7196 research outputs found
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Solvent Selection for Circular Designs - Bridging Process needs and Sustainability Goals
No full textPharmaceutical industries play a crucial role in enhancing global health outcomes; however, like many other sectors, they also encounter significant environmental challenges. The extraction of raw materials and the manufacture of active pharmaceutical ingredients (APIs) result in considerable waste production, substantial resource consumption, and environmental pollution. Transitioning from traditional linear economic models to circular processes presents an opportunity for more sustainable pharmaceutical operations that benefit both communities and the environment. The circular economy framework—grounded in resource efficiency, waste minimization, and material regeneration—offers a path toward comprehensive sustainability in pharmaceutical practices. This is particularly relevant in the area of solvent usage, which accounts for over half the input mass and associated waste in most processes. This article examines the application of circular economy principles to solvent selection within process design, highlighting its significance as a central component of sustainable pharmaceutical development
Nonclinical teratogenicity safety assessment of CRBN-engaging targeted protein degraders: Points to consider.
No full textTargeted protein degraders (or degraders) are an emerging small molecule drug modality with transformative therapeutic potential. Currently, most degraders are developed for severe life-threatening disorders and engage the E3 ligase cereblon. One barrier to the broader use of degraders is the potential risk of embryofetal toxicity with cereblon-engaging degraders, exemplified by thalidomide. Thalidomide (and analogs, known as immunomodulatory drugs) binds cereblon and modifies its substrate repertoire, leading to degradation of intended and multiple unintended neosubstrates. Some cereblon-engaging degraders have been engineered to avoid the degradation of unintended neosubstrates implicated in teratogenicity, specifically SALL4. Mechanistic links between SALL4 degradation by thalidomide and human teratogenicity have been established; further, SALL4 degradation by thalidomide (and its analogs) has been linked to teratogenicity in susceptible nonclinical species. It is generally accepted that SALL4 degradation is unlikely to be the only mechanism of teratogenicity associated with thalidomide and its analogs. Currently, best practices to evaluate the teratogenicity risk of cereblon-engaging degraders have not been established. Here, we present points to consider in the teratogenicity safety assessment of cereblon-engaging degraders from the perspective of an IQ consortium working group
Physiologically Based Pharmacokinetic Modeling of Midostaurin and Metabolites at Steady-state to Bridge Drug Interaction Scenarios In Lieu of Clinical Trials
No full textMidostaurin and its active metabolites are substrates, mixed inhibitors/inducers of cytochrome P450 (CYP)3A4. The main objective of this study was to develop/refine a physiologically based pharmacokinetic (PBPK) model that incorporated recent clinical drug-drug interaction (DDI) data with midazolam after multiple dosing. The goal of this work was to qualify the pharmacokinetic (PK) model simulations of midostaurin and its metabolites, and to apply it to predict untested clinical DDI scenarios with potential comedications. The Simcyp PBPK model of midostaurin and its two metabolites was refined from a previously published model through further optimization of CYP3A4 inhibition/induction potency and was qualified to simulate midostaurin steady-state PK. The incorporation of these parameters enabled DDI predictions of high midostaurin doses on the PK of midazolam and oral contraceptives (OC) containing ethinyl estradiol. Additionally, scaling factors for in vitro breast cancer resistance protein (BCRP) and the organic anion transporting polypeptide (OATP1B) inhibition were applied to account for the observed single dose DDI with rosuvastatin and further extrapolated to predict steady-state DDI with other OATP1B drug substrates. The overall prediction results showed minimal impact of midostaurin at high doses on CYP3A substrates or an effect on the exposure of OATP1B substrates. In summary, the midostaurin PBPK model was retrospectively refined, requalified and used to simulate the steady-state perpetrator DDI of midostaurin and its metabolites. This PBPK modeling approach and the resulting model predictions were implemented into the midostaurin product label (up to 100 mg b.i.d.) without the need for confirmatory clinical studies
Scientific and Regulatory Policy Committee Points to Consider* for Determining and Reporting Cause of Death/Moribundity in Non-Rodent Species in Toxicity Studies.
No full textThe Cause of Death in Non-Rodents (CODN) Working Group is an initiative under the Scientific and Regulatory Policy Committee (SRPC) of the Society of Toxicologic Pathology (STP), focused on understanding existing practices and expectations among pharmaceutical companies, academic entities, and contract research organizations (CROs) when it comes to identifying and reporting the "Cause of Death" (COD) or moribundity for early or unplanned necropsies in non-rodent animal species (mainly non-human primates [NHP] and dogs) within both GLP (Good Laboratory Practice) and non-GLP toxicity studies. A survey was sent out to STP members to collect data on industry practices for determining COD in animals that underwent unscheduled euthanasia or were found deceased. Other non-rodent animals (such as pigs and rabbits) were also included to evaluate different approaches taken with various species. The insights obtained led to the development of "Points to Consider" for establishing and documenting the COD in large animal toxicity studies. Four key considerations include utilizing information from both control and treated animals in the study, consideration of COD for cohabiting or co-shipped non-study animals, including additional evaluations to help rule-in or rule-out specific causes, and recording the COD consistently in pathology databases or reports as a standard practice
The European Federation for Medicinal Chemistry and Chemical Biology (EFMC) Best Practice Initiative: Hit to Lead
No full textThe Hit to Lead (H2L) process is an integral part of contemporary drug discovery, encompassing the optimization of validated Hit structures into Lead molecules. High quality leads build confidence, through activity and property profiles as well as preliminary biological data, which might include validating pharmacologic hypotheses along the way, indicating that further investment in the structure(s) and target would be worthwhile. Leads have line of sight to a development candidate and bring an understanding of what priorities Lead Optimisation should address. In this set of best practices, we detail the essential criteria that characterise a good lead, which include establishing SAR from analogues and assessing preliminary DMPK indicators, selectivity and early safety parameters. We highlight the importance of identifying liabilities of the lead series and demonstrating that each can be individually modulated whilst maintaining on target potency. We make the case for having physicochemical properties as critical optimization parameters and how ligand efficiency metrics can enable this. Then we go over general tactics that can be used to convert hits into a lead series. These include essential steps that, when performed early, increase the chance of success such as deconstructive SAR, pharmacophore and bioactive conformation determination and scaffold optimization. Finally, we suggest decision making criteria to substantiate confidence in further investment or, as importantly, making a recommendation to cease further work on a series
A ‘One-Shot’ Strategy for Preparative Chiral SFC with Chiroptical Detection Accelerates Purification and Enhances Characterization for Drug Discovery
No full textThe advantages of a streamlined SFC chiral workflow for preparative chromatographic resolution of the enantiomers of investigational new compounds for pharmaceutical discovery on 10-20 mg scale with on-line chiroptical detection is described. The workflow has been designed to supply milligram amounts of enantiopure material using a universal gradient elution approach. Implementation of a faster and more labor efficient chiral purification workflow was the primary objective, with the secondary objective being an on-line collection of stereochemical information for separated enantiomers with the return of weighed compounds with acceptable purity. Column selection is carried out by gradient analytical SFC screening of six columns in 20 minutes, while preparative resolution is carried out in a single injection using an 8-minute gradient with on-line polarimetric detection to assign and confirm the stereochemical identity of eluted enantiomers. Additionally, electrospray ionization mass spectrometry detection is employed to facilitate fraction collection as well as product identification. The new workflow was piloted over a several month period and has proved to be an effective strategy for small scale preparative enantioseparations. Although these smaller-scale chiral separations currently constitute only a sixth of submissions in our laboratory, the one-shot workflow offers clear advantages for rapidly providing enantiopure material for initial in-vitro testing, reducing purification and evaporation cycle times and labor requirements
Adding Value to Terpenes: Copper-Catalyzed Oxidation of α-Pinene in Water under Micellar Conditions
No full textThe development of new protocols and catalytic systems for sustainable conversion of renewables such as terpenes into value-added molecules is currently in high demand. In this work, three new coordination compounds featuring mono-, di-, and tricopper(II) cores were easily assembled in aqueous ethanol medium from copper(II) nitrate, aminoalcohols, and 5-nitroisophthalic acid (H2nipa). The obtained products were formulated as [Cu(H3tea)(H2O)2](nipa)∙H2O (1), {[Cu2(μ3-dap)(μ-Hnipa)(μ3-nipa)(H2O)]∙H2O}n (2), and {[Cu3(μ3-Hmdea)2(μ4-nipa)(nipa)(H2O)3]}n (3) {H3tea, trietanolamine; Hdap, 1,3-diamino-2-propanol; H2mdea, methyldiethanolamine}. The compounds 1−3 were fully characterized, and their crystal structures disclose an ionic monocopper complex (1) and 1D coordination polymers (2, 3) with distinct secondary building units. The catalytic performance of 1−3 was evaluated under micellar aqueous-medium conditions, while studying the mild oxidation of α-pinene with tert-butyl hydroperoxide in an aqueous 1% solution of PS-750-M surfactant. Compound 1, a water-soluble complex, proved to be the most promising catalyst for the oxidation of α-pinene under micellar conditions, leading to high substrate conversion (87%) and yielding up to 54% of the main products (tert-butylperoxy-2-pinene, verbenone, and pinene oxide). Compound 2, a partially water-soluble 1D coordination polymer, also exhibits a notable catalytic behavior with the conversion of α-pinene of 87.5% and considerable total yield of the main products (44%). Apart from diversifying the types of self-assembled copper(II) cores with distinct nuclearity 4 and structural features, this work also opened up the use of such copper derivatives in the area of micellar catalysis toward the transformation of terpenes into value-added products
Intermediates data sharing - contribution for 2025
No full textYearly donation of Ames test data for small molecules that are intermediates in drug substance synthesis. We are part of an industry consortium and benefit from data donated by other companies. No Novartis project is disclosed
Small scale model for predicting transportation-induced particle formation in biotherapeutics.
No full textUnderstanding protein adsorption and aggregation at the air-liquid interfaces of protein solutions is an important open challenge in biopharmaceutical, medical, and biotechnological applications, among others. Proteins, being amphiphilic, adsorb at the surface, partially unfold, and form a viscoelastic film through non-covalent interactions. Mechanical agitation of the surface can break this film up, releasing insoluble protein particles into the solution. These aggregates are usually highly undesirable and even toxic in cases, such as for biopharmaceutical application. Therefore, it is imperative to be able to predict the behavior of such solutions undergoing surface agitation during handling, usually transport or mixing. We apply the findings on the viscoelastic protein film, formed at the air-liquid interface, to the prediction of surface mediated aggregation in selected protein solutions of direct biopharmaceutical relevance. Our broad study of Brewster angle microscopy and aggregation monitoring across multiple size ranges by micro-flow imaging, light scattering, and size exclusion chromatography shows that formation of protein particles is driven by the adsorption rate as compared to the rate of surface turnover and that surface film dynamics in the quiescent phase directly affect aggregation. We demonstrate how these learnings can be directly applied to the design of a novel small scale biopharmaceutical stability study, simulating relevant transport conditions. More generally, we show the impact of adsorption dynamics at the air-liquid interface on the stability of a distinct protein solution, as a general contribution to understanding different colloidal and biological interfacial systems
Thiazole-Based IL-17 Inhibitors Discovered by Scaffold Morphing
No full textThe pro-inflammatory cytokine interleukin-17A (IL-17) plays an important role in the body's defense against bacterial and fungal infections. However, overexpression of IL-17 has been associated with several diseases, including rheumatoid arthritis, asthma, psoriasis, and even cancer. The role of IL-17 in psoriasis has been confirmed by clinical use of IL-17 antibodies, e. g. secukinumab (Cosentyx®). Ongoing research is focused on discovering low molecular weight IL-17 inhibitors. In this publication, we present thiazole-based IL-17 inhibitors discovered through a scaffold-morphing strategy. This strategy involved ring-opening of a known scaffold and utilization of a chalcogen interaction between thiazole-sulfur and central amide-oxygen to maintain the coplanar conformation found in the parent compound. The new scaffold enabled the generation of highly potent compounds with good overall profile. The optimized compounds 11 and 15 demonstrated good exposure in rats after oral dosing. Importantly, compound 11 exhibited no adverse effects in a rat tolerability study after a four-day administration of up to 300 mg/kg/day