Hazardous Reagent Substitution: A Pharmaceutical Perspective / Edition 1

by Rakesh Kumar Sharma, Rakeshwar Bandichhor

Overview

In recent years, a significant amount of progress has been made using green chemistry in the synthesis of synthetically useful compounds and molecules by replacing hazardous chemicals with greener alternatives. However, there is still room for improvement, especially in the pharmaceutical sector where new drugs are being formulated. This book examines green approaches to overcoming hazardous organic transformations. Summarizing recent developments, the book features a detailed description of some of the high impact active pharmaceutical ingredients that have been developed considering green chemistry approaches. It explores the design, engineering and process development and the calculations to account for waste. The book includes strategies to further advance green approaches in the development of generic pharmaceutical industries and features novel, innovative approaches that promote waste-free organic synthesis. This book is of interest to industrialists working in pharmaceuticals and researchers working in green chemistry.

Product Details

ISBN-13:	9781782620501
Publisher:	RSC
Publication date:	12/12/2017
Series:	Green Chemistry Series , #52
Pages:	194
Product dimensions:	6.15(w) x 9.20(h) x (d)

About the Author

Rakesh Kumar Sharma is Professor and Coordinator of Green Chemistry Network Centre, University of Delhi, India.

Rakeshwar Bandichhor is an Associate Director at Dr. Reddy's Laboratories, India.

Read an Excerpt

CHAPTER 1

Introduction to Hazardous Reagent Substitution in the Pharmaceutical Industry

RAKESHWAR BANDICHHOR

Integrated Product Development, Innovation Plaza, Dr Reddy's Laboratories Ltd, Bachupally, Qutubullapur, R.R.Dist. 500090, Telangana, India

Email: [e-mail]

Role of Reagents in the Development of Organic Synthesis

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.

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.

1.1.1 Inorganic Material in the Synthesis of APIs

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.

1.1.2 Organic Material in the Synthesis of APIs

Manufacturing of APIs is an inevitable aspect of continuing health industry 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.

1.2 Process Mass Intensity (PMI)

PMI 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.

1.3 Stoichiometry of the Reagent

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. 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.

1.4 Green Chemistry: Selection of Reagent

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. 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.

1.5 Positive Impacts of Hazardous Reagent Substitution During Manufacturing

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 endproduct 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.

1.6 Catalysts: Alternative Reaction Facilitators

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.

(Continues…)

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Table of Contents

Introduction to Hazardous Reagent Substitution in the Pharmaceutical Industry;
Recyclability of Reagents;
Recoverable Polymer-supported DMAP Derivatives;
Synthesis of Atorvastatin;
Synthesis of Raloxifene;
Synthesis of Montelukast;
Development of a Safe, Scalable, Azide-free Synthesis of 1-Aryl-1H-tetrazoles Using Diformylhydrazine;
New Directions from Academia