Zhen-Feng Wu

Process optimization by response surface design and characterization study on geniposide pharmacosomes

The objective of this study was to prepare and characterize geniposide-pharmcosomes (GP-PMS) and optimize the process and formulation variables using response surface methodology. Tetrahydrofuran was used as a reaction medium, GP and phospholipids were resolved into the medium, and GP-PMS was formed after the organic solvent was evaporated off under vacuum condition. The process and formulation variables were optimized by central composite design (CCD) of response surface methodology (RSM). The phospholipid-to-drug ratio (X1), reaction temperature (X2) and the drug concentration (X3) were selected as independent variables and the yield (%) of GP ‘present as a complex’ in the PMS was used as the dependent variable. The physico-chemical properties of the complex obtained by optimal parameters were investigated by means of Fourier transform infrared spectrophotometry (FT-IR), differential scanning calorimetry, n-octanol/water partition coefficient (P) and particle size analysis. Multiple linear regression analysis for optimization by CCD revealed that the higher the yield of GP ‘present as a complex’ in the GP-PMS was obtained wherein the optimal settings of X1, X2 and X3 are 3, 50°C and 5.5 mg/mL, respectively. The DSC and IR studies of GP-PMS by the optimal settings demonstrated that GP and phospholipids in the GP-PMS were combined by non-covalent bond, not forming a new compound. GP-PMS could significantly increased the lipophilicify of GP, and P of GP-PMS in n-octanol and water was about 20 multiples more than that of GP material. Pharmacosomes could be an alternative approach to improve the absorption and permeation of biologically active constituents.

The importance of solidification stress on the redispersibility of solid nanocrystals loaded with harmine

Due to limited understanding about effect of solidification stress on the redispersibility of drug nanocrystals, the impact of the different type and concentration of stabilizers and cryoprotectants, as well as the solidification temperature on the redispersibility of nanocrystals were systematically investigated. Harmine nanosuspensions were transformed into harmine solid nanocrystals (HAR-SNC) via different stress of solidification process including freezing, lyophilization and spray-drying. The effect of different concentrations of stabilizers and cryoprotectants on redispersibility of HAR-SNC was also investigated, respectively. The results showed that the redispersibility of HAR-SNC at the aggressive freezing temperature stress was better more than those of conservative and moderate stress condition. The HPMC was effective enough to protect HAR-SNC from damage during lyophilization, which could homogeneously be adsorbed into the surface of nanocrystals to prevent the agglomerates. The sucrose and sorbitol achieved excellent performance that protected HAR-SNC from crystal growth during lyophilization. The CMS-Na played an outstanding role in protecting the HAR-SNC from breakage during spray-drying, due to the steric barrier effect of high viscosity polymeric stabilizers. It was concluded that HAR-SNC was subjected to agglomeration or crystal growth during solidification, and the degree of agglomeration or crystal growth varied with the type and the amounts of stabilizers used, as well as stress conditions applied. The polymeric stabilizers were more effective to protect HAR-SNC from the damage during solidification process.

A novel high-pressure precipitation tandem homogenization technology for drug nanocrystals production – a case study with ursodeoxycholic acid

Abstract To overcome the limitations of the conventional particle size reduction technologies, a novel combinative particle size reduction method for the effective production of homogeneous nanosuspensions was investigated. Ursodeoxycholic acid, a poorly soluble drug representative, was tried to prepare nanosuspension by homogenization technology and high-pressure precipitation tandem homogenization technology. It was shown that the combinative approach could significantly improve the particle size reduction effectiveness over conventional homogenization approach. The Box–Behnken design analysis for process optimization revealed that the acceptable UDCA-NS was obtained wherein the optimal values of A, B, C and D were 10%, 500 bar, 0.125 and 600 bar, respectively. SEM results demonstrated that no significant aggregation or crystals growth could be observed in the freeze-dried UDCA nanocrystals. The DSC and XRD results showed that UDCA remained in a crystalline state. Dissolution velocities of the freeze-dried UDCA-NS powder were distinctly superior compared to those of the crude powder and physical mixture. The high-pressure precipitation tandem homogenization technology can be a good choice for nanosuspension preparation of poorly soluble UDCA, due to high efficiency of particle size reduction.

Structural Stabilities and Transformation Mechanism of Rhynchophylline and Isorhynchophylline by Ultra Performance Liquid Chromatography/Time-of-Flight Mass Spectrometry (UPLC/Q-TOF-MS)

To reveal the structural stabilities and transformation mechanism of rhynchophylline (RIN) and isorhynchophylline (IRN), HPLC and UPLC-Q-TOF-MS method were developed for the qualitative and quantitative analysis of the conversion rate. The method was validated for linearity, inter- and intra-day precisions, repeatability and stability. All the quantitative determination method validation results were satisfactory. Under the optimized chromatographic conditions, the effect of various heat temperatures, retention time, and solvent polarities on conversion rate and equilibrium were systematically investigated for the first time. Besides, a model relating the retention yield value and time-temperature was built to predict the t0.5 and Ea of the conversion rate by the Arrhenius equation. The experimental results proved to be in good accordance with the predicted values. Furthermore, UPLC-Q-TOF-MS analysis was performed to verify the transformation mechanism and provide valuable information for stability analysis of the conversion products.

The Roles of Vitrification of Stabilizers/Matrix Formers for the Redispersibility of Drug Nanocrystals After Solidification: a Case Study

To elucidate the roles of vitrification of stabilizers/matrix formers for the redispersibility of drug nanocrystal powder after solidification at storage stress, the influence of different drying methods and storage stresses on stability of drug nanocrystals was systemically investigated. A poorly soluble drug, baicalin, used as model drug was converted into baicalin nanocrystals (BCN-NC). The residual moisture contents of BCN-NC were applied at two different stress conditions defined as “conservative” (<1%) and “aggressive” (>1%), respectively. The influence of different stabilizers, matrix formers, and storage stresses on the redispersibility of BCN-NC powder was systemically investigated, respectively. The results showed that storage stresses had significantly influence the redispersibility of BCN-NC. Aggressive storage temperature and residual moisture could be unfavorable factors for stability of drug nanocrystals, due to the exacerbation of aggregation of BCN-NC induced by vitrification. It was demonstrated that vitrification of spray-dried BCN-NC was dependent on temperature and time. The polymeric stabilizers hydroxypropylmethylcellulose (HPMC) and sodium carboxymethyl starch (CMS-Na) with high glass transition temperature (Tg) played more important role in protecting the BCN-NC from breakage during storage, compared to the surfactants Tween 80, d-α-tocopherol acid polyethylene glycol 1000 succinate (TPGS), or RH 40. Besides, the polyvinylpyrrolidone K30 (PVP K30) and lactose with high Tg were effective matrix formers for preserving the redispersibility of BCN-NC. It was concluded that the vitrification transition of stabilizers/matrix formers could be responsible for aggregation of drug nanocrystals during storage, which was a time-dependent process. The suitable residual moisture contents (RMC) and Tg were very important for preserving the stability of drug nanocrystals during storage.

An Effective Vacuum Assisted Extraction Method for the Optimization of Labdane Diterpenoids from Andrographis paniculata by Response Surface Methodology

An effective vacuum assisted extraction (VAE) technique was proposed for the first time and applied to extract bioactive components from Andrographis paniculata. The process was carefully optimized by response surface methodology (RSM). Under the optimized experimental conditions, the best results were obtained using a boiling temperature of 65 °C, 50% ethanol concentration, 16 min of extraction time, one extraction cycles and a 12:1 liquid-solid ratio. Compared with conventional ultrasonic assisted extraction and heat reflux extraction, the VAE technique gave shorter extraction times and remarkable higher extraction efficiency, which indicated that a certain degree of vacuum gave the solvent a better penetration of the solvent into the pores and between the matrix particles, and enhanced the process of mass transfer. The present results demonstrated that VAE is an efficient, simple and fast method for extracting bioactive components from A. paniculata, which shows great potential for becoming an alternative technique for industrial scale-up applications.

Application of Plackett-Burman Design and Box-Behnken Design to Achieve Process Optimization for Geniposide Submicron Emulsion

The objective of this study was to prepare and characterize geniposide submicron emulsion (GP-SME) loaded the geniposide phytosomes (GP-PS) geniposide and optimize the process variables. The physicochemical properties of GP-PS obtained were investigated by means of differential scanning calorimetry. A screening experiment with Plackett-Burman design and response surface methodology with Box-Behnken design was used to optimize the process parameters of GP-SME. The optimum process conditions were finally obtained by using a desirability function. The differential scanning calorimetry studies of GP-PS demonstrated that GP and phospholipids in the GP-PS were combined by noncovalent bond, not forming a new compound. A Plackett-Burman design was initially employed and it was found that stirring velocity, homogenization pressure and homogenization cycles were the most important variables that affected the particles size, polydispersity index, and entrapment efficiency of GP-SME. Results showed that the optimum stirring velocity, homogenization pressure, and cycles were 16000 rpm, 50 Mpa, and 10 cycles, respectively. The mean diameter, polydispersity index, and entrapment efficiency of GP-SME were 258.2 nm, 0.243, 72.56%, respectively.

A Novel Forming Method of Traditional Chinese Medicine Dispersible Tablets to Achieve Rapid Disintegration Based on the Powder Modification Principle

Slow disintegration and poor solubility are common problems facing the dispersible tablets of Traditional Chinese Medicine (TCM). In an early study, the research group found that co-grinding of extracts and silica could achieve a rapid disintegration effect, though the mechanism of this effect was not thoroughly elucidated. In this study, Yuanhu Zhitong dispersible tablets (YZDT) were selected as a model drug to explore the mechanism of rapid disintegration and dissolution. First, eight types of silica were used to prepare modified YZDT, and their disintegration time and amount of dissolution within 5 min were measured. Next, the powder properties of eight types of silica were investigated. By correlation analysis, it was found that the average pore size and density of silica were closely related to the effect of promoting disintegration. It was determined that the co-grinding of silica and extracts provided high porosity for the raw material drug, and its abundant narrow channels provided a strong static pressure for water penetration to achieve a rapid disintegration effect. Meanwhile, it was found that the addition of silica had a certain effect on promoting dissolution. Our results provide a highly operational approach for improving the disintegration and dissolution of TCM dispersible tablets. Meanwhile, this approach is also beneficial for establishing a high-quality evaluation index for silica.

Support Vector Regression Approach to Predict the Design Space for the Extraction Process of Pueraria lobata

A support vector regression (SVR) method was introduced to improve the robustness and predictability of the design space in the implementation of quality by design (QbD), taking the extraction process of Pueraria lobata as a case study. In this paper, extraction time, number of extraction cycles, and liquid–solid ratio were identified as critical process parameters (CPPs), and the yield of puerarin, total isoflavonoids, and extracta sicca were the critical quality attributes (CQAs). Models between CQAs and CPPs were constructed using both a conventional quadratic polynomial model (QPM) and the SVR algorithm. The results of the two models indicated that the SVR model had better performance, with a higher R2 and lower root-mean-square error (RMSE) and mean absolute deviation (MAD) than those of the QPM. Furthermore, the design space was predicted using a grid search technique. The operational range was extraction time, 24–51 min; number of extraction cycles, 3; and liquid–solid ratio, 14–18 mL/g. This study is the first reported work optimizing the design space of the extraction process of P. lobata based on an SVR model. SVR modeling, with its better prediction accuracy and generalization ability, could be a reliable tool for predicting the design space and shows great potential for the quality control of QbD.