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"Pharmaceutical Preparations"
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Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions
Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.
Journal Article
Copper-mediated synthesis of drug-like bicyclopentanes
Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences
1
. Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as
para
-phenyl ring replacements
2
. These structures are often generated from [1.1.1]propellane via opening of the internal C–C bond through the addition of either radicals or metal-based nucleophiles
3
–
13
. The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.
A one-step, three-component radical coupling of [1.1.1]propellane by a photoredox reaction mediated by a copper catalyst produces drug-like bicyclopentanes.
Journal Article
Advancing the use of genome-wide association studies for drug repurposing
Genome-wide association studies (GWAS) have revealed important biological insights into complex diseases, which are broadly expected to lead to the identification of new drug targets and opportunities for treatment. Drug development, however, remains hampered by the time taken and costs expended to achieve regulatory approval, leading many clinicians and researchers to consider alternative paths to more immediate clinical outcomes. In this Review, we explore approaches that leverage common variant genetics to identify opportunities for repurposing existing drugs, also known as drug repositioning. These approaches include the identification of compounds by linking individual loci to genes and pathways that can be pharmacologically modulated, transcriptome-wide association studies, gene-set association, causal inference by Mendelian randomization, and polygenic scoring.Genome-wide association studies (GWAS) have revealed important biological insights into complex diseases. The authors review approaches that leverage GWAS to identify opportunities for repurposing existing drugs, including single-loci mapping to drug targets, transcriptome-wide association studies, gene-set association, causal inference by Mendelian randomization and polygenic scoring.
Journal Article
Influence of Ageing on the Pharmacodynamics and Pharmacokinetics of Chronically Administered Medicines in Geriatric Patients: A Review
As people age, the efficiency of various regulatory processes that ensure proper communication between cells and organs tends to decline. This deterioration can lead to difficulties in maintaining homeostasis during physiological stress. This includes but is not limited to cognitive impairments, functional difficulties, and issues related to caregivers which contribute significantly to medication errors and non-adherence. These factors can lead to higher morbidity, extended hospital stays, reduced quality of life, and even mortality. The decrease in homeostatic capacity varies among individuals, contributing to the greater variability observed in geriatric populations. Significant pharmacokinetic and pharmacodynamic alterations accompany ageing. Pharmacokinetic changes include decreased renal and hepatic clearance and an increased volume of distribution for lipid-soluble drugs, which prolong their elimination half-life. Pharmacodynamic changes typically involve increased sensitivity to various drug classes, such as anticoagulants, antidiabetic and psychotropic medications. This review examines the primary age-related physiological changes in geriatrics and their impact on the pharmacokinetics and pharmacodynamics of medications.
Journal Article
Making and marketing medicine in Renaissance Florence
A study of the Speziale al Giglio apothecary shop in fifteenth-century Florence, Italy.
Book
Advances in Chitosan-Based Nanoparticles for Drug Delivery
Nanoparticles (NPs) have an outstanding position in pharmaceutical, biological, and medical disciplines. Polymeric NPs based on chitosan (CS) can act as excellent drug carriers because of some intrinsic beneficial properties including biocompatibility, biodegradability, non-toxicity, bioactivity, easy preparation, and targeting specificity. Drug transport and release from CS-based particulate systems depend on the extent of cross-linking, morphology, size, and density of the particulate system, as well as physicochemical properties of the drug. All these aspects have to be considered when developing new CS-based NPs as potential drug delivery systems. This comprehensive review is summarizing and discussing recent advances in CS-based NPs being developed and examined for drug delivery. From this point of view, an enhancement of CS properties by its modification is presented. An enhancement in drug delivery by CS NPs is discussed in detail focusing on (i) a brief summarization of basic characteristics of CS NPs, (ii) a categorization of preparation procedures used for CS NPs involving also recent improvements in production schemes of conventional as well as novel CS NPs, (iii) a categorization and evaluation of CS-based-nanocomposites involving their production schemes with organic polymers and inorganic material, and (iv) very recent implementations of CS NPs and nanocomposites in drug delivery.
Journal Article