Pharmaceutical Compounds Research Articles

In Silico identification of dengue NS5 phytochemical inhibitors as potential antiviral drug compounds via molecular docking

<i>In Silico</i> identification of dengue NS5 phytochemical inhibitors as potential antiviral drug compounds via molecular docking

Elemental Composition of Commercially Available Cannabis Rolling Papers.

With the recent legalization of cannabis in multiple jurisdictions and widespread use as a medical treatment, there has been an increased focus on product safety and the potential impacts of contaminants on human health. One factor that has received little attention is the possible exposure to potentially hazardous levels of toxic elements from rolling (smoking) papers. The elemental composition of rolling papers is largely unregulated, with a minority of jurisdictions regulating papers only when they are part of a final cannabis product. This study reports the concentrations of 26 elements in commercially available rolling papers and estimates potential maximum exposures relative to USP232 and ICH Q3D dosages in pharmaceutical compounds. Exposure estimates indicate that the concentrations of several elements in some products, particularly Cu, Cr, and V, may present a potential hazard to frequent users. Several elements, including Ag, Ca, Ba, Cu, Ti, Cr, Sb, and possibly others, are likely present in elevated quantities in some papers due to product design and manufacturing processes. Our results further suggest that Cu-based pigments are used by a number of manufacturers and that regular use of these products might result in exposures as high as 4.5-11 times the maximum exposure limits. Further research to quantify the contribution of rolling papers to elemental exposure under realistic smoking conditions is warranted.

Paediatric clinical study of 3D printed personalised medicines for rare metabolic disorders

Rare diseases are infrequent, but together they affect up to 6–10 % of the world’s population, mainly children. Patients require precise doses and strict adherence to avoid metabolic or cardiac failure in some cases, which cannot be addressed in a reliable way using pharmaceutical compounding. 3D printing (3DP) is a disruptive technology that allows the real-time personalization of the dose and the modulation of the dosage form to adapt the medicine to the therapeutic needs of each patient. 3D printed chewable medicines containing amino acids (citrulline, isoleucine, valine, and isoleucine and valine combinations) were prepared in a hospital setting, and the efficacy and acceptability were evaluated in comparison to conventional compounded medicines in six children. The inclusion of new flavours (lemon, vanilla and peach) to obtain more information on patient preferences and the implementation of a mobile app to obtain patient feedback in real-time was also used. The 3D printed medicines controlled amino acid levels within target levels as well as the conventional medicines. The deviation of citrulline levels was narrower and closer within the target concentration with the chewable formulations. According to participants’ responses, the chewable formulations were well accepted and can improve adherence and quality of life. For the first time, 3DP enabled two actives to be combined in the same formulation, reducing the number of administrations. This study demonstrated the benefits of preparing 3D printed personalized treatments for children diagnosed with rare metabolic disorders using a novel technology in real clinical practice.

Raman Technology for Process Control: Waste Shell Demineralization for Producing Transparent Polymer Foils Reinforced with Natural Antioxidants and Calcium Acetate By-Products

Waste biogenic materials derived from seafood exploitation represent valuable resources of new compounds within the blue bioeconomy concept. Here, we describe the effectiveness of Raman technology implementation as an in-line tool for the demineralization process control of crustaceans or gastropods. Transparent chitin polymeric foils and calcium acetate by-products were obtained from three waste crustacean shells (C. sapidus, S. mantis, and M. squinado) using a slow, green chemical approach employing acetic acid. Progressive mineral dissolution and increasing of the Raman characteristic signal of chitin is shown in a time-dependent manner using NIR-Raman spectroscopy, while resonance Raman shows intact carotenoids in reacted shells after 2 weeks. Chitin foil products are species-specific, and the demineralization bath of the waste shell mixture can be effectively tracked by Raman tools for solvent control and decision making for the recovery of calcium acetate by-products. Comparatively obtained calcium acetate from Rapana venosa snail shells, the subject of Raman analyses, allowed assessing by-product identity, hydration status, purity, and suitability as recrystallized material for further use as a pharmaceutical compound derived from different crustaceans or gastropod species. Cross validation of the results was done using FT-IR, XRD, and SEM-EDX techniques. A hand-held flexible TacticID Raman system with 1064 nm excitation demonstrated its effectiveness as a rapid, in-line decision making tool during process control and revealed excellent reproducibility of the lab-based instrument signal, suitable for in situ evaluation of the demineralization status and solvent saturation control.

Late-stage meta-C-H alkylation of pharmaceuticals to modulate biological properties and expedite molecular optimisation in a single step.

Catalysed C-H activation has emerged as a transformative platform for molecular synthesis and provides new opportunities in drug discovery by late-stage functionalisation (LSF) of complex molecules. Notably, small aliphatic motifs have gained significant interest in medicinal chemistry for their beneficial properties and applications as sp3-rich functional group bioisosteres. In this context, we disclose a versatile strategy with broad applicability for the ruthenium-catalysed late-stage meta-C(sp2)-H alkylation of pharmaceuticals. This general protocol leverages numerous directing groups inherently part of bioactive scaffolds to selectivity install a variety of medicinally relevant bifunctional alkyl units within drug compounds. Our strategy enables the direct modification of unprotected lead structures to quickly generate an array of pharmaceutically useful analogues without resorting to de novo syntheses. Moreover, productive late-stage modulation of key biological characteristics of drug candidates upon remote C-H alkylation proves viable, highlighting the major benefits of our approach to offer in drug development programmes.

Synergistic integration of ZrO2-enriched reduced graphene oxide-based nanostructures for advanced photodegradation of tetracycline hydrochloride.

The escalating demand for the antibiotic drug tetracycline hydrochloride (TCH) contributes to an increased release of its residues into land and water bodies, which poses risks to both aquatic life and human health. Therefore, it is precedence to effectively degrade TCH residues to protect environment from their long-term impacts. In this aspect, the present study entails the synthesis of zirconia (ZrO2) nanostructures and focuses on the enhancement in the catalytic performance of ZrO2 nanostructures by employing reduced graphene oxide (RGO) as a solid support to synthesize ZrO2-enriched RGO-based photocatalysts (ZrO2-RGO) for the degradation of TCH. The study delves into comprehensive spectroscopic and microscopic investigations and their photodegradation assessments. Powder XRD and HR-TEM studies depicted the phase crystallinity and also displayed uniform distribution of ZrO2 nanostructures with spherical morphology within ZrO2-RGO. This corresponds to high surface-to-volume ratios, providing a substantial number of active sites for light absorption and generation of e--h+ pairs. Moreover, the heterojunctions created between RGO and ZrO2 nanostructures promoted the interspecies electron transfer which prolonged the recombination time of e- and h+ than pure ZrO2 nanostructures, accounted for enhanced degradation of TCH using ZrO2-RGO. The photocatalytic activity of as-synthesized materials were examined under visible and UV light irradiation.Thedegradation efficiency of ~ 73.82% was achieved using ZrO2-RGO-based photocatalystwith rate constant k = 0.007023 min-1 under visible-light illumination.Moreover, under UV-light, the degradation rate was explicated to be k = 0.01017 min-1 with ~ 85.56% degradation of TCH antibiotics within 180 mins. Hence, the synthesized ZrO2-enriched RGO-based photocatalysts represents a promising potential for the effective degradation of pharmaceutical compounds, particularly TCH under visible and UV-light irradiation.

Long-term impact of wastewater effluent discharge on groundwater: Identification of contaminant plume by geochemical, isotopic, and organic tracers' approach

Infiltration of effluents from wastewater treatment plants (WWTP) into groundwater can be a source of Contaminants of Emerging Concern (CECs), such as pharmaceutical compounds, that are not fully removed during the treatment processes. A multi-tracer approach, based on hydrogeochemical, isotopic, and organic tracers, is applied in the Vistrenque Aquifer (Gard, France) to assess the dispersion of such unintentional plumes and its potential implication on groundwater quality for CECs in a small catchment area. In this area, a point source of WWTP effluent causes contaminant infiltration and unintentional transfer to the aquifer. This strong impact of an urban effluent was revealed from the Br/Cl ratio, boron concentrations and δ11B isotopic signature of the groundwater in the direct vicinity of the infiltration point. With increasing distance from that point, dilution with groundwater rapidly attenuates the urban signal from these hydrogeochemical and isotopic tracers. Nevertheless, a gadolinium anomaly, resulting from discharges of urban wastewater containing the contrast agents used for magnetic resonance imaging (MRI), highlights the presence of a wastewater plume further along the flow line, that comes with a series of organic molecules, including pharmaceutical residues. Monitoring persistent or reactive molecules along the plume provides a more detailed understanding of the transfer of CECs into groundwater bodies. This highlights the relevance of pharmaceutical compounds as co-tracers for WWTP plume delineation. The present multi-tracer approach for groundwater resource vulnerability towards CECs allows a more in-depth understanding of contaminant transfer and their fate in groundwater.

Treatment of pharmaceutical wastewater by a sequential KMnO4/CoFe2O4-mediated catalytic ozonation process

Pharmaceutical compounds, which are of utmost concern, have found their way into natural water bodies, causing numerous problems for both human health and ecosystems. In this study, an integrated system including potassium permanganate (PM) pre-oxidation, followed by a heterogeneous catalytic ozonation process (HCOP) using CoFe2O4 magnetic nanoparticles (CF MNPs), and an activated sludge-based biological treatment (BT) was employed for the first time to treat pharmaceutical wastewater (PWW). In this regard, the effluent from PM pre-oxidation process was used as a batch for the HCOP, and the effluent was used as a batch for the BT process. The results showed that PM pre-treatment of PWW (PM dose = 1264 mg/L and pH = 8.0) reduced the COD content of the PWW from 900 ± 50 to 443 ± 10 mg/L within 120 min of reaction time. The application of HCOP for further treatment of PWW dramatically enhanced COD and TOC removal compared with the single ozonation process (SOP). Under optimum conditions (pH = 10, O3 = 4.0 mg/L, and CF MNPs = 1000 mg/L), HCOP successfully reduced the COD and TOC contents of PWW by 37 % and 46.1 %, respectively, after 120 min of treatment. The consecutive combination of PM pre-treatment followed by HCOP exhibited good potential and reduced COD by over 69 %, resulting in a residual COD of less than 280 mg/L. A biodegradability ratio of over 81 % and residual COD of 54 mg/L for the PWW treated by the PM/HCOP/BT integrated system indicated that biodegradability was enhanced, and a high fraction of refractory organic compounds was effectively removed. In conclusion, the PM/HCOP/BT integrated system is an efficient, synergistic, and easy-to-operate technique for enhancing the biodegradability of PWW.

Competitive sorption experiments reveal new regression models to predict PhACs sorption on carbonaceous materials

Sorption of hydrophobic organic contaminants onto thermally altered carbonaceous materials (TACM) constitutes a widely used technology for remediation of polluted waters. This process is typically described by sorption isotherms, with one of the most used models, the Polanyi-Dubinin-Manes (PDM) equation, including water solubility (Sw) as a normalizing factor. In case of pharmaceutical active compounds (PhACs), Sw depends on the pH of the environment due to the ionic/ionizable behavior of these chemicals, a fact frequently ignored in sorption studies of PhACs. In this work, we set the theoretical framework to include the variation of Sw with pH in the definition of the PDM model, and we applied this approach to describe the effect of ambient pH in the competitive sorption of three commonly detected PhACs (carbamazepine, ibuprofen, and sulfamethoxazole) onto three carbonaceous sorbents (biochar, powder activated carbon, and colloidal activated carbon). Changes in the ambient pH and hence in the hydrophobicity of the compounds could explain the strong variations observed in single-solute sorption and also in competitive sorption. Furthermore, Sw was used as a parameter for the linear regression model of sorption coefficients of our experiments, suggesting the incorporation of this variable as an improvement to existing approaches for prediction of PhACs sorption onto TACM.

Synthesis of a Multi-Template Molecular Imprinted Bulk Polymer for the Adsorption of Non-Steroidal Inflammatory and Antiretroviral Drugs

In this paper, we report the synthesis of a multi-template molecularly imprinted polymer (MIP) to target and extract naproxen, ibuprofen, diclofenac, emtricitabine, tenofovir disoproxil, and efavirenz from wastewater bodies. A bulk polymerization procedure was used to synthesize the MIP and non-imprinted polymer (NIP). The specific recognition sites for each target were obtained through the removal of the imprinted targeted compounds. The interaction of antiretroviral drugs (ARVs) and non-steroidal anti-inflammatory drugs (NSAIDs) compounds with the MIP was studied under various conditions such as pH, mass, concentration, and time factors. The results demonstrated the optimum conditions were 55 mg of MIP, pH 7.0, a concentration of 5 mg L−1, and a contact time of 10 min. For every compound studied, the extraction efficiencies for ARVs and NSAIDs in aqueous solutions was &gt;96%. The adsorption capacity for the MIP was &gt;0.91 mg·g−1. Adsorption obeys a second-order rate, and the Freundlich model explains the adsorption isotherm data. This study demonstrated that the synthesized multi-template MIP has huge potential to be employed for the removal of ARVs and NSAIDs from the environment as well as in drug purification or recovery processes.

Late-Stage Saturation of Drug Molecules.

The available methods of chemical synthesis have arguably contributed to the prevalence of aromatic rings, such as benzene, toluene, xylene, or pyridine, in modern pharmaceuticals. Many such sp2-carbon-rich fragments are now easy to synthesize using high-quality cross-coupling reactions that click together an ever-expanding menu of commercially available building blocks, but the products are flat and lipophilic, decreasing their odds of becoming marketed drugs. Converting flat aromatic molecules into saturated analogues with a higher fraction of sp3 carbons could improve their medicinal properties and facilitate the invention of safe, efficacious, metabolically stable, and soluble medicines. In this study, we show that aromatic and heteroaromatic drugs can be readily saturated under exceptionally mild rhodium-catalyzed hydrogenation, acid-mediated reduction, or photocatalyzed-hydrogenation conditions, converting sp2 carbon atoms into sp3 carbon atoms and leading to saturated molecules with improved medicinal properties. These methods are productive in diverse pockets of chemical space, producing complex saturated pharmaceuticals bearing a variety of functional groups and three-dimensional architectures. The rhodium-catalyzed method tolerates traces of dimethyl sulfoxide (DMSO) or water, meaning that pharmaceutical compound collections, which are typically stored in wet DMSO, can finally be reformatted for use as substrates for chemical synthesis. This latter application is demonstrated through the late-stage saturation (LSS) of 768 complex and densely functionalized small-molecule drugs.

Proteomics study the potential targets for Rifampicin-resistant spinal tuberculosis.

Introduction: The escalating global surge in Rifampicin-resistant strains poses a formidable challenge to the worldwide campaign against tuberculosis (TB), particularly in developing countries. The frequent reports of suboptimal treatment outcomes, complications, and the absence of definitive treatment guidelines for Rifampicin-resistant spinal TB (DSTB) contribute significantly to the obstacles in its effective management. Consequently, there is an urgent need for innovative and efficacious drugs to address Rifampicin-resistant spinal tuberculosis, minimizing the duration of therapy sessions. This study aims to investigate potential targets for DSTB through comprehensive proteomic and pharmaco-transcriptomic analyses. Methods: Mass spectrometry-based proteomics analysis was employed to validate potential DSTB-related targets. PPI analysis confirmed by Immunohistochemistry (IHC) and Western blot analysis. Results: The proteomics analysis revealed 373 differentially expressed proteins (DEPs), with 137 upregulated and 236 downregulated proteins. Subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses delved into the DSTB-related pathways associated with these DEPs. In the context of network pharmacology analysis, five key targets-human leukocyte antigen A chain (HLAA), human leukocyte antigen C chain (HLA-C), HLA Class II Histocompatibility Antigen, DRB1 Beta Chain (HLA-DRB1), metalloproteinase 9 (MMP9), and Phospholipase C-like 1 (PLCL1)-were identified as pivotal players in pathways such as "Antigen processing and presentation" and "Phagosome," which are crucially enriched in DSTB. Moreover, pharmaco-transcriptomic analysis can confirm that 58 drug compounds can regulate the expression of the key targets. Discussion: This research confirms the presence of protein alterations during the Rifampicin-resistant process in DSTB patients, offering novel insights into the molecular mechanisms underpinning DSTB. The findings suggest a promising avenue for the development of targeted drugs to enhance the management of Rifampicin-resistant spinal tuberculosis.

In silico anticancer activity of isoxazolidine and isoxazolines derivatives: DFT study, ADMET prediction, and molecular docking

This study presents a comprehensive analysis of six isoxazolidine and isoxazoline derivatives, employing a multifaceted approach that integrates Density Functional Theory (DFT), AdmetSAR analysis, and molecular docking simulations to explore their electronic, pharmacokinetic, and anticancer properties. Utilizing DFT analysis with the B3LYP-D3BJ functional and the 6-311++G(d,p) basis set, molecular geometries were optimized, and vibrational frequencies in the IR spectrum were evaluated, offering insights into the molecular structure and stability of the pharmaceutical compounds. Electrostatic potential maps were analyzed to predict functional group reactivity and protein-substrate interactions. Frontier Molecular Orbital (FMO) analysis and Density of States (DOS) plots revealed varying stability levels among the compounds, with 1b, 2b, and 3b exhibiting slightly higher stability. Chemical potential and hardness analyses highlighted stronger binding affinity for compounds 1b and 2b, suggesting stronger potential interactions. AdmetSAR analysis predicted favorable human intestinal absorption (HIA) rates for all compounds, with compound 3b showing superior oral effectiveness. Molecular docking and dynamics simulations were conducted targeting the receptor (PDB: 1JU6). Molecular docking simulations confirmed the high affinity of these compounds towards the target protein 1JU6, particularly compound 3b, which exhibited the most favorable binding energy of -8.50 kcal/mol. Molecular dynamics simulations demonstrated the superior stability of ligand 3b over 1b and 5-FU over 100 ns, suggesting its potential for further study. The 3b-protein complex exhibited stability through hydrophobic and hydrogen bond interactions, with 3b demonstrating reduced solvent exposure compared to 1b and 5-FU. This study underscores the promising role of compound 3b in anticancer treatments, providing a solid foundation for future drug development and optimization efforts.

Cu(III)‐CF3 Compound‐Activated DMSO: An Efficient Oxidizing Reagent to Convert Alcohols to Ketones

AbstractIn this study high‐valent Cu(III) trifluoromethyl compounds in combination with DMSO is shown to be an efficient and mild oxidizing system for the conversion of alcohols to ketones (aldehydes as well). Trifluoromethoxylated sulfonium species is proposed to be initially formed that engages in crucial steps of alkoxy replacement at sulfonium center and deprotonative collapse of the resulting alkoxysulfonium intermediate in the presence of a base. This reaction is highly selective without over‐oxidation, and can tolerate a broad range of functional groups owing to mild oxidizing ability of the Cu(III)‐CF3/DMSO system and the inert N2 conditions. This method can be applied to the synthesis and functionalization of commercial drug compounds. This study illustrates an unusual reactivity property of high‐valent Cu(III) trifluoromethyl compounds beyond the conventional CF3 group transfer reactivity, and opens up new opportunities for developing novel reactions of Cu(III)‐CF3 compounds. The combined use of high‐valent Cu(III)‐CF3 compound and DMSO is anticipated to find more applications to develop other novel and useful oxidation reactions.

Do Chemformers Dream of Organic Matter? Evaluating a Transformer Model for Multistep Retrosynthesis.

Synthesis planning of new pharmaceutical compounds is a well-known bottleneck in modern drug design. Template-free methods, such as transformers, have recently been proposed as an alternative to template-based methods for single-step retrosynthetic predictions. Here, we trained and evaluated a transformer model, called the Chemformer, for retrosynthesis predictions within drug discovery. The proprietary data set used for training comprised ∼18 M reactions from literature, patents, and electronic lab notebooks. Chemformer was evaluated for the purpose of both single-step and multistep retrosynthesis. We found that the single-step performance of Chemformer was especially good on reaction classes common in drug discovery, with most reaction classes showing a top-10 round-trip accuracy above 0.97. Moreover, Chemformer reached a higher round-trip accuracy compared to that of a template-based model. By analyzing multistep retrosynthesis experiments, we observed that Chemformer found synthetic routes, leading to commercial starting materials for 95% of the target compounds, an increase of more than 20% compared to the template-based model on a proprietary compound data set. In addition to this, we discovered that Chemformer suggested novel disconnections corresponding to reaction templates, which are not included in the template-based model. These findings were further supported by a publicly available ChEMBL compound data set. The conclusions drawn from this work allow for the design of a synthesis planning tool where template-based and template-free models work in harmony to optimize retrosynthetic recommendations.

COVID-19 Pandemic Modulates the Environmental Contamination Level of Enteric Bacteria from WWTPs

The COVID-19 pandemic was a challenge for the whole world, and it had major secondary effects on humans and environmental health. The viral infection induced, in many situations, secondary bacterial infections, especially enteric infections, by destabilizing the balance of the gastrointestinal microbiota. The large-scale use of antibiotics and biocides for both curative and preventive purposes has resulted in an increase in bacterial resistance, and at the same time, the possibility of pathogenic microorganism multiplication and their dissemination to natural environments. Wastewater is the main vector of fecal microorganisms that favors their dissemination into natural aquatic ecosystems. The present paper aims to analyze the effect of the COVID-19 pandemic on the microbiological quality of wastewater from sewage treatment plants in Romania and its impact on receiving rivers. In order to highlight different and important areas in Romania, three cities from the east, center and west were selected for a microbiological evaluation of their WWTP influents and effluents from the pre-COVID-19 period and during the COVID-19 pandemic peak period, when the COVID-19 pandemic had a direct impact on WWTP microbial compositions. Our study shows that a higher level of contamination with fecal bacteria is linked to a higher COVID-19 incidence. The increased usage of pharmaceutical compounds, in turn, increases the number of resistant bacteria reaching the environment via WWTP effluents.

ICH S1 prospective evaluation study: weight of evidence approach to predict outcome and value of 2-year rat carcinogenicity studies. A report from the regulatory authorities subgroup.

Introduction: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) initiated a process in 2012 to revise the S1B Guideline "Testing for Carcinogenicity of Pharmaceuticals". Previous retrospective analysis indicated the importance of histopathological risk factors in chronic toxicity studies, evidence of endocrine perturbation, and positive genetic toxicology results as potentially predictive indicators of carcinogenic risk. In addition, a relationship between pharmacodynamic activity and carcinogenicity outcome in long-term rodent studies has been reported. It was postulated that these factors could be evaluated in a Weight-of-Evidence (WoE) approach to predict the outcome of a 2-year rat study. Methods: The ICH S1B(R1) Expert Working Group (EWG) conducted a Prospective Evaluation Study (PES) to determine the regulatory feasibility of this WoE approach. Drug Regulatory Authorities (DRAs) evaluated 49 Carcinogenicity Assessment Documents (CADs), which describe the WoE for submitted pharmaceutical compounds. Each compound was categorized into a carcinogenic risk category including a statement of the value of the 2-year rat study. The outcome of the completed 2-year rat studies was evaluated in relation to the prospective CAD to determine the accuracy of predictions. Results: Based on the results of the PES, the EWG concluded that the evaluation process for assessing human carcinogenic risk of pharmaceuticals described in ICH S1B could be expanded to include a WoE approach. Approximately 27% of 2-year rat studies could be avoided in cases where DRAs and sponsors unanimously agreed that such a study would not add value. Discussion: Key factors supporting a WoE assessment were identified: data that inform carcinogenic potential based on drug target biology and the primary pharmacologic mechanism of the parent compound and major human metabolites; results from secondary pharmacology screens for this compound and major human metabolites that inform carcinogenic risk; histopathology data from repeated-dose toxicity studies; evidence for hormonal perturbation; genotoxicity data; and evidence of immune modulation. The outcome of the PES indicates that a WoE approach can be used in place of conducting a 2-year rat study for some pharmaceuticals. These data were used by the ICH S1B(R1) EWG to write the R1 Addendum to the S1B Guideline published in August 2022.

Environmental risk assessment of selected pharmaceuticals in hospital wastewater in nothern Vietnam

Pharmaceuticals are progressively employed in both human and veterinary medicine and increasingly recognized as environmental contaminants. This study investigated the occurrence of selected pharmaceuticals in influent and effluent of wastewater treatment plants of 12 hospitals in Hanoi and 3 northern cities of Vietnam during dry and rainy seasons. In addition, environmental risk of pharmaceuticals in both hospital influents and effluents were evaluated based on risk quotients (RQs). Nine selected pharmaceutical compounds including sulfamethoxazole (SMX), naproxen (NPX), diclofenac (DCF), ibuprofen (IBU), acetaminophen (ACT), carbamazepine (CBM), iopromide (IOP), atenolol (ATN), and caffeine (CAF) were frequently detected in most influent and effluent wastewaters of 12 investigated hospitals. Detected compound levels exhibited a wide range, from as low as 1 ng/L for DCF to as high as 61,772 ng/L for ACT. Among these compounds, ACT, CAF, SMX, and IOP were consistently detected at substantial concentrations in both influents and effluents. This investigation also highlighted potential risks posed by SMX, ACT, and CAF residues present in influents and effluents of hospital wastewater treatment plants (WWTPs) to aquatic ecosystem. These finding are expected to provide scientific-based evidence for the development of hospital waste management and environmental management programs in Vietnam.

Solvent Replacement Strategies for Processing Pharmaceuticals and Bio-Related Compounds—A Review

An overview of solvent replacement strategies shows that there is great progress in green chemistry for replacing hazardous di-polar aprotic solvents, such as N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidinone (NMP), and 1,4-dioxane (DI), used in processing active industrial ingredients (APIs). In synthetic chemistry, alcohols, carbonates, ethers, eucalyptol, glycols, furans, ketones, cycloalkanones, lactones, pyrrolidinone or solvent mixtures, 2-methyl tetrahydrofuran in methanol, HCl in cyclopentyl methyl ether, or trifluoroacetic acid in propylene carbonate or surfactant water (no organic solvents) are suggested replacement solvents. For the replacement of dichloromethane (DCM) used in chromatography, ethyl acetate ethanol or 2-propanol in heptanes, with or without acetic acid or ammonium hydroxide additives, are suggested, along with methanol acetic acid in ethyl acetate or methyl tert-butyl ether, ethyl acetate in ethanol in cyclohexane, CO2-ethyl acetate, CO2-methanol, CO2-acetone, and CO2-isopropanol. Supercritical CO2 (scCO2) can be used to replace many organic solvents used in processing materials from natural sources. Vegetable, drupe, legume, and seed oils used as co-extractants (mixed with substrate before extraction) can be used to replace the typical organic co-solvents (ethanol, acetone) used in scCO2 extraction. Mixed solvents consisting of a hydrogen bond donor (HBD) solvent and a hydrogen bond acceptor (HBA) are not addressed in GSK or CHEM21 solvent replacement guides. Published data for 100 water-soluble and water-insoluble APIs in mono-solvents show polarity ranges appropriate for the processing of APIs with mixed solvents. When water is used, possible HBA candidate solvents are acetone, acetic acid, acetonitrile, ethanol, methanol, 2-methyl tetrahydrofuran, 2,2,5,5-tetramethyloxolane, dimethylisosorbide, Cyrene, Cygnet 0.0, or diformylxylose. When alcohol is used, possible HBA candidates are cyclopentanone, esters, lactone, eucalytol, MeSesamol, or diformylxylose. HBA—HBA mixed solvents, such as Cyrene—Cygnet 0.0, could provide interesting new combinations. Solubility parameters, Reichardt polarity, Kamlet—Taft parameters, and linear solvation energy relationships provide practical ways for identifying mixed solvents applicable to API systems.

Enabling superior drug loading in lipid-based formulations with lipophilic salts for a brick dust molecule: Exploration of lipophilic counterions and in vitro-in vivo evaluation

Lipid-based formulations (LbFs) are an extensively used approach for oral delivery of poorly soluble drug compounds in the form of lipid suspension and lipid solution. However, the high target dose and inadequate lipid solubility limit the potential of brick dust molecules to be formulated as LbFs. Thus, the complexation of such molecules with a lipophilic counterion can be a plausible approach to improve the solubility in lipid-based solutions via reducing drug crystallinity and polar surface area. The study aimed to enhance drug loading in lipid solution for Nilotinib (Nil) through complexation or salt formation with different lipophilic counterions. We synthesized different lipophilic salts/ complexes via metathesis reactions and confirmed their formation by 1H NMR and FTIR. Docusate-based lipophilic salt showed improved solubility in medium-chain triglycerides (∼7 to 7.5-fold) and long-chain triglycerides (∼30 to 35-fold) based lipids compared to unformulated crystalline Nil. The increased lipid solubility could be attributed to the reduction in drug crystallinity which was further confirmed by the PXRD and DSC. Prototype LbFs were prepared to evaluate drug loading and their physicochemical characteristics. The findings suggested that structural features of counterion including chain length and lipophilicity affect the drug loading in LbF. In addition, physical stability testing of formulations was performed, inferring that aliphatic sulfate-based LbFs were stable with no sign of drug precipitation or salt disproportionation. An in vitro lipolysis-permeation study revealed that the primary driver of absorptive flux is the solubilization of the drug and reduced amount of lipid. Further, the in vivo characterization was conducted to measure the influence of increased drug load on oral bioavailability. Overall, the results revealed enhanced absorption of lipophilic salt-based LbF over unformulated crystalline Nil and conventional LbF (drug load equivalent to equilibrium solubility) which supports the idea that lipophilic salt-based LbF enhances drug loading, and supersaturation-mediated drug solubilization, unlocking the full potential of LbF.