Number

297-EN

Section

General Section

Use

Abstract

This case story describes how using enzymatic processes instead of chemical processes may result in substitution of hazardous substances. Fewer steps during synthesis and low solvent use are the major benefits. Energy savings, fewer safety and disposal issues, and improved product quality also lead to cost benefits.

Substituted substances

Alternative Substances

Reliability of information

Evidence of assessment: there is evidence of an official (positive) assessment of the substitution
Evidence of implementation: there is evidence that the solution was implemented and in use at time of publication

Reason substitution

other toxic effects
ecotoxicity
CMR
neurotoxicant

Other type of alternative

Enzymatic processes

Hazard Assessment

Substances to be substituted: Reactants and solvents in the substituted process are a mixture of very toxic and carcinogenic substances. Dichloromethane is a Substance of very high concern and is included on the REACH restriction list, according to Article 73 of Regulation (EG) No. 1907/2006. (REACH Regulation). Ammonia is added as a pH-stabiliser in an alternative process. It is not listed on the SDSC. N,N-Dimethylaniline is not listed in the SUBSPORTplus Database. Phosphorus pentachloride is not listed in the SUBSPORTplus Database. Dichloro(dimethyl)silane has (v)P(v)BT properties, according to Annex of Regulation (EG) No. 1907/2006. (REACH Regulation). Dichloromethane is a Substance of very high concern and is included on the REACH restriction list, according to Article 73 of Regulation (EG) No. 1907/2006. (REACH Regulation). Butan-1-olis not listed in the SUBSPORTplus Database. Alternative substances: Ammonia, anhydrous is not listed in the SUBSPORTplus Database. Water is not listed in the SUBSPORTplus Database and has no harmonised classification according to Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation). Biocatalyst There is no detailed information on the used enzymes.

Description of Substitution

Biotechnological processes are usually performed at room temperature, using water as a solvent, because no large amounts of toxic substances or heavy metals are necessary. The wastewater can then be purified essentially by biological treatment. This makes biotechnological production advantageous from both an environmental and economic point of view, compared to chemical methods. Active substances in this case story are enzymes. They can be used in solution or fixed on a substrate, or as part of a polyfunctional enzymatic system, e.g. in living cells, free in a reaction medium or fixed on a substrate. This good practice example illustrates an enzymatic conversion of Penicillin G to 6-aminopenicillanic acid. Penicillin G is an antibiotics derived from Penicillium fungi. Penicillin antibiotics are the first medicines that were effective against many previously serious diseases. They are still widely used in the treatment of bacterial infections caused by susceptible, usually Gram-positive, organisms. 6-aminopenicillanic acid is used as the main starting block for the preparation of numerous semisynthetic penicillins. The following table illustrates consumption levels for the conversion of 1000 t Penicillin G.

Chemical method	Enzymatic method
Consumption of reactants
1000 t Penicillin G, potassium salt	1000 t Penicillin G, potassium salt
800 t N,N-dimethylaniline
600 t Phosphorus pentachloride
300 t Dimethyldichlorosilane
	45 t Ammonia
	0,5 – 1 t Biocatalyst
Consumption of solvents
10000 m3 Water
4200 m3 Dichloromethane
4200 m3 Butanol

There are still other products that can be prepared using enzymatic methods with environmental advantages:
•Aspartame
•7-amino cephalosporanic acid
•Anticonvulsive LY300164.

Case/substitution evaluation

Preparation of 6-aminopenicillanic acid can take place in two ways: chemical and enzymatic. According to this report the enzymatic report is favourable from an economic and environmental point of view. The SUBSPORTplus team is not aware of potential disadvantages with the method described, although the utilised biocatalyst is not described in detail.

State of implementation

In use

Availability of Alternative

on the market

Type of information supplier

Authority
Research

Type of publication and availability

Free available

Publication source: author, company, institute, year

European Commission (2006) Reference Document on Best Available Techniques for the Manufacture of Organic Fine Chemicals.

Date, reviewed

November 26, 2021