical momentum, including Copper-64/Copper-67, a chemically matched theranostic radionuclide pair that reduces chelator-related variability and streamlines diagnostic therapeutic supply chains, Lutetium Lu-177 dotatate, an FDA approved radioligand therapy, and Lutetium Lu-177 vipivotide tetraxetan, a prostate cancer targeted radioligand therapy illustrate the clinical momentum of this field, yet hurdles remain in large-scale isotope supply, formulation robustness, and regulatory harmonization. This review highlights key innovations in vector design, radionuclide production, and formulation; explores how artificial intelligence is transforming imaging and therapy planning; and clarifies the shifting regulatory landscape for clinical translation. By highlighting both current achievements and future research priorities, we provide a comprehensive framework by integrating productions challenges, formulation considerations, and regulatory harmonization into a unified perspective that deliver precision imaging and personalized therapy.
{"title":"Radiopharmaceuticals: Status, Regulatory Landscape and Future Perspective","authors":"Heena Maithania, Rijo John, Raghunandhan Painoori, Jasmin Monpara, Shankar Swaminathan, Rahul Kalhapure","doi":"10.1208/s12249-026-03346-1","DOIUrl":"10.1208/s12249-026-03346-1","url":null,"abstract":"<div><p>Radiopharmaceuticals are biologically active molecules labeled with radionuclides that have advanced the possibility of the nuclear medicine. They support non-invasive, high-resolution diagnostic imaging of molecular and physiological processes in vivo. The techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) utilize short-lived β⁺ and γ-emitting isotopes to generate highly sensitive, three-dimensional assessments of biological function. In therapeutic applications, radionuclides that emit β⁻ particles, α particles, or Auger electrons enable targeted delivery of cytotoxic radiation to diseased tissues, while limiting off-target exposure to the healthy cells. The choice of radionuclide is guided by decay characteristics, half-life, production feasibility, and cost, and is coupled to a small molecule, peptide, antibody, or nanoparticle via bifunctional chelators that ensure in-vivo stability and precise biodistribution. Recent approvals highlight this clinical momentum, including Copper-64/Copper-67, a chemically matched theranostic radionuclide pair that reduces chelator-related variability and streamlines diagnostic therapeutic supply chains, Lutetium Lu-177 dotatate, an FDA approved radioligand therapy, and Lutetium Lu-177 vipivotide tetraxetan, a prostate cancer targeted radioligand therapy illustrate the clinical momentum of this field, yet hurdles remain in large-scale isotope supply, formulation robustness, and regulatory harmonization. This review highlights key innovations in vector design, radionuclide production, and formulation; explores how artificial intelligence is transforming imaging and therapy planning; and clarifies the shifting regulatory landscape for clinical translation. By highlighting both current achievements and future research priorities, we provide a comprehensive framework by integrating productions challenges, formulation considerations, and regulatory harmonization into a unified perspective that deliver precision imaging and personalized therapy.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-26DOI: 10.1208/s12249-026-03341-6
Guangpu Fang, Changhao Jia, Zhiqi Guan, Fan Li, Zheng Li, Wenlong Li
This study aims to establish a multi-objective spray drying process optimization framework, with andrographolide (ADG) amorphous solid dispersion serving as a model drug. The proposed framework integrates Box-Behnken design (BBD), artificial neural networks (ANN), and an adaptive grey wolf optimizer (AGWO). Molecular docking was employed to screen potential polymeric carriers, and in vitro dissolution experiments were conducted to identify the carrier with the best solubilizing performance. Single-factor experiment and BBD trial were carried out to evaluate the effects of key process parameters on energy consumption, drying loss, drug release, and yield. A multi-response ANN model was then developed based on BBD data. To enhance the model’s generalization ability and account for process variability, virtual samples were introduced to augment the training dataset. AGWO was subsequently applied to perform inverse optimization and identify the optimal process parameter combination. Experimental validation demonstrated good agreement with the model predictions. X-ray diffraction analysis (XRD) and Fourier-transform infrared (FT-IR) analyses confirmed the amorphous transformation of ADG and its satisfactory short-term physical stability. The proposed method provides a feasible and intelligent strategy for multi-objective optimization in pharmaceutical formulation development.
{"title":"Multi-Objective Spray Drying Process Optimization via BBD-ANN-AGWO Framework: Case of Andrographolide Amorphous Solid Dispersions","authors":"Guangpu Fang, Changhao Jia, Zhiqi Guan, Fan Li, Zheng Li, Wenlong Li","doi":"10.1208/s12249-026-03341-6","DOIUrl":"10.1208/s12249-026-03341-6","url":null,"abstract":"<div><p>This study aims to establish a multi-objective spray drying process optimization framework, with andrographolide (ADG) amorphous solid dispersion serving as a model drug. The proposed framework integrates Box-Behnken design (BBD), artificial neural networks (ANN), and an adaptive grey wolf optimizer (AGWO). Molecular docking was employed to screen potential polymeric carriers, and <i>in vitro</i> dissolution experiments were conducted to identify the carrier with the best solubilizing performance. Single-factor experiment and BBD trial were carried out to evaluate the effects of key process parameters on energy consumption, drying loss, drug release, and yield. A multi-response ANN model was then developed based on BBD data. To enhance the model’s generalization ability and account for process variability, virtual samples were introduced to augment the training dataset. AGWO was subsequently applied to perform inverse optimization and identify the optimal process parameter combination. Experimental validation demonstrated good agreement with the model predictions. X-ray diffraction analysis (XRD) and Fourier-transform infrared (FT-IR) analyses confirmed the amorphous transformation of ADG and its satisfactory short-term physical stability. The proposed method provides a feasible and intelligent strategy for multi-objective optimization in pharmaceutical formulation development.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In recent years, the application of nanotechnology has gained remarkable attention for addressing the formulation challenges of monoterpenes, which are limited by their volatility, low aqueous solubility, and chemical instability. Since release behavior determines their bioavailability and pharmacological efficacy, this study conducted a comparative kinetic analysis of monoterpene release from different nanocarriers to establish a generalized release model. Experimental data were fitted to eight kinetic models (zero-order, first-order, Higuchi, Hixson–Crowell, square root of mass, three-second-root of mass, Weibull, and Korsmeyer–Peppas), and the best-fitting models were selected based on correlation coefficient (R2), error percentage, and normalized error values. To overcome the limitations of single-metric model selection, a Unified Release Fit Index (URFI) was introduced, integrating correlation strength and multiple error-based criteria into a single composite score, thereby enabling robust and consistent comparison across heterogeneous release datasets. Overall, this study establishes a unified statistical framework for analyzing the release kinetics of monoterpenes from nanocarriers. The Weibull model demonstrated the highest predictive performance across the analyzed datasets, exhibiting superior fitting quality for lipid-based and polymeric nanocarriers. The Korsmeyer–Peppas and Higuchi models ranked second, particularly effective in describing diffusion-controlled release in systems with hydrophilic matrices such as chitosan and dextrin. These findings highlight the robustness and versatility of the Weibull model as a universal descriptor for heterogeneous release kinetics of monoterpenes, while the Korsmeyer–Peppas model remains valuable for mechanistic interpretation of diffusion-dominated systems.
{"title":"Comparative Kinetic Modeling and Mathematical Analysis of Monoterpene Release from Nanocarrier Systems","authors":"Morteza Maleki, Maryam Mehrabi, Masomeh Mehrabi, Soroor Sadegh Malvajerd","doi":"10.1208/s12249-026-03332-7","DOIUrl":"10.1208/s12249-026-03332-7","url":null,"abstract":"<div><p>In recent years, the application of nanotechnology has gained remarkable attention for addressing the formulation challenges of monoterpenes, which are limited by their volatility, low aqueous solubility, and chemical instability. Since release behavior determines their bioavailability and pharmacological efficacy, this study conducted a comparative kinetic analysis of monoterpene release from different nanocarriers to establish a generalized release model. Experimental data were fitted to eight kinetic models (zero-order, first-order, Higuchi, Hixson–Crowell, square root of mass, three-second-root of mass, Weibull, and Korsmeyer–Peppas), and the best-fitting models were selected based on correlation coefficient (R<sup>2</sup>), error percentage, and normalized error values. To overcome the limitations of single-metric model selection, a Unified Release Fit Index (URFI) was introduced, integrating correlation strength and multiple error-based criteria into a single composite score, thereby enabling robust and consistent comparison across heterogeneous release datasets. Overall, this study establishes a unified statistical framework for analyzing the release kinetics of monoterpenes from nanocarriers. The Weibull model demonstrated the highest predictive performance across the analyzed datasets, exhibiting superior fitting quality for lipid-based and polymeric nanocarriers. The Korsmeyer–Peppas and Higuchi models ranked second, particularly effective in describing diffusion-controlled release in systems with hydrophilic matrices such as chitosan and dextrin. These findings highlight the robustness and versatility of the Weibull model as a universal descriptor for heterogeneous release kinetics of monoterpenes, while the Korsmeyer–Peppas model remains valuable for mechanistic interpretation of diffusion-dominated systems.\u0000</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Globally, fungal keratitis has become a major health concern, particularly in tropical and humid regions. The disease burden is exacerbated because of the underlying complexity of fungal pathogens, delayed or insufficient diagnosis, and limitations in existing therapeutic strategies, often leading to progressive corneal damage and impaired vision. Additional challenges include insufficient therapy optimization and variable efficacy of topical and systemic antifungal treatments, which may be influenced by factors such as rapid ocular drug clearance, ineffective ocular penetration, and the increasing prevalence of antifungal resistance. Conventional diagnostic techniques, such as microscopy and culture, continue to serve as reference standards but have limitations due to comparatively modest sensitivity and the prolonged turnaround times. In comparison, recent advances in diagnostic techniques, including CRISPR-based assays, PCR, MALDI-ToF MS, and in vivo confocal microscopy, as well as the novel drug-delivery nanocarriers, have been reported to show noticeable improvements in diagnostic accuracy and therapeutic outcomes. Furthermore, emerging DNA-based gene therapies and RNA-based therapeutics, along with advanced ocular drug carriers, have shown promising outcomes in preclinical research and early-phase clinical trials, suggesting potential advantages in enhanced tissue targeting and reduced therapeutic resistance. However, before widespread clinical acceptability, extensive clinical validation, long-term safety evaluations, and cost assessments are required, as existing findings are mainly limited to short-term and experimental research. This review focuses on the pathophysiology of fungal keratitis while underscoring the unmet diagnostic and therapeutic needs. It further explores the potential for developing translatable technologies aimed at predictive diagnosis and the effective management of this sight-threatening condition.
{"title":"Bridging Gaps in Fungal Keratitis Management: Novel Diagnostics, Drug Delivery Systems, and Gene Therapies","authors":"Riya Shivgotra, Bindu Soni, Hossamaldeen Bakrey, Parminder Kaur, Subheet Kumar Jain","doi":"10.1208/s12249-026-03368-9","DOIUrl":"10.1208/s12249-026-03368-9","url":null,"abstract":"<div><p>Globally, fungal keratitis has become a major health concern, particularly in tropical and humid regions. The disease burden is exacerbated because of the underlying complexity of fungal pathogens, delayed or insufficient diagnosis, and limitations in existing therapeutic strategies, often leading to progressive corneal damage and impaired vision. Additional challenges include insufficient therapy optimization and variable efficacy of topical and systemic antifungal treatments, which may be influenced by factors such as rapid ocular drug clearance, ineffective ocular penetration, and the increasing prevalence of antifungal resistance. Conventional diagnostic techniques, such as microscopy and culture, continue to serve as reference standards but have limitations due to comparatively modest sensitivity and the prolonged turnaround times. In comparison, recent advances in diagnostic techniques, including CRISPR-based assays, PCR, MALDI-ToF MS, and <i>in vivo</i> confocal microscopy, as well as the novel drug-delivery nanocarriers, have been reported to show noticeable improvements in diagnostic accuracy and therapeutic outcomes. Furthermore, emerging DNA-based gene therapies and RNA-based therapeutics, along with advanced ocular drug carriers, have shown promising outcomes in preclinical research and early-phase clinical trials, suggesting potential advantages in enhanced tissue targeting and reduced therapeutic resistance. However, before widespread clinical acceptability, extensive clinical validation, long-term safety evaluations, and cost assessments are required, as existing findings are mainly limited to short-term and experimental research. This review focuses on the pathophysiology of fungal keratitis while underscoring the unmet diagnostic and therapeutic needs. It further explores the potential for developing translatable technologies aimed at predictive diagnosis and the effective management of this sight-threatening condition.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-25DOI: 10.1208/s12249-026-03339-0
Sara R. Gad, Mina Y. George, Riham I. El-Gogary, Rania M. Hathout
Herbal drugs have been investigated for multiple neurodegenerative diseases because of their multi-targeted mechanisms of action and relatively low toxicity profile. However, due to their unfavorable physicochemical properties that limit their action, nanocarriers are warranted to enhance their delivery and hence their therapeutic effect. In this study, an intranasal microemulsion (ME) of the lipophilic molecule glycyrrhetinic acid (GA), a triterpenoid derived from licorice root that is widely known for its antioxidant and anti-inflammatory properties, was developed for the treatment of Alzheimer’s disease (AD). Pseudo-ternary phase diagrams were constructed and the prepared ME systems were optimized using Simplex lattice mixture experimental design. The selected loaded lauroglycol MEs (GA-ME LG) were of droplet size 5.61 ± 0.01 nm and PDI of 0.521 ± 0.032. They showed a significantly high physical stability up to 3 months at room temperature and in the refrigerator. The ex vivo permeation study across sheep nasal mucosa revealed that GA-loaded ME LG exhibited a significant increase in steady-state flux after 8 h compared to GA suspension by 5.67-fold (p < 0.05). SCOP-induced memory impairment in rats was ameliorated by intranasal injection of GA ME LG at a concentration of 1 mg/kg, in a comparable way to the oral route (at a dosage 50 times higher than MEs) (p < 0.05). Additionally, GA ME LG counteracted SCOP-induced oxidative damage (p < 0.05). Collectively, GA-loaded MEs can deliver GA to the brain efficiently and might offer potential treatment for AD patients.
{"title":"Breaking Barriers: Intranasal Microemulsions for the Efficient Nose-to-brain Delivery of Glycyrrhetinic Acid","authors":"Sara R. Gad, Mina Y. George, Riham I. El-Gogary, Rania M. Hathout","doi":"10.1208/s12249-026-03339-0","DOIUrl":"10.1208/s12249-026-03339-0","url":null,"abstract":"<div><p>Herbal drugs have been investigated for multiple neurodegenerative diseases because of their multi-targeted mechanisms of action and relatively low toxicity profile. However, due to their unfavorable physicochemical properties that limit their action, nanocarriers are warranted to enhance their delivery and hence their therapeutic effect. In this study, an intranasal microemulsion (ME) of the lipophilic molecule glycyrrhetinic acid (GA), a triterpenoid derived from licorice root that is widely known for its antioxidant and anti-inflammatory properties, was developed for the treatment of Alzheimer’s disease (AD). Pseudo-ternary phase diagrams were constructed and the prepared ME systems were optimized using Simplex lattice mixture experimental design. The selected loaded lauroglycol MEs (GA-ME LG) were of droplet size 5.61 ± 0.01 nm and PDI of 0.521 ± 0.032. They showed a significantly high physical stability up to 3 months at room temperature and in the refrigerator. The <i>ex vivo</i> permeation study across sheep nasal mucosa revealed that GA-loaded ME LG exhibited a significant increase in steady-state flux after 8 h compared to GA suspension by 5.67-fold (<i>p</i> < 0.05). SCOP-induced memory impairment in rats was ameliorated by intranasal injection of GA ME LG at a concentration of 1 mg/kg, in a comparable way to the oral route (at a dosage 50 times higher than MEs) (<i>p</i> < 0.05). Additionally, GA ME LG counteracted SCOP-induced oxidative damage (<i>p</i> < 0.05). Collectively, GA-loaded MEs can deliver GA to the brain efficiently and might offer potential treatment for AD patients.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-026-03339-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-25DOI: 10.1208/s12249-026-03328-3
C. A. Amor, A. Nardi-Ricart, J. R. Ticó, D. Samarkanova, M. Miñarro Carmona
In this paper a novel method to obtain the heat transfer coefficient Kv value by the gravimetric method without using product temperature sensors is described. The sublimation front temperature is measured manometrically (indirectly by measuring the pressure). The key finding is a method to obtain the Kv value by using a primary drying model with a tailored algorithm. The authors have named it the gravi-manometric method. Kv values at different pressures are presented for two different containers: a freeze-drying stainless-steel cup, and for nested vials. The traditional gravimetric method has been compared against the new gravi-manometric method. Product temperature measurement can be challenging in applications with complex accessibility, as in large batch freeze dryers or when using protective membranes which enclose the product. This novel method is presented as an affordable and simple procedure by which the Kv value is obtained. The gravi-manometric method has the advantage that all the Kv values for a whole batch of vials can be obtained, as it is not limited to a discrete number of product temperature sensors.
{"title":"An Affordable and Simple Novel Approach to Obtain the Heat Transfer Coefficient (Kv) for Primary Drying Models Without Product Temperature Sensors","authors":"C. A. Amor, A. Nardi-Ricart, J. R. Ticó, D. Samarkanova, M. Miñarro Carmona","doi":"10.1208/s12249-026-03328-3","DOIUrl":"10.1208/s12249-026-03328-3","url":null,"abstract":"<div><p>In this paper a novel method to obtain the heat transfer coefficient Kv value by the gravimetric method without using product temperature sensors is described. The sublimation front temperature is measured manometrically (indirectly by measuring the pressure). The key finding is a method to obtain the Kv value by using a primary drying model with a tailored algorithm. The authors have named it the gravi-manometric method. Kv values at different pressures are presented for two different containers: a freeze-drying stainless-steel cup, and for nested vials. The traditional gravimetric method has been compared against the new gravi-manometric method. Product temperature measurement can be challenging in applications with complex accessibility, as in large batch freeze dryers or when using protective membranes which enclose the product. This novel method is presented as an affordable and simple procedure by which the Kv value is obtained. The gravi-manometric method has the advantage that all the Kv values for a whole batch of vials can be obtained, as it is not limited to a discrete number of product temperature sensors.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-026-03328-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-24DOI: 10.1208/s12249-026-03363-0
Valentin Stahl, Muhammad Farooq Umer, Jozef Al-Gousous, Thomas Nawroth, Wei-Jhe Sun, Fang Wu, Wenlei Jiang, Zongming Gao, Peter Langguth
In disintegration and dissolution (D&D) testing, high media viscosity, resembling ingested food, is rarely considered for simulated fed state investigations. However, it can strongly alter tablet breakdown and drug release, depending on the formulation factors. A viscous hydroxypropyl methyl cellulose (HPMC) solution as a D&D medium was used to match a blended FDA-standardized meal in terms of viscosity and pH, mimicking postprandial stomach content. However, compendial disintegration and dissolution apparatuses are not specifically designed to be operated with highly viscous media. Overall, tablet D&D performance is considerably slowed down due to high viscosity but is significantly influenced by the tablet’s composition and physical properties, e.g., porosity. There are excipients that can increase coning already in fasted state media, for instance, insoluble fillers like microcrystalline cellulose or dicalcium phosphate. Under poor hydrodynamic conditions, those substances’ negative effects can even be exacerbated. This leads to artefactual dissolution behavior, which did not align with expectations derived from the tablet’s properties. A novel computerized numerical control (CNC)-based D&D apparatus is developed and applied to avoid these phenomena by moving the samples through the medium instead of fluid agitation around the tablet. The movement pattern is three-dimensional at a specified velocity and can be adjusted to desired conditions. Different test tablet formulations with varying soluble and insoluble fillers were used to demonstrate that the approach using the novel CNC apparatus overcomes the challenges of highly viscous media and clearly distinguishes tablets as expected, according to their composition.
{"title":"Overcoming the Challenges of Viscous Simulated Fed State Media with a Computerized Numerical Control Tablet Disintegration and Dissolution Tester","authors":"Valentin Stahl, Muhammad Farooq Umer, Jozef Al-Gousous, Thomas Nawroth, Wei-Jhe Sun, Fang Wu, Wenlei Jiang, Zongming Gao, Peter Langguth","doi":"10.1208/s12249-026-03363-0","DOIUrl":"10.1208/s12249-026-03363-0","url":null,"abstract":"<div><p>In disintegration and dissolution (D&D) testing, high media viscosity, resembling ingested food, is rarely considered for simulated fed state investigations. However, it can strongly alter tablet breakdown and drug release, depending on the formulation factors. A viscous hydroxypropyl methyl cellulose (HPMC) solution as a D&D medium was used to match a blended FDA-standardized meal in terms of viscosity and pH, mimicking postprandial stomach content. However, compendial disintegration and dissolution apparatuses are not specifically designed to be operated with highly viscous media. Overall, tablet D&D performance is considerably slowed down due to high viscosity but is significantly influenced by the tablet’s composition and physical properties, e.g., porosity. There are excipients that can increase coning already in fasted state media, for instance, insoluble fillers like microcrystalline cellulose or dicalcium phosphate. Under poor hydrodynamic conditions, those substances’ negative effects can even be exacerbated. This leads to artefactual dissolution behavior, which did not align with expectations derived from the tablet’s properties. A novel computerized numerical control (CNC)-based D&D apparatus is developed and applied to avoid these phenomena by moving the samples through the medium instead of fluid agitation around the tablet. The movement pattern is three-dimensional at a specified velocity and can be adjusted to desired conditions. Different test tablet formulations with varying soluble and insoluble fillers were used to demonstrate that the approach using the novel CNC apparatus overcomes the challenges of highly viscous media and clearly distinguishes tablets as expected, according to their composition.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-026-03363-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-24DOI: 10.1208/s12249-026-03355-0
Rizwan Shaikh, Swaroop J. Pansare, Bhanu P. Dongala, Sunil K. Thota, Mohammad T. H. Nutan, Daniela Z. Bazan, Mansoor A. Khan, Ziyaur Rahman
The objectives of the present work were to simultaneously quantify digoxin (DGX) and its impurities by a common analytical method, compare dissolution data of a FDA approved commercial products by DGX tablets USP monograph, and apply the developed method to assess quality of the product. A UPLC method was developed and validated as per ICH guideline. An FDA approved formulation of DGX tablets was evaluated for quality (assay and dissolution), and stability by storing it at 30 °C/75% RH and 40 °C/75% RH conditions. Dissolution testing was performed in water and 0.1 N HCl as per the USP monograph. The UPLC method was specific, and linear over 100–2000 ng/ml with good accuracy > 98.6% and precision < 3.3% for all the analytes (DGX, digoxigenin, digoxigenin monodigitoxoside and digoxigenin bisdigitoxoside). The tablets met USP specification of assay > 98% and dissolution of > 85% in 20 min in water medium. However, the drug degrades into impurities in the acidic medium and fluorospectrometric method was non-specific in quantifying drug and impurities as per the USP monograph. Dissolution decreased by almost 30% on exposure to stability conditions and did not meet the specification due to an increase in the drug crystallinity as supported by the X-ray powder diffraction data. In summary, the developed UPLC method can be applied to assess the quality of DGX tablets, and dissolution testing in the acidic medium and fluorospectrometric method was non-discriminatory and non-specific for routine quality control test.
{"title":"Appropriateness of Dissolution Methods on Evaluation of Digoxin Product Quality","authors":"Rizwan Shaikh, Swaroop J. Pansare, Bhanu P. Dongala, Sunil K. Thota, Mohammad T. H. Nutan, Daniela Z. Bazan, Mansoor A. Khan, Ziyaur Rahman","doi":"10.1208/s12249-026-03355-0","DOIUrl":"10.1208/s12249-026-03355-0","url":null,"abstract":"<div><p>The objectives of the present work were to simultaneously quantify digoxin (DGX) and its impurities by a common analytical method, compare dissolution data of a FDA approved commercial products by DGX tablets USP monograph, and apply the developed method to assess quality of the product. A UPLC method was developed and validated as per ICH guideline. An FDA approved formulation of DGX tablets was evaluated for quality (assay and dissolution), and stability by storing it at 30 °C/75% RH and 40 °C/75% RH conditions. Dissolution testing was performed in water and 0.1 N HCl as per the USP monograph. The UPLC method was specific, and linear over 100–2000 ng/ml with good accuracy > 98.6% and precision < 3.3% for all the analytes (DGX, digoxigenin, digoxigenin monodigitoxoside and digoxigenin bisdigitoxoside). The tablets met USP specification of assay > 98% and dissolution of > 85% in 20 min in water medium. However, the drug degrades into impurities in the acidic medium and fluorospectrometric method was non-specific in quantifying drug and impurities as per the USP monograph. Dissolution decreased by almost 30% on exposure to stability conditions and did not meet the specification due to an increase in the drug crystallinity as supported by the X-ray powder diffraction data. In summary, the developed UPLC method can be applied to assess the quality of DGX tablets, and dissolution testing in the acidic medium and fluorospectrometric method was non-discriminatory and non-specific for routine quality control test.\u0000</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-026-03355-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-24DOI: 10.1208/s12249-026-03336-3
Catherine L. Brockus, Likitha Venkatesh
The ICH Guideline M10, adopted by the EMA in July 2022 and implemented in January 2023, recommends that stability testing of quality controls (QCs) should match actual sample analyte concentrations, prompting adjustments in QC levels when samples exceed analytical ranges. Laboratories continue long-term stability (LTS) testing on ultra-high concentration quality controls (UHQCs) which are often defined by multiples of the upper limit of quantification (ULOQ) rather than observed maximum concentrations (Cmax). Based on recommendations for implementation of the M10 Guideline regarding Phase 3 clinical trials, we questioned the need for further LTS testing at UHQC levels beyond Phase 2. To address LTS timeline challenges, incurred sample reproducibility (ISR) data from clinical studies were compiled, evaluating their relevance to Cmax and utilizing a Random Intercept Model (RIM) as a tool for establishing stability profiles for drug analytes. Analysis showed most UHQCs estimated using simple ULOQ multiples may not accurately reflect Cmax. Clinical ISR data provided evidence of stability across analyte concentrations within patient matrices with a high degree of confidence. Predictive tools based on ISR data were proposed as a practical approach to demonstrate stability. ISR data can support claims of analyte stability including at ultra-high concentrations, consistent with the M10 guideline and established LTS from validation testing. Using ISR from clinical reports reduces reliance on lengthy LTS testing, offering a robust, efficient method for establishing stability profiles from real-world samples to accomplish regulatory expectations while optimizing workflows.
{"title":"Use of Incurred Sample Reproducibility Data to Support Long Term Stability of Therapeutic Antibodies in Clinical Bioanalytical Methods","authors":"Catherine L. Brockus, Likitha Venkatesh","doi":"10.1208/s12249-026-03336-3","DOIUrl":"10.1208/s12249-026-03336-3","url":null,"abstract":"<div><p>The ICH Guideline M10, adopted by the EMA in July 2022 and implemented in January 2023, recommends that stability testing of quality controls (QCs) should match actual sample analyte concentrations, prompting adjustments in QC levels when samples exceed analytical ranges. Laboratories continue long-term stability (LTS) testing on ultra-high concentration quality controls (UHQCs) which are often defined by multiples of the upper limit of quantification (ULOQ) rather than observed maximum concentrations (Cmax). Based on recommendations for implementation of the M10 Guideline regarding Phase 3 clinical trials, we questioned the need for further LTS testing at UHQC levels beyond Phase 2. To address LTS timeline challenges, incurred sample reproducibility (ISR) data from clinical studies were compiled, evaluating their relevance to Cmax and utilizing a Random Intercept Model (RIM) as a tool for establishing stability profiles for drug analytes. Analysis showed most UHQCs estimated using simple ULOQ multiples may not accurately reflect Cmax. Clinical ISR data provided evidence of stability across analyte concentrations within patient matrices with a high degree of confidence. Predictive tools based on ISR data were proposed as a practical approach to demonstrate stability. ISR data can support claims of analyte stability including at ultra-high concentrations, consistent with the M10 guideline and established LTS from validation testing. Using ISR from clinical reports reduces reliance on lengthy LTS testing, offering a robust, efficient method for establishing stability profiles from real-world samples to accomplish regulatory expectations while optimizing workflows.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 3","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号