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A survey of solvent usage for papers published in Organic Process Research & Development has been carried out for the years 1997–2012. Three solvent categories were studied: (i) solvents of concern, (ii) dipolar aprotic solvents, and (iii) neoteric solvents. In the analysis of dipolar aprotic solvent use it was found that nearly 50% of DMF/DMAc/NMP/DMSO usage is attributed to nucleophilic substitution reactions (mostly SNAr and SN2 reactions). Ideas on how to minimise the use of these four solvents in nucleophilic substitution reactions are presented, and it is hoped that these ideas will be adopted by chemists looking at SN type reactions at all stages of development. The only neoteric solvent showing any significant use is 2-methyltetrahydrofuran; usage of this solvent grew rapidly during the survey period.

A DSC chart can be turned into a phase diagram generally only with the aid of other experimental information, such as solubility measurements or slurrying experiments. There are several ways of presenting phase behaviour diagrammatically. It is shown how to produce a phase diagram and how to avoid some of the potential errors of the experimental measurements.

The development of a sustainable commercial salt formation process for gefapixant citrate (MK-7264), an investigational new P2X3 antagonist for the treatment of chronic cough, is described. Due to ...

The world’s first non-phosgene polycarbonate process from CO2 has been developed and industrialized by Asahi Kasei Corporation (Japan). Hitherto, all polycarbonates (PCs) have been produced using CO as a raw material. Among them, most PCs have been produced by so-called the “phosgene process” using highly toxic phosgene (COCl2) and large amounts of solvents (probable human carcinogen CH2Cl2 and water). The phosgene process has many environmental and safety problems. However, technological barriers have hindered realizing the non-phosgene PC process. The Asahi Kasei Process has not only solved the problems of the phosgene process but also contributed to sustainability (reduction of CO2 emission, materials saving, and energy saving). High-quality PC and high-purity monoethylene glycol (MEG) are produced in high yields, respectively, without waste and wastewater, starting from CO2, ethylene oxide (EO), and bisphenol A (BPA). In the monomer (diphenyl carbonate: DPC) production process, innovative reactive dis...

Reusing the mother liquor fraction in crystallization processes significantly increases the product yield but also leads to an accumulation of impurities. In this work, we investigated how a mother liquor recycle operation affects the crystallization of paracetamol as a result of the gradual buildup of the impurity 4-nitrophenol. The results show that the rate of impurity buildup decreases with increasing number of cycles until the amount of the impurity remains the same. The number of cycles required to reach the steady state increases when larger fractions of mother liquor are reused. A simple model was used to describe the impurity buildup and to estimate the largest possible mother liquor recycle fraction required to obtain the maximum achievable product yield while still maintaining the desired product specifications. The presented work shows how to optimize mother liquor recycle conditions that will lead to enhanced process efficiency by reducing product and solvent waste.

In this work the application of green chemistry principles such as process intensification and the replacement of reagents and solvents to more benign alternatives were coupled with the advantages of continuous manufacturing. The reduction of lipophilic aromatic aldehydes using an aqueous alkaline solution of NaBH4 was achieved by means of mechanical shearing and kneading provided by a custom-made batch reactor at the lab scale and a twin screw extruder at the kilo scale. The process was run continuously for 17 min to yield 1.41 kg of product (89% purity). The benefits of running the process in a continuous manner instead a conventional fed-batch mode were discussed in terms of both environmental and economic factors.

Using the Teasdale method, purge factor estimates for six impurities identified as mutagenic alerts in the synthesis of MK-8876 are compared to actual measured amounts of these impurities determined via appropriate analytical methods. The results from this comparison illustrate the conservative nature of purge factor estimates, meaning that overprediction of mutagenic impurity purging is unlikely when using this method. Industry and regulatory acceptance of the purge factor estimation method may help minimize analytical burden in pharmaceutical development projects.

For the purpose of a industrial process of cellulosic ethanol production, an efficient β-glucosidase was evolved by L-Shuffling starting from three parental genes (i.e., Chaetomium globosum glucosi...

The robustness and adaptability of a continuous oscillatory baffled reactor (COBR) in organic syntheses of vanisal sodium and aspirin were tested whilst meeting the stringent regulatory standards. In one week-long continuous operation, vanisal sodium was produced to a purity level of 99.94%, aspirin to a level of 99.57%. The loss of product during the cleaning process amounted to 0.001% and 0.005% for vanisal sodium and aspirin, respectively. The data of the continuous syntheses show that the operation of the COBR is robust and consistent throughout the week-long period. The cleaning stage that was used after each production campaign exhibited a first-order kinetics and was effective and efficient.

A scale-up of a new process for the production of 2-chloro-5-trifluoromethyl-benzonitrile by a Sandmeyer reaction of 2-Chloro-5-trifluoromethylaniline with copper cyanide/sodium cyanide is described. To ensure a safe implementation, a safety evaluation of the process was carried out, which is described in the following. The new process gives a better working environment and better productivity due to shorter reaction time.

An investigation into the acidification step of the zafirlukast nitroacid process was conducted by varying a range of parameters, including acid molarity, addition time, final pH, and temperature. A significant and unexpected improvement in product quality was achieved by using dilute rather than concentrated acid, independent of the final pH, and without a reduction in yield. The change to the dilute-acid process could be accommodated within the constraints of the existing registered process.

Recovery of catalysts from homogeneous reaction mixtures is a major problem in the fine chemicals industry if the amount or the price of catalyst are not negligible. Product purification costs and ...

An example of an improvement in recovering ammonia in a dipeptide manufacturing process is described. The synthetic method, which makes use of the ammonolysis reaction, has been studied and found to produce dipeptides of satisfactory quality in high yield on a large scale. However, the treatment of unreacted ammonia in the ammonolysis reaction caused a reduction in the productivity and increased the production cost during actual manufacture. Therefore, a method to recover the unreacted ammonia has been investigated through simulations and trial runs using model solutions. Consequently, the modified process provided an improvement in the productivity and cost savings. In addition, the recovered ammonia could possibly be used for recycling. It was verified in a lab experiment that the reused ammonia did not lower the quality of the dipeptide.

A simple model for the continuous recycle of mother liquors from a crystallization or precipitation is discussed. It is shown that the impurity profile of the mother liquors, at moderate recycle levels, quickly reaches a steady state according to (1 − xn+1)/(1 − x), where n is the number of times the process is operated and x is the fraction of mother liquors recycled. Practical applications of the procedure are discussed, and it is shown that a relatively small amount of laboratory work would be required to test a real system under the continuous recycle conditions. An example of the successful application of the procedure to a multitonne per annum manufacturing operation is described.

This paper presents a laboratory study examining the dissolution kinetics of ibuprofen crystals in water containing a phosphate buffer (pH 7.20) at 37 °C, examining the influences of initial undersaturation ratio, agitation rate, crystal habit, and particle size. For each experiment, the concentration during the dissolution process was followed using UV spectroscopy, ATR-FTIR, and FBRM methods. The dissolution profiles were correlated using eight mathematical models, and the dissolution rate parameters were determined. The Weibull model, the Korsmeyer–Peppas model, and the first-order kinetics model gave better correlation results than the other models used in this paper for the dissolution of ibuprofen crystals. The particle size distribution slightly shifted to the right after dissolution, confirming that smaller particles with higher surface areas dissolved more rapidly. During dissolution, two distinct behaviors were obtained at different levels of undersaturation ratio; therefore, it is postulated th...

Boronic acids and boronate esters are commonly used reagents in Suzuki–Miyaura coupling chemistry which are known to be weakly mutagenic in microbial assays. In this paper, we describe an inductively coupled plasma mass spectrometer method (ICP-MS) for the analysis of boron at low parts per million levels. Boronic acid and ester levels are then calculated stoichiometrically in a drug substance based on the determination of boron with good sensitivity (LOQ of 0.8 ppm). The paper outlines some of the important aspects of the method and instrument features such as use of organic diluent, spray chamber configuration, and its optimization which are critical for analysis of trace inorganic species in drug substances.

Cyclic peptides have found numerous and wide ranging applications that include drug molecules, nanomaterials, and chiral chromatography stationary phases. However, in the crucial cyclization step, high dilution conditions are often required, resulting in large volumes of solvent being consumed to prepare relatively small quantities of product. This paper demonstrates the synthesis of a cyclic nonapeptide with in-line solvent recycling via organic solvent nanofiltration (OSN) resulting in a significant reduction in the solvent load of the reaction and concomitant improvement in process mass intensification (PMI). The membrane was used to remove the reaction product from the reaction vessel, as the cyclic peptide product shows limited stability in the presence of an excess of reaction reagent. In comparison to the standard batch reaction, no loss in yield or product purity was observed for the OSN process tested. The proof-of-concept study outlined in this paper was performed on a real active pharmaceutical...

This multiauthor review article aims to bring readers up to date with some of the current trends in the field of process analytical technology (PAT) by summarizing each aspect of the subject (sensor development, PAT based process monitoring and control methods) and presenting applications both in industrial laboratories and in manufacture e.g. at GSK, AstraZeneca and Roche. Furthermore, the paper discusses the PAT paradigm from the regulatory science perspective. Given the multidisciplinary nature of PAT, such an endeavour would be almost impossible for a single author, so the concept of a multiauthor review was born. Each section of the multiauthor review has been written by a single expert or group of experts with the aim to report on its own research results. This paper also serves as a comprehensive source of information on PAT topics for the novice reader.

A variety of chemical compounds, intermediates, and reagents are used during the process of synthesizing active pharmaceutical ingredients (APIs). Some of these chemicals, intermediates, and reagents, as well as byproducts of synthetic processes, can have toxic properties and be present as impurities at low levels in the API or final drug formulation. If present at high concentrations, the toxic impurities could cause adverse health effects in humans. This paper describes a simple and rapid approach for selective removal of acrolein from APIs using iodixanol as a model API. Several scavengers were tested, and the resins which showed highest binding efficiency and selectivity were chosen for further evaluations. The kinetics of acrolein scavenging in the presence of the API iodixanol and the scavenging capacity of resins were demonstrated in this paper. The most complete scavenging is obtained with PS-NH2 which removes 97.8% of acrolein without any substantial removal of the API during 20 min of reaction time.

Raman spectroscopy is one of a number of potential in situ process analysis technologies (PATs) for application in crystallization processes. In this paper, the use of Raman spectroscopy in the cooling crystallization of mannitol is investigated. Mannitol has three known polymorphs (α, β, and δ) that can be assessed using Raman spectroscopy. Although several multivariate spectroscopic methods for measuring both the dissolved concentration and the polymorphic form using Raman exist, their application requires significant calibration and/or that several assumptions be made about the relationship between the concentration and the Raman spectra. In this paper, a novel and simple calibration-free univariate method for monitoring supersaturation during the cooling crystallization of mannitol is demonstrated. The use of the method to successfully monitor the transformation process of the metastable α form to the stable β form in aqueous solution is also presented.

Kepner-Tregoe decision analysis was formally used as an aid to route selection, as outlined in the preceding paper. Over 40 paper routes were assessed for suitability for both immediate and longer term manufacture of AZD7545, a compound in the early stages of development. Eight routes were then investigated in full in the laboratory, and a further four in part, over a period of 3−4 months. From this exercise, the preferred long-term manufacturing route was identified before the first pilot scale manufacture had been completed. This route selection exercise worked well in this case where a large number of potential routes had to be considered using limited resources. It was also an effective means of bringing some long-term manufacturing issues to the fore at an early stage in development.

This paper is a continuation of our previous work, which reviewed the main factors that inhibit fine chemical and pharmaceutical reactor scalability. For scalable reactor design, it is suggested to first identify potential scale-up obstacles and then use shortcut calculations for their evaluation. This approach is demonstrated in this paper for the asymmetric transfer hydrogenation of acetophenone to its chiral alcohols, in the presence of the homogeneous catalyst, (1 R,2 S-amino-indanol/pentamethylcyclopentadienylrhodium) with isopropanol as hydrogen donor. The investigation reveals that removal of the by-product acetone from the reaction system shortens the required reaction time to achieve high conversion and reduces enantioselectivity erosion. A simple search algorithm is presented which can be used in principle for liquid reactions systems, where stripping of a reaction product or by-product is beneficial. The algorithm identified that the most influential factors that accelerate acetone removal are ...

This paper discusses different aspects of laboratory information management systems in life science applications. Although different LIM systems are available on the market, the state of the art LIMS do not fulfill all requirements regarding flexibity and process connectivity. A fully web oriented LIM system is described in the article. The approach shown in the paper presents a system's model based on modern web oriented software technologies. It includes planning tools, a virtualized lab, and on-line process adaptation as well as an interface for computational data processing and data mining.

The foregoing papers (Bernasconi, E.; Lee, J.; Roletto, J.; Sogli, L.; Walker, D. Org. Process Res. Dev. 2002, 6, 152 and Bernasconi, E.; Genders, D.; Lee, J.; Longoni, D.; Martin, C. R.; Menon, V.; Roletto, J.; Sogli, L.; Walker, D.; Zappi, G.; Zelenay, P.; Zhang, H. Org. Process Res. Dev. 2002, 6, 158) describe a high-yielding, all-aqueous process for the preparation of 3-exomethylene-7(R)-glutaroylaminocepham-4-carboxylic acid 1(S)-oxide (3) from fermented cephalosporin C broth via enzyme transformations and electrochemical reduction without isolation of any precursors. In this paper we describe the efficient recovery of 3 from aqueous solution, by extractive esterification employing diphenyldiazomethane, and the conversion of the obtained bis(diphenylmethyl) ester (4) into intermediates both for Ceftibuten (1) and cefaclor (8). Several routes to the key Ceftibuten building block, diphenylmethyl 7(R)-aminoceph-3-em-4-carboxylate (6) are described. This key building block is acylated, deblocked, and pur...

Kepner-Tregoe Decision Analysis is a logic-based tool that has been used by AstraZeneca to prioritise the investigation of alternative routes to drug candidates. This paper describes how the tool can be used in route selection work, with subsequent papers discussing application to AstraZeneca projects.

The lack of stereochemical control has been a major hurdle in synthesizing β-nucleosides in large scale. This paper reports a study of the effects of different catalysts used in the synthesis of β-nucleosides. The effects of time and temperature on α- and β-anomers are illustrated in this paper. The yield and selectivity of the β-nucleoside have been improved vastly at temperatures between −30 and −40 °C and by using SnCl4 as the catalyst.

The production of chirality with maximum economy is one of the most challenging tasks of today's pharmaceutical industry. Apart from the use of inherent chirality (starting material from the chiral pool, e.g., amino acid derivatives, carbohydrates), the creation of chiral centers via biocatalysis or asymmetric synthesis is commonly used. Another way to obtain pure enantiomers is the separation of racemates via kinetic resolution through preferred crystallization or preparative chromatography on chiral stationary phases. This paper emphasizes this last method, explains the possibilities of this technique, especially in its application form as simulated moving bed (SMB) chromatography, and shows its benefits and limitations. Therefore, comparisons to classical batch elution chromatographic processes as well as other unit operations (such as crystallization, etc.) must take cost calculations into account. In this paper, a theoretical comparison of optimized SMB and batch elution processes by simulation studi...

Sonochemistry, or the application of power ultrasound to chemical processes, is a technology that has undergone very intensive research and development in the last 15−20 years, with respect to both its range of application and the methods employed for its implementation at industrial manufacturing scales. In a series of two papers, the authors review progress of the application of ultrasound to chemistry and chemical processing, and the development of equipment and scale-up methods. This first paper focuses on chemistry and also covers mechanisms of action of ultrasound and its in situ detection and measurement. Part 2 will deal with the application of ultrasound to crystallization processes (sonocrystallization) and with scale-up and equipment development.

The risk assessment and control of N-nitrosamine impurities in medicines is a topic of great concern for patients, regulators, and the pharmaceutical industry. This paper discusses a modeling appro...

This paper describes the development of an improved and scalable method for the manufacture of nemiralisib, a phosphatidylinositol-3-kinase delta inhibitor. Incorporation of three consecutive catal...

In this paper, we report, for the first time, that a multiphase catalytic hydrogenation of 3-butyn-2-ol over Pd/Al2O3 catalyst has successfully been running in a continuous oscillatory baffled reac...

This scientific paper presents an overview of continuous solution crystallization in the pharmaceutical industry. Since the specific knowledge spectrum of precipitation is very broad, topics coveri...

This paper describes the process development conducted toward the multi-kilogram synthesis of a novel transported pro-drug of R-baclofen. The key steps in the synthesis were the enzyme-catalyzed ki...

Solid-state deracemization via temperature cycles is a technique that has been shown to be effective to isolate the pure enantiomer of a conglomerate-forming compound. This process has a large number of operating parameters that can be adjusted according to system-specific properties. On the one hand, this feature makes the process flexible and prone to optimization. On the other hand, the design space is so large that experimental optimization of the process can become long and cumbersome. In this work, we achieve two results. First, we show that deracemization via temperature cycles works very effectively for two new experimental systems, namely, the chiral compounds 2-(benzylideneamino)-2-(2-chlorophenyl)acetamide (CPG) and 3,3-dimethyl-2-((naphthalen-2-ylmethylene)amino)butanenitrile (tLEU). Second, we propose a new approach for the design of an effective deracemization process via temperature cycles for a new compound. Therefore, in this work, we investigate the effect of different operating conditions, namely, the initial enantiomeric excess, the cooling rate, the temperature range, and the catalyst concentration, on the performance of deracemization via temperature cycles for the new compounds CPG and tLEU and for N-(2-methylbenzylidene)phenylglycine amide (NMPA), which was already studied in a previous paper. On the basis of these outcomes, we conclude by proposing a model-free screening strategy for the design of an effective deracemization process via temperature cycles for a new compound., Organic Process Research & Development, 24 (8), ISSN:1083-6160, ISSN:1520-586X

A scalable process for the novel monobactam antibiotic LYS228 has been developed. This paper covers a novel scalable process for producing β-lactam 10 in the multiple kilogram scale. An alternative...

This paper describes recent efforts to apply flow technology in the preparation of the key amino alcohol intermediate 3b so as to address manufacturability issues present in the batch process of a ...

Our efforts toward the process development of drug candidate 1 are described in a series of two papers. This manuscript focuses on the synthesis of kilogram quantities of acid precursor 2 to provid...

This paper describes the synthesis of kilogram quantities of the sulfonamide moiety 3 involved in a coupling reaction with acid moiety 2 to provide batches of drug candidate 1 for preclinical studi...

Continuous crystallization has recently gained attention in industrial crystallization. This paper summarizes the study of continuous antisolvent crystallization of α-lactose monohydrate using etha...

In this paper, we extend the substrate class of Buchwald–Hartwig amination to quaternary ammonium salts. In the presence of Pd(OAc)2 and t-BuXPhos, the coupling of aryl- or arylmethyltrimethylammon...

Within this paper, we present the design, development, and scale-up of a process for a continuous Matteson reaction to produce a key intermediate toward the β-lactamase inhibitor vaborbactam. This includes the successful implementation of the continuous concept at a multiton production scale for the API at Patheon, part of Thermo Fisher Scientific. The first-generation continuous flow production with its discontinuous downstream processing was further developed to a fully continuous production through installation of a continuous loop reactor. This enabled increased productivity and energy efficiency, eliminated volume and time bottlenecks, and reduced waste.

In our previous paper, kinetic parameters for the thermal polymerization of methyl methacrylate (MMA) inhibited with 4-methoxyphenol (MEHQ) were determined by isothermal and nonisothermal calorimet...

This paper describes the process development conducted toward the multi-kilogram synthesis of a hemiadipic acid pro-drug of buprenorphine. The major challenges were to control the levels of the dibuprenorphine monoadipate impurity and to improve the robustness of the final recrystallization. Modification of the reaction conditions limited the levels of the impurity formed during the reaction, and an additional point of control was introduced, a reslurry with dichloromethane. The solid-state properties of the pro-drug were fully investigated, and extensive polymorph screening was undertaken. An unusual low-temperature endothermic event was observed in the differential scanning calorimetry thermogram. This low-temperature event was further investigated using variable-temperature X-ray powder diffraction and variable-temperature solid-state nuclear magnetic resonance spectroscopy. It was concluded that this event was likely to be associated with a reversible, minor conformational change of the adipate side c...