By harnessing an enzyme-driven, solvent-free synthesis combined with a continuous flow microreactor system, the researchers achieved complete product conversion without hazardous chemicals.
Clascoterone (cortexolone 17α-propionate) is a first-in-class topical anti-androgen approved in 2020 for the treatment of acne in patients aged 12 years and older. It works by blocking androgen receptors in the skin, thereby suppressing hormonal signals that drive excess sebum production and inflammation. Beyond acne, clascoterone shows potential for managing dermatitis and eczema due to its anti-inflammatory and skin barrier–enhancing properties. Despite its therapeutic promise, conventional chemical synthesis of clascoterone faces major challenges. The final step typically involves harsh acids and toxic solvents such as acetonitrile, toluene, and chloroform. These steps not only raise environmental and safety concerns but also suffer from side reactions and incomplete conversion, leading to low yields and costly purification.
A study (DOI:10.1016/j.bidere.2025.100025) published in BioDesign Research on 30 April 2025 by Chenghua Gao & Aitao Li’s team, Hubei University, developes an eco-friendly and highly efficient method to synthesize clascoterone, paving the way for safer, cost-effective, and scalable industrial manufacturing.
To address the limitations of conventional solvent-based synthesis of clascoterone, the researchers designed a systematic strategy combining enzyme catalysis with solvent-free processing. They began by replacing hazardous aprotic solvents with alcohols that could serve dual roles—as both reaction medium and alcohol donor—for the regioselective alcoholysis of cortexolone dipropionate. Methanol, ethanol, isopropanol (IPA), and isobutanol (IBA) were evaluated under controlled conditions, and the impact of alcohol proportion on conversion efficiency was carefully studied. The team then conducted a broader screening of alcohol donors, focusing on those with carbon chain lengths of three to six, while excluding longer-chain alcohols, diols, and triols due to impractical cost or handling constraints. Based on cost, reactivity, and operational feasibility, IPA was ultimately selected as the optimal solvent and donor. With this foundation, the researchers optimized the reaction by systematically varying enzyme loading and temperature. Enzyme concentration was increased up to 25 g/L, with efficiency plateauing beyond 20 g/L, while temperature optimization identified 50–60 °C as the range for maximal catalytic activity without compromising enzyme stability. Finally, to overcome kinetic bottlenecks inherent to batch reactors, the process was transferred to a continuous-flow microreactor system. IPA and IBA proved superior to methanol and ethanol, maintaining high conversion efficiencies even at elevated proportions, with IPA achieving greater than 90% efficiency as the sole reaction medium. Broader screening confirmed branched alcohols as more effective than linear analogues, reinforcing IPA as the practical choice for industrial application. Under optimized batch conditions, a conversion rate of 98.3% was achieved within 24 hours, though further progress was limited by mass transfer constraints. Transitioning to the microreactor system overcame these barriers, enabling full conversion (>100%) at a substrate concentration of 4 g/L with residence times over 94 minutes. The apparent rate constant rose dramatically to 3.586 h⁻¹, more than thirty times higher than in batch reactors, demonstrating the superior efficiency, selectivity, and scalability of the microreactor-based process.
The new process marks a major advance in pharmaceutical manufacturing. By eliminating toxic solvents, the method reduces environmental risks and simplifies purification, cutting down both cost and waste. The use of immobilized enzymes in a solvent-free, flow-based system also enhances reproducibility and scalability, key requirements for industrial adoption. Beyond clascoterone, this platform technology could be applied to a wide range of steroid drugs that require selective esterification, such as betamethasone valerate, as well as other bioactive molecules where regioselective modification is essential.
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References
DOI
10.1016/j.bidere.2025.100025
Original Source URL
https://doi.org/10.1016/j.bidere.2025.100025
Funding information
This work was funded by the National Key Research and Development Program of China (2019YFA0905000) and was supported by the Key Science and Technology Innovation Project of Hubei Province (No. 2021BAD001), the Innovation Base for Introducing Talents of Discipline of Hubei Province (No. 2019BJH021) and the Research Program of State Key Laboratory of Biocatalysis and Enzyme Engineering.
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