Some reactions use water as a solvent, for example in the manufacture of inorganic compounds such as , , , and organic compounds such as and . Water is not a harmful solvent but it is a precious resource and it is important to ensure that it is not wasted.
Pharmaceutical chemistry is becoming increasingly complex with multi-step processing, where the product from one step becomes a starting material for the next step, until the finished drug product is synthesized. Bulk chemicals which are intermediates of the finished product may be transferred between organic synthesis plants for various technical, financial and legal considerations. Most intermediates and products are produced in a series of batch reactions on a campaign basis. Manufacturing processes operate for discrete periods of time, before materials, equipment and utilities are changed to prepare for a new process. Many organic synthesis plants in the pharmaceutical industry are designed to maximize their operating flexibility, due to the diversity and complexity of modern medicinal chemistry. This is achieved by constructing facilities and installing process equipment that can be modified for new manufacturing processes, in addition to their utility requirements.
Process safety programmes are implemented in the pharmaceutical industry due to the complex chemistry, hazardous materials and operations in bulk chemical manufacturing (Crowl and Louvar 1990). Highly hazardous materials and processes may be employed in multi-step organic synthesis reactions to produce the desired drug substance. The thermodynamics and kinetics of these chemical reactions must be evaluated, since they may involve highly toxic and reactive materials, lachrymators and flammable or explosive compounds.
Organic synthesis reactions may create major process safety risks from highly hazardous materials, fire, explosion or uncontrolled chemical reactions which impact the community surrounding the plant. Process safety can be very complex in organic synthesis. It is addressed in several ways: by examining the dynamics of chemical reactions, properties of highly hazardous materials, design, operation and maintenance of equipment and utilities, training of operating and engineering staff, and emergency preparedness and response of the facility and local community. Technical guidance is available on process hazard analysis and management activities to reduce the risks of chemical synthesis operations (Crowl and Louvar 1990; Kroschwitz 1992).
Wastes from chemical synthesis are complex due to the variety of hazardous materials, reactions and unit operations (Kroschwitz 1992; Theodore and McGuinn 1992). Organic synthesis processes may generate acids, bases, aqueous or solvent liquors, cyanides and metal wastes in liquid or slurry form. Solid wastes may include filter cakes containing inorganic salts, organic by-products and metal complexes. Waste solvents in organic synthesis are usually recovered by distillation and extraction. This allows the solvents to be reused by other processes and reduces the volume of liquid hazardous wastes to be disposed of. Residues from distillation (still bottoms) need to be treated before they are disposed. Typical treatment systems include steam stripping to remove solvents, followed by microbiological treatment of other organic substances. Volatile organic and hazardous substance emissions during organic synthesis operations should be controlled by air pollution control devices (e.g., condensers, scrubbers, venturi impingers).
Acute and chronic health risks may result from worker exposures to hazardous chemicals during synthesis operations. Chemicals with acute health effects can damage the eyes and skin, be corrosive or irritating to body tissues, cause sensitization or allergic reactions or be asphyxiants, causing suffocation or oxygen deficiency. Chemicals with chronic health effects may cause cancer, or damage the liver, kidneys or lungs or affect the nervous, endocrine, reproductive or other organ systems. Health and safety hazards may be controlled by implementing appropriate control measures (e.g., process modifications, engineering controls, administrative practices, personal and respiratory protective equipment).
In the , the product itself is used as the solvent. However, other reactions use organic solvents which readily evaporate into the atmosphere unless great care is used to contain them. Wherever possible alternative solvents are used which are not harmful, one example being the , which are replacing paints that use volatile organic compounds such as the hydrocarbons which are harmful to the atmosphere. Supercritical (liquid) carbon dioxide is widely used as a solvent in the extraction of caffeine from coffee beans and in the latest drycleaning equipment it replaces chlorinated solvents such as perchloroethene, C2Cl4.
Chemical synthesis processes use organic and inorganic chemicals in batch operations to produce drug substances with unique physical and pharmacological properties. Typically, a series of chemical reactions are performed in multi-purpose reactors and the products are isolated by extraction, crystallization and filtration (Kroschwitz 1992). The finished products are usually dried, milled and blended. Organic synthesis plants, process equipment and utilities are comparable in the pharmaceutical and fine chemical industries. A schematic diagram of an organic synthesis process is given in .
In organic chemistry, some types of reaction have inherently better atom economies. Addition, condensation and rearrangement reactions will generally have higher atom economies than either elimination or substitution. For example the addition of chlorine to ethene, to form 1,2-dichloroethane (an important reaction in the manufacture of poly(chloroethene) (PVC)) has an atom economy of 100%:
Waste water from synthesis operations may contain aqueous liquors, wash water, discharges from pumps, scrubbers and cooling systems, and fugitive leaks and spills (EPA 1995). This waste water may contain many organic and inorganic substances with different chemical compositions, toxicities and biodegradabilities. Trace amounts of raw materials, solvents and by-products may be present in aqueous mother liquors from crystallizations and wash layers from extractions and equipment cleaning. These waste waters are high in BOD, COD and TSS, with varying acidity or alkalinity and pH values ranging from 1 to 11.
Basic production of bulk drug substances may employ three major types of processes: fermentation, organic chemical synthesis, and biological and natural extraction (Theodore and McGuinn 1992). These manufacturing operations may be discrete batch, continuous or a combination of these processes. Antibiotics, steroids and vitamins are produced by fermentation, whereas many new drug substances are produced by organic synthesis. Historically, most drug substances were derived from natural sources such as plants, animals, fungi and other organisms. Natural medicines are pharmacologically diverse and difficult to produce commercially due to their complex chemistry and limited potency.
It is very desirable to develop manufacturing processes with less hazardous solvents. Ethyl acetate, alcohols and acetone are preferable to highly toxic solvents such as benzene, chloroform and trichloroethylene. Whenever possible, some materials should be avoided due to their physical properties, ecotoxicity or persistence in the environment (e.g., heavy metals, methylene chloride) (Crowl and Louvar 1990). Substituting aqueous washes for solvents during filtrations in bulk chemical production reduces liquid wastes and vapour emissions. Also, substituting aqueous for solvent-based solutions during tablet coating reduces environmental, health and safety concerns. Pollution prevention is promoted by improving and automating process equipment, as well as performing routine calibration, servicing and preventive maintenance. Optimizing organic synthesis reactions increases product yields, often decreasing the generation of wastes. Incorrect or inefficient temperature, pressure and material control systems cause inefficient chemical reactions, creating additional gaseous, liquid and solid wastes.