Quality By Design Research Articles

Navigating the intricate in-vivo journey of lipid nanoparticles tailored for the targeted delivery of RNA therapeutics: a quality-by-design approach.

RNA therapeutics, such as mRNA, siRNA, and CRISPR-Cas9, present exciting avenues for treating diverse diseases. However, their potential is commonly hindered by vulnerability to degradation and poor cellular uptake, requiring effective delivery systems. Lipid nanoparticles (LNPs) have emerged as a leading choice for in vivo RNA delivery, offering protection against degradation, enhanced cellular uptake, and facilitation of endosomal escape. However, LNPs encounter numerous challenges for targeted RNA delivery in vivo, demanding advanced particle engineering, surface functionalization with targeting ligands, and a profound comprehension of the biological milieu in which they function. This review explores the structural and physicochemical characteristics of LNPs, in-vivo fate, and customization for RNA therapeutics. We highlight the quality-by-design (QbD) approach for targeted delivery beyond the liver, focusing on biodistribution, immunogenicity, and toxicity. In addition, we explored the current challenges and strategies associated with LNPs for in-vivo RNA delivery, such as ensuring repeated-dose efficacy, safety, and tissue-specific gene delivery. Furthermore, we provide insights into the current clinical applications in various classes of diseases and finally prospects of LNPs in RNA therapeutics.

Paclitaxel loaded Capmul MCM and tristearin based nanostructured lipid carriers (NLCs) for glioblastoma treatment: screening of formulation components by quality by design (QbD) approach.

Paclitaxel (PTX), a naturally occurring diterpenoid isolated from Taxus brevifolia, is a first-line drug for the treatment of glioblastoma; however, it suffers from the disadvantages of poor water solubility and nonspecific biodistribution, which cause serious side effects in the human body. The marketed formulation suffers from serious side effects, such as allergic reactions, neutropenia, and neuropathy, which require safe and effective formulations of PTX. In the present study, PTX was entrapped in a solid-liquid lipid mixture with the aid of a surfactant using a modified solvent evaporation technique. Higher entrapment of the impressive stability of the formulation was achieved by employing quality design-based strategies. Optimized levels by employing a numerical optimization technique for each factor, that is, surfactant concentration (X1), lipid concentration (X2), and amount of organic solvent (X3) were 0.3%, 0.76% & 8.3 ml respectively. The resultant formulation exhibited a particle size of 121.44 nm, entrapment efficiency of 94.27%, and zeta potential of -20.21 mV with unimodal size distribution. A reduction in the % crystalline index from 48 to 3.4% ensured the amorphous form of the entrapped drug inside the formulation, which precludes the fear of leakage and instability of the formulation. Cell line studies conducted on U87MG Cell lines also suggested that the NLC of paclitaxel are more effective than those of pure PTX. In summary, PTXNLC seem to be a superior alternative carrier system for the formulation industry to obtain higher entrapment with excellent stability.

Optimizing rosemary oil nanoemulsion loaded with nelfinavir and epigallocatechin gallate: A Design Expert® endorsed approach for enhanced neuroAIDS management

This study focuses on optimizing the delivery of Nelfinavir (NFV), a vital protease inhibitor in antiretroviral therapy, and Epigallocatechin gallate (EGCG), a potent adjunctive anti- human immunodeficiency virus (anti-HIV) agent found in green tea. The challenge lies in NFV's low intrinsic dissolution rate, significant p-gp efflux, and high hepatic metabolism, necessitating frequent and high-dose administration. Our objective was to develop a nanoemulsion loaded with NFV and EGCG to enhance oral delivery, expediting antiretroviral effects for NeuroAIDS treatment. After meticulous excipient screening, we selected Tween 40 as the surfactant and polyethylene glycol 400 (PEG 400) as the co-surfactant. Employing a Quality by Design (QbD) approach with statistical multivariate methods, we optimized the nanoemulsion that exhibited a droplet size of 83.21 nm, polydispersity index (PDI) of 2.289, transmittance of 95.20 %, zeta potential of 1.495 mV, pH of 6.95, refractive index of 1.40, viscosity of 24.00 ± 0.42 mPas, and conductivity of 0.162 μS/cm. Pharmacokinetic studies demonstrated superior in vivo absorption of the optimized nanoemulsion compared to NFV and EGCG suspension. The optimized nanoemulsion showcased higher Cmax of NFV (9.75 ± 1.23 μg/ml) and EGCG (27.7 ± 1.22 μg/ml) in the brain, along with NFV (26.44 ± 1.44 μg/ml) and EGCG (313.20 ± 5.53 μg/ml) in the plasma. This study advocates for the potential of NFV and EGCG-loaded nanoemulsion in combination antiretroviral therapy (cART) for effective NeuroAIDS management.

QbD decorated ellagic acid loaded polymeric nanoparticles: Factors influencing desolvation method and preliminary evaluations

Polymeric nanoparticles are one of the emerging drug delivery systems in the field of oncology. Ellagic acid is a polyphenolic compound with vast effects like anti-cancer, anti-viral, and anti-oxidant. The ellagic acid nanoparticles was prepared by desolvation method. Formulating ellagic acid NPs using BSA enhances the stability and solubility of ellagic acid. Quality by design (QbD) based approach was adopted to improve the final quality and effectiveness of the formulation. The Critical quality attribute (CQAs) was defined and risk assessment was performed with the help of the Ishikawa fishbone diagram. Solubility analysis was done for the drug with methanol, ethanol, water, and acetone. Preliminary studies were performed to study the effect of type of desolvating agent, the concentration of polymer the pH of the polymer solution, amount of desolvating agent on the particle size and entrapment efficiency of the nanoparticles. A greater quantity of desolvating agent results in a narrower particle size because of thorough desolvation, and the increased encapsulation efficiency is linked to reduced protein-protein interactions. Desolvation process can cause the protein to gradually change structure, form clumps, and eventually form nanoparticles, so might be its shows increase in entrapment efficiency. A desolvating agent volume of 4 ml resulted in a particle size of 1724 ± 1.27 nm. When the amount of desolvating agent was increased to 6 ml and 8 ml, the particle size decreased to 160 ± 0.66 nm and 218 ± 0.47 nm, respectively. Fourier Transform Infrared Spectroscopy (FTIR) data showed no incompatibilities were observed between drug and polymer. In-vitro dissolution showed the nanoparticles may follow the control release pattern over 24 hours. All the formulated batches of zeta potential were found to be in the range −30 mV to +30 mV which indicated good colloidal stability of the NPs and the PDI value ranging from 0.18 to 2.8. The higher drug encapsulation of the drug was more than 50 % which gives higher drug release at a site of action and in-vitro drug release of more than 80 % may improve the dosage frequency. The in vitro drug release data was also studied by various kinetic models. The in vitro drug release analysis shows sustained release of drug from nanoparticles and follow Korsmeyer-Peppas model. All these findings were in good agreement which may open a new gateway for future research in the field of oral oncology.

Quality by Design Approach Driven Development and Validation of Reverse Phase‐High‐Performance Liquid Chromatography Methodology for Dual Quantification of Aspirin and Rivaroxaban

ABSTRACTClinical trials have shown that combining a modest dose of Rivaroxaban (RIV) with Aspirin (ASP) is more effective than ASP alone in reducing cardiovascular mortality, myocardial infarction, and stroke. A high‐performance liquid chromatography method developed using Quality by Design (QbD) effectively estimates ASP and RIV for routine pharmaceutical analysis. The Plackett‐Burman design assessed key factors including organic phase volume, mobile phase pH, flow rate, temperature, and injection volume using an Ishikawa fish‐bone diagram for risk assessment. These parameters were then optimized via Box‐Behnken design in 15 trials. The method meets the International Council For Harmonization standards with a mobile phase ratio of 45:55 (v/v) acetonitrile: buffer (pH 3, adjusted with orthophosphoric acid), a flow rate of 1 mL/min, a column temperature of 30°C, and an injection volume of 20 µL. A Phenomenex Luna C18 column (250 × 4.6 mm, 5 µm particle size) with detection at 251 nm ultra‐violet wavelength. The retention times of 4.54 min for ASP and 5.81 min for RIV were obtained. Validation confirmed linear ranges: 40–200 µg/mL for ASP and 2–10 µg/mL for RIV, with excellent recovery rates (ASP: 99.30%–101.9%; RIV: 98.52%–101.84%). Developed using QbD principles, the method proved specific, accurate, precise, sensitive, and robust for routine quality control of both compounds in pharmaceutical formulations.

Determination and Quantification of Related Impurity Substances in Elvitegravir Drug Substance by Full Factorial Design Evaluated Liquid Chromatography Method

ABSTRACTHerein, our work deals with developing a rapid, accurate, and reliable high‐performance liquid chromatographic technique with the application of quality by design (QbD) experimental tool to quantify Elvitegravir drug (Integrase inhibitors of antiretroviral drug) and its novel related impurities at low levels. Further, this unique method has been validated to prove its consistency. Separation of N‐methyl Elvitegravir (Impurity‐I), 2‐fluoro Elvitegravir (Impurity‐II), and Elvitegravir isopropyl ester (Impurity‐III) in Elvitegravir drug substance was executed by using Kinetex C18 column (150 mm × 2.1 mm × 1.7 µm) with water, acetonitrile, formic acid, and triethylamine (690:300:6:2, v/v/v/v/), mobile phase (MB‐A) and acetonitrile, formic acid and triethylamine (990:6:2, v/v/v), MB‐B. This developed analytical technique gave a well‐separated peak at the retention times of 9.126 min (Elvitegravir), 7.713 min (Impurity‐I), 7.972 min (Impurity‐II), and 8.548 min (Impurity‐III) adequate with the peak properties as per the United States Pharmacopeia guideline. The method's sensitivity and linearity are established by its detection and quantification limits at low levels with a correlation coefficient of 0.998. The method's repeatability, specificity, and accuracy suggest that this developed technique is a reliable determination strategy for Elvitegravir drug substance and its related impurities (Impurity‐I, Impurity‐II, and Impurity‐III) in a simple, feasible, and affordable way.

QbD-driven Formulation Development and Evaluation of Genistein Nanoparticles for Prostate Cancer

Background: Genistein (GEN) shows significant anticancer potential, particularly against prostate cancer. However, its clinical application is limited by poor water solubility, rapid metabolism and excretion, low bioavailability, and lack of targeted delivery to cancer cells, hindering its effectiveness as a chemopreventive or therapeutic agent. Objective: In this study, poly-ε-caprolactone (PCL) nanoparticles incorporating polyvinyl alcohol (PVA) as a stabilizer were engineered to encapsulate genistein (GEN) effectively. Utilizing a Quality by Design (QbD) methodology, the development and optimization of these nanoparticles were systematically approached. Methods: GEN-loaded PCL nanoparticles (NPs) were prepared using the Solvent Evaporation Technique, ideal for encapsulating hydrophobic drugs. A Plackett–Burman design (PBD) identified key factors, followed by a Box–Behnken design (BBD) to optimize nanoparticle quality. The NPs were evaluated for particle size, zeta potential (ZP), polydispersity index (PDI), morphology, encapsulation efficiency (EE), in vitro drug release, and cytotoxicity. Results: The optimized formulation containing PCL, PVA, and Volume of organic solvent as 43.7 mg, 6.2 mg, and 10.0 ml, respectively was chosen because it showed EE (%) of 94.0%, average particle size of 150 nm, PDI of 0.10, ZP of -28.0 and exhibited sustained release of GEN for around four days. The antiproliferative activities of GEN PCL NPs were confirmed by the MTT test in vitro on malignant prostate carcinoma cell lines (PC3). Flow cytometric analysis showed that the inhibition of cell proliferation of more potent GEN PCL NPs is comparable with the effects of free GEN. Conclusion: The findings indicate that genistein-loaded PCL nanoparticles have the potential to augment the anticancer efficacy of genistein, both in vitro and in vivo. This suggests their promise as a viable candidate for prostate cancer treatment.

Bedaquiline Delivery Innovations: A Review on Advancing MDR-TB Treatment Strategies

Abstract: Multidrug-resistant tuberculosis (MDR-TB) poses a persistent challenge to global health, necessitating continuous efforts to enhance treatment efficacy. Bedaquiline, a cornerstone in MDR-TB management, presents biopharmaceutical challenges that impact its therapeutic potential. This review provides a comprehensive analysis of recent innovations in drug delivery strategies designed to optimize Bedaquiline's efficacy and improve MDR-TB treatment outcomes. Through a systematic examination of various delivery systems, including nanotechnology and formulation advancements, we explore their potential in addressing drug solubility and bioavailability challenges. Emphasizing the integration of Quality by Design (QbD) principles, this review aims to present a cohesive overview of evolving Bedaquiline delivery innovations, providing valuable insights for researchers and healthcare practitioners working towards advancing MDR-TB treatment strategies.

Modeling and Simulations in Latin-American Generic Markets: Perspectives from Chilean Local Industry, Regulatory Agency, and Academia.

In the last 20 years, modeling and simulations (M&S) have gained increased attention in pharmaceutical sciences. International industry and world-reference agencies have used M&S to make cost-efficient decisions through the model-informed drug development (MIDD) framework. Modeling tools include biopredictive dissolution models, physiologically based pharmacokinetic models (PBPK), biopharmaceutic models (PBBM), and virtual bioequivalence, among many others. Regulatorily, health agencies are becoming more and more open to accept the use of M&S to support regulatory applications, including setting dissolution specifications, quality-by-design (QbD), postapproval changes (SUPAC), etc. Nonetheless, the potential of M&S has been only barely explored in Latin America (Latam) across different actors: industry, regulatory agencies, and even academia. In this manuscript, we discuss the challenges and opportunities for implementing M&S approaches in Latam. Perspectives of regional experts were shared in a workshop. Attendance (professionals from industry, regulator, academia, and clinicians) also shared their views via survey. The rational development of bioequivalent generics was considered the main opportunity for M&S in regional market, particularly the use of PBPK and PBBM. Nonetheless, a critical mass of modeling scientists is needed before Latin American industry and regulators can actually benefit from M&S. Collaborations (e.g., Academia-Industry and Academia-Regulatory) may be a path to develop applied research projects and train the future modelers. Reaching that critical mass, scientists from industry may apply modeling across generic drug development process and life cycle, while regulatory scientists may issue guidelines in local language to support regional industry. Only at that stage could the full potential of MIDD be reached in Latin American generic markets.

Preparation of Ibuprofen-Loaded Inhalable γCD-MOFs by Freeze-Drying Using the QbD Approach

Background/Objectives: Research on cyclodextrin-based metal-organic frameworks (CD-MOFs) is still in its infancy, but their potential for use in drug delivery—expressly in the lung—seems promising. We aimed to use the freeze-drying method to create a novel approach for preparing CD-MOFs. MOFs consisting of γ-cyclodextrin (γCD) and potassium cations (K+) were employed to encapsulate the poorly water-soluble model drug Ibuprofen (IBU) for the treatment of cystic fibrosis (CF). Methods: Using the LeanQbD® software (v2022), we designed the experiments based on the Quality by Design (QbD) concept. According to QbD, we identified the three most critical factors, which were the molar ratio of the IBU to the γCD, incubation time, and the percentage of the organic solvent. light-, scanning electron microscope (SEM) and laser diffraction were utilized to observe the morphology and particle size of the samples. In addition, the products were characterized by Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD), Fourier Transform Infrared Spectroscopy (FT-IR) and nuclear magnetic resonance spectroscopy (NMR). Results: Based on characterizations, we concluded that a γCD-MOF/IBU complex was also formed using the freeze-drying method. Using formulations with optimal aerodynamic properties, we achieved 38.10 ± 5.06 and 47.18 ± 4.18 Fine Particle Fraction% (FPF%) based on the Andersen Cascade Impactor measurement. With these formulations, we achieved a fast dissolution profile and increased IBU solubility. Conclusions: This research successfully demonstrates the innovative use of freeze-drying to produce γCD-MOFs for inhalable IBU delivery. The method enabled to modify the particle size, which was crucial for successful pulmonary intake, emphasizing the need for further investigation of these formulations as effective delivery systems.

Scientifc Validation and Chromatographic Method Development for the Estimation of Piperine in Herbal Formulation Babbularishta: A Quality Control Strategy for Critical Quality Attributes

Background: Babbularishta is an Ayurvedic medicine in liquid form used for the treatment of phthisis, skin diseases, urinary disorders,, and breathing problems. It is also beneficial in cases of blood disorders, acne, dermatitis, hemoptysis, lung injury, asthma, persistent cough, whooping cough, etc. Objective: The functional role of this study is to develop a simple, novel, precise, accurate, reliable, and selective RP-HPLC method for the estimation of piperine content in herbal drug formulations (Babbularista). Methods: A traditional approach to method development could fail to meet the desired separation. Consideration of the current regulatory requirement for analytical method development and RP-HPLC method for routine analysis of piperine in the herbal formulation has been optimized using an analytical Quality by Design (QbD) approach. Three laboratory formulations and three marketed preparations of Babularishta were investigated for organoleptic parameters, physicochemical parameters, and validation. The mobile phase composition (methanol and water % as A), pH (B), and flow rate (mL/min as C) were selected as independent variable,. In contrast, retention time (min. as Y2), area (AU as Y1) is selected as dependent variables. Results: The fingerprinting method was developed and optimized by using the AQbD approach. Piperine content was found to be in Piper nigrum (Marica) 3.01±0.01527 % w/w and in Piper longum (Pipali) 2.74±0.01154% w/w in Babbularista. Conclusion: An attempt has been made to develop quality control parameters of Babbularista by developing a suitable and sensitive HPLC methods for the quantitation of piperine in herbal drug formulations (Babbularista). The developed method was found to be simple, accurate, precise,, and economical for the estimation of piperine in herbal formulations.

Advancing Analytical Excellence: A Comprehensive Exploration of ICH Q14 in the Lifecycle of Analytical Procedure Development and Optimization

This research article addresses the complexities of analytical process development and optimization in line with the principles set out in the Commission's Effectiveness of the Requirements for Medicinal Products for Human Use (ICH) Q14 guidelines. Focusing on the pharmaceutical and chemical industry, this article describes the early stages of development in terms of sustainable lifestyles. The first study explores the important role of analytical procedures in ensuring product quality and regulatory compliance, introduces ICH Q14 and explains its scope and objectives. The fundamental principles of audit development are reviewed in depth, including risk assessment, design, and the interaction between Audit Objectives (ATP) and Methodology. Operational Development Region (MODR). Concepts such as Design of Operations (DoE) and Quality by Design (QbD) are under scrutiny for their development and optimization. Real-life case studies demonstrate the application of Q14 principles and demonstrate successful examples of effective methods and continuous improvement in drug screening, drug purity testing and environmental analysis. Looking ahead, this article explores how new technologies, potentially innovative regulations and international cooperation will shape the development landscape. Challenges such as the complexity of new compounds and the need for sustainable practices are addressed and the need for business professionals to be flexible and innovative is emphasized. In summary, this research article can serve as a general guide for professionals in the pharmaceutical and chemical industry, providing insight into the content, eight owners, and use of development analysis. Using the principles defined in ICH Q14, community auditors can investigate the changing landscape and make further progress on quality assurance.

Curcumin-loaded zein nanoparticles: A quality by design approach for enhanced drug delivery and cytotoxicity against cancer cells

Zein, a maize protein, has been explored for constructing potential biomaterial due to its hydrophobic nature, self-assembly capability, and biocompatibility. In its nanoparticulate form, zein is a promising material for drug delivery applications, particularly in cancer treatment. Despite the importance of colloidal stability for effective drug delivery, systematic studies investigating the effect of various surface modifying agents (MAs) on the zein nanoparticles (ZNPs)-based formulations are limited. This study employs quality-by-design (QbD) approach to optimize curcumin-loaded ZNPs, enhancing colloidal stability, size, and drug-encapsulation efficiency using different MAs for potential cancer therapy. Gum arabic (GA) emerged as the optimal stabilizer, with GA-stabilized curcumin-loaded ZNPs (GA-Cur-ZNPs) achieving a particle size of 184.8 ± 2.85 nm, zeta potential of −23.4 ± 0.56 mV and 87.1 ±1.55 % drug encapsulation efficiency, along with excellent colloidal stability over two months. The optimal formulation also demonstrated sustained release of Cur over 72 h. GA-Cur-ZNPs demonstrated lower IC50 values and higher anti-proliferative effects on three different cancer cell lines compared to the free drug, while also exhibiting superior intracellular uptake. With negligible toxicity to human dermal fibroblast cells, the optimized Cur-GA-ZNPs show promise for safe and effective killing of cancer cells.

Analyzing the Chiral Purity of Pharmaceuticals: The Application of Cyclodextrin-Based Chiral Selectors in Capillary Electrophoresis

The current review provides a focused analysis of the application of capillary electrophoresis (CE) techniques to determine the chiral purity of pharmaceuticals, with a specific emphasis on cyclodextrin- (CD) based chiral selectors (CSs), highlighting advancements, methodologies, and trends in this area as reported in studies published from 2010 to 2024. The review emphasizes CE’s evolution as a critical tool in this field, discussing its advantages, such as high efficiency, flexibility, relatively low costs, and minimal environmental impact, which make it well-suited for modern pharmaceutical applications. Additionally, it underscores the importance of CE in meeting stringent regulatory requirements for chiral drug substances. A significant shift in method optimization has occurred in the last ten years, shifting from the traditional One-Factor-at-a-Time (OFAT) strategy to the Design-of-Experiments (DoE) approach; this shift has enabled more systematic and robust method development. Furthermore, a common trend in recent years is the application of Quality-by-Design (QbD) principles in method development and optimization, ensuring higher reliability and efficiency. Additionally, there is an increasing focus on developing CE methods capable of detecting both achiral and chiral impurities simultaneously, which enhances the comprehensiveness of the analysis. This review seeks to guide future research and development in optimizing CE methodologies for pharmaceutical applications.

Optimising nanoparticles: harnessing quality by design through 3-level factorial design and box-behnken methodology

Nanoparticles (NPs) have become essential elements in a number of scientific and industrial domains, such as materials research, drug delivery, and diagnostics, because of their special qualities and potential for focused uses. An ideal formulation procedure is essential to maximising the effectiveness and efficiency of nanoparticles. In order to optimise the formulation and production processes for nanoparticles, this research investigates the application of Quality by Design (QbD) principles in conjunction with sophisticated statistical approaches, namely the 3-level factorial design and the Box-Behnken methodology. The Quality by Design methodology is a methodical approach that prioritises predetermined goals, in-depth process comprehension, and careful control grounded in reliable science and quality risk management. When QbD is incorporated into nanoparticle optimisation, reliable and repeatable formulations that adhere to specifications with little variation are guaranteed. To look into how different factors interact and affect the properties of nanoparticles, the 3-level factorial design is used. With this design approach, a thorough understanding of the process variables can be obtained by exploring a broad variety of component values. Critical quality attributes (CQAs) include important parameters such drug encapsulation efficiency, zeta potential, polydispersity index (PDI), and particle size. These parameters are methodically examined to determine the ideal amounts of each. To further refine the 3-level factorial design, the Box-Behnken methodology is applied. Without the requirement for extensive combination testing, this response surface methodology (RSM) is especially useful for building second-order polynomial models and investigating quadratic response surfaces. By enabling a more accurate comprehension of the interactions between inputs and responses, the Box-Behnken design improves the optimisation process and makes it easier to identify the ideal circumstances for nanoparticle synthesis. By utilising both approaches in tandem, this work methodically determines ideal formulation parameters that minimise nanoparticle size and polydispersity while optimising stability and drug loading efficiency. The outcomes highlight how important a QbD framework is for directing the creation of reliable nanoparticle systems that function consistently and predictably.

Understanding Isoniazid Crystals Agglomeration Through Quality by Design and Artificial Neural Network Analysis

Introduction: The aims of this study were to determine and govern critical sources of variability in the process and to investigate the effect of excipients and processing conditions on the critical quality attributes (CQAs) of isoniazid (INZ) crystal agglomerates using a quality-bydesign (QbD) paradigm along with risk-based approach. Methods: The QbD paradigm is thoroughly exercised to determine the CQAs and to, link these CQAs to agglomerate properties and to recognize potentially significant input variables. Considering this, a risk assessment tool was executed with different excipients and processing conditions to define their effect on CQAs of agglomerates. Potential risk factors were recognized using an Ishikawa diagram and then investigated using principal component analysis and an artificial neural network. After that, all agglomerates were optimized using the design of the experiment. Results: The optimized INZ crystal agglomerates were characterized using various tools such as X-ray diffractometry, Fourier transform infrared spectroscopy, scanning electron microscopy, differential scanning calorimetry, gas chromatography, and stability testing. These characterizations confirmed that INZ did not undergo any structural modifications in the agglomerates. Conclusion: The results indicate that the QbD principles and risk assessment tool provide a valuable means to fully understand directly compressible INZ crystal agglomerates, which could be considered an exceptional alternative to the granulation method.

Development and Validation of HSPiP- and Optimization-Assisted Method to Analyze Tolterodine Tartrate in Pharmacokinetic Study

A new approach was applied for the development of a precise, simple, and economic analytical process for the accurate analysis of tolterodine tartrate (TOT) in its bulk and tablet using HSPiP- and quality by design (QbD)-assisted methods. The HSPiP program predicted several solvents and their right ratios for the mobile phase, followed by simulating the experimental solubility data in various predicted solvents. QbD was used to identify the impact of the composition and the mobile phase flow rate on the peak area and retention time. TOT was estimated using an Agilent TC C18 column employing an optimized mobile phase. The HSPiP shortened the solvent selection time with high reliability, whereas QbD identified critical factors. The optimized composition and process variables were used to develop an analytical method for TOT estimation. Various analytical validation parameters were estimated with constructed linearity of 5–30 μg/mL and a percent recovery yield value of 100.36%. To ensure the reliability of the optimized method, we estimated validation parameters (linearity, specificity, precision, accuracy, robustness, and ruggedness) to comply with the ICH guidelines. Considering the high recovery yield, good regression coefficient, low detection limit, and low noise ratio, the optimized method was accurate and precise with a high degree of specificity, rapid process, and reproducibility for the quantitative estimation of tolterodine from both oral analytes (I and II). The validated method was implemented for pharmacokinetic study in rats for quantitative estimation of the analytes with high accuracy, sensitivity, and reproducibility.

Experiences and Initiatives on Pharmacokinetics Modeling and Simulation Data analyses: Perspectives from the Brazilian Health Regulatory Agency (ANVISA).

The landscape of drug product development and regulatory sciences is evolving, driven by the increasing application of systems thinking and modeling and simulation (M&S) techniques, especially from a biopharmaceutics perspective. Patient-centric quality standards can be achieved within this context through the application of quality by design (QbD) principles and M&S, specifically by defining clinically relevant dissolution specifications (CRDS). To this end, it is essential to bridge in vitro results to drug product in vivo performance, emphasizing the need to explore the translational capacity of biopharmaceutics tools. Physiologically based M&S analyses offer a unique avenue for integrating the drug, drug product, and biological properties of a target organism to study their interactions on the pharmacokinetic response. Accordingly, Physiologically Based Biopharmaceutics Modeling (PBBM) has seen increasing use to support drug development and regulatory applications globally. In Brazil, a Model-Informed Drug Development (MIDD) policy and strategic project are not yet established, limiting applicability of M&S techniques. Drawing from the experience of the ANVISA-Academia PBBM Working Group (WG), this article assesses the opportunities and challenges for pharmacometrics (PMx) in Brazil and proposes strategies to advance the adoption of M&S analyses into regulatory decision-making.

Hansen parameters and GastroPlus assisted optimized topical elastic liposomes to treat breast cancer using a novel isatin derivative

Breast cancer treatment is a global health challenge using conventional toxic chemotherapeutic agents. A novel isatin could be a promising alternative. An isatin derivative (TM-19) was synthesized and characterized using NMR (nuclear magnetic resonance), mass spectrometry, Fourier transform infrared (FTIR), and differential scanning calorimetry (DSC). HSPiP and GastroPlus predictive software were used to predict suitable solvents for solubility and in vivo oral pharmacokinetics in humans (fasted condition), respectively. Based on predictive findings, topical elastic liposomes (phosphatidylcholine as PC and span 80 by film hydration method) was prepared, characterized, and optimized using QbD (quality by design). QbD identified the impact of composition on response variables (Y1 for size, Y2 for polydispersity index, Y3 for zeta potential, and Y4 for %EE). In vitro cytotoxicity study was carried out against MCF-7 cell lines. Low molecular weight and lipophilic TM-19 was crystalline in nature (255 g/mol). GastroPlus program predicted limited in vivo dissolution and poor oral absorption (10.4 %). Results confirmed the highest TM-19 solubility in DMSO (dimethyl sulfoxide) ˃ chloroform ˃ PEG 400 (polyethylene glycol 400). Considering experimental and predicted data, topical delivery of TM-19 using optimized (desirability parameter value = 0.97) elastic liposomes (TF1) was quite promising due to optimal size (344 nm), high %EE (61.7 %), low PDI (0.45), and optimal zeta potential (− 12.34 mV). TM-19 loaded TF1 elicited concentration dependent cytotoxic effect (˃ 90 % at 10 µM) against MCF-7 as compared to TM-19 suspension.

Integrating the Quality-by-Design (QbD) Approach in the Development of Febuxostat-loaded Proniosomal Gel for Topical Delivery

Integrating the Quality-by-Design (QbD) Approach in the Development of Febuxostat-loaded Proniosomal Gel for Topical Delivery