QbD Approach Research Articles

Development of Validated Stability Indicating HPTLC Method for Estimation of Febuxostat in Bulk and Tablet Dosage Form by Using QBD Approach

Objective: Development of a simple, reliable, time-tested, stability-focused HPTLC method for determining febuxostat (FEB) in bulk and pharmaceutical formulation.Methods: Chloroform, methanol, and formic acid (6.7:2.9:0.1v/v/v) served as the mobile phase, and precoated aluminum TLC plates served as the stationary phase. Active drug FEB was subjected to a densitometric measurement (absorbance mode at 312 nm). The present study performed a comprehensive stress test of FEBas per ICH Q1A(R2) guidelines. FEB has undergone forced degradation by acid, alkali (0.5N HCl and NaOH), oxidative (3% H2O2), H2O and photolytic effect. Results: Calibration plots using HPTLC linear regression analysis indicated a strong correlation (r2 = 0.999) between concentrations from 150 to 900 ng/spot. Accuracy, recoverability, robustness, and documentation are some of the aspects of the method that have been verified. The LoD was 189 ng and the LoQ was 395 ng per location. FEB was not degraded under acid, UV, water, peroxide and photolytic conditions but showed degradation under alkaline conditions. Conclusion: Stability studies and quantification of FEB in bulk and pharmaceutical dose forms by QBD methodology have both been shown to benefit from the suggested HPTLC method. This technique can be utilized as a stability indicator because it successfully isolates the medication from the degradation product.

QbD based antifungal drug-loaded ophthalmic liposomal formulation for the management of fungal keratitis: In vitro, ex vivo and in vivo pharmacokinetic studies

An attempt has been made for controlling the drug release of antifungal drug fluconazole (FCZ) thereby formulating nanoliposomes (NLs) with increasing residence time by applying QbD approach. FCZ, an antifungal agent, having a low partition coefficient (logP 0.5) exhibits limited bioavailability due to washing off by tear fluid calls for repeated administration of dose; narrowing patient compliance. Box-Behnken design was applied for formulating thin-film hydration-based liposomes bearing FCZ; considering lipid amount, sonication time, and hydration time as independent variables. FCZ loaded NLs (FCZ-NLs) were optimized on the basis of particle size (268 ± 3.6 nm), ζ potential (−23.15 ± 3.12 mV), and % entrapment efficiency (69.75 ± 4.45%). The amount of cryoprotectant for lyophilization was also optimized. Zero-order release kinetics was close-fitting and higher ex-vivo permeation flux was observed for FCZ-NLs compared to marketed formulation. No hemolysis and ocular irritation were observed in a preclinical study. AUC (0–∞), MRT, and drug availability above the MIC of FCZ-NLs were increased up to 2.36, 3.05, and 4.57 folds, respectively as compared to the marketed formulation. The optimized FCZ-NLs could be further exploited as a potential ocular drug delivery system.

Multivariate Optimization for Determination of Favipiravir, a SARS-CoV-2 Molecule, by the Reverse-Phase Liquid Chromatographic Method Using a QbD Approach.

The object of the analytical work is to develop an analytical multivariate optimization for the determination of Favipiravir (FAV), a SARS-CoV-2 molecule, by the reverse-phase liquid chromatographic method using the analytical quality by design approach. FAV is used as an antiviral drug. Box-Behnken design is utilized for the optimization of the experiment and to identify the critical method parameters like the volume of acetonitrile, temperature and flow rate. Further, these factors are used to design the suitable mathematical models and illustrate their effect on various responses. This newly developed method utilized C18 column (5μm, 100 × 4.6 mm) and a temperature of 40°C with a flow rate of 0.5 mL/min. The mobile phase is composed of acetonitrile and ammonium acetate buffer (pH 4), in the ratio of 20:80v/v and the wavelength of HPLC UV-Detector was fixed to 323nm. This method is validated according to International Council for Harmonization Q2 (R1) guidelines. The System suitability is performed and the retention time of Favipiravir is 3.4min. The linearity range is obtained at 0.062 - 4 μg/mL with a correlation coefficient (r2 = 0.9979). The recovery is found to be in the range of 98.84-100%. Thus, the intended method is found to be simple and robust.

Development and Validation of Quality by Design based RP-HPLC Method for determination of Tenofovir Alafenamide Fumarate from Bulk drug and Pharmaceutical dosage form and its application to Forced Degradation Studies

The present research work entails the development and validation of a simple, robust and sensitive stability indicating reverse phase high performance liquid chromatographic method using Quality by Design methodology for estimation of Tenofovir alafenamide fumarate in bulk drug and its marketed dosage form. Chromatographic separation was performed in isocratic mode using Inertsil C18 column, mobile phase composed of Acetonitrile: ammonium formate buffer pH 5(40: 60) at a flow rate of 1mL/min with Photo Diode Array (PDA) detection at 261nm. A Box-Behnken statistical design with 3 factors and 3 levels was selected for the optimization study. Interaction effects of Critical Quality Parameters (Buffer pH, Organic Phase-% acetonitrile, flow rate) were evaluated for critical quality attributes (Retention time, NTP and symmetry factor). The optimized method was validated according to the current International Conference Harmonization (ICH) Q2 R1 guidelines. The method was found to be linear, covering the range from 1.5 μg/mL – 4.5 μg/mL with correlation coefficient r2 of 0.9996 and precision was found to be less than 2%. Limit of Detection and Limit of Quantification was found to be 1µg/mL and 1.2µg/mL respectively. Accuracy was between 99% and 102%. Forced degradation study was conducted under degradation conditions like light, oxidation, dry heat, acidic, basic, hydrolysis in order to establish the intrinsic stability of molecule. The method was successfully applied for the determination of the drug in commercial dosage form. This holistic stability indicating chromatographic method focused on QbD approach ensured reproducibility and was found to be useful for routine analysis of Tenofovir alafenamide fumarate.

Implementation of QBD Approach in Analytical Method Development of Fluvastatin by UV-VIS Spectrophotometry

Quality by design (QbD) is a systematic process for pharmaceutical development recommended by regulatory agencies like USFDA. Development of various pharmaceutical processes including analytical methods by applying Quality by design aids in ensuring the robustness of the method. An analytical method was developed for the estimation of fluvastatin by applying QbD approach by UV-VIS spectrophotometry. Solvent 0.1 N NaOH was utilised and 302.4 nm was the wavelength for measurement of absorbance. Effect of input variables on spectrum characteristics were studied for selection of critical parameters and developed method was validated as per ICH Q 2 R1 regulatory guidelines. Linearity of the drugs was ascertained over the conc range 5-40 mcg/ml (microgram/ml). The accuracy was found within acceptable limit with SD 0.05079-0.78188 %; and the precision study was shown acceptable data as % RSD 0.6259-0.6559 for FVT. The stability of the method was studied by minor variation in the wavelength and minor change in the normality of solvent. The developed method is rigid, robust and efficient for the estimation of FVT from the dosage form. QbD was applied to build rigid robust method through risk assessment at early stage and defining the design space at the later stage. The analytical methods, developed based on the QbD concept are more robust and reduce the number of out of trend (OOT) and out of specification (OOS) results during the actual usage in quality control.

Paclitaxel and Myrrh oil Combination Therapy for Enhancement of Cytotoxicity against Breast Cancer; QbD Approach

Paclitaxel (PX), plant alkaloid, is a chemotherapeutic agent intended for treating a wide variety of cancers. The objective of the present study was to formulate and evaluate the anticancer activity of PX loaded into a nanocarrier, mainly PEGylated nanoemulsion (NE) fabricated with myrrh essential oil. Myrrh essential oil has been estimated previously to show respectable anticancer activity. Surface modification of the formulation with PEG-DSPE would help in avoiding phagocytosis and prolong the residence time in blood circulation. Various NE formulations were developed after operating (22) factorial design, characterized for their particle size, in vitro release, and hemolytic activity. The optimized formula was selected and compared to its naked counterpart in respect to several characterizations. Quantitative amount of protein absorbed on the formulation surfaces and in vitro release with and without serum incubation were evaluated. Ultimately, MTT assay was conducted to distinguish the anti-proliferative activity. PEGylated PX-NE showed particle size 170 nm, viscosity 2.91 cP, in vitro release 57.5%, and hemolysis 3.44%, which were suitable for intravenous administration. A lower amount of serum protein adsorbed on PEGylated PX-NE surface (16.57 µg/µmol) compared to naked counterpart (45.73 µg/µmol). In vitro release from PEGylated NE following serum incubation was not greatly affected (63.3%), in contrast to the naked counterpart (78.8%). Eventually, anti-proliferative effect was obtained for PEGylated PX-NE achieving IC50 38.66 µg/mL. The results obtained recommend PEGylated NE of myrrh essential oil as a candidate nanocarrier for passive targeting of PX.

QBD approach for the development of hesperetin loaded colloidal nanosponges for sustained delivery: In-vitro, ex-vivo, and in-vivo assessment

Hesperetin (HT) is a polyphenolic compound with anti-carcinogenic, tumor necrosis, and anti-oxidant properties. The present study reports the fabrication, optimization, and evaluation of HT-loaded nanosponges (HTN)- based gel (HTNG) for sustained anti-inflammatory effect. HTN formulation was prepared by quasi emulsion solvent diffusion method using a 42 factorial design. HTN was subjected to different solid and liquid state characterizations and subsequently loaded in carbopol gel. The effects of pro-inflammatory cytokines (IL- 1β and IL-6) were evaluated using RAW 264.7 macrophage cells, and the anti-inflammatory potential was tested in rats. Tiny, porous, and spherical HTN retarded the drug release (39.98%) up to 8 h compared to the pure drug (70.74%) and physical mixture (73.72%) and followed the Higuchi-matrix model. HTNG had a strong downregulating effect on cytokines. It showed no skin irritation and 18.52% skin permeation at 8 h. Further, HTNG-treated rats exhibited 33.16% inflammation inhibition compared to the control group. In conclusion, nanosponges significantly retarded the topical delivery and could circumvent the bioavailability issues associated with HT.

In situ gelling nanosuspension as an advanced platform for fluticasone propionate nasal delivery

In this work we present the development of in situ gelling nanosuspension as advanced form for fluticasone propionate nasal delivery. Drug nanocrystals were prepared by wet milling technique. Incorporation of drug nanocrystals into polymeric in situ gelling system with pectin and sodium hyaluronate as constitutive polymers was fine-tuned attaining appropriate formulation surface tension, viscosity and gelling ability. Drug nanonisation improved the release profile and enhanced formulation mucoadhesive properties. QbD approach combining formulation and administration parameters resulted in optimised nasal deposition profile, with 51.8% of the dose deposited in the middle meatus, the critical region in the treatment of rhinosinusitis and nasal polyposis. Results obtained in biocompatibility and physico-chemical stability studies confirmed the leading formulation potential for safe and efficient nasal corticosteroid delivery.

An Integrative QbD Approach for the Development and Optimization of Controlled Release Compressed Coated Formulation of Water-Soluble Drugs

Controlled release dosage forms maintain regulated pharmacokinetic profile of drug substance within its therapeutic window by ensuring constant plasma concentrations. Controlled release formulations not only increase the therapeutic efficacy of drug substances but also reduce their dose-related side effects. Present investigation was conducted to develop, optimize, and validate compressed coated controlled release tablet formulation for highly water-soluble drug substances which have no rate-controlling factor towards its release from dosage form. Drug dispersed waxy core tablet, press coated within the swellable hydrophilic polymeric barrier layer, was developed and optimized via quality by design approach (QbD) using Box-Behnken design. The optimized formulation was characterized and validated using in vitro quality control parameters. Attributes identified under SUPAC guidelines, such as drug release rates at 30 min, 6 h, and 12 h, were considered as the critical quality attributes (CQAs) that significantly affected efficiency of the compressed coated controlled release tablets. CQAs screened using risk assessment and Pareto chart analyses were used for optimizing controlled release dosage form. Findings revealed that tablets containing drug to wax ratio of 1:1, hydrophilic swellable polymer concentration of 200 mg, and prepared using compression pressure of 6.5 kg/cm2 exhibited the highest desirability indices in terms of controlling the release rate of drug substance. Optimized formulation was also evaluated for swelling rate, erosion rate, and other post-compression parameters, including release kinetics. Fickian diffusion-based zero-order controlled release of BCS class I drug substance was achieved through the developed dosage form.

Anti-oxidant Containing Nanostructured Lipid Carriers of Ritonavir: Development, Optimization, and In Vitro and In Vivo Evaluations

Acquired immunodeficiency syndrome (AIDS) is a condition caused by the infection of a retrovirus namely, human immunodeficiency virus (HIV). Currently, highly active anti-retroviral therapy (HAART), a combination of anti-viral drugs belonging to different classes is considered to be effective in the management of HIV. Ritonavir, a protease inhibitor (PI), is one of the most important components of the HAART regimen. Because of its lower bioavailability and severe side effects, presently, ritonavir is not being used as a PI. However, this drug is being used as a pharmacokinetic boosting agent for other PIs such as lopinavir and in lower doses. The current study aimed to develop nanostructured lipid carriers (NLCs) encapsulating ritonavir to reduce its side effects and enhance oral bioavailability. Ritonavir-loaded NLCs were developed using a combination of two different solid lipids and liquid lipids. Alpha-tocopherol, a well-known anti-oxidant, was used as an excipient (liquid lipid) in the development of NLCs which were prepared using a simple hot-emulsion and ultrasonication method. Drug-excipient studies were performed using Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). QbD approach was followed for the screening and optimization of different variables. The developed NLCs were characterized for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE). Furthermore, NLCs were studied for their in vitro drug release profile, and finally, pharmacokinetic parameters were determined using in vivo pharmacokinetic studies. The optimized NLC size was in the range of 273.9 to 458.7 nm, PDI of 0.314 to 0.480, ZP of −52.2 to − 40.9 mV, and EE in the range of 47.37 to 74.51%. From in vitro drug release, it was found that the release of drug in acidic medium was higher than phosphate buffer pH 6.8. Finally, in vivo pharmacokinetic studies revealed a 7-fold enhancement in the area under the curve (AUC) and more than 10-fold higher Cmax with the optimized formulation in comparison to pure drug suspension.Graphical

The use of modern QbD approaches in the pharmaceutical development of technology of liposomal eye drops

The use of modern QbD approaches in the pharmaceutical development of technology of liposomal eye drops

QbD Approached in Method Development, Validation and Degradation Profiling of Aripiprazole a Antidepressent Agent

The aim of present research work was to develop simple, precise and rapid RP-HPLC method for analysis of Aripiprazole in tablet dosage form using QbD Method. RP-HPLC method was developed for the estimation of Aripiprazole in tablet dosage form with the help of QbD approaches. The proposed methods were applied for the determination of drug in tablet dosage form. In this method concentration of each drug was obtained by using the absorptivity values calculated for drug wavelength 254nm and solving the equation. A rapid and reliable RP-HPLC method was developed and validated estimation of Aripiprazole in tablet dosage form. The RP-HPLC method was performed C18 (100mm x 4.6 mm,)2.5 μm particle size in gradient mode, and the sample was analyzed using methanol 80 ml and 20 ml (pH 3.3 0.05% OPA with TEA) as a mobile phase at a flow rate of 0.7 ml/min and detection at nm. By the retention time for Aripiprazole found 3.29 min respectively. The method was applied to marketed tablet formulations. The tablet assay was performed for combination was validated for accuracy, precision, linearity, specificity, and sensitivity in accordance with ICH guidelines. Validation related the method is specific, rapid, accurate, precise, reliable, and reproducible. Calibration plots by both HPLC were linear over the 10-50μg/ml for Aripiprazole respectively, and recoveries from tablet dosage form were between 99.48 and 100.02 %. The method can be used for routine of the quality control in pharmaceuticals. The RP-HPLC method was found to be simple, economical and rapid as compared to MS method was found to be more accurate, precise and robust. Both these methods can be used for routine analysis of Aripiprazole in tablet dosage form.

Investigation of the effect of polymers on dermal foam properties using the QbD approach

Dermal foams are promising drug delivery systems due to their many advantages and ease of application. Foams are also considered a novelty in the field of dermatology. In particular, they are beneficial for the treatment of skin conditions where patients have highly inflamed, swollen, infected and sensitive skin, as the application of the foam to the skin surface to be treated minimizes the need for skin contact. In order to formulate foams, it is necessary to know which material and process parameters influence the quality characteristics of foams and which methods can be used to study foams; this part of the research is assisted by the QbD approach. By using the QbD concept, it contributed during the development process to ensure quality-based development. With initial risk assessment, the critical material attributes (CMAs) and the critical process parameters (CPPs) were identified to ensure the required critical quality attributes (CQAs). During the initial risk assessment, five high-risk CQAs, namely foam volume stability, foam expansion, cross point, the initial values of the number and size of bubbles, and three medium-risk CQAs, namely spreadability, relative foam density and viscosity of the liquid system were identified and investigated. In this research, different types of polymers (xanthan gum, hydroxyethylcellulose, different types of hyaluronic acids) were used to improve the properties of foam formulations. The formulations containing xanthan gum and high molecular weight hyaluronic acid had good foam properties and will be appropriate delivery systems for an active pharmaceutical ingredient. Overall, the polymer content had a great effect on the properties of the foams. Different polymers affect the properties of foams in different ways. When used in combination, the methods reinforce each other and help to select a formula for dermal application.

QbD Approach For Anti-Cancer Drugs - A Review

Background: Several analytical approaches for assessing anti-cancer drugs in pharmaceutical formulations have been developed over the last few years. QbD plays an important role in establishing accurate analytical methods to analyze anti-cancer compounds. Quality by Design has become a risk analysis and a science-based strategy, implemented by experimental methods to optimize system output with known variables for data. The influence of highly complex and correlations of input variables on the output reactions of pharmaceutical drugs and empirical approaches have been widely used to explain the design of experiments. Objective: The efficiency of the anti-cancer drugs and their formulation in the various dosage forms has been made convenient with the help of QbD designs such as Plackett Burman, full factorial design, etc. QbD contains various steps, which help enhance and sustain the quality of the drug in its dosage form. Conclusion: This review covers a basic, efficient, and accurate analytical approach technique using Quality by Design for anti-cancer drugs. Thus, an outline of the experimental methods used in anti-cancer drugs was identified and discussed.

Development of a retention prediction model in ion-pair reversed-phase HPLC for nucleoside triphosphates used as mRNA vaccine raw materials

The International Conference on Harmonization guidelines for quality on pharmaceutical development recommends a systematic development approach including robustness studies which assure performance of manufacturing and analytical method development of drug product. It was demonstrated that the retention prediction model for nucleoside triphosphates (NTPs) on ion-pair reversed-phase HPLC was developed by a highly accurate Kawabe’s model which supports the development of robust HPLC methods. As NTPs and its derivatives are typically used for Messenger ribonucleic acid (mRNA) vaccine production, adenosine-5′-triphosphate (ATP), guanosine-5′-triphosphate (GTP), cytidine-5′-triphosphate (CTP), 5-methylcytidine-5′-triphosphate (m5-CTP), uridine-5′-triphosphate (UTP), 5-methyluridine-5′-triphosphate (m5-UTP), pseudouridine-5′-triphosphate (Ψ-UTP) and N1-methylpseudouridine-5′-triphosphate (m1Ψ-UTP) were applied for prediction model development. By a comparison of the predicted retention factor in eight studied samples with the retention factor measured under six isocratic conditions, the absolute prediction error was 0.075 and also the prediction error (%) was 2.70%. In practical examples, analytical method for residual ATP, GTP, CTP, and m1Ψ-UTP in the commercial mRNA-based drugs and purity method for UTP derivatives were optimized by QbD approach. The design space for the minimum resolution between adjacent peaks was simulated with the models developed to evaluate the robustness of peak separation, and the optimal mobile phase condition was also simulated. As a conclusion, the desired peak was successfully separated under the optimized condition, and we thought that these retention models could optimize the mobile phase condition of the NTP analysis method for applying to various quality tests, such as quantity, purity and identity test for NTPs and its derivates in the mRNA-based drugs.

The development of biodegradable hemostatic and absorbable sponges containing chlorhexidine digluconate and their in vitro characterization—A QbD approach

The development of biodegradable hemostatic and absorbable sponges containing chlorhexidine digluconate and their in vitro characterization—A QbD approach

Quality assessment and Analytical Quality by Design-based RP-HPLC method development for quantification of Piperine in Piper nigrum L.

BackgroundPiper nigrum L. is one of the widely used herbs in Ayurvedic medicine. Piperine is a major phytoconstituent that is responsible for most of the activity of the herb. Quality assessment and standardization of such phytoconstituents is the need of the hour. The present study aims at developing a Quality by design (QbD)-based RP-HPLC Method for marker-based standardization of Piper nigrum L. fruits along with its quality assessment.ResultsThe quality assessment of the crude sample was carried out by evaluating pharmacognostic parameters and analysis of toxic contaminants. The analytical target profile and critical quality attributes were determined and 22 factorial design was employed for optimization of the method. By performing the experiments as per the QbD concept the optimized mobile phase was identified as Acetonitrile and Water with 0.05% Acetic acid in the ratio of 70:30, with a flow rate of 1 mL/min and UV detection at 342 nm. The retention time of Piperine was found to be 5.5 min and the amount of Piperine in crude P. nigrum fruits and its extract was found to be 3.6% w/w 5.62% w/w, respectively. The Pharmacognostic parameters showed the results within specified limits and the crude drug sample showed the absence of toxic contaminants in it thus indicating the purity of the drug.ConclusionThe utilization of the QbD approach leads to the development of a more precise and reliable method for the quantification of phytocompounds.

Preparation and optimization of berberine phospholipid complexes using QbD approach and in vivo evaluation for anti-inflammatory, analgesic and antipyretic activity

Preparation and optimization of berberine phospholipid complexes using QbD approach and in vivo evaluation for anti-inflammatory, analgesic and antipyretic activity

A New HPLC Stability Indicating Method and Validation for Simultaneous Quantitation of Bilastine and Montelukast Sodium in API and Marketed Formulation by QbD Approach

A new HPLC stability indicating method was developed and optimized by using a statistical tool, design expert 13.0.1.0 (Stat-Ease) for simultaneous quantitation of bilastine and montelucast sodium in marketed tablet dosage form. Randomized response surface methodology with two factor central composite design was utilized for mobile phase optimization and the effect of the independent variables, flow rate and volume of organic phase on critical quality attributes, resolution and retention time was studied. The analytes were resolved on a inertsil C18 (150 × 4.6 mm) column with 5 μm particle size. Within the design space the optimum chromatographic condition chosen was 0.1% orthophosphoric acid with acetonitrile at 60:40 (%v/v) having a flow rate of 1 min/mL for 10 min. The retention time (Rt) for bilastine and montelucast sodium was 2.445 and 3.787 min, respectively. The method was completely validated as per the current ICH guidelines. Forced degradation was carried out in acidic, basic, photolytic, neutral, oxidation, thermal conditions to prove the stability indicating property of HPLC method. The method’s applicability was studied by determining bilastine and montelucast sodium in the marketed tablet dosage form. This validated RP-HPLC stability indicating method can be suggested for routine quality control analysis in industries and research laboratories for the fixed dose marketed tablet formulation.

Improvement of solubility and dissolution rate of Repaglinide by Liquisolid Compact technique: QbD approach

Improvement of solubility and dissolution rate of Repaglinide by Liquisolid Compact technique: QbD approach