Development of the Composition and Technology for Obtaining Mini-Tablets of Propranolol Hydrochloride Using the Quality by Design Approach

Objective: The main objective of this research is to develop an immediate release Rupatadine fumarate 10 mg tablets formulation by direct compression, through a Quality by Design approach in Costa Rica.Methods: According to a Quality by Design approach; Target Product Profile, Quality Target Product Profile, and the Critical Quality Attributes were defined. In the preformulation study, compatibility tests were carried out between the raw materials. The Critical Material Attributes were established using Quality Risk Management. Three formulation prototypes were prepared by direct compression and its Critical Process Parameters were defined. The analysis of the prototypes was realized in terms of organoleptic properties, identification, potency, content uniformity, dissolution, disintegration, friability and loss by drying.Results: All the prototypes showed a white or slightly pink surface, potency between 90.0 –110.0 % of the labeling, an acceptance value for the content uniformity lower than the specification (AV < 15), the dissolved amount of active pharmaceutical ingredient was greater than 85.0 % at 30 minutes, friability less than 1.0 %, a disintegration time less than 15 minutes and moisture content less than 2.0 %.Conclusions: The approaching of a Quality by Design model to the current development allowed to obtain satisfactory results in the three formulation prototypes. The excipients to be used can be lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, pregelatinized starch, magnesium stearate, stearic acid, and PVP K-30.

Objectives: The aim of this study was to formulate a novel BCS class II antifungal formulation of itraconazole and optimise its critical quality attributes (CQAs) using a Quality by Design (QbD) approach. Methods: Material attributes and CQAs were identified using risk assessment according to the International Conference of Harmonization (ICHQ9) quality guidelines. The material attributes were found to be the ratios of surfactant (Tween 80) and co-surfactant (Transcutol). The CQA selected for optimization was dissolution. A screening design was performed on the surfactant and co-surfactant to fix the ratio of Smix, resulting in four optimized ratios: 1:1, 1:3, 5:3, and 5:1. Pseudo ternary phase diagrams were constructed, and ranges for excipients were fixed. Based on the results of the screened ratios, a Mixture Design – Design of Experiment (DoE) was used for optimization. Findings: Optimized runs of ten runs for dissolution were achieved by the application of the mixture design, with formulation F2 showing a maximum release of 93.35%. Novelty: Quality by Design (QbD) can be utilized to optimize the CQAs of a novel BCS class II antifungal formulation, itraconazole. Keywords: QbD, Screening design, Mixture design, Extreme vertices, SEDDS, Itraconazole

In the current investigations, mouth dissolving tablets (MDT) were developed by applying quality by design (QbD) approach. Direct compression method was applied for the preparation of MDT containing aspirin using 32 factorial design with quantity of drug, microcrystalline cellulose (MCC) and crosscarmellose sodium (CCS) as dependant variables. MCC and CCS were used as superdisintegrants. Sodium stearyl fumarate was used as lubricant. Developed MDT were evaluated for characteristics like hardness, friability, disintegration time (DT) and in vitro drug release . Design Expert 11.0 described adequately impact of selected variables (MCC and CCS) at various levels for response under study (DT and friability). The optimized batch showed disintegration time of 15-28 secs, friability within 1% and in vitro drug release of 75-98% after 30 mins, respectively. The present study of experimental design revealed that MCC and CCS are fruitful at low concentration to develop the optimized formulation. As per the results obtained from the experiments, it can be concluded that QbD is an effective and efficient approach for the development of quality into MDT with the application of QTPP, risk assessment and critical quality attributes (CQA).&#x0D; Dhaka Univ. J. Pharm. Sci. 20(1): 19-29, 2021 (June)

Background: Despite being in use for over 50 years, the physicochemical challenges posed by methyldopa remain ever present. Methyldopa is not only significantly hygroscopic, but also prone to oxidative and hydrolytic degradation that can be accelerated by moisture. Poor compression behaviour, another limitation of methyldopa, leaves the formulation scientist with a constellation of formulation hurdles that must be faced, understood, and overcome. This is a task that can be tackled using elements of the Quality by Design (QbD) approach. Objective: The study aimed at developing an optimal formulation of methyldopa into 250 mg immediate release tablets by direct compression using elements of QbD. Method: Excipients of pharmaceutical grade were selected for the candidate formulation, preliminary concentrations set for each and settings for mixing and compression variables established. The risk posed by all these factors was evaluated using Failure Modes and Effects Analysis (FMEA). The preliminary experiment was executed using a 12 run Plackett Burman design. A 16 run Box-Behnken experimental design successfully aided in the identification of excipient concentrations and manufacturing conditions that yield tablets of optimal quality. Results: FMEA revealed that magnesium stearate, colloidal silica, sodium starch glycolate (SSG), citric acid monohydrate, mixing speed, duration of pre-lubrication mixing, duration of lubrication and compression speed were critical risk factors. The optimal formulation was achieved at the following settings: 1 % m/m magnesium stearate, 1 % m/m colloidal silica, 3.9 % m/m sodium starch glycolate, 1.7 % m/m citric acid monohydrate, mixing speed of 101 rpm, 6 minutes of pre-lubrication mixing, 2 minutes of lubrication and compression speed of 20 rpm. Conclusion: The QbD tools used in this study enabled, not only achievement of optimal quality, but also a better understanding of the impact of critical formulation variables on tablet quality. Challenges to pharmaceutical development can be effectively overcome using the QbD approach.

The quality by design (QbD) approach was applied for optimizing the formulation of model antidiabetic drug Linagliptin (LIN) mucoadhesive microspheres (MS) through design of experiment (DoE). To Optimize LIN-MS a quality target product profile (QTPP) was established in which critical quality attributes (CQAs) such as MVD, % encapsulation efficiency (% EE) and t50 drug release were quantified. As critical material attributes (CMA) viz., Keltone (KE), Carbopol (CA) and Pectin (PC) were chosen and evaluated their effect on CQAs. Response surface design (RSM) viz., Central Composite Design (CCD) was studied to evaluate effects of CMA on stated CQAs within the design space. The main effect was observed with varied levels of KE, CA and PC on CQAs. Numerical optimization by point prediction method was applied to generate optimized formula with predicted response, later the experimental responses were validated and ratified within the design space. The results suggest QbD through DoE appears to be a useful approach for the rational design, optimization and characterization of LIN-MS.

Objective Over the last few decades, there have been advancements in our comprehension of the design and development of topical semisolid formulations; however, they still follow an empirical development. Our study focuses on building a framework for designing and developing topical semisolid products using ‘Quality by Design’ (QbD) approach. Methods A literature review was conducted to identify and list the factors related to the design and development of topical semi-solid dosage forms using Quality by Design approach. The information extracted from the relevant articles was used to build a QbD framework based on four main pillars: Define the Quality Target Product Profile (QTPP); identify Critical Quality Attributes (CQAs); identify Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs); understand how CMAs and CPPs affect CQAs and establish a control strategy. Results Some typical elements of the QTPP for topical products include dosage form, route of administration, shelf life, critical quality attributes of the final formulation. Critical material attributes such as characteristics of API (molecular weight, lipophilicity, solubility, metamorphosis events, and polymorphism), characteristics of excipients, and critical process parameters (temperature, heating and cooling rates, mixing speed, pumping speed, order of addition) are identified and explained for their impact on CQAs. Conclusions Proper characterization of the API and drug delivery system will increase the likelihood of developing a stable, pleasing, and tolerable topical formulation and minimize the risk of failure.

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.

The quality by design (QbD) approach was applied for optimizing the formulation of Escitalopram oxalate (ES) orodispersible tablets (ODTs) using Design-Expert Software. To Optimize ES-ODTs a quality target product profile was established in which critical quality attributes (CQAs) such as wetting time, dispersion time, disintegration time and drug release rates were defined and quantified. As critical formulation parameters (CFP) that were evaluated for their effect on the CQA. Percentage of Crospovidone (CP) and Croscaramellose (CCS) were choosen. Response surface methodology (RSM) such as Central Composite Design (CCD) was used to evaluate the effects of the CFPs on the CQAs of the final product. The main factor affecting disintegration, wetting time, dispersion time and release rate was the combination of CP and CCS. Disintegration time, wetting time and dispersion time were found to be sensitive to the percentage of CP and CCS. From the results a design space could be created. The results suggest QbD appears to be a useful approach for the rational design of ES-ODTs. The chosen model helps to visualize the different effects of the CFPs on the CQAs.

Objective Metered-dose inhalers (MDIs) containing corticosteroids are widely prescribed for the treatment of asthma and chronic obstructive pulmonary disease, but the high cost of brand-name products limits access in developing countries. A quality by design (QbD) approach offers a systematic framework for developing cost-effective generic alternatives while ensuring consistent product quality. Significance Our findings demonstrate that a QbD framework can accelerate formulation optimization, enhance product reliability, and support patient access to affordable, high-quality corticosteroid inhalers. Methods Beclomethasone dipropionate (BDP) MDI formulation was developed and optimized using QbD principles, focusing on establishing critical quality attributes (CQAs) and defining the design space for key formulation parameters. CQAs were identified through risk assessment. Results A mixture/I-optimal design was employed to optimize ethanol (5–15%), oleic acid (0.05–2%), and HFA-134a propellant (82.8–94.75%). Statistical modeling in Design-Expert (Stat-Ease Inc., Minneapolis, MN) defined the control space and an optimized formulation region for these components. Formulations within this space consistently met target specifications, including a mass median aerodynamic diameter (MMAD) of 3.26 ± 0.17 μm (target < 5 μm), fine particle fraction (FPF) of 60.4 ± 2% (target ≥ 55%), and delivered dose uniformity (DDU) of 99.7 ± 1.5% (target: 75–125%). The model showed high predictability, with R 2 values of 0.98, 0.88, and 0.93 for MMAD, FPF, and DDU, respectively. Conclusion QbD approach enabled the development of a robust design space for a generic BDP MDI. The optimized formulation demonstrated comparable performance to the reference product, supporting the development of more affordable inhaled corticosteroid therapies.

Background/Objectives: Carbamazepine is widely used as a first-line treatment for pediatric patients with benign epilepsy. However, most commercial formulations have doses of 100 mg or higher, limiting their suitability for pediatric use. The aim of this study was to develop mini orally disintegrating tablets (ODTs) containing 50 mg of carbamazepine, utilizing direct compression technology, specifically tailored to meet the unique needs of pediatric patients. Methods: The development was carried out following a Quality by Design (QbD) approach, beginning with preformulation studies using the SeDeM expert system. Various co-processed excipients (PROSOLV® ODT and PARTECK® ODT) and non-co-processed excipients (L-HPC LH11 and L-HPC NBD-022) were evaluated. Additionally, modifications to the radius parameter of the SeDeM expert system were investigated to improve formulation design. Results: Optimized Formulations 13 and 14 achieved disintegration times below 1 min, hardness values between 25 and 60 N, and friability under 1%, fulfilling the predefined Critical Quality Attributes (CQAs). Tablets were successfully produced with a diameter of 5 mm and a weight below 100 mg. Moreover, reducing the SeDeM incidence radius from 5.0 to values between 4.0 and 3.5 proved viable, enabling the inclusion of excipients previously considered unsuitable and broadening formulation options without compromising quality. Conclusions: This study demonstrates the feasibility of producing small, fast-disintegrating, and mechanically robust 50 mg carbamazepine ODTs tailored for pediatric patients. It also validates the adjustment of SeDeM parameters as an effective strategy to expand excipient selection and enhance formulation flexibility in pediatric drug development.

Quality by Design for the Development of Additively Manufactured Patient-Specific Bone Implants and Scaffolds

Quality by design (QbD) is a systematic, scientific, risk-based approach to product development and manufacturing process to consistently deliver the quality product. In this chapter, application, benefits, opportunities, regulatory requirements involved in quality by design of pharmaceutical products are discussed. In quality by design approach, during development, the developer defines quality target product profile (QTPP) and identifies critical quality attributes (CQA). Critical process parameters (CPP) of unit operations which impacts critical quality attributes need to be identified to understand the impact of critical material attributes (CMA) on quality attributes of the drug product. Quality by design approach is defined in ICH guidelines Q8 – Pharmaceutical Development, Q9 – Quality Risk Management, Q10 – Pharmaceutical Quality System. This chapter describes the implementation of new concepts in quality by design like design of experiments to achieve design space, control strategy to consistently manufacture quality product throughout the product lifecycle.

Although various quality by design (QbD) approaches have been used to establish a design space to obtain robust drug formulation and process parameters, the effect of excipient variability on the design space and drug product quality is unclear. In this study, the effect of microcrystalline cellulose (MCC) variability on drug product quality was examined using a design space for immediate-release tablets of amlodipine besylate. MCC variability was assessed by altering the manufacturer and grade. The formulation was developed by employing the QbD approach, which was optimized using a D-optimal mixture design. Using 36 different MCCs, the effect of MCC variability on the design space was assessed. The design space was shifted by different manufacturers and grades of MCC, which resulted in associations between the physicochemical properties of MCC and critical quality attributes (CQAs). The correlation between the physicochemical properties of MCCs and CQAs was assessed through a statistical analysis. A predictive model correlating the physicochemical properties of MCCs with dissolution was established using an artificial neural network (ANN). The ANN model accurately predicted dissolution with low absolute and relative errors. The present study described a comprehensive QbD approach, statistical analysis, and ANN to comprehend and manage the effect of excipient variability on the design space.

Implementation of a quality by design approach in the potato chips frying process

This study highlights the advantages of using a Quality by Design (QbD) approach in order to gain a more comprehensive understanding of the freeze-drying process of pravastatin-loaded long-circulating liposomes (LCL-PRAV). Within the QbD paradigm, the present study aimed to establish the design space for the optimization of freeze-dried LCL-PRAV by means of Design of Experiment (DOE). The encapsulated solute retention (ESR), the average particle size, and zeta potential after freeze-drying, the residual moisture content, the macroscopic cake appearance, the glass transition temperature (Tg) of the freeze-dried cake, and the primary drying time were defined as critical quality attributes (CQAs) for the freeze-dried final product. Further on, the influence of lyoprotectant type, freezing rate, shelf temperature during primary drying, and the presence of an annealing step on the CQAs was investigated through a 21-run D-optimal experimental design. Three-dimensional response surfaces were generated to complete the statistical analysis and for a better understanding of the influence of variables and their interactions on the responses. The developed model was then used to build the design space for the freeze-dried liposomes, within which the product quality was assured and the process variability was minimized.