intensity ( PMI ). 5 This metric quantifies process input mass ( e . g . solvent , water , reagents ) per mass of output produced . Typically , solvents and water are the largest contributions to PMI . Figure 1 shows how a process can be redesigned to reduce it .
The separation steps across a pharmaceutical synthesis usually contribute significantly to its PMI . The distillation and drying steps alone are often a major element of the energy requirements of a process . Typically , flow chemistry enables an increase in mass- and heat-transfer processes , avoiding temperature gradients , heat-accumulation or temperature hotspots , which can cause a loss in reaction selectivity . 6 This is also actionable for highly exothermic reactions . 7
Making the right decisions regarding chemical processes can be driven through strategic design of synthetic routes and selecting the reagents wisely . Some of the major pharmaceutical and biotech companies , created a dataset based on scaled-up reactions . 8 This contains almost 2,000 reactions , to help chemists to choose the most favourable retrosynthetic pathways for product manufacturing .
Using a PMI prediction calculator based on historical information and virtually screening through the database and predictive data
a can help to discriminate among the most efficient and plausible greener routes . Moreover , PMI calculation can provide a useful comparison between different synthetic routes and optimise a proposed synthetic step , always considering the waste management strategies .
Towards greener reactions
Progressing towards more sustainable reactions requires the development of environmentally friendly synthetic routes for both starting materials and APIs . Valuable strategies in this effort include one-pot synthesis and multicomponent reactions ( MCRs ), which are particularly effective when using multiple substrates simultaneously or sequentially in the chemical reaction .
These approaches play a crucial role in minimising intermediate purification challenges , resulting in high atom economy and significant waste reduction . Furthermore , the adoption of catalytic processes is a promising alternative , contributing substantially to waste reduction throughout the reaction .
To minimise the use of external energy within a synthesis strategy , unconventional means of energy delivery , such as microwave irradiation , sonochemistry and photochemistry , are being developed . 9 While the latter has a long history , its traditional reliance on energy-intensive UV light requiring specific equipment has led to challenges related to poor functional group tolerance .
However , a contemporary shift is underway towards utilising abundant and chemically inert visible light , even extending to infrared . Unlike thermal activation , the rapid absorption of radiation energy elevates the acceptor to a higher energy level , demonstrating tremendous potential . In medicinal chemistry , photochemistry finds frequent application in catalytic challenges and is widely integrated with flow chemistry .
Typically , the use of protection groups in the synthetic route requires additional solvents , other auxiliaries and an increase in the number of reaction steps , unless strategies are used that improve the chemoselectivity of a reaction . This can be achieved through technologies including flow chemistry , click chemistry and biocatalysis .
Enzymatic chemistry using natural biocatalysts has many benefits over their chemical counterparts , given that they are compatible with mild reaction conditions , such as ambient pressure and temperature , and can become compatible with a growing number of solvents . Another advantage of enzymes is their chemo- , regio- and stereoselectivities for specific substrates , without any need for additional derivatisation , protection and deprotection steps . 10
Case study : Boronic drugs
Organoboron compounds are isosteres of carboxylic acids . Due to the reversible electrophilicity of boronic acid groups , they are commonly used as reversible covalent groups to incorporate into peptides in order to inhibit proteases .
Boron-containing groups have been used as prodrugs , either boronic esters for their corresponding acids , such as FDA-approved
Figure 2 - Talabostat ( a ) & photochemical reaction to aminoboronic acids used in it ( b ) b
20 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981