Molecular Pharmaceutics最新文献

{"title":"Construction of Bispecific T-Cell Engager Radiotracer and Its Micro-PET Evaluation in Pancreatic Cancer.","authors":"Dan Wen, Qi Wang, Jin Ding, Zilei Wang, Shiyu Lin, Hao Zhang, Xiaohong Huang, Xiaokun Ma, Xingguo Hou, Suping Li, Hua Zhu, Zhi Yang","doi":"10.1021/acs.molpharmaceut.5c00072","DOIUrl":"10.1021/acs.molpharmaceut.5c00072","url":null,"abstract":"<p><p>Mucin 17 (MUC17), a transmembrane mucin, is overexpressed in pancreatic cancer and is associated with tumor proliferation and metastasis. CD3 is an indispensable molecule on the surface of T lymphocytes, which is associated with T cell activation and participates in immune responses. Here, we developed a bispecific T-cell engager radiotracer, ⁸⁹Zr-M17C3, targeting MUC17 and CD3, to enable noninvasive PET imaging of both tumor cells and T-cell infiltration in pancreatic cancer. ⁸⁹Zr-M17C3 was synthesized by conjugating AMG199 with zirconium-89 and verified for its radiochemical purity and in vitro stability. The ⁸⁹Zr-M17C3 probe demonstrated excellent radiochemical purity (>99%) and stability (maintained ≥99% over 120 h). Cellular uptake assays and binding affinity studies were conducted to evaluate the probe's specificity for MUC17 and CD3. Micro-PET/CT imaging and biodistribution studies were performed in MUC17-expressing nude mice and CD3 humanized mice to assess probe uptake in tumors and T-cell-infiltrated tissues. In MUC17-expressing AsPC-1 tumors, probe uptake was significantly higher than in MUC17-negative PANC-1 tumors (SUVmax: 2.26 ± 0.18 vs 1.13 ± 0.14, <i>P</i> < 0.001) and was confirmed to be MUC17-dependent through blocking studies. In CD3 humanized mice, the probe was able to visualize both T-cell infiltration and MUC17-positive tumors, with peak uptake in AsPC-1 tumors (SUVmax: 2.35 ± 0.46) and spleen (SUVmax: 2.19 ± 0.40) at 216 h. Immunohistochemical analysis confirmed the spatial correlation between MUC17 expression and CD3-positive T-cell infiltration in AsPC-1 tumors but not in PANC-1 tumors. In summary, the ⁸⁹Zr-M17C3 radiotracer exhibited high affinity for MUC17 and CD3 and successfully differentiated MUC17-positive tumors from MUC17-negative tumors while simultaneously providing insight into the T-cell distribution. This study highlights the potential of ⁸⁹Zr-M17C3 as a versatile imaging tool to support patient stratification and therapeutic monitoring in tumor-targeted immunotherapy, particularly for bispecific T-cell engager-based approaches such as AMG199.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2276-2286"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143727092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Composition of Lipid-Based Formulations on First-Pass Drug Metabolism after Oral Administration.","authors":"Yusuke Tanaka, Rikuto Fukaishi, Daiki Okamoto, Takanori Kurakazu, Tokio Nakai, Haruya Yagi, Shinji Sakuma","doi":"10.1021/acs.molpharmaceut.4c01299","DOIUrl":"10.1021/acs.molpharmaceut.4c01299","url":null,"abstract":"<p><p>This study aimed to elucidate the drug absorption mechanisms after oral administration of lipid-based formulations (LBFs), emphasizing the impact of their composition on first-pass drug metabolism. Ketoconazole (KTZ), a CYP3A substrate, was loaded into two types of LBFs: a long-chain LBF (type II-LC) and a lipid-free formulation (type IV). Following oral administration of type II-LC, the systemic exposure of KTZ was lower compared to that for the type IV and a control suspension. However, pretreatment with 1-aminobenzotriazole, a nonspecific CYP inhibitor, revealed equivalent in vivo exposure among the formulations tested. The absorption of KTZ from type II-LC in the early period was slower than that from the suspension and type IV. Experiments on in vitro digestion in sequence with in vitro permeation across a dialysis membrane showed that the drug permeation rate for type II-LC was extremely low. This was probably due to the reduction in free drug molecules in the donor compartment via the incorporation of KTZ into mixed micelles comprising digestion products derived from type II-LC and bile components. Furthermore, luminal concentration measurements revealed that gastric emptying was delayed when a type II-LC was administered. The reduced free drug concentration and transient delay in gastric emptying of KTZ resulted in the slower absorption of KTZ for type II-LC. The product of the fraction of drug absorbed and fraction of the drug not metabolized in the gut wall (Fa × Fg) calculated from the systemic and portal plasma concentration-time courses of KTZ was 0.185 for type II-LC and 0.327 for suspension. Since the luminal concentration measurement demonstrated complete absorption of KTZ from the gastrointestinal tract (Fa ≅ 1), the Fa × Fg values can be regarded as Fg. In conclusion, the lower in vivo exposure following oral administration of type II-LC was attributed to reduced Fg, that is, slower drug absorption from the jejunum resulted in low KTZ concentration in enterocytes, leading to enhanced metabolic efficiency. Our findings can be valuable when selecting excipients for designing LBFs with the preferred in vivo performance for highly metabolized drugs.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2098-2107"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Voices in <i>Molecular Pharmaceutics</i>: Meet Dr. Jayeeta Bhaumik who Converts Lignin from Waste to Biomaterials.","authors":"Jayeeta Bhaumik","doi":"10.1021/acs.molpharmaceut.5c00242","DOIUrl":"10.1021/acs.molpharmaceut.5c00242","url":null,"abstract":"","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1733-1734"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrasound-Driven Nitric Oxide Generation for Enhanced Sonodynamic-Photothermal Therapy.","authors":"Kun Zhang, Weirong Kong, Dewu Lin, Xiaobing Wang, Pan Wang","doi":"10.1021/acs.molpharmaceut.4c01401","DOIUrl":"10.1021/acs.molpharmaceut.4c01401","url":null,"abstract":"<p><p>Recently, green gas therapy based on nitric oxide (NO) has gained considerable attention in cancer treatment. The supplementation of exogenous NO and its controlled release represent promising strategies for adjuvant tumor therapy. In this study, we developed a novel ultrasound (US)-triggered NO generation and release nanoplatform that integrates NO therapy, sonodynamic therapy, and photothermal therapy (PTT) into a collaborative therapeutic modality. An environmentally friendly biomacromolecule, polydopamine, was employed to coload chlorin e6 (Ce6) and NO donor (BNN6), resulting in the nanocomposite PDA-Ce6/BNN6 (PCB). A single US stimulus simultaneously activated Ce6 to produce reactive oxygen species (ROS) and promoted BNN6 to release NO. The dual effects of ultrasonic mechanical action and physiological modulation by NO substantially improved local vascular function and enhanced tumor cell permeability, thereby increasing the targeted accumulation of PCB within tumors. Reactive nitrogen species (RNS) derived from NO and ROS further exacerbated oxidative damage and enhanced the sensitivity of tumor cells to hyperthermia. Both in vitro and in vivo experiments demonstrated that ultrasonic stimulation of NO/ROS/RNS combined with PTT effectively inhibited tumor cell growth and proliferation. The findings suggest that NO gas therapy based on extracorporeal US can significantly amplify the efficacy of PTT and offer new insights for developing other combined strategies aimed at physically regulating deep tumors.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2182-2192"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chitosan-Coated Silver Nanourchins for Imatinib Mesylate Delivery: Biophysical Characterization, <i>In-Silico</i> Profiling, and Anti-Colon Cancer Efficacy.","authors":"Sankha Bhattacharya, Aalind Joshi, Vishal Beldar, Ashwani Mishra, Satyam Sharma, Rehan Khan, Mohammad Rashid Khan","doi":"10.1021/acs.molpharmaceut.4c01241","DOIUrl":"10.1021/acs.molpharmaceut.4c01241","url":null,"abstract":"<p><p>This study investigates the synthesis and characterization of silver nanourchins coated with chitosan (IMT-CS-AgNUs) as a novel platform for the delivery of imatinib mesylate (IMT) for the treatment of colon cancer. <i>In-silico</i> analysis discovered 10 key metabolites for IMT, which have associated respiratory and neurotoxic risks. Molecular docking studies showed the high affinity binding of IMT to critical proteins, including BCL2 (-6.637 kcal/mol), Caspase-6, and EGFR, which proved its potential therapeutic value. IMT-CS-AgNUs were prepared by ionic gelation, and the nanoparticles had a size of 192.98 nm, with an entrapment efficiency of 85.7%. The FTIR and XRD structural characterization confirmed that the nanocarriers were stable and amorphous in nature. In vitro studies of HCT116 cells showed significantly increased cytotoxicity with an IC50 of 0.4 μg/mL; apoptosis by 42.5% and ROS generation by 47.8% when compared to only IMT. The release of drugs from the nanoparticles was sustained over 85% over 60 h, selectively inhibited pathogenic bacteria without harming beneficial microbes, and showed antiangiogenic activity, which is validated through the HET-CAM assay. Gene expression analyses showed that there was marked downregulation of BCL2 and upregulation of apoptotic genes. Pharmacokinetic studies in Wistar rats showed improved bioavailability by 1.8, which allows targeted drug concentrations in the colon with lessened systemic toxicity. Thus, the development of IMT-CS-AgNUs represents a potent approach for targeted colon therapy against cancer, providing therapeutic efficacy, controlled drug release, and added safety.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1983-2018"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Preliminary Evaluation of a ¹²⁵I-Labeled Radioligand ([¹²⁵I]iodotrazoline) for In Vitro Detection of Imidazoline-2 Binding Site in the Brain.","authors":"Donglan Huang, Yiming Guo, Mengchao Cui, Hualong Fu","doi":"10.1021/acs.molpharmaceut.4c01445","DOIUrl":"10.1021/acs.molpharmaceut.4c01445","url":null,"abstract":"<p><p>Astrocytes exert multiple functions within the brain, including regulating neuroinflammation and maintaining homeostasis, and the reactive astrocytes are implicated in many neurodegenerative disorders. Imidazoline-2 binding site (I₂BS) has been established as a reliable biomarker for precisely quantifying reactive astrocytes. Here, we reported the development of [¹²⁵I]iodotrazoline ([¹²⁵I]<b>8</b>), a novel I₂BS radioligand with high affinity (<i>K</i>_i = 6.8 nM) and exceptional selectivity over α₂-adrenoceptors (>1400 folds). <i>In vitro</i> autoradiography (ARG) using rat brain sections revealed a heterogeneous distribution of [¹²⁵I]<b>8</b>, with high signals in the medulla, midbrain, pons, and hypothalamus. Pretreatment with unlabeled I₂BS-selective ligands, BU224 and FTIMD, reduced the binding by >30%, indicating high <i>in vitro</i> specificity for I₂BS. <i>Ex vivo</i> ARG results confirmed this distribution pattern in the rat brain. Biodistribution results in mice demonstrated a rapid brain uptake of [¹²⁵I]<b>8</b> (3.35% ID/g at 2 min postinjection) with slow washout. Metabolite analysis exhibited the desirable biostability of [¹²⁵I]<b>8</b> in the rat brain. Altogether, this work provides a new ¹²⁵I-labeled radioligand featuring a novel 2-trans-styryl-imidazoline scaffold, which shows significant specificity binding for I₂BS <i>in vitro</i>, serving as a valuable tool for I₂BS detection and astrocyte-related pathology research.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2224-2232"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iBCS: 4. Application of the Inhalation Biopharmaceutics Classification System to the Development of Orally Inhaled Drug Products.","authors":"Ben Forbes, Per Bäckman, Antonio Cabal, Andy Clark, Carsten Ehrhardt, Jayne E Hastedt, Anthony J Hickey, Guenther Hochhaus, Wenlei Jiang, Stavros Kassinos, Philip J Kuehl, Bo Olsson, David Prime, Yoen-Ju Son, Simon Teague, Ulrika Tehler, Jennifer Wylie","doi":"10.1021/acs.molpharmaceut.4c01534","DOIUrl":"10.1021/acs.molpharmaceut.4c01534","url":null,"abstract":"<p><p>This is the fourth paper in a series describing an inhalation biopharmaceutics classification system (iBCS), an initiative supported by the Product Quality Research Institute. The paper examines the application of the inhalation Biopharmaceutics Classification System (iBCS) through the drug discovery, development, and postapproval phases for orally inhaled drug products (OIDP) and for the development of generic OIDPs. We consider the implication of the iBCS class in terms of product performance and identify the practical gaps that must be filled to enable the classification system to be adopted into day-to-day practice. Consideration is given to the critical experimental data required and the methods for their generation with a focus on: (i) dose to the lungs, (ii) drug solubility in relevant media and methods to model the dissolution of respirable formulations, and (iii) pulmonary drug permeability. As described in three prior publications, the iBCS was developed to classify inhaled drugs based on physicochemical and biorelevant product attributes in a manner that will allow formulators and discovery chemists to identify and mitigate product development risks. It was not established to enable <i>in vitro</i> determination of bioequivalence between orally inhaled drug products. However, once analytical methods are in place to correctly classify inhaled drugs, the system has the potential to provide an understanding of the development risks associated with both establishing bioequivalence between two drug products and enabling postapproval changes based on product iBCS class.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"1740-1751"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral Lipid-Based Nanomedicine for the Inhibition of the cGAS-STING Pathway in Inflammatory Bowel Disease Treatment.","authors":"Léo Guilbaud, Cheng Chen, Inês Domingues, Espoir K Kavungere, Valentina Marotti, Hafsa Yagoubi, Wunan Zhang, Alessio Malfanti, Ana Beloqui","doi":"10.1021/acs.molpharmaceut.4c01297","DOIUrl":"10.1021/acs.molpharmaceut.4c01297","url":null,"abstract":"<p><p>Harnessing the effect of the cyclic GMP-AMP Synthase-STimulator of INterferon Genes (cGAS-STING) signaling pathway has emerged as a promising approach to developing novel strategies for the oral treatment of inflammatory bowel disease (IBD). In this work, we screened different cGAS-STING inhibitors <i>in vitro</i> in murine macrophages. Then, we encapsulated the cGAS-STING inhibitor H-151 within lipid nanocapsules (LNCs), owing to their inherent ability to induce the secretion of glucagon-like peptide 2 (GLP-2), a re-epithelizing peptide, upon oral administration. We demonstrated that our formulation (LNC(H-151)) could induce GLP-2 secretion and selectively target the cGAS-STING pathway and its downstream key markers (including TBK1 and pTBK1) while reducing the expression of pro-inflammatory cytokines associated with the cGAS-STING pathway (TNF-α and CXCL10) in murine macrophages. In an <i>in vivo</i> acute dextran sodium sulfate (DSS)-induced colitis mouse model, the oral administration of LNC(H-151) significantly reduced pro-inflammatory cytokines to levels comparable to the CTRL Healthy group while promoting mucosal healing. The therapeutic potential of this scalable and cost-effective nanomedicine warrants further investigation as an alternative for the oral treatment of IBD.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2108-2121"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utilizing PET Imaging To Visualize Immune Activation and Tumor Apoptosis.","authors":"Yuan Feng, Zhaoguo Lin, Wenzhu Hu, Xingyi Wang, Zihan Zhang, Xiaoli Lan, Xiao Zhang","doi":"10.1021/acs.molpharmaceut.4c01314","DOIUrl":"10.1021/acs.molpharmaceut.4c01314","url":null,"abstract":"<p><p>Immunotherapy-induced tumor apoptosis is one of the crucial pathways in tumor cell death. This study aimed to explore the potential of PET imaging for noninvasively visualizing pivotal processes in immunotherapy, specifically immune activation and tumor apoptosis, by targeting granzyme-B and caspase-3. Bioinformatic analyses validated granzyme-B and caspase-3 expression in cancer tissues and their associations with immune infiltration and patient prognosis using the GEPIA and TIMER databases. Two radiolabeled probes, [⁶⁸Ga]Ga-GZP and [⁶⁸Ga]Ga-AC3, were used to specifically target granzyme-B and caspase-3 for PET imaging, respectively. CT26 xenograft tumor models were assigned to PD-1 inhibitor or PBS control groups to receive treatment every 3 days, with imaging conducted at baseline and after each treatment. Imaging results showed significantly increased tumor uptake of both [⁶⁸Ga]Ga-GZP and [⁶⁸Ga]Ga-AC3 in the ICB-treated group compared to controls, indicating early molecular changes in immune activation and tumor apoptosis. Immunofluorescence analysis further supported these findings, revealing upregulated granzyme-B and caspase-3 expression in treated tumor tissues. Immunohistochemistry also confirmed increased T-cell infiltration and elevated levels of effector molecules, such as IFN-γ and TNF-α, in the ICB group. This study demonstrates that granzyme-B and caspase-3 PET/CT can noninvasively visualize early molecular changes in immunotherapy-induced CD8⁺ T cell activation and tumor apoptosis. These noninvasive diagnostic techniques hold significant promise for future clinical applications, particularly for a more accurate evaluation of immunotherapy efficacy.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2122-2130"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is There Polyamorphism in Amorphous Indomethacin? Investigating the Physicochemical Properties of Amorphous Indomethacin with Different Thermal History.","authors":"Daniele Musumeci, Ji Zhou, Jiajun Xie He, Thomas Rades, Inês C B Martins","doi":"10.1021/acs.molpharmaceut.4c01276","DOIUrl":"10.1021/acs.molpharmaceut.4c01276","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Polyamorphism in organic molecules is a poorly understood and controversial phenomenon related to amorphous materials. Although very few studies, including our own, have demonstrated the existence of polyamorphism in drug molecules, this solid-state phenomenon is still very elusive and the investigation of its occurrence in other drugs is fundamental to understand its formation. Indomethacin (IND) has been recently discussed in the literature as a potential drug exhibiting polyamorphism. Its amorphous forms obtained by quench-cooling (QC) at different temperatures have shown distinct dissolution and physical stability properties. However, temperature can induce degradation which can potentially influence the physicochemical properties of the drugs. Here we have investigated what role degradation products may play in the physicochemical properties of amorphous IND obtained at different QC temperatures and explored the potential formation of polyamorphism in IND. Amorphous IND obtained by QC at 165-220 °C revealed similar molecular near order, suggesting lack of structural variation between the differently prepared amorphous forms. The glass transition temperature slightly decreased when the QC temperature increased. Both the onset of crystallization and relaxation time consistently increased (being more notorious at a QC temperature of 180 °C), suggesting that the amorphous IND obtained at higher QC temperatures presents lower molecular mobility and as a consequence higher physical stability. Thermogravimetric analysis revealed that IND degradation starts to occur right after its melting temperature (i.e., 165 °C), being more evident after 180 °C. Considering that a melting point depression was observed for all amorphous IND samples, especially for the ones obtained at higher temperatures (i.e., higher than 180 °C), we hypothesized that the formation of degradation products is the cause for the observed differences in the thermal and physical stability properties of the amorphous IND obtained at different QC temperatures. Moreover, real-time dissolution experiments of amorphous IND films, QC from different temperatures, demonstrated that the dissolution performance decreased gradually, but substantially, as the preparation temperature of the samples increased. Similar experiments where amorphous IND was QC from different temperatures in the absence of oxygen and where amorphous IND was spiked with highly thermally degraded amorphous IND at 2%, 5% and 10% w/w prepared by QC from 165 °C to room temperature, unequivocally demonstrated that the degradation products formed during exposure of IND to high temperatures substantially inhibit the dissolution of amorphous IND. This study demonstrates that the differences in the physicochemical properties of differently prepared amorphous forms of drugs are not necessarily a result of polyamorphism and that special attention should be paid to the potential formation of degradation products and their inf","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":"2065-2076"},"PeriodicalIF":4.5,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}