Water-soluble Drugs Research Articles

Correlation of rivaroxaban solubility in mixed solvents for optimization of solubility using machine learning analysis and validation

In this study, the solubility of rivaroxaban, a poorly water-soluble drug, was investigated in mixed solvent systems to address challenges in pharmaceutical formulation and bioavailability enhancement. Solubility optimization is essential for the effective delivery and therapeutic performance of rivaroxaban, as its low aqueous solubility limits oral bioavailability and necessitates innovative approaches for drug formulation. The study explored the role of primary alcohols combined with dichloromethane in improving solubility, emphasizing their industrial relevance in crystallization, purification, and drug manufacturing processes. To complement experimental insights, machine learning models were employed to predict rivaroxaban solubility based on temperature, solvent type, and mass fraction of dichloromethane. Three models—AdaBoost Gaussian process regression (ADAGPR), AdaBoost multilayer perceptron (ADAMLP), and AdaBoost LASSO regression (ADALASSO)—were evaluated using , RMSE, and MAPE metrics. Among these, ADAGPR demonstrated superior performance with an R² score of , outperforming ADAMLP and . It also achieved the lowest total RMSE and MAPE , confirming its predictive precision and reliability. Optimal solubility conditions were identified at with a mass fraction of 0.8190 in a dichloromethane-methanol mixture, yielding a predicted solubility of . These findings highlight the potential of combining chemical engineering principles with advanced predictive modeling to optimize solubility in complex solvent systems, offering significant value to pharmaceutical development and process optimization.

A water-soluble drug nanoparticle-loaded in situ gel for enhanced precorneal retention and its transduction mechanism of pharmacodynamic effects.

Timolol maleate (TM), a hydrophilic small molecule, is widely used in the clinical management of glaucoma. However, the complex physiological barriers of the eyes result in suboptimal bioavailability for traditional ophthalmic formulations. To address these challenges, we have developed an innovative pharmaceutical formulation. The nanoparticles (NPs) were formulated by a multi-step optimization process involving a Plackett-Burman design (PBD), steepest ascent design (SAD), and Box-Behnken design (BBD) to obtain TM-HA/CS@ED NPs. It was then encapsulated in an in situ gel (ISG) system consisting of deacetylated gellan gum (DGG) and xanthan gum (XG) to yield the TM-HA/CS@ED NPs ISG. The formulation demonstrated favorable safety in a series of ocular irritation assays and was characterized as a pseudoplastic fluid by rheological analyses, enhancing spreadability on the ocular surface and prolonging the retention time. Moreover, the NPs exposed after ISG dissolution exhibited strong mucosal adhesion and hydrophobicity, facilitating the hydrophilic TM to penetrate the corneal barrier. In vitro and in vivo retention evaluations and tear elimination pharmacokinetic study confirmed that TM-HA/CS@ED NPs ISG showed superior precorneal retention ability, and favorable sustained drug concentrations, resulting in sustained and stable transcorneal permeation into the eyes and significant intraocular pressure (IOP) lowering efficacy with a duration of 12h. These results provide valuable insights into the design of ophthalmic drug delivery systems for water-soluble drugs and therapeutic interventions for glaucoma.

In-vitro Lipolysis, Stability and Pharmacodynamic Study of Cilnidipine Loaded Self-emulsifying Drug Delivery System

Aims: The aim of this research work was to investigate the potential ability of cilnidipine- loaded-Self-Emulsifying Drug Delivery System (SEDDS) to improve the solubility and oral bioavailability of cilnidipine. Background: The therapeutic value of drugs is constrained by the low oral bioavailability of BCS class II drugs. In order to improve the solubility and oral bioavailability of poorly water-soluble drugs, SEDDS are frequently utilised. Methods: To develop the cilnidipine-loaded-SEDDS formulation, Canola oil as the oil phase, tween 80 as the surfactant, and PEG 300 as the co-surfactant were used. The SEDDS formulation was evaluated based on stability study per ICH guidelines, drug precipitation during in-vitro lipolysis study under fasted and fed state, and in vivo pharmacodynamic study in Wistar rats. The content of the drug was determined by assay of SEDDS formulation using the official method of cilnidipine. Results: The pharmacodynamic study demonstrated that cilnidipine-loaded SEDDS formulation significantly produced a rapid antihypertensive effect (within 2 h) that lasted for 24 h in comparison to drug suspension. During the in vitro lipolysis study, the concentration of the drug recovered from the aqueous phase under both fasted and fed state was more than 90% after 10 minutes, with a minute amount of drug involved in precipitation. At stability conditions of 30 ± 2°C/65 ± 5%RH for a duration of six months, the SEDDS formulation was found to be stable. The content of cilnidipine in the SEDDS formulation was found to be 98.4%. Conclusion: A BCS class-II drug's oral bioavailability and dissolution might be improved using the self-emulsifying drug delivery method.

Human milk improves the oral bioavailability of the poorly water-soluble drug clofazimine.

Clofazimine is an emerging drug for the treatment of cryptosporidiosis in infants. As a poorly water-soluble drug, the formulation of clofazimine in age-appropriate vehicles is challenging and often results in the use of off-label formulations. Milk-based vehicles such as human milk and bovine milk have been investigated as age-appropriate formulations and shown to increase the solubilisation of poorly water-soluble drugs via enhanced solubility in lipid digestion products in vitro. We hypothesised that administration of clofazimine within a milk-based vehicle would enhance bioavailability for infant patients. Towards this objective, suspensions of clofazimine in human and bovine milk were orally administered separately to piglets and rats and the subsequent plasma concentrations were compared to those after administration of an aqueous drug suspension. Initial investigations with a rodent model showed a significant increase (258%) in the oral bioavailability of clofazimine when administered with human milk. Similarly, the oral bioavailability of clofazimine was significantly higher when administered in both human (154%) and bovine milk (175%) using a neonatal piglet model, suggesting comparable enhancement in oral bioavailability could be achieved with human or bovine milk. These findings demonstrate the potential of human milk in particular to provide an effective administration vehicle for clofazimine administration to infants without the need for additional excipients.

Exploration of Enalapril-Lacidipine Co-Amorphous System with Superior Dissolution, In vivo Absorption and Physical Stability via Incorporated into Mesoporous Silica.

In the present study, enalapril (ENP) was taking as a potential co-former to fabricate co-amorphous system with lacidipine (LCDP). The ENP/LCDP co-amorphous system was firstly prepared with or without mesoporous SiO2 and characterized by DSC, XRD and SEM technologies. The potential molecular interactions were evaluated by FTIR spectrums. Furthermore, the dissolution and pharmacokinetics behavior of various formulations were also carried out. It was demonstrated that the completely co-amorphization was obtained at ENP/LCDP 2:1 molar ratio by the intermolecular interactions between ENP and LCDP. The ENP/LCDP co-amorphous system significantly improve the dissolution rate of LCDP and ENP respectively. Compared to the naked ENP/LCDP co-amorphous system, remarkable enhancement of dissolution rate and bioavailability of model drugs was observed by incorporated the co-amorphous system into mesoporous SiO2, and a superior physical stability was also observed after accelerated study. Raman mapping revealed that the less microstructure phase separation could be the main reason for the better stability in presence of mesoporous SiO2. In conclusion, ENP could be successfully used as a potential co-former to fabricate co-amorphous system with poorly water-soluble drugs and collaborates the co-amorphous with mesoporous SiO2 become a promising strategy to achieve stable amorphous formulation for further enhancement of dissolution rate and bioavailability.

Formulation development and scale-up of dutasteride liquisolid tablets

Introduction Liquisolid (LS) technology is particularly advantageous for poorly water-soluble drugs administered in very low doses because of the improved dissolution rate and superior content uniformity. However, there is a lack of research papers describing the application of this concept on an industrial scale. Thus, we present trials conducted to develop tablets containing 0.5 mg of water-insoluble dutasteride (DTS) according to the LS approach. Methods We divided the study into two stages: developing a placebo formulation and producing LS tablets containing DTS on a pilot scale. We tested all the manufactured tablets for mass uniformity, resistance to crushing, disintegration time, dissolution, stability, and presence of impurities. Results We demonstrated that a standard high-shear granulator mixer with a spraying system is effective for LS formulation development and transfer to the pilot scale. We were able to compress the system into tablets with the desired assay, content uniformity, dissolution, and mechanical strength. Conclusion Multiple operations can be performed on one piece of equipment – that is, pre-mixing a carrier, wetting of the carrier with a solution of an active ingredient in a nonvolatile liquid, mixing of the resulted mass with a coating agent, as well as additional excipients. Preparation of powder blends ready for tableting in line with the one-pot process approach is especially advantageous for the safety of staff engaged in the manufacturing of highly potent drug products.

Developing Soluplus®-Based Microparticle Amorphous Solid Dispersions with High Drug Loading for Enhanced Celecoxib Dissolution via Electrospraying.

Amorphous solid dispersion (ASD) is one of the most studied strategies for improving the dissolution performance of poorly water-soluble drugs, but ASDs often have low drug loadings, thereby necessitating larger dosage sizes. This study intended to create Soluplus® (SOL)-based microparticle ASDs with high drug loading (up to 60 w/w%) and long-term stability (at least 16months) using electrospraying to enhance the dissolution of poorly water-soluble celecoxib (CEL). X-ray diffraction (XRD) and differential scanning calorimetry (DSC) analyses showed that the electrosprayed SOL-CEL microparticles were amorphous, and Fourier transform infrared spectroscopy (FTIR) data indicated the presence of hydrogen bonding between SOL and CEL in the microparticles, which helped stabilize the ASDs. In vitro dissolution studies demonstrated that these ASDs improved the CEL dissolution rate by up to 8.2-fold compared to the crystalline form. Electrospraying presents a promising alternative to conventional methods like hot-melt extrusion (HME) and spraying drying (SD) for the production of ASDs, providing simplicity, high drug loading capability and long-term stability, thus catering to a variety of poorly water-soluble drugs.

Niosomes: A Revolutionary Approach for Skin Cancer Treatment

Skin cancer is one of the most common types of cancer globally, with melanoma and non-melanoma being the two primary forms. Melanoma tends to be less frequent but more dangerous, while non-melanoma types, including squamous and basal cell carcinoma, are more prevalent. Caucasian populations are at a higher risk of developing skin cancer due to their skin's susceptibility to ultraviolet (UV) radiation. According to recent data, skin cancer ranks as the seventeenth most common cancer worldwide. An emerging approach to treating skin conditions, including skin cancer, is using niosomes, an advanced drug delivery system. Niosomes are vesicles made from non-ionic surfactants, stabilized by cholesterol, that encapsulate drugs. They have gained prominence because they address several issues related to traditional topical treatments, such as poor solubility, instability, low bioavailability, and rapid drug breakdown. This review article focuses on the use of niosomes in dermatology, particularly for drug delivery through the skin. Niosomes offer several distinct advantages, making them an ideal choice for topical drug delivery. Their unique structure allows them to transport both water-soluble and fat-soluble drugs effectively. Additionally, they enhance drug permeation through the skin, improve drug stability, and allow for extended drug release. These properties make niosomes a valuable tool in clinical settings, providing potential benefits for a range of skin-related therapies. With their growing popularity, niosomes are shaping the future of innovative and more efficient topical drug delivery methods.

Nanosponges : Formulation And Evaluation Of Nanosponges

This review aims that the study of to formulate and evaluate nonosponges as a Novel drug delivery systems, exploiting their potential to improve the biological availability of drug with long half lives. Nanosponges, tiny mesh structure with enhanced ability to encapsulate water and lipid soluble drug, have gained significant attention in the field of pharmaceuticals. These spherical colloidal particles possess a hydrophobic core, allowing for the transport of therapeutic molecules with both hydrophilic and hydrophobic properties composed of 3D network with long -chain polyester backbones and cross -linkers, nonosponges can be synthesized through the treatment of cyclodextrins with appropriate cross-linkers. The study will investigate the physicochemical properties, in-vitro release profile and biological efficiency of nonosponges, providing insights into their potential applications in pharmaceutical technology.

In vitro Analysis of the Pharmaceutical Interactions between Verapamil Hydrochloride and Citric Acid

The objective of this study is to investigate the combination of drug-drug interactions involving different functional groups by assessing the interaction of a BCS class IV compound (Verapamil Hydrochloride) with Citric acid in various ratios, thereby enhancing the understanding of pharmacological implications. This study elucidated the compatibility between Verapamil Hydrochloride (HCl) and Citric acid, demonstrating an approach to enhance the solubility, permeability, and bioavailability of poorly water-soluble drugs in pharmaceutical applications. The method of solvent evaporation was utilized for the preparation of solid dispersions. This process involved dissolving the active pharmaceutical ingredient and citric acid in ethanol, evaporating the solvent to yield a solvent-free film, and mechanically reducing the residue using a mortar and pestle. The resultant fine powder was sieved through a 40-mesh filter and appropriately stored in vials for subsequent analyses. FT-IR spectra and an HPLC-sensitive method were employed to evaluate the solubility profile and interaction dynamics of the compound. FT-IR spectra of VPM HCl and its physical mixtures with citric acid at ratios of 1:3, 1:5, and 1:7 were obtained using an FT-IR spectrophotometer. The spectra revealed structural and functional group alterations, quantified by analyzing the magnitude and cumulative area of the peaks corresponding to the structural constituents. In accordance with the established linearity, the retention times for VPM HCl, Sample 1, Sample 2, and Sample 3 were recorded as 6.8 ± 0.2, 2.7 ± 0.1, 5.5 ± 0.2, and 3.8 ± 0.1 minutes, respectively, across a concentration range of 1–100 µg/mL. For all analytes, the intra-assay and inter-assay biases were observed to be within 15% and 13.4%, respectively. Furthermore, In vitro evaluations of physical combinations of Verapamil HCl and Citric acid samples revealed minimal interaction. These findings emphasize the stability and compatibility of Verapamil HCl and citric acid, demonstrating citric acid’s role as a reliable excipient for enhancing drug solubility and bioavailability without compromising therapeutic integrity.

Preparation of curcumin submicron particles by supercritical antisolvent method with external adjustable annular gap nozzle

The supercritical antisolvent (SAS) method can effectively improve the bioavailability of poorly water-soluble drugs. However, the current supercritical equipment and processes were not fully developed, making industrialization difficult to achieve. Therefore, an externally adjustable annular gap nozzle and its supporting equipment were designed. Curcumin was used as a model drug, ethanol as the solvent, and supercritical carbon dioxide (SC-CO2) as the antisolvent. Building on single-factor experiments, a Box-Behnken Design-Response Surface Methodology (BBD-RSM) was employed to systematically investigate the effects of four process parameters—crystallizer pressure (12–16 MPa), crystallizer temperature (313–323 K), solution concentration (1–2 mg/mL), and CO2/solution flow rate ratio (133–173 g/g)—on the morphology and particle size of curcumin particles. Using scanning electron microscopy (SEM) and dynamic light scattering (DLS) analyses, morphologies and mean diameter ranges were examined. To look into how the SAS process affects TML’s chemical and physical characteristics, X-ray diffraction analysis (XRD) and Fourier-transform infrared spectroscopy (FT-IR) were further performed. Experimental results show that, flow ratio of CO2/solution had the greatest effect of particle size, followed by crystallizer temperature and solution concentration, while crystallizer pressure had the least influence. The optimum process conditions are operational conditions were set with a crystallizer pressure of 15 MPa, crystallizer temperature of 320 K, solution concentration of 1.2 mg/mL, and flow ratio of CO2/solution of 134 g/g, resulting in curcumin submicron particles with an average particle size of 808 nm being obtained. This study demonstrated the feasibility of an externally adjustable annular gap nozzle and its associated equipment in the SAS process, showcasing significant potential for reducing particles size and enhancing the bioavailability of poorly water-soluble drugs.

Mechanistic Insights into Amorphous Solid Dispersions: Bridging Theory and Practice in Drug Delivery.

Improving the bioavailability of poorly water-soluble drugs presents a significant challenge in pharmaceutical development. Amorphous solid dispersions (ASDs) have garnered substantial attention for their capability to augment the solubility and dissolution rate of poorly water-soluble drugs, thereby markedly enhancing their bioavailability. ASDs, characterized by a metastable equilibrium where the active pharmaceutical ingredient (API) is molecularly dispersed, offer enhanced absorption compared to crystalline forms. This review explores recent research advancements in ASD, emphasizing dissolution mechanisms, phase separation phenomena, and the importance of drug loading and congruency limits on ASD performance. Principal occurrences such as liquid-liquid phase separation (LLPS) and supersaturation are discussed, highlighting their impact on drug solubility, absorption and subsequent bioavailability. Additionally, it addresses the role of polymers in controlling supersaturation, stabilizing drug-rich nanodroplets, and inhibiting recrystallization. Recent advancements and emerging technologies offer new avenues for ASD characterization and production and demonstrate the potential of ASDs to enhance bioavailability and reduce variability, making possible for more effective and patient-friendly pharmaceutical formulations. Future research directions are proposed, focusing on advanced computational models for predicting ASD stability, use of novel polymeric carriers, and methods for successful preparations.

Unveiling the impact of preparation methods, matrix/carrier type selection and drug loading on the supersaturation performance of amorphous solid dispersions.

Amorphous solid dispersions (ASDs) are widely recognized for their potential to enhance the solubility of poorly water-soluble drugs, with factors such as molecular mobility, intermolecular interactions, and storage conditions playing critical roles in their performance. However, the influence of preparation methods on their performance remains underexplored, especially regarding their supersaturation performance. To address this gap, the present study systematically investigates ASDs of ibuprofen (IBU, used as a model drug) prepared using two widely utilized techniques (solvent evaporation, SE, and melt-quench cooling, M-QC). Three different matrices/carriers (Soluplus®, SOL, povidone, PVP, and copovidone, PVPVA) were employed to evaluate the combined influence of preparation method, matrix/carrier type, and drug loading on ASD performance. Supersaturation behavior during dissolution, particularly its dependence on the Sink Index (SI), was a key focus. All ASDs showed successful amorphization, but molecular near-order structures differed based on the preparation method. ATR-FTIR spectroscopy revealed stronger molecular interactions in M-QC ASDs (compared to SE). Dissolution studies under supersaturation conditions (SI = 0.1 and SI = 0.2) highlighted significant performance differences. M-QC ASDs consistently exhibited higher in vitro AUC(0→t) values under non-sink conditions compared to crystalline IBU. Conversely, SE ASDs showed improved supersaturation primarily under low SI conditions, especially with SOL at low drug loadings. The findings underscore the need for a systematic approach in developing ASDs, considering preparation method, matrix type, drug loading and dissolution study conditions collectively. These factors significantly influence dissolution behavior and supersaturation, emphasizing that they should not be independently studied but evaluated comprehensively to optimize ASD performance.

Soluplus Stabilized Amorphous Dispersions for Enhanced Oral Absorption of Felodipine.

Overcoming the poor aqueous solubility of small-molecule drugs is a major challenge in developing clinical pharmaceuticals. Felodipine (FLDP), an L-type calcium calcium channel blocker, is a poorly water-soluble drug. The study aimed to explore the potential applications of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus) stabilized amorphous dispersions for augmenting the oral delivery of poorly water-soluble drugs. Soluplus-stabilized amorphous FLDP (FLDP-SSAs) was prepared using a two-phase mixing method. The samples were analyzed for their microscopic and macroscopic behavior using polarized light microscopy (PLM), differential scanning calorimetry (DSC), molecular simulation, and in vitro dissolution studies. Subsequently, the pharmacokinetics of FLDP-SSAs were evaluated. The maximum drug-to-Soluplus mass ratio of FLDP-SSAs was 50:50, with a drug concentration of 8.0 mg/mL. They exhibited an amorphous nature, as confirmed by PLM and DSC. FLDPSSAs generated nanoparticles with a particle size of approximately 50 nm during in vitro dissolution. Compared to FLDP oral solution, FLDP-SSAs exhibited higher solubility due to their amorphous nature and the generation of nanoparticles. The area under the curve (AUC) for oral FLDP-SSAs was 16.7-fold larger than that of the FLDP suspension. FLDP-SSAs could stabilize FLDP in an amorphous state and serve as drug carriers to enhance oral absorption.

Self-Emulsifying Drug Delivery Systems (SEDDS): Transition from Liquid to Solid-A Comprehensive Review of Formulation, Characterization, Applications, and Future Trends.

Self-emulsifying drug delivery systems (SEDDS) represent an innovative approach to improving the solubility and bioavailability of poorly water-soluble drugs, addressing significant challenges associated with oral drug delivery. This review highlights the advancements and applications of SEDDS, including their transition from liquid to solid forms, while addressing the formulation strategies, characterization techniques, and future prospects in pharmaceutical sciences. The review systematically analyzes existing studies on SEDDS, focusing on their classification into liquid and solid forms and their preparation methods, including spray drying, hot-melt extrusion, and adsorption onto carriers. Characterization techniques such as droplet size analysis, dissolution studies, and solid-state evaluations are detailed. Additionally, emerging trends, including 3D printing, hybrid systems, and supersaturable SEDDS (Su-SEDDS), are explored. Liquid SEDDS (L-SEDDS) enhance drug solubility and absorption by forming emulsions upon contact with gastrointestinal fluids. However, they suffer from stability and leakage issues. Transitioning to solid SEDDS (S-SEDDS) has resolved these limitations, offering enhanced stability, scalability, and patient compliance. Innovations such as personalized 3D-printed SEDDS, biologics delivery, and targeted systems demonstrate their potential for diverse therapeutic applications. Computational modeling and in silico approaches further accelerate formulation optimization. SEDDS have revolutionized drug delivery by improving bioavailability and enabling precise, patient-centric therapies. While challenges such as scalability and excipient toxicity persist, emerging technologies and multidisciplinary collaborations are paving the way for next-generation SEDDS. Their adaptability and potential for personalized medicine solidify their role as a cornerstone in modern pharmaceutical development.

Physical isolation strategy in multi-layer self-nanoemulsifying pellets: Improving dissolution and drug loading efficiency of ramipril.

Liquid self-nanoemulsifying drug delivery systems (SNEDDS) face challenges related to stability, handling, and storage. In particular, lipophilic and unstable drugs, such as ramipril (RMP) and thymoquinone (THQ), face challenges in oral administration due to poor aqueous solubility and chemical instability. This study aimed to develop and optimize multi-layer self-nanoemulsifying pellets (ML-SNEP) to enhance the stability and dissolution of ramipril (RMP) and thymoquinone (THQ). Liquid SNEDDS containing RMP and black seed oil (as a natural source of THQ) were prepared and characterized. The fluid-bed coating process was optimized by evaluating critical parameters such as inlet temperature, product temperature, air flow rate, atomizing air pressure, spray rate, and column height. Single-layer (SL-SNEP) and multi-layer (ML-SNEP) self-nanoemulsifying pellets were developed by applying various functional layers onto nonpareil sugar spheres. The pellets were characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and in vitro dissolution studies. Optimized fluid-bed coating parameters resulted in high coating recovery (>80%) and excellent mono-pellet percentages (≥97%). SEM analysis revealed well-defined, completely solidified layers in ML-SNEP. DSC and XRD studies suggested RMP amorphization. In vitro dissolution studies showed >86% RMP and THQ release within 60 minutes for both SL-SNEP and ML-SNEP. The physical isolation strategy significantly improved drug loading efficiency, with ML-SNEP showing 109% RMP loading efficiency compared to 55% in SL-SNEP. The addition of moisture sealing and anti-adherent layers had no negative impact on drug release, with SNEP-5L (including the anti-adherent layer) showing higher dissolution efficiency for both RMP and THQ. This study successfully developed and optimized ML-SNEP as a novel approach for enhancing the stability and release of RMP and THQ. The physical isolation strategy was a key approach in enhancing drug loading efficiency while preserving the advantageous dissolution properties of liquid SNEDDS. This approach offers valuable insights for developing advanced oral drug delivery systems for poorly water-soluble and labile drugs.

Development of hyaluronic acid/β-cyclodextrin semi-interpenetrating network hydrogels for prolonged delivery of water-soluble sunitinib malate.

Sunitinib malate (SUM), widely used in cancer treatment for its anti-VEGF properties, has also been explored for ocular neovascular diseases. For ocular applications, sustained drug release is essential to reduce dosing frequency. Hyaluronic acid (HA)-based hydrogels are commonly used for controlled drug delivery, but their hydrophilicity leads to rapid drug diffusion, especially for water-soluble drugs like SUM. To address this, β-cyclodextrin (β-CD) polymers (2-300kDa) were incorporated into tyramine-conjugated HA (HA-TA) (200-400kDa) networks to extend drug release via the formation of host-guest inclusion complexes. SUM-CD intermolecular interactions were identified and characterised by 1H NMR and FTIR spectroscopies, and NOESY spectra further confirmed a 1 SUM: 2 β-CD inclusion complex. β-CD polymers (10% w/v) were integrated into HA-TA (0.25, 0.5, 1% w/v) networks enzymatically crosslinked using horseradish peroxidase and hydrogen peroxide, forming semi-interpenetrating polymer network hydrogels. These gels exhibited faster gelation, enhanced swelling behaviour, higher drug loading capacity, a denser matrix, and a longer SUM release duration compared to HA-TA hydrogels. In an in vitro flow model, post-gelation loading of SUM led to a longer release duration than pre-loading, with release continuing over 20days. The HA-CD semi-IPN hydrogel therefore warrants further exploration for its potential ocular applications.

Effect of polyoxylglycerides-based excipients (Gelucire®) on ketoprofen amorphous solubility and crystallization from the supersaturated state

Polyoxylglycerides-based solid mixtures, commercially known as Gelucire®, are excipients commonly used for bioavailability improvement of poorly water-soluble drugs. However, their effect on solutions containing hydrophobic drugs above crystalline solubility has not yet been explored. The goal of this study was to investigate the impact of a mix of two commercial Gelucire® with high HLB values (Gelucire®50/13 and Gelucire®48/16) on the amorphous solubility and crystallization from supersaturated solutions of ketoprofen, used as model drug. The results evidenced a strong interaction between Gelucire® components and the drug-rich nanodroplets generated upon liquid–liquid phase separation. This led to two important consequences: on one hand, the drug amorphous solubility was decreased, together with the amorphous-to-crystalline solubility ratio; on the other hand, the enlargement and coalescence of the drug-rich droplets were prevented. This stabilizing effect towards the drug-rich phase was comparable to, or even stronger than, that obtained with traditional amorphous polymers (PVP or HPMC) and contributed to inhibiting drug crystallization. Notably, the impact of Gelucire® on drug crystallization from the supersaturated state depended on its micellar behaviour: the monomeric form (below 50 μg/mL) accelerated the formation of crystals, whereas pre-micellar aggregates (50–500 μg/mL) and solubilizing micelles (above 500 μg/mL) inhibited drug crystallization. These findings will contribute to a better understanding of the behaviour of supersaturated drug solutions in the presence of Gelucire® and will facilitate the rational design of supersaturating drug delivery systems containing these excipients.

Design of indomethacin novel small molecule hydrogels for concomitant release and permeability increases.

With the expansion of gel research, organic small molecule gels are beginning to gain attention. Whether the small-molecule gel approach can be a new formulation strategy of solubilization and permeation promotion for poorly soluble drugs needs to be explored in this study. The model ingredient indomethacin (IND) as a nonsteroidal anti-flammatory drug shows limited therapeutic application mainly due to its low water solubility. Herein, the IND small molecule hydrogel was design to co-formed with a small molecule ligand by integrating theory-model-experiment techniques. Then, the formed IND small molecule hydrogels (i.e., IND-MEG hydrogel and IND-ARG hydrogel) with meglumine (MEG) or arginine (ARG) appeared typical 3-D network with good rheology. In comparison to crystalline IND, the solubilities of IND-MEG hydrogel and IND-ARG hydrogel exhibited 506.71-fold and 479.63-fold improvements, respectively. Meanwhile, both IND hydrogels performed significantly enhanced release rate and degree, and maintained supersaturation for a long time arising from the complexation reaction of IND and ligand, which was revealed by phase solubility and fluorescence quenching studies. Furthermore, the designed IND hydrogels significantly promoted IND membrane permeability compared to the commercial IND hydrogel, and enhanced the development potential of novel IND hydrogels for oral and transdermal applications. Therefore, this study provides a new formulation technique to increase the solubility/release and permeability of poorly water-soluble drugs by designing their small molecule hydrogel systems.

Characterization of Alpha Mangostin Loaded-Mesoporous Silica Nanoparticle and the Impact on Dissolution and Physical Stability.

Improving drug solubility is crucial in formulating poorly water-soluble drugs, especially for oral administration. The incorporation of drugs into mesoporous silica nanoparticles (MSN) is widely used in the pharmaceutical industry to improve physical stability and solubility. Therefore, this study aimed to elucidate the mechanism of poorly water-soluble drugs within MSN, as well as evaluate the impact on the dissolution and physical stability. Alpha mangostin (AM) was adopted as a model of a poorly water-soluble drug, while MSN with the pore size of 45 Å (MSN45) and 120 Å (MSN120) were used as Mesoporous materials. AM-loaded MSN (AM/MSN45 and AM/MSN120) was prepared by solvent evaporation method. The amorphization of AM/MSN45 and AM/MSN120 was confirmed by the halo pattern observed in the powder X-ray diffraction pattern and the absence of the melting peak and the glass transition of AM in the DSC curves. This signified the successful incorporation of AM into MSN. FT-IR measurements suggested the formation of hydrogen bond interaction between the carbonyl group of AM and the silica surface of MSN. In the dissolution test, the presence of the AM within MSN improved the dissolution rate and generated the supersaturation of AM. However, the difference of pores size of MSN could affect the dissolution profile of AM within MSN. Additionally, it retained the X-ray halo patterns after 30 d of storage at 25 oC and 0% RH. In conclusion, AM-loaded mesoporous silica significantly improved the dissolution and physical stability.