Quality by Design Approach for Development of W/O Type Microemulsion-Based Transdermal Systems for Atenolol

The objective of the present investigation was to develop microemulsion-based transdermal systems of highly water soluble drug, Atenolol, by quality by design technique. Atenolol-loaded W/O microemulsions were optimized using D-optimal design with concentrations of oil, surfactants mixture, and water as independent variables, which was converted into microemulsion-based gel (MBG). The results of in vitro permeation of the optimized batch of Atenolol-loaded MBG revealed significant increase in permeability parameters as compared to its convention gel. All results suggested suitability of W/O type MEs as carriers for transdermal delivery of highly water soluble drug, Atenolol.     

Development of a Fast and Robust UHPLC Method for Apixaban In-Process Control Analysis

In-process control (IPC) is an important task during chemical syntheses in pharmaceutical industry. Despite the fact that each chemical reaction is unique, the most common analytical technique used for IPC analysis is high performance liquid chromatography (HPLC). Today, the so-called “Quality by Design” (QbD) principle is often being applied rather than “Trial and Error” approach for HPLC method development. The QbD approach requires only for a very few experimental measurements to find the appropriate stationary phase and optimal chromatographic conditions such as the composition of mobile phase, gradient steepness or time (tG), temperature (T), and mobile phase pH. In this study, the applicability of a multifactorial liquid chromatographic optimization software was studied in an extended knowledge space. Using state-of-the-art ultra-high performance liquid chromatography (UHPLC), the analysis time can significantly be shortened. By using UHPLC, it is possible to analyse the composition of the reaction mixture within few minutes. In this work, a mixture of route of synthesis of apixaban was analysed on short narrow bore column (50 × 2.1 mm, packed with sub-2 µm particles) resulting in short analysis time. The aim of the study was to cover a relatively narrow range of method parameters (tG, T, pH) in order to find a robust working point (zone). The results of the virtual (modeled) robustness testing were systematically compared to experimental measurements and Design of Experiments (DoE) based predictions.     

An Experimental Design Approach to Quantitative Expression for Quality Control of a Multicomponent Antidiabetic Formulation by the HILIC Method

A rapid and reproducible hydrophilic liquid chromatography (HILIC) process was established for concomitant determination of remogliflozin etabonate (RE), vildagliptin (VD), and metformin (MF) in a formulation. A face-centered central composite experimental design was employed to optimize and predict the chromatographic condition by statistically studying the surface response model and design space with desirability close to one. A HILIC column with a simple mobile phase of acetonitrile (65% v/v) and 20 mM phosphate buffer (35% v/v, pH 6, controlled with orthophosphoric acid) was used to separate RE, VD, and MF. RE, VD, and MF were separated in 3.6 min using an isocratic mode mobile phase flow at a flow rate of 1.4 mL at room temperature, and the analytes were examined by recording the absorption at 210 nm. The developed HILIC method was thoroughly validated for all parameters recommended by ICH, and linearity was observed in the ranges 20–150 µg/mL, 10–75 µg/mL, and 50–750 µg/mL for RE, VD, and MF, respectively, along with excellent regression coefficients (r² > 0.999). The calculated percentage relative deviation and relative error ascertained the precision and accuracy of the method. The selectivity and accuracy were further confirmed by the high percentage recovery of added standard drugs to the formulation using the standard addition technique. The robustness of the HILIC processes was confirmed by developing a half-normal probability plot and Pareto chart, as the slight variation of a single factor had no significant influence on the assay outcomes. Utilization of the optimized HILIC procedure for concurrent quantification of RE, VD, and MF in solid dosage forms showed accurate and reproducible results. Hence, the fast HILIC method can be regularly employed for the quality assurance of pharmaceutical preparations comprising RE, VD, and MF.     

Development and Validation of a Stability-Indicating UPLC Method for the Determination of Hexoprenaline in Injectable Dosage Form Using AQbD Principles

A novel and efficient stability-indicating, reverse phase ultra-performance liquid chromatographic (UPLC^®) analytical method was developed and validated for the determination of hexoprenaline in an injectable dosage form. The development of the method was performed using analytical quality by design (AQbD) principles, which are aligned with the future requirements from the regulatory agencies using AQbD principles. The method was developed by assessing the impact of ion pairing, the chromatographic column, pH and gradient elution. The development was achieved with a Waters Acquity HSS T3 (50 × 2.1 mm i.d., 1.8 µm) column at ambient temperature, using sodium dihydrogen phosphate 5 mM + octane-1-sulphonic acid sodium salt 10 mM buffer pH 3.0 (Solution A) and acetonitrile (Solution B) as mobile phases in gradient elution (t = 0 min, 5% B; t = 1 min, 5% B; t = 5 min, 50% B; t = 7 min, 5% B; t = 10 min, 5% B) at a flow rate of 0.5 mL/min and UV detection of 280 nm. The linearity was proven for hexoprenaline over a concentration range of 3.50–6.50 µg/mL (R² = 0.9998). Forced degradation studies were performed by subjecting the samples to hydrolytic (acid and base), oxidative, and thermal stress conditions. Standard solution stability was also performed. The proposed validated method was successfully used for the quantitative analysis of bulk, stability and injectable dosage form samples of the desired drug product. Using the AQbD principles, it is possible to generate methodologies with enhanced knowledge, which can eventually lead to a reduced regulatory risk, high quality data and lower operational costs.     

Acylglycerols of Myristic Acid as New Candidates for Effective Stigmasterol Delivery—Design,Synthesis, and the Influence on Physicochemical Properties of Liposomes

New carriers of phytosterols; acylglycerols containing natural myristic acid at sn-1 and sn-3 positions and stigmasterol residue linked to sn-2 position by carbonate and succinate linker have been designed and synthesized in three-step synthesis from dihydroxyacetone (DHA). The synthetic pathway involved Steglich esterification of DHA with myristic acid; reduction of carbonyl group of 1,3-dimyristoylpropanone and esterification of 1,3-dimyristoylglicerol with stigmasterol chloroformate or stigmasterol hemisuccinate. The structure of the obtained hybrids was established by the spectroscopic methods (NMR; IR; HRMS). Obtained hybrid molecules were used to form new liposomes in the mixture with model phospholipid and their effect on their physicochemical properties was determined, including the polarity, fluidity, and main phase transition of liposomes using differential scanning calorimetry and fluorimetric methods. The results confirm the significant effect of both stigmasterol-containing acylglycerols on the hydrophilic and hydrophobic region of liposome membranes. They significantly increase the order in the polar heads of the lipid bilayer and increase the rigidity in the hydrophobic region. Moreover, the presence of both acylglycerols in the membranes shifts the temperature of the main phase transition towards higher temperatures. Our results indicate stabilization of the bilayer over a wide temperature range (above and below the phase transition temperature), which in addition to the beneficial effects of phytosterols on human health makes them more attractive components of novel lipid nanocarriers compared to cholesterol.     

遵循OBE理念的制药工程专业认识实习教学设计与实施*

依据工程教育专业认证OBE理念,阐述了制药工程专业毕业生的能力要求,认识实习学习成果定位、教学内容设计、教学实施策略、学习成果数据处理与评价、教学质量持续改进等,对于当前认识实习课程教学中所存在的问题与不足,提升认识实习课程教学质量,促进专业认证以及制药工程专业课程建设具有指导与借鉴意义。     

Ultra high performance liquid chromatography method development for separation of omeprazole and related substances on core‐shell columns using a Quality by Design approach

An updated and improved method for analysis of omeprazole/esomeprazole and related substances on core‐shell columns was developed using Fusion LC Method Development?. The method was optimized with respect to column type, column temperature, mobile phase pH level, and gradient time. Four different core‐shell columns were examined to develop a method suitable for both high performance‐ and ultra‐high performance liquid chromatography using a Quality by Design approach. The final method offers two alternative columns: Poroshell EC C18 (3.0 × 100 mm, 2.7 µm) or Poroshell HPH (3.0 × 100 mm, 2.7 µm) with the same gradient elution condition and mobile phase composition. Total run time is 18 min with 12 min of gradient elution. Phosphate buffer (15 mM, pH 7.8) is selected as the aqueous mobile phase and acetonitrile as the organic mobile phase. Column temperature is set at 40°C and ultraviolet detection at 302 nm. Furthermore, by studying parameters in a systematic way, an understanding of the effect of the input parameters enhances the method robustness and should allow for regulatory flexibility in terms of post‐approval changes. Compared to the current United States Pharmacopeia method, the updated method is faster, more efficient and performs well above acceptance criteria.     

基于OBE理念的大学化学课程思政案例设计与实践

为更好地服务工程教育专业认证(以下简称工程认证),基于成果导向理念(OBE),重点挖掘工程认证标准涉及到的思政元素,从设计思路、教学目标、导入设计和教学过程等方面进行了大学化学课程思政案例设计与实践。并从过程性考核、专业学习成效、调查问卷和主观描述性反馈等方面对课程思政实施效果进行了评价,结果表明：在OBE理念下,课程思政建设有效地提升了学生的学习成绩、学习兴趣和综合素质,取得了良好的教学效果。     

A Quality by Design and green LC technique for the determination of mast cell stabilizer and histamine receptor antagonist (Olopatadine HCl) in multiple formulations

Mast cell stabilizer and histamine receptor antagonist olopatadine hydrochloride (OPT) assay method predicated on LC have been established for the analysis in multiple formulations. The current method dealt with ophthalmic solution, nasal spray, and tablet formulation products. The isocratic chromatography method was optimized and validated with a Boston green C8 column (150 × 4.6 mm, 5 μm i.d.). Sodium dihydrogen phosphate buffer (pH 3.5) with acetonitrile in the ratio of 75:25 (v/v) was used as a mobile phase at a flow rate of 1.0 mL min⁻¹ and at the column temperature of 30°C, and the detection was done at 299 nm. The method was validated as per International Council for Harmonisation (ICH) guidelines and United States Pharmacopoeia (USP). The accuracy results ranged from 99.9 to 100.7%, % relative standard deviation (RSD) from the precision was 0.5, and correlation coefficient from the linearity experiment was > 0.999. Solution stability was established for 24 h at room temperature and refrigerator conditions, and it was found that the solutions were stable. Using quality by design-based experiment designs, critical quality attributes were studied and it was found that the method was robust. In all the forced degradation studies peak purity was passed, and no interference was found at the retention time of the active component. The method validation data demonstrated that the developed method is linear, precise, accurate, specific, robust, and stable for the determination of OPT from multiple formulations. Analytical eco-scale tool, Green Analytical Procedure Index (GAPI) tool, and the National Environmental Method Index (NEMI) were used to evaluate the greenness of the method, and the analytical eco-score of 77 for the presented method was found to be excellent.     

Development of a validated liquid chromatographic method for quantification of sorafenib tosylate in the presence of stress‐induced degradation products and in biological matrix employing analytical quality by design approach

The current research work envisages an analytical quality by design‐enabled development of a simple, rapid, sensitive, specific, robust and cost‐effective stability‐indicating reversed‐phase high‐performance liquid chromatographic method for determining stress‐induced forced‐degradation products of sorafenib tosylate (SFN). An Ishikawa fishbone diagram was constructed to embark upon analytical target profile and critical analytical attributes, i.e. peak area, theoretical plates, retention time and peak tailing. Factor screening using Taguchi orthogonal arrays and quality risk assessment studies carried out using failure mode effect analysis aided the selection of critical method parameters, i.e. mobile phase ratio and flow rate potentially affecting the chosen critical analytical attributes. Systematic optimization using response surface methodology of the chosen critical method parameters was carried out employing a two‐factor–three‐level–13‐run, face‐centered cubic design. A method operable design region was earmarked providing optimum method performance using numerical and graphical optimization. The optimum method employed a mobile phase composition consisting of acetonitrile and water (containing orthophosphoric acid, pH 4.1) at 65:35 v/v at a flow rate of 0.8 mL/min with UV detection at 265 nm using a C₁₈ column. Response surface methodology validation studies confirmed good efficiency and sensitivity of the developed method for analysis of SFN in mobile phase as well as in human plasma matrix. The forced degradation studies were conducted under different recommended stress conditions as per ICH Q1A (R2). Mass spectroscopy studies showed that SFN degrades in strongly acidic, alkaline and oxidative hydrolytic conditions at elevated temperature, while the drug was per se found to be photostable. Oxidative hydrolysis using 30% H₂O₂ showed maximum degradation with products at retention times of 3.35, 3.65, 4.20 and 5.67 min. The absence of any significant change in the retention time of SFN and degradation products, formed under different stress conditions, ratified selectivity and specificity of the systematically developed method.     

Cell‐Surface Engineering by a Conjugation‐and‐Release Approach Based on the Formation and Cleavage of Oxime Linkages upon Mild Electrochemical Oxidation and Reduction

We report a strategy to rewire cell surfaces for the dynamic control of ligand composition on cell membranes and the modulation of cell–cell interactions to generate three‐dimensional (3D) tissue structures applied to stem‐cell differentiation, cell‐surface tailoring, and tissue engineering. We tailored cell surfaces with bioorthogonal chemical groups on the basis of a liposome‐fusion and ‐delivery method to create dynamic, electroactive, and switchable cell‐tissue assemblies through chemistry involving chemoselective conjugation and release. Each step to modify the cell surface: activation, conjugation, release, and regeneration, can be monitored and modulated by noninvasive, label‐free analytical techniques. We demonstrate the utility of this methodology by the conjugation and release of small molecules to and from cell surfaces and by the generation of 3D coculture spheroids and multilayered cell tissues that can be programmed to undergo assembly and disassembly on demand.     

以标准为风向标的化学与生活课程教学设计

公共选修课是高等教育课程体系的重要组成部分,在大学生综合素质的教育和培养方面发挥着重要作用。化学与生活是面对非化学专业开设的一门公共选修课程,其主要内容包括与衣、食、住、行等相关的化学知识。本文将国家标准应用于化学与生活课程的教学设计中,以标准为载体设计教学情境,引导学生了解国家标准中的相关规定,掌握使用标准文件分析问题的方法。促使学生客观地认识化学学科,了解化学学科在生活中的作用,规避化学产生的危害,培养学生的科学素养,使学生学会利用化学知识改善自己的生活,提高生活质量。     

师范生化学教学设计能力构成、水平层级及发展进阶研究

教学设计能力是师范生教学能力培养的重要组成部分。利用定性与定量相结合的研究方法从“教学设计知识”“教学设计技能”“教学设计态度与意识”等3个维度构建了师范生化学教学设计能力的构成模型及水平层级模型。开发了教学案例分析和问卷等2种测评工具对师范生化学教学设计能力进行实证研究,探查了师范生在“中学化学教学设计与实践”课程中化学教学设计能力的发展进阶。结果表明:师范生教学设计知识由单一发展为多样化,教学设计的技能从没有角度进阶到了多角度,教学设计态度与意识从不积极、不自信发展为积极且自信。     

An Outline of the Latest Crystallographic Studies on Inhibitor-Enzyme Complexes for the Design and Development of New Therapeutics against Tuberculosis

The elucidation of the structure of enzymes and their complexes with ligands continues to provide invaluable insights for the development of drugs against many diseases, including bacterial infections. After nearly three decades since the World Health Organization’s (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. The structural elucidation of enzyme-ligand complexes is fundamental to identify hot-spots, define possible interaction sites, and elaborate strategies to develop optimized molecules with high affinity. This review offers a critical and comprehensive overview of the most recent structural information on traditional and emerging mycobacterial enzymatic targets. A selection of more than twenty enzymes is here discussed, with a special emphasis on the analysis of their binding sites, the definition of the structure–activity relationships (SARs) of their inhibitors, and the study of their main intermolecular interactions. This work corroborates the potential of structural studies, substantiating their relevance in future anti-mycobacterial drug discovery and development efforts.     

基于本科生科研意识培养的教学设计——以“原电池的原理及应用”为例

无机化学课程理论深奥,计算繁杂,学生学习较为困难。通过优化“原电池的原理及应用”教学设计,即在讲述原电池的工作原理基础上,让学生学习了其在测定溶液pH、离子浓度和电化学生物传感器中等方面的应用,提高学生的学习热情,达到学生学以致用的目的,逐步培养起本科生的科研意识。     

以“位构性”模型建构和学科能力发展的必修“原子结构 元素周期律”教学设计和实践*

在高中必修阶段“原子结构 元素周期律”主题已有研究的基础上,将“位构性”系统模型与学科能力活动任务相结合,提出了本研究的理论框架,进行了单元整体的教学设计并实施。通过预设学生的表现水平,设计各课时的评价任务,过程性地诊断学生在各个课时中“位构性”模型建构与学科能力的发展水平,描述学生在本章学习过程中的发展变化,促进了学生“证据推理与模型认知”等核心素养的发展。最后,归纳出以“位构性”模型建构和学科能力发展的“原子结构 元素周期律”在教学实践中的有效策略。以期能够对日后开展“原子结构 元素周期律”主题的教学设计与实践能够提供参考和建议。     

基于OBE理念的“化学教学设计与实施”课程建设与教学实践*

介绍了化学教师教育核心课程“化学教学设计与实施”课程建设和教学实践过程。该过程基于OBE理念,以培养中学化学骨干教师的成果为导向,确立课程目标,并围绕“素养为本”的化学教学设计过程模型建构课程、组织课程内容、设计课程教法、运用多元课程评价方式一体化进行课程整体变革设计,精准指向师范生未来职业发展必备素养。研究表明,成功实现了教学改革和教学相长,实现了全国同行认可的辐射效果。同时针对课程不足,提出了进一步改进方向和措施,并对未来做出了展望。     

Optimization of Wall Material of Freeze-Dried High-Bioactive Microcapsules with Yellow Onion Rejects Using Simplex Centroid Mixture Design Approach Based on Whey Protein Isolate,Pectin, and Sodium Caseinate as Incorporated Variables

For the food sector, onion rejects are an appealing source of value-added byproducts. Bioactive compounds were recovered from yellow onion rejects using a pulse electric field process at 6000 v and 60 pulses. The onion extract was encapsulated with whey protein isolate (WPI), pectin (P), and sodium caseinate (SC) with a mass ratio of 1:5 (extract/wall material, w/w). A Simplex lattice with augmented axial points in the mixture design was applied for the optimization of wall material for the encapsulation of onion reject extract by freeze-drying (FD). The optimal wall materials were 47.6 g/100 g (SC), 10.0 g/100 g (P), and 42.4 g/100 g (WPI), with encapsulation yield (EY) of 85.1%, total phenolic content (TPC) of 48.7 mg gallic acid equivalent/g DW, total flavonoid content (TFC) of 92.0 mg quercetin equivalent/g DW, and DPPH capacity of 76.1%, respectively. The morphological properties of the optimal encapsulate demonstrated spherical particles with a rough surface. At optimal conditions, the minimum inhibitory concentration (MIC) of the extract (mean diameter of inhibition zone: 18.8 mm) was shown as antifungal activity against Aspergillus niger.     

基于工程教育理念的“化工设计基础”实践与理论深度融合式教学*

为解决化工类课程普遍存在的创新与实践能力培养不足的问题,从工程教育专业认证的要求出发,以化工设计基础课程为例,对课程目标、教学内容、教学模式、考核评价等方面进行改革。实践表明,改革方案可实现理论与实践的深度融合,有效提升了学生专业知识、实践能力与工程师素养,提高化学工程教育质量。     

基于真实问题情境的课堂教学——以金属钠的性质与制备为例

以“钠钾合金热消融法治疗癌症”为情境主线,围绕该法治疗癌症的原理、探索过程中遇到的困境以及成本高低3个核心问题探索金属钠的性质及制备,让学生在真实情境中学习化学知识和学科思维方式,提升能力。