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Potential genotoxic impurities in medications are an increasing concern in the pharmaceutical industry and regulatory bodies because of the risk of human carcinogenesis. To prevent the emergence of these impurities, it is crucial to carefully examine not only the final product but also the intermediates and key starting material (KSM) used in drug synthesis. During the related substances analysis of KSM of Famotidine, an unknown impurity in the range of 0.5–1.0% was found prompting the need for isolation and characterization due to the possibility of its to infiltrate into the final product. In this study, the impurity was isolated and characterized as 5-(2-chloroethyl)-3,3-dimethyl-3,4-dihydro-2H-1,2,4,6-thiatriazine 1,1-dioxide using multiple instrumental analysis, uncovering a structural alert that raises concern. Considering the potential impact of impurity on human health, an in silico genotoxicity assessment was established using Derek and Sarah tool in accordance with ICH M7 guideline. Furthermore, molecular docking and molecular dynamics simulation were performed to evaluate the specific interaction of the impurity with DNA. The findings reveal consistent interaction of the impurity with the dG-rich region of the DNA duplex and binding at the minor groove. Both in silico prediction and molecular dynamic study confirmed the genotoxic character of the impurity. The newly discovered impurity in famotidine has not been reported previously, and there is currently no analytical method available for its identification and control. A highly sensitive HPLC-UV method was developed and validated in accordance with ICH requirements, enabling quantification of the impurity at trace level in famotidine ensuring its safe release. [ABSTRACT FROM AUTHOR]

The increasing use of UV filters, such as benzophenone-3 (BP-3) and titanium dioxide nanoparticles (TiO2 NPs), has raised concerns regarding their ecotoxicological effects on the aquatic environment. The aim of the present study was to examine the embryo-larval toxicity attributed to BP-3 or TiO2 NPs, either alone or in a mixture, utilizing zebrafish (Danio rerio) as a model after exposure to environmentally relevant concentrations of these compounds. Zebrafish embryos were exposed to BP-3 (10, 100, or 1000 ng/L) or TiO2 NPs (1000 ng/L) alone or in a mixture (BP-3 10, 100, or 1000 ng/L plus 1000 ng/L of TiO2 NPs) under static conditions for 144 hr. After exposure, BP-3 levels were determined by high-performance liquid chromatography (HPLC). BP-3 levels increased in the presence of TiO2 NPs, indicating that the BP-3 degradation decreased in the presence of the NPs. In addition, in the presence of zebrafish, BP-3 levels in water decreased, indicating that zebrafish embryos and larvae might absorb BP-3. Data demonstrated that, in general, environmentally relevant concentrations of BP-3 and TiO2 NPs, either alone or in a mixture, did not significantly induce changes in heart and spontaneous contractions frequencies, levels of reactive oxygen species (ROS), morphological and morphometric parameters as well as mortality rates during 144 hr exposure. However, the groups exposed to TiO2 NPs alone and in a mixture with BP-3 at 10 ng/L exhibited an earlier significant hatching rate than the controls. Altogether, the data indicates that a potential ecotoxicological impact on the aquatic environment exists. [ABSTRACT FROM AUTHOR]

AbstractAimsMethodsResultsConclusionThis study examines microencapsulation as a method to enhance the stability of natural compounds, which typically suffer from inherent instability under environmental conditions, aiming to extend their application in the pharmaceutical industry.We explore and compare various microencapsulation techniques, including spray drying, freeze drying, and coacervation, with a focus on spray drying due to its noted advantages.The analysis reveals that microencapsulation, especially via spray drying, significantly improves natural compounds’ stability, offering varied morphologies, sizes, and efficiencies in encapsulation. These advancements facilitate controlled release, taste modification, protection from degradation, and extended shelf life of pharmaceutical products.Microencapsulation, particularly through spray drying, presents a viable solution to the instability of natural compounds, broadening their application in pharmaceuticals by enhancing protection and shelf life. [ABSTRACT FROM AUTHOR]

3D electron diffraction (3DED) is increasingly employed to determine molecular and crystal structures from micro-crystals. Indomethacin is a well known, marketed, small-molecule non-steroidal anti-inflammatory drug with eight known polymorphic forms, of which four structures have been elucidated to date. Using 3DED, we determined the structure of a new ninth polymorph, σ, found within an amorphous solid dispersion, a product formulation sometimes used for active pharmaceutical ingredients with poor aqueous solubility. Subsequently, we found that σ indomethacin can be produced from direct solvent evaporation using dichloromethane. These results demonstrate the relevance of 3DED within drug development to directly probe product formulations.

England's 10 national parks are renowned for their landscapes, wildlife, and recreational value. However, surface waters in the national parks may be vulnerable to pollution from human‐use chemicals, such as active pharmaceutical ingredients (APIs), because of factors like ineffective wastewater treatment, seasonal tourism, a high proportion of elderly residents, and the presence of low‐flow water bodies that limit dilution. The present study determined the extent of API contamination in the English national parks by monitoring 54 APIs in 37 rivers across all national parks over two seasons. Results were compared to existing data sets for UK cities and to concentration thresholds for ecological impacts and antimicrobial resistance selection. Results revealed widespread contamination of the national parks, with APIs detected at 52 out of 54 sites and in both seasons. Thirty‐one APIs were detected, with metformin, caffeine, and paracetamol showing the highest mean concentrations and cetirizine, metformin, and fexofenadine being the most frequently detected. While total API concentrations were generally lower than seen previously in UK cities, locations in the Peak District and Exmoor had higher concentrations than most city rivers. Fourteen locations had concentrations of either amitriptyline, carbamazepine, clarithromycin, diltiazem, metformin, paracetamol, or propranolol above levels of concern for fish, invertebrates, and algae or for selection for antimicrobial resistance. Therefore, API pollution of the English national parks appears to pose risks to ecological health and potentially human health through recreational water use. Given that these parks are biodiversity hotspots with protected ecosystems, there is an urgent need for improved monitoring and management of pharmaceutical pollution and pollution more generally not only in national parks in England but also in similar environments across the world. Environ Toxicol Chem 2024;43:2422–2435. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

The aim of the article. To study of the incidence of diabetes mellitus in Ukraine and to determine the prospects for the use and pharmaceutical development of antidiabetic drugs. Materials and methods. Data from the State Registers of Medicinal Products of Ukraine, of Wholesale and Retail Prices for Medicinal Products declared in Ukraine under an international non-proprietary or generic name (01.01.2024). Were used: systematic and comparative analysis, processing and synthesis, and generalization to determine the forecasted prospects. Results. In Ukraine the number of diabetes patients increased by 11% in the group of children and adolescents; in the group of elderly patients – by 12.5%, among the adult working – 20%, diabetes of the II type predominates. The trend of increase in the number of studies on the search for therapeutic alternatives for the treatment of type II diabetes and list of medicines on the pharmaceutical market has been revealed. In Ukraine drugs for oral use include APIs of the following pharmacological groups: sulfonylureas; meglitinides; biguanides; thiazolidinedione; α-glucosidase inhibitors; DPP-4 inhibitors; SGLT-2 inhibitors. Mechanism of action of the new class of oral hypoglycemic agents, approved by the FDA, consists in blocking SGLT-2 proteins from the proximal convoluted tubule in the kidney, leads to the prevention of reabsorption and excretion of the glucose molecule. This allows its use in combination with insulin and other antidiabetic drugs for the treatment of type I and II diabetes in patients of various age categories. According to the volume of clinical studies, SGLT-2 inhibitor SGLT-2 derivative gliflozin API drugs are the second largest group of antidiabetic drugs recommended for use by FDA and EMA regulatory bodies. Conclusions. The pharmaceutical development of mono and combined drugs with APIs SGLT-2 inhibitors gliflozin derivatives in combination with APIs with metformin, DPP-4 inhibitors, APIs thiazolidinedione derivatives is promising for solving the problem of diabetes treatment and prevention of complications for patients of different age groups including working population in Ukraine.

The degradation of ciprofloxacin hydrochloride (CFX), an extensively utilized antibiotic for bacterial infections, has been studied through the application of advanced oxidation processes (AOPs) including hydrodynamic cavitation (HC), ozonation (O3), the Fenton reaction, chemical oxidation, and hybrid AOPs such as HC/O3 and Fenton/O3. Among these, the hybrid combination of HC/O3 demonstrated the highest CFX degradation of 99.82 % within 180 min having an initial concentration of 1000 ppm. The optimization of the HC/O3 process was conducted by varying parameters including initial concentration, pH, ozone (O3) gas flowrate, and temperature. Throughout the degradation process, CFX underwent intermediate formation, which gradually degraded over time. [ABSTRACT FROM AUTHOR]

This paper presents an efficient and practical protocol for the synthesis of rufinamide (anti-epileptic drugs) active pharmaceutical ingredient (API) and several process impurities by a 1,3-dipolar cycloaddition reaction, starting from commercially available benzyl bromides. The earlier reported syntheses of rufinamide had encountered challenges in isolating by-products from the mother liquor. In this work, the impurities were synthesized via the retrosynthesis route to serve as reference samples for assessing the purity level of drugs. These impurities, characterized by the presence of N-group and azole derivatives, find wide-range applications in academic and industrial settings, including organic synthesis, drug discovery, polymer chemistry, chemical biology, and supramolecular chemistry. The primary objective of this synthesis was to propose a reliable and pragmatic method for producing rufinamide and its impurities to address diverse scientific and industrial requirements. The protocol outlined in this research aims to contribute to the development of robust methodologies for the synthesis of pharmaceuticals and associated impurities, with potential implications for drug development and chemical research. [ABSTRACT FROM AUTHOR]

SCIENTIFIC RELEVANCE. Russia is pursuing a consistent government policy of import substitution and increasing the localisation of pharmaceutical manufacturing. The Strategy for the Development of the Pharmaceutical Industry until 2030 (Pharma-2030) includes the target share of medicinal products from the List of Strategic Medicines that should be fully localised. Since biotechnological medicinal products have high consumption growth rates and are listed as strategic medicines, it is a priority to study their production localisation process.AIM. This study aimed to analyse the degree of biopharmaceutical manufacturing localisation in Russia, considering the country of origin of active pharmaceutical ingredients (APIs).MATERIALS AND METHODS. The study used the State Register of Medicines and sales data of the DSM Group marketing agency. The authors used custom software for the Node.js® platform to determine the degree of production localisation.RESULTS. The analysis showed that the production process was fully localised for 25.6% (in packages) and 26.6% (in roubles) of all biotechnological medicinal products consumed in Russia in 2022. Imported medicinal products dominated the consumption structure, with a share of 33.9% in packages and 31.3% in roubles. Medicinal products with localised secondary packaging accounted for 5.8% in packages and 25.9% in roubles. Finished dosage forms produced using imported APIs had a significant share of 23.7% in packages and 6.2% in roubles. Russian APIs were used to produce 79% of the biotechnological medicinal products listed as strategic medicines, which corresponded to the full localisation of a share of the consumption structure of 10.8% in packages and 32.3% in roubles.CONCLUSIONS. The Russian biotechnological market remains heavily dependent on imported finished medicinal products and APIs. Although the Pharma-2030 target for the production of strategic biotechnological products has been achieved, the quantitative indicators show the necessity to increase output and localisation.

Worldwide thin layer chromatography (TLC) is still in very much use in various different application fields (e.g. natural products chemistry, monitoring the organic/enantioselective synthesis, and routine analysis in analytical laboratories). Herein is presented an account of the efficient resolution/enantioseparation of racemic and non-racemic mixtures of several different types of active pharmaceutical ingredients, and biologically important compounds by TLC using a direct approach along with quantitative determination and isolation of native forms via non-covalent diastereomer formation. Different approaches and mechanisms of direct enantioseparation using different chiral reagents are discussed. It provides a route for a wide range of chiral stationary phases (CSPs) which can be in-home thought out, produced, assessed, and customized. The achievements and new challenges in the field are presented. Besides, it presents a very useful coverage for the non-specialists to the subject who want to understand where this study fits into the existing literature in this general area. [ABSTRACT FROM AUTHOR]

The morphology of crystalline active pharmaceutical ingredients (APIs) can significantly affect their product properties, so that its control during manufacturing is crucial. To address this, a newly augmented commercial milliliter‐scale facility and knowledge‐based workflow were developed with the aim of identifying optimal process conditions for producing more equant‐shaped crystals. The design includes minimal material usage, inline imaging, and independent temperature and supersaturation control through evaporative crystallization. The methodology enables the identification of process conditions for equant‐shaped crystals across diverse APIs. These findings contribute to advancing pharmaceutical research and development by providing a reliable approach to optimize crystal morphology. [ABSTRACT FROM AUTHOR]

Despite advances in cancer treatment, many types of cancer still have high mortality rates, and the existing therapies can cause considerable side effects. Therefore, discovering new therapies, especially ones with fewer side effects, is desirable to improve the outcomes for cancer patients. Ionic liquids (ILs) have emerged as potential candidates for cancer treatment because of their particular physicochemical properties, which can be tailored for specific applications. In recent years, interest in exploring the potential of ILs in cancer treatment has been growing, and several studies have demonstrated the effectiveness of ILs in inhibiting cancer‐cell growth. This review provides insight into the anticancer potential of ILs, exploring the diverse applications and the underlying mechanisms behind the cytotoxicity toward cancer cells of ILs. Understanding the mechanisms behind the cytotoxicity of ILs can aid in the design and optimization of IL‐based cancer therapies. By focusing on specific pathways and targets, IL‐based cancer therapies may be developed that offer new possibilities for treating this devastating disease. [ABSTRACT FROM AUTHOR]

This study introduces a novel approach for enhancing the transdermal permeability of ibuprofen through the skin by utilising a rotating magnetic field (RMF). The core objective is to systematically evaluate the influence of a 50 Hz RMF on ibuprofen's skin permeability across various formulation types, each employing distinct physical forms and excipients. The experimental setup involved Franz cells with skin as the membrane, exposed to a 50 Hz RMF in conjunction with specific formulations. Subsequent comprehensive analysis revealed a notable increase in the transdermal transport of ibuprofen, irrespective of the formulation employed. Notably, the differences in the initial 30 min of permeation were particularly pronounced. Crucially, this investigation establishes that the application of a 50 Hz RMF resulted in a remarkable over-sevenfold increase in ibuprofen permeability compared to the control group without RMF exposure. It is noteworthy that in all semi-solid pharmaceutical formulations tested, RMF effectively reduced the delay time to zero, underscoring the efficiency of RMF in overcoming barriers to transdermal drug delivery. This research positions the application of RMF as a highly promising and innovative technology, significantly enhancing the transdermal penetration of anti-inflammatory and analgesic drugs through the skin. The demonstrated effectiveness of RMF across diverse formulations suggests its potential in transdermal drug delivery, offering a novel and efficient strategy for improving therapeutic outcomes in the administration of ibuprofen and potentially other pharmaceutical agents. [ABSTRACT FROM AUTHOR]

The constant demand for sustainable approaches to pharmaceutical synthesis has thrived the enzyme catalysis (biocatalysis) field. The most sought‐after features like high specificity, environmentally benign, and biodegradable nature have rendered enzymatic processes predominantly eco‐friendly. Owing to these merits, biocatalysis is now being developed extensively to exploit their applications in designing alternate and sustainable synthetic routes for manufacturing pharmaceuticals, in line with green chemistry principles. Further, combining multiple enzymes in one‐pot is a highly efficient methodology as it eliminates intermediate isolation, shifts equilibrium in the forward direction, and proceeds in ambient aqueous conditions. This review highlights the importance of recently developed multienzyme cascade synthesis of pharmaceutically important bioactive molecules by relating them with their well‐known chemical route. [ABSTRACT FROM AUTHOR]

The pharmaceutical industry has traditionally employed batch processing as a means of synthesizing active pharmaceutical ingredients (APIs) on a commercial scale. Batch manufacturing enables API synthesis in large quantities in order to meet regulations. Yet, this strategy remains cumbersome, is labor‐intensive, and creates complex logistical networks. In recent decades, batch API processing has gradually eroded American economic competitiveness and has led to the offshoring of API manufacturing from the United States. Today it is estimated that +80% of APIs are manufactured overseas.[1] Meanwhile, disruptions from the Coronavirus Disease (SARS‐CoV‐2) have exacerbated weaknesses in the global supply chain, culminating with widespread shortages of critical life‐saving drugs.[2] These shortages have emphasized the importance of reshoring drug manufacturing to the U.S. and fostered a regulatory landscape that seeks advanced methods of API manufacturing in order to bolster America's supply chain resiliency.[3] Recently, increased attention has been directed towards continuous drug manufacturing to enable nonstop API production within modular stand‐alone flow systems. Continuous manufacturing (CM) facilitates modular automation, offers new avenues towards process intensification, and even enables in‐line analytical monitoring from raw materials to packaged products. This strategy offers better conversion, increased safety, reduced waste, and overall cost savings versus traditional batch‐style processing. The rise of advanced API manufacturing, coupled with the current regulatory landscape, offers a rare window of opportunity to convert traditional batch pharmaceutical processes into continuous, streamlined production systems to on‐shore API manufacturing and eliminate drug shortages. This review will outline the current state‐of‐the‐art in the CM of APIs and will highlight the translation of chemistry and unit operations from batch processes to modular CM systems. [ABSTRACT FROM AUTHOR]

Contamination of water resources by active pharmaceutical ingredient wastes is among major environmental concerns. To prevent major disruptions of aquatic life, an efficient and environmentally-friendly turbidity removal procedure of common contaminants such as paracetamol should be established. In this study, several natural deep eutectic solvents (NADESs) were screened to reduce the turbidity of simulated water contaminated with paracetamol below the standard turbidity limit recommended by the National Water Quality Standards for Malaysia (50 NTU). The optimal operating parameters (NADES dosage, stirring time and operating pH) were determined. Under optimized conditions, stearic acid-based NADES achieved the highest turbidity removal of 97.5 %. High coagulation performances were investigated based on molecular interaction using COSMO-RS (COnductor like Screening MOdel for Real Solvents) σ-profile and σ-potential (histogram of charge density distribution over molecular surface) and showed high affinity between the NADES compounds and paracetamol. Thus, NADESs are promising candidates for turbidity removal of paracetamol from water and are viable in further investigations for effluent treatment applications.

Pre-concentration can reduce the total production costs in the pharmaceutical industry. Organic solvent forward osmosis (OSFO) is a suitable pre-concentration method because of its nonthermal nature, low capital cost, and potential for achieving high-degree concentrations. In a previous study, we first demonstrated a high-degree OSFO concentration. Sucrose octaacetate (SoA) in MeOH was concentrated to 52 wt% using polyethylene glycol (PEG)-400 as the osmotic agent, but the concentrated solution had a concentration of 17% PEG-400 because of the reverse solute flux. This result does not meet the typical purity standards required for pharmaceutical production, indicating the need to determine a suitable osmotic agent that can be used for practical purposes. This study proposes a practical osmotic agent for OSFO pre-concentration. First, osmotic agents were screened from a practical perspective. Polypropylene glycol (PPG)-400 was selected, owing to its low toxicity, good solubility, and low viscosity. Subsequently, the OSFO concentration was demonstrated using PPG-400 as the osmotic agent. SoA in MeOH was concentrated from 9.4 wt% to 48 wt%. The final feed solution contained only 0.04 wt% PPG-400. This result is the first demonstration of successful pharmaceutical pre-concentration using OSFO that satisfies the typical purity requirement in pharmaceutical production.

Biocompatible metal-organic framework MIL-100(Fe) was used as a container for a model hydrophobic active pharmaceutical ingredient, ibuprofen, in composite films based on gelatin, pectin, and kappa-carrageenan. According to powder X-ray diffraction and scanning electron microscopy data, the metal-organic framework retained the crystal structure and its particles were uniformly distributed throughout the hydrocolloid matrix. Testing of the obtained film materials under simulated biological conditions using chromatography–mass spectrometry analysis showed that they are applicable as a dosage form for slow release of active pharmaceutical ingredients. [ABSTRACT FROM AUTHOR]

Crystal morphology plays a critical role in the processability and physicochemical behavior of active pharmaceutical ingredients. Manipulating crystal morphology involves consideration of crystallization conditions such as temperature, supersaturation, and solvent choice. Typically, experimental screenings on a small scale are conducted to find targeted crystal morphologies. However, results from such small-scale experiments do not assure direct success at a larger scale, particularly if the small-scale setup differs significantly from a conventional stirred crystallizator. In this study, we successfully validated the morphologies observed in the small-scale experiments of an exemplary API, Bitopertin, when scaled up by a factor of 200, through the maintenance of identical process conditions and geometrical vessel relations. This successful scalability highlights the significant potential of small-scale crystallization studies to provide a reliable foundation for further exploration in large-scale endeavors. [ABSTRACT FROM AUTHOR]

Biocatalysts can accelerate the catalysis of a chemical reaction that is difficult to synthesize with typical chemical methods. The global enzyme market size is predicted to expand at a CAGR of 6.5% from 2021 to 2028. Enzymatic reactions are highly chemo, regio, and stereoselective and produce various fine chemicals such as drugs, agrochemicals, and fragrance molecules. Peroxidases (PO) (EC 1.11.1.x) are a large class of enzymes that play an important role in various biological processes. Chloroperoxidase (CPO, EC 1.1.1.10) is a versatile fungal haem-thiolate protein that is useful in the asymmetric synthesis of chiral building blocks and has an important role in a number of biological processes. CPO's main biological role is chlorination, although it also catalyses haem PO, catalase (CAT), and reactions similar to cytochrome P450. However, CPO performs both oxidation and stereo-specific halogenation of chemical molecules. The haem and vanadium POs are produced by Caldariomyces fumago, and Curvularia inaequalis, respectively, and are capable of halogenating the flavanones, naringenin, and hesperetin, at C-6 and C-8 in the presence of either Cl− or Br−. In this review, we discussed the various applications of CPO including synthesis of epoxides, drugs, halogenation of thymol, nitriles, the Aza-Achmatowicz reaction, and biomedical applications such as cancer and biosensors. In light of these novel features, we have provided a detailed review of CPOs and their applications in various stereoselective chemical transformations of industrial relevance. [ABSTRACT FROM AUTHOR]

From boon molecules to molecules contributing to rising concern has been the sojourn of antibiotics. The problem of antibiotic contamination has gotten worse due to antibiotics' pervasive use in every aspect of the environment. One such consequence of pollution is the increase in infections with antibiotic resistance. All known antimicrobials being used for human benefit lead to their repetitive and routine release into the environment. The misuse of antibiotics has aggravated the situation to a level that we are short of antibiotics to treat infections as organisms have developed resistance against them. Overconsumption is not just limited to human health care, but also occurs in other areas such as aquaculture, livestock, and veterinary applications for the purpose of improving feed and meat products. Due to their harmful effects on non-target species, the trace level of antibiotics in the aquatic ecosystem presents a significant problem. Since the introduction of antibiotics into the environment is more than their removal, they have been given the status of persistent pollutants. The buildup of antibiotics in the environment threatens aquatic life and may lead to bacterial strains developing resistance. As newer organisms are becoming resistant, there exists a shortage of antibiotics to treat infections. This has presented a very critical problem for the health-care community. Another rising concern is that the development of newer drug molecules as antibiotics is minimal. This review article critically explains the cause and nature of the pollution and the effects of this emerging trend. Also, in the latter sections, why we need newer antibiotics is questioned and discussed. [ABSTRACT FROM AUTHOR]

Bioavailability is an important biopharmaceutical characteristic of active pharmaceutical ingredients (APIs) that is often correlated with their solubility in water. One of the methods of increasing solubility is freeze drying (lyophilization). The article provides a systematic review of studies published from 2012 to 2022 aimed at optimizing the properties of active pharmaceutical ingredients by freeze drying. This review was carried out in accordance with the recommendations of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). In general, 141 modifications of 36 APIs attributed to 12 pharmacological groups were reported in selected publications. To characterize the products of phase modification after lyophilization, a complex of analytical methods was used, including microscopic, thermal, X-ray, and spectral approaches. Solubility and pharmacokinetic parameters were assessed. There is a tendency to increase solubility due to the amorphization of APIs during lyophilization. Thus, the alcohol lyophilizate of dihydroquercetin is "soluble" in water compared to the initial substance belonging to the category "very poorly soluble". Based on the analysis of the literature, it can be argued that lyophilization is a promising method for optimizing the properties of APIs. [ABSTRACT FROM AUTHOR]

Our current unhealthy lifestyle and the exponential surge in the population getting affected by a variety of diseases have made pharmaceuticals or drugs an imperative part of life, making the development of innovative strategies for drug discovery or the introduction of refined, cost‐effective and modern technologies for the synthesis of clinically used drugs, a need of the hour. Ever since their discovery, free radicals and radical cations or anions as reactive intermediates have captivated the chemists, resulting in an exceptional utilization of these moieties throughout the field of chemical synthesis, owing to their unprecedented and widespread reactivity. Sticking with the idea of not judging the book by its cover, despite the conventional thought process of radicals being unstable and difficult to control entities, scientists and academicians around the globe have done an appreciable amount of work utilizing both persistent as well as transient radicals for a variety of organic transformations, exemplifying them with the synthesis of significant biologically active pharmaceutical ingredients. This review truly accounts for the organic radical transformations including radical addition, radical cascade cyclization, radical/radical cross‐coupling, coupling with metal‐complexes and radical cations coupling with nucleophiles, that offers fascinating and unconventional approaches towards the construction of intricate structural frameworks of marketed APIs with high atom‐ and step‐economy; complementing the otherwise employed traditional methods. This tutorial review presents a comprehensive package of diverse methods utilized for radical generation, featuring their reactivity to form critical bonds in pharmaceutical total synthesis or in building key starting materials or intermediates of their synthetic journey, acknowledging their excellence, downsides and underlying mechanisms, which are otherwise poorly highlighted in the literature. Despite great achievements over the past few decades in this area, many challenges and obstacles are yet to be unraveled to shorten the distance between the academics and the industry, which are all discussed in summary and outlook. [ABSTRACT FROM AUTHOR]

India has a sparkling pharmaceutical sector that holds a distinguished place by producing and supplying high-quality and affordable medicines across the globe. Ensuring the quality and safety of the marketed medicinal products is one of the most important components of the drug regulatory framework and assessment of the quality of medicines is usually achieved by referring to the public standards of the official Pharmacopoeia. In India, the Indian Pharmacopoeia (IP) is published at regular intervals to fulfill the requirements of the Drugs and Cosmetics Act, 1940 to ensure the quality of medicines being manufactured and/or marketed in India. The present article aims to provide an overview of the history of the IP, its standards-setting process, and the current status of monographs in the 9th edition of the IP 2022. Special focus is placed on the newly added and upgraded general chapters and monographs within the IP 2022. There are a total of 223 general chapters and 3152 drug monographs available under various categories in the IP 2022. This study also highlights a total of 92 new drug monograph additions and 412 monograph revisions in the IP 2022. It is anticipated that the standards laid down in the IP 2022 will play an imperative role in delivering quality medicines to patients within and outside India.

The use of agrochemical and pharmaceutical active ingredients is essential in our modern society. Given the increased concern and awareness of the potential risks of some chemicals, there is a growing need to align with ‘green chemistry’ and ‘safe and sustainable by design’ principles and thus to evaluate the hazards of agrochemical and pharmaceutical active ingredients in early stages of R&D. We give an overview of the current challenges and opportunities to assess the principle of biodegradability in the environment. Development of new medium/high-throughput methodologies, combining predictive tools and wet-lab experimentation are essential to design biodegradable chemicals early in the active ingredient discovery and selection process.

[Display omitted] Solubility is a critical parameter in drug formulation to achieve the desired therapeutical concentration. Most drugs are weak acids or bases and, therefore, exhibit low solubility and poor oral availability. The main aim of this work is the use of Deep Eutectic Systems (DESs) for improving the solubility of drugs in aqueous medium. In this case, we use DESs formed by choline chloride and sugars (xylitol, fructose, glucose and sorbitol) at different proportions of water. These compounds present low toxicity, and thus can be used in syrups or liquid formulations. Different physicochemical properties, such as density, refractive index, and surface tension, were obtained. In addition, a rheological study of the different systems was carried out. Finally, these DESs were applied to analyse the solubility of the following active principles: caffeine (Class I) and furosemide (Class IV) of the Biopharmaceutics Classification System (BCS). The selection of the drugs attends to different reasons. On one hand, we want to develop a new liquid formulation for model drug furosemide and, on the other hand, the study of caffeine, instead, will be used as a model for comparing purposes. Solubility results show that the systems that best solubilize caffeine are those with the highest water content; however, they do not reach the levels of solubility of pure water. On the other hand, for furosemide, a great increase in solubility was observed, especially for systems formed by xylitol and, fundamentally, in the system with the lowest water content. Obtaining an increase in solubility of up to 4530 times. These systems provide an opportunity to improve the formulation of drugs in the liquid medium of active ingredients that are poorly soluble in an aqueous medium. [ABSTRACT FROM AUTHOR]

India's pharmaceutical sector has been one of the largest manufacturers of generic drugs globally. During the pandemic, most countries were dependent on imports of generic drugs from India. However, India has been relying on resources from China for Active Pharmaceutical Ingredients (APIs) which are the raw material for preparing generic drugs. We considered, in our analysis, branded product groups of Paracetamol and Amoxicillin due to their extensive use in the treatment of COVID-19. From a thorough market analysis of both the drugs, we conclude that firms have a monopoly over their brands but compete within the same product group and operate in their respective market under varying prices within certain bandwidths which resembles the feature of monopolistic competitive market. We have introduced compensating function a la Helpman (1981) in the pharmaceutical goods market with the assumption that an 'ideal product' exists among the pharmaceutical goods. Given the framework, this paper explores a general equilibrium model set in a monopolistic competitive product market for branded drugs. We concluded through our propositions that expanding the pharmaceutical sector will increase the employment of unskilled labor under no capacity constraint. We will observe an increase in wages of unskilled labor only under full employment conditions wherein we would observe that the expansion of pharmaceutical good will increase wages in the unskilled labor market. However we obtain an intriguing result wherein we obtain that despite instances of limiting trade dependence on China through implementation of policies like 'Aatmanirbhar Bharat' and 'profit linked incentive schemes', yet to maintain the status quo in the global market for generic drugs, India's dependence on China would increase, owing to API imports due to the pandemic crisis. While India can grab the opportunity in the form of increased demand for pharmaceutical goods to increase the employment level of the economy but this improvement in welfare is also dependent on the degree of dependency of API India has on China. The Indian government has recognized the same through the incorporation of 'Covid-Suraksha' and PLI schemes to minimize import dependency, and accelerate the development of APIs and the production of indigenous drugs. [ABSTRACT FROM AUTHOR]

Many purine derivatives are active pharmaceutical ingredients of significant importance in the therapy of autoimmune diseases, cancers, and viral infections. In many cases, their medical use is limited due to unfavorable physicochemical and pharmacokinetic properties. These problems can be overcome by the preparation of the prodrugs of purines or by combining these compounds with nanoparticles. Herein, we aim to review the scientific progress and perspectives for polymer-based nanoparticles as drug delivery systems for purines. Polymeric nanoparticles turned out to have the potential to augment antiviral and antiproliferative effects of purine derivatives by specific binding to receptors (ASGR1—liver, macrophage mannose receptor), increase in drug retention (in eye, intestines, and vagina), and permeation (intranasal to brain delivery, PEPT1 transport of acyclovir). The most significant achievements of polymer-based nanoparticles as drug delivery systems for purines were found for tenofovir disoproxil in protection against HIV, for acyclovir against HSV, for 6-mercaptopurine in prolongation of mice ALL model life, as well as for 6-thioguanine for increased efficacy of adoptively transferred T cells. Moreover, nanocarriers were able to diminish the toxic effects of acyclovir, didanosine, cladribine, tenofovir, 6-mercaptopurine, and 6-thioguanine. [ABSTRACT FROM AUTHOR]

The rising trend towards continuous production in the field of small-scale crystallization has generated many creative concepts for apparatuses for the production of active pharmaceutical ingredients. One of these promising apparatuses is the Slug Flow Crystallizer (SFC), which enables the adjustment of the particle size distribution and the achievement of high yields through its alternating slug flow. To realize and understand the crystallization inside the SFC, high experimental effort has been necessary until now. Therefore, a mechanistic model considering the hydrodynamics of slug flow, the energy and mass balances, and the crystallization phenomena of growth and agglomeration inside the apparatus was developed. Its purpose is to improve the understanding of the process, estimate the effects of operating parameters on target properties, and predict crystallization behavior for different substance systems with minimal experimental effort. Successful modeling was validated with experimental results for the substance system l-alanine/water. Furthermore, the robustness of the model was evaluated, and guidelines were presented, enabling the transfer of the model to new substance systems. [ABSTRACT FROM AUTHOR]

The interest in buccal drug delivery is under consideration due to some distinct properties compared to the traditional pharmaceutical formulations for oral administration: significantly higher bioavailability, a faster absorption rate of the drug, and substantial compliance for special needs patients. Oral films are obtained through various technologies, from conventional tools to 3D and 4D printing approaches. This minireview aims to describe the current additive manufacturing technologies in oral film fabrication, display their advantages and limitations, and discuss various formulation strategies. It also provides advanced data regarding synthetic and natural polymers used in 3D printing technologies for oral films. Moreover, it shows the most recent studies with 3D-printed orodispersible films and mucoadhesive buccal films manufactured through previously analyzed methods. Finally, conclusions and future perspectives are also briefly summarized. [ABSTRACT FROM AUTHOR]

The major issue with active pharmaceutical ingredients (APIs) is their slow dissolution rate and solubility. This makes them less likely to get into the body and less bioavailable. About 40 % of the drugs already on the market and 90 % being made have APIs that do not dissolve well in water. To deal with this problem, authors have designed eutectic mixture (EMs) of different drugs (danazol, griseofulvin, mefenamic acid, tolfenamic acid and tadalafil) with zinc chloride; studied their interaction and thermodynamic parameters using Density Functional Theory (DFT) computation. DFT calculations confirm an increase in the dipole moment of their EMs in comparison of APIs alone which increases the solubility. The change in Gibbs free energy of formation of EMs in the gaseous phase shows their feasibility ans stability. [ABSTRACT FROM AUTHOR]

Forced degradation studies have been used to simplify analytical methodology development and achieve a deeper knowledge about the inherent stability of active pharmaceutical ingredients (API) and drug products. This provides insight into degradation species and pathways. Identification of impurities in pharmaceutical products is closely related to the selection of the most appropriate analytical methods like HPLC-UV, LC-MS/MS, LC-NMR, GC-MS, and capillary electrophoresis. Herein, recent trends in analytical perspectives during 2018–April 14, 2021, are discussed based on forced and impurity degradation profiling of pharmaceuticals. Literature review showed that several methods have been used for experimental design and analysis conditions such as matrix type, column type, mobile phase, elution modes, detection wavelengths, and therapeutic category. Thus, since these factors influence the separation and identification of the impurities and degradation products, we attempted to perform a statistical analysis for the developed methods according to the abovementioned factors. [ABSTRACT FROM AUTHOR]

Levocetirizine is an orally administrated, second‐generation antihistaminic active pharmaceutical ingredient that has been used to treat symptoms of allergy and long‐term hives for over 25 years. Despite the wide use of this compound, its crystal structure has remained unknown. Here we report the application of 3D electron diffraction (3D ED)/Micro‐crystal electron diffraction (MicroED) to determine the crystal structure of Levocetirizine dihydrochloride directly from crystalline powders that were extracted from commercially available tablets containing the compound. We also showcase the utility of dynamical refinement to unambiguously assign absolute configuration. The results highlight the immense potential of 3D ED/MicroED for structure elucidation of components of microcrystalline mixtures that obviates the need to grow large‐size single crystals and the use of complementary analytical techniques, which could be important for identification as well as for primary structural characterization. [ABSTRACT FROM AUTHOR]

Caged phosphines have unique structures and provide many advantageous properties that can be fine-tuned to develop efficient catalytic systems. Our research group recently introduced a highly water-soluble caged phosphine: PTABS (KapdiPhos), which is a derivatized form of triazaphosphaadamantane, and explored its applicability as a strongly π-accepting ligand in combination with metals such as Pd or Cu in a variety of cross-coupling reactions of biologically relevant halonucleosides as well as chloroheteroarenes. This account details our journey from ideation to the various catalytic applications of the ligands and eventually to its commercialization. 1 Introduction 2 Derivatization of PTA to PTABS and Its Applications 2.1 Nucleoside Modification 2.2 Heteroarene Modification 3 Conclusion 4 Summary and Future Outlook [ABSTRACT FROM AUTHOR]

Due to the growing importance of synthesizing active pharmaceutical ingredients (APIs) in enantiomerically pure form, new methods of asymmetric synthesis are being sought. Biocatalysis is a promising technique that can lead to enantiomerically pure products. In this study, lipase from Pseudomonas fluorescens, immobilized on modified silica nanoparticles, was used for the kinetic resolution (via transesterification) of a racemic mixture of 3-hydroxy-3-phenylpropanonitrile (3H3P), where the obtaining of a pure (S)-enantiomer of 3H3P is a crucial step in the fluoxetine synthesis pathway. For additional stabilization of the enzyme and enhanced process efficiency, ionic liquids (ILs) were used. It was found that the most suitable IL was [BMIM]Cl; a process efficiency of 97.4 % and an enantiomeric excess (ee%) of 79.5 % were obtained when 1 % (w/v) of that IL in hexane was applied and the process was catalyzed by lipase immobilized on amine-modified silica.

The fast development of diagnostic and therapeutic radionuclide technologies requires enhanced legislative regulation of radiopharmaceuticals. The article addresses the challenge of classifying radiopharmaceuticals depending on the manufacturing technology, radionuclide properties, and clinical use. The review covers the current legislative and regulatory requirements for radiopharmaceutical medicinal products. It also describes the trends in radiopharmaceutical regulation development in Russia and the Eurasian Economic Union, taking into account the corresponding legislative frameworks.

The search for alternative and effective therapies to fight cancer is one of the main goals of the pharmaceutical industry. Recently, ionic liquids (ILs) have emerged as potential therapeutic agents with antitumor properties. The goal of this study was to synthesize and evaluate the bioactivity of different ILs coupled with the active pharmaceutical ingredient (API) valproate (VPA) as an antitumor agent. The toxicity of the prepared ionic liquids was evaluated by the MTT cell metabolic assay in human neuroblastoma SH-SY5Y and human primary Gingival Fibroblast (GF) cell lines, in which they showed inhibitory effects during the study period. In addition, low cytotoxicity against GF cell lines was observed, suggesting that these compounds are not toxic to human cell lines. [C2OHDMiM][VPA] demonstrated an outstanding antitumor activity against SH-SY5Y and lower activity against the non-neoplastic GF line. The herein assessed compounds played an important role in the modulation of the signaling pathways involved in the cellular behavior. This work also highlights the potential of these ILs-API as possible antitumor agents.

[Display omitted] • The permeability of drugs was investigated in the presence of a rotating magnetic field (RMF). • The RMF may increase the permeability of active pharmaceutical ingredients (APIs). • The enhancement of API permeation through the skin in the presence of RMF depends on the type of API used (variable diffusion profiles). The paper presents a method of increasing the permeability of various active substances through the skin by means of a rotating magnetic field. The study used 50 Hz RMF and various active pharmaceutical ingredients (APIs) such as caffeine, ibuprofen, naproxen, ketoprofen, and paracetamol. Various concentrations of active substance solutions in ethanol were used in the research, corresponding to those in commercial preparations. Each experiment was conducted for 24 h. It was shown that, regardless of the active compound used, an increase in drug transport through the skin was observed with RMF exposure. Furthermore, the release profiles depended on the active substance used. Exposure to a rotating magnetic field has been shown to effectively increase the permeability of an active substance through the skin. [ABSTRACT FROM AUTHOR]

Enzymes such as lipases and proteases have been used as catalysts in nearly anhydrous organic solvents such as diisopropyl ether and hexane to carry out stereospecific and selective enzymatic resolutions of carboxylic acid derivatives such as 2-bromohexadecanoic acid, which may be used for prevention and treatment of bone loss-related diseases and ß-phenyllactic acid, which has a role as a human metabolite. [ABSTRACT FROM AUTHOR]

In this work, the solid–liquid equilibrium (SLE) of four binary systems combining two active pharmaceutical ingredients (APIs) capable of forming co-amorphous systems (CAMs) was investigated. The binary systems studied were naproxen-indomethacin, naproxen-ibuprofen, naproxen-probucol, and indomethacin-paracetamol. The SLE was experimentally determined by differential scanning calorimetry. The thermograms obtained revealed that all binary mixtures investigated form eutectic systems. Melting of the initial binary crystalline mixtures and subsequent quenching lead to the formation of CAM for all binary systems and most of the compositions studied. The experimentally obtained liquidus and eutectic temperatures were compared to theoretical predictions using the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state and conductor-like screening model for real solvents (COSMO-RS), as implemented in the Amsterdam Modeling Suite (COSMO-RS-AMS). On the basis of the obtained results, the ability of these models to predict the phase diagrams for the investigated API–API binary systems was evaluated. Furthermore, the glass transition temperature (Tg) of naproxen (NAP), a compound with a high tendency to recrystallize, whose literature values are considerably scattered, was newly determined by measuring and modeling the Tg values of binary mixtures in which amorphous NAP was stabilized. Based on this analysis, erroneous literature values were identified. [ABSTRACT FROM AUTHOR]

Asymmetric oxidation processes have constituted a valuable tool for the synthesis of active pharmaceutical ingredients (APIs), especially for the preparation of optically active sulfoxides, compounds with interesting biological properties. Classical approaches for these oxidative procedures usually require the application of non-sustainable conditions that employ hazardous reagents and solvents. In the last decades, chemists have tried to combine the preparation of valuable compounds of high yields and selectivities with the development of more sustainable protocols. To achieve this objective, greener solvents, reagents, and catalysts are employed, together with the use of novel chemical techniques such as flow catalysis or photocatalysis. The last efforts in the development of greener approaches for the preparation of APIs and their intermediates using oxidative procedure will be reviewed herein. Most of these approaches refer to biocatalytic methods, in which mild reaction conditions and reagents are employed, but other novel techniques such as photocatalysis will be described. [ABSTRACT FROM AUTHOR]

The nature and strength of interactions for an anti-HIV drug, Lamivudine, were studied in a pure crystal form of the drug and the ligand–receptor complexes. High-resolution single-crystal X-ray diffraction studies of the tetragonal polymorph allowed the drug's experimental charge density distribution in the solid state to be obtained. The QM/MM calculations were performed for a simplified model of the Lamivudine complex with deoxycytidine kinase (two complexes with different binding modes) to reconstruct the theoretical charge density distribution. The peculiarities of intramolecular interactions were compared with previously reported data for an isolated molecule. Intermolecular interactions were revealed within the quantum theory of 'Atoms in Molecules', and their contributions to the total crystal energy or ligand–receptor binding energy were evaluated. It was demonstrated that the crystal field effect weakened the intramolecular interactions. Overall, the energies of intermolecular interactions in ligand–receptor complexes (320.1–394.8 kJ/mol) were higher than the energies of interactions in the crystal (276.9 kJ/mol) due to the larger number of hydrophilic interactions. In contrast, the sum of the energies of hydrophobic interactions was found to be unchanged. It was demonstrated by means of the Voronoi tessellation that molecular volume remained constant for different molecular conformations (250(13) Å3) and increased up to 399 Å3 and 521(30) Å3 for the Lamivudine phosphate and triphosphate. [ABSTRACT FROM AUTHOR]

This mini-review focuses on the various roles that ionic liquids (ILs) play in the development and applications of biopolymer-based drug delivery systems (DDSs). Biopolymers are particularly attractive as drug delivery matrices due to their biocompatibility, low immunogenicity, biodegradability, and strength, whereas ILs can assist the formation of drug delivery systems. In this work, we showcase the different strategies that were explored using ILs in biopolymer-based DDSs, including impregnation of active pharmaceutical ingredients (APIs)-ILs into biopolymeric materials, employment of the ILs to simplify the process of making the biopolymer-based DDSs, and using the ILs either as dopants or as anchoring agents. [ABSTRACT FROM AUTHOR]