QbD-based formulation development of resveratrol nanocrystal incorporated into soluble mesoporous material: Pharmacokinetic proof of concept study.

Resveratrol (RSV) has powerful antioxidant activities. However, the bioavailability is still limited due to low solubility and transport issues. Nanocrystal technology has been introduced to address these issues; however, the bulky formulation of the nanocrystal process through nanosuspension faces a big challenge in terms of stability and scale-up ability. This work aimed to enhance the bioavailability of RSV through nanocrystal formulation incorporated into soluble mesoporous carriers for superior solid-state stability and feasibility. This formulation was designed and developed rationally through scientific justification in the nanocrystal formulation along with quality by design paradigm. Box-Behnken design was applied to determine the optimized formulation based on the particle size and distribution, drug loading, zeta potential, and supersaturation parameters. The nanocrystal was formed through evaporation of drug, polymer, and surfactant in the solvent incorporated into mesoporous material. The nanocrystal was evaluated by vibrational spectroscopy, thermal analyses, and SEM and TEM photographs, followed by crystallinity evaluation. The results indicated that the factors only affected the particle size variation, zeta potential, drug loading, and the time to reach the supersaturation peak level. The optimized formulation was achieved by 68 % desirability value, producing 133.3 ± 1.2 nm particle size and -24.6 mV zeta potential. The physical and chemical evaluation characterization indicated no interaction between RSV and carrier. In addition, there was no difference in crystallinity between the RSV nanocrystal and native RSV. Moreover, the RSV nanocrystal improved the bioavailability nearly twice compared to the RSV suspension.

Drug-Coformer Loaded-Mesoporous Silica Nanoparticles: A Review of the Preparation, Characterization, and Mechanism of Drug Release.

Drug-coformer systems, such as coamorphous and cocrystal, are gaining recognition as highly effective strategies for enhancing the stability, solubility, and dissolution of drugs. These systems depend on the interactions between drug and coformer to prevent the conversion of amorphous drugs into the crystalline form and improve the solubility. Furthermore, mesoporous silica (MPS) is also a promising carrier commonly used for stabilization, leading to solubility improvement of poorly water-soluble drugs. The surface interaction of drug-MPS and the nanoconfinement effect prevent amorphous drugs from crystallizing. A novel method has been developed recently, which entails the loading of drug-coformer into MPS to improve the solubility, dissolution, and physical stability of the amorphous drug. This method uses the synergistic effects of drug-coformer interactions and the nanoconfinement effect within MPS. Several studies have reported successful incorporation of drug-coformer into MPS, indicating the potential for significant improvement in dissolution characteristics and physical stability of the drug. Therefore, this study aimed to discuss the preparation and characterization of drug-coformer within MPS, particularly the interaction in the nanoconfinement, as well as the impact on drug release and physical stability.

Resveratrol Nanocrystal Incorporated into Mesoporous Material: Rational Design and Screening through Quality-by-Design Approach.

Bioflavonoids from grape seeds feature powerful antioxidant and immunostimulant activities, but they present problems related to solubility and bioavailability. Nanocrystal (NC) incorporated into a mesoporous carrier is a promising strategy to address these issues. However, the preparation of this formulation involves the selection of factors affecting its critical quality attributes. Hence, this study aimed to develop an NC formulation incorporating resveratrol into a soluble mesoporous carrier based on rational screening design using a systematic and continuous development process, the quality-by-design paradigm. A mesoporous soluble carrier was prepared by spray-drying mannitol and ammonium carbonate. The NC was obtained by introducing the evaporated solvent containing a drug/polymer/surfactant and mesoporous carrier to the medium. A 26-2 fractional factorial design (FFD) approach was carried out in the screening process to understand the main effect factors. The type and concentration of polymer and surfactant, resveratrol loading, and solvent were determined on the NC characteristics. The results indicated that drug loading, particle size, and solubility were mainly affected by RSV loading, PEG concentration, and Kolliphor EL concentration. The polymer contributed dominantly to reducing the particle size and enhancing solubility in this screening design. The presence of surfactants in this system made it possible to prolong the supersaturation process. According to the 26-2 FFD, the factors selected to be further developed using a statistical technique according to the quality-by design-approach, Box Behnken Design, were Kolliphor EL, PEG400, and RSV loading.

A Novel Desloratadine-Benzoic Acid Co-Amorphous Solid: Preparation, Characterization, and Stability Evaluation.

Low physical stability is the limitation of the widespread use of amorphous drugs. The co-amorphous drug system is a new and emerging method for preparing a stable amorphous form. Co-amorphous is a single-phase amorphous multicomponent system consisting of two or more small molecules that are a combination of drugs or drugs and excipients. The co-amorphous system that uses benzoic acid (BA) as an excipient was studied to improve the physical stability, dissolution, and solubility of desloratadine (DES). In this study, the co-amorphous formation of DES and BA (DES⁻BA) was prepared by melt-quenching method and characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), and polarized light microscopy (PLM). Dissolution, solubility, and physical stability profiles of DES⁻BA were determined. The DES crystals were converted into DES⁻BA co-amorphous form to reveal the molecular interactions between DES and BA. Solid-state analysis proved that the co-amorphous DES⁻BA system (1:1) is amorphous and homogeneous. The DSC experiment showed that the glass transition temperature (Tg) of tested DES⁻BA co-amorphous had a higher single Tg compared to the amorphous DES. FTIR revealed strong interactions, especially salt formation. The dissolution rate and solubility of co-amorphous DES⁻BA (1:1) obtained were larger than the DES in crystalline form. The PXRD technique was used to assess physical stability for three months at 40 °C with 75% RH. The DES⁻BA co-amorphous system demonstrated better physical stability than a single form of amorphous DES. Co-amorphous DES⁻BA has demonstrated the potential for improving solid-state stability, as the formation of DES⁻BA co-amorphous salt increased solubility and dissolution when compared to pure crystalline DES. This study also demonstrated the possibility for developing a DES⁻BA co-amorphous system toward oral formulations to improve DES solubility and bioavailability.

Synthesis, characterization, and stability study of desloratadine multicomponent crystal formation.

This study describes the formation of multicomponent crystal (MCC) of desloratadine (DES). The objective of this study was to discover the new pharmaceutical MCC of DES using several coformers. The MCC synthesis was performed between DES and 26 coformers using an equimolar ratio with a solvent evaporation technique. The selection of the appropriate solvent was carried out using 12 solvents. The preview of the MCC of DES was performed using polarized light microscopy (PLM). The formation of MCC was confirmed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The accelerated stability of MCC at 40 °C and relative humidity of 75% was investigated using PXRD and FTIR. Depending on the prior evaluation, DES and benzoic acid (BA) formed the MCC. PLM and SEM results showed that crystal habit of combination between DES and BA differed from the constituent components. Moreover, the diffractogram pattern of DES-BA was distinct from the constituent components. The DSC thermogram showed a new peak which was distinct from both constituent components. The FTIR study proved a new spectrum. All characterizations indicated that a new solid crystal was formed, ensuring the MCC formation. In addition, DES-BA MCC had both chemical and physical stabilities for a period of 4 months.

Development and optimization of a meloxicam/ß-cyclodextrin complex for orally disintegrating tablet using statistical analysis.

The purpose of this research was to develop an inclusion complex of meloxicam (MEL)/ß-cyclodextrin (ß-CD) incorporated into an orally disintegrating tablet (ODT), using statistical analysis to optimize the ODT formulation based on a quality by design (QbD) approach. MEL/ß-CD complexation was performed by kneading, co-precipitation and spray drying methods under different molar ratios. Fourier transform infrared spectroscopy, X-ray diffraction and thermal analysis were utilized to evaluate the complexes. A central composite design (α = 2) was applied to optimize and assess the influence of Primojel, Primellose and crushing strength (CS) as independent variables on tablet friability, disintegration behavior, wicking properties and drug release. The spray drying method induced formation of an amorphous complex and enhanced solubility and drug release of MEL. Furthermore, a QbD-based statistical analysis was successfully utilized to optimize the ODT formulation. Primojel, Primellose and CS showed unique main effects and interactions at different levels. CS was the dominant factor, affecting friability, disintegration behavior and drug release, while wicking properties were affected by Primojel and its interaction with Primellose. Therefore, according to the overlay plot, CS was dominant factor in determining the optimum region based on a QbD approach.

Improving mechanical properties of desloratadine via multicomponent crystal formation.

We report the first multicomponent crystal of desloratadine, an important anti-histamine drug, with a pharmaceutically acceptable coformer of benzoic acid. The single crystal structure analysis revealed that this novel multicomponent crystal is categorized as salt due to the proton transfer from benzoic acid to the desloratadine molecule. By forming the salt multicomponent crystal, we demonstrated that the tabletability and plasticity of the multicomponent crystal was improved from the parent drug. In addition, neither capping nor lamination tendency was observed in the desloratadine-benzoic acid multicomponent crystal. The existence of a layered structure and slip planes are proposed to be associated with this improvement. The desloratadine-benzoate in this case shows an improved solubility in water and HCl 0.1N media and a better dissolution profile in water. However, the dissolution rate in HCl 0.1N media was found to be essentially indifference.

Improvement of Meloxicam Solubility Using a ß-Cyclodextrin Complex Prepared via the Kneading Method and Incorporated into an Orally Disintegrating Tablet.

Purpose: The aim of this research was to formulate and develop an orally disintegrating tablet (ODT) that incorporated a MEL/ß-CD complex, using a quality by design (QbD) approach to enhance solubility and drug release. Methods: Multiple regression linear analysis was conducted to develop the kneading process and ODT formulation. Mixing time and amount of solvent were used as independent variables in kneading process optimisation, while the superdisintegrants were used to obtain the desired formulation. Fourier transform infrared spectroscopy and differential scanning calorimetry were performed for complex characterization. Results: MEL/ß-CD complexation was successful in enhancing MEL solubility. The results suggest that increasing the amount of solvent and mixing time enhances drug loading and drug release. However, increased solvent amounts present the problem of removing the solvent. Primojel and Polyplasdone had a significant effect on the water wicking and tablet disintegration process (p<0.05), although Polyplasdone negatively affected tablet hardness. Both an optimized KN process and ODT formulation were obtained using a QbD approach. Conclusion: Incorporation of the MEL/ß-CD complex during ODT formulation using the QbD approach serves as a model for ODT product development, with optimal product performance based on the specification of quality target product profiles. To understand more specific phenomena, one point in the middle of the design for each factor should be added to more powerfully estimate this effect and avoid the lack of estimate due to an inadequate equation.