Establishment of an LC-MS/MS method for quantification of lifitegrast in rabbit plasma and ocular tissues and its application to pharmacokinetic study.

Lifitegrast, a lymphocyte function-associated antigen 1 antagonist, was approved by the FDA for the treatment of dry eye disease. Cornea and conjunctiva have been reported to be the sites of action of lifitegrast. To investigate the pharmacokinetics of lifitegrast, a sensitive analytical method for the determination of lifitegrast in various biological matrices such as plasma and ocular tissues is required. However, only limited information about the analytical method for lifitegrast in biological samples is available. In the present study, we aimed to develop a new liquid chromatography-tandem mass spectrometry method for the determination of lifitegrast in rabbit plasma, cornea, conjunctiva, and sclera. Lifitegrast-d6 was used as an internal standard (IS). To prepare the biological samples, protein precipitation using acetonitrile was utilized. Analytes were separated from endogenous interferences on an Atlantis dC18 (5 µm, 2.1 × 150 mm), and a mixture of 0.1 % formic acid and acetonitrile was used as the mobile phase. The mass transition of precursor to product ion was monitored at 615.2 â†’ 145.0 for lifitegrast and 621.2 â†’ 145.1 for IS. The calibration curves were linear over the concentration range from 2 to 500 ng/mL for plasma and 5 to 500 ng/mL in ocular tissue homogenates. Intra- and inter-day accuracy ranged from 95.76 to 106.80 % in the plasma and 94.42 to 112.80 % in the ocular tissues. Precision was within 8.56 % in the plasma and 9.72 % in the ocular tissues. The short-term, long-term, auto-sampler, and freeze-thaw stabilities of lifitegrast were validated. The developed method was applied to a pharmacokinetic study of lifitegrast in rabbits. Following ophthalmic administration, only 3.26 % of administered lifitegrast was absorbed into the systemic circulation. Peak tissue concentrations were observed at 0.5 h after dosing, and topically administered lifitegrast was mainly distributed in the cornea and conjunctiva. The finding of this study is expected to be used in further pharmacokinetic studies and formulation development.

Evaluation of subvisible particles in human immunoglobulin and lipid nanoparticles repackaged from a multi-dose vial using plastic syringes.

The multi-dose vial (MDV) is widely used for most biopharmaceuticals that are repackaged in plastic syringes before use. However, subvisible particle formation with the use of plastic syringes containing silicone oil (SO syringes) for handling therapeutic proteins can be problematic. This study aimed to evaluate the extent of and trends in microparticle (>1 µm) formation and accumulation in repackaged syringes from MDVs containing human immunoglobulin (IgG) and lipid nanoparticles (LNPs). Light obscuration (LO) and flow imaging (FI) were used to analyze the microparticles. The number of microparticles observed with the use SO syringes was greater than that with SO-free syringes, and the number of microparticles continuously increased as did the number of times of repackaging in syringes for both drugs. However, a large variation was observed across different brands of SO syringes. In contrast, using a different technique of drug withdrawal from the vial significantly reduced the number of microparticles. Furthermore, the use of filter-integrated needles or the inclusion of stabilizers such as acetyl-arginine and Tween 20 into the formulation also helped reduce particle formation.

Control Strategy for Excipient Variability in the Quality by Design Approach Using Statistical Analysis and Predictive Model: Effect of Microcrystalline Cellulose Variability on Design Space.

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.

A formulation development strategy for dual-release bilayer tablets: An integrated approach of quality by design and a placebo layer.

Although dual-release mechanism bilayer tablets containing one drug in both immediate- and sustained-release layers are widely used to improve therapeutic efficiency, studies quantitatively analyzing the drug amount released from each layer and the mutual effect of each layer's mechanical properties on drug product quality are limited. Here, the formulation of a dual-release bilayer tablet containing sarpogrelate HCl was optimized with a placebo layer and quality by design (QbD) approach. The placebo layer was developed to replace the active pharmaceutical ingredient and its mechanical properties were evaluated. The formulation was developed using the placebo layer to quantitatively analyze the drug released from each layer. The mixture design and Monte Carlo simulation enabled robust design space identification. The mutual effect of each layer's mechanical properties on drug product quality was confirmed by multivariate analysis using the optimal settings in the design space. The optimized formulation was characterized by comparison with a reference drug for various quality attributes and in vivo pharmacokinetic parameters, which ensured the bioequivalence of the optimized bilayer tablet with the reference drug. This study shows that the integration of QbD and a placebo layer is an effective optimization strategy for dual-release bilayer tablets containing one drug in different layers.

Development of a Robust Control Strategy for Fixed-Dose Combination Bilayer Tablets with Integrated Quality by Design, Statistical, and Process Analytical Technology Approach.

Control strategy and quality by design (QbD) are widely used to develop pharmaceutical products and improve drug quality; however, studies on fixed-dose combination (FDC) bilayer tablets are limited. In this study, the bilayer tablet consisted of high-dose metformin HCl in a sustained-release layer and low-dose dapagliflozin l-proline in an immediate-release layer. The formulation and process of each layer were optimized using the QbD approach. A d-optimal mixture design and response surface design were applied to optimize critical material attributes and critical process parameters, respectively. The robust design space was developed using Monte Carlo simulations by evaluating the risk of uncertainty in the model predictions. Multivariate analysis showed that there were significant correlations among impeller speed, massing time, granule bulk density, and dissolution in the metformin HCl layer, and among roller pressure, ribbon density, and dissolution in the dapagliflozin l-proline layer. Process analytical technology (PAT) was used with in-line transmittance near-infrared spectroscopy to confirm the bulk and ribbon densities of the optimized bilayer tablet. Moreover, the in vitro drug release and in vivo pharmacokinetic studies showed that the optimized test drug was bioequivalent to the reference drug. This study suggested that integrated QbD, statistical, and PAT approaches can develop a robust control strategy for FDC bilayer tablets by implementing real-time release testing based on the relationships among various variables.

Off-label use of plastic syringes with silicone oil for intravenous infusion bags of antibodies.

The formation of particulates in post-manufacture biopharmaceuticals continues to be a major concern in medical treatment. This study was designed to evaluate the content of micro-sized particles using flow imaging of antibodies in intravenous infusion bags. Intravenous immunoglobulin (IVIG) and Avastin® were selected as model drugs and plastic syringes with and without silicone oil (SO) were used to transfer the drugs into the bags (0.9% saline or 5% dextrose). Antibodies exposed to SO had significantly increased levels of microparticles in both diluents, suggesting SO accelerates particle formation, especially at a higher antibody concentration. Even before the drop stress, their count exceeded the USP guideline. Dropping the bags in the presence of SO produced larger microparticles. Meanwhile, air bubbles were retained longer in saline suggesting more protein film formation on its air-water interface. Overall, both drugs were conformationally stable and produced less particles in dextrose than in saline.

Process Analytical Technology Tools for Monitoring Pharmaceutical Unit Operations: A Control Strategy for Continuous Process Verification.

Various frameworks and methods, such as quality by design (QbD), real time release test (RTRT), and continuous process verification (CPV), have been introduced to improve drug product quality in the pharmaceutical industry. The methods recognize that an appropriate combination of process controls and predefined material attributes and intermediate quality attributes (IQAs) during processing may provide greater assurance of product quality than end-product testing. The efficient analysis method to monitor the relationship between process and quality should be used. Process analytical technology (PAT) was introduced to analyze IQAs during the process of establishing regulatory specifications and facilitating continuous manufacturing improvement. Although PAT was introduced in the pharmaceutical industry in the early 21st century, new PAT tools have been introduced during the last 20 years. In this review, we present the recent pharmaceutical PAT tools and their application in pharmaceutical unit operations. Based on unit operations, the significant IQAs monitored by PAT are presented to establish a control strategy for CPV and real time release testing (RTRT). In addition, the equipment type used in unit operation, PAT tools, multivariate statistical tools, and mathematical preprocessing are introduced, along with relevant literature. This review suggests that various PAT tools are rapidly advancing, and various IQAs are efficiently and precisely monitored in the pharmaceutical industry. Therefore, PAT could be a fundamental tool for the present QbD and CPV to improve drug product quality.

Pharmacokinetics of eperisone following oral administration in healthy Korean volunteers.

Eperisone is an oral muscle relaxant used to treat musculoskeletal diseases, which exhibits high pharmacokinetic (PK) variability in bioequivalence studies. The aim of this study was to characterize the PKs of eperisone following its oral administration to Korean volunteers through the conduct of a noncompartmental and population analysis. A total of 360 concentration-time measurements collected on two separate occasions from 15 healthy volunteers during a bioequivalent study of eperisone 50 mg (Murex® ) were used in the PK analysis. Noncompartmental analysis was performed using WinNonLinTM and population analysis was performed using NONMEM® . The possible influence of thirty demographic and pathophysiological characteristics on the PKs of eperisone were explored. Based on noncompartmental analysis mean eperisone elimination half-life, apparent clearance (CL/F), and apparent volume of distribution were estimated to be 3.81 h, 39.24 × 103  l/h × 103  L, respectively. During population PK modeling a two-compartment model with first-order absorption rate constant (typical population K a  = 1.5 h-1 ) and first-order elimination (typical population CL/F and apparent volume of distribution in the central compartment [V c /F] = 30.8 × 103  l/h and 86.2 × 103  l, respectively) best described the PKs of eperisone. Interindividual variability in CL/F and V c /F were estimated to be 87.9% and 130.3%, respectively and interoccasion variability in CL/F and V c /F were estimated to be 23.8% and 30.8%, respectively. Aspartate aminotransferase level and smoking status were identified as potential covariates that may influence the CL/F of eperisone. This is the first study to develop a disposition model for eperisone and investigate the potential influence of covariate factors on it PK variability.

Enhanced Oral Bioavailability of Resveratrol by Using Neutralized Eudragit E Solid Dispersion Prepared via Spray Drying.

In this study, we designed amorphous solid dispersions based on Eudragit E/HCl (neutralized Eudragit E using hydrochloric acid) to maximize the dissolution of trans-resveratrol. Solid-state characterization of amorphous solid dispersions of trans-resveratrol was performed using powder X-ray diffraction, scanning electron microscopy, and particle size measurements. In addition, an in vitro dissolution study and an in vivo pharmacokinetic study in rats were carried out. Among the tested polymers, Eudragit E/HCl was the most effective solid dispersion for the solubilization of trans-resveratrol. Eudragit E/HCl significantly inhibited the precipitation of trans-resveratrol in a pH 1.2 dissolution medium in a dose-dependent manner. The amorphous Eudragit E/HCl solid dispersion at a trans-resveratrol/polymer ratio of 10/90 exhibited a high degree of supersaturation without trans-resveratrol precipitation for at least 48 h by the formation of Eudragit E/HCl micelles. In rats, the absolute oral bioavailability (F%) of trans-resveratrol from Eudragit E/HCl solid dispersion (10/90) was estimated to be 40%. Therefore, trans-resveratrol-loaded Eudragit E/HCl solid dispersions prepared by spray drying offer a promising formulation strategy with high oral bioavailability for developing high-quality health supplements, nutraceutical, and pharmaceutical products.

Control Strategy for Process Development of High-Shear Wet Granulation and Roller Compaction to Prepare a Combination Drug Using Integrated Quality by Design.

In this study, we developed a control strategy for a drug product prepared by high-shear wet granulation and roller compaction using integrated quality by design (QbD). During the first and second stages, we optimized the process parameters through the design of experiments and identified the intermediate quality attributes (IQAs) and critical quality attributes (CQAs) relationship, respectively. In the first stage, we conducted an initial risk assessment by selecting critical process parameters with high impact on IQAs and CQAs and confirmed the correlation between control and response factors. Additionally, we performed Monte Carlo simulations by optimizing the process parameters to deriving and building a robust design space. In the second stage, we identified the IQAs and CQAs relationship for the control strategy, using multivariate analysis (MVA). Based on MVA, in the metformin layer, dissolution at 1 h was significantly correlated with intrinsic dissolution rate and granule size, and dissolution at 3 h was significantly correlated with bulk density and granule size. In dapagliflozin layer, dissolution at 10 min and 15 min was significantly correlated with granule size. Our results suggest that the desired drug quality may result through IQAs monitoring during the process and that the integrated QbD approach utilizing MVA can be used to develop a control strategy for producing high-quality drug products.

Model-Based Scale-Up Methodologies for Pharmaceutical Granulation.

In the pharmaceutical industry, it is a major challenge to maintain consistent quality of drug products when the batch scale of a process is changed from a laboratory scale to a pilot or commercial scale. Generally, a pharmaceutical manufacturing process involves various unit operations, such as blending, granulation, milling, tableting and coating and the process parameters of a unit operation have significant effects on the quality of the drug product. Depending on the change in batch scale, various process parameters should be strategically controlled to ensure consistent quality attributes of a drug product. In particular, the granulation may be significantly influenced by scale variation as a result of changes in various process parameters and equipment geometry. In this study, model-based scale-up methodologies for pharmaceutical granulation are presented, along with data from various related reports. The first is an engineering-based modeling method that uses dimensionless numbers based on process similarity. The second is a process analytical technology-based modeling method that maintains the desired quality attributes through flexible adjustment of process parameters by monitoring the quality attributes of process products in real time. The third is a physics-based modeling method that involves a process simulation that understands and predicts drug quality through calculation of the behavior of the process using physics related to the process. The applications of these three scale-up methods are summarized according to granulation mechanisms, such as wet granulation and dry granulation. This review shows that these model-based scale-up methodologies provide a systematic process strategy that can ensure the quality of drug products in the pharmaceutical industry.

New Preclinical Development of a c-Met Inhibitor and Its Combined Anti-Tumor Effect in c-Met-Amplified NSCLC.

c-Met is a receptor tyrosine kinase with no commercially available product despite being a pivotal target in cancer progression. Unlike other c-Met inhibitors that fail clinically, ABN401 is a newly synthesized c-Met inhibitor that is not potentially degraded by aldehyde oxidase (AO) in human liver cytosol. This study aimed to determine the physicochemical stability, pharmacokinetics in beagle dogs, and therapeutic effect of ABN401 in a c-Met-amplified non-small-cell lung cancer (NSCLC) patient-derived xenograft (PDX) model. ABN401 was found to be a weak basic compound, with pKa and log P values of 7.49 and 2.46, respectively. It is poorly water-soluble but soluble at acidic pH. The accelerated storage stability is dependent on temperature, but the purity remains at over 97% after 6 months. The bioavailability is approximately 30% in dogs and it is highly efficient in the PDX model, achieving around 90% tumor growth inhibition in combination with erlotinib. These observations indicate that the compound is acceptable for the next phase of trials.

Pharmacokinetic Study of a Soft Gelatin Capsule and a Solid-Supersaturatable SMEDDS Tablet of Dutasteride in Beagle Dogs.

BACKGROUND AND OBJECTIVE: Dutasteride, an analog of testosterone, a 5α-reductase inhibitor is widely used in the treatment of moderate to severe symptomatic benign prostatic hyperplasia. The aim of this study was to compare the pharmacokinetic characteristics of dutasteride in beagle dogs after oral administration of a conventional soft gelatin capsule (Avodart®) and a novel solid-supersaturatable soft-microemulsifying drug delivery system (SMEDDS) tablet. METHODS: In this comparative dissolution study, the dissolution of dutasteride was pH-independent for both formulations. Noncompartmental analysis and modeling approaches were carried out to determine the pharmacokinetic parameters of dutasteride. RESULTS: Approximately 90% of the drug dissolved in all media within 15 min, indicating that there was little difference in the dissolution rate of the solid-supersaturatable SMEDDS tablets and that of the commercial soft gelatin capsules. Using t test analysis, no statistically significant difference was detected in the pharmacokinetic parameters of the two formulations. The test/reference geometric mean ratios were 1.087 (90% confidence intervals 0.8529-1.3854) for the area under the plasma concentration versus time curve from 0 to the last time point (48 h) with a measurable concentration and 1.094 (90% confidence intervals 0.8909-1.3454) for maximum plasma concentration. Unfortunately, the bioequivalent criterium (0.8-1.25) was not met due to the small sample size, but the results of this study suggest a possible bioequivalence of dutasteride in the two formulations. CONCLUSION: Based on the results of this study, the development of a tablet dosage form of dutasteride using a solid-supersaturatable SMEDDS should be considered for humans.

Development of a Resveratrol Nanosuspension Using the Antisolvent Precipitation Method without Solvent Removal, Based on a Quality by Design (QbD) Approach.

The purpose of this study was to develop a resveratrol nanosuspension with enhanced oral bioavailability, based on an understanding of the formulation and process parameters of nanosuspensions and using a quality by design (QbD) approach. Particularly, the antisolvent method, which requires no solvent removal and no heating, is newly applied to prepare resveratrol nanosuspension. To ensure the quality of the resveratrol nanosuspensions, a quality target product profile (QTPP) was defined. The particle size (z-average, d90), zeta potential, and drug content parameters affecting the QTPP were selected as critical quality attributes (CQAs). The optimum composition obtained using a 3-factor, 3-level Box-Behnken design was as follows: polyvinylpyrrolidone vinyl acetate (10 mg/mL), polyvinylpyrrolidone K12 (5 mg/mL), sodium lauryl sulfate (1 mg/mL), and diethylene glycol monoethyl ether (DEGEE, 5% v/v) at a resveratrol concentration of 5 mg/mL. The initial particle size (z-average) was 46.3 nm and the zeta potential was -38.02 mV. The robustness of the antisolvent process using the optimized composition conditions was ensured by a full factorial design. The dissolution rate of the optimized resveratrol nanosuspension was significantly greater than that of the resveratrol raw material. An in vivo pharmacokinetic study in rats showed that the area under the plasma concentration versus time curve (AUC0-12h) and the maximum plasma concentration (Cmax) respectively, than those of the resveratrol raw material. Therefore, the prepara values of the resveratrol nanosuspension were approximately 1.6- and 5.7-fold higher,tion of a resveratrol nanosuspension using the QbD approach may be an effective strategy for the development of a new dosage form of resveratrol, with enhanced oral bioavailability.

Preparation and Evaluation of Resveratrol-Loaded Composite Nanoparticles Using a Supercritical Fluid Technology for Enhanced Oral and Skin Delivery.

We created composite nanoparticles containing hydrophilic additives using a supercritical antisolvent (SAS) process to increase the solubility and dissolution properties of trans-resveratrol for application in oral and skin delivery. Physicochemical properties of trans-resveratrol-loaded composite nanoparticles were characterized. In addition, an in vitro dissolution-permeation study, an in vivo pharmacokinetic study in rats, and an ex vivo skin permeation study in rats were performed. The mean particle size of all the composite nanoparticles produced was less than 300 nm. Compared to micronized trans-resveratrol, the trans-resveratrol/hydroxylpropylmethyl cellulose (HPMC)/poloxamer 407 (1:4:1) nanoparticles with the highest flux (0.792 µg/min/cm2) exhibited rapid absorption and showed significantly higher exposure 4 h after oral administration. Good correlations were observed between in vitro flux and in vivo pharmacokinetic data. The increased solubility and flux of trans-resveratrol generated by the HPMC/surfactant nanoparticles increased the driving force on the gastrointestinal epithelial membrane and rat skin, resulting in enhanced oral and skin delivery of trans-resveratrol. HPMC/surfactant nanoparticles produced by an SAS process are, thus, a promising formulation method for trans-resveratrol for healthcare products (owing to their enhanced absorption via oral administration) and for skin application with cosmetic products.

Application of the Discrete Element Method for Manufacturing Process Simulation in the Pharmaceutical Industry.

Process simulation using mathematical modeling tools is becoming more common in the pharmaceutical industry. A mechanistic model is a mathematical modeling tool that can enhance process understanding, reduce experimentation cost and improve product quality. A commonly used mechanistic modeling approach for powder is the discrete element method (DEM). Most pharmaceutical materials have powder or granular material. Therefore, DEM might be widely applied in the pharmaceutical industry. This review focused on the basic elements of DEM and its implementations in pharmaceutical manufacturing simulation. Contact models and input parameters are essential elements in DEM simulation. Contact models computed contact forces acting on the particle-particle and particle-geometry interactions. Input parameters were divided into two types-material properties and interaction parameters. Various calibration methods were presented to define the interaction parameters of pharmaceutical materials. Several applications of DEM simulation in pharmaceutical manufacturing processes, such as milling, blending, granulation and coating, were categorized and summarized. Based on this review, DEM simulation might provide a systematic process understanding and process control to ensure the quality of a drug product.

Comprehensive Study of Intermediate and Critical Quality Attributes for Process Control of High-Shear Wet Granulation Using Multivariate Analysis and The Quality by Design Approach.

A robust manufacturing process and the relationship between intermediate quality attributes (IQAs), critical quality attributes (CQAs), and critical process parameters (CPPs) for high-shear wet granulation was determined in this study. Based on quality by the design (QbD) approach, IQAs, CQAs, and CPPs of a telmisartan tablet prepared by high-shear wet granulation were determined and then analyzed with multivariate analysis (MVA) to evaluate mutual interactions between IQAs, CQAs, and CPPs. The effects of the CPPs on the IQAs and CQAs were quantitatively predicted with empirical models of best fit. The models were used to define operating space, and an evaluation of the risk of uncertainty in model prediction was performed using Monte Carlo simulation. MVA showed that granule size and granule hardness were significantly related to % dissolution. In addition, granule FE (Flow Energy) and Carr's index had effects on tablet tensile strength. Using the manufacture of a clinical batch and robustness testing, a scale-up from lab to pilot scale was performed using geometric similarity, agitator torque profile, and agitator tip speed. The absolute biases and relative bias percentages of the IQAs and CQAs generated by the lab and pilot scale process exhibited small differences. Therefore, the results suggest that a risk reduction in the manufacturing process can be obtained with integrated process parameters as a result of the QbD approach, and the relationship between IQAs, CQAs, and CPPs can be used to predict CQAs for a control strategy and SUPAC (Scale-Up and Post-Approval Guidance).

Scale-Up Strategy in Quality by Design Approach for Pharmaceutical Blending Process with Discrete Element Method Simulation.

An approach combining quality by design (QbD) and the discrete element method (DEM) is proposed to establish an effective scale-up strategy for the blending process of an amlodipine formulation prepared by the direct compression method. Critical process parameters (CPPs) for intermediate critical quality attributes (IQAs) were identified using risk assessment (RA) in the QbD approach. A Box-Behnken design was applied to obtain the operating space for a laboratory-scale. A DEM model was developed by the input parameters for the amlodipine formulation; blending was simulated on a laboratory-scale V-blender (3 L) at optimal settings. The efficacy and reliability of the DEM model was validated through a comparison of simulation and experimental results. Change of operating space was evaluated using the validated DEM model when scaled-up to pilot-scale (10 L). Pilot-scale blending was simulated on a V-blender and double-cone blender at the optimal settings derived from the laboratory-scale operating space. Both pilot-scale simulation results suggest that blending time should be lower than the laboratory-scale optimized blending time to meet target values. These results confirm the change of operating space during the scale-up process. Therefore, this study suggests that a QbD-integrated DEM simulation can be a desirable approach for an effective scale-up strategy.

Effects of granulation process variables on the physical properties of dosage forms by combination of experimental design and principal component analysis.

The current study was to understand how process variables of high shear wet granulations affect physical properties of granules and tablets. The knowledge gained was intended to be used for Quality-by-Design based process design and optimization. The variables were selected based on the risk assessment as impeller speed, liquid addition rate, and wet massing time. Formulation compositions were kept constant to minimize their influence on granules properties. Multiple linear regression models were built providing understanding of the impact of each variable on granule hardness, Carr's index, tablet tensile strength, surface mean diameter of granules, and compression behavior. The experimental results showed that the impact of impeller speed was more dominant compared to wet massing time and water addition rate. The results also revealed that quality of granules and tablets could be optimized by adjusting specific process variables (impeller speed 1193 rpm, water spray rate 3.7 ml/min, and wet massing time 2.84 min). Overall desirability was 0.84 suggesting that the response values were closer to the target one. The SEM image of granules showed that spherical and smooth granules produced at higher impeller speed, whereas rough and irregular shape granules at lower speed. Moreover, multivariate data analysis demonstrated that impeller speed and massing time had strong correlation with the granule and tablet properties. In overall, the combined experimental design and principal component analysis approach allowed to better understand the correlation between process variables and granules and tablet attributes.

Quality by Design (QbD) approach to optimize the formulation of a bilayer combination tablet (Telmiduo®) manufactured via high shear wet granulation.

A bilayer tablet, which consisted of telmisartan and amlodipine besylate, was formulated based on a Quality by Design (QbD) approach. The control and response factors were determined based on primary knowledge and the target values of the control tablet (Twynsta®). A D-optimal mixture design was used to obtain the optimal formulations in terms of D-mannitol, crospovidone, and MCC for the telmisartan layer, and CCM-Na, PVP K25, and Prosolv for the amlodipine layer. The quantitative effects of the different formulation factors on the response factors were accurately predicted using the equations of best fit and a strong linearity was observed between the predicted and actual values of the response factors. The optimized bilayer tablet was obtained using a numeric optimization technique and was characterized compared with a control (Twynsta®) by using various physical evaluations and in vivo pharmacokinetic parameters. The physical stability of Telmiduo® was greater than that of Twynsta® owing to the improvement of formulation factors. The in vivo pharmacokinetic parameters suggested that Telmiduo® might have pharmaceutical equivalence and bioequivalence with Twynsta®. Therefore, the bilayer tablet that consisted of telmisartan and amlodipine besylate could be produced using a more economical and simpler method than that used to produce Twynsta®. Moreover, the suitability of QbD for effective product development in the pharmaceutical industry was shown.