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Background: The drugs categorized under BCS class II and IV are poorly water-soluble, which in turn affects their dissolution and bioavailability. To overcome these limitations, namely, poor solubility and bioavailability, several approaches have been tried so far, like, co-solvency, size reduction or micronization, complexation, adsorption on high surface area carriers, etc. Objective: The present article aims to explore the utilization of the liquisolid technique to improve the dissolution profile of curcumin and quercetin, used as a combination in a solid dosage form. It covers the study of the impact of various carriers employed in liquisolid technology on drug dissolution profiles; Avicel pH 101, Fujicalin and Neusilin were used as carriers in this study. Methods: The solubility of the drugs was evaluated in various non-volatile solvents except water to select the vehicle having maximum solubility. All formulations were then prepared using curcumin and quercetin in a ratio of 2:1 (150 mg curcumin : 75 mg Quercetin), comprising a proportion of 40-60% w/w of the total mass of the formulation and were estimated for post-compression parameters. During the final processing of the liquisolid compacts, the carrier is to coating material ratio was kept consistent, i.e., 20:1. Results: Powder X-ray Diffraction (PXRD) and Fourier Transform Infrared Spectroscopy (FTIR) were utilized to analyze drug-excipient interaction; these studies stated no evidence of any physical or chemical interaction between drug(s) and the excipients. The final product was then evaluated for the liquid adsorption capacity and in vitro release of the drugs as a combination, and it was observed that these two properties were found to be significantly improved in the liquisolid compacts. result: The overall result supports improved dissolution for both the drugs by using neusilin as the carrier. The results indicated that a combination of quercetin and curcumin can be considered for formulation in drug concentration (40 %) in Castor oil using neusilin as carrier and aerosil as coating material. Conclusion: The outcomes indicated that the combination of Neusilin as the carrier and castor oil as a non-volatile solvent was the best-performing formulation appropriate for targeting an improved dissolution profile. other: No

The goal of the current work was to do an orderly assessment of flow of powders and granules using compendial and non-compendial procedure. Angle of repose, Tapped density, Carr's compressibility file, Bulk density, Hausner’s ratios were assessed. Moreover, flow was described utilizing powder rheometer wherein delicate force transducer screens the forces created as consequence of the sample displacement, another technique FT4 powder rheometer. The Freeman Technology (FT4 powder rheometer) is intended to describe powders undergoing different circumstances in manners that look like wide scale creation climate. Techniques incorporate security and irregular flow rate, compressibility, shear cell, air circulation, porousness, divider contact and union. The FT4 has demonstrated application on the whole powders preparing ventures, including drugs, fine synthetic substances, cosmetics, food, additives and powder covering. The FT4 application connect to filling, hopper flow, Tablet pressure, wet granulation, end point, flow added substance determination and enhancement, moisture impacts, static change, feeding, stirring, separation, caking, processing, Wall grating, grip, hopper configuration etc.

Background Ceftazidime, a third-generation cephalosporin, is widely used in the treatment of lung infections, often given as “off-label” nebulization. There is a need to develop a sensitive and robust analytical method to compute aerodynamic properties of ceftazidime following nebulization. Objective The current study entails development of a simple, accurate, and sensitive HPLC method for ceftazidime estimation, employing the principles of analytical quality-by-design (AQbD) and Monte Carlo simulations. Method Selection of critical material attributes (CMAs) affecting method performance was accomplished by factor screening exercises. Subsequently, the influential CMAs, i.e., mobile phase ratio and flow rate, were systemically optimized using a face-centered cubic design for the chosen critical analytical attributes (CAAs). The factor relationship(s) between CMAs and CAAs was explored employing a 3 D-response surface and 2 D-contour plots, followed by numerical as well as graphical optimization, for establishing the optimal chromatographic conditions. The obtained method operable design region was validated by Monte Carlo simulations for defect rate analysis. Results The optimized HPLC conditions for estimating ceftazidime were acetonitrile to acetic acid solution (75:25) as mobile phase at a flow rate of 0.7 mL/min, leading to Rt of 4.5 min and peak tailing ≤2. Validation studies, as per International Conference on Harmonization Q2(R1) guidance, demonstrated high sensitivity, accuracy, and efficiency of the developed analytical method with an LOD of 0.075 and LOQ of 0.227 µg/mL. Application of this chromatographic method was extrapolated for determining aerodynamic performance by nebulizing ceftazidime at a flow rate of 15 L/min using a next-generation impactor. The study indicated superior performance, sensitivity, and specificity of the developed analytical system for quantifying ceftazidime. Conclusions Application of an AQbD approach, coupled with Monte Carlo simulations, aided in developing a robust HPLC method for estimationof ceftazidime per se and on various stages of impactor. Highlights (i) QbD-enabled development of robust RP-HPLC method for ceftazidime quantification, (ii) Analytical method optimization employing Risk Assessment and Design of Experiments, (iii) Design space verification and defect rate analysis using Monte Carlo simulations, (iv) Chromatographic method validation as per ICH Q2 R1 guidelines and (v) Quantitative estimation of ceftazidime on various stages of impactor

Cancer, a complex series of diseased conditions, contributes to a significant health problem and is a leading cause of mortalities across the world. Lately, with the advent of improved diagnostics and imaging techniques, and newer advanced oral chemotherapeutics; millions of cancer affected people can lengthen their life span. Despite all the challenges associated with an active chemotherapeutic molecule like microenvironment and the intestinal barrier of the gastrointestinal tract (GIT) etc., the oral delivery remains the most acceptable route of drug administration. In this regard, nanotechnology has played a significant role in the counteracting the challenges encountered with newly developed molecules and aiding in improving their bioavailability and targetability to the tumour site, while administering through the oral route. Several literature instances document the usage of nanostructured drug delivery systems such as lipid-based, polymerbased or metallic nanomaterials to improve the efficacy of chemotherapy. Besides, sitespecific targeted surface-modified drug delivery system designed to deliver the active molecule has opened up to the newer avenues of nanotechnology. However, the issue of potential toxicity allied with nanotechnology cannot be compromised and thus, needs specific ethical regulations and guidelines. The various in vitro models have been developed to evaluate the in vitro toxicity profile which can be further correlated with the invivo model. Thus, this review provides a summarized account of the various aspects related to the role of nanotechnology in cancer therapy and various related issues thereof; that must be triumphed over to apprehend its full promise.

Sorafenib tosylate (SFB) is a multikinase inhibitor that inhibits tumour growth and proliferation for the management of breast cancer but is also associated with issues like toxicity and drug resistance. Also, being a biopharmaceutical class II (BCS II) drug, its oral bioavailability is the other challenge. Henceforth, this report intended to encapsulate SFB into a biocompatible carrier with biodegradable components, i.e., phospholipid. The microemulsion of the SFB was prepared and characterized for the surface charge, morphology, micromeritics and drug release studies. The cell viability assay was performed on 4T1 cell lines and inferred that the IC50 value of sorafenib-loaded microemulsion (SFB-loaded ME) was enhanced compared to the naïve SFB at the concentrations of about 0.75 µM. More drug was available for the pharmacological response, as the protein binding was notably decreased, and the drug from the developed carriers was released in a controlled manner. Furthermore, the pharmacokinetic studies established that the developed nanocarrier was suitable for the oral administration of a drug by substantially enhancing the bioavailability of the drug to that of the free SFB. The results bring forth the preliminary evidence for the future scope of SFB as a successful therapeutic entity in its nano-form for effective and safer cancer chemotherapy via the oral route.

The current work entails QbD-enabled preparation of methotrexate-loaded nanoparticles (NPs) using zein as the release-controlling natural polymer. Initially, quality risk estimationand factor screening studies using Taguchi design were undertaken to delineate “vital few” process and material attributes among “plausible so many”. Further, formulation optimization using central composite design and validation using correlation plots and percent predictive bias was carried out. Optimized NPs exhibited mean size of 159 nm, zeta potential of 14.85 mV and entrapment of 50.23%. In vitro dissolution kinetic modelling unearthed non-Fickian drug release extension mechanism from the proposed zein NPs. In vitro MTT and apoptosis assay using MCF-7 cells and cellular uptake studies using Caco-2 cells indicate remarkably superior anticancer potential of zein NPs over pure methotrexate, ascribable to their nanometric size and cationic nature. In vivo pharmacokinetic studies in rat construed significant enhancement by 2.15-fold in AUC48h (pmax (pmax (p1/2 (pin vitro/in vivo correlations (IVIVC) and kinetic modeling construed the robustness and prognostic ability of drug release studies. Robustness of the nanoformulation was ratified under refrigerated storage through six months’stability studies. Overall, the studies unequivocally indicate development of a stable nanoparticulate formulation with significantly enhanced extent, extension and consistency of biopharmaceutical performance, along with improved anticancer potential of methotrexate.

Nanostructured drug delivery formulations have lately gained enormous attention, contributing to their systematic development. Issuance of quality by design (QbD) guidelines by ICH, FDA, and other federal agencies, in this regard, has notably influenced the overall development of drug products, enabling holistic product and process understanding. Owing to the applicability of QbD paradigms, a science lately christened as formulation by design (FbD) has been dedicated exclusively to QbD-enabled drug product development. Consisting of the principal elements of design of experiments (DoE), quality risk management (QRM), and QbD-enabled product comprehension as the fundamental tools in the implementation of FbD, a variety of drug nanocargos have been successfully developed with FbD paradigms and reported in the literature. FbD aims to produce novel and advanced systems utilizing nominal resources of development time, work effort, and money. A systematic FbD approach envisions the entire developmental path through pivotal milestones of risk assessment, factor screening and optimization (both using appropriate experimental designs), multivariate statistical and optimum search tools, along with response surface modeling, usually employing suitable computer software. The design space is one of the fundamental elements of FbD providing the most sought-after regulatory flexibility to pharma companies, postapproval. The present paper provides a bird's eye view of the fundamental aspects of FbD terminology, methodology, and applications in the development of a wide range of nanocargos, as well as a discussion of trends from both technological and regulatory perspectives.

The present research work encompasses systematic development of a simple, fast, sensi- tive, reproducible and cost-effective reversed-phase high-performance liquid chromatographic (RP-HPLC) method, applying the principles of Quality by design (QbD) for quantification of raloxifene hydrochloride (RLX). Reversed-phase chromatography was carried out using Waters Acquity high-performance liquid chro- matographic system (HPLC), equipped with photodiode array (PDA) detector controlled by Empower 2® software, using a Hibar Purospher® STAR C18 (250 x 4.6 mm; 5 μm) HPLC column. Initial risk assessment followed by screening studies was carried out using a four-factor-eight-run fractional factorial design (FFD). Subsequently, optimization studies were carried out employing a central composite design (CCD) with flow rate and mobile phase ratio as the critical method parameters (CMPs), and tailing factor (TF), % assay and theoretical plate count (TPC) as the critical analytical attributes (CAAs). The optimal chromatographic sepa- ration was conducted using graphical and numerical optimization with the mobile phase composition of methanol and sodium acetate buffer (pH 4) in the ratio of 50:50 (% v/v) at a flow rate of 1mL/min, an oven temperature of 40°C at a λmax of 287 nm. Linearity was observed in the concentration range of 0.5-100 μg/mL, with a correlation coefficient of 0.999. Further, the LOD and LOQ were found to be 0.5432 ng/mL and 1.6461 ng/mL respectively. The developed method was validated as per the ICH Q2 (R1) guidelines, and the principles and science of analytical quality by design (AQbD) for establishing a high degree of linearity, accuracy, precision, sensitivity and robustness, for estimating RLX in bulk drugs and marketed formulations.

The present work describes Quality by design (QbD)-oriented development of a reverse phase high performance liquid chromatographic (RP-HPLC) method for quantification of methotrexate (MTX). Initially, for performing HPLC studies with UV detector, an appropriate wavelength was selected using a novel technique of Principal Component Analysis (PCA). Risk assessment study was performed, followed by factor screening study using a fractional factorial design (FFD). Subsequently, factor optimization was conducted using a central composite design (CCD), with flow rate and mobile phase ratio as the critical method parameters (CMPs), and tailing factor (TF), theoretical plate count (TPC) and % assay selected as the critical analytical attributes (CAAs). Polynomial modeling was performed to embark upon an optimal solution, followed by numerical and graphical optimization. Chromatographic separation was conducted using the mobile phase composition of acetonitrile (ACN) and ammonium acetate buffer (10 mM, pH 6) in the ratio of 25:75 v/v, flow rate of 0.8 mL/min, column oven temperature of 40 °C, and UV detection at 257 nm. Further, the analytical method was validated as per ICH Q2(R1) guidelines for linearity, accuracy, precision, sensitivity and robustness, ratifying that all the parameters were within the acceptable limits for quantification of MTX.

Raloxifene hydrochloride, a second-generation selective estrogen receptor modulator, has been approved for the management of breast cancer. However, it is known to exhibit poor (~ 2%) and inconsistent oral bioavailability in humans, primarily ascribable to its low aqueous solubility, extensive first-pass metabolism, P-gp efflux, and presystemic glucuronide conjugation. The present research work entails the systematic development and evaluation of SLNs of RLX for its enhanced biopharmaceutical performance against breast cancer. Factor screening studies were conducted using Taguchi design, followed by optimization studies employing Box-Behnken design. Preparation of SLNs was carried out using glyceryl monostearate and Compritol® 888 ATO (i.e., lipid), Phospholipid S-100 (i.e., co-surfactant), and TPGS-1000 (i.e., surfactant) employing solvent diffusion method. The optimized formulation was evaluated for zeta potential, average particle size, field emission scanning electron microscope, transmission electron microscopy, and in vitro release study. Further, MCF-7 cells (cell cytotoxicity assay, apoptosis assay, and reactive oxygen species assay) and Caco-2 cells (cell uptake studies and P-gp efflux assay) were employed to evaluate the in vitro anticancer potential of the developed optimized formulation. In vivo pharmacokinetic studies were conducted in Sprague–Dawley rats to evaluate the therapeutic profile of the developed formulation. The optimized SLN formulations exhibited a mean particle size of 109.7 nm, PDI 0.289 with a zeta potential of − 13.7 mV. In vitro drug dissolution studies showed Fickian release, with release exponent of 0.137. Cell cytotoxicity assay, apoptosis assay, and cellular uptake indicated 6.40-, 5.40-, and 3.18-fold improvement in the efficacy of RLX-SLNs vis-a-vis pure RLX. Besides, the pharmacokinetic studies indicated quite significantly improved biopharmaceutical performance of RLX-SLNs vis-a-vis pure drug, with 4.06-fold improvement in Cmax, 4.40-fold in AUC(0-72 h), 4.56-fold in AUC(0-∞), 1.53-fold in Ka, 2.12-fold in t1/2, and 1.22-fold in Tmax. Further, for RLX-SLNs and pure drug, high degree of level A linear correlation was established between fractions of drug dissolved (in vitro) and of drug absorbed (in vivo) at the corresponding time-points. Stability studies indicated the robustness of RLX-SLNs when stored at for 3 months. Results obtained from the different studies construe promising the anticancer potential of the developed RLX-SLNs, thereby ratifying the lipidic nanocarriers as an efficient drug delivery strategy for improving the biopharmaceutical attributes of RLX.

The current studies endeavour to develop and validate a simple, sensitive and robust reversed- phase (RP) high-performance liquid chromatography (HPLC) methodology for quantitative estimation of voriconazole (VRC), following systematic principles of Analytical Quality-by-Design (AQbD). A comprehensive risk assessment plan, followed by factor screening studies employing Taguchi design, was executed to select “vital few” critical method parameters, influencing critical analytical attributes. Subsequently, response surface optimisation studies were conducted on the identified critical method parameters, viz., mobile phase ratio and flow rate, with chosen critical analytical attributes, viz., peak area, theoretical plate count, retention time and peak tailing, employing a Central Composite Design. The design space, demarcating the optimal method operating conditions, was identified using graphical optimisation and subsequently validated employing Monte Carlo simulations. The optimal solution consisted of acetonitrile and acetic acid solution (0.05 %, pH 4) as mobile phase (50:50 v/v), flow rate of 1 mL/ min with a detection wavelength of 256 nm, exhibiting linearity between 0.1 and 50 μg/mL in methanol and Hanks balanced salt solution. Validation studies confirmed precision (97.78-103.42 %), accuracy (98.99-102.34 %), and suitability of the developed analytical method for effective quantification of VRC with high sensitivity (LOD: 0.031 μg/mL; LOQ: 0.093 μg/mL). The validated analytical technique was successfully ratified for quantification of VRC in drug nanoformulations too. In a nutshell, the application of AQbD and Monte Carlo simulations aided in developing a robust analytical method for the estimation of VRC per se as well as in drug nanoformulations.

Bioactives are documented to exhibit diverse pharmacological activities, however, their low and inconsistent bioavailability primarily pose serious impediment against their potential therapeutic usage. Efforts, therefore, have been undertaken to systematically develop nanostructured lipidic carriers of chrysin, a vital flavonoid, employing Capmul PG-12 (i.e., liquid lipid), glyceryl monostearate (i.e., solid lipid), stearylamine, Phospholipid S-100 (i.e., cosurfactant) and Poloxamer 188 (i.e., surfactant). NLCs were formulated using hot-melt dispersion-high pressure homogenization method and optimized using Face-Centred Cubic Design. Afterwards, stearylamine was conjugated with biotin as ligand through EDC-NHS coupling reaction and biotin-staerylamine complex formation was ratified using H-1NMR and FTIR. It was further used instead of SA for the preparation of biotin-conjugated-optimized NLCs (Bio-NLCs). Mean particle size of consequent Bio-NLCs was found to be 246.4 nm and zeta potential as 11.4 mV. In vitro release studies indicated sustained drug release characteristics from NLCs over 48 h. Cell line studies conducted on coumarin6-loaded Bio-NLCs in demonstrated remarkably superior cellular uptake over naive NLCs and pure dye. Marked improvement in absorption parameters was observed during in vivo pharmacokinetics for Bio-NLCs and NLCs vis-a-vis pure chrysin suspension. However, the improvement for naive NLCs was relatively lower than that of Bio-NLCs. Almost 5.20-folds augmentation in Cmax (p < 0.005), 8.94-folds in AUC0-24 (p < 0.001), 7.46-folds in AUC0-∞ (p < 0.001) and 7.25-folds in Ka (p < 0.01), signify improved degree of drug absorption and retention of Bio-NLCs. Stability studies indicated the robustness of Bio-NLCs, when stored under refrigerated storage conditions for 3 months. By and large, the current work demonstrates high potential of Bio-NLCs for distinctly improved biopharmaceutical performance of chrysin.

The current studies investigate the application of quality by design-enabled type III self-emulsifying delivery system (Type III-SEDDS) of sorafenib tosylate (SFN) in improving its biopharmaceutical attributes. Initially, lipidic and emulsifying excipients were selected by carrying out solubility and phase titration experiments. After screening studies using Taguchi OA design, Type III-SEDDS were further optimised using D-optimal mixture design. The prepared formulations were assessed for globule size, zeta potential and percent of drug release. Following graphical optimisation, the optimum formulation was earmarked and further supersaturated to form saturated Type III-SEDDS (Sat-Type III-SEDDS) using a combination of HPMC and PVP to improve the stability of the formulation for a prolonged period. In vitro drug release of Type III-SEDDS study indicated approximately 8-fold improvement in dissolution rate over the pure powder drug. Cell uptake studies demonstrated higher uptake of dye-loaded Type III-SEDDS formulations in Caco-2 cells vis-a-vis plain dye. Cytotoxicity assay on Hep G2 cells revealed significant reduction in cell growth with Type III- and Sat-Type III-SEDDS vis-a-vis the pure drug. Furthermore, in situ permeation studies carried out using Wistar rats exhibited nearly 8.3- to 10.2-fold augmentation in permeation and absorption parameters of the drug from the Type III- and Sat-Type III-SEDDS, respectively, vis-a-vis the pure drug. Pharmacokinetic studies indicated nearly 3.98- and 3.62-fold improvement in AUC0–72, and 8.01- and 5.42-fold in Cmax, along with 0.25-fold decrease in Tmax of the drug from Type III- and Sat-Type III-SEDDS, respectively, in comparison with the SFN suspension. Furthermore, high degree of level A linear correlation was established between fractions of drug dissolved (in vitro) and of drug absorbed (in vivo) at the corresponding time points for Sat-Type III-SEDDS and pure drug, whereas the Type III-SEDDS exhibited a nonlinear relationship. Stability studies indicated the robustness of Sat-Type III-SEDDS, when stored at 25 °C for 3 months. Overall, the manuscript documents the successful systematic development of SFN-loaded Sat-Type III-SEDDS with distinctly improved biopharmaceutical performance.

Ferulic acid (FA) is a ubiquitous natural plant bioactive with distinctive promise in neurodegenerative disorders. However, its therapeutic efficacy gets compromised owing to its poor aqueous solubility, inadequate permeability across lipophilic barriers, and extensive first-pass metabolism. The current studies, therefore, were undertaken to systematically develop chitosan-coated solid lipid nanoparticles (SLNs) using QbD paradigms for improved efficacy of FA in the management of Alzheimer's disease (AD). SLNs of FA were formulated employing Compritol as lipid and polysorbate 80 as surfactant and optimised using a 32 Central Composite Design (CCD). The optimized formulation, surface-coated with chitosan using ionic gelation, exhibited particle size of 185 nm, entrapment efficiency of 51.2 % and zeta potential of 12.4 mV. FTIR and DSC studies verified the compatibility of FA with formulation excipients, PXRD construed significant loss of drug crystallinity, while FESEM depicted existence of uniform spherical nanoparticles with little aggregation. Notable improvement in ex vivo mucoadhesion and permeation studies using goat nasal mucosa, coupled with extension in in vitro drug release, was obtained with SLNs. Substantial improvement with SLNs in cognitive ability through the reduction in escape latency time during behavioural studies, together with significant improvement in various biochemical parameters and body weight gain was observed in AD-induced rats. Histopathological images of different rat organs showed no perceptible change(s) in tissue morphology. Overall, these preclinical findings successfully demonstrate improved anti-AD efficacy, superior nasal mucoadhesion and permeation, extended drug release, improved patient compliance potential, safety and robustness of the developed lipidic nanoconstructs of FA through intranasal route.

The objectives of the present research work were systematic development of novel in situ gel formulation containing nanoparticles for localised delivery of moxifloxacin against bacterial periodontitis. PLGA nanoparticles were prepared and optimised in a systematic manner. Factor screening was performed with the help of half-factorial design to identify the influential factors, while response surface optimisation of the nanoparticles was conducted using central composite design. The optimum nanoparticle formulation was chosen on the basis of lower particle size, higher drug entrapment and controlled drug release characteristics up to 1 week time period, while the optimum in situ gel was selected on the basis of faster gelling and higher viscosity and gel strength properties for improved retention in the periodontium. In vivo histopathological studies and in vivo gamma scintigraphy studies revealed the extended release, superior efficacy and enhanced retention of nanoparticle-loaded in situ gelling system. Results obtained from in vivo histopathological studies after 1 week treatment with in situ gel formulation containing nanoparticles of moxifloxacin were found to be better than with 3 weeks treatment of marketed gel formulation. Overall, the studies ratify successful development of an effective site-specific drug delivery system with enhanced biopharmaceutical attributes for the periodontitis treatment.

Numerous oral treatment options have been reported for neurological disorders, especially Alzheimer's disease (AD). Galantamine (GAL) is one of such drugs duly approved for management of AD. However, it exhibits poor brain penetration, low intestinal permeation and requires frequent dosing in AD treatment. The present studies, accordingly, were undertaken to develop DSPE-PEG 2000-based micelles loaded with GAL for efficient brain uptake, improved and extended pharmacokinetics, along with reduced dosing regimen.Mixed nanomicelles (MNMs) were systematically formulated using QbD approach, and characterized for morphology, entrapment efficiency andin vitrodrug release.Studies on CaCo-2 and neuronal U-87 cell lines exhibited substantial enhancement in the cellular permeability and uptake of the developed MNMs. Pharmacokinetic studies performed on rats showed significantly improved values of plasma AUC (i.e., 2.28-fold, p 0.001), ostensibly due to bypassing of hepatic first-pass metabolism and improved intestinal permeability, together with significant rise in MRT (2.08-fold, p 0.001) and tThe preclinical findings of the developed nanocarrier systems successfully demonstrate the notable potential of enhanced drug efficacy, extended duration of action and improved patient compliance.

Since decades, the plant bioactives have shown tremendous promise in the therapeutic management of cancer. Lately, many synthetic drugs and natural bioactive molecules have been used in combination for potential synergism in cancer therapeutics. Sorafenib (SFN) and chrysin (CHR) form one of such promising combinations with definitive synergistic potential in cancer therapy. This has, however, given rise to analytical challenges, as it becomes quite difficult to identify and quantify two or more active moieties simultaneously in the presence of each other. Herein, we report the development and validation of an HPTLC densitometric method for analysis of SFN and CHR, in combination, followed by studying the effect of biological matrix (i.e., plasma), on the assay of both the molecules. Solvent system, comprising of toluene: n-hexane: isopropyl alcohol (7:2:1), was employed for chromatographic separation with Rf values of 0.3 and 0.5, for SFN and CHR, respectively. Validation studies established linearity for the concentrations ranging from 20 to 800 ng/band for each of the molecules, along with high degree of accuracy, precision (intra- and inter-day), ruggedness, robustness, and sensitivity of the liquid chromatographic method. Specificity studies using plasma as the biological matrix, exhibited well-resolved peaks of both the molecules, coupled with high recovery values too. The aforesaid method was finally applied to the estimation of real plasma levels in Wistar rats, following co-administration of SFN and CHR as a suspension. In a nutshell, the validated analytical method can be productively applied for simultaneous estimation of SFN and CHR, for routine analysis, in drug formulations and in biological matrices like plasma.

The present work describes the systematic development of a simple, rapid, sensitive, robust, effective and cost-effective reversed-phase high performance liquid chromatographic method for quantitative analysis of ferulic acid using analytical quality by design paradigms. Initially, apt wavelength for the analysis of ferulic acid was selected employing principal component analysis as the chemometric tool. An Ishikawa fishbone diagram was constructed to delineate various plausible variables influencing analytical target profile, viz. peak area, theoretical plate count, retention time and peak tailing as the critical analytical attributes. Risk assessment using risk estimation matrix and factor screening studies employing Taguchi design aided in demarcating two critical method parameters, viz. mobile phase ratio and flow rate affecting critical analytical attributes. Subsequently, the optimum operational conditions of the liquid chromatographic method were delineated using face-centred composite design. Multicollinearity among the chosen factors for optimization was analyzed by the magnitude of variance inflation factor optimized analytical design space, providing optimum method performance, was earmarked using numerical and graphical optimization and corroborated using Monte Carlo simulations. Validation, as per the ICH Q2(R1) guidelines, ratified the efficiency and sensitivity of the developed novel analytical method of ferulic acid in the mobile phase and the human plasma matrix. The optimal method used a mobile phase, comprising of acetonitrile: water (47:53% v/v, pH adjusted to 3.0 with glacial acetic acid), at a flow rate of 0.8 mL·min−1, at a λmax of 322 nm using a C18 column. Use of principal component analysis unearthed the suitable wavelength for analysis, while analytical quality by design approach, along with Monte Carlo simulations, facilitated the identification of influential variables in obtaining the “best plausible” validated chromatographic solution for efficient quantification of ferulic acid.

Resveratrol (RSV) has shown to possess anti-cancer potential in various studies; however, its poor water solubility, extensive first-pass metabolism, and photostability issues have limited its clinical application. Therefore, the aim of the current investigation was to formulate and optimize a nanostructured lipid carriers (NLCs) based parenteral formulation of RSV for its effective delivery to breast cancer cells. NLCs loaded with RSV (RSV-NLCs) were formulated by the modified solvent injection technique and were systematically optimized using a three level-three factor Box-Behnken design. The optimized RSV-NLCs exhibited an optimum particle size of 88.3 ± 3.1 nm and high entrapment efficiency of 88.0 ± 2.6%. These optimized NLCs were further investigated for the targeting potential using folic acid as the targeting moiety and cell cytotoxicity experiments revealed high cytotoxic effects of folate modified NLCs (RSV-FA-NLCs) compared to unmodified NLCs on MCF-7 cells with high levels of over-expressed folate receptors suggesting the high potential of targeted NLCs in enhancing the therapeutic concentration of RSV to breast cancer cells. In vivo pharmacokinetic studies demonstrated a nine-fold increase in AUC values obtained with RSV-FA-NLCs (57.92 ± 4.15 μg h/mLh) in comparison to free RSV (6.37 ± 1.16 μg h/mLh). The promising results from this investigation corroborated the tremendous potential of lipidic nanocarriers in augmenting the therapeutic potential of RSV.

Engineered nanomaterials have emerged as an important area in biomedical research due to their potential to improve human health. Many nanocomposites and new polymers are in the development phases, or have been introduced as preventive or therapeutic products and devices. However, some key safety issues related to acute and chronic use of these nanomaterials must be addressed prior to consideration for product development. Regulatory processes have evolved due to challenges in characterization of complex compositions and toxicological attributes of physical and chemical components. Composition and characteristic considerations include (i) nano, small size and low molecular weight materials that could penetrate the blood–brain and other physiological barriers causing neuro- and geno-toxicity and (ii) potential to generate free radicals that elicit oxidative stress and inflammation. Additionally, several other factors such as shape, surface area, dose, surface modifications and safety considerations should also be included in the design specification to avoid late-stage plausible product failure due to toxicology concerns. Environmental exposure to nanomaterials is another area of research that should address the impact of manufacturing and metabolic products generated by the application of nanomaterials in pharmaceuticals. This book chapter presents current knowledge on the biological fate, behavior and toxicity of different classes of nanomaterials and their impact on the environment.

The present studies describe quality-by-design-based design and characterization of cationic self-nanoemulsifying formulations of paclitaxel for improving its biopharmaceutical attributes. Solubility and phase titration experiments were designed to select the lipidic and emulsifying excipients. Two different types of lipidic nanoformulations were developed using medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs). The nanoformulations were optimized by mixture designs and subjected to evaluation for globule size, zeta potential, drug release, and intestinal permeability. Following apt mathematical modeling, the optimum nanoformulation was earmarked using numerical optimization. Further, cationic formulations were developed for both LCT- and MCT-containing formulations and subjected to performance evaluation. The optimized formulations were extensively evaluated, where an in vitro drug release study indicated 2.7-fold improvement in dissolution rate from optimized cationic nanoformulations over powder pure drug. Ex vivo and in situ evaluation performed on Wistar rats exhibited nearly six- to eightfold enhancement in permeation and absorption parameters of the drug for the optimized cationic nanoformulation as compared to the pure paclitaxel. Pharmacokinetic studies indicated nearly 13.4-fold improvement in AUC and Cmax, along with 1.8-fold reduction in Tmax of the drug from cationic nanoformulations as compared to the pure drug suspension. Moreover, nanoformulation containing long-chain lipids exhibited superior performance (1.18-fold improvement in drug absorption) over medium-chain lipids. Cytotoxicity evaluation of cationic nanoformulations on MCF-7 cells revealed significant reduction in growth vis-a-vis the pure drug. Overall, the current paper reports successful systematic development of paclitaxel-loaded cationic self-nanoemulsifying systems with distinctly improved biopharmaceutical performance.

The present studies describe the systematic development and validation of a simple, rapid, sensitive and cost-effective reversed-phase high-performance liquid chromatographic bioanalytical method for the estimation of valsartan in rat plasma employing analytical quality by design (AQbD) principles quality risk management was applied for identifying the critical method parameters (CMPs) and subsequently method optimization was performed employing Box–Behnken design by selecting mobile phase pH, flow rate and % organic modifier as the CMPs and evaluated for critical analytical attributes (CAAs) such as peak area, retention time, peak tailing and number of theoretical plates. The developed method was then transferred to bioanalysis, where liquid–liquid extraction process was used for separating the drug from rat plasma. The optimization of extraction process was performed with the help of face-centered cubic design by selecting centrifugation speed and centrifugation time as the CMPs for maximizing % recovery, signal-to-noise ratio and purity threshold of the drug peak after extraction as the CAAs. Optimum chromatographic solution was chosen by mathematical and graphical search techniques, and design space was demarcated. Validation studies performed for the developed method indicated linearity ranging between 5 and 100 ng.mL−1, whereas accuracy and precision study showed good percent recovery (99–102%) along with % relative standard deviation within ±2%. Sensitivity evaluation revealed limit of detection and limit of quantification were found to be 0.76 ng.mL−1 and 2.29 ng.mL−1, respectively. In a nutshell, the present work demonstrates significant merits of AQbD approach for holistic process understanding and analytical method development and validation with enhanced robustness and performance.

Osteomyelitis encompasses various skeletal disorders that can cause significant morbidity to patients. Currently, osteomyelitis caused by bacterial microorganisms requires long treatment with limited specificity, leading to recurrence, and a need for extensive surgical debridement in patients. Thus, there is a critical need to develop alternative and more effective therapeutic strategies to overcome moderate therapeutic efficacy. Here, we discuss the feasibility of nanotechnology-based approaches for the management of osteomyelitis. Nanostructured drug delivery systems have high drug loading with minimal side effects and can be translated for the management of infected wounds. In Chapter 11, we review the nanoformulations under development and their potential for clinical translation.

Metal–organic frameworks (MOFs) have gained much attention and proliferate as porous nanoscaled hybrid polymer–metal composites. These polymeric nanomaterials possess innumerable applications such as gas storage, gas/vapor separation, sensor, catalysis, imaging, luminescence, drug delivery and biomedical applications. The structure of MOFs is characterized by an open framework that can be porous. MOFs consist of transition-metal cations, polydentate organic linkers, and metal ions linked through coordination bonds. The unique physical and chemical characteristics of MOFs are attributed to both their organic and inorganic component. This unique blend of properties makes them suitable for application in the field of material science, biology, and nanotechnology-based drug delivery. Biodegradability, excellent porosity, high loading capacity, and ease of surface modification are the major advantages offered by them. Accordingly, this chapter provides a an overview of various types of MOFs, their characterization and applications in diverse disciplines of biomedical sciences, with particular focus on drug delivery and theranostics; highlighting the stability and toxicity issues of MOFs, along with their market potential.

Several randomized clinical trials have divulged that administration of antioxidants during chemotherapy decreases the effectiveness of treatment. Hence, the characteristic feature of this article is extensive assessment of putative benefits and potential risks of natural and synthetic antioxidant supplementation, administered with chemotherapy, based upon the available preclinical and clinical data. After analyzing mixed results, it was concluded that current FDA guidelines should be followed before supplementing antioxidants during cytotoxic treatment. Nevertheless, contradictory experimental animal models opposing human clinical trials discourage the concurrent administration of antioxidants ostensibly owing to the possibility of tumor protection and reduced survival.

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% H2 O2 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.