Solubilization Technology Research Articles

Novel Fimasartan Fluidized Solid Dispersion and Its Tablet: Preparation, Crystallinity, Solubility, Dissolution, and Pharmacokinetics in Beagle Dogs.

Fimasartan, an angiotensin II receptor antagonist, exhibits low bioavailability due to its poor solubility; consequently, using solubilization technologies is essential to improve its bioavailability. In this study, novel fimasartan fluidized solid dispersion (FFSD) was developed using a fluid bed granulator to enhance the drug solubility andoral bioavailability. An appropriate FFSD was prepared in 50% ethanol using a fluid bed granulator, and its drug dissolution, morphology, and crystallinity were evaluated in comparison to the powdered drug. Moreover, the dissolution in various pH conditions and pharmacokinetics of the FFSD tablet in beagle dogs were investigated compared to the commercial fimasartan tablet. Among the hydrophilic polymers tested, hydroxypropyl methylcellulose (HPMC)showed the highest solubility. The FFSD, composed of fimasartan, HPMC, and microcrystalline cellulose at the weight ratio of 20:10:25, gave a granular aggregation of several particles with a smooth surface. The drug in this FFSD existed as an amorphous state, leading to a greatly increased drug dissolution. The FFSD tablet was prepared by compressing a mixture of FFSD, mannitol, croscarmellose sodium, and magnesium stearate at the weight ratio of 55:40:5:1. The FFSD tablet gave significantly higher drug dissolution, plasma concentrations, maximum plasma concentration (Cmax) andarea under the whole blood concentration-time curve (AUC) values than did the commercial fimasartan tablet. In the beagle dogs, the FFSD tablet (140.39±27.40ng·h/ml) had about a 1.7-fold higher AUC than the commercial fimasartan tablet (80.58±22.18 ng·h/ml), indicating an enhancement in thebioavailability. This novel FFSD tablet could be a potential oral pharmaceutical product with the improved oral bioavailability of fimasartan.

Novel Approaches and Emerging Trends in Hydrotropic Solubilization Technology

Hydrotropic solubilization technology enhances the solubility and bioavailability of poorly water-soluble drugs, a major challenge in pharmaceutical research. This review discusses hydrotropic agents’ structures, the solubilization process, and factors affecting drug solubility. It explores optimizing agent concentrations, the role of computer modeling and QSAR studies, and hydrotropes’ impact on overcoming biological barriers and improving pharmacokinetics and pharmacodynamics. The review highlights hydrotropic compounds’ potential in advancing pharmaceutical formulations and clinical applications.

Comparative Pharmacokinetic Study of Standard Astaxanthin and its Micellar Formulation in HealthyMale Volunteers.

Astaxanthin is a naturally occurring carotenoid with high anti-oxidant properties, but it is a very lipophilic compound with low oral bioavailability. This study was conducted to compare the pharmacokinetic parameters of a novel astaxanthin preparation based on micellar solubilization technology, NovaSOL® 400-mg capsules (Test product), and those of astaxanthin 400-mg capsules (reference product), after single oral dose administration to healthy male adults. A single oral dose (400 mg equivalent to 8 mg astaxanthin) of test and reference astaxanthin were administered with 240 mL of water to 12 volunteers according to crossover design, in two phases, with a washout period of 1week in between. Blood samples were collected at hourly intervals for the first 12 h, then at 24.0, 48.0, and 72.0 h after administration. Aliquots of plasma were centrifuged and the clear supernatant was injected into the high performance liquid chromatography-diode array detection (HPLC-DAD) system. Plasma concentration of astaxanthin versus time profiles were constructed, and the primary pharmacokinetic parameters, maximum concentration (Cmax), area under concentration time curve from time of administration (0) to time (t) [AUC0-t] or to infinity ∞, [AUC0-∞], half-life (T½) and time to reach Cmax (Tmax)were calculated. The test micellar astaxanthin reached a Cmax of 7.21 µg/ml after 3.67 h compared to only 3.86 µg/ml after 8.5 h for the reference native astaxanthin. Micellar formulation of astaxanthin is capable of producing a high concentration of astaxanthin in plasma in a shorter time, thereby expected to provide faster potential therapeutic efficacy.

The Impact of Polymers on Enzalutamide Solid Self-Nanoemulsifying Drug Delivery System and Improved Bioavailability.

Enzalutamide (ENZ), marketed under the brand name Xtandi® as a soft capsule, is an androgen receptor signaling inhibitor drug actively used in clinical settings for treating prostate cancer. However, ENZ's low solubility and bioavailability significantly hinder the achievement of optimal therapeutic outcomes. In previous studies, a liquid self-nanoemulsifying drug delivery system (L-SNEDDS) containing ENZ was developed among various solubilization technologies. However, powder formulations that included colloidal silica rapidly formed crystal nuclei in aqueous solutions, leading to a significant decrease in dissolution. Consequently, this study evaluated the efficacy of adding a polymer as a recrystallization inhibitor to a solid SNEDDS (S-SNEDDS) to maintain the drug in a stable, amorphous state in aqueous environments. Polymers were selected based on solubility tests, and the S-SNEDDS formulation was successfully produced via spray drying. The optimized S-SNEDDS formulation demonstrated through X-ray diffraction and differential scanning calorimetry data that it significantly reduced drug crystallinity and enhanced its dissolution rate in simulated gastric and intestinal fluid conditions. In an in vivo study, the bioavailability of orally administered formulations was increased compared to the free drug. Our results highlight the effectiveness of solid-SNEDDS formulations in enhancing the bioavailability of ENZ and outline the potential translational directions for oral drug development.

Current advances of anticancer drugs based on solubilization technology

Current advances of anticancer drugs based on solubilization technology

Development, optimization and in-vivo pharmacokinetic evaluation of flubiprofen nanocrystal tablets for efficient chronotherapy against rheumatoid arthritis

In an effort to enhance drug solubility for buccal mucosal delivery, various strategies such as nanoemulsions, cyclodextrin inclusions, and solid dispersions have been explored, but these methods often face limitations. An emerging solubilization technology, drug nanocrystals, offers a promising alternative due to their high drug loading capacity and scalability for large-scale production. The current study aimed to create solid nanocrystals of flurbiprofen (FP-NC) through a wet milling process to significantly improve water solubility, regardless of pH, and consequently enhance bioavailability. FP-NC was further used to formulate tablets and compressed coatings with carboxymethyl xanthan gum (CXG) and sodium alginate (SA). The compression coating process has been optimized using Quality by Design principles. Utilizing the desirability approach, we identified an optimal formulation with 56.05 mg of CXG, 74.96 mg of SA, and a coating material weight of 249.98 mg. This formulation achieves desired chronotherapeutic characteristics with a lag time (LT) of 5.99 h and T90% of 11.48 h. We conducted in-vitro and ex-vivo drug release studies and compared them with in-vivo pharmacokinetic parameters, employing level A in-vitro in-vivo correlation (IVIVC). Notably, the continuous ex-vivo method exhibited a stronger correlation compared to traditional in-vitro drug release assessments. This suggests that our novel drug release system using the NC compressed coating technique holds promise for achieving chronotherapeutic effects with improved bioavailability.

Advances in eggshell membrane separation and solubilization technologies.

Eggshell membranes (ESM) contain 90% protein, 3% lipids, 2% sugars, and small amounts of minerals such as calcium and magnesium. Of the 90% of proteins present, 472 proteins species have been identified. ESM provide the initial mineralization platform for eggshell formation, and can be used for to produce adsorbents, cosmetics, and medical products because of their special physical structure and chemical composition. The special physical structure of the eggshell membrane, with disulfide bonds between and within the protein molecules and the cross-linking of lysine-derived and heterochain chains between the eggshell membrane, makes the membrane very difficult to dissolve, with a maximum solubility rate of only 62%. Also, the insolubility of ESM limits its development and use also any related research. Based on the physical structure and chemical composition of the eggshell membrane, this paper reviews the latest research on eggshell membrane separation and membrane protein solubilization to provide a reference for promoting the separation, dissolution, and rational development and use of the avian eggshell membrane.

Nanocomplexation is a promising strategy to enhance the solubility and anti-Ichthyophthirius multifiliis activity of magnolol

The protozoan parasite Ichthyophthirius multifiliis infects a wide range of freshwater fish species worldwide and causes Ichthyophthiriasis, also called white spot disease, resulting in mass mortality and great economic losses to global aquaculture. Despite more and more chemotherapeutic drugs being found effective against I. multifiliis, the native poorly solubility for most hydrophobic compounds including natural products caused activity decline and even loss, limiting the further application in the control of aquatic animal diseases. The concern about water-insoluble drugs accentuates the urgent need for solubilization technologies and methods. Here we propose a nano-complexation technology to overcome the concerns of natural products' insolubility. Based on this technology, the magnolol-nanocomplexes were successfully prepared with various mass ratios of magnolol to peptone. The data of particle size and PDI revealed that magnolol particle size was decreased from micro to nanoscale after complexation with peptone, with enhanced water solubility. Images obtained from transmission electron microscopy (TEM) visually displayed the morphological characteristics of magnolol nanoparticles after complexation with peptone and the average particle size was calculated as 63.69–82.84 nm using the ImageJ software. Furthermore, differential scanning calorimetry (DSC) and Fourier Transform Infrared (FTIR) spectroscopy were employed to investigate the complexation mechanism, which suggested that the hydrogen bond interactions were formed between magnolol and peptone that contributed to the stabilization for magnolol-nanocomplex. Lastly, the antiparasitic efficacy of magnolol-nanocomplex was both significantly improved after complexation with peptone against I. multifiliis infection at all life stages in vitro and in vivo. These findings indicated that animal proteins, peptone, could be used as a nanocarrier to improve the water solubility and antiparasitic effects of natural product magnolol. Altogether, this study first proposes a promising strategy to enhance the solubility and activity of hydrophobic drugs against aquatic animal diseases, which might be hoping to be further applicate in the aquaculture industry.

Current Trends on Solid Dispersions: Past, Present, and Future.

Solid dispersions have achieved significant interest as an effective means of enhancing the dissolution rate and thus the bioavailability of a range of weakly water-soluble drugs. Solid dispersions of weakly water-soluble drugs with water-soluble carriers have lowered the frequency of these problems and improved dissolution. Solid dispersion is a solubilization technology emphasizing mainly on, drug-polymer two-component systems in which drug dispersion and its stabilization is the key to formulation development. Therefore, this technology is recognized as an exceptionally useful means of improving the dissolution properties of poorly water-soluble drugs and in the latest years, a big deal of understanding has been accumulated about solid dispersion, however, their commercial application is limited. In this review article, emphasis is placed on solubility, BCS classification, and carriers. Moreover, this article presents the diverse preparation techniques for solid dispersion and gathers some of the recent technological transfers. The different types of solid dispersions based on the carrier used and molecular arrangement were underlined. Additionally, it summarizes the mechanisms, the methods of preparing solid dispersions, and the marketed drugs that are available using solid dispersion approaches.

Lipid-based solubilization technology via hot melt extrusion: promises and challenges

Introduction Self-emulsifying drug delivery systems (SEDDS) are a promising strategy to improve the oral bioavailability of poorly water-soluble drugs (PWSD). The excipients of SEDDS enable permeation through the mucus and gastro-intestinal barrier, inhibiting efflux transporters (e.g. P-glycoprotein) of drugs. Poor drug loading capacity and formulation instability are the main setbacks of traditional SEDDS. The use of polymeric precipitation inhibitors was shown to create supersaturable SEDDS with increased drug payload, and their solidification can help to overcome the instability challenge. As an alternative to several existing SEDDS solidification technologies, hot melt extrusion (HME) holds the potential for lean and continuous manufacturing of supersaturable solid-SEDDS. Despite being ubiquitously applied in solid lipid and polymeric processing, HME has not yet been widely considered for the preparation of SEDDS. Areas covered The review begins with the rationale why SEDDS as the preferred lipid-based delivery systems (LBDS) is suitable for the oral delivery of PWSD and discusses the common barriers to oral administration. The potential of LBDS to surmount them is discussed. SEDDS as the flagship of LBDS for PWSD is proposed with a special emphasis on solid-SEDDS. Finally, the opportunities and challenges of HME from the lipid-based excipient (LBE) processing and product performance standpoint are highlighted. Expert opinion HME can be a continuous, solvent-free, cost-effective, and scalable technology for manufacturing solid supersaturable SEDDS. Several critical formulations and process parameters in successfully preparing SEDDS via HME are identified.

Key technologies in dosage form design of Chinese medicinal liquid preparations: application of component solubility and solubilization technology

Modern liquid forms of Chinese medicine(CM), such as oral liquid, are similar to traditional decoction, but there are deficiencies in the selection and design of the dosage form, and the solubility of the pre-preparation material is critical. The property system for Chinese medicinal materials(CMMs) was established according to the previous research. The present study established the dosage form design strategy of oral liquid preparations of CM with the solubility as the core, and pointed out the relationship between the saturated volume of component(V_(i-n)) and daily dosage of preparation(V_d) was the key to the dosage form design. To be specific, the prescription can be designed into liquid preparation directly when V_(i-n)≤V_d, while V_(i-n)>V_d, the suitable solubilization technologies are needed. At present, the available solubilization technologies include the addition of excipients such as solubilizers/cosolvents, pH adjustment of the solution, and synergistic solubilization of intermediates and components for the preparation of pharmaceuticals. As reported, the polysaccharides of CM have shown great potential in the solubilization of insoluble components of CM, and they have certain prospects as a new solubilizing excipient.

Enhanced Fe-bound phosphate availability by the combined use of Mg-modified biochar and phosphate-solubilizing bacteria

The formation of insoluble phosphate in soils and resulting overfertilization causes a large environmental risk. Although phosphate-solubilizing bacteria (PSB) can solubilize Ca-bound phosphate well by acidification, they often have a low capacity to solubilize Fe-bound phosphate (Fe-P). In this study, a novel Mg-modified lignin biochar (MB) was prepared via the chemical impregnation method to improve the ability of PSB to dissolve FePO4. The results show that dissolved phosphate rapidly increased to approximately 0.9 mM over 3 days in the FePO4 + PSB + MB system. The system with MB was more effective to increase FePO4 dissolution by 17 times and increase the amount of organic acids production by 2 times than that without the MB. The characterization results indicated that the polymerization and rearrangement of FePO4 occurred when the FePO4 particles attached to the surface of the MB, resulting in the formation of Fe(III)2Fe(II)(P2O7)2 crystals on the surface of the MB. The Mg on the surface of the MB can induce the preferential orientation of the [210] crystal plane of the Fe(III)2Fe(II)(P2O7)2, which can be preferentially dissolved by PSB, causing an increase in Fe-P solubility. This study provides a new method for the development of insoluble phosphate solubilization technology to limit the overfertilization of soil and offers a clear understanding of the interactions among biochar, Fe-P, and PSB.

Solubilization and changes of physicochemical properties of baicalin by nano sponge, and toxicity of zebrafish liver

As a new type of drug carrier, nano-sponge (NS) can remarkably improve the solubility of poorly soluble drug components, significantly increase the efficacy of drugs and their bioavailability. Baicalin (BA) has many biological activities, such as anti-inflammatory, bacteriostatic and etc. But due to its poor solubility, BA cannot play a role in the clinic. Therefore, it is urgent to find a suitable solubilization technology to improve the solubility of BA. In this paper, we optimized the preparation process of NS based on β-cyclodextrin (β-CD), and then prepared the baicalin nano-sponges (BA-NS). The successful preparation of BA-NS was verified by modern analysis methods. BA loading capacity and efficiency (BLC and BLE), solubilizing effect, in vitro release rate and liver toxicity were investigated. The results showed that the BLC and BLE were 18.02 ± 0.36% and 86.64 ± 0.86%, solubility in water was 31 times than that of pure BA, and release rate in different media could reach 80%. Zebrafish liver toxicity test showed no obvious toxicity. The above results showed that NS had a significant solubilizing effect on BA and was safe and non-toxic, and proved that NS maybe have broad prospects in the research of poorly soluble drugs.

Industry Update: the Latest Developments in the Field of Therapeutic delivery, April 2019

April 2019 was perhaps remarkable for the amount of industry news about gene therapy, and notably the announcement by a global contract development and manufacturing organization, Catalent, that it was creating a capability in gene therapy product development and manufacturing through its acquisition of Paragon Bioservices, Inc (MD, USA). This move followed just a few weeks after another similar major contract development and manufacturing organization gene therapy acquisition. There was other encouraging gene and cell therapy news reported from AveXis (IL, USA), Ajinomoto Bio-Pharma (CA, USA), Kiadis Pharma (Amsterdam, The Netherlands), Fibrocell (PA, USA), Autolus Therapeutics plc (London, UK), ReNeuron (Surrey, England) and Kite Pharma (CA, USA). Also, there was plenty of therapeutic delivery technology innovation announced, including Calixar's (Lyon, France) membrane protein stabilization drug discovery technology, the Eli Lilly (IN, USA)/Avidity Biosciences LLC (CA, USA) deal around antibody oligonucleotide conjugates, ViiV Healthcare's regulatory filing for its long-acting anti-HIV-1 intramuscular injection, Marinomed Biotech's (Vienna, Austria) solubilization technology and an EU approval filing for Novo Nordisk's (Bagsværd, Denmark) oral delivery formulation of glucagon-like peptide-1 analog semaglutide. Diseases and treatment approaches that currently figure strongly in many biotech and big pharma pipelines and portfolios, notably nonalcoholic steatohepatitis and immuno-oncology, were as ever in the news, along with a number of rare disease therapies. As always, information sources employed to provide the materials used in compiling this update included company press releases, conference news and other news websites.

Solid dispersions: A technology for improving bioavailability

An unending challenge in pharmaceutical industry is related to poor solubility of maximum drugs To overcome this problem various technologies have been developed but none appears to be a promising one Solid dispersion is a solubilization technology emphasizing basically on drug polymer two component systems in which drug dispersion and its stabilization is the key for formulation development Therefore this technology has been realized as extremely useful tool in improving the dissolution properties of poorly water soluble drugs and in recent years a great deal of knowledge has been accumulated about solid dispersion but their commercial application is limited This review summarizes our current understanding of various methods used for the preparation of solid dispersions emphasizing the elementary aspects of this significant technology

Improved solubility and increased biological activity of NeoSol™RCL40, a novel Red Clover Isoflavone Aglycones extract preparation

Red clover (Trifolium pratense L., Fabaceae; RCL), a perennial plant rich in isoflavones, is a natural alternative for menopausal symptoms, as well as antiaging and antioxidant. Isoflavone preparations usually contain aglycones and β-glycosides. Aglycones, the active moieties, are absorbed slowly and unevenly due to reduced water solubility and biotransformation from β-glycosides. NeoSol™RCL40 is a novel RCL isoflavone aglycones preparation based on active solubilization technologies. In the present study, NeoSol™RCL40 was shown to induce solubilization of isoflavones and to increase estrogenic and antioxidative effects in comparison to a standard RCL extract (RCLE). NeoSol™RCL40 was prepared from RCLE using as host molecules either 2-pyrrolidone, 1-ethenyl homopolymer (PVP), γ-cyclodextrin, or maltodextrin. Solubilisation assays, performed by means of HPLC-UV, showed that solubilization of isoflavone aglycones was highest with RCLE processed with PVP, which was therefore selected for functional assays. In comparison to RCLE, NeoSol™RCL40 containing the same amount of isoflavone aglycones displayed 3.4 times higher estrogenicity in MCF-7 cell, 1.9–2.0 higher antioxidant activity in the DPPH and in the FRAP assay, and was cytoprotective in PC12 cells. As a whole, results support the ability of NeoSol™RCL40 to promote isoflavones solubilization leading to increased biological activity. NeoSol™RCL40 is therefore an interesting novel preparation providing improved availability of active isoflavones aglycones.

Phospholipid based self-nanoemulsifying self-nanosuspension (p-SNESNS) as a dual solubilization approach for development of formulation with diminished food effect: Fast/fed in vivo pharmacokinetics study in human

The novel self- nanoemulsifying self-nanosuspension (SNESNS) combines the advantages of two efficient solubilization technologies; the nanoemulsion and the nanosuspension. The aim of this study is to test the efficiency of phospholipid based self-nanoemulsifying self-nanosuspension (p-SNESNS) formulation as a powerful tool to diminish the food effect on bioavailability of lurasidone hydrochloride as BCS Class II model drug. Phospholipid was incorporated into SNESNS to increase the solubilization power of the in-situ formed nanoemulsion and facilitate the dispersion of the in-situ formed nanosized drug particles. P-SNESNS was evaluated for particle size, Polydispersity index, in vitro dissolution and transmission electron microscopy (TEM). The drug amount dissolved after water dilution of LSD p-SNESNS was ~2 folds that dissolved after dilution of non-phospholipid SNESNS. The self-nanosuspension obtained by aqueous dilution of p-SNESNS kept the cubic morphology of LSD macroparticles. The high in vitro dissolution of LSD in the non-sink dissolution media (water and Phosphate buffer pH6.8) indicated that the p-SNESNS formulation had successfully increased the drug solubility irrespective of pH of the medium. The pharmacokinetics parameters of LSD p-SNESNS in humans were the same in both the fasted and fed states and were similar to those of LSD capsules in the fed state. Our results propose that p-SNESNS could be promising to increase patient compliance and drug efficiency of BCS class II antipsychotics by diminishing the food effect on their oral absorption and preventing the necessity to administer them with food.

Predicting biopharmaceutical performance of oral drug candidates – Extending the volume to dissolve applied dose concept

The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro – in vivo and in vivo – in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery.

Formation and structure of fine multi-particle layered organo-modified zirconium dioxides fabricated by Langmuir–Blodgett technique

Formation and structure of multilayered organization of organo-modified zirconium dioxide are investigated by surface pressure–area (π–A) isotherms, out-of-plane and in-plane X-ray diffraction (XRD) analysis, and atomic force microscopy (AFM). In this study, solubilization technology of inorganic fine particles into general solvent has proposed and formation technology of highly ordered single-particle layer has also established by using that inorganic solution as “spreading solution” of the interfacial film. The surface modification of zirconia particles is performed using several long-chain carboxylic acids of different lengths. Accordingly, it is easily achieve a regular arrangement of ZrO2 particles to overcome the relatively weak van der Waals interactions between the inorganic materials. A Langmuir monolayer of these particles is extremely condensed. A multi-particle layered structure is constructed by the Langmuir–Blodgett (LB) technique. The out-of-plane XRD measurement of multilayered organization of stearate-modified ZrO2 particles confirms sharp peaks at 59Å. AFM images on a mesoscopic scale of this single-particle layer of stearate-modified ZrO2 show the aggregate of particles with 50nm diameters. However, fine particles with ∼5nm diameter are confirmed from high-resolution AFM observations in the case of single-particle layers transferred at low surface pressure. That is to say, a regular periodic structure along the c-axis and a hierarchical aggregated particle form are fabricated by Langmuir and LB techniques.

Model predicting impact of complexation with cyclodextrins on oral absorption

Significant effort and resource expenditure is dedicated to enabling low-solubility oral drug delivery using solubilization technologies. Cyclodextrins (CD) are cyclic oligosaccharides which form inclusion complexes with many drugs and are often used as solubilizing agents. It is not clear prior to developing a drug delivery device with CD what level of absorption enhancement might be achieved; modeling can provide useful guidance in formulation and minimize resource intensive iterative formulation development. A model was developed to enable quantitative, dynamic prediction of the influence of CD on oral absorption of low solubility drug administered as a pre-formed complex. The predominant effects of CD considered were enhancement of dissolution and slowing of precipitation kinetics, as well as binding of free drug in solution. Simulation results with different parameter values reflective of typical drug and CD properties indicate a potential positive (up to five times increase in drug absorption), negative (up to 50% decrease in absorption) or lack of effect of CD. Comparison of model predictions with in vitro and in vivo experimental results indicate that a systems-based dynamic model incorporating CD complexation and key process kinetics may enable quantitative prediction of impact of CD delivered as a pre-formed complex on drug bioavailability.