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In our modern life, our quality of life has become strongly dependent on the various products of industrial organic synthesis. These various products include antibiotics to cure infectious diseases, analgesics to alleviate pain, blood pressure regulating drugs, oral contraceptive pills and steroids.
The origins of the pharmaceutical industry dates back to 1912 when the German researcher Paul Ehrlich discovered acriflavine, a dye obtained from cal tar which was used as an antiseptic in World War I to kill the parasites that cause sleeping sickness (Encyclopaedia Britannia Online, 2011), caused by protozoa of the species Trypanosoma brucei and transmitted by the tsetse fly (U.S. National Library of Medicine, 2011). Acriflavine was eventually also used in the treatment of gonorrhoea before it was then replaced by the antibiotics (Encyclopaedia Britannia Online, 2011).
In 1921, Sir Alexander Flemming discovered the bacteriolytic substance Lysozyme in tissues and secretions and in 1928 he discovered that a mould culture that he accidently cultured on a culture plate prevented the growth of staphylococci. He named this mould penicillin which was then produced by the pharmaceutical industry as an antibiotic in the treatment of infections. In 1945 Flemming was award the Noble prize in medicine for this discovery (Nobleprize.org, 2011). Another important discovery which also led to the joint award of the noble prize in medicine in 1923 was the discovery of insulin by Frederick Grant Banting and John James Rickard Macleod (Nobleprize.org, 2011). Both discoveries resulted in significant growth for the pharmaceutical industry.
With time the pharmaceutical industry expanded rapidly due to new discoveries which lead to increase in regulations and legislations by bodies such as the U.S. Food and Drug Administration (FDA).
Over the past few years, it has become evident that the discoveries and achievements of organic synthesis were developed in an era when the toxic properties or the reagents and solvents used during the synthesis were not yet known. Now, it is evident that the pharmaceutical industry is responsible for great quantities of hazardous toxic wastes that are created and released into the environment. This has lead to introduction of green chemistry and sustainable chemistry, the recycling and reusage of chemicals, and laws that impose the treatment of used chemicals to render them less hazardous and proper disposal of industrial waste.
In 1994, the concept of Benign by design Chemistry was presented by Paul T. Anastas from the U.S. environmental protection agency (Anastas, 1994). In Benign by design chemistry, it is emphasized that synthetic chemists should be concerned about the environment and pollution prevention and must avoid at all costs environmental problems that are usually caused during chemical synthesis.
In the early 1960s and 1970s the government allowed the release of toxic products into the environment in certain limited quantities. Eventually with time, it was required that waste produced by the industry is treated before it is released into the environment. Now, the trend is that the way to deal with pollution is not to create it in the first place, that is to reduce and prevent pollution at its source (Anastas, 1994). In 1991, Anastas and Warner, developed the 12 principles of Green Chemistry (Sigma Aldrich, 2011).
It is easier and better to prevent the generation of waste then to treat it and clean it up. When synthetic routes are developed this should be kept in mind so as to prevent waste generation during synthesis (Environmental Protection Agency, 2010).
Atom Economy/ synthetic efficiency
Atom economy was introduced by Trost in 1991 (Li & M, 2008) who presented a set of guiding principles for evaluating the efficiency of a chemical process and which were then included and incorporated into the twelve principles of Green chemistry (Li & M, 2008).
Atom economy describes the efficiency of a chemical process by calculating the required quantity of raw material and reactants in a chemical process and how much of this quantity was converted into the desired product.
During the development of synthetic routes, the higher the ratio of starting material that is incorporated into the final product, the better (Environmental Protection Agency, 2010).
If maximum incorporation of the starting materials into the final product cannot be achieved then ideally, the quantities of side products should be minute and environmentally innocuous.
Less Hazardous Chemical Synthesis
During the design of synthetic routes, substances that are generated should be those that possess no toxicity or little toxicity to humans and the environment (Environmental Protection Agency, 2010).
Designing Safer Chemicals
When designing chemical products, focus on minimizing the toxicity of such chemicals on the environment and humans must be considered and at the same time they are designed to carry out their desired function (Environmental Protection Agency, 2010)
Safer Solvents and Auxiliaries
The use of auxiliary substances such as solvents and separation agents should be avoided during chemical reactions and synthesis (Environmental Protection Agency, 2010). The largest amount of auxiliary waste is associated with solvent usage. Gonzales et al., state that 80% of the waste generated by the API industry is related to solvent use (Tucker, 2006).
Although solvents are not an integral part of the compounds undergoing the reaction, they are used for example for dissolving reactants, for extractions, for separating mixtures and for cleaning reactors.
As part of Green chemistry efforts, cleaner solvents or replacements are trying to be used today.
The best solvent is water which is the only natural solvent. There were various studies that show that water can be used as a solvent for organic reactions to take place one of which was published in 1980, where Rideout and Breslow reported that Diels Alder reactions could be greatly accelerated by using water as a solvent instead of organic solvents (Rideout DC, Breslow R (1980) Hydrophobic acceleration of Diels-Alder reactions. J AmChem Soc 102:7816-7817. As cited in (Li & M, 2008)) .
Carbon dioxide is also another green solvent with the advantages that it is renewable, non-flammable, and readily evaporating. It has a fast drying time, great ability to dissolve organic compounds, and an excellent flow ability because of its low viscosity compared with other solvents including water. One special feature of liquid and supercritical CO2 is its high mixability with gases, which offers high efficiency (and often higher selectivity) in reactions
such as hydrogenations with hydrogen gas and oxidations with air (Beckman EJ (2003) Oxidation reactions in CO2: Academic exercise or future green processes? Environ Sci
Technol 37:5289-5296. ). Another feature of CO2 is its rapid separation from catalysts and products by simple depressurization and recapture (Li & M, 2008).
Design for Energy Efficiency
Energy requirements of chemical processes should minimised and when possible, synthesis should be conducted at ambient temperature and pressure (Environmental Protection Agency, 2010)
Use of Renewable Feedstocks
Ideally renewable raw materials or feedstock should be used if it is technically and economically practicable (Environmental Protection Agency, 2010)
Derivatization (use of blocking groups, protection/ deprotection, temporary modification of physical/chemical processes) should be minimized or avoided as such processes require additional reagents which result in an increase in the total waste produced (Environmental Protection Agency, 2010).
Catalytic reagents are superior to stoichiometric reagents as catalytic reactions use small quantities of chemicals for transformation to take place (Environmental Protection Agency, 2010).
A prime cause of high amounts of waste generated per kilogram of product (E factor) is due to the use of stoichiometric inorganic reagents for reactions such as reductions with metals and metal halides, oxidations with permanganate and dichromate, friedel-crafts acylations and nitrations (Sheldon, 1997). This can be prevented by using clean catalytic technologies such as catalytic hydrogenation/reduction, oxidation and carbonylation.
An example of a catalytic hydrogenation/reduction is reductive O-alkylation:
R1CHO + R2OH + H2 â†’ R1CH2OR2 + H2O
which can be used to replace the Williamson ether synthesis reaction:
R1CH2Cl + R2ONa â†’R1CH2OR2 + NaCl
which produces stoichiometric amounts of sodium chloride (Sheldon, 1997).
Reactions involving catalytic oxidation using mild oxidants such as hydrogen peroxide play an important role in the reduction of the E factor and increasing the atom efficiency of a reaction. Hydrogen peroxide is widely used since it is convenient to handle, it isn't very costly and its only by-product is water (Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977-1986. As cited in (Gharnati, Döring, & Arnold, 2009).
Two examples were catalytic oxidation can be used is during the oxidation of secondary and benzylic alcohols to ketones and aldehydes respectively using hydrogen peroxide and imidazolium decatungstate as a catalyst (Gharnati, Döring, & Arnold, 2009).
The oxidation of a secondary alcohol into a ketone using imidazolium decatungstate as a catalyst and hydrogen peroxide (Gharnati, Döring, & Arnold, 2009).
The oxidation of a benzylic alcohol into an aldehyde using imidazolium decatungstate as a catalyst and hydrogen peroxide (Gharnati, Döring, & Arnold, 2009).
An important industrial reaction involving catalytic carbonylation is the monsato process. The monsato process involves the use of methanol and carbon monoxide in the presence of Rhodium- Iodine ion co-catalysts to produce acetic acid at 150 - 200°C and 30-60 atmospheres (Jones, 2000).
Design for Degradation
Chemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment ie they are biodegradable (Environmental Protection Agency, 2010).
Real-time analysis for Pollution Prevention
To avoid the formation and to control hazardous substances, real-time analysis and in process monitoring should be conducted during synthesis (Environmental Protection Agency, 2010).
Inherently Safer Chemistry for Accident Prevention
Substances used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions, and fires (Environmental Protection Agency, 2010).
Impact of Solvent Use by the Pharmaceutical industry
Organic solvents are used in many pharmaceutical products. in some, the solvents are used during the manufacture of the drug product and in some such as rubbing alcohol, the solvent is the product itself.
Solvents are used during the whole process of the manufacture of the drug, starting from the production of the API and its purification, the blending of the material into its final form (American Chemistry Council, 2011) and the cleaning of the various equipment that was used during the process.
Approximately, solvents contribute 50% of the materials used in the manufacture of bulk APIs (Hargreaves & Manley, 2009). It has also been calculated that for the manufacture of a batch, 80-90% of the total mass in the process, is due to solvents [Constable , D.J.C. , Jiménez - González , C. , and Henderson , R.K. ( 2007) Org. Process Res. Dev. , 11 , 133 - 137 .] as cited in (Slater & Savelski, 2009).
Composition of Process mass intensity showing that solvents and water contribute to â‰ˆ80% of the process mass intensity (Hargreaves & Manley, 2009).
Since these solvents are not used up in the stoichiometric reactions, after they are used, they are either recycled or disposed of as waste. This is very significant as the amount of waste generated from the process ranges from 25 to over than 100kg of solvent per kilogram of API ( Sheldon, 1997 as cited in (Slater & Savelski, 2009)).
The Solvent Life cycle
The major stages of the Solvent life cycle are: manufacture, transportation, usage and ultimate disposal. This shows that reductions in solvent use and recycling does not only reduce the waste generate by the manufacturing process, but also the waste generated to manufacture such solvent. It also means that there are less expenses due to transportation of the solvent and hence a reduction of CO2 emissions into the atmosphere during transportation.
Today, many processes are designed in a way so as to reduce the amount of solvents used and to recycle the solvents that are used in the process so as to save costs on fresh solvents and their disposal.
Figure shows the life cycle of a solvent.
Figure Life cycle flow chart for solvent usage. Primary life cycle stages are represented by rectangles (Clark & Tavener, 2007)
Solvents are mostly manufactured from petrochemical feedstocks by the cracking and distillation of the crude oil fraction. There are also those solvents that are obtained from by-products from other chemical reactions (Clark & Tavener, 2007). Such solvents include acetone and acetonitrile. Acetone is the by-product in the manufacture of propylene oxide, acetic acid and hydroquinone (Reed Business Information Limited, 2011) , while acetonitrile is the by-product from the manufacture of acrylonitrile which is used in plastic products and resins (Major, 2009).
Since the solvent has to distributed from the place of manufacture to the site where it will be used, ideally the solvent must be chosen from a local supplier to reduce the costs of transport and the environmental impact of transportation (CO2 emissions into the atmosphere) on the environment.
Manufacturing processes are usually designed to have minimal involvement of solvents and those solvents which are used in the process are then recovered, recycled and reused in the subsequent processes. The energy involved to recovery and purify used solvents, is taken into account when designing the process. It is estimated that about 50% of the total energy that is used in the chemical processes is to purify the products and used in recycled streams. In the case of biphasic systems, separation and recovery of solvents is very efficient and less energy intensive (Clark & Tavener, 2007).
Solvent choice is very important during the design of the manufacturing process. The dielectric constant, viscosity, density, polarity, melting point, reactivity, flash point and volatility of the solvent should be considered. For example fluorous solvents are highly advantageous, as they distill quite easily due to their medium - high volatility and so they don't require a high energy input when compared to other liquids such as ionic liquids which have low volatility.
Figure Typical polarity and volatility characteristics of alternative reaction media (Clark & Tavener, 2007)
During the process of solvation, the molecules of the solvent interact usually via electrostatic forces, Van der Waals forces or hydrogen bond formation, with the molecules or ions of the solute. The molecules or ions of the solute are then surrounded by the solvent molecules. (IUPAC, 2010).
Energy is required to break the attractions between the solvent-solvent and solute-solute interactions (free energy). When the ions of the solute are released from the crystal lattices and associate with the molecules of the solvent, energy is released (energy of solvation). In order for the solvent to dissolve a compound, the solvation energy of the system must be greater than that of free energy (Clark & Tavener, 2007).
Figure Free Energy diagram for solvent-solute interaction (Clark & Tavener, 2007)
This is particularly useful, when deciding which solvent to use for dissolution of a solute in a system to prevent the use of superheating the solvent and therefore an increase in energy consumption or the addition of surfactants (Clark & Tavener, 2007).
Even though solvents maybe recycled or reused via recovery methods such as distillation and biphasic separation, eventually the solvent will be disposed of. Volatile organic solvents are usually incinerated and the heat energy from the process can be recovered at the same time. Supercritical CO2 is not hazardous to the environment and it is released to the environment by venting the reaction. Waste water from aqueous phase reactions has to be thermally or biologically treated before it is released into the environment (Clark & Tavener, 2007).
Figure Solvent incineration flow chart (Clark & Tavener, 2007)
The use of solvents during the synthesis of the API
The manufacture of an active pharmaceutical, involves various multiple reactions, requiring various raw materials (including solvents) and generating high quantities of wastes and emissions. The wastes and emissions not only depend on the raw materials used during the manufacture of the drug but also on the equipment used and the manufactuing process that is employed.
The steps for the manufacture of the drug product are namely chemical synthesis, separation techniques such crystallisation, purification and drying of the API. This is then followed by formulation, mixing and compounding operation to convert the manufactured API into a final usable dosage form (United States Environmental Protection Agency, 1997).
According to GMP, all raw materials including solvents must be tested according to set specifications to confirm their identity and quality before their use in the manufacturing process.
Apart from the testing of raw materials, in process controls such as pH testing, KF analysis and assay should also be carried out during the manufacture of the drug.
For the finished drug product, apart from testing the product for quality, all documentation must be checked by the Head of production and the quality assurance department to make sure that manufacture was done as required by the laws of GMP and to also make sure that the obtained yield of the batch is within the limits of the theoretical yield (McGraw Hill Encyclopedia of Technology a cited in (United States Environmental Protection Agency, 1997)).
Figure shows an example of a chemical synthesis process, showing the equipment used during the reactions and the points where wastes and emissions might be generated.
(United States Environmental Protection Agency, 1997)
The process starts with the addition of the raw materials, usually consisting of at least one solvent into a batch reaction vessel such as the kettle-type reactor shown in figure.
(United States Environmental Protection Agency, 1997)
Liquids are drawn into the reactor from drums and storage tanks by pumping or vacuum while solids are usually fed manually into the reactor or in some cases through a vacuum system. Once the raw materials are fed into the reactor, the reaction takes place (United States Environmental Protection Agency, 1997). The reaction is controlled by the operators and by automated computer systems such as the SCADA (supervisory control and data acquisition).
Reactors are usually attached to condensers and distillation columns so that spent solvents may be recovered so that they can then be reused for the same process next time the manufacture takes place or sold to other industries for other processes. Apart from condensers and distillation columns, reactors usually have air pollution control devisies attached to them, the control the emission of volatile organic compounds from vented gases (United States Environmental Protection Agency, 1997).
Once the reaction takes place, it is vital to separate the substance from the reaction solution and to remove any impurities. A washing and a separation step such as extraction, decantation, centrifugation and crystallisation is carried out. Extration and crystallisation are carried out using solvents and at this stage the quantity of solvents used is usually higher than the quantity used during the reaction stage (United States Environmental Protection Agency, 1997).
Liquid mixtures are separated on the basis of their differences in their solubility. A solvent is usually added and this solvent will preferentially combine with one of the components of the mixture. Extractions are carried out in various equipment such as agitated reaction vessels, vertical cylinders, or in a column with internals to mechanically enhance the contact between the two liquid phases (Crume et al., 1992) (United States Environmental Protection Agency, 1997).
Crystallization is a commonly used separation technique where a supersaturated solution is created so that crystals of the desired compound are obtained The degree of supersaturation depends on the solubility of the desired compound. If the solubility increases with temperature, supersaturation can be achieved by cooling the solution. If the solubility is independent of or decreases with temperature, then evaporating a portion of the solvent will create supersaturation. Supersaturation can also be induced by adding a third component in the system. The third component forms a mix with the original solvent in which the solute is considerably less soluble (USEPA 1979) (United States Environmental Protection Agency, 1997).
In the case of carrying out crystallisation by cooling the solution, there will be relativley little volatile organic compound emmisions. But if cyrtallisation is done by solvent evapoartion, the potential for VOC emission will be higher (USEPA 1993) (United States Environmental Protection Agency, 1997).
After the separation stages are carried out, purification of the drug is carried out in order to make sure that the level of impurities are kept to a minimum. This is usually achieved through additional sepration stages, many by recrystallization. At this stage, any solvents that were used during the reaction and the seperation step are removed from the products, generating solvent waste.
The final step in the chemical synthesis of a drug is the drying stage which removes any residual solvents. This step release additional solvent wastes and volatile organic compounds into the environment (United States Environmental Protection Agency, 1997).
Uses of solvents for the cleaning of equipment used in the sysntehsis of the API
Synthetic API manufacturing involves many pieces of equipment for reaction and separation processes. Such equipment include glass lined reactors, blenders, centrifuges, dryers and various piping equipment associated with such equipment.
The cleaning process is a lengthy one and it uses large quantities of solvents. The process starts with the introduction of the solvent into the reactors, cirulation of the solcvent through al the pipes and equipment and then the solvent is heated and refluxed through an overhead riser and condenser so as to wet the surfaces and remove any residues by dissolution in the solvent. This process is usually repeated from 5-10 times in order to remove all residues that would have remained from the manufacture process (Verghese, 2003).
A variety of materials such as glass, polytetrafluoroethylene (PTFE), hastelloy, stainless steel and polymers are used in the construction of process equipment (Verghese, 2003). When cleaning such equipment care must be taken when choosing the material to clean it with. For example methanol is a solvent which is fequrently used during the manufacture of APIs and hence it is ideal to used it for the cleaning of the equipment that was used for the process. The idea behind using the same process solvent that was used during the manufacutre of the API for the cleaning of the equipment is due to the fact that it will most likely be the solvent in which the API is will be the most soluble in (Verghese, 2003). Methanol, is compatible with many materials but care must be taken if in any part of the equipment is reinforce with an elastomer such as the PVC tygon due to its poor solvent resistance (McConvile, 2002). Apart from methanol, other solvents which are frequently used to clean equipment are acetone, dimethyl formamide and ethyl acetate (Verghese, 2003).
Apart from the fact that APIs are usually soluble in organic solvents, other advantages of using organic solvents include the availability of such solvents since they are used in the manufacturing process and since most of the time the same solvent will be used in the next batch, solvent residue analysis in the equipment may be simple or not necessary (Verghese, 2003).
Although, it has been mentioned that the chances of the API being soluble in organic solvents is high, care has to be taken with degredation products of the active ingredient as these may be present in the equipment to be cleaned and they might not be soluble in the solvent. Also, care must be taken when handling solvents, as most of them are highly flammable and toxic if inhaled.
Solvent substitution and the use of aqueous cleaning for API manufacturing processes have been driven by a number of factors. These include environmental and health and safety issues which have led to various regulatory pressures and laws, the relatively high costs of solvents and problems with storage and disposal (Verghese, 2003).
Source: Development Document for Proposed Effluent Limitations Guidelines and Standards for the Pharmaceutical Manufacturing Point Source Category, US EPA, Washington, DC., February 1995. (United States Environmental Protection Agency, 1997)
Applicable regulations in the US include 40 CFR Parts 9 and 63 National Emission Standard for Hazardous Air Pollutants (NESHAP), and the pharmaceutical Maximum Achievable Control Technology (MACT) standards. Water effluent limit guidelines are covered under 40 CFR Parts 136 and 439. (Verghese, 2003).