QbD enabled optimization study of the variable concentration of phospholipid and stabilizer in the development of liposomal pastilles of solid dispersion polymeric composite of antihypertensive drug

Background: Discontinuation and poor compliance with long-term oral medicine are major therapeutic issues in psychosis treatment. Poorer long-term outcomes may result from non-compliance as well as a higher chance of relapse. In order to sustain therapeutic drug plasma levels, co-administration of oral antipsychotics is necessary for commercially available longacting injections of second-generation antipsychotics, as they have a lag period of approximately three weeks during the drug release process. Methods: Poly(lactic-co-glycolic acid) (PLGA) encapsulated microspheres loaded with risperidone were fabricated in the current research for intramuscular administration. The single emulsion solvent evaporation technique was applied for the fabrication of microspheres. Risperidone microspheres were prepared using PLGA grade 75:25. Particle size, drug content and entrapment efficiency with a central composite design were the main optimization parameters for the formulation. The microspheres were characterized by different techniques, namely Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffractometry (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The drug content, entrapment efficiency, morphology, particle size, and in vitro release profiles, along with release kinetics of the risperidone microspheres, were studied. Results and Discussion: The microspheres produced by the single emulsion solvent evaporation approach show smooth and spherical morphology, with particle size ranging from 3 μm to 6 μm, drug content of 99.7%, and entrapment efficiency of 98.2% with little burst release of 3% to 10%, providing drug release for 45 days and exhibiting zero order release kinetics and Korsmeyer- Peppas model for non-fickian drug release from the polymeric matrix. By applying the Quality by Design (QbD) approach and formulation parameters, microspheres with appropriate particle size, morphology, enhanced drug content, entrapment efficiency and desirable drug release profile for depot formulation can be obtained successfully. Conclusion: The optimized microspheres, in comparison to the marketed Risperdal Consta™, show enhanced potential for a better depot formulation, which can further improve patient compliance.

The purpose of this study was to implement Quality by Design (QbD) concept to Solid Lipid Nanoparticles (SLN) containing Asenapine maleate (AM) in order to identify critical process and formulation variables which can affect product quality such as particle size (PS) and entrapment efficiency (EE). Initially, risk assessment using ishikawa diagram and preliminary investigation of critical variables was carried out. Two statistical designs were used to optimize critical variables which can affect product quality attributes i.e. PS and EE. Plackett Burman Design (PBD) was used to screen 8 variables and results showed that lipid concentration, surfactant concentration and sonication time had significant effect on PS and EE. These critical factors were further optimized using Central Composite Design (CCD), a type of response surface methodology, to assess its effect on PS and EE. Design space was identified and implementation of control strategy for responses generated quality of the desired product. Design space was generated for SLN for reducing intra-batch and inter-batch variability in formulation development process. Analysis of robustness of design space predicted that the formulation must be prepared in established design space to reduce batch variations. The results conclusively demonstrated the potential of QbD concept to build quality in SLN formulation.

Chemoprevention is a strategy which uses drugs which are traditionally not used as anti-cancer drugs; however, they prevent the carcinogenesis. Meloxicam (MLX) is traditionally used as a non-steroidal anti-inflammatory drug (NSAID), but it has been proven to have activity against colorectal cancer. Subsequently MLX seems to be a likely candidate to be utilized in the chemopreventive therapy of colorectal cancer. However, MLX poses shortcomings with respect to its dose required to elicit cytotoxicity. To improve the formulation, we used Quality by design (QbD) for optimization. QbD is a method that employs quality-improving scientific methods that build quality into the formulation by isolating the factors which affect the critical quality attributes of the formulation. The aim of the present study was to utilize the principles of QbD to formulate MLX into a formulation so as to exploit its potential to the fullest. Conventional (CLM) and PEGylated liposomes (MPL) of MLX was prepared using hydrogenated soya phosphatidylcholine (HSPC), distearyl phosphatidyl glycerol (DSPG), cholesterol and 1, 2-distearoyl- phosphatidylethanolamine-methyl-polyethyleneglycol conjugate-2000 sodium salt (MPEG 2000 DSPE). The liposomes were prepared using thin film hydration method. The optimization of the formulation was done by employing the QbD approach. The formulation was optimized on the basis of the factors which were affecting the critical quality attributes (CQAs) such as particle size and entrapment efficiency. The final optimized formulation was characterized by assessing the particle size, percent entrapment efficiency, zeta potential, long-term stability, morphology, in vitro release and in vitro cytotoxic activity. PEGylated liposomes having high percent entrapment efficiency (87.25 %±0.72%) could be obtained. The entrapment of drug in the liposomes was confirmed using Differential Scanning Calorimetry (DSC), Fourier Transform Infrared spectroscopy (FT-IR) and Powder X-Ray diffraction (PXRD) studies. The mean particle size of the liposomes was 113 nm±67nm and they were found to exhibit sustained release profile (56.59 %±0. 43% drug in 24h). The Small Angle Neutron Scattering (SANS) analysis revealed that the liposomes were uniform sized LUVs (nm) and were spherical in shape. The shape of the liposomes was further confirmed by transmission electron microscopy (TEM). Long term stability study indicated that the formulation was stable for three months. Sulphorhodamine B (SRB) cytotoxicity assay was carried out in HT-29 cell to prove that the PEGylated liposomal formulations had higher cytotoxicity than the conventional liposomes after 48 hours of incubation. The study affirmed that MLX loaded PEGylated liposomes had superior in vitro cytotoxicity as compared to the free drug as well as conventional liposomes. QbD resulted in the fabrication of a stable liposomal formulation with all the desirable characteristics. Hence, MLX loaded PEGylated liposomes can be considered to be a promising system for the delivery of MLX.

Objective: The objective of this study was to develop a polymeric composite of the poorly soluble antidepressant drug felodipine with help of PVP K-30 and PEG 6000, using a Quality by Design (QbD) approach to enhance its solubility and, consequently, its bioavailability. Methods: In this work, the quality target product profile (QTTP) was defined and Critical Quality Attributes (CQAs) were identified. Additionally, risk assessment analyses were carried out using the Ishikawa fishbone diagram to identify the Critical Material Attributes (CMAs) and/or Critical Process Parameters (CPPs) associated with the development of polymeric composite that could influence the Critical Quality Attributes (CQAs) of the drug product. The solubility of felodipine hydrochloride was improved by creating various polymeric composites with various concentrations of Poly Vinyl Pyrrolidone K30 (PVP-K 30) and Poly Ethylene Glycol 600 (PEG 600) by solvent evaporation method as Critical material attribute (CMA) as identified by risk assessment study and the and CQAs viz drug solubility, drug content and drug release. These composites were designed using a 32 Face Central composite Design (FCCD) with a face-centered approach implemented in Design Expert software. Results: After defining QTTP and CQA, risk assessment analysis was successfully used to identify CMA as well as CPPs. A total of thirteen PVP-PEG polymeric composites were developed and evaluated for FTIR spectra, Differential Scanning Colorimetry (DSC), X-Ray diffraction (XRD), and Scanning electron Microscopy (SEM). Data optimization was performed using response surface methodology, including contour and overlay plots. Solubility, drug content, and drug release of the optimized batch were found to be 21.55 mg/ml, 100%, and 78.314%, respectively. Three Validation Check batches (VC1-VC3) were developed and validated. Percent error for solubility ranges between-0.0019 to 0.0061, drug content ranges between 0.0005 to 0.0031 and solubility ranges between 0.0005 to 0.0011 that were very close to the predicted value, hence verifying the optimized data. Thus, by carefully using the QbD technique, the solubility of felodipine was enhanced by the effective development of a PVP-PEG polymeric composite. Conclusion: The QbD approach was to be an effective tool to develop an optimized polymeric composite of PVP 30K and PEG 6000 of felodipine with improved solubility without exhaustive research.

Aim: Aim of the current study is to prepare and characterize sulfasalazine-loaded liposomes to improve the bioavailability of the drug and to lessen the adverse effects of the drug. Background: Diseases like inflammatory bowel disease can be treated by anti-inflammatory agents like “Sulfasalazine,” It can also be used to treat ulcerative colitis and Crohn’s disease. The biological half-life of sulfasalazine is 5-10hr; as in the case of conventional therapy, there is a chance of missing the dose. Therefore, frequent administration of drugs is essential to maintain the desired steady-state level. The side effects are thrombocytopenia, megaloblastic anemia, bone marrow depression, folic acid deficiency, impairment of male fertility (Oligospermia), intestinal nephritis due to 5-ASA, diarrhoea, headache, and skin rashes. The bioavailability of sulfasalazine is 15%. This work was undertaken to enhance bioavailability and decrease the side effects. Objective: The main objective of the study is to improve the solubility of sulfasalazine by formulating a liposomal drug delivery system. The major objective is to develop a liposomal formulation with good stability and the highest entrapment efficiency. Methods: Liposomes were produced by the thin-film hydration method. Nine formulations of liposomes were prepared by varying the concentrations of soya lecithin and cholesterol and changing the drug ratio. The obtained liposomes were characterized for surface morphology, FTIR, particle size, zeta potential, drug content, entrapment efficiency, and in-vitro diffusion studies. Results: Among the nine formulations of liposomes, F3 was found to be the best formulation with an entrapment efficiency of 97.8% and a zeta potential value of -37.2mV. Liposomes followed first-order kinetics with a non-fickian diffusion pathway. Conclusions: Sulfasalazine loaded liposomes were prepared with good stability and the highest entrapment efficiency.

The purpose of present study was to optimize rizatriptan (RZT) chitosan (CS) nanoparticles using ionic gelation method by application of quality by design (QbD) approach. Based on risk assessment, effect of three variables, that is CS %, tripolyphosphate % and stirring speed were studied on critical quality attributes (CQAs); particle size and entrapment efficiency. Central composite design (CCD) was implemented for design of experimentation with 20 runs. RZT CS nanoparticles were characterized for particle size, polydispersity index, entrapment efficiency, in-vitro release study, differential scanning calorimetric, X-ray diffraction, scanning electron microscopy (SEM). Based on QbD approach, design space (DS) was optimized with a combination of selected variables with entrapment efficiency > 50% w/w and a particle size between 400 and 600 nm. Validation of model was performed with 3 representative formulations from DS for which standard error of − 0.70–3.29 was observed between experimental and predicted values. In-vitro drug release followed initial burst release 20.26 ± 2.34% in 3–4 h with sustained drug release of 98.43 ± 2.45% in 60 h. Lower magnitude of standard error for CQAs confirms the validation of selected CCD model for optimization of RZT CS nanoparticles. In-vitro drug release followed dual mechanism via, diffusion and polymer erosion. RZT CS nanoparticles were prepared successfully using QbD approach with the understanding of the high risk process and formulation parameters involved and optimized DS with a multifactorial combination of critical parameters to obtain predetermined RZT loaded CS nanoparticle specifications.

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: The current research aims to deliver Aceclofenac in a controlled manner through a microsponges-loaded drug delivery system for the treatment of inflammation. Methods: The formulations were prepared by the Quasi-emulsion solvent diffusion method and characterized for particle size and drug entrapment efficiency. For the optimization of the formulation through the Quality by Design (QbD) approach, Quality target product profiles (QTPP) were set up considering various key factors that affect the quality of the formulation. Further optimization of the important factors in relation to the major Critical Quality Attributes (CQAs) was conducted by applying full factorial design using the Design of Expert Software (11.0 software, Stat-Ease, Inc., USA). The optimized formulation was incorporated into the gel, and characterized for morphological analysis by Scanning Electron Microscopy (SEM), drug content, and ex-vivo permeation studies (DD solver, Version 2.0). Results: It was found that process parameters such as drug-to-polymer ratio, the volume of the internal phase, and concentration of the emulsifier and polyvinyl alcohol (PVA), played a crucial role in improving the drug entrapment efficiency and particle size. On the other hand, stirring time did not significantly affect the particle size. Through Design of Expert (DOE) analysis, a PVA concentration of 0.641 mg/ml and an internal phase volume of 12.5 ml were identified to be the ideal concentrations to obtain the optimized microspongal gel formulation (MS4). Characterization studies were carried out on MS4, which displayed a drug encapsulation of 94%, with a Cmax of 81.62 mg/ml, and a Tmax of 12 h. Stability studies carried out as per the International Conference of Harmonization (ICH) guidelines confirmed no noticeable change in physical appearance and drug content. Conclusion: Overall, this study focused on optimizing the formulation of microsponges for efficient dermal drug delivery, considering various critical variables and process parameters. The resulting optimized formulation demonstrated promising drug release and potential for the effective management of inflammation disorders.

The objective of this study was to enhance the solubility of Methylprednisolone by choosing micronized form of drug and to enhance patient compliance by formulating it as dispersible tablets using quality by design (QbD) approach. Dispersible tablets of Methylprednisolone were developed by 23 factorial design. In this study independent variables were concentrations of MCC 102, CCS and Magnesium stearate and dependent variables were disintegration time, hardness and dissolution. The resulting data was fitted into Design Expert Software (Trial Version) and analyzed statistically using analysis of variance (ANOVA). The response surface plots were generated to determine the influence of concentration of MCC 102, CCS and magnesium stearate on responses. The tablets were prepared by direct compression method by choosing micronized form of drug and formulations were evaluated for the standard of dispersible tablets. Results showed that no significant drug-polymer interactions in FTIR studies. According to QbD suggestion the formulation O1 (Desirability- 0.73) with MCC-38mg, CCS-3.5mg and magnesium stearate-2.5mg was formulated and evaluated. The disintegration time was found to be 69 seconds, hardness was found to be 64N and in vitro dissolution with in 30minutes. Optimized O1 formulation was within the limits of standards of dispersible tablets with increased water solubility and better patient compliance. Stability study on optimized O1 formulation showed that there is no significant changes during study period. Thus, O1 formulation was found to be stable. The study indicates that formulation of Methylprednisolone dispersible tablets by using QbD approach is a promising formulation development method.
 Keywords: Dispersible tablets, Methylprednisolone, Direct compression, Quality by Design and ANOVA.

Optimization and evaluation of gastroretentive ranitidine HCl microspheres by using design expert software

The intention of this study is to achieve higher entrapment efficiency (EE) of berberine chloride (selected hydrophilic drug) using nanoprecipitation technique. The solubility of drug was studied in various pH buffers (1.2–7.2) for selection of aqueous phase and stabilizer. Quality by design (QbD)-based 32 factorial design were employed for optimization of formulation variables; drug to polymer ratio (X1) and surfactant concentration (X2) on entrapment efficiency (EE), particle size (PS) and polydispersity index (PDI) of the nanoparticles. The nanoparticles were subjected to solid state analysis, in vitro drug release and stability study. The aqueous phase and stabilizer selected for the formulations were pH 4.5 phthalate buffer and surfactant F-68, respectively. The formulation (F-6) containing drug to polymer ratio (1:3) and stabilizer (F-68) concentration of 50 mM exhibited best EE (82.12%), PS (196.71 nm), PDI (0.153). The various solid state characterizations assured that entrapped drug is amorphous and nanoparticles are fairly spherical in shape. In vitro drug release of the F-6 exhibited sustained release with non-Fickian diffusion and stable at storage condition. This work illustrates that the proper selection of aqueous phase and optimization of formulation variables could be helpful in improving the EE of hydrophilic drugs by nanoprecipitation technique.

The current study aimed to develop a topical emulgel of dasatinib (DTB) for rheumatoid arthritis (RA) treatment to reduce systemic side effects. The quality by design (QbD) approach was employed to optimize DTB-loaded nano-emulgel using a central composite design (CCD). Emulgel was prepared using the hot emulsification method, and then the particle size (PS) was reduced using the homogenization technique. The PS and % entrapment efficiency (% EE) were found to be 172.53 ± 3.33 nm (0.160 ± 0.014 PDI) and 95.11 ± 0.16%, respectively. The nano-emulsion (CF018 emulsion) in vitro drug release profile showed sustained release (SR) up to 24 h. MTT assay results from an in vitro cell line study revealed that formulation excipients had no effect, whereas emulgel showed a high degree of internalization. Furthermore, emulgel treatment significantly reduced LPS-induced TNF-α production in RAW 264.7 cells. The spherical shape was depicted in FESEM images of optimized nano-emulgel (CF018 emulgel) formulation. Ex vivo skin permeation was significantly increased when compared to the free drug-loaded gel (FDG). In vivo data revealed that the optimized CF018 emulgel is a non-irritant and is safe. In terms of paw swelling, the FCA-induced arthritis model demonstrated that the CF018 emulgel reduced paw swelling percentage compared to adjuvant-induced arthritis (AIA) control group. Following clinical testing in the near future, the designed preparation could be a viable alternative treatment for RA.

Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. The objective of the present study was to formulate and evaluate liposomes loaded with Indomethacin. Liposome of Indomethacin was made by thin film hydration method. Phospholipids and cholesterol were used to make multilamellar vesicles. Six batches of liposomes were prepared based on the different weight ratio of Phospholipids and cholesterol. Differential scanning calorimetry (DSC) study conducted to study in any incompatibility. Liposomes were produced by the thin-film hydration method. Six formulations of liposomes were prepared by varying the concentrations of Phospholipids and cholesterol and changing the drug ratio. The obtained liposomes were characterized for surface morphology, FTIR, particle size, zeta potential, drug content, entrapment efficiency, and in-vitro diffusion studies. Among the Six formulations of liposomes, F5 was found to be the best formulation with entrapment efficiency of 85.81% and a zeta potential value of -28.4mV. Liposomes followed Peppas release kinetics. Indomethacin loaded liposomes were prepared with good stability and the highest entrapment efficiency

The objective of the current research to investigate the transdermal delivery of phytosomal Manjistha extract gel (MJE gel). The optimized formulation was prepared and evaluated for different parameters. MJE-loaded phytosomes were prepared by solvent evaporation method using rotary evaporator. The formulation was prepared with a variable concentration of lecithin (0.15–0.25% w/v), with stirring speed of the round bottom flask (80–160 rpm). Design expert software was used for the optimization of MJE-loaded phytosomal formulations. Central composite design-based factorial design was applied and evaluated for vesicular size and entrapment efficiency as dependent variables. The optimized formulation was further characterized with vesicle size, zeta potential, in vitro release. The Carbopol 934 was used to convert the phytosomal formulation (F10) into phytosomal gel and evaluated for ex vivo permeation to check the difference in permeation profile in compare to conventional MJE gel. The optimized MJE-loaded phytosomal formulation (F10) showed the vesicular size of 122.15 ± 3.73 nm, entrapment efficiency of 96.25 ± 2.45% with PDI value of 0.98 ± 0.06. Among the drug release kinetic models, the formulation followed the Higuchi model with drug release of 84.2 ± 4.1% in 12 h. Transmission electron micrograph showed the uniform structure and spherical shape. The prepared phytosomal gel shows prolonged release and enhanced permeation compared to conventional MJE gel.

The research focuses on the development and optimization of ifosfamide nanostructured lipid carriers for oral delivery with the application of response surface methodology. The objectives of the study were to develop a formulation for ifosfamide to be delivered orally, overcome the instability of the drug in acidic environment during oral administration, to sustain the release, drug leakage during storage and low loading capacity. A modified solvent diffusion method in aqueous system was applied to prepare nanostructured lipid nanoparticles. Hydrophilic polymers such as chitosan and sodium alginate were used as coating materials. Glycerol mono oleate and oleic acid were used as solid and liquid lipid, respectively. Poloxamer is used as stabilizers. The central composite rotatable design consisting of three-factored factorial design with three levels was used in this study. The physiochemical characterization included evaluation of surface morphology, particle size and surface charge of the drug in the delivery system. The in vitro drug release, entrapment and drug loading efficiency and as well as the storage stability were evaluated. The results showed that the optimal formulation was composed of drug/lipid ratio of 1:3, organic/aqueous phase ratio of 1:10 and concentration of surfactant of 1 % w/v. Ifosfamide nanostructured lipid carrier under the optimized conditions gave rise to the entrapment efficiency of 77 %, drug loading of 6.14 %, mean diameter of 223 nm and zeta potential value of −25 mV. Transmission electron microscopy analysis showed spherical particles. The in vitro experiment proved that ifosfamide from the delivery system released gradually over the period of 72 h. Sodium alginate cross-linked chitosan nanostructured lipid carrier demonstrated enhanced stability of ifosfamide, high entrapment efficiency and sustained release.