Synthesis Of Active Pharmaceutical Ingredients Research Articles

Anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients.

A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.

A More Sustainable Process for Preparation of the Muscarinic Acetylcholine Antagonist Umeclidinium Bromide.

A more sustainable process for the synthesis of the long-acting muscarinic acetylcholine antagonist umeclidinium bromide is described. Specifically, we report the synthesis of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate, a key intermediate in the preparation of umeclidinium bromide, in good yields using triethylamine, as well as the identification and characterization of the by-product formed in this reaction. This new method of synthesis leads to an improvement in yield over that of previously reported protocols using potassium carbonate as base (65.6 % versus 38.6 %). Moreover, in the final synthetic step of the process to obtain umeclidinium bromide, we were able to replace the use of toxic solvents (acetonitrile/chloroform) with water. The use of this green solvent allowed precipitation of the active pharmaceutical ingredient (API) from the reaction medium with high purity and in high yield. Overall, we have developed a more efficient and environmentally friendly process for the synthesis of the umeclidinium bromide API with a higher overall yield (37.8 % versus previously reported overall yield of 9.7 %).

Waste generation, product yield evaluation and exergy analysis during bisphosphonate synthesis and medical drug production processes

Abstract Introduction of the waste of the pharmaceutical industry to the biosphere creates unusual potential disease patterns. Achieving the active pharmaceutical ingredient (API) production by utilizing the minimum energy and generating as little waste as possible are among the reasonable cleaner production practices. Zoledronic acid is the API of some bone-disease drugs. It is synthesized via the reaction of 1h-imidazole-1-yl- acetic acid hydrochloride with phosphorous acid and phosphorous halogen at moderate temperatures. The product is later separated by crystallization in water. Since the concentration of API is very low in the finished product, generally 50 g of API satisfies the annual market demand. Chemical processes are generally investigated to determine the most convenient production procedures and equipment. In the studies performed in small scale set up, it is important to foresee an upscale design. Exergy utilization is among the considerations in process design and there is almost no information available in the literature yet, regarding the exergy analysis of the production processes of pharmaceuticals. “Cradle to grave” exergy analyses, beginning with the raw materials and ending with retail packaging of a pharmaceutical product is studied here by referring to bisphosphonate production. Although the synthesis stage of this study refers to the production of a single API, the packaging stage of the process refers to the entire pharmaceutical industry, where similar practices are employed. During the chemical synthesis of zoledronic acid under GMP (good manufacturing practice) conditions, the most energy consuming step was found to be crystallization. On the other hand, the most energy consuming step during sterile finished product manufacturing was filling, followed by sterilization of the primary packaging equipment and the materials, and the operation of the HVAC system. The initial cumulative degree of perfection (CDP) was calculated to be 1.47 × 10−2% for the API synthesis, however exergy efficiency of the synthesis process to 2.29 × 10−2% with increasing the yield through process optimization. The CDP of the finished product was 17% and 75% before and after packaging of the finished product, respectively. Synthesis at the maximum attainable conversion ratio and the highest exergy efficiency assures minimum waste generation.

Opportunity in the turmoil

“When I worked at Cambrex, I learned that generics are kind of boring,” says Kenneth Drew, senior director of North American sales and business development at Flamma, an Italian manufacturer of active pharmaceutical ingredients (APIs). Drew began his sales career at Cambrex in 2007, moving to Flamma in 2010. “All people wanted to talk about was price,” he says. The sector was defined by an all-too-familiar and simple strategy, Drew recalls, whereby generic drug companies knocked each other out by selling cut-rate commodity versions of what often had been billion-dollar branded drugs. Competition in the generics market, he says, had the brutal qualities of an arms race. Today, things are changing. Flamma and Cambrex, pharmaceutical service firms that emphasize the exclusive synthesis of APIs for customers developing branded drugs, now see an opening to grow their generics operations by putting special expertise in chemistry to work. With the traditional commodity-generics

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry.

Within the “compartmentalised smart factory” approach of the ONE-FLOW project the implementation of different catalysts in “compartments” provided by Pickering emulsions and their application in continuous flow is targeted. We present here the development of heterogeneous Pd catalysts that are ready to be used in combination with biocatalysts for catalytic cascade synthesis of active pharmaceutical ingredients (APIs). In particular, we focus on the application of the catalytic systems for Suzuki–Miyaura cross-coupling reactions, which is the key step in the synthesis of the targeted APIs valsartan and sacubitril. An immobilised enzyme will accomplish the final product formation via hydrolysis. In order to create a large interfacial area for the catalytic reactions and to keep the reagents separated until required, the catalyst particles are used to stabilise Pickering emulsions of oil and water. A set of Ce–Sn–Pd oxides with the molecular formula Ce0.99−xSnxPd0.01O2−δ (x = 0–0.99) has been prepared utilising a simple single-step solution combustion method. The high applicability of the catalysts for different functional groups and their minimal leaching behaviour is demonstrated with various Suzuki–Miyaura cross-coupling reactions in batch as well as in continuous flow employing the so-called “plug & play reactor”. Finally, we demonstrate the use of these particles as the sole emulsifier of oil–water emulsions for a range of oils.

2‐Hydroxypyridine‐N‐oxide (HOPO): Equivocal in the ames assay

2-Hydroxypyridine-N-oxide (HOPO) is a useful coupling reagent for synthesis of active pharmaceutical ingredients. It has been reported to be weakly mutagenic in the Ames assay (Ding W et al. []: J Chromatogr A 1386:47-52). According to the ICH M7 guidance (2014) regarding control of mutagenic impurities to limit potential carcinogenic risk, mutagens require control in drug substances such that exposure not exceeds the threshold of toxicological concern. Given the weak response observed in the Ames assay and the lack of any obvious structural features that could confer DNA reactivity we were interested to determine if the results were reproducible and investigate the role of potentially confounding experimental parameters. Specifically, Ames tests were conducted to assess the influence of compound purity, solvent choice, dose spacing, toxicity, type of S9 (aroclor vs phenobarbital/β-napthoflavone), and lot variability on the frequency of HOPO induced revertant colonies. Initial extensive testing using one lot of HOPO produced no evidence of mutagenic potential in the Ames assays. Subsequent studies with four additional lots produced conflicting results, with an ∼2.0-fold increase in revertant colonies observed. Given the rigor of the current investigation, lack of reproducibility between lots, and the weak increase in revertants, it is concluded that HOPO is equivocal in the bacterial reverse mutation assay. It is highly unlikely that HOPO poses a mutagenic risk in vivo; therefore, when it is used as a reagent in pharmaceutical synthesis, it should not be regarded as a mutagenic impurity, but rather a normal process related impurity. Environ. Mol. Mutagen. 59:312-321, 2018. © 2018 Wiley Periodicals, Inc.

Continuous flow biocatalysis.

The continuous flow synthesis of active pharmaceutical ingredients, value-added chemicals, and materials has grown tremendously over the past ten years. This revolution in chemical manufacturing has resulted from innovations in both new methodology and technology. This field, however, has been predominantly focused on synthetic organic chemistry, and the use of biocatalysts in continuous flow systems is only now becoming popular. Although immobilized enzymes and whole cells in batch systems are common, their continuous flow counterparts have grown rapidly over the past two years. With continuous flow systems offering improved mixing, mass transfer, thermal control, pressurized processing, decreased variation, automation, process analytical technology, and in-line purification, the combination of biocatalysis and flow chemistry opens powerful new process windows. This Review explores continuous flow biocatalysts with emphasis on new technology, enzymes, whole cells, co-factor recycling, and immobilization methods for the synthesis of pharmaceuticals, value-added chemicals, and materials.

Asymmetric Amination of α‐Chiral Aliphatic Aldehydes via Dynamic Kinetic Resolution to Access Stereocomplementary Brivaracetam and Pregabalin Precursors

AbstractOver the last decades biocatalysis has emerged as an indispensable and versatile tool for the asymmetric synthesis of active pharmaceutical ingredients (APIs). In this context, especially transaminases (TAs) have been successfully used for the preparation of numerous α‐chiral, optically pure amines, serving as important building blocks for APIs. Here we elaborate on the development of transaminases recognizing the α‐chiral centre adjacent to an aldehyde moiety with aliphatic residues, opening up concepts for novel synthetic routes to the antiepileptic drugs Brivaracetam and Pregabalin. The transformation proceeded via dynamic kinetic resolution (DKR) based on the bio‐induced racemisation of the aldehyde enantiomers, enabling the amination of the racemic substrates with quantitative conversions. Medium, substrate as well as enzyme engineering gave access to both (R)‐ and (S)‐enantiomers of the amine precursors of the stereocomplementary drugs in high optical purity, representing a short route to mentioned APIs.magnified image

The Application of a Continuous Grignard Reaction in the Preparation of Fluconazole

The application of continuous methods in the synthesis of active pharmaceutical ingredients continues to receive significant attention in the academic as well as the industrial research communities. One of the major advantages of continuous methods is the ability to safely access kinetic synthons as well as highly reactive reagents that are typically unavailable through traditional batch methods. In this work, we report the high‐yielding, clean formation of an aryl‐turbo Grignard and its selective addition to a highly‐enolizable 1,3‐dichloroacetone, for the continuous synthesis of a key intermediate for fluconazole, a widely‐prescribed anti‐fungal agent. In addition, process optimization of the final API was also carried out to arrive at a semi‐continuous method to this essential medicine.

Nippon Shokubai invests in APIs

Nippon Shokubai is entering the business of producing active pharmaceutical ingredients (APIs) for peptide and nucleic acid drugs. The company will build a plant in Suita, Japan, where it opened an API synthesis lab last year. The facility will be able to produce APIs in quantities ranging from milligrams to kilograms. Nippon Shokubai, best known as the world’s largest producer of superabsorbent polymers used in diapers and sanitary pads, has a strategy to expand in the medical field over the next three years.

Main group mechanochemistry.

Over the past decade, mechanochemistry has emerged as a powerful methodology in the search for sustainable alternatives to conventional solvent-based synthetic routes. Mechanochemistry has already been successfully applied to the synthesis of active pharmaceutical ingredients (APIs), organic compounds, metal oxides, coordination compounds and organometallic complexes. In the main group arena, examples of synthetic mechanochemical methodologies, whilst still relatively sporadic, are on the rise. This short review provides an overview of recent advances and achievements in this area that further validate mechanochemistry as a credible alternative to solution-based methods for the synthesis of main group compounds and frameworks.

Role of Biocatalysis in Sustainable Chemistry.

Based on the principles and metrics of green chemistry and sustainable development, biocatalysis is both a green and sustainable technology. This is largely a result of the spectacular advances in molecular biology and biotechnology achieved in the past two decades. Protein engineering has enabled the optimization of existing enzymes and the invention of entirely new biocatalytic reactions that were previously unknown in Nature. It is now eminently feasible to develop enzymatic transformations to fit predefined parameters, resulting in processes that are truly sustainable by design. This approach has successfully been applied, for example, in the industrial synthesis of active pharmaceutical ingredients. In addition to the use of protein engineering, other aspects of biocatalysis engineering, such as substrate, medium, and reactor engineering, can be utilized to improve the efficiency and cost-effectiveness and, hence, the sustainability of biocatalytic reactions. Furthermore, immobilization of an enzyme can improve its stability and enable its reuse multiple times, resulting in better performance and commercial viability. Consequently, biocatalysis is being widely applied in the production of pharmaceuticals and some commodity chemicals. Moreover, its broader application will be further stimulated in the future by the emerging biobased economy.

Power Dissipation and Power Number Correlations for a Retreat-Blade Impeller under Different Baffling Conditions

Glass-lined tanks/reactors provided with a torispherical (dish) bottom and equipped with a retreat-blade impeller (RBI) are commonly used in the industrial syntheses of Active Pharmaceutical Ingredients (APIs). The power, P, dissipated by the RBI in the liquid in the tank is critical to many mixing processes, especially since the power per unit liquid volume, P/V, controls many mixing phenomena. Despite their common industrial use, limited information on P for RBIs and the corresponding nondimensional Power number, Po, is available. Here, P values for an RBI in liquids of very different viscosities at different agitation speeds and for different baffling configurations, i.e., unbaffled, partially baffled (with a single “beavertail” baffle), and fully baffled (four rectangular baffles), were measured experimentally in a scaled-down version of a typical reactor for API synthesis. The corresponding Po values were obtained for a large range of the Reynolds number, Re (1 < Re < 400,000). Po was found to vary s...

Biocatalytic resolution of (R,S)-styrene oxide using a novel epoxide hydrolase from red mung beans

Chiral epoxides are commercially important starting materials for synthesis of active pharmaceutical ingredients and agrochemicals. A major challenge in synthetic chemistry is to produce such compounds in high yield with purity. There have been numerous current advances in the field of biotransformation particularly, hydrolytic kinetic resolution of epoxides using newly discovered enzymes (e.g. epoxide hydrolases). Epoxide hydrolase (EH) is a promising biocatalyst for the synthesis, as it enables racemic preparation of various epoxides and/or their corresponding diols in enantiopure form. In present study, partially purified epoxide hydrolase enzyme isolated from red mung beans was used for the first time for enantioselective hydrolysis of (R,S)-styrene oxide to (R)-1-phenyl-1,2-ethanediol. It was found that the optimal reaction temperature, buffer pH, and substrate concentration were 40°C, 7.5 and 20mM, respectively. Under optimized reaction conditions, conversion, Vmax and Km values were ∼44%, 8.2×10−3mol/L/min and 4.5mol/L, respectively.

A systematic reactor design approach for the synthesis of active pharmaceutical ingredients

Today’s highly competitive pharmaceutical industry is in dire need of an accelerated transition from the drug development phase to the drug production phase. At the heart of this transition are chemical reactors that facilitate the synthesis of active pharmaceutical ingredients (APIs) and whose design can affect subsequent processing steps. Inspired by this challenge, we present a model-based approach for systematic reactor design. The proposed concept is based on the elementary process functions (EPF) methodology to select an optimal reactor configuration from existing state-of-the-art reactor types or can possibly lead to the design of novel reactors. As a conceptual study, this work summarizes the essential steps in adapting the EPF approach to optimal reactor design problems in the field of API syntheses. Practically, the nucleophilic aromatic substitution of 2,4-difluoronitrobenzene was analyzed as a case study of pharmaceutical relevance. Here, a small-scale tubular coil reactor with controlled heating was identified as the optimal set-up reducing the residence time by 33% in comparison to literature values.

Development and validation of a general derivatization HPLC method for the trace analysis of acyl chlorides in lipophilic drug substances

Acyl chlorides are important acylating agents in the synthesis of active pharmaceutical ingredients. Determining the residual acyl chlorides in drug substances is a challenge due to their high reactivity and the matrix interferences from drug substances and their related impurities. This paper describes a general derivatization HPLC method for the determination of aromatic and aliphatic acyl chlorides in lipophilic drug substances. Since most drug substances have weak absorptions in the visible range (above 380nm), the nitro-substituted anilines and nitro-substituted phenylhydrazines were selected as the derivatization reagents due to their weak basicity and red-shift of UV absorption spectra. The maximum wavelength and absorption intensity of nitro-substituted anilines decreased after derivatization with acyl chlorides, whereas the derivatization products of nitro-substituted phenylhydrazines showed the slight increases of maximum wavelength and absorbance intensity. Hence, 2-nitrophenylhydrazine was selected as the suitable derivatization reagent because the derivatives have the maximum UV wavelength absorbance at 395nm, which could largely minimize the matrix interferences. The optimization of the concentration of 2-nitrophenylhydrazine is important for the sensitivity and stability of derivatives. Other reaction conditions including reaction temperature, time and the influence of three competitive solvents (water, methanol and ethanol) on the reaction efficiency were also studied. After derivatization with 100μgmL-1 2-nitrophenylhydrazine at room temperature for 30min, the method was validated for high specificity and sensitivity with the detection limits in the range of 0.01-0.03μgmL-1. The proposed method was applied as a generic method to determine the residual acyl chlorides in lipophilic drug substances.

Stereoselective Catalytic Synthesis of Active Pharmaceutical Ingredients in Homemade 3D-Printed Mesoreactors.

3D-printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D-printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best-performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous-flow synthesis of biologically active chiral 1,2-amino alcohols (norephedrine, metaraminol, and methoxamine) through a two-step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.

Stereoselective Catalytic Synthesis of Active Pharmaceutical Ingredients in Homemade 3D‐Printed Mesoreactors

Abstract3D‐printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D‐printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best‐performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous‐flow synthesis of biologically active chiral 1,2‐amino alcohols (norephedrine, metaraminol, and methoxamine) through a two‐step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.

Rapid Production of Submicron Drug Substance Particles by Supersonic Spray Drying

Many newly developed active pharmaceutical ingredients (APIs) are poorly soluble in water and thus have a dissolution-limited bioavailability. The bioavailability of Biopharmaceutical Classification System (BCS) class II APIs increases if they dissolve faster; this can be achieved by increasing their surface-to-volume ratio, for example, through formulation as submicron particles. In this paper, we develop a supersonic spray dryer that enables rapid synthesis of submicron-sized APIs at room temperature. Dispersing gas is accelerated to supersonic velocities in the divergent portion of a de Laval nozzle. The API solution is directly injected in the divergent portion and fully nebulized by impinging high velocity gas and pressure gradients across shocks at the exit of the nozzle. In such a device, we produce crystalline danazol particles with a Sauter mean diameter as small as 188 nm at a production rate up to 200 mg/h. The smallest particles with the narrowest size distributions are formed in overexpanded flows with a shock front close to the nozzle exit. Moreover, we demonstrate the scalability up to 1500 mg/h by increasing the danazol solution concentration; in this case, the Sauter mean diameter of the spray-dried particles increases to 772 nm.

Minimizing E-factor in the continuous-flow synthesis of diazepam and atropine

Minimizing the waste stream associated with the synthesis of active pharmaceutical ingredients (APIs) and commodity chemicals is of high interest within the chemical industry from an economic and environmental perspective. In exploring solutions to this area, we herein report a highly optimized and environmentally conscious continuous-flow synthesis of two APIs identified as essential medicines by the World Health Organization, namely diazepam and atropine. Notably, these approaches significantly reduced the E-factor of previously published routes through the combination of continuous-flow chemistry techniques, computational calculations and solvent minimization. The E-factor associated with the synthesis of atropine was reduced by 94-fold (about two orders of magnitude), from 2245 to 24, while the E-factor for the synthesis of diazepam was reduced by 4-fold, from 36 to 9.