Certificate of Analysis
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A CoA is a document issued by a companies’ QA/QC-department that confirms that a product meets its product specification and is part of the quality control of a product batch. The CoA commonly contains results obtained from laboratory tests of an individual batch of a product. There are different international standards to which a product can be tested, for example: Ph. Eur. | EP – (European Pharmacopoeia) USP – (United States Pharmacopeia)
Food & Drug Administration approved
The Food and Drug Administration is a federal agency of the United States Department of Health and Human Services, one of the United States federal executive departments. FDA is important because it is intended to have companies produce their goods to certain standards and it presents this fact in a clear overview using FDA certificates. When a company is (US) FDA approved, it shows the American government has declared the API or medicine as safe and it can be sold, imported, or used in the United States. The USA is not the only country with a regulatory agency like FDA. Most other countries have agencies that are responsible for the national safety of pharmaceutical products. Some different kinds of organizations include:
EMA (European Medicines Agency, European Union)
MHRA (Medicines and Healthcare products Regulatory Agency, United Kingdom)
PMDA (Pharmaceuticals and Medical Devices Agency, Japan)
CDSCO (Central Drugs Standard Control Organization, India)
Alkylating agents are a vital subcategory of pharmaceutical active pharmaceutical ingredients (APIs) that play a significant role in cancer treatment. These compounds possess the ability to attach alkyl groups to the DNA molecule, effectively disrupting its structure and preventing cell replication. This mechanism of action makes alkylating agents potent chemotherapy drugs for various types of cancers.
Alkylating agents are often classified based on their chemical structure, which includes nitrogen mustards, ethylenimines, nitrosoureas, and alkyl sulfonates, among others. Each subclass exhibits unique chemical properties and therapeutic applications. For instance, nitrogen mustards like cyclophosphamide and mechlorethamine are used to treat lymphomas and leukemia, while nitrosoureas such as carmustine and lomustine are effective against brain tumors.
The alkylating agents' mode of action involves the transfer of alkyl groups to cellular components, primarily DNA. This leads to the formation of DNA adducts, cross-links, and DNA strand breaks, ultimately hindering DNA replication and causing cell death. The indiscriminate nature of alkylating agents can also affect healthy cells, leading to various side effects such as bone marrow suppression and gastrointestinal disturbances.
Despite their potential side effects, alkylating agents remain valuable tools in cancer therapy due to their broad spectrum of activity against different types of tumors. Ongoing research focuses on developing more selective and targeted alkylating agents to improve their therapeutic index and minimize adverse effects. The use of alkylating agents in combination with other chemotherapy drugs or radiation therapy is also being explored to enhance treatment outcomes and reduce drug resistance.
In conclusion, alkylating agents are an essential subclass of pharmaceutical APIs widely employed in cancer treatment. Their ability to disrupt DNA structure and impede cell replication makes them effective against various types of tumors, although careful management of side effects is necessary. Ongoing advancements and research continue to refine their therapeutic potential in the fight against cancer.
Anticancer drugs belong to the pharmaceutical API (Active Pharmaceutical Ingredient) category designed specifically to combat cancer cells. These powerful medications play a crucial role in cancer treatment and are developed to target and destroy cancerous cells, preventing their growth and spread.
Anticancer drugs are classified based on their mode of action and can include various types such as chemotherapy drugs, targeted therapy drugs, immunotherapy drugs, and hormonal therapy drugs. Chemotherapy drugs work by interfering with the cell division process, thereby inhibiting the growth of cancer cells. Targeted therapy drugs, on the other hand, are designed to attack specific molecules or genes involved in cancer growth, minimizing damage to healthy cells. Immunotherapy drugs stimulate the body's immune system to recognize and destroy cancer cells. Hormonal therapy drugs are used in cancers that are hormone-dependent, such as breast or prostate cancer, to block the hormones that fuel cancer cell growth.
These APIs are typically synthesized through complex chemical processes in state-of-the-art manufacturing facilities. Stringent quality control measures ensure the purity, potency, and safety of these drugs. Anticancer APIs undergo rigorous testing and adhere to stringent regulatory guidelines before being approved for clinical use.
Due to their critical role in cancer treatment, anticancer drugs are in high demand worldwide. Researchers and pharmaceutical companies continually strive to develop new and more effective APIs in this category to enhance treatment outcomes and minimize side effects. The ongoing advancements in the field of anticancer drug development offer hope for improved cancer therapies and better patient outcomes.
For the past decade, research in our group has focused on the continuous generation of hazardous reagents using a range of reactor designs and experimental techniques, particularly toward the synthesis of APIs. In this Account, we therefore introduce chemical generator concepts that have been developed in our laboratories for the production of toxic, explosive, and short-lived reagents. We have defined three different classes of generators depending on the reactivity/stability of the reagents, featuring reagents such as Br 2 , HCN, peracids, diazomethane (CH 2 N 2 ), or hydrazoic acid (HN 3 ). The various reactor designs, including in-line membrane separation techniques and real-time process analytical technologies for the generation, purification, and monitoring of those hazardous reagents, and also their downstream transformations are presented. This Account should serve as food for thought to extend the scope of chemical generators for accomplishing more efficient and more economic processes.
In addition to conditions that are outside of the operation range of conventional stirred tank reactors, reagents possessing a high hazard potential and therefore not amenable to batch processing can be safely utilized (forbidden chemistry). Because of the small reactor volumes, risks in case of a failure are minimized. Such hazardous reagents often are low molecular weight compounds, leading generally to the most atom-, time-, and cost-efficient route toward the desired product. Ideally, they are generated from benign, readily available and cheap precursors within the closed environment of the flow reactor on-site on-demand. By doing so, the transport, storage, and handling of those compounds, which impose a certain safety risk especially on a large scale, are circumvented. This strategy also positively impacts the global supply chain dependency, which can be a severe issue, particularly in times of stricter safety regulations or an epidemic. The concept of the in situ production of a hazardous material is generally referred to as the “generator” of the material. Importantly, in an integrated flow process, multiple modules can be assembled consecutively, allowing not only an in-line purification/separation and quenching of the reagent, but also its downstream conversion to a nonhazardous product.
In recent years, a steadily growing number of chemists, from both academia and industry, have dedicated their research to the development of continuous flow processes performed in milli- or microreactors. The common availability of continuous flow equipment at virtually all scales and affordable cost has additionally impacted this trend. Furthermore, regulatory agencies such as the United States Food and Drug Administration actively encourage continuous manufacturing of active pharmaceutical ingredients (APIs) with the vision of quality and productivity improvements. That is why the pharmaceutical industry is progressively implementing continuous flow technologies. As a result of the exceptional characteristics of continuous flow reactors such as small reactor volumes and remarkably fast heat and mass transfer, process conditions which need to be avoided in conventional batch syntheses can be safely employed. Thus, continuous operation is particularly advantageous for reactions at high temperatures/pressures (novel process windows) and for ultrafast, exothermic reactions (flash chemistry).
For the past 10 years, a significant portion of our group’s research has been directed toward the generation of hazardous and/or unstable reagents in continuous flow environments, many times in extreme temperature and pressure regimes. As safety is one of the main drivers to implement continuous processes, in particular in the pharmaceutical industry, hazardous but more atom- and cost-economic routes are increasingly incorporated into the synthesis. Therefore, continuously broadening the chemical generator scope is of paramount importance. In this Account, numerous contributions to this field are highlighted with an emphasis on chemical generator concepts that were developed within the past decade in our group for continuous on-site on-demand production of toxic, explosive, and short-lived reagents. For further hazardous chemistries performed in continuous flow environments, several other review articles are recommended. 4
To overcome the transport, storage, and handling predicament of hazardous reagents, they are best produced in situ from benign precursors, on-site and on-demand whenever they are needed and in volumes that match the demand. 3 The risk is further reduced through real-time use of the dangerous chemical by an immediate transformation into a nonhazardous product directly upon its generation. The safest way to do so is their synthesis by continuous flow processes in small-structured reactors (e.g. microreactors). 4 This concept of continuous in situ production of hazardous materials is commonly referred to as the “generator” of this material. 5 The defining characteristic of these flow reactors is their comparatively small reactor volume which minimizes the severity in case of an accident because less material and energy is released. In addition, head space issues are eliminated, and an extraordinary heat and mass transport is achieved. As a result, hazardous reagents and process conditions can be safely employed which otherwise would be difficult, if not impossible, to implement in a traditional batch setup. Continuous processing therefore opens up the toolbox of “forbidden chemistries” to be safely carried out. 4
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In addition, the high dependency on the global supply chain, changing market situation, and quality of the shipped material has a significant impact on the end-user. This vulnerability becomes even more severe nowadays because authorities in low-cost countries increasingly tighten environmental and safety controls on raw material manufacturers. 2 The prospect of keeping the supply chain short is therefore of major interest to the chemical industry. By eliminating bottlenecks in the supply chain, the agility of production is increased, and a rapid response to a changing market is facilitated.
The concern toward the utilization of hazardous materials is not only related to their handling by the operator but also to their transportation and on-site storage, in particular on a large scale. Indeed, many potentially powerful reagents are imposed with stringent transport, storage, and preventive maintenance restrictions or are even not amenable to be transported or stored due to their instability and/or toxicity. The transportation of dangerous goods is strictly controlled and governed through national and international regulations. 1 Each mode of transport has its own set of regulations, which vary considerably from one country to another and are revised continuously. 1
The most direct, atom-economic, and sustainable synthetic routes frequently require the use of highly reactive, often toxic and short-lived reagents. Despite their advantages, many of such hazardous reagents are banned from laboratories in both industry and academia in a conventional chemical environment, and alternative routes employing easier to handle materials are chosen instead. However, this strategy is unattractive with respect to scale-up because it generally proves to be more laborious, generates more waste material, and is thus neither cost nor environmentally effective.
Classical chemical generators for the continuous production of simple, reactive molecules such as F2, O2, O3, or H2 have been in use for decades. Most of them operate via electrolysis and are commercially available. However, with the growing interest in continuous flow operations by the pharmaceutical industry for active pharmaceutical ingredient (API) manufacturing and the accompanied demand to access new process windows,6 custom-built generators for explosive, toxic, and short-lived reagents are constantly being developed. Both the now common access to flow equipment and technological advances in this field led to the emergence of a new generation of chemical generators. depicts the general concept for such generators for the on-site on-demand production of hazardous reagents. They are generated from nontoxic, readily accessible and ideally low-cost precursors and, if necessary, purified in-line to produce a continuous stream of the reagent, which is then further consumed by an appropriate substrate in a downstream reaction in a fully contained fashion. Before product collection, an in-line quench to destroy any remaining hazardous material can be incorporated.
Additionally, by integrating process analytical technologies (PAT), real-time data can be acquired for process monitoring and process control for ensuring product quality.7 Rapid in-line reaction analysis is of particular importance when working with highly hazardous material, transient intermediates, or high temperature/pressure systems, because standard off-line sampling techniques are highly undesirable. In-line PAT tools such as NMR, UV/vis, or IR are particularly easy to implement into continuous flow reactors.8 Furthermore, process control systems can be employed to automate the process.9
A reagent produced in a chemical generator often needs in-line purification to remove undesired byproducts and to transfer it into a solvent suitable for subsequent downstream transformations. One of the most powerful purification methods relies on the use of membranes for the separation of a desired reagent or intermediate.10 Two membrane-based separation techniques have been used to conquer the field of continuous flow synthesis: liquid–liquid and gas–liquid separators. The liquid–liquid separation technique depends on the exploitation of surface forces and the difference in wetting properties of the liquids onto a porous membrane.11 This concept is typically applied when the reagent is generated within an aqueous environment. After extraction into a suitable organic solvent, membrane separation takes place: the organic or “wetting” phase passes through the hydrophobic membrane, while the aqueous phase is retained. On the other hand, the gas–liquid separation takes advantage of the selective permeability of the membrane for hydrophobic low molecular weight compounds in gaseous form. The most commonly employed semipermeable membrane for the separation and purification of hazardous reagents is the gas-permeable Teflon AF-2400 membrane, which is housed inside the so-called tube-in-tube reactor.12 In this device, the gaseous reagent is generated inside the inner AF-2400 tubing and then diffuses through this membrane and instantly reacts with the substrate that is carried within the outer gas impermeable tubing.
Pursuant to our definition, a modern chemical generator should guarantee the most atom- and cost-effective route toward the desired end-product. Therefore, the hazardous material has to be a simple, low molecular weight and versatile compound and be produced from inexpensive, benign precursors. Where necessary, the reagent can be purified/separated in-line prior to the downstream transformation. We categorize these generators according to reagent stability into three classes: generators for (1) stable reagents, (2) reagents with limited stability, and (3) unstable reagents ( ). All three classes are discussed in this Account ( ).
This type of reagents is too unstable to be transported or stored in their pure form. Therefore, to minimize the hazard of exothermic decomposition and in further consequence violent explosion, they often are delivered in diluted form. The shipping is restricted, and based on the concentration, various safety measures apply.
Peracids are strong oxidizing reagents used for epoxidations, hydroxylations, and the Baeyer–Villiger oxidation. They are also very unstable and, depending on the concentration, prone to explosive decompositions. Performic acid (HCO3H) in concentrations >50% is highly reactive: it readily decomposes upon heating and explodes when rapidly heated to 80–85 °C; at room temperature, it may ignite or explode when combined with flammable substances. In view of our group’s interest in the synthesis of opioid-derived APIs,27 a telescoped continuous process toward a noroxymorphone precursor (4) was established that comprised the C14 hydroxylation of naturally occurring oripavine (2) employing HCO3H as the key step.28 Performic acid was generated in situ from formic acid (HCO2H) and 30% aqueous hydrogen peroxide (H2O2) which then rapidly oxidized the diene moiety of oripavine at 100 °C to provide 14-hydroxymorphinone (3) and the corresponding N-oxide (Scheme 8). A subsequent continuous solvent switch, hydrogenation in a packed-bed hydrogenator, and palladium catalyzed N-methyl oxidation furnished 1,3-oxazolidine derivative 4.
Open in a separate windowSimilar continuous flow approaches for generating peracids in situ were also reported by Kolehmainen and coworkers29 and Siegfried Ltd.30
Lithium diisopropylamide (LDA) is pyrophoric as a solid, but its solutions are generally not; therefore, it is commercially typically available as a solution in THF/hexanes. However, because LDA solutions are known to be unstable upon prolonged storage, it is generally prepared in situ from diisopropylamine and n-butyl lithium (n-BuLi). To control the exotherm produced during the LDA generation and enable its safe production on larger scale, several research groups have developed continuous flow strategies.31 We described a multistep protocol where in situ generated LDA is immediately consumed by an ester to form the corresponding highly reactive lithium enolate intermediate 5 (Scheme 9).32 The process is then integrated with an electrophilic addition step and an in-line water quench to furnish the α-functionalized esters 6. Because of the enhanced mass transfer, higher temperatures compared to batch (0 vs −78 °C) can be applied for both LDA and enolate generation.
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