Soluble Drugs Research Articles

Machine learning based modeling for estimation of drug solubility in supercritical fluid by adjusting important parameters

Here, we employed machine learning models to predict how well Capecitabine drug would dissolve in supercritical carbon dioxide as the green solvent. The vision is to investigate the drug suitability for processing of nanodrugs with enhanced bioavailability in the body. In the employed data set, P (pressure) and T (temperature) serve as inputs, and Y, the solubility, is the only output for building the models. This study uses DT (Decision Tree) and MLP (Multilayer perceptron) as the core models. However, the raw and individual form of conventional algorithms may not provide accurate and general results. Ensemble methods like boosting improve the model performance. Also, single and ensemble models mounted on these models have hyper-parameters whose optimization affects the final models. Meta-heuristic algorithms are popular for tuning hyper-parameters. In this research, we used a new hybrid framework by coupling the basic models with the Adaboost algorithm (as an ensemble method) and PO and CS algorithms (as optimizers) to obtain four different models. The MLP model boosted with Adaboost and tuned with PO algorithm showed the best fitting accuracy among all models. This model reduces the RMSE error rate to 1.71, MSE to 2.92, and MAE to 1.42.

An updated landscape on nanopharmaceutical delivery for mitigation of colon cancer.

Globally, colorectal cancer (CRC) continues to rank among the leading causes of cancer-related death. Systemic toxicity, multidrug resistance, and nonspecific targeting often pose challenges to conventional therapy for CRC. Because it is a complex disease with a complex genetic and environmental pathophysiology, advanced therapeutic strategies are needed. Nanotechnology presents a potential solution that may maximize therapeutic efficacy while minimizing negative effects by enabling personalized delivery of anticancer drugs. This review focuses on recent developments in colorectal drug delivery systems based on nanotechnology. Numerous nanomaterials, including liposomes, dendrimers, micelles, exosomes, and gold nanoparticles, are developed and used. Distinctive characteristics of mentioned nanocarriers are discussed along with strategies that can be employed for enhancing the delivery of drugs to colorectal cancer cells. The review also quotes the most relevant preclinical and clinical studies that show how these nanomaterials improve drug solubility, stability, and targeted delivery while overcoming the shortcomings of conventional therapies. Nanotechnology has made CRC treatment very efficient and advanced, which has opened up new possibilities for targeted drug delivery. Preclinical and clinical studies have also proved that the use of nano-formulations in colon-specific delivery systems have significant results, indicating potential for better patient outcomes. Future research can be done in order to overcome the hurdles regarding biocompatibility, expansion, and regulatory challenges. Large-scale clinical trials and nanomaterial formulation optimization should be the main goals of future research to confirm the efficacy and safety of these novel treatments.

Inhibition of HIV-1 infection with curcumin conjugated PEG-citrate dendrimer; a new nano formulation

BackgroundNano-drug delivery systems have become a promising approach to overcoming problems such as low solubility and cellular uptake of drugs. Along with various delivery devices, dendrimers are widely used through their unique features. PEG-citrate dendrimers are biocompatible and nontoxic, with the ability to improve drug solubility. Curcumin, a naturally occurring polyphenol, has multiple beneficial properties, such as antiviral activities. However, its optimum potential has been significantly hampered due to its poor water solubility, which leads to reduced bioavailability. So, the present study attempted to address this issue and investigate its antiviral effects against HIV-1.MethodThe G2 PEG-citrate dendrimer was synthesized. Then, curcumin was conjugated to it directly. FTIR, HNMR, DLS, and LCMS characterized the structure of products. The conjugate displayed an intense yellow color. In addition, increased aqueous solubility and cell permeability of curcumin were achieved based on flow cytometry results. So, it could be a suitable vehicle for improving the therapeutic applications of curcumin. Moreover, cell toxicity was assessed using XTT method. Ultimately, the SCR HIV system provided an opportunity to evaluate the level of HIV-1 inhibition by the curcumin-dendrimer conjugate using a p24 HIV ELISA kit.ResultsThe results demonstrated a 50% up to 90% inhibition of HIV proliferation at 12 μm and 60 μm, respectively. Inhibition of HIV-1 at concentrations much lower than CC50 (300 µM) indicates a high potential of curcumin-dendrimer conjugate against this virus.ConclusionThereby, curcumin-dendrimer conjugate proves to be a promising tool to use in HIV-1 therapy.

Nanoemulsions of betulinic acid stabilized with modified phosphatidylcholine increase the stability of the nanosystems and the drug's bioavailability

Betulinic acid (BA) is a natural compound with significant potential for treating various diseases, including cancer and AIDS, and possesses additional anti-inflammatory and antibacterial properties. However, its clinical application is limited because of its low solubility in water, which impairs its distribution within the body. To overcome this challenge, nanoemulsions have been developed to improve the bioavailability of such poorly soluble drugs. This study investigated modified phosphatidylcholine (PC), where some fatty acids were replaced with conjugated linoleic acid (CLA) to stabilize BA nanoemulsions. The modified PC was used to prepare nanoemulsions with droplet sizes of up to 45 nanometers. These nanoemulsions maintained stability for 60 days at room temperature (25°C±2°C) and under refrigeration (5°C±1°C), with no signs of instability. Nanoemulsions stabilized with CLA-modified PC achieved a higher drug encapsulation rate (93.5±4.3 %) than those using natural PC (82.8±4.2 %). In an in vivo model, both nanoemulsion formulations significantly increased BA absorption, with CLA-modified PC enhancing absorption by 21.3±1.3 times and natural PC by 20±2.3 times compared to the free drug. This suggests that nanoemulsions with modified PC could improve the stability and efficacy of BA in clinical applications.

Mechanisms of drug release from a melt-milled, poorly soluble drug substance

Increasing the dissolution kinetics of low aqueous soluble drugs is one of the main priorities in drug formulation. New strategies must be developed, which should consider the two main dissolution mechanisms: surface reaction and diffusion.One promising tool is the so-called solid crystal suspension, a solid dispersion consisting of purely crystalline substances. In this concept, reducing the drug particle size and embedding the particles in a hydrophilic excipient increases the dissolution kinetics. Therefore, a solid crystal suspension containing submicron drug particles was produced via a modified stirred media milling process. A geometrical phase-field approach was used to model the dissolution behavior of the drug particles.A carrier material, xylitol, and the model drug substance, griseofulvin, were ground in a pearl mill. The in-vitro dissolution profile of the product was modeled to gain a deep physical understanding of the dissolution process. The used numerical tool has the potential to be a valuable approach for predicting the dissolution behavior of newly developed formulation strategies.

Impact of sink conditions on drug release behavior of controlled-release formulations

Developing a controlled release (CR) formulations is a complex and iterative process, often requiring preclinical or clinical studies to establish in vitro-in vivo correlations. This can be particularly challenging for poorly soluble drugs due to the non-sink conditions encountered in vitro. Although compendial dissolution methods (e.g., USP II, IV) have historically been used to understand the dissolution performance of CR formulations, there is increasing interest in more physiologically relevant experimental techniques to improve the predictive ability. In this study, traditional USP apparatus as well as the biorelevant absorptive dissolution apparatus were employed to understand the impact of apparatus type and sink condition on the release mechanisms of CR formulations and in turn evaluate the application of absorptive dissolution apparatus for dissolution testing of CR formulations. Release mechanisms were further analyzed using the Peppas equations, providing additional mechanistic insights. The release behavior showed a strong dependence on sink conditions for drugs with low intrinsic solubility, while highly soluble drugs were unaffected by dissolution conditions. Interestingly, the dissolution mechanism was found to be independent of the apparatus type. The study clearly underscores the importance of considering the sink conditions in developing more predictive and biorelevant dissolution testing methods for CR formulations. Furthermore, the study highlights the potential impact on the sink and resultant differences in the drug release mechanisms as a function of the dose.

Optimization of drug solubility inside the supercritical CO2 system via numerical simulation based on artificial intelligence approach

In this research paper, we explored the predictive capabilities of three different models of Polynomial Regression (PR), Extreme Gradient Boosting (XGB), and LASSO to estimate the density of supercritical carbon dioxide (SC-CO2) and the solubility of niflumic acid as functions of the input variables of temperature and pressure. The optimization of hyperparameters for these models is achieved using the innovative Barnacles Mating Optimizer (BMO) algorithm. For SC-CO2 density estimation, PR exhibits remarkable accuracy, showing an R-squared value of 0.99207 for data fitting. XGB performs admirably with an R2 of 0.92673, while LASSO model demonstrates good predictive ability, showing an R2 of 0.81917. Furthermore, we assess the models’ performance in predicting the solubility of niflumic acid. PR exhibits excellent predictive capabilities with an R2 of 0.96949. XGB also delivers strong performance, yielding an R-squared score of 0.92961. LASSO performs well, achieving an R-squared score of 0.82094. The results indicated promising performance of machine learning models and optimizer in estimating drug solubility in supercritical CO2 as the solvent applicable for pharmaceutical industry.

Berberine-Loaded PVCL-PVA-PEG Self-Assembled Micelles for the Treatment of Liver Fibrosis.

Liver fibrosis is a necessary pathological process in many chronic liver diseases. Studies have shown that the progression of chronic liver disease can be slowed by rational intervention in hepatic fibrosis. Berberine (BBR), a natural extract of Phellodendron amurense, inhibits the development of liver fibrosis through several mechanisms. However, the clinical application of BBR is limited due to its low solubility. Drug delivery systems have been developed to improve the solubility of hydrophobic drugs and increase their efficacy in treating the liver fibrosis. In this study, a biocompatible nanomicelle was constructed by thin-film dispersion method using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG) as a carrier to encapsulate BBR (PVCL-PVA-PEG/BBR-MCs) to improve the solubility of BBR and reduce the systemic side effects. The ability to inhibit HSC-T6 cell activation of PVCL-PVA-PEG/BBR-MCs was evaluated in vitro. The anti-hepatic fibrosis effects of PVCL-PVA-PEG/BBR-MCs were investigated in vivo. PVCL-PVA-PEG/BBR-MCs have a uniform spherical shape with a mean particle size of 60.04 ± 0.027 nm and a potential of 1.49 ± 0.32 mV. It had an encapsulation efficiency of 98.52% ± 0.70 and drug loading content of 6.16% ± 0.04. Compared to free BBR, PVCL-PVA-PEG/BBR-MCs significantly inhibited HSC-T6 cell activation and TGF-β1-induced HSC-T6 cell migration in vitro. In vivo biodistribution experiments showed significantly improved hepatic distribution of PVCL-PVA-PEG/DiD-MCs compared to free DiD, suggesting that PVCL-PVA-PEG micelles enhance the ability of BBR to enter the liver and improve therapeutic efficacy. After treatment, PVCL-PVA-PEG/BBR-MCs significantly improved fibrotic liver structure and reduced collagen deposition in comparison to the CCl4-treated group; the treatment outcome was more effective than that of the free BBR group. Our results demonstrate the advantages of encapsulating BBR in PVCL-PVA-PEG micelles and highlight the potential of PVCL-PVA-PEG/BBR-MCs as a therapeutic strategy for the treatment of liver fibrosis.

An Advanced Hydrogel Dressing System with Progressive Delivery and Layer-to-Layer Response for Diabetic Wound Healing

Wound healing in diabetic patients presents a significant challenge due to delayed inflammatory responses, which obstruct subsequent healing stages. In response, we have developed a progressive, layer-by-layer responsive hydrogel, specifically designed to meet the dynamic requirements of diabetic wounds throughout different healing phases. This hydrogel initiates with a glucose-responsive layer formed by boronate ester bonds between 4-arm-poly (ethylene glycol) succinimidyl glutarate (4arm-PEG-SG) and 3-aminophenylboronic acid. This configuration ensures precise control over the physicochemical properties, facilitating accurate drug release during the healing process. Furthermore, we have incorporated an active pharmaceutical ingredient ionic liquid (API) composed of diclofenac and L-carnitine. This combination effectively tackles the solubility and stability issues commonly associated with anti-inflammatory drugs. To further refine drug release, we integrated matrix metalloproteinase-9 (MMP-9)-sensitive gelatin microcapsules, ensuring a controlled release and preventing the abrupt, uneven drug distribution often seen in other systems. Our hydrogel's rheological properties closely resemble human skin, offering a more harmonious approach to diabetic wound healing. Overall, this progressive layer-by-layer responsive wound management system, which is a safe, efficient, and intelligent approach, holds significant potential for the clinical treatment of diabetic wounds. Statement of SignificanceThe two main problems of diabetic wounds are the long-term infiltration of inflammation and the delayed repair process. In this experiment, a glucose-responsive hierarchical drug delivery system was designed to intelligently adjust gel properties to meet the needs of inflammation and repair stage of wound healing, accelerate the transformation of inflammation and repair stage, and accelerate the process of repair stage. In addition, in order to achieve accurate drug release in anti-inflammatory layer hydrogels and avoid sudden drug release due to poor solubility of anti-inflammatory small molecule drugs, we constructed a ionic liquid of active pharmaceutical ingredients (API-ILs) using diclofenac and L-carnitine as raw materials. It was wrapped in MMP-9 enzyme active gelatin microcapsule to construct a double-reaction anti-inflammatory layer gel to achieve accurate drug release. These findings highlight the potential of our system in treating diabetic wounds, providing a significant advance in wound treatment.

Effect of biosurfactants on the self-assembly behavior and drug encapsulation for branched block copolymers

For the past few years, block copolymers have attracted extensive attention in the field of drug delivery. In this work, the hyperbranched PEO-PPO block copolymer H1304 having the same PEO segments and PPO segments as the commercially available 4-branched block copolymer Tetronic1304 was synthesized. Compared with T1304, H1304 was characterized by lower cloud point, smaller critical micelle concentration (CMC), larger micellar size and better drug solubilization capacity. The effect of three biosurfactants lecithin (PC), alkyl glycogen (APG), sodium deoxycholate (NaDC) on the aggregation behavior of H1304 and T1304 were researched. Meanwhile, the solubilization and in vitro release properties of hydrophobic anticancer drug podophyllotoxin were also evaluated. The addition of PC or APG to form a mixed micelle reduced the cloud point and CMC, optimized the drug carrier characteristics. NaDC exhibited different effects due to its unique disclike surface structure. NaDC formed back-to-back aggregates, which interfered the self-assembly process of block copolymer and in turn caused variation of the copolymer micellar properties. The study of mixed systems consisting of biosurfactants and block copolymers will help to change the performance of copolymers in various pharmaceutical fields and contribute to the application of copolymers as drug carriers in drug delivery systems.

Dissolution, phase behavior and mass transport of amorphous solid dispersions in aspirated human intestinal fluids

Amorphous solid dispersions (ASDs) typically show improved dissolution and generate supersaturated solutions, enhancing the oral bioavailability of poorly soluble drugs. To gain insights into intraluminal ASD behavior, we utilized two poorly soluble drugs with different crystallization tendencies, atazanavir and posaconazole, prepared as ASDs at a 10% drug loading with hydroxypropyl methylcellulose acetyl succinate (HPMCAS). We evaluated their release in aspirated fasted-state human intestinal fluid (FaHIF), and multi-component fasted-state simulated intestinal fluid (composite-FaSSIF), characterizing the supersaturation profiles and drug-rich nanodroplets that formed. Complete release was observed for atazanavir ASDs over a 90 min period. Flux for dissolved atazanavir ASDs remained high over the experimental time period of 3 h. In contrast, posaconazole solution concentrations were initially high and then decreased. Likewise, flux was initially high and then decreased where these changes are attributed to crystallization of the drug. Generation of spherical nano-sized amorphous droplets of ∼100-150 nm was found to occur in ex vivo FaHIF media for both ASDs, maximizing the diffusive flux during the supersaturation window. Moreover, buffer capacity differences were postulated to influence release rates of ASDs in simulated vs aspirated fluids. Importantly, the solution phase phenomena observed during ASD release in simulated fluids, namely amorphous nanodroplet formation and drug crystallization, were also found to occur in aspirated luminal fluids.

Bridging the gap between in vitro and in vivo solubility-permeability interplay

Use of solubilization carriers for poorly soluble drugs may disturb transmembrane absorption by lowering the activity of drug molecules, which is known as the solubility-permeability interplay. However, although many in vitro studies have indicated the negative impacts of use of solubilization carriers for oral absorption, in vivo studies that showed the interplay effect are limited. This study provides systematic in vitro, in situ, and in vivo investigation of the interplay effect of cyclodextrin using dexamethasone as a model drug. The evaluation methods included permeation through polymeric, artificial lipid, cell, and intestinal closed-loop membranes. Then, the results were compared with oral administration studies in mice and dogs. Although the interplay effect was clearly observed in the in vitro studies, no obvious interplay was found in the in vivo studies, suggesting that the interplay effect is more prominent in the in vitro permeation studies. Absence of in vivo interplay was attributed to the dilution effect in the gastrointestinal tract, interaction of the drug with living components, and clearance of the drug after membrane permeation. Overall, this investigation clearly demonstrated the applicability and limitations of in vitro permeation studies for predicting the interplay effects of solubilizers after the oral administration.

ω-Carboxyl terminated cellulose esters are effective crystallization inhibitors for challenging drugs

Polymeric additives are widely used to delay drug crystallization from supersaturated solutions, which is critical for enhancing oral bioavailability by amorphous solid dispersion (ASD). The efficacy of these polymers relies on their capacity to inhibit nucleation and subsequent crystal growth. Drug nucleation is pivotal to crystallization; therefore, effective polymers are essential for suppressing nucleation from supersaturated solutions. We studied the performance of cellulose ω-carboxyalkanoates designed as crystallization inhibitors by measuring their influence on nucleation induction times of poorly soluble drugs celecoxib, posaconazole, and enzalutamide, from supersaturated solutions. In the absence of polymers, crystallization occurred within 5 to 15 minutes for all three drugs. Polymer hydrophobicity strongly influenced effectiveness in crystallization inhibition. Hydrophobic polymers prolonged induction times for up to 8 hours, while hydrophilic polymers were less effective, except for cellulose acetate glutarate (CA1.18-GA1.21; degrees of substitution acetate 1.18, glutarate 1.21). The cellulose ω-carboxyalkanoates had glass transition temperatures well above 100 °C, outstanding for ASD stability requirements. We investigated the impact of these designed polymers on surface tension and found that it only weakly influenced crystallization inhibition. Among the nine crafted cellulose derivatives, water-soluble CA1.18-GA1.21 emerged as a highly promising ASD polymer, preventing crystallization for 2-8 hours for all fast-crystallizing model compounds.

Formulation optimization of chitosan surface coated solid lipid nanoparticles of griseofulvin: A Box-Behnken design and in vivo pharmacokinetic study.

Solid lipid nanoparticles (SLNs) are becoming increasingly favored for their robust biocompatibility and their capacity to enhance drug solubility, particularly for drugs with limited water solubility. This study delves into the effectiveness of the hot melt sonication technique in fabricating SLNs with high drug loading capabilities and sustained release characteristics. Griseofulvin (GF), chosen as a representative drug due to its poor water solubility, was encapsulated into SLNs composed of stearic acid. Optimization of chitosan-coated GF-loaded SLNs (CS-GF-SLN) was conducted using a Box-Behnken design. Utilizing the desirability approach, optimal parameters were determined, including a lipid quantity of 450.593 mg, chitosan content of 268.67 mg, and sonication duration of 2.14 hours. These parameters resulted in a zeta potential of -34.8 mV and a particle size (PS) of 56.87 nm. Following optimization, the refined formulation underwent comprehensive assessment across various parameters. Notably, the drug encapsulated within SLNs exhibited sustained release over three days, as illustrated by the in-vitro drug release profile. The optimized formulation demonstrated a bioavailability enhancement by approximately 1.7 to 2.0 times compared to the conventional formulation. Furthermore, administration of drug-loaded SLNs to a macrophage cell line demonstrated no cytotoxicity, affirming their suitability as conventional drug delivery platforms for GF.

REVIEW ARTIKEL: PENINGKATAN KELARUTAN SENYAWA OBAT ANTIMALARIA MENGGUNAKAN METODE MODIFIKASI KO-KRISTAL

Malaria is an infectious disease caused by the Plasmodium parasite that infects humans through the bite of female Anopheles mosquitoes. Most antimalarial drugs have limitations in terms of solubility. Drug solubility is a very important parameter that determines the effectiveness of the drug, with good drug solubility, the drug can achieve optimal bioavailability and pharmacological effects, based on this, efforts are needed to overcome these problems in order to provide effective and efficient therapy to patients using existing antimalarial drugs that have been modified in their physicochemical properties so that their solubility increases. The purpose of this study was to review various studies that used the co-crystal modification method to increase the solubility of antimalarial drug compounds. This study was designed using the Narrative Review method, article searches were carried out using two databases, namely Google Scholar and PubMed, with the keywords "Co-crystal" OR "Antimalaria". In this study, 7 articles were found that met the inclusion and exclusion criteria. The selected articles are articles that discuss antimalarial drugs (artesunate, artemisinin, pyrimethamine) developed by the co-crystal method which experienced a multi-fold increase in solubility compared to its pure preparation. The co-crystal method can be a solubility enhancing solution for antimalarial drugs that have low solubility in water, increasing the solubility of antimalarial drugs causes the bioavailability of the drug to increase, so that the drug can provide good therapeutic effects.

Beyond Creams and Gels: The Emergence of Emulgels in Pharmaceutical Science

Background: Emulgels combine the properties of emulsions and gels, offering a unique drug delivery system that enhances the solubility and stability of hydrophobic drugs. This study reviews recent advancements in emulgels and their potential in pharmaceutical applications. Objective: To systematically review the current state of research on emulgels, focusing on formulation techniques, characterization methods, and therapeutic applications. Methods: A comprehensive literature search was conducted using databases such as PubMed, Scopus, and Web of Science, covering studies published from 2010 to 2023. Inclusion criteria included articles discussing formulation techniques, characterization, and therapeutic applications of emulgels. Data extraction and quality assessment were performed independently by two reviewers. Results: Various formulation techniques, such as high-energy emulsification, phase inversion, and solvent evaporation, have been explored to enhance the bioavailability of hydrophobic drugs. Recent advancements introduced novel methods like microfluidization and ultrasound-assisted emulsification to improve formulation efficiency. Characterization techniques, including rheological analysis, particle size determination, and drug release studies, are crucial for optimizing emulgel formulations. Several patents have been filed, reflecting innovative approaches in emulgel technology, such as incorporating nanomaterials and targeted delivery systems. Therapeutic applications of emulgels have been extensively studied in dermatology, pain management, and antimicrobial therapy, showing promising results in enhancing drug efficacy and patient compliance. Conclusion: Emulgels present a versatile and efficient drug delivery system with significant potential in various therapeutic areas. Future research should focus on the large-scale production of emulgels and their long-term stability to facilitate their transition from research to clinical practice.

Anticancer Activities of Synthesized Niosome Nanoparticles Using Artemisia Annua Extract: Caspase3 and Caspase9 Apoptosis Gene Expression Analysis in Breast Cancer Cell Line (MCF-7)

Introduction: Pharmaceutical formulation of nanoparticles is widely used due to achieving targeted and stable drug release, improving drug solubility and reducing side drug reactions. One of the ways to improve the survival of cancer patients is the treatment using nanocarriers for anticancer drugs. The aim of this study was to synthesize encapsulated nisomes containing the extract of the Artemisia annua and investigate the anticancer and apoptotic effects against breast cancer cell lines. Methods: In this study, a Niosomes nanocarrier was made and then the extract of Gondwash herb was loaded into it. Its physical and chemical properties were confirmed using SEM, dynamic light scattering (DLS) and zeta potential. Likewise, the encapsulation percentage and release pattern of the extract were investigated. Finally, its anticancer effects against the breast cancer cell line (MCF_7) were investigated and the expression level of apoptotic genes Caspase3 and Caspase9 was studied using Real Time PCR method. At the end, statistical analysis was done by GraphPad Prism software, and cytotoxicity and gene expression data were analyzed by one-way analysis of variance. Results: The findings showed that the synthesized nanocarrier newsom containing the extract had a spherical structure and its size was 208.1 nanometers, the encapsulation percentage was 62.35% and the surface charge was 22.5. Similarly, newsome nanocarrier containing the extract had significant anticancer effects compared to the free extract and increased the expression of caspase 3 and caspase 9 genes by 1.184 ± 0.34 (P<0.05) and 1.68 ± 0.81, respectively. (P<0.05). Conclusion: The results showed that the nisome containing the extract of the Gondwash herb increases the anti-cancer and apoptotic effects significantly, and therefore, with further studies in the future, nisome can be used as a targeted drug delivery system for anti-cancer purposes.

The Particle Drifting Effect: A Combined Function of Colloidal and Drug Properties.

The particle drifting effect, where nanosized colloidal drug particles overcome the diffusional resistance of the aqueous boundary layer adjacent to the intestinal wall and increase drug absorption rates, is drawing increasing attention in pharmaceutical research. However, mechanistic understanding and accurate prediction of the particle drifting effect remain lacking. In this study, we systematically evaluated the extent of the particle drifting effect affected by drug and colloidal properties, including the size, number, and type of the moving species using biphasic diffusion experiments combined with computational fluid dynamics simulations and mass transport analyses. The results showed that the particle drifting effect is a sequential reaction of particle dissolution/dissociation in the diffusional boundary layer, followed by absorption of the free drug. Therefore, factors affecting the rate-limiting step, which can be either process or both under different circumstances, alter the particle drifting effect. Experimental results also agree with the theory that the particle dissolution rate is dependent on particle size, concentration, and drug solubility. In addition, rapid bile micelle dissociation and bile salt absorption facilitated drug absorption by the particle drifting effect. Our findings explain the highly dynamic nature of the particle drifting effect and will contribute to rational formulation development and better bioavailability prediction for formulations containing colloidal particles.

Unlocking Drug Potential by Enhancing Poor Drug Solubility and Bioavailability through Hot-Melt Extrusion

Unlocking Drug Potential by Enhancing Poor Drug Solubility and Bioavailability through Hot-Melt Extrusion

Determination of morphine sulfate anti-pain drug solubility in supercritical CO2 with machine learning method

Accurate solute solubility measuring and modeling in supercritical carbon dioxide (ScCO2) would address the best working conditions and thermodynamic boundaries for material processing with this type of fluid. Theory- and data-driven methods are two general modeling approaches. Using theory-driven methods, the solubility is estimated based on the principles of thermodynamics, while data-driven methods are developed by training the algorithms. Despite acceptance of each of these methods, more experimental solubility data are still needed to promote modeling performances. In this study, for the first time, solubility of morphine sulfate is determined and modeled by a set of 13 semi-empirical (theory-driven) and random forest (data-driven) models. Using a laboratory system with an ultraviolet-visible (UV-Vis) spectroscopy, the experimental solubilities including 48 data points were obtained at different temperatures (308–338 K) and pressures (12–27 MPa). The minimum (0.806 × 10−5) and maximum (5.902 × 10−5) equilibrium mole fractions were observed at working pressures of 12 and 27 MPa, respectively, both at the same temperature of 338 K. It was indicated that random forest model (with AARD% of 1.29%) had an excellent predictive performance against semi-empirical models (with AARD% from 9.33 to 19.76%). The results showed that solute molecular weight had the highest effect on random forest modeling. Using modeling results from Chrastil and Bartle models, total and vaporization enthalpies of dissolution of morphine sulfate in ScCO2 were found to be 35.12 and 59.04 kJ/mole, respectively.