Pub Date : 2025-12-24DOI: 10.1016/j.xphs.2025.104145
Rafeek F. Shokry
The specification for a combination product represents a critical covenant of its quality. Too often, the current intellectual framework for forging this covenant remains a fragmented patchwork of legacy pharmaceutical and medical device paradigms. This paper argues that significant product failures are not random accidents but predictable consequences of these historical limitations. We therefore propose a novel, deductive framework—Quality by Design in Specification (QbD-S)—that complements existing empirical methods to address this systemic challenge. This paper presents a formal intellectual engine, the Universal Attribute Generator (UAG), which deconstructs therapeutic failure into five foundational Tenets and uses a rigorous "Interrogatory Filter" (Stress > Capacity) to systematically derive a comprehensive set of quality attributes. This framework introduces the Criticality Vector to contextualize consequence by adding the dimension of "Context" to the standard scalar of "Severity," and mandates a Structured Falsification Protocol to build scientific confidence in its conclusions. The ultimate output is a "Master Control Strategy"—a binding regulatory mandate that legislates the "Fate" of each attribute, enabling either "Input-Controlled" Real-Time Release or mandating traditional "Symptom-Controlled" testing. QbD-S provides a systematic engine for translating patient needs into a scientifically rigorous and defensible covenant of quality.
{"title":"Forging certainty: A novel framework for the specification of combination products","authors":"Rafeek F. Shokry","doi":"10.1016/j.xphs.2025.104145","DOIUrl":"10.1016/j.xphs.2025.104145","url":null,"abstract":"<div><div>The specification for a combination product represents a critical covenant of its quality. Too often, the current intellectual framework for forging this covenant remains a fragmented patchwork of legacy pharmaceutical and medical device paradigms. This paper argues that significant product failures are not random accidents but predictable consequences of these historical limitations. We therefore propose a novel, deductive framework—Quality by Design in Specification (QbD-S)—that complements existing empirical methods to address this systemic challenge. This paper presents a formal intellectual engine, the Universal Attribute Generator (UAG), which deconstructs therapeutic failure into five foundational Tenets and uses a rigorous \"Interrogatory Filter\" (Stress > Capacity) to systematically derive a comprehensive set of quality attributes. This framework introduces the Criticality Vector to contextualize consequence by adding the dimension of \"Context\" to the standard scalar of \"Severity,\" and mandates a Structured Falsification Protocol to build scientific confidence in its conclusions. The ultimate output is a \"Master Control Strategy\"—a binding regulatory mandate that legislates the \"Fate\" of each attribute, enabling either \"Input-Controlled\" Real-Time Release or mandating traditional \"Symptom-Controlled\" testing. QbD-S provides a systematic engine for translating patient needs into a scientifically rigorous and defensible covenant of quality.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104145"},"PeriodicalIF":3.8,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843876","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}
Many active pharmaceutical ingredients (APIs) currently being developed are poorly soluble in water, which enhances their solubility and bioavailability critical challenges. The evaporation/condensation (EV) method, wherein crystalline APIs are dissolved in organic solvents and adsorbed onto porous materials, is used to improve the solubility of APIs. However, the use of residual organic solvents during evaporation is challenging. Recently, the sealed heating (SH) method, in which a mixture of porous materials and a sublimated API is heated in a sealed container, has been reported as an alternative to the EV method. This study focuses on mesoporous silica (MPS-4R or -2R) as a porous material. The SH method was used to investigate the adsorption of ibuprofen (IBU) on MPSs. In the PXRD study, the IBU crystals were amorphized using the SH method. The elution rate of SH mixture containing 10 wt% IBU was approximately 2.7 times higher than that of the IBU crystals at 10 min after the start of the test. Based on these results, the SH method is a novel approach for amorphizing and enhancing the solubility of poorly water-soluble drugs without the use of organic solvents.
{"title":"New method for adsorbing the pharmaceuticals on mesoporous silica: Adsorption behavior of ibuprofen on mesoporous silica via the sealed and heating method","authors":"Yayoi Kawano , Kazuya Nomura , Nobuyuki Natori , Takuma Oba , Chihiro Ozawa , Kaoru Hirose , Takehisa Hanawa","doi":"10.1016/j.xphs.2025.104140","DOIUrl":"10.1016/j.xphs.2025.104140","url":null,"abstract":"<div><div>Many active pharmaceutical ingredients (APIs) currently being developed are poorly soluble in water, which enhances their solubility and bioavailability critical challenges. The evaporation/condensation (EV) method, wherein crystalline APIs are dissolved in organic solvents and adsorbed onto porous materials, is used to improve the solubility of APIs. However, the use of residual organic solvents during evaporation is challenging. Recently, the sealed heating (SH) method, in which a mixture of porous materials and a sublimated API is heated in a sealed container, has been reported as an alternative to the EV method. This study focuses on mesoporous silica (MPS-4R or -2R) as a porous material. The SH method was used to investigate the adsorption of ibuprofen (IBU) on MPSs. In the PXRD study, the IBU crystals were amorphized using the SH method. The elution rate of SH mixture containing 10 wt% IBU was approximately 2.7 times higher than that of the IBU crystals at 10 min after the start of the test. Based on these results, the SH method is a novel approach for amorphizing and enhancing the solubility of poorly water-soluble drugs without the use of organic solvents.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104140"},"PeriodicalIF":3.8,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843880","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}
Pub Date : 2025-12-24DOI: 10.1016/j.xphs.2025.104139
Benjamin A Kuzma, Sharareh Senemar, Tannaz Ramezanli, Priyanka Ghosh, Sam G Raney, Grazia Stagni
Dermal microdialysis involves the insertion of a probe into the dermis beneath an application site for a topical drug product (TDP). The probe measures local, unbound, active pharmaceutical ingredient (API or drug) concentrations in the dermis. The resulting dermal concentration-time profile is a combination of the simultaneous drug absorption and disposition (by distribution/elimination into surrounding tissues and into the dermal vasculature). For orally or subcutaneously administered drug products, the absorption process is estimated through deconvolution of plasma concentrations utilizing the unit impulse response (UIR) obtained from an intravenous administration. In this study, we implemented a retrodialysis/microdialysis (termed "dermal infusion") approach to deliver metronidazole (MTZ) directly into the dermis allowing measurement of dermal disposition parameters (dermal clearance and dermal volume of distribution) and thus the calculation of MTZ's dermal UIR (dUIR); The dUIR allowed for the estimation of the absorption process or in vivo dermal flux (input-rate) and cumulative amount (CA) permeated from MTZ TDP application. The in vivo (Yucatan mini-pig) CA permeated were compared with in vitro permeation testing data (human) to build a retrospective in vitro - in vivo relationship (IVIVR). The internal validation for Cmax and AUC0-48hr prediction errors indicated a reliable IVIVR. These results suggest that the dermal infusion approach can be used to study dermal API disposition, which can aid in the comprehension of in vivo cutaneous pharmacokinetic (cPK) data. Furthermore, a mechanistic cPK understanding is essential for the successful development of new topical therapeutics and assessment of bioequivalence of TDPs, alike.
{"title":"Dermal disposition characterization and development of a retrospective level A in vitro-in vivo relationship for topical metronidazole products.","authors":"Benjamin A Kuzma, Sharareh Senemar, Tannaz Ramezanli, Priyanka Ghosh, Sam G Raney, Grazia Stagni","doi":"10.1016/j.xphs.2025.104139","DOIUrl":"10.1016/j.xphs.2025.104139","url":null,"abstract":"<p><p>Dermal microdialysis involves the insertion of a probe into the dermis beneath an application site for a topical drug product (TDP). The probe measures local, unbound, active pharmaceutical ingredient (API or drug) concentrations in the dermis. The resulting dermal concentration-time profile is a combination of the simultaneous drug absorption and disposition (by distribution/elimination into surrounding tissues and into the dermal vasculature). For orally or subcutaneously administered drug products, the absorption process is estimated through deconvolution of plasma concentrations utilizing the unit impulse response (UIR) obtained from an intravenous administration. In this study, we implemented a retrodialysis/microdialysis (termed \"dermal infusion\") approach to deliver metronidazole (MTZ) directly into the dermis allowing measurement of dermal disposition parameters (dermal clearance and dermal volume of distribution) and thus the calculation of MTZ's dermal UIR (dUIR); The dUIR allowed for the estimation of the absorption process or in vivo dermal flux (input-rate) and cumulative amount (CA) permeated from MTZ TDP application. The in vivo (Yucatan mini-pig) CA permeated were compared with in vitro permeation testing data (human) to build a retrospective in vitro - in vivo relationship (IVIVR). The internal validation for C<sub>max</sub> and AUC<sub>0-48hr</sub> prediction errors indicated a reliable IVIVR. These results suggest that the dermal infusion approach can be used to study dermal API disposition, which can aid in the comprehension of in vivo cutaneous pharmacokinetic (cPK) data. Furthermore, a mechanistic cPK understanding is essential for the successful development of new topical therapeutics and assessment of bioequivalence of TDPs, alike.</p>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":" ","pages":"104139"},"PeriodicalIF":3.8,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843897","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}
Treatment of breast cancer is severely hindered by dose-limiting toxicity and acquired Tamoxifen (Tam) resistance. This study investigated the synergistic anti-cancer effect and molecular mechanism of green-synthesized Copper Oxide Nanoparticles (CuO NPs) when combined with Tam against the MCF−7 human breast cancer cell line. CuO NPs were successfully produced using an aqueous extract of Artemisia sieberi as a dual reducing/capping agent. Characterization confirmed the formation of stable nanoparticles, evidenced by a Surface Plasmon Resonance (SPR) peak at 552 nm, an average size of ∼36 nm (TEM), and excellent colloidal stability with a highly negative Zeta Potential (-33.5 mV). The MTT assay demonstrated that the combination regimen exhibited a strong synergistic cytotoxic effect (CI<1) toward MCF−7 cells. Synergy was achieved even at low concentrations, such as 15.0 μg/mL CuO NPs:1.0 μM Tam (CI=0.99), with the most potent synergy (CI=0.69) observed at the maximum dose. Quantitative analysis via Annexin V/PI flow cytometry confirmed this enhancement, showing the combination reduced the viable cell population to a minimal 4.87 %. Mechanistically, RT−qPCR analysis revealed a maximal perturbation of the mitochondrial apoptotic pathway. The combined treatment simultaneously maximized the up-regulation of the pro-apoptotic gene BAX and the down-regulation of the anti-apoptotic gene BCL−2. This synergistic action resulted in a 16.74-fold increase in the critical BAX/BCL−2 ratio, approximately two times greater than either monotherapy. These findings validate CuO NPs co-administration with Tamoxifen as a promising strategy for overcoming acquired Tamoxifen resistance.
{"title":"Augmenting the cytotoxicity and apoptosis induction of green synthesized copper oxide nanoparticles from Artemisia sieberi by combining with tamoxifen: Mechanism involving Bax/Bcl-2 modulation","authors":"Saeed Seghatoleslami , Mohammadreza Pourmohammad , Homa Mahmoudzadeh , Jina Khayatzadeh","doi":"10.1016/j.xphs.2025.104143","DOIUrl":"10.1016/j.xphs.2025.104143","url":null,"abstract":"<div><div>Treatment of breast cancer is severely hindered by dose-limiting toxicity and acquired Tamoxifen (Tam) resistance. This study investigated the synergistic anti-cancer effect and molecular mechanism of green-synthesized Copper Oxide Nanoparticles (CuO NPs) when combined with Tam against the MCF−7 human breast cancer cell line. CuO NPs were successfully produced using an aqueous extract of <em>Artemisia sieberi</em> as a dual reducing/capping agent. Characterization confirmed the formation of stable nanoparticles, evidenced by a Surface Plasmon Resonance (SPR) peak at 552 nm, an average size of ∼36 nm (TEM), and excellent colloidal stability with a highly negative Zeta Potential (-33.5 mV). The MTT assay demonstrated that the combination regimen exhibited a strong synergistic cytotoxic effect (CI<1) toward MCF−7 cells. Synergy was achieved even at low concentrations, such as 15.0 μg/mL CuO NPs:1.0 μM Tam (CI=0.99), with the most potent synergy (CI=0.69) observed at the maximum dose. Quantitative analysis via Annexin V/PI flow cytometry confirmed this enhancement, showing the combination reduced the viable cell population to a minimal 4.87 %. Mechanistically, RT−qPCR analysis revealed a maximal perturbation of the mitochondrial apoptotic pathway. The combined treatment simultaneously maximized the up-regulation of the pro-apoptotic gene BAX and the down-regulation of the anti-apoptotic gene BCL−2. This synergistic action resulted in a 16.74-fold increase in the critical BAX/BCL−2 ratio, approximately two times greater than either monotherapy. These findings validate CuO NPs co-administration with Tamoxifen as a promising strategy for overcoming acquired Tamoxifen resistance.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104143"},"PeriodicalIF":3.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834190","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}
Pub Date : 2025-12-23DOI: 10.1016/j.xphs.2025.104142
Marcel Passon , Stefaan De Smedt , Hristo L. Svilenov
Antibodies with ultralong complementarity-determining regions (ulCDRs) have unique antigen-binding features with considerable potential for biomedical applications. Despite this potential, their stability and developability remain largely unexplored from a pharmaceutical perspective. Here, we present a systematic analysis of Fab fragments containing ulCDRs using assays for therapeutic antibody candidate selection. Fluorescence- and light-scattering-based analyses across a broad pH range revealed that ulCDR Fabs exhibit good thermal stability and minimal aggregation. Furthermore, we used relative solubility measurements and light scattering to evaluate the colloidal stability of the Fabs and identified the ulCDR as a key determinant of weak self-association. In addition, stress and storage studies demonstrated that ulCDR Fabs maintain high stability under mechanical stress and at elevated temperature. The results show that ulCDR Fabs display overall favorable physical stability. At the same time, colloidal properties governed by weak ulCDR-driven self-interactions represent the main factor likely to differentiate individual antibodies within this class.
{"title":"A pharmaceutical developability perspective on antibodies with ultra-long CDRs","authors":"Marcel Passon , Stefaan De Smedt , Hristo L. Svilenov","doi":"10.1016/j.xphs.2025.104142","DOIUrl":"10.1016/j.xphs.2025.104142","url":null,"abstract":"<div><div>Antibodies with ultralong complementarity-determining regions (ulCDRs) have unique antigen-binding features with considerable potential for biomedical applications. Despite this potential, their stability and developability remain largely unexplored from a pharmaceutical perspective. Here, we present a systematic analysis of Fab fragments containing ulCDRs using assays for therapeutic antibody candidate selection. Fluorescence- and light-scattering-based analyses across a broad pH range revealed that ulCDR Fabs exhibit good thermal stability and minimal aggregation. Furthermore, we used relative solubility measurements and light scattering to evaluate the colloidal stability of the Fabs and identified the ulCDR as a key determinant of weak self-association. In addition, stress and storage studies demonstrated that ulCDR Fabs maintain high stability under mechanical stress and at elevated temperature. The results show that ulCDR Fabs display overall favorable physical stability. At the same time, colloidal properties governed by weak ulCDR-driven self-interactions represent the main factor likely to differentiate individual antibodies within this class.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104142"},"PeriodicalIF":3.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834138","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}
Pub Date : 2025-12-23DOI: 10.1016/j.xphs.2025.104144
Jakob Tobias Lynnerup , Tim Lillotte , Dennis Oversohl , Maximilian Feldmueller , Annette Bauer-Brandl , Martin Brandl , Uwe Münster , Maximilian Karl
Drug release from four different formulations of the poorly soluble drug emodepside was determined in absence and presence of an absorptive sink (absorptive compartment separated by a barrier) by analyzing both molecularly dissolved and apparently dissolved drug concentrations in parallel. To this end, microdialysis and in situ 2nd derivative UV spectroscopy were employed. Two dose strengths each were investigated of crystalline conventional release tablets, pH-dependent hydroxypropyl methylcellulose acetate succinate-based amorphous solid dispersion (ASD) tablets, pH-independent polyvinylpyrrolidone vinyl acetate ASD tablets, and a polyethylene glycol 400 (PEG400)-based oral solution. The presence of the absorptive sink did significantly increase the (molecularly dissolved) supersaturation in the case of the PEG400-based oral solution as compared to previously published dissolution data while the supersaturation enhancement caused by the absorptive sink for the other formulations was moderate to marginal. This indicates that, for different formulation types, the dynamic interplay between dissolution, supersaturation, colloid-association, and precipitation is captured better by combined dissolution-permeation. Furthermore, the predictive potential of combined dissolution-permeation testing compared to mere dissolution testing was evaluated. The extent and duration of both molecular and apparent dissolution were compared to human plasma concentration time curves to establish in vitro in vivo correlation (IVIVC). Likewise, the initial flux as well as cumulative amount permeated across the PAMPA barrier of the dissolution-permeation assays were compared to human plasma concentration time curves to establish IVIVCs. While apparent dissolution yielded poor IVIVC, both molecular dissolution and dissolution-permeation yielded good and comparable IVIVCs. Finally, a refined mechanistic understanding is derived from the aforementioned dissolution and dissolution-permeation data to explain the observed differences.
{"title":"Can an absorptive sink improve the predictivity of biomimetic two-stage dissolution testing? Comparative IVIVC of various formulations of the poorly soluble drug emodepside","authors":"Jakob Tobias Lynnerup , Tim Lillotte , Dennis Oversohl , Maximilian Feldmueller , Annette Bauer-Brandl , Martin Brandl , Uwe Münster , Maximilian Karl","doi":"10.1016/j.xphs.2025.104144","DOIUrl":"10.1016/j.xphs.2025.104144","url":null,"abstract":"<div><div>Drug release from four different formulations of the poorly soluble drug emodepside was determined in absence and presence of an absorptive sink (absorptive compartment separated by a barrier) by analyzing both molecularly dissolved and apparently dissolved drug concentrations in parallel. To this end, microdialysis and in situ 2nd derivative UV spectroscopy were employed. Two dose strengths each were investigated of crystalline conventional release tablets, pH-dependent hydroxypropyl methylcellulose acetate succinate-based amorphous solid dispersion (ASD) tablets, pH-independent polyvinylpyrrolidone vinyl acetate ASD tablets, and a polyethylene glycol 400 (PEG<sub>400</sub>)-based oral solution. The presence of the absorptive sink did significantly increase the (molecularly dissolved) supersaturation in the case of the PEG<sub>400</sub>-based oral solution as compared to previously published dissolution data while the supersaturation enhancement caused by the absorptive sink for the other formulations was moderate to marginal. This indicates that, for different formulation types, the dynamic interplay between dissolution, supersaturation, colloid-association, and precipitation is captured better by combined dissolution-permeation. Furthermore, the predictive potential of combined dissolution-permeation testing compared to mere dissolution testing was evaluated. The extent and duration of both molecular and apparent dissolution were compared to human plasma concentration time curves to establish in vitro in vivo correlation (IVIVC). Likewise, the initial flux as well as cumulative amount permeated across the PAMPA barrier of the dissolution-permeation assays were compared to human plasma concentration time curves to establish IVIVCs. While apparent dissolution yielded poor IVIVC, both molecular dissolution and dissolution-permeation yielded good and comparable IVIVCs. Finally, a refined mechanistic understanding is derived from the aforementioned dissolution and dissolution-permeation data to explain the observed differences.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104144"},"PeriodicalIF":3.8,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834120","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}
Pub Date : 2025-12-21DOI: 10.1016/j.xphs.2025.104138
Eqram Rahman , Alain Michon , Parinitha Rao , John H Joseph , Woffles T L Wu , Jean D A Carruthers , William Richard Webb
Botulinum neurotoxin type A (BoNT/A) formulations differ mainly in excipients, which determine stability, aggregation, and diffusion. Using multi-scale in silico modelling (AesthetiSIM™), we evaluated excipient substitution across six marketed products. The 150 kDa neurotoxin backbone showed lower RMSD (3.6 ± 0.4 Å) than the 900 kDa complex (4.8 ± 0.6 Å, p = 0.019). Among excipients, trehalose formed 23.1 ± 2.7 hydrogen bonds and −106 ± 6 kcal/mol interaction energy, outperforming sucrose (19.8 ± 2.5 bonds, −93 ± 5 kcal/mol) and lactose (9.6 ± 1.8 bonds, −74 ± 5 kcal/mol). Trehalose combined with HSA yielded synergistic stabilization with 30.1 ± 3.2 bonds, interaction energy of −112 ± 7 kcal/mol, and reduced RMSD to 3.1 ± 0.3 Å. Coarse-grained simulations showed the lowest aggregation with trehalose–HSA (mean cluster size 2.4 ± 0.4 molecules), compared with sucrose (3.7 ± 0.7) and lactose (5.4 ± 1.0, p < 0.001). Finite element modelling predicted diffusion radii of 1.25 ± 0.05 mm for trehalose–HSA versus 1.36 ± 0.06 mm with sucrose (p = 0.014). Reformulated PRABO and LETYBO with trehalose–HSA achieved the longest durations (186 ± 8 and 184 ± 9 days), followed by INCO (176 ± 7), ONA (170 ± 8), DAXI (167 ± 10), and ABO (160 ± 7). Reconstitution with 0.5 mL per 100 units minimized spread (1.22 ± 0.04 mm) and maximized persistence (188 ± 9 days, p < 0.01 vs 2.5 mL). Across molecular, mesoscopic, and tissue levels, trehalose–HSA consistently provided superior stability, aggregation resistance, and duration, offering a rational basis for next-generation BoNT/A formulations.
{"title":"Excipient substitution in botulinum toxin type A formulations: Insights from multi-scale in silico modelling","authors":"Eqram Rahman , Alain Michon , Parinitha Rao , John H Joseph , Woffles T L Wu , Jean D A Carruthers , William Richard Webb","doi":"10.1016/j.xphs.2025.104138","DOIUrl":"10.1016/j.xphs.2025.104138","url":null,"abstract":"<div><div>Botulinum neurotoxin type A (BoNT/A) formulations differ mainly in excipients, which determine stability, aggregation, and diffusion. Using multi-scale in silico modelling (AesthetiSIM™), we evaluated excipient substitution across six marketed products. The 150 kDa neurotoxin backbone showed lower RMSD (3.6 ± 0.4 Å) than the 900 kDa complex (4.8 ± 0.6 Å, <em>p</em> = 0.019). Among excipients, trehalose formed 23.1 ± 2.7 hydrogen bonds and −106 ± 6 kcal/mol interaction energy, outperforming sucrose (19.8 ± 2.5 bonds, −93 ± 5 kcal/mol) and lactose (9.6 ± 1.8 bonds, −74 ± 5 kcal/mol). Trehalose combined with HSA yielded synergistic stabilization with 30.1 ± 3.2 bonds, interaction energy of −112 ± 7 kcal/mol, and reduced RMSD to 3.1 ± 0.3 Å. Coarse-grained simulations showed the lowest aggregation with trehalose–HSA (mean cluster size 2.4 ± 0.4 molecules), compared with sucrose (3.7 ± 0.7) and lactose (5.4 ± 1.0, <em>p</em> < 0.001). Finite element modelling predicted diffusion radii of 1.25 ± 0.05 mm for trehalose–HSA versus 1.36 ± 0.06 mm with sucrose (<em>p</em> = 0.014). Reformulated PRABO and LETYBO with trehalose–HSA achieved the longest durations (186 ± 8 and 184 ± 9 days), followed by INCO (176 ± 7), ONA (170 ± 8), DAXI (167 ± 10), and ABO (160 ± 7). Reconstitution with 0.5 mL per 100 units minimized spread (1.22 ± 0.04 mm) and maximized persistence (188 ± 9 days, <em>p</em> < 0.01 vs 2.5 mL). Across molecular, mesoscopic, and tissue levels, trehalose–HSA consistently provided superior stability, aggregation resistance, and duration, offering a rational basis for next-generation BoNT/A formulations.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104138"},"PeriodicalIF":3.8,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145819888","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}
Pub Date : 2025-12-20DOI: 10.1016/j.xphs.2025.104137
Kassem AL Attabi , Farag M.A. Altalbawy , Deepak J , Anupama Routray , Karthikeyan A , Harjot Singh Gill , Yashwant Singh Bisht , Rafid Kamal Jameel , Ahmed Aldulaimi , Rafid Jihad Albadr , Mariem Alwan , Abdolali Yarahmadi Kandahari
Benzimidazole, a compound valued for its distinct physicochemical characteristics and diverse applications, is the focus of this investigation into its dissolution behavior across various monosolvents. This research employs sophisticated machine learning algorithms, including K-nearest neighbors (KNN), ensemble learning (EL), random forest, decision tree, and adaptive boosting, alongside thermodynamic models such as Apelblat, λh, NRTL, and Margules, to model and predict solubility. A detailed dataset consisting of 171 experimental points, where 136 are used for training and 35 for testing, was curated to encompass 19 monosolvents, including water, methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol, n-pentanol, acetonitrile, acetone, 2-butanone, 1,4-dioxane, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, and butyl acetate. The models utilized key input variables including monosolvent type, monosolvent molar mass (g/mol), and temperature (K) which significantly govern Benzimidazole’s solubility. Sensitivity analysis conducted via Monte Carlo simulations identified monosolvent type as the most influential parameter, followed by temperature and monosolvent molar mass, with sensitivity values of 4.28439, 3.54761, and 2.958176, respectively. The dataset underwent thorough validation to ensure its robustness for data-driven modeling. Model performance assessments demonstrated that adaptive boosting achieved superior predictive precision, yielding the highest R² values and the lowest RMSE and AARE percentages across training and test datasets. These findings emphasize the effectiveness of machine learning, especially adaptive boosting, in providing accurate and efficient solubility predictions. The developed machine learning framework provides an economical complement to experimental methods, facilitating rapid and cost-effective prediction of solubility behavior.
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