Chapter 1: Introduction to Hazardous Reagent Substitution in the Pharmaceutical Industry

What we have perceived over the years is that in vitro synthesis per se has a reputation of sharing similarities with in vivo chemical transformations (biochemical). Functional enzymes can be considered the most sophisticated green catalysts (a catalyst is different from reagent as it does not get consumed) found to be effective in cascading reactions in biological systems. However, the basic difference between synthesis and biosynthesis is that synthetic processes can be considered by and large inclusive of biosynthetic ones, whereas biosynthetic processes cannot include all possible synthetic transformations. Organic synthesis is a science that dictates the use of reactants, reagents (interchangeably used) and a set of materials towards yielding products. Interaction among all partners in the reaction, functional group susceptibility towards reagents, and their energies are the driving forces in synthetic events.

Since most of the reactions take place in solution, the selection of solvent(s) based on their dielectric constants and polarity is extremely important. There are some reactions where one of the reagents or reactants acts as a solvent. By definition, a reagent is a substance that is added to a reaction mixture to yield a chemical reaction.¹ 

There are different types of reagents, e.g. inorganic acids, inorganic bases, organic acids, organic bases, epoxides, halides, azides, organometallics, carbenes, carbenoids, diazonium salts, hydrazines, phospines, ylides, silicon based reagents, oxidizing and reducing agents, etc. These reagents play pivotal roles in the manufacturing of goods of varied interests e.g. pharmaceuticals, commodity materials and materials coming from interdisciplinary industries for societal consumption.

The use of inorganic materials, as one of the few essentials in chemical synthesis including the manufacturing of Active Pharmaceutical Ingredients (APIs), typically leads to waste generation. These are found to be primarily complex due to a variety of reasons, e.g. nature of the material, reaction conditions and unit operations. Chemical processes can generate acids, bases, aqueous or solvent liquors, and cyanides including metal wastes in liquid or slurry form. In organic synthesis waste solvents, either hazardous or non-hazardous, are usually recovered by distillation. Distillation is an excellent way of reusing and reducing liquid hazardous waste. In addition, the distillation left-over (solid residue) needs to be treated in such a way that there is no hazard left before it is dispensed as effluent. There are a number of strategies to achieve this, including the removal of solvents by steam stripping followed by microbiological treatment. Inorganic material in the chemical industry also includes a number of catalysts. The features of heterogeneous inorganic-material-based catalysis can be exploited by understanding the reactivity profile of such materials. Moreover, the same material can perform differently depending on overall unique structure and surfaces; therefore, it is important to measure these attributes and map the reactivity potential towards a variety of chemical transformations. It has become possible to characterize inorganic materials at the molecular level and leverage their catalytic potential. These inorganics also have the potential to offer hazardous reagent substitution to a great extent.² 

Manufacturing of APIs is an inevitable aspect of continuing health industry³  and this involves the use of a myriad of organic entities to accomplish the material production task. Some of these organics will become integral parts of the molecule but most of them turn out to be unwanted ones contributing to a high Process Mass Intensity (PMI) or E-factor. These unwanted materials may be hazardous in nature as they may be toxic and to a great extent they may cause environmental imbalance due to an ever-increasing carbon footprint.

There are situations during manufacturing operations where organic and hazardous substance emissions should be controlled by appropriate control devices e.g. condensers, scrubbers, etc. Waste effluents from manufacturing operations contain organic and inorganic components, wash water, discharges from pumps, scrubbers and temperature controlling systems, and fleeting leaks and spills. These effluent chemicals may be of different chemical compositions, and toxic and/or genotoxic in nature. In order to minimize these hazardous unwanted materials one needs to design such a process that provides only the desired product along with the minimum possible unwanted materials. The challenges associated with this would offer opportunities to substitute hazardous chemicals/reagents with non-hazardous ones giving rise to safer by-products.

PMI⁴  is directly linked to the use of reactants/reagents, including water. Higher PMIs that are linked with hazardous reagents will have an exponentially high impact on cost, health and the environment. PMI is the ratio of the sum of inputs and desired product output as shown in Scheme 1.1.

As shown in Scheme 1.1, raw materials (starting material, reagents and solvents) A, B and C have been used with the quantities of 50, 20 and 5 kg respectively to give rise 5 kg D. The calculated PMI of 15 clearly reflects that the process is inefficient.

In another case, if this reaction outcome featured in Scheme 1.1 goes to a next step as an intermediate to afford product H (3 kg), after reacting with reaction partners E (40 kg), F (15 kg) and G (4 kg) as shown in Scheme 1.2, the overall PMI for product H will be calculated by omitting the value of D.

PMI is the biggest problem that any industry faces and the nature of the waste generated is another negative paradigm. There is no well-defined widely accepted mechanism in place to monitor the health impacts of chemical waste post its disposal in water streams. In fact, life cycle management of chemical waste—that may prove extremely hazardous even at ppm and ppb levels—is poorly established.

PMI-related health hazards can never be avoided but can be minimized by chemistry and engineering excellence by design at the beginning of the process.

Stoichiometry and atom economy are closely associated with any chemical transformation. A highly atom economical chemical process is considered as a transformation where most of the atoms present in the reactant or reagents (but not in all cases) are incorporated in the product.⁵  The atom economy is measured as a ratio of product and all reactant and reagents (when used as reactants) used multiplied by 100, and reflects that lesser amounts of reactants used is directly proportional to higher atom economy. This calculation is widely accepted for multistep processes too. Usually in such a calculation, intermediates that are formed and consumed in the next step are omitted. There are certain assumptions made about all the components of the reaction as shown in Scheme 1.3.

In this hypothetical synthesis, in order to calculate the atom economy for intermediate EE, reactants G and R are factored in, whereas the calculation of atom economy for product Y, all the reactants G, R, N, H, M, S are considered.

For instance, a reactant is considered as any material that gets incorporated into an intermediate, product or by-product during the synthesis e.g. certain component of protecting groups and reagents used in stoichiometric quantities (or more than that). Anything used in catalytic quantities is omitted from the calculation as they do not contribute to any of the intermediates or product(s). Solvents are also not considered as part of the atom economy calculation.

The higher the stoichiometry of the reactant/reagent, i.e. >1 equivalence would lead to poor atom economy and higher PMI. There are many reactions that require more than one equivalence of reactants or reagents. Historically, it was perceived that not all reagents and reactants were safe, therefore it has been imperative to design a process that would not involve stoichiometric amounts or (more than that) of these. Comparatively, catalytic processes are considered to be much safer than conventional reagent-based transformations.

Understandably, Green Chemistry is seen as the ‘right way’ of doing chemistry in any phase of the process development. The business impact of Green Chemistry cannot be realised if it does not provide greener alternatives that enable a rise in optimal output in any given transformation. There are many hazardous reagents used for extremely important transformations but these are associated with high environmental impacts. One of the important areas of development in Green Chemistry is the selection of safer reagent(s), considering the nature of transformations. Reagent selection must arguably be guided by 12 Green Chemistry principles. Visiting these principles while designing the manufacturing processes could shed light on certain characteristics of reagents, allowing the selection of non-hazardous reagents. In fact, these principles do not only aid in finding safer reagent(s) but also help in reviewing the processes entirely. Chemists across both academia and industry mainly focus on achieving the highest yield in any given chemical transformation without considering anything that might add to the inefficiency of the overall process. A quest arises for the consideration of other Green Chemistry components when it is perceived that the yield is not going to be great. More often, Green Chemistry is considered last due to various reasons. In general, raw material cost, ease, and timely availability of raw material or reagent drive the decision-making in route selection. There appears to be opportunities to use the recommendations of reagent selection guidelines made available by various pharmaceutical industries in the literature. The most recent one is a very comprehensive reagent selection guideline made available by GSK.⁶  During discovery research, a specific reagent is used that is not necessarily the ideal one and this provides the opportunity for chemists to use an alternative reagent for the same transformation during development followed by scale-up. One has to make smart choices while opting for alternate reagents, considering certain guidelines otherwise it amounts only to unproductive time-consuming efforts. It becomes more challenging when we deal with generics as the best possible set of reagents available in the market have already been tried by innovator companies and others; however, the newly discovered potential alternates would not have readily been available during the manufacturing of the branded medicine when there was no competition for that particular product. These new reagents need to be assessed for commercial- and manufacturing-scale viability before the entire product development and manufacturing strategies are finalized. Moreover, in order to use safer and greener alternative reagents, it is important to refer to the established reagent selection guideline toolbox and scientific rationale towards finalizing the set of reagents for any given transformation. The reagent selection guidelines are made available by considering the impact on health due to exposure of the reagents or their by-products, safety, environmental impact, their projected carbon footprint, transformational output and, last but not the least their contribution, towards over all process ‘greenness’.

Biocatalysts are broadly accepted as the best reagent alternates provided such processes do not employ large amounts of water or any other solvent, demanding reaction conditions, and organic solvents in the downstream processes.

Moreover, reagent selection in my opinion is an ever-evolving science that has potential to contribute to the wellbeing of human health, business and the environment.

The pharmaceutical industry has an increasing and lasting impact on society, in a both positive and negative sense. The negative impacts of not only pharmaceuticals but the chemical industry in general can be gauged considering the level of pollution, chemically-induced life-threating diseases, and ecological imbalance. Despite the significant amount of effort made by scientists to prevent and avoid the negative impact of chemicals on health and the environment there are certain areas that need attention. For instance, the availability of cost-effective safer or non-hazardous material, whether reactant(s), reagent(s) or product(s), is essential for business, scientists, workers, consumers and the environment.

The manufacturing of medicines is not different from any material generation at a commercial scale. However, the waste associated with pharmaceutical material production is roughly 100 kg per kg of desired product. Traditionally, by virtue of the various reaction types that are involved in the production of medicines, a number of reagents are required to effect these reactions. These reagents may not necessarily be safe to handle and the impacts of these and their by-products on health, the environment, ecosystems and food chains are not well understood. Chemists need to be inquisitive about finding alternatives for at least known hazardous reagents. Suitable safer and greener reagents for any given transformation can lead to efficient processes with lower E-factor.

The Green Chemistry tool box is considered ideal in such cases where one needs to find non-hazardous reagents for the manufacturing of medicines or materials at a large scale. Hazardous reagent substitution has the potential to contribute to sustainability as it can help minimize the generation of waste; by-products of these reagents may ultimately pose less of a risk to human health and the environment. Using non-hazardous reagents during development becomes extremely important when processes get transferred to the manufacturing facility. The scale at which generic industries operate to cater for the worldwide commercial needs of the medicine is multi-fold in comparison to the scale up batches taken during development. During process development, a number of critical parameters are identified and studied as a part of the process robustness analysis. However, a slight change in these parameters would lead to an impaired process efficiency. Due to bigger batches to obtain higher quantities of product in one go (ranging from 5 to 100 kg and sometimes more than this), a multi-fold increase in reagent quantity is unavoidable and there will be distinctive advantages if a robust process is developed by using non-hazardous reagents and solvents. These include: (1) operators may not be exposed to the hazardous chemicals; and (2) consistent output and product isolation may be simpler. In addition to this, there may not be any hazardous by-product going out as an effluent. Nevertheless, a thermodynamically stable end-product may or may not be hazardous, therefore life cycle assessment must be undertaken to understand the fate of the any chemical substance that eventually becomes a part of our ecosystem.⁷ 

Catalysts are considered to be alternative reaction facilitators that have functionally in common in chemical processes and in the biological system (in the case of enzymes). In general, a catalyst can be any substance that accelerates chemical transformations without being exhausted in the reaction.

Catalysts are of different types and are used in various chemical transformations. Some catalysts are derived from metals in combination with strategically-designed organic molecules (ligands), which are known as organometallic catalysts, and others are typically organic compounds that have hydrogen bonds with substrate(s) and are considered organocatalysts. Nearly all enzymes that have properties of catalysing chemical reactions are referred to as biocatalysts.

Organometallic catalysts are chemical entities that contain a metal–carbon bond and have found great application in industrial processes. Catalytic transformations can be further divided into two categories: (1) homogeneous catalysis, where all the component of the reaction including the catalysts are in same phase; and (2) heterogeneous catalysis, where the reactants and catalysts are in different phases. In most heterogeneous catalytic systems, the catalyst is in the solid phase and the reactants are liquids or gases.

The olefin metathesis reaction is one of the top-rated organometallic catalyst reactions, representing a powerful tool for the formation of carbon–carbon bonds, was discovered by Nobel Laureates, Y. Chauvin, Richard Schrock and Robert Grubbs.⁸  Development of pre-catalysts by the modification of the original ruthenium complex reported by Grubbs and co-workers has led to more robust and active catalysts. These have been used in material production at a commercial scale.⁹ 

Other transition metal-based (mainly palladium) organometallic catalysed transformations have gained similar reputations as metathesis. Recently, Richard F. Heck, Ei-ichi Negishi and Akira Suzuki received a Nobel Prize for advancing these catalysts for the manufacturing of materials of varied interest.¹⁰ 

Organocatalysts have also been used quite intensively and have been found to effect chemical transformation without contributing much to the waste generated after product isolation. Several research groups showed that the simple amino acid proline catalysed enantioselective cross-Aldol reactions between acetone and different aldehydes to offer corresponding products. In addition to this, chiral imidazolinium salts are found to activate α,β-unsaturated aldehydes for asymmetric Diels–Alder reactions. In general, small organic catalysts are found to effect challenging transformations. Pioneering work by MacMillan and others led organocatalysts to become one of the pillars of sustainable processes. There are other emerging organocatalysts, e.g. thiourea-based diversified entities, phosphates, NHCs and chiral squaramide–amine bifunctional moieties, known to be effective in the synthesis of products of varied interest including pharmaceuticals.¹¹ 

Biocatalysts have a high degree of potential, much above to all known synthetic catalytic systems employed in the area of chemical transformations. Biocatalysis can be considered as any chemical transformation achieved by: (1) using natural or genetically engineered enzymes; (2) using fermentation technology; and (3) using a whole cell system. All these strategies have been shown to offer efficient processes with improved PMI and selectivity.¹² 

Non-catalytic transformations employ stoichiometric quantities of hazardous reagents (in a significant number of cases) and exhaustive workup. These transformations tend to offer poor yields, even in some cases where chemical conversion is extremely good. This is due to repetitive muddled workup towards improving product quality by removing reagent by-product, substrate and product-related impurities. On the other hand, transformations that employ catalysts as alternatives to hazardous reagents leave behind an insignificant amount of catalyst, substrate and product-related impurities. In general, catalytic transformations provide several advantages, e.g. high yields, help in shortening the route, lower PMI/E-factors, higher stereo-, chemo- and regioselectivities, less demanding reaction conditions and efficient workup towards product isolation.

There are numerous reagents known for chemical transformations. The nature of reagents can be classified based on their reactivity and hazardous features. Some of the reagents are reducing and some are oxidizing in nature. In addition to this, a few are metal based.

Not only reagents but all chemicals are classified into various hazard classes considering their physiochemical properties that are associated with negative health impacts. Each class of chemical is symbolized with a warning danger symbol as given in Table 1.1.¹³ 

Most of the reagents used for chemical transformation can be classified according to their hazardous nature. Azides, acetylides, diazo, nitoso, and haloamines are found to be explosive in nature. In addition to this, hydrogen peroxide, hypochlorites, nitric acid, CrO₃, and Dess–Martin periodinane are classified as oxidizing chemicals, whereas Ethers, Al(OⁱPr)₃, and Bu₃SnH are considered flammable. There are some reagents, e.g. phosgenes, hydrogen cyanide and nicotine, SeO₂, DDQ, and NaBH₄, that are considered toxic. Acetanilide, ammonium persulfates, Mn(OAc)₃, and glues and resins are adjudged to be harmful to a great extent. Most of the organometallic reagents, along with acids and caustic soda, OsO₄, NBS, and LAH, are determined to be corrosive. Experimentally it has been proven that benzene, beryllium, asbestos, vinyl chloride, arsenic, Hg, Pb, Cd, ethanol and nitrous acid fall in the category of either carcinogens, teratogens or mutagens.

Many other hazardous reagents exist and more interestingly the question arises of what would their non-hazardous alternatives be? Recent advances in this area reveal that there are a new set of non-hazardous reagents developed for several types of chemical transformations as shown in Table 1.2.

Most of the organic transformations can be categorized into five classes: oxidation; reduction; C–C; C–X; and C–N bond formation directly or through activated species. Using relatively safer reagents, the manganese sulphate/Oxone/water system is found to be a very effective oxidizing agent in converting several substrates, i.e. aromatic amines, benzylic methyl/alcohol, to corresponding products. A number of enzymes have also been found to effect oxidation at high yields. Reduction in general, more specifically asymmetric hydrogenations using transition-metal-based catalysts, direct reduction by using biocatalysts and chemical as well as biocatalysis-based Dynamic Kinetic Resolution (DKR), are some of the methods that have employed non-hazardous reagents in recent years. C–C, C–X and C–N bond formation are achieved by exploiting transition metals, photochemical strategies and C–H activation. The reagents used in these transformations are considered non/less-hazardous in nature.

Chapter 2 details the recyclability of reagents in the context of the industrial sector that has played a significant role in processing pharmaceuticals and, as a result, helped in ensuring the affordability of medicines to under-privileged societies. However, the disposal of drugs into water supplies, rivers, lakes and other waterways have put pharmaceutical chain supplies under environmental surveillance. As a consequence, a great deal of effort by the industrial researchers and engineers is now being directed towards the redesigning of existing synthetic protocols with the aid of Green Chemistry principles and practices such as elimination of hazardous substances, reuse and recycling of reagents, use of biosynthetic routes and solvent substitution practice. In this direction there have been extraordinary efforts made by several reputed companies like Pfizer, GSK, Novartis etc. as they have come up with some brilliant recovery and recycling strategies. However, the collective efforts of environmentalists, regulators, manufacturers and policy makers are still required to find solutions to the global environmental problem of hazardous waste management. Considering these, it is worth recommending the topic featured in Chapter 2.

Chapter 3, entitled Recoverable Polymer-Supported DMAP Derivatives, features the application of a specific polymer-supported reagent in the synthesis. The scientific fraternity worldwide is looking at E-factor reduction in synthesis as a unique opportunity to greenify the industrial processes by devising newer, safer and less/non-hazardous reagent systems. In this context, the field of polymer-supported catalysis will continue to play an important role as it allows for chemists to recycle critical species as well as reduce the overall carbon footprint of synthesis. This is especially important in the face of global climate challenges this entire generation is witnessing; in which the utilization of the principles of Green Chemistry will only become more and more vital, not only to chemistry, but to the general manufacturing practices. Although this chapter is focused on supported N-heterocyclic organocatalysts, there exist many other elegant examples underlying the importance that this field will continue to have in synthesis, and this may pave the way in finding alternative non-hazardous reagent systems for hazardous ones. This chapter is recommended considering the potentialities of polymer-supported DMAP derivatives to be recovered at a large scale if employed.

Chapter 4 discusses the synthesis of atorvastatin. Atorvastatin is marketed by Pfizer and is considered possibly the most commercially successful small molecule medicine ever launched. It is used for the treatment of hyperlipidaemia and hypercholesterolemia. The synthesis of atorvastatin evolved from the usage of hazardous reagents to the development of the processes with entirely non-hazardous reagents, therefore this chapter has been included with great interest.

Chapter 5 details the synthesis of raloxifene. Earlier synthesis of this involving hazardous reagents at a manufacturing scale posed a great challenge in terms of handling, operation and workups. These reagents were found to be unsafe and to have proven toxicity (in the majority of the cases). If not avoided, these reagents will defy the purpose of Green Chemistry in the current scenario. In this chapter, the synthesis of raloxifene is considered. Raloxifene is an estrogen agonist/antagonist, commonly considered a selective estrogen receptor modulator (SERM) centric to women health. Considering the evolving trends of switching from the use of hazardous to less-hazardous reagents as well as the use of ionic liquid in one of the syntheses as a relatively non-hazardous component, this chapter has been included.

Chapter 6 describes the synthesis of montelukast, an orally active selective leukotriene receptor antagonist that inhibits the cysteinyl leukotriene (CysLT₁) receptor. It was developed by Merck and Company and is currently marketed under the brand name of Singulair^®. Montelukast is one of the most prescribed allergy drugs for the treatment of asthma in the United States with sales of about $4.5 billion a year (before the expiry of its patent in 2012). Merck made significant efforts to develop a commercial manufacturing process that used less-hazardous reagents. Subsequently, other generic companies also worked towards developing non-infringing and cost-effective processes, therefore this chapter has found its place in the book.

Chapter 7 details the development efforts towards a practical means to prepare 1-(4-chloro-3-fluoro-2-iodophenyl)-1H-tetrazole via reaction of an aryl diazonium salt (derived from the appropriate aniline) with diformylhydrazine. The most commonly employed methods to synthesize 1-aryl-1H-tetrazoles involve the use of azides, which can pose significant safety challenges. The use of diformylhydrazine affords the desired tetrazoles under conditions that are mild, convenient, safe and scalable, and circumvents the need to use azides. The other added advantage of this approach is that the entire sequence of reactions (diazotization of the amine followed by reaction with diformylhydrazine) can be carried out under aqueous conditions, rendering it a very attractive non-hazardous reagent application in the synthesis of the pharmaceutically-relevant tetrazole intermediate. These features prompted us to include this chapter in the book.

Chapter 8 features an interesting discussion on new directions from academia. The industry/academia interface for effective collaboration has great importance in the current scenario. Research and development efforts towards non-hazardous reagent substitution in the organic synthesis and processes of medicines (APIs) may effectively be possible provided multiple and meaningful interfaces exist without any barrier. Some case studies along these lines have been discussed, which encouraged us to include this chapter in the book.

The substitution of hazardous reagents with less or non-hazardous ones is one of the most essential parts of risk management in the work place, whether it is a research and development or manufacturing set-up. There are certain reagents such as HCN, diazo-based reagents, phosgenes etc. that are restricted, or their use requires additional authorisation and protections. In general, the substitution of hazardous reagents and safety during production of medicines are non-negotiable requirements. These are only possible by usage of non or less-hazardous reagents as a result of chemistry and engineering intervention along with in-built process safety. Manufacturing processes are often linked with unchartered events due to the significant amount of heat exchange. It is important to identify the source of exothermic behaviour and have control measures in place. It is sometimes found that pressure builds up in reactors due to the fast reactivity of reagents with the substrate leading to disruption. There are other factors that govern safe practices at chemical plants, requiring systematic risk analysis of potentially hazardous chemicals and processes at scale. The risk assessment is performed considering reaction and workup temperatures, exotherm triggering temperatures, amount of pressure build-up, moisture/water sensitivity towards reactants, reagents and products, air and light sensitivity, and abrupt ignition. In addition to this, solvent compatibility, pyrophoric behaviour, peroxide formation due to the solvent or any other components of the reaction, stability towards temperature, shock and friction are also the part of hazard assessment. In order to avoid exothermic, destructive incidents, runaway reactions and exposure of hazardous reagents and chemicals, continuous manufacturing based on flow technology has taken momentum to replace the batch mode manufacturing of the products. In this direction, Novartis and MIT are running a massive collaborative project successfully.²³ 

Particularly, in organic synthesis, a myriad of reagent alternatives has been discovered. Less-hazardous reagents for chemical- or biocatalysis-based asymmetric hydrogenation/reduction have been found to be very effective in the manufacturing of APIs. The USA Environmental Protection Agency started the Presidential Green Chemistry Challenge Award, to be given to industry scientists for work towards greener processes. Some of the processes feature the replacement of hazardous reagents/catalysts to less-hazardous ones, e.g. in 1997, BHC Company (now BASF Corporation) synthesized ibuprofen in three catalytic steps with high atom economy, winning a Presidential Green Chemistry Challenge Award.

Boot's synthesis of ibuprofen employs reagents/reactants such as aluminium trichloride, hydroxylamine, 2-chlorobutyl ester and sodium ethoxide and none of them can be classified as non-hazardous reagents/reactants. Aluminium chloride is known to be moisture-sensitive and causes irritation to the skin and respiratory system. Hydroxyl amine is heat-sensitive and sodium ethoxide is flammable, therefore an award winning green synthesis of ibuprofen featuring catalysts (replacing hazardous reagents) has been devised. In this improved synthesis, hydrogen fluoride (catalyst and solvent), Ra-Ni and Pd catalysts are used as shown in Scheme 1.4.

This synthesis has great features as 99% of input atoms (considering the recovery of the acetic acid by-product) were incorporated into the product and overall process efficiency was improved. This is only possible due to hazardous reagents' substitution and process improvement of a synthesis which has six stoichiometric chemical transformations with 40% atom economy.²⁴  There are other challenging transformations that have been managed using safer reagents and safer processes and have won similar awards. In 1999, Lilly Research Laboratories developed a process for the formation of an anti-epilepsy molecule using yeast that avoided Cr-related waste.²⁵  Similarly, in the year 2000, Roche Colorado Corporation (Corden Pharma Colorado) worked on Ganciclovir eliminating two hazardous solid wastes and more than ten hazardous chemicals.²⁶  After two years, in 2002, Pfizer demonstrated outstanding work on Sertraline, doubling overall yield by process intensification.²⁷  Merck has won this award back to back in 2005 and 2006 for the highly atom economical production of Aprepitant²⁸  and green synthesis of β-amino acids of Sitagliptin.²⁹  In the same year, Codexis employed directed evolution technology towards developing biocatalysts that have been used in the synthesis of most a cost-effective chiral building block of Lipitor.³⁰  In 2010, Merck and Codexis jointly developed a transaminase enzyme that improved the stereoselectivity and process of the manufacture of Sitagliptin.³¹  Recently, in 2014, Professor Shannon S. Stahl at the University of Wisconsin-Madison won this award through developing a Cu/aerial O₂-based catalyst system that has the potential to oxidize alcohol towards synthesizing complex APIs.³²  An ultimate attempt to make reagents safe and revolutionize industry practices is envisioned through 3D printing technology, synonymously known as additive manufacturing. This technology has the potential to carry out productions at a commercial scale. Hybridized and fabricated reaction-ware with inert polypropylene and catalyst composite-silicone material offers flexibility in the design and use for the specific needs of chemical transformation. Based on this technology, a sealed reactor can be designed to perform multistep processes which will make not only the pharmaceutical but the entire chemical industry safer and more efficient.³³  Very recently Noël's group has devised an artificial leaf considered as a reactor prototype which is potentially believed to work sustainably in the presence of sunlight as a mini-factory to produce chemical products including medicines. This technology is inspired by nature and once it becomes commercially viable this will revolutionize the chemical industry.³⁴