Formulation and Evaluation of Butenafine Hydrochloride-Incorporated Solid Lipid Nanoparticles as Novel Excipients for the Treatment of Superficial Fungal Infections.

Objectives: The objective of the present study was to develop natural excipient-based solid lipid nanoparticles (SLN) of butenafine hydrochloride (BUTE) using a modified solvent emulsification technique and to evaluate the competence of aloe vera nanolipidgel in enhancing the penetration of BUTE. Materials and Methods: BUTE-SLNs were prepared using a 23 factorial design to correlate the effect of formulation components on the BUTE-SLN. Particle size, polydispersity index (PDI), zeta potential, entrapment performance, and drug loading were assessed in the formed SLNs. The fabricated BUTE-SLN was evaluated for transmission electron microscopy, fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction study studies and revealed the encapsulation of BUTE in lipid in the amorphous state. BUTE-SLN-based aloe vera gel was formulated and evaluated compared with the marketed product with respect to primary skin irritation, hydration, skin permeation, and antifungal activity. Results: The BUTE-SLN aloe vera gel, optimized for its formulation, features excellent slip properties and controlled drug release. DSC and XRD studies confirm its amorphous nature with effective drug entrapment. The gel provides enhanced skin deposition, improved antifungal activity, and reduced irritation. This makes it a cost-effective and innovative alternative to traditional dosage forms. BUTE-SLN promisingly showed no irritation, higher hydrating potential, slow and sustained release, and enhanced antifungal activity. With an aim to target deeper skin strata, minimize the side effects of drugs and symptomatic impact of fungal infection, and shorten the duration of therapy, BUTE-SLN was successfully prepared. The mean particle size and PDI were 261.25 ± 2.38 nm and 0.268 ± 0.01, respectively. Conclusion: BUTE-SLN gel offers improved topical delivery of BUTE with significantly higher compatibility and antifungal activity than the marketed formulation.

Development, evaluation of critical method variables and stability assessment using a Box-Behnken design for the determination of organic impurities in a pharmaceutical dosage form of a centrally acting muscle relaxant drug chlorzoxazone.

This study validates a stability-indicating LC method for detecting organic impurities in the chlorzoxazone dosage form. Using a Waters X-Select R HSS T3 analytical column, mobile phase of it was made by mixing of water, methanol, and glacial acetic acid in the ratio of 700:300:10 (v/v/v). The drug product and drug substance were subjected to the stress conditions such as acid, base, oxidation, heat, and photolysis as per the recommendations of the International Conference on Harmonization (Q2) methodology. The study revealed the susceptibility of 4-chloro-2-aminophenol to alkaline environments, emphasizing peak homogeneity and stability. The method verification, per ICH guidelines and USP<1225>, established precision, specificity, linearity, accuracy, and robustness for quality control. The mean impurity recovery ranged from 95.5% to 105.2%, the correlation coefficient (r) was greater than 1.000, and the RSD values (n = 6) ranged from 0.6% to 5.1% across the LOQ-150% ranges. Full-factorial design tested final method conditions, evaluating multiple parameters concurrently. Graphical optimization within the design space defined strong method requirements, ensuring consistent and reliable outcomes. The study develops and validates chlorzoxazone stability-indicating methods, employing advanced statistical approaches like design of experiments and factorial design, with resilient conditions established through graphical optimization of the design space.

Improvement of Bioavailability of Sildenafil Citrate Through Taste Masked Orodispersible Film for Pulmonary Hypertension Management.

The oral bioavailability of sildenafil citrate is approximately 43%, primarily limited by the low aqueous solubility and first-pass effect. Considering the drug properties and biopharmaceutical considerations, this study aimed to develop an immediate release, taste masked orodispersible film (ODF) of sildenafil citrate for the efficient management of pulmonary arterial hypertension (PAH). The optimization was done by applying 32 full-factorial design. The drug-loaded film was prepared and evaluated for the physical and mechanical parameters like; thickness, disintegration time, tensile strength, elongation, swelling index, content uniformity, disintegration and in vitro drug release in pH 6.2 stimulated salivary fluid. The FTIR and DSC data proved excellent compatibility between the drug and polymers used. The time taken for disintegration by the optimized film was about 62.66 s, while the drug release was observed ~ 96% in 10 min. Pharmacokinetic studies exhibited better sildenafil plasma level (p < 0.05) and Cmax (p < 0.001) of orally disintegrating film which is significantly higher than the oral drug solution. The AUC0-8 (24874.425 ± 1234.45 ng. h/mL) in the oromucosal application was 1.2-fold more (p < 0.0001) than the control. The presence of sweetening and flavoring agents in the formulation masked the drug bitterness, resulting in a higher intake of the formulation in rats compared to the unmasked drug solution, as observed with in vivo taste masking studies. The importance of ODF as a feasible, effective, and optimal approach for delivering sildenafil citrate via oromucosal administration for the treatment of PAH was successfully highlighted by these results.

Unraveling the interplay of common groundwater ions in arsenic removal by sulfide-modified nanoscale zerovalent iron.

Sulphidation of nZVI (S-nZVI) has shown to significantly improve the arsenic removal capacity of nZVI, concurrently modifying the sequestration mechanism. However, to better apply S-nZVI for groundwater arsenic remediation, the impact of groundwater coexisting ions on the efficacy of arsenic uptake by S-nZVI needs to be investigated. This present study evaluates the potential of S-nZVI to remove arsenic in the presence of typical groundwater coexisting ions such as Cl-, HA, HCO3-, PO43- and SO42- through batch adsorption experiments. Individually, PO43- and HA had a dominant inhibition effect, while SO42- promoted As(III) removal by S-nZVI. Conversely, for As(V) removal, HCO3- and SO42- impeded the removal process. X-ray spectroscopic investigation suggests that the coexisting ions can either compete with arsenic for the adsorption sites, influence the S-nZVI corrosion rates and/or generate distinct corrosion products, thereby interfering with arsenic removal by S-nZVI. To investigate the cumulative effects of these ions, a 25-1 Fractional Factorial Design of experiments was employed, wherein the concentration of all the ions were varied simultaneously in an optimized manner, and their impact on arsenic removal by S-nZVI was observed. Our results shows that when these ions are present concurrently, PO43-, SO42- and HA still exerted a dominant influence on As(III) removal, whereas HCO3- was the main ions affecting As(V) removal, although the combined influence of the ions was not merely a summation of their individual effects. Overall, the finding of our study might provide valuable insight for predicting the actual performance of S-nZVI in field-scale applications for the remediation of arsenic-contaminated groundwater.

13-Week repeated-dose toxicity study of optimized aqueous extract of Moringa oleifera leaves in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Moringa oleifera (Moringaceae family), commonly known as horseradish or tree of life, is traditionally used for various diseases, such as diabetes, hypercholesterolemia, neurological disorders, among others. AIM OF THE STUDY: To evaluate the toxicological profile of the oral use of an aqueous extract of Moringa oleifera leaves for 13 weeks in mice. MATERIALS AND METHODS: Initially, a factorial design (23) was carried out to optimize aqueous extraction using as variables; the extraction method and proportion of drug. The 13-week repeated-dose toxicity trial used female and male mice, with oral administration of aqueous extract of Moringa oleifera leaves at doses of 250, 500, and 1000 mg/kg. The animals were evaluated for body weight, water and feed intake, biochemical and hematological parameters, urinalysis, ophthalmology and histopathology of the liver, spleen and kidneys. RESULTS: The extraction efficiency was evidenced by the extraction by maceration at 5%, obtaining the optimized extract of Moringa oleifera (OEMo). The oral administration of OEMo did not promote significant difference (p > 0.05) in the weight gain, food and water consumption of the control animals and those treated with 250 and 500 mg/kg. However, treatment with 1000 mg/kg promoted a reduction (p < 0.05) in food intake and body weight from the 7th week onwards in male and female mice. No alterations were detected in the hematological and histological parameters in the concentrations tested for both sexes. The highest concentration treatment (1000 mg/kg) promoted an increase in transaminases in males and females. All concentrations promoted a significant decrease (p < 0.05) in the serum lipid profile of mice. CONCLUSION: This study developed an optimized extract of Moringa oleifera leaves, which should be used with caution in preparations above 500 mg/kg for the long term because it leads to significant changes in liver enzymes. On the other hand, the extract proved to be a promising plant preparation for hyperlipidemia in mice.

Maximizing the Use of Ivermectin Transethosomal Cream in the Treatment of Scabies.

In an effort to tackle the skin reactions frequently observed with topical application of ivermectin (IVM), a study was conducted to develop and optimize transethosomes (TESMs) loaded with IVM for scabies treatment. A three-factor, two-level (23) full factorial design was employed. Soyabean phosphatidylcholine concentration (A), ethanol concentration (B) and Span 60 amount (C) were studied as independent factors, while entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and drug release after 6 h (Q6h) were characterized. The skin sensitivity of the optimized formulation was evaluated by skin irritation test and histopathological examination. The EE% ranged from 88.55 ± 0.576% to 94.13 ± 0.305%, PS was from 318.033 ± 45.61 nm to 561.400 ± 45.17 nm, PDI was from 0.328 ± 0.139 to 0.671 ± 0.103, ZP was from -54.13 ± 1.09 mV to -60.50 ± 2.34 mV and Q6h was from 66.20 ± 0.30% to 93.46 ± 0.86%. The IVM-loaded transethosomal cream showed lower skin irritation and a more intact epidermal layer with intact keratinocyte, compared to the marketed cream which showed severe destruction of the keratin layer. Therefore, patient compliance can be improved by encapsulating IVM within TESMs to minimize its skin reactions.

Investigation into Influence of Tensile Properties When Varying Print Settings of 3D-Printed Polylactic Acid Parts: Numerical Model and Validation.

Material Extrusion (MEX), particularly Fused Filament Fabrication (FFF), is the most widespread among the additive manufacturing (AM) technologies. To further its development, understanding the influence of the various printing parameters on the manufactured parts is required. The effects of varying the infill percentage, the number of layers of the top and bottom surfaces and the number of layers of the side surfaces on the tensile properties of the printed parts were studied by using a full factorial design. The tensile test results allowed a direct comparison of each of the three parameters' influence on the tensile properties of the parts to be conducted. Yield strength appears to be the most affected by the number of layers of the top and bottom surfaces, which has twice the impact of the number of layers of the side surfaces, which is already twice as impactful as the infill percentage. Young's modulus is the most influenced by the number of layers of the top and bottom surfaces, then by the infill percentage and finally by the number of layers of the side surfaces. Two mathematical models were considered in this work. The first one was a polynomial model, which allowed the yield strength to be calculated as a function of the three parameters mentioned previously. The coefficients of this model were obtained by performing tensile tests on nine groups of printed samples, each with different printing parameters. Each group consisted of three samples. A second simplified model was devised, replacing the numbers of layers on the side and top/bottom surfaces with their fractions of the cross-section surface area of the specimen. This model provided results with a better correlation with the experimental results. Further tests inside and outside the parameter ranges initially chosen for the model were performed. The experimental results aligned well with the predictions and made it possible to assess the accuracy of the model, indicating the latter to be sufficient and reliable. The accuracy of the model was assessed through the R2 value obtained, R2 = 92.47%. This was improved to R2 = 97.32% when discarding material infill as an input parameter.

The Effects of Pulsed Electrospinning Process Variables on the Size of Polymer Fibers Established with a 23 Factorial Design.

In the present study, the influence of the electrical parameters of the pulsed electrospinning process, such as the electrical voltage, the frequency of pulses, and the pulse duration, on the structure of obtained nonwovens was determined for the first time. It was found that all the parameters studied strongly influence the average diameter of the obtained fibers and that the pulsed electrospinning process carried out under specific conditions makes it possible to obtain, among other things, bimodal nonwovens. A 23 factorial design was used to determine how the selected electrical parameters of the pulsed electrospinning process affect the structure of the resulting electrospun mats. It is shown, among other things, that by appropriately selecting the parameters of the electrospinning process, the thickness of fibers can be controlled, resulting in nonwovens with a desired morphology.

Investigating Best Practices for Ecological Momentary Assessment: Nationwide Factorial Experiment.

BACKGROUND: Ecological momentary assessment (EMA) is a measurement methodology that involves the repeated collection of real-time data on participants' behavior and experience in their natural environment. While EMA allows researchers to gain valuable insights into dynamic behavioral processes, the need for frequent self-reporting can be burdensome and disruptive. Compliance with EMA protocols is important for accurate, unbiased sampling; yet, there is no "gold standard" for EMA study design to promote compliance. OBJECTIVE: The purpose of this study was to use a factorial design to identify optimal study design factors, or combinations of factors, for achieving the highest completion rates for smartphone-based EMAs. METHODS: Participants recruited from across the United States were randomized to 1 of 2 levels on each of 5 design factors in a 2×2×2×2×2 design (32 conditions): factor 1-number of questions per EMA survey (15 vs 25); factor 2-number of EMAs per day (2 vs 4); factor 3-EMA prompting schedule (random vs fixed times); factor 4-payment type (US $1 paid per EMA vs payment based on the percentage of EMAs completed); and factor 5-EMA response scale type (ie, slider-type response scale vs Likert-type response scale; this is the only within-person factor; each participant was randomized to complete slider- or Likert-type questions for the first 14 days or second 14 days of the study period). All participants were asked to complete prompted EMAs for 28 days. The effect of each factor on EMA completion was examined, as well as the effects of factor interactions on EMA completion. Finally, relations between demographic and socioenvironmental factors and EMA completion were examined. RESULTS: Participants (N=411) were aged 48.4 (SD 12.1) years; 75.7% (311/411) were female, 72.5% (298/411) were White, 18.0% (74/411) were Black or African American, 2.7% (11/411) were Asian, 1.5% (6/411) were American Indian or Alaska Native, 5.4% (22/411) belonged to more than one race, and 9.6% (38/396) were Hispanic/Latino. On average, participants completed 83.8% (28,948/34,552) of scheduled EMAs, and 96.6% (397/411) of participants completed the follow-up survey. Results indicated that there were no significant main effects of the design factors on compliance and no significant interactions. Analyses also indicated that older adults, those without a history of substance use problems, and those without current depression tended to complete more EMAs than their counterparts. No other demographic or socioenvironmental factors were related to EMA completion rates. Finally, the app was well liked (ie, system usability scale score=82.7), and there was a statistically significant positive association between liking the app and EMA compliance. CONCLUSIONS: Study results have broad implications for developing best practices guidelines for future studies that use EMA methodologies. TRIAL REGISTRATION: ClinicalTrials.gov number NCT05194228; https://clinicaltrials.gov/study/NCT05194228.

Green analytical quality by design RP-HPLC technique with fluorimetric detection for simultaneous assay of cinnarizine and dompridone.

A green and sensitive factorial design-assisted reversed-phase high-performance liquid chromatography (RP-HPLC) approach with fluorimetric detection has been developed for simultaneous determination of cinnarizine and domperidone in pure materials, commercial single and combined tablets. Both drugs are co-formulated in one dosage form and are commonly used for the effective treatment of motion sickness in the ratio of 4 : 3 for cinnarizine and domperidone, respectively. To achieve the developed method's best performance and reliability, a 23 full factorial design was applied during the optimization of chromatographic conditions. Subsequently, isocratic elution on a C18 column with a mobile phase mixture of methanol and 0.02 M potassium dihydrogen phosphate buffer (85 : 15 v/v, pH 3.0) was performed to achieve the best separation. Moreover, the flow rate of 0.8 ml min-1 was applied during the analysis with fluorescence detection at λex 283 nm/λem 324 nm. The elution process was time effective; it consumed less than 6 min for a complete run as retention time for cinnarizine and domperidone, was 4.5 and 3.5, respectively. Good linearity of the proposed method was achieved within the concentration ranges of 0.2-4.5 and 0.4-5.0 µg ml-1 for domperidone and cinnarizine, respectively. The suggested approach was carefully validated according to the International Council for Harmonization (ICH) guidelines. Moreover, green analytical procedure index (GAPI), national environmental methods index (NEMI), analytical greenness (AGREE) and analytical eco-scale methods were applied to assess and confirm method greenness.

Optimization and quality evaluation of functional pasta made from germinated finger millet, buckwheat, and black gram.

The investigation was conducted to optimize process variables to manufacture functional pasta from composite flour. The selected grains were steeped, germinated, dried, and milled to produce flour. The flours were mixed at optimized proportions (57.31% buckwheat flour, 12.68% finger millet flour, and 30% paheli dal flour) to produce composite flour. The full factorial experimental design opted for optimization of process variables namely, moisture content (mc) (28, 30, 32, and 34%) and mixing speed (60, 80, 100, and 120 rpm). The optimized multi-grain pasta showed shorter processing time, in-range cooking loss, and higher cooking weight and water absorption capacity (WAC). The highest overall acceptability was recorded for multi-grain pasta processed at 60 rpm with an initial mc of 32%. Proximate analysis of optimized multi-grain pasta showed that pasta contained protein (13.95%), crude fiber (5.05%), ash (2.05%), a lower amount of fat (0.74%), and carbohydrates (71.71%).

Diltiazem Hydrochloride Floating Matrix Tablet: Formulation and in vitro-in vivo Evaluation.

BACKGROUND: Diltiazem hydrochloride is a calcium channel-blocker with a plasma elimination half-life of 4.4 ± 1.3 h and has a narrow absorption window. So, this work aimed to prepare a gastro-retentive floating matrix tablet. METHODS: The direct compression method was used to manufacture tablets. 32 factorial design was applied for optimization, taking Hydroxypropyl Methylcellulose K100M (HPMC K 100M) and the amount of sodium bicarbonate as independent factors and cumulative percentage release at 1 h, at 6 h, and at 12 h and floating lag time as dependent variables. RESULTS: The high amount of HPMC K100M and sodium bicarbonate shows good results. The optimized preparation was evaluated for differential scanning calorimetry, in-vivo gastric retention in male albino rabbits, kinetic modeling, and stability study. An in vivo study revealed gastric retention of tablets up to 6 h in healthy male Albino rabbits. The stability study indicated no significant change in the buoyancy and release profiles of the drug. CONCLUSION: From this study, it can be concluded that the gastro-retentive diltiazem hydrochloride floating matrix tablet was successfully prepared and retained inside the rabbit stomach for up to 6 h and was stable under accelerated stability study.

Aspergillus niger as an efficient biological agent for separator sludge remediation: two-level factorial design for optimal fermentation.

Background: The booming palm oil industry is in line with the growing population worldwide and surge in demand. This leads to a massive generation of palm oil mill effluent (POME). POME is composed of sterilizer condensate (SC), separator sludge (SS), and hydro-cyclone wastewater (HCW). Comparatively, SS exhibits the highest organic content, resulting in various environmental impacts. However, past studies mainly focused on treating the final effluent. Therefore, this pioneering research investigated the optimization of pollutant removal in SS via different aspects of bioremediation, including experimental conditions, treatment efficiencies, mechanisms, and degradation pathways. Methods: A two-level factorial design was employed to optimize the removal of chemical oxygen demand (COD) and turbidity using Aspergillus niger. Bioremediation of SS was performed through submerged fermentation (SmF) under several independent variables, including temperature (20-40 °C), agitation speed (100-200 RPM), fermentation duration (72-240 h), and initial sample concentration (20-100%). The characteristics of the treated SS were then compared to that of raw sludge. Results: Optimal COD and turbidity removal were achieved at 37 °C 100 RPM, 156 h, and 100% sludge. The analysis of variance (ANOVA) revealed a significant effect of selective individual and interacting variables (p < 0.05). The highest COD and turbidity removal were 97.43% and 95.11%, respectively, with less than 5% error from the predicted values. Remarkably, the selected optimized conditions also reduced other polluting attributes, namely, biological oxygen demand (BOD), oil and grease (OG), color, and carbon content. In short, this study demonstrated the effectiveness of A. niger in treating SS through the application of a two-level factorial design.

Analysis of Fluorescent Carbon Nanodot Formation during Pretzel Production.

Baked pretzels are a popular choice for a quick snack, easily identifiable by their classic twisted shape, glossy exterior, and small salt crystals sprinkled on top, making them a standout snack. However, it is not commonly known that compounds with fluorescent properties can be formed during their production. Carbon nanodots (CNDs) with an average size of 3.5 nm were isolated and identified in bakery products. This study delved into the formation of CNDs in pretzel production using a fractional factorial experimental design. The research revealed that the baking temperature had the most significant impact on the concentration of CNDs, followed by the concentration of NaOH in the immersion solution, and then the baking time. This study highlights the unique role of the NaOH immersion step, which is not typically present in bread-making processes, in facilitating the formation of CNDs. This discovery highlights the strong correlation between the formation of CNDs and the heat treatment process. Monitoring and controlling these factors is crucial for regulating the concentration of CNDs in pretzel production and understanding nanoparticle formation in processed foods for food safety.

Quality-by-Design-Driven Nanostructured Lipid Scaffold of Apixaban: Optimization, Characterization, and Pharmacokinetic Evaluation.

Apixaban, an anticoagulant, is limited in its efficacy due to poor solubility, low bioavailability, and extensive metabolism. This study investigates the application of nanostructured lipid carriers (NLCs) to enhance the bioavailability of Apixaban. NLCs were prepared using the high-pressure homogenization method. The influence of independent variables, viz., the amount of Tween 80, HPH pressure, and the number of HPH cycles, were studied using a 23 factorial design. The average particle size, PDI, zeta potential, and entrapment efficiency of the optimized NLCs were found to be 232 ± 23 nm, with 0.514 ± 0.13 PDI and zeta potential of about -21.9 ± 2.1 mV, respectively. Additionally, concerning the thermal and crystallographic properties of the drug, the NLCs showed drug entrapment without altering its potency. The in-vitro drug release studies revealed an immediate release pattern, followed by sustained release for up to 48 h. In-vivo pharmacokinetic experiments demonstrated that Apixaban-loaded NLCs exhibited higher values of t1/2 (27.76 ± 1.18 h), AUC0-∞ (19,568.7 ± 1067.6 ng·h/mL), and Cmax (585.3 ± 87.6 ng/mL) compared to free drugs, indicating improved bioavailability. Moreover, a decrease in the elimination rate constant (Kel) reflected the sustained effect of Apixaban with NLCs. NLCs offer improved oral absorption rates and enhanced therapeutic impact compared to free drugs, potentially reducing dose frequency and improving patient outcomes.

Karanjin-loaded soya lecithin-based ethosomal nanogel for the therapeutic intervention of psoriasis: formulation development, factorial design based-optimization,in vitroandin vivoassessment.

This study aimed to develop and optimize karanjin-loaded ethosomal nanogel formulation and evaluate its efficacy in alleviating symptoms of psoriasis in an animal model induced by imiquimod. These karanjin-loaded ethosomal nanogel, were formulated to enhance drug penetration into the skin and its epidermal retention. Karanjin was taken to formulate ethosomes due to its potential ani-psoriatic activity. Ethosomes were formulated using the cold method using 32full factorial designs to optimize the formulation components. 9 batches were prepared using two independent variablesX1: concentration of ethanol andX2: concentration of phospholipid whereas vesicle size (Y1) and percentage entrapment efficiency (Y2) were selected as dependent variables. All the dependent variables were found to be statistically significant. The optimized ethosomal suspension (B3) exhibited a vesicle size of 334 ± 2.89 nm with an entrapment efficiency of 94.88 ± 1.24% and showed good stability. The morphology of vesicles appeared spherical with smooth surfaces through transmission electron microscopy analysis. X-ray diffraction analysis confirmed that the drug existed in an amorphous state within the ethosomal formulation. The optimized ethosome was incorporated into carbopol 934 to develop nanogel for easy application on the skin. The nanogel underwent characterization for various parameters including spreadability, viscosity, pH, extrudability, and percentage drug content. The ethosomal formulation remarkably enhanced the skin permeation of karanjin and increased epidermal retention of the drug in psoriatic skin compared to marketed preparation and pure drug. A skin retention study showed that ethosomal nanogel formulation has 48.33% epidermal retention in 6 h.In vivo,the anti-psoriatic activity of karanjin ethosomal nanogel demonstrated significant improvement in psoriasis, indicated by a gradual decrease in skin thickness and scaling as reflected in the Psoriasis Severity Index grading. Therefore, the prepared ethosomal nanogel is a potential vehicle for improved topical delivery of karanjin for better treatment of psoriasis.

AQbD-guided development and validation of an innovative extraction procedure and stability-indicating RP-HPLC method for quantification of posaconazole in tablet formulation.

OBJECTIVE: The objective of this work is to develop a stability-indicating HPLC method for the quantification of posaconazole (PCZ) in tablet formulation using an Analytical Quality by Design (AQbD) approach. MATERIALS AND METHODS: The development process involved the Design of Experiments (DOE) utilizing distinctive constraints mixture design for mobile phase ratio optimization and a 2-level factorial design for selection of extraction diluent compositions. Key responses measured included % assay and system suitability parameters. Method operable design regions (MODR) were determined, and final optimum conditions were selected. Forced degradation studies were conducted to assess method stability. RESULTS: The optimized HPLC method employed a Zorbax C18 column with a mobile phase consisting of pH 3.5 10mM phosphate buffer, acetonitrile, and methanol in a ratio of 30:53:17% v/v/v. The method demonstrated stability-indicating capabilities, with PCZ degradation observed in acidic and oxidative environments, while remaining stable in alkali. Peak purity analysis from Empower software confirmed the absence of interaction with degradants. Validation according to ICH Q2 (R2) guidelines showed precision, linearity over the range of 0.25 to 376µg/mL, and accuracy demonstrated through recovery studies from 50 to 150%. CONCLUSION: The developed HPLC method utilizing AQbD approach is specific, robust, precise, and accurate for the quantification of PCZ in tablet formulations, thus suitable for routine analysis.

Quality-by-design driven approach in the formulation of an anti-ulcer and gastro-protective oral suspension.

OBJECTIVE: This work aims to present a Quality-by-Design (QbD) step-by-step methodology to formulate anti-ulcer and gastro-protective oral suspensions. METHODS: Sucralfate was used as a drug model. The Quality Target Product Profile was established early during preformulation. Viscosity, resuspendability, pH, and density were assessed through the screening of several suspension platforms based on different prototype compositions. A compatibility study between the active pharmaceutical ingredient and the excipients was performed by thermal analysis and infrared spectroscopy. An Ishikawa fishbone diagram and Failure Mode and Effect Analysis were employed to identify the Critical Material Attributes (CMAs), Critical Process Parameters (CPPs), and Critical Quality Attributes (CQAs). CMAs' and CPPs' impact on identified CQAs was further assessed through a 22 full factorial experimental design at normal conditions after manufacture and one month at super-accelerated stress conditions. Results: The lead prototype exhibited no physicochemical incompatibilities. The risk assessment tools revealed that the concentration of the wetting agent and the total concentration of thickening agents represented critical factors for the quality profile of the preparation in terms of viscosity. The optimized formulation comprising 1.125 w/v% total concentration of Natrosol 250 HX and Avicel RC 591 exhibited an enhanced performance according to the established profile. CONCLUSIONS: The analytical and physicochemical tests showed the robustness and compliance of the final preparation with the quality profile. The proposed step-by-step methodology based on QbD, Design of Experiments, and Quality Risk Management presented in our research holds practical implications for local industries and formulation scientists involved in the development of oral suspensions.

Formulation, Optimization and In-Vivo Characterization of Thermosensitive In-Situ Nasal Gel Loaded with Bacoside a for Treatment of Epilepsy.

The intranasal route has demonstrated superior systemic bioavailability due to its extensive surface area, the porous nature of the endothelial membrane, substantial blood flow, and circumvention of first-pass metabolism. In traditional medicinal practices, Bacopa monnieri, also known as Brahmi, is known for its benefits in enhancing cognitive functions and potential effects in epilepsy. This study aimed to develop and optimize a thermosensitive in-situ nasal gel for delivering Bacoside A, the principal active compound extracted from Bacopa monnieri. The formulation incorporated Poloxamer 407 as a thermogelling agent and HPMC K4M as the Mucoadhesive polymer. A 32-factorial design approach was employed for Optimization. Among the formulations. F7 exhibited the most efficient Ex-vivo permeation through the nasal mucosa, achieving 94.69 ± 2.54% permeation, and underwent a sol-gel transition at approximately 30.48 °C. The study's factorial design revealed that gelling temperature and mucoadhesive strength were critical factors influencing performance. The potential of in-situ nasal Gel (Optimized Batch-F7) for the treatment of epilepsy was demonstrated in an in-vivo investigation using a PTZ-induced convulsion model. This formulation decreased both the occurrence and intensity of seizures. The optimized formulation F7 showcases significant promise as an effective nasal delivery system for Bacoside A, offering enhanced bioavailability and potentially increased efficacy in epilepsy treatment.

A Quality by Design (QbD) driven gradient high performance liquid chromatography method development for the simultaneous estimation of dasatinib and nilotinib in lipid nanocarriers.

Tyrosine kinase inhibitors (TKIs) are effective as a targeted treatment for chronic myeloid leukemia (CML), which can selectively suppress BCR-ABL1 kinase activity. CML therapy with TKIs combination has been supported by in-vitro, in-vivo, and patient-based data where the nilotinib-dasatinib co-administration has exerted superior anticancer efficacy with greater cellular uptake, less resistance to chemotherapy, and no additive adverse events encountered. Therefore, it is essential to develop a suitable analytical method for the simultaneous estimation of these drugs in the developed novel lipid nanocarriers like liposomes. Design of Experiment (DoE) has been implemented as a tool of QbD to systematically investigate the relation between the HPLC method attributes and analytical responses, i.e., chromatographic detection, quantification, and peak properties for dasatinib and nilotinib. An Ishikawa diagram is constructed to delineate possible influencing variables to the analytical performances. Afterward, 4 factors 2 level full factorial design (FFD) was employed to model and identify the main effects and interaction effects between the factors selected after the initial risk assessment. The suggested design space for optimized chromatographic conditions by QbD analysis is linear within the selected range of drug concentrations, accurate and precise, sensitive, and robust according to the ICH guidelines. The optimal method is comprised of a 1 mL/min flow rate of mobile phase (ACN and 20 mM KH2PO4 of pH 7.00) in gradient mode at 25 °C column temperature for 20 µL sample injection volume and detection wavelength fixed at 297 nm. Most importantly, this novel HPLC method is simple and selective enough to evaluate dasatinib and nilotinib content in the lipid nanocarriers.