droxy-6-(hydroxymethyl)oxan-2-yl]oxyoxane-3,4,5-triol dihydrate (trehalose dihydrate), and (3S,4S,5S,6R)-6-(hydroxymethyl)oxane-2,3,4,5-tetrol (mannose) in the mixtures of ethanol and water from (278.2 to 298.2) K were determined. The solubilities of all the four saccharides in ethanol−water mixtures increased as equilibrium temperature increased. The solubilities of trehalose dihydrate, xylose, and mannose decreased as ethanol mass fraction in the mixed solvent increased. Maltose monohydrate solubility decreased when ethanol mass fraction in the mixed solvent was less than 0.9. The solubilities of xylose and mannose were predicted with A-UNIFAC, and the average relative deviations (ARD) values were less than 22 %. The solubilities of maltose monohydrate and trehalose dihydrate were calculated with the modified UNIQUAC model. New interaction parameters were calibrated. The ARD values for trehalose dihydrate solubility and maltose monohydrate solubility are 28.6 % and 17.9 %, respectively.

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This paper was designed to assess the value of quality by design (QbD) to improve the manufacturing process understanding of botanical drug products. Ethanol precipitation, a widely used unit operation in the manufacture of botanical drug products was employed to illustrate the use of QbD, taking the process of danshen (the dry root of Salvia miltiorrhiza Bunge) as an example. The recovery of four active pharmaceutical ingredients (APIs) and the removal of saccharides were used to represent the performance of ethanol precipitation. Potentially critical variables, including density of concentrate, ethanol consumption, and settling temperature were identified through risk assessment methods. Design of experiments (DOE) was used to evaluate the effects of the potentially critical factors on the performance of ethanol precipitation. It was observed that higher density of concentrate leads to higher removal of saccharides, but results in lower recovery of APIs. With the rise of ethanol consumption, the recovery of different APIs behaves in different ways. A potential design space of ethanol precipitation operation was established through DOE studies. The results in this work facilitate the enhanced understanding of the relationships between multiple factors (material attributes and process parameters) and the performance of ethanol precipitation. This case study demonstrated that QbD is a powerful tool to develop manufacturing process of botanical drug products.

A novel analytical quality by design approach for developing a chromatographic fingerprint was established for analyzing complex traditional Chinese medicine, using a licorice standard decoction as an example. Considering the characteristics of integrity and ambiguity, the resolution of eight common peaks, total peak number, capacity factor distributions, and peak purity were selected as potential critical method attributes for assessing the quality of the chromatographic fingerprint. A central composite design was used to evaluate the relationship between critical method attributes and critical method parameters, including column temperature, wavelength, flow rate, formic‐acid concentration, and gradient parameters. A standard probability method was employed to calculate the design space of the fingerprint analysis parameters and evaluate the robustness of the methodology. The optimized high‐performance liquid chromatography fingerprint conditions were acetonitrile and 0.1% formic acid water gradient elution (0‐5 min, 5–19% A; 5–10 min, 19% A; 10–50 min, 19–42% A; 50–54 min, 42–100% A; 54–60 min, 100% A), column temperature 25±5°C, detection wavelength 265 nm. The design space of fingerprint analytical method based on the analytical quality by design approach not only met the requirements of the fingerprint analysis, but also improved the robustness and applicability of the fingerprint method.

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A botanical injection is a special drug preparation with extremely high safety requirements. Therefore, many separation technologies, such as ethanol precipitation and liquidÀliquid extraction, are applied in the manufacturing process of botanical injections to purify efficacy compounds and remove impurities. In this work, second ethanol precipitation and 1-butanol extraction were compared in the purification of the concentrated supernatant of danshen (the dried root of Salvia miltiorrhiza). These two separation technologies showed satisfactory recovery of phenolic compounds and similar removal of total protein. LiquidÀliquid extraction removed more saccharides than second ethanol precipitation. Accordingly, the purity of phenolic compounds increased remarkably after liquidÀliquid extraction. According to the characteristics of the two separation technologies, the combination technology of "ethanol precipitation þ liquidÀliquid extraction" showed more advantages in drug safety and product quality control than the combination technology of "ethanol precipitation þ second ethanol precipitation".

Polysulphone (PSF) microcapsules containing 1-octanol were prepared with solvent extraction method for the recovery of caprolactam. One-step and two-step processes were, respectively, applied to prepare microcapsules. In order to get high extractant loading, a loading method with the assistance of ultrasound has been developed. With the two-step preparation process the extractant loss can be avoided. A very high extractant loading ratio of 5.96 g g À1 and the maximum uptake to caprolactam of 65.6 mg g À1 were achieved. Under the action of ultrasound the extractant loading efficiency is greatly intensified. With the one-step process 1-octanol loading ratio is highly limited. Only 1.74 g g À1 loading ratio and 29.9 mg g À1 uptake to caprolactam were realized. Meanwhile the extractant loss in the one-step process is serious. Considering extraction capacity and extractant loss in the preparation process, it is suggested that PSF microcapsules containing 1-octanol should be prepared with the two-step process. To fasten mass transfer rate, microcapsules with relatively smaller size are desired.

The aim of this study was to present a novel analytical quality by design (AQbD) approach for developing an HPLC method to analyze herbal extracts. In this approach, critical method attributes (CMAs) and critical method parameters (CMPs) of the analytical method were determined using the same data collected from screening experiments. The HPLC-ELSD method for separation and quantification of sugars in Codonopsis Radix extract (CRE) samples and Astragali Radix extract (ARE) samples was developed as an example method with a novel AQbD approach. Potential CMAs and potential CMPs were found with Analytical Target Profile. After the screening experiments, the retention time of the D-glucose peak of CRE samples, the signal-to-noise ratio of the D-glucose peak of CRE samples, and retention time of the sucrose peak in ARE samples were considered CMAs. The initial and final composition of the mobile phase, flow rate, and column temperature were found to be CMPs using a standard partial regression coefficient method. The probability-based design space was calculated using a Monte-Carlo simulation method and verified by experiments. The optimized method was validated to be accurate and precise, and then it was applied in the analysis of CRE and ARE samples. The present AQbD approach is efficient and suitable for analysis objects with complex compositions.