Design and optimization of a greener sinomenine hydrochloride preparation process considering variations among different batches of the medicinal herb

The current methods used to industrially produce sinomenine hydrochloride involve several issues,including high solvent toxicity,long process flow,and low atomic utilization efficiency,and the greenness scores of the processes are below 65 points.To solve these problems,a new process using anisole as the extractant was proposed.Anisole exhibits high selectivity for sinomenine and can be connected to the subsequent water-washing steps.After alkalization of the medicinal material,heating extraction,water washing,and acidification crystallization were carried out.The process was modeled and optimized.The design space was constructed.The recommended operating ranges for the critical process parameters were 3.0–4.0 h for alkalization time,60.0–80.0℃ for extraction temperature,2.0–3.0(volume ratio)for washing solution amount,and 2.0–2.4 mol·L^(-1) for hydrochloric acid concentration.The new process shows good robustness because different batches of medicinal materials did not greatly impact crystal purity or sinomenine transfer rate.The sinomenine transfer rate was about 20%higher than that of industrial processes.The greenness score increased to 90 points since the novel process proposed in this research solves the problems of long process flow,high solvent toxicity,and poor atomic economy,better aligning with the concept of green chemistry.

Design and optimization of purification process of sinomenine hydrochloride

Sinomenine hydrochloride is generally produced from Caulis Sinomenii. At present, the purification process in industrial production suffers from large amount of solid waste, high solvent toxicity, and low sinomenine hydrochloride yield. In this study, a new purification process for sinomenine hydrochloride was proposed by using the extract obtained from acid extraction of Caulis Sinomenii as the starting material.The process included the following steps: alkalization, extraction, water washing, acid–water stripping,drying, and crystallization. 1-Heptanol was used as the extractant. The distribution coefficients of sinomenine and sinomenine hydrochloride in 1-heptanol–water system were 27.4 and 0.0167, respectively.The dissociation constants of sinomenine hydrochloride were 8.27 and 11.24, respectively. Process parameters of the new purification process were optimized with experimental design. The extractant1-heptanol and sinomenine hydrochloride in the crystallization mother solution can be recycled in the new process. The purity of the obtained sinomenine hydrochloride crystals exceeded 85%, and the yield was about 70%. Compared with current industrial processes, safer extractant, less solid waste, and higher sinomenine hydrochloride yield can be achieved using the new purification process of sinomenine hydrochloride provided in this study.

Preparation and evaluation of sinomenine hydrochloride patch

The sinomenine hydrochloride （SH） patch, a topical drug delivery system, was prepared and characterized. The in vitro release was studied according to the paddle-over-disk method in the appendix of Chinese Pharmacopeia （appendix XD, 2005）. Stability of SH patch was evaluated at accelerated testing conditions （40 ℃, 75% RH）. Pharmacological and pharmacokinetics study were also performed. It was found that the release of SH from patches depended on pH value of the release medium. There were no significant differences between SH patches stored for 6 mon and those stored for 0 mon in the drug content, initial adhesion, lasting stickiness, peeling strength and in vitro release. SH patches exhibited better anti-inflammatory activity as well as analgesic efficacy. More importantly, primary pharmacokinetic parameters of SH patch, such as Cmax and AUC, were much lower than those of SH solution dosed orally. In conclusion, the patch might be a promising delivery system for SH, which bypassed the gastrointestinal tract and was a convenient, efficacious, safe and non-invasive delivery method.