Search Results (153)

The objective of the current research is to investigate the role of Neusilin US2 as a porous carrier for improving the drug loading and stability of Ezetimibe (EZB) by hot melt extrusion (HME). The amorphous solid dispersions (ASDs) were developed from 10–40% of drug loading using Kollidon VA 64 (Copovidone) as a polymer matrix and Neusilin US2 as a porous carrier. The solid-state characterization of EZB was studied using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). The formulation blends were characterized for flow properties, and CTC (compressibility, tabletability, compactibility) profile. The in-vitro drug release profiles were studied in 0.1 N HCl (pH 1.2). The incorporation of Neusilin US2 has facilitated the development of ASDs up to 40% of drug loading. The CTC profile has demonstrated excellent tabletability for the ternary (EZB, copovidone and Neusilin) dispersions over binary dispersion (EZB and copovidone) formulations. The tablet formulations with binary (20%) and ternary (30% and 40%) dispersions have demonstrated complete dissolution of the drug in 30 min in 0.1 N HCl (pH 1.2). The incorporation of copovidone has prevented the recrystallization of the drug in the solution state. Upon storage of formulations at accelerated conditions, the stability of ternary dispersion tablets was preserved attributing to the entrapment of the drug within Neusilin pores thereby inhibiting molecular mobility. Based on the observations, the current research concludes that it is feasible to incorporate Neusilin US2 to improve the drug loading and stability of ASD systems. Full article

Background/Objectives: Propranolol HCl (PPH), a nonselective beta-adrenergic receptor blocker, is employed as an anti-hypertensive, anti-anginal, anti-arrhythmic, and anti-migraine agent. Given its utility in chronic conditions, developing a sustained-release dosage form becomes imperative to optimize therapeutic outcomes while enhancing patient adherence and minimizing side effects. In this study, we employed a widely adopted matrix-based system to develop PPH sustained-release (PPH-SR) matrix tablets, ensuring the uniform dispersion of the drug within the polymeric matrix to regulate its release rate. Methods: Utilizing cellulose-based polymers, specifically HPMC K100M and ethyl cellulose (EC), as matrix formers, nine different formulations were prepared at varying drug-to-polymer ratios. We employed a wet granulation method, followed by compression of the dried granules, to fabricate round-shaped biconvex PPH-SR tablets. Results: Among these different formulations, formulation 2 (F2), comprising 40 mg PPH and 50 mg HPMC K100M (along with other excipients), showed excellent flowability, as evidenced by Carr’s index and angle of repose values of 12.50 and 28.50, respectively. Additionally, the mechanical properties of F2 tablets showed a hardness of 12.34 ± 0.91 KP, an average weight of 200.45 ± 1.87 mg, with a friability of 0.20%, and a content uniformity of 98.36%. Moreover, in vitro release characteristics of F2 tablets demonstrated a sustained-release behavior, with 94.3 ± 10.2% drug release over 24 h. A comparative analysis with marketed tablets yielded similarity and dissimilarity factors of 64 and 8, respectively. Furthermore, the release profile of F2 exhibited a high degree of linearity with the Korsmeyer–Peppas model (R² of 0.977), showcasing its reliability and predictability. Conclusions: In essence, this in-house developed PPH sustained-release formulation can improve patient adherence, reduce side effects, and improve therapeutic outcomes. These results align with our objective of enhancing the therapeutic efficacy of PPH and affirm the broader relevance of innovative formulation strategies in addressing the challenges of chronic disease management. Full article

Submicron particles are widely used in industrial applications due to their unique physical and mechanical properties that enhance the performance of composite materials. In particular, boron carbide particles are valued for their exceptional hardness and high wear resistance and are especially valuable in protective coatings and aerospace applications. However, these particles can agglomerate, significantly impairing their effectiveness. When this occurs during the development of composite materials, physical and mechanical properties are negatively affected. In this paper, a chemical-free method using a non-destructive, open-system dry mechanical deagglomeration technique is developed, leaving the primary particles unaltered, while breaking up strong adhesions between primary particles resulting from the manufacturing process. This method was tested for the deagglomeration of as-received boron carbide submicron particles, with an average primary particle diameter of d₅₀ = 300 nm, and its effect on particle size distribution is presented. Furthermore, X-ray diffraction and true density measurements were carried out on the raw powder. Submicron particles in the dry and as-received state were poured into an experimental mold without a dispersing agent or a protective atmosphere. Static pressure was applied up to 141 MPa to produce tablets at room temperature, finding that 70 MPa yielded the best results in terms of homogeneity, dispersibility, and reproducibility. In order to break apart the densified pressed tablets, ultrasonication was applied before running particle size measurements in the wet dispersed state. Using a tri-laser diffraction light scattering technique, it was determined that particle size distribution followed a Gaussian curve, indicating that this method is suitable to regain the primary submicron particles with uniform properties. It is also shown that applying ultrasound on the as-received powder alone failed to cause the complete deagglomeration of strongly adhering primary particles. These findings suggest that there is no significant wear on the primary particles and no alteration of their surface chemistry, due to the lack of any chemically supported mechanisms such as the alteration of surface charge or the adsorption of surfactants. Furthermore, as the static pressure exerts an immediate impact on all particles in the mold, there is a clear economical advantage in terms of a shorter processing time over other deagglomeration methods such as high shear mixing. Full article

Radiation transfer in layers of densely packed aggregates of hydroxyapatite nanoparticles was studied for a spectral range from 300 to 1100 nm using diffuse reflectance measurements and the modeling of the light transfer properties of the layers. The studied samples of dispersed biogenic hydroxyapatite were obtained from animal bone material (bovine bones) using fast pyrolysis followed by grinding and pressing into tablets. A distinctive feature is the high reflectivity (high albedo) of the obtained samples, which is practically independent of the wavelength in the studied spectral range and comparable to the reflectivity of the diffuse reflectance standard based on Spectralon. The modeling of the light transfer properties of the studied samples within the framework of the effective medium theory (using coherent potential approximation) made it possible to establish the weak dependence of the mean scattering-free path and the mean transport-free path of light propagation in the medium on the wavelength, which is consistent with the features observed in the experiment. Possible prospects for the use of nanostructured hydroxyapatite as photonic material are discussed. Full article

Objectives: We investigated the compression mechanisms for loxoprofen sodium (LXP), which is known to occur as a dihydrate, and identified parameters that influence the tablet hardness of LXP tablets prepared by the wet granulation method. Method: LXP granules were prepared with water or ethanol as the solvent, dried under various conditions and sieved for particle size control, with 1% Mg-st added before tablet compression. Results: The findings indicated that both the granulation solvent and drying temperature significantly impacted the tablet hardness. Granules prepared with ethanol exhibited higher hardness as compared with those prepared with water. The tablet hardness varied with varying drying temperatures. Discussion: Principal component analysis (PCA) identified positive correlations between the tablet hardness and the surface free energy (SFE), polar component (γ(p)), and cohesion, and a negative correlation with the dispersive component (γ(d)). Granules prepared with ethanol exhibited a higher γ(p), likely due to the differing solubility in ethanol and water, leading to enhanced interparticle binding. This study confirmed that use of the eutectic mixture of LXP and Mg-st exerted no significant influence. Crystal structure analysis indicated that the hydration states varied according to the drying temperature, suggesting the higher γ(p) in anhydrous forms, due to the lower hydrophobicity, contributed to increased tablet hardness. Conclusion: This research offers insights for optimizing the formulation conditions to improve the LXP tablet hardness. Appropriate selection of the solvent and drying temperature mitigates tablet hardness issues, while assessment of SFE can help in the selection of suitable additives. Full article

The aim of this study was to investigate the influence of solid dispersion (SD) formulation factors on improvement of the bioavailability and pharmacokinetic profile of clopidogrel after peroral administration using an in vitro–in silico approach. A clopidogrel-specific, physiologically based biopharmaceutical model (PBBM) was developed and validated to predict absorption and distribution of clopidogrel after peroral administration of the tested formulations. Clopidogrel solid dispersions were prepared using two polymers (poloxamer 407 and copovidone) and a drug-to-polymer ratio of 1:5 and 1:9. The results of the in vitro dissolution test under pH–media change conditions showed that the type and ratio of polymers notably influenced the release of clopidogrel from the SDs. It can be observed that an increase in the polymer content in the SDs leads to a decrease in the release of clopidogrel from the SDs. The predictive power of the constructed clopidogrel-specific PBBM was demonstrated by comparing the simulation results with pharmacokinetic data from the literature. The in vitro dissolution data were used as inputs for the PBBM to predict the pharmacokinetic profiles of clopidogrel after the peroral administration of SDs. SDs with copovidone (1:5) and poloxamer (1:9) showed the potential to achieve the highest drug absorption and bioavailability, with an improvement of over 100% compared to an immediate-release (IR) tablet. The sample with poloxamer (1:9) may have the potential to reduce inter-individual variability in clopidogrel pharmacokinetics due to absorption in the cecum and colon and associated lower first-pass metabolism in the liver. This suggests that distal intestine may be the targeted delivery site for clopidogrel, leading to improved absorption and bioavailability of the drug. This study has shown that an in vitro–in silico approach could be a useful tool for the development and optimization of clopidogrel formulations, helping in decision making regarding the composition of the formulation to achieve the desired pharmacokinetic profile. Full article

Background/Objectives: Thickened waters are commonly used for dysphagic patients to ensure hydration, facilitate safer swallowing, and administer oral therapies, yet their impact on drug dissolution remains unclear. This study aims to investigate how thickening agents, viscosity, and solid oral dosage form (SODF) formulations influence drug release in gelled vehicles. Methods: Twelve commercially available thickened waters, including both ready-to-use products and powders for extemporaneous preparation, were used to disperse crushed sodium pravastatin tablets. The resulting preparations were evaluated for their rheological properties and dissolution performance. Results: Thickened water products vary in consistency, with starch-based thickeners providing more consistent results than gum-based ones. Pravastatin release profiles closely matched the original tablets with starch thickeners, while gum-based thickeners showed greater variability, primarily influenced by viscosity. Conclusions: These findings emphasize the importance of selecting the appropriate thickening agent for controlling drug release in thickened water products, highlighting the need to balance patient compliance with the potential impact on drug release during product development. Full article

Poor water solubility remains a significant challenge in the pharmaceutical industry that limits the therapeutic efficacy and bioavailability of many active pharmaceuticals. Soluplus^® (SLP), an amphiphilic graft copolymer made of polyethylene glycol, polyvinyl caprolactam, and polyvinyl acetate, has been gaining interest in recent years as it addresses these limitations by acting as a versatile carrier. Its ability to form stable amorphous dispersions and enhance drug solubility, as well as its physicochemical properties, support its role as a key excipient in advanced drug delivery systems. Recent investigations have demonstrated the adaptability of SLP in addressing drug delivery requirements, offering controlled release, improved targeting, and superior therapeutic outcomes. This review examines some key formulation methods that make use of SLP, including hot-melt extrusion, spray drying, electrospinning, drug–polymer layering, and capsule and tablet formulations, highlighting the capacity of SLP to overcome formulation challenges. Biomedical applications of SLP have also been explored, with a focus on its role in improving the delivery of antitumoral, anti-inflammatory, antimicrobial, and antiparasitic drugs. Full article

Background/Objectives: Only a few studies performed at industrial scale in non-simulated conditions have investigated the effect of input variability from the product’s lifecycle on product quality. The purpose of this work was to identify the root causes for the low and variable hardness of core tablets prepared using high-shear wet granulation through batch statistical modeling and to verify the short- and long-term effectiveness of the improvement actions. Methods: The novelty of this study is the use of multivariate methods for the complex assessment of a wide data set belonging to two proportional composition strengths, manufactured at an industrial scale, with different tablet shapes and sizes, with the aim of identifying inter-related active ingredient and process variables with the highest impact on hardness value and for defining optimal processing conditions leading to a robust product. Results: Four main variables affecting the output variable were identified: API particle size, nozzle type used for granulation, wet discharge, and drying intensity. These were included in an updated control strategy (3 out of 4 variables having to be within the desired ranges: API d0.5 < 45 microns; granulation nozzle that ensures liquid dispersion into droplets; gentle wet discharge and drying processes). In the case of the product studied, the newly defined process conditions could even accommodate d0.5 up to 70 microns and still ensure adequate core tablet hardness (at least 30% above the lower specification limit) for the successive film-coating step. Conclusions: Besides the beneficial impact of reducing the risk for out-of-specification hardness results, this study also offered the benefit of cost avoidance and yield improvement. The improvement was confirmed through the significant average hardness increase (15–20%) and between-batch variability decrease, leading to decent sigma quality levels (2.5) for the control phase batches. Full article

Background/Objectives: Following tooth extraction, resveratrol (RSV) can support healing by reducing inflammation and microbial risks, though its poor solubility limits its effectiveness. This study aims to develop a solid nanocomposite by embedding RSV in lipid nanoparticles (mLNP) within a hydrophilic matrix, to the scope of improving local delivery and enhancing healing. Hydroxyapatite (HXA), often used as a bone substitute, was added to prevent post-extraction alveolus volume reduction. Methods: The mLNP-RSV dispersion was mixed with seven different polymers in various mLNP/polymer ratios. Following freeze-drying, the powders were redispersed, and the resulting dispersions were tested by DLS experiments. Then, the best two nanocomposites underwent extensive characterization by SEM, XRD, FTIR, Raman spectroscopy, and thermal analysis as well as in vitro partitioning studies aimed at verifying their ability to yield the mLNP-RSV from the hydrophilic matrix to a lipophilic tissue. The characterizations led to identify the best nanocomposite, which was further combined with HXA to obtain hybrid nanocomposites, further evaluated as pharmaceutical powders or in form of mini-tablets. Results: PEG-based nanocomposites emerged as optimal and, following HXA insertion, the resulting powders revealed adequate bulk properties, making them useful as a pharmaceutical intermediate to produce ≈59 mm³ mini-tablets, compliant with the post-extraction socket. Moreover, they were proven ex vivo to be able to promote RSV and GA accumulation into the buccal tissue over time. Conclusions: The here-proposed mini-tablet offers an innovative therapeutic approach for alveolar wound healing promotion as they led to a standardized dose administration, while being handy and stable in terms of physical solid identity as long as it takes to suture the wound. Full article

Background/Objectives: This study aimed to develop gastroretentive tablets based on mucoadhesive–floating systems with encapsulated gentian (Gentiana lutea, Gentianaceae) root extract to overcome the low bioavailability and short elimination half-life of gentiopicroside, a dominant bioactive compound with systemic effect. The formulation also aimed to promote the local action of the extract in the stomach. Methods: Tablets were obtained by direct compression of sodium bicarbonate (7.5%) and solid lipid microparticles (92.5%), which were obtained with lyophilizing double emulsions. A quality by design (QbD) was employed to evaluate the impact of formulation factors and processing parameters on emulsion viscosity, powder characteristics (moisture content, encapsulation efficiency, flowability), and tablet characteristics (floating lag time, gentiopicroside release, and assessment of dispersibility during in vitro dissolution). Results: The trehalose content and high-shear-homogenization (HSH) time of primary emulsion were critical factors. Trehalose content positively influenced emulsion viscosity, moisture content, floating lag time, encapsulation efficiency, and the release rate of gentiopicroside. HSH time positively affected powder stability and negatively gentiopicroside release. The selected powder had a high gentiopicroside encapsulation efficiency (95.13%), optimal stability, and good flowability. The developed tablets exhibited adequate floating lag time (275 s), mucoadhesive properties, and gentiopicroside biphasic release (29.04% in 45 min; 67.95% in 6 h). Furthermore, the optimal tablet formulation remained stable for 18 months and was primarily digested by duodenal enzymes. Conclusions: Dual-mechanism gastroretentive tablets with encapsulated gentian root extract were successfully developed. The in vitro digestion study demonstrated that the optimal formulation effectively resisted gastric enzymes, ensuring the release of its contents in the small intestine, even in the case of premature gastric evacuation. Full article

Background/Objectives: The combination of isoniazid (INH) and rifampicin (RIF) is indicated for the treatment maintenance phase of tuberculosis (TB) in adults and children. In Brazil, there is no current reference listed drug for this indication in children. Farmanguinhos has undertaken the development of an age-appropriate dispersible tablet to be taken with water for all age groups from birth to adolescence. The primary objective of this work was to develop and validate a physiologically-based biopharmaceutics model (PBBM) in GastroPlus^TM, to link the product’s in vitro performance to the observed pharmacokinetic (PK) data in adults and children. Methods: The PBBM was developed based on measured or predicted physico-chemical and biopharmaceutical properties of INH and RIF. The metabolic clearance was specified mechanistically in the gut and liver for both parent drugs and acetyl-isoniazid. The model incorporated formulation related measurements such as dosage form disintegration and dissolution as inputs and was validated using extensive literature as well as in house clinical data. Results: The model was used to predict the exposure in children across the targeted dosing regimen for each age group using the new age-appropriate formulation. Probabilistic models of efficacy and safety versus exposure, combined with real world data on children, were utilized to assess drug efficacy and safety in the target populations. Conclusions: The model predictions (systemic exposure) along with clinical data from the literature linking systemic exposure to clinical outcomes confirmed that the proposed dispersible pediatric tablet and dosing regimen are anticipated to be as safe and as effective as adult formulations at similar doses. Full article

Celecoxib (CEL), a nonsteroidal anti-inflammation drug (NSAID), is categorized as a Class II drug (low solubility, high permeability) in the Biopharmaceutics Classification System (BCS). The aim of this study is to develop a novel formulation of CEL nanosuspensions in the form of dried powder for tableting or capsuling. In this study, CEL was formulated into nanosuspensions to improve its solubility. CEL nanosuspensions were prepared using the precipitation method followed by high-pressure homogenization. Drying of the nanosuspensions was performed by spray drying and freeze drying. We examined the impact of various formulation and processing parameters on the nanoparticles. The CEL nanoparticles were characterized by particle size analysis, differential scanning calorimetry (DSC), powder X-Ray diffraction (PXRD), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and dissolution tests. The choice of solvent, stabilizer, and surfactant appeared to have significant impacts on the crystallization and particle size and, consequently, the solubility of the CEL nanoparticles. CEL chemical stability was maintained throughout both drying processes. Both spray-dried and freeze-dried CEL nanosuspensions showed rapid dissolution profiles compared to raw CEL due to the nanosized particle dispersion with the presence of a lag phase. The freeze-dried nanosuspension showed a slight delay in the first 20 min compared to the spray-dried nanosuspension, after which dissolution progressed with a lag phase that represents aggregation. Full article

Itraconazole (ITZ), a broad-spectrum triazole antifungal agent, exhibits remarkable pharmacodynamic and pharmacokinetic properties. However, the low solubility of ITZ significantly reduces its oral bioavailability. Furthermore, it has been reported that this medication can result in dose-related adverse effects. Therefore, the objective of this study was to enhance the solubility of ITZ through the utilization of various polymers and to manufacture personalized and programmable release ITZ tablets. Five different polymers were selected as water-soluble carriers. Thirty percent w/w ITZ was mixed with seventy percent w/w of the polymers, which were then extruded. A series of physical and chemical characterization studies were conducted, including DSC, PXRD, PLM, and in vitro drug release studies. The results demonstrated that ITZ was dispersed within the polymers, forming ASDs that markedly enhanced its solubility and dissolution rate. Consequently, soluplus^® was employed as the polymer for the extrusion of ITZ-loaded filaments, which were subsequently designed and printed. The in vitro drug release studies indicated that the release of ITZ could be regulated by modifying the 3D structure design. Overall, this study found that the combination of HME and 3D printing technologies could represent an optimal approach for the development of personalized and precise drug delivery dosages. Full article

Background: Melt-based 3D printing technologies are currently extensively evaluated for research purposes as well as for industrial applications. Classical approaches often require intermediates, which can pose a risk to stability and add additional complexity to the process. The Advanced Melt Drop Deposition (AMDD) technology, is a 3D printing process that combines the principles of melt extrusion with pressure-driven ejection, similar to injection molding. This method offers several advantages over traditional melt-based 3D printing techniques, making it particularly suitable for pharmaceutical applications. Objectives: This study evaluates the AMDD printing system for producing solid oral dosage forms, with a primary focus on the thermo-stable polymer polyvinyl alcohol (PVA). The suitability of AMDD technology for creating amorphous solid dispersions (ASDs) is also examined. Finally, the study aims to define the material requirements and limitations of the raw materials used in the process. Methods: The active pharmaceutical ingredients (APIs) indometacin and ketoconazole were used, with PVA 4-88 serving as the carrier polymer. Powders, wet granulates, and pellets were investigated as raw materials and characterized. Dissolution testing and content analyses were performed on the printed dosage forms. Solid-state characterization was conducted using differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Degradation due to thermal and mechanical stress was analyzed using nuclear magnetic resonance spectroscopy (NMR). Results/Conclusions: The results demonstrate that the AMDD 3D printing process is well-suited for producing solid dosage forms. Tablets were successfully printed, meeting mass uniformity standards. Adjusting the infill volume from 30% to 100% effectively controlled the drug release rate of the tablets. Solid-state analysis revealed that the AMDD process can produce amorphous solid dispersions with enhanced solubility compared to their crystalline form. The experiments also demonstrated that powders with a particle size of approximately 200 µm can be directly processed using AMDD technology. Full article