In a stirred tank reactor, during catalysis with immobilized cephalosporin C acylase (CCA), the microenvironmental pH dropped to 7.2 in a nonbuffered system (with the pH maintained at 8.5 by adding alkali) due to the existence of diffusional resistance. Moreover, the immobilized CCA only catalyzed five batch reactions, suggesting that the sharp pH gradient impaired the enzyme stability. To buffer the protons produced in the hydrolysis of cephalosporin C by CCA, phosphate and bicarbonate buffers were introduced. When CCA was catalyzed with 0.1 M ammonium bicarbonate buffer, no obvious gradient between the bulk solution and intraparticle pH was detected, and the catalysis of 15 batch reactions was achieved. Accordingly, with 0.2 M ammonium bicarbonate buffer in a packed bed reactor, the immobilized CCA exhibited continuous catalysis with high conversion rates (≥95%) for 21 days. Reactions with ammonium bicarbonate buffer showed significant increases in the stability and catalytic efficiency of the immobilized CCA in different reactors compared to those in nonbuffered systems.
Shudong Zhang,Qiang Wan,Xiaolin Xu,Yidan Xing,Jiafeng Ding,Shizhuang Yang,Weiwei Sun,Mengmeng Lu,Baoliang Pan
The objective of this study was to evaluate a novel oil-based suspension as a potential parenteral drug delivery system for drugs with poor water solubility. Most of the new active pharmaceutical ingredients are weak acid or basic drugs with pH-dependent solubility. To limit this dependence, use of micro-environmental pH-modifying solid dispersions (micro pHm SD) has been proved to increase the bioavailability of these drugs. Toltrazuril (TOL), a weakly acidic drug with poor aqueous and pH-dependent solubility, was studied as a model drug. Recently, studies on TOL with focus on the parenteral injection are rarely to find in the literature. A novel parenteral oil-based TOL suspension was prepared containing TOL micro pHm SD (TSD) powders suspended in oil-based vehicles and the optimal formulation was screened. The stability of this formulation was assessed considering particle size distribution, settling volume ratio, redispersibility, thermal stability, and drug content. The optimized white oil-based TOL pHm SD suspension (W-TSDS) showed significant improved stability and shear-thinning behavior. In particular, fumed silica as suspending agent positively influenced the physical stability of the formulation. Furthermore, W-TSDS showed good injectability using 21 G needles and more rapid and sustained drug release compared to TSD powders in vitro. In the in vivo safety evaluation, W-TSDS showed good histocompatibility in rabbits injected subcutaneously or intramuscularly. We believe these findings provide an alternative choice of dosage form for the delivery of new active pharmaceutical ingredients.
Drugs with pH-dependent solubility that have poor water solubility can be identified in the drug discovery pipeline. Some of them have poor oral absorption, which can result in insufficient efficacy. Micro-environmental pH-modifying solid dispersion (micro pHm SD) is a promising approach to overcome the poor oral absorption of these drugs. In the present study, toltrazuril (TOL), a weakly acidic drug with poor aqueous and pH-dependent solubility, was used as a model drug. Using micro pHm SD, a novel oral oil-based suspension of TOL SD (TSDS) was developed, and the stability of this formulation was evaluated based on particle size, settling volume ratio, redispersibility, thermal stability, and drug content. The optimized soybean oil-based TSDS (S-TSDS) had high physicochemical stability and good histocompatibility with common inflammatory reactions. The results of the in vitro dissolution analysis showed that S-TSDS rapidly and markedly released the drug and provided higher efficacy and longer persistence against coccidiosis (above 90.9%) in rabbits. This technique could increase the oral absorption and bioavailability of new drug candidates.
危险品化学品经营许可证（带存储）