Precipitation Inhibitor Research Articles

Enhanced Oral Bioavailability of Curcumin Using a Supersaturatable Self-Microemulsifying System Incorporating a Hydrophilic Polymer; In Vitro and In Vivo Investigations

A supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) with a reduced amount of surfactant and incorporation of a polymer precipitation inhibitor, Eudragit® E PO was developed. The optimized S-SMEDDS formulation (SS-15) consisted of 55% surfactants, 40% oils, and 5% Eudragit® E PO (curcumin at 44.4mg/g of the formulation). The precipitation profiles from the supersaturation assay revealed that the curcumin S-SMEDDS performed as a better inhibitor of curcumin precipitation in simulated gastric fluid over a 240-min study than the normal curcumin SMEDDS and an aqueous curcumin suspension. In addition, the mean droplet size of the curcumin S-SMEDDS (21.6±0.1nm) was significantly smaller than the SMEDDS (28.1±0.3nm). The curcumin S-SMEDDS exhibited a threefold reduction of Caco-2 cell toxicity when compared to the curcumin SMEDDS because of the reduced toxic effect of the surfactant present in the SMEDDS formulation. In addition, the absorptive permeability across the Caco-2 monolayer of curcumin in the S-SMEDDS was significantly higher than for the unformulated curcumin (~5-folds). The plasma concentration-time profiles from the oral absorption studies in rats dosed with the curcumin S-SMEDDS showed a 1.22- and 53.14-fold increased absorption of curcumin, compared to the SMEDDS and the aqueous suspension, respectively. The curcumin S-SMEDDS was stable under both intermediate and accelerated conditions after 6months of storage.

Choline chloride/monoethylene glycol deep eutectic solvent as a new asphaltene precipitation inhibitor

ABSTRACTIn this research work, a family of green solvents named deep eutectic solvents (DES) was used as asphaltene precipitation inhibitor for the first time as per our knowledge, i.e., choline chloride:monoethylene glycol acid (1:1). Ultraviolet–visible (UV–vis) spectrometry was used to estimate the precipitation onset point of asphaltene and to evaluate the impact of the DES to increase their resistance against the precipitant effect. A microscopic method was used to monitor the agglomeration trend during titration. The distribution of asphaltene particles monitored by dynamic light scattering (DLS) showed a value of 1,419 nm for inhibitor-free sample, while for sample with the DES was 1,039 nm under similar conditions.

Mesoporous silica-based dosage forms improve bioavailability of poorly soluble drugs in pigs: case example fenofibrate.

Mesoporous silicas (SLC) have demonstrated considerable potential to improve bioavailability of poorly soluble drugs by facilitating rapid dissolution and generating supersaturation. The addition of certain polymers can further enhance the dissolution of these formulations by preventing drug precipitation. This study uses fenofibrate as a model drug to investigate the performance of an SLC-based formulation, delivered with hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor, in pigs. The ability of biorelevant dissolution testing to predict the in vivo performance was also assessed. Fenofibrate-loaded mesoporous silica (FF-SLC), together with HPMCAS, displayed significant improvements in biorelevant dissolution tests relative to a reference formulation consisting of a physical mixture of crystalline fenofibrate with HPMCAS. In vivo assessment in fasted pigs demonstrated bioavailabilities of 86.69 ± 35.37% with combination of FF-SLC and HPMCAS in capsule form and 75.47 ± 14.58% as a suspension, compared to 19.92 ± 9.89% with the reference formulation. A positive correlation was identified between bioavailability and dissolution efficiency. The substantial improvements in bioavailability of fenofibrate from the SLC-based formulations confirm the ability of this formulation strategy to overcome the dissolution and solubility limitations, further raising the prospects of a future commercially available SLC-based formulation.

Development of a Video-Microscopic Tool To Evaluate the Precipitation Kinetics of Poorly Water Soluble Drugs: A Case Study with Tadalafil and HPMC.

Many drug candidates today have a low aqueous solubility and, hence, may show a low oral bioavailability, presenting a major formulation and drug delivery challenge. One way to increase the bioavailability of these drugs is to use a supersaturating drug delivery strategy. The aim of this study was to develop a video-microscopic method, to evaluate the effect of a precipitation inhibitor on supersaturated solutions of the poorly soluble drug tadalafil, using a novel video-microscopic small scale setup. Based on preliminary studies, a degree of supersaturation of 29 was chosen for the supersaturation studies with tadalafil in FaSSIF. Different amounts of hydroxypropyl methyl cellulose (HPMC) were predissolved in FaSSIF to give four different concentrations, and the supersaturated system was then created using a solvent shift method. Precipitation of tadalafil from the supersaturated solutions was monitored by video-microscopy as a function of time. Single-particle analysis was possible using commercially available software; however, to investigate the entire population of precipitating particles (i.e., their number and area covered in the field of view), an image analysis algorithm was developed (multiparticle analysis). The induction time for precipitation of tadalafil in FaSSIF was significantly prolonged by adding 0.01% (w/v) HPMC to FaSSIF, and the maximum inhibition was reached at 0.1% (w/v) HPMC, after which additional HPMC did not further increase the induction time. The single-particle and multiparticle analyses yielded the same ranking of the HPMC concentrations, regarding the inhibitory effect on precipitation. The developed small scale method to assess the effect of precipitation inhibitors can speed up the process of choosing the right precipitation inhibitor and the concentration to be used.

Study on Pitting Corrosion of Carbon Steel Induced By Cerium (III) Ions

: In this work, pitting corrosion of carbon steel in sodium chloride solution induced by a precipitation inhibitor, cerium(III) ions, was investigated. Upon in situ 3D microscope observation, pitting corrosion was immediately seen on carbon steel in sodium chloride solution containing cerium (III) ions; however, no local corrosion occurred in solutions containing zinc ions. The mechanism of precipitation film formation was investigated using electrochemical impedance spectroscopy and potentiodynamic polarization curves. Results showed that the inhibition efficiency increased after applying a weak cathodic polarization on the electrode in the sodium chloride solution containing cerium(III) or zinc ions. Simultaneously, anodic polarization was provided as a comparison, demonstrating the unprofitability of the accelerated anode process to the precipitation film formation. A minimal change of film resistance after anodic or cathodic polarization in sodium chloride solution was also shown. By applying cathodic polarization, the oxygen reduction reaction was accelerated in the cathode areas on the metal surface, increasing the local OH- concentration that promoted the precipitation reaction. This indicates that the corrosion resistance of the precipitation film is related to the local concentration of hydroxyl ions. Additionally, in the polarization curve measurements, the Ecorr of the electrode in Zn2+-containing sodium chloride solution is more negative than that in sodium chloride solution; however, the Ecorr of the electrode in Ce3+-containing solution is more positive than that in sodium chloride solution. A galvanic mechanism of local corrosion was explored to explain the pitting corrosion on carbon steel induced by cerium(III) ions. Before the measurement, one electrode was immersed in inhibitor-containing sodium chloride solution for a certain time to simulate the places covered with precipitation film, and another electrode was immersed in sodium chloride solution and acted as the breakage. The different changes of galvanic current show that the corrosion was severely suppressed after adding zinc ions in the sodium chloride solution; however, cerium(III) ions failed to suppress the corrosion and the defects gradually evolved into pits. In the zinc ion-containing sodium chloride solution, the open circuit potential of the bare place without precipitation is more positive than the place covered with precipitation film, which resulted in the bare places becoming small cathodes. Under the cathodic polarization, oxygen receives electrons on the cathode and generates hydroxyl ions. The precipitation film is then fixed by Zn(OH)2 precipitation immediately. However, the open circuit potential of the electrode in cerium(III) ion-containing sodium chloride solution shifted toward a more positive value than that in the sodium chloride solution. The bare places with negative potentials act as small anodes in the cerium(III) ion-containing sodium chloride solution. Moreover, Ce(III) is a precipitation inhibitor and has a similar inhibition mechanism with zinc ions. Combine the results of EIS and galvanic current measurements, the defects, where under the anodic polarization and no hydroxyl ions is generated to react with Ce(III), undergo serious corrosion and develop into pits. In general, the different potentials between the bare and covered places led to the galvanic effect that is attributed to the precipitation film repair and pitting corrosion. X-ray photoelectron spectroscopy and scanning electron microscopy were applied to confirm the composition and morphology of the precipitation films. Keywords: precipitation inhibitor; EIS; Polarization; XPS; pitting corrosion

Enhanced release of poorly water-soluble drugs from synergy between mesoporous magnesium carbonate and polymers

The need to combat poor water solubility has increased interest in supersaturating drug delivery systems. In this study, amorphous mesoporous magnesium carbonate (MMC) was used as a drug carrier to achieve supersaturation of tolfenamic acid and rimonabant, two drug compounds with low aqueous solubility. The potential synergy between MMC and hydroxypropyl methylcellulose (HPMC), a polymer commonly included as a precipitation inhibitor in drug delivery systems, was explored with the aim of extending the time that high supersaturation levels were maintained. Release was studied under physiological conditions using USP-2 dissolution baths. A new small-scale method was developed to enable measurement of the initial drug release occurring when the MMC is immersed in the water phase. It was shown that MMC and HPMC together resulted in significant supersaturation and that the polymer enabled both the achievement of a higher API concentration and extension of the supersaturation period. The new small-scale release method showed that the release was linearly increasing with the dose and that similar release rates were observed for the two model compounds. It was hence concluded that the MMC release was diffusion limited for the compounds explored.

A Polyvinylpyrrolidone-Based Supersaturable Self-Emulsifying Drug Delivery System for Enhanced Dissolution of Cyclosporine A.

A novel supersaturable self-emulsifying drug delivery system (S-SEDDS) of cyclosporine A (CyA)—a poorly water-soluble immunosuppressant—was constructed in order to attain an apparent concentration–time profile comparable to that of conventional SEDDS with reduced use of oil, surfactant, and cosolvent. Several hydrophilic polymers, including polyvinylpyrrolidone (PVP), were employed as precipitation inhibitors in the conventional SEDDS, which consists of corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil, ethanol, and propylene glycol. PVP-incorporated pre-concentrate (CyA:vehicle ingredients:PVP = 1:4.5:0.3 w/v/w) spontaneously formed spherical droplets less than 120 nm within 7 min of being diluted with water. In an in vitro dialysis test in a biorelevant medium such as simulated fed and/or fasted state intestinal and/or gastric fluids, PVP-based S-SEDDS exhibited a higher apparent drug concentration profile compared to cellulose derivative-incorporated S-SEDDS, even displaying an equivalent concentration profile with that of conventional SEDDS prepared with two times more vehicle (CyA:vehicle ingredients = 1:9 w/v). The supersaturable formulation was physicochemically stable under an accelerated condition (40 °C/75% RH) over 6 months. Therefore, the novel formulation is expected to be a substitute for conventional SEDDS, offering a supersaturated state of the poorly water-soluble calcinurin inhibitor with a reduced use of vehicle ingredients.

Evaluation of a polyether-based polycarboxylate as precipitation inhibitor for calcium carbonate and calcium sulfate

Evaluation of a polyether-based polycarboxylate as precipitation inhibitor for calcium carbonate and calcium sulfate

Solid dispersions enhance solubility, dissolution, and permeability of thalidomide

Thalidomide (THD) is a BCS class II drug with renewed and growing therapeutic applicability. Along with the low aqueous solubility, additional poor biopharmaceutical properties of the drug, i.e. chemical instability, high crystallinity, and polymorphism, lead to a slow and variable oral absorption. In this view, we developed solid dispersions (SDs) containing THD dispersed in different self-emulsifying carriers aiming at an enhanced absorption profile for the drug. THD was dispersed in lauroyl macrogol-32 glycerides (Gelucire® 44/14) and α-tocopherol polyethylene glycol succinate (Kolliphor® TPGS), in the presence or absence of the precipitation inhibitor polyvinylpyrrolidone K30 (PVP K30), by means of the solvent method. Physicochemical analysis revealed the formation of semicrystalline SDs. X-ray diffraction and infrared spectroscopy analyses suggest that the remaining crystalline fraction of the drug in the SDs did not undergo polymorphic transition. The impact of the solubility-enhancing formulations on the THD biopharmaceutical properties was evaluated by several in vitro techniques. The developed SDs were able to increase the apparent solubility of the drug (up to 2–3x the equilibrium solubility) for a least 4 h. Dissolution experiments (paddle method, 75 rpm) in different pHs showed that around 80% of drug dissolved after 120 min (versus 40% of pure crystalline drug). Additionally, we demonstrated the enhanced solubility obtained via SDs could be translated into increased flux in a parallel artificial membrane permeability assay (PAMPA). In summary, the results demonstrate that SDs could be considered an interesting and unexplored strategy to improve the biopharmaceutical properties of THD, since SDs of this important drug have yet to be reported.

Enhancement of physical stability and bioaccessibility of tangeretin by soy protein isolate addition.

Soy protein isolate (SPI) was selected to fabricate supersaturated self-emulsifying nanoemulsions, aiming to enhance physical stability and bioaccessibility of hydrophobic tangeretin. Dissolution studies demonstrated that tangeretin had the highest solubility in Tween 80, followed by oil phase solutions, and polymer solutions. Supersaturated tangeretin in oil phases easily formed crystals. That metastable zone was found to vary with its initial concentrations. After encapsulation by nanoemulsions, the addition of glycerol compressed the retention amount of tangeretin from 76% to 53%, but benefited the transparency. Whereas, the combination of glycerol and SPI could not only maintain high-loading tangeretin (>85%), but also provide high transparency for nanoemulsions. When tangeretin concentration was 4.83mM, combination of 50% glycerol and 1% SPI could maintain around 88% tangeretin in the nanoemulsion within one month. Its bioaccessibility of different systems were at 60-65%. These findings can provide useful information for protein to be a potential precipitation inhibitor.

High-Throughput Excipient Discovery Enables Oral Delivery of Poorly Soluble Pharmaceuticals.

Polymeric excipients are crucial ingredients in modern pills, increasing the therapeutic bioavailability, safety, stability, and accessibility of lifesaving products to combat diseases in developed and developing countries worldwide. Because many early-pipeline drugs are clinically intractable due to hydrophobicity and crystallinity, new solubilizing excipients can reposition successful and even failed compounds to more effective and inexpensive oral formulations. With assistance from high-throughput controlled polymerization and screening tools, we employed a strategic, molecular evolution approach to systematically modulate designer excipients based on the cyclic imide chemical groups of an important (yet relatively insoluble) drug phenytoin. In these acrylamide- and methacrylate-containing polymers, a synthon approach was employed: one monomer served as a precipitation inhibitor for phenytoin recrystallization, while the comonomer provided hydrophilicity. Systems that maintained drug supersaturation in amorphous solid dispersions were identified with molecular-level understanding of noncovalent interactions using NOESY and DOSY NMR spectroscopy. Poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (poly(NIPAm-co-DMA)) at 70 mol % NIPAm exhibited the highest drug solubilization, in which phenytoin associated with inhibiting NIPAm units only with lowered diffusivity in solution. In vitro dissolution tests of select spray-dried dispersions corroborated the screening trends between polymer chemical composition and solubilization performance, where the best NIPAm/DMA polymer elevated the mean area-under-the-dissolution-curve by 21 times its crystalline state at 10 wt % drug loading. When administered to rats for pharmacokinetic evaluation, the same leading poly(NIPAm-co-DMA) formulation tripled the oral bioavailability compared to a leading commercial excipient, HPMCAS, and translated to a remarkable 23-fold improvement over crystalline phenytoin.

Biopharmaceutic Profiling of Salts to Improve Absorption of Poorly Soluble Basic Drugs

AZD1175 and AZD2207 are 2 highly lipophilic compounds with a significant risk of not achieving therapeutic plasma concentrations due to solubility-limited absorption. The compounds have the same molecular weight and minimal structural differences. The aim of the present work was to investigate whether salts could be applied to improve the intestinal absorption, and the subsequent in vivo exposure. Drug solubilities, dissolution rates, and degree of supersaturation and precipitation were determined in biorelevant media. Dog studies were performed, in the absence and presence of a precipitation inhibitor (hydroxypropyl methylcellulose). Finally, a human phase I study was performed. For AZD1175, there was a good agreement between dissolution rates, in vivo exposure in dog, and the obtained exposure in human with the selected hemi-1,5-naphthalenedisulfonate of the compound. For AZD2207, the picture was more complex. The same counter ion was selected for the study in man. In addition, the chloride salt of AZD2207 showed promising data in the presence of a precipitation inhibitor in vitro and in dog that, however, could not be repeated in man. The differences in observations between the 2 compounds could be attributed to the difference in solubility and to the degree of supersaturation in the gastric environment rather than in the intestine.

Effect of Disulfite on the Solubility of Molybdate and Passivation of Iron in Concentrated LiBr Solution

[Introduction]Absorption refrigerator utilizes highly corrosive concentrated LiBr solution as an absorbent for water vaper. In order to inhibit corrosion of carbon steel, LiOH and key inhibitor of Li2MoO4 are added into the absorbent. LiNO3 is also used as a strong passivator in order to accelerate passivation of steel especially at a startup stage. Because of the limited solubility of Li2MoO4 in the absorbent, its concentration diminishes during long-term operation not only by consumption by the reaction with steel but also by precipitation at lower temperature part of refrigerator, i.e. in an absorber. In this research, concentration change of molybdate in the absorbent is studied at the absorber temperature (40ºC) and additives that inhibit the precipitation of Li2MoO4 are searched. The effect of precipitation inhibitor on the passivation of iron are also evaluated through electrochemical measurements. [Experimental]The composition of the test solution is 17.3 mol kg-1 LiBr + 0.1 mol kg-1 LiOH with initial concentration of Li2MoO4 of 3.0×10-3 mol kg-1, where Li2MoO4 is supersaturated at 40ºC. The change in concentration of Li2MoO4 over time is measured at 40ºC. Several oxoacid salts are tested as a precipitation inhibitor for Li2MoO4. Electrochemical measurements are carried out for iron in the deaerated test solution at 155ºC in order to examine the effect of precipitation inhibitor (sodium disulfite) on the passivation of iron. [Results and discussion]The concentration of molybdate in the test solution (initially 3.0×10-3 mol kg-1) reduced gradually at 40ºC and became almost constant around 5.0×10-4 mol kg-1. The addition of sodium carbonate, sodium nitrate, sodium borate, sodium phosphate was not effective at all, while sodium sulfate delayed the concentration decrease of molybdate. Sodium disulfite and sodium sulfite (1.0×10-2 mol kg-1) showed noticeable effect: sodium disulfite, in particular, kept the molybdate concentration above 2 × 10-3 mol kg-1 at 40ºC for long time. The effect of disulfite was kept even after the test solution experienced heating up to 155 ºC with additional passivator of lithium nitrate. The time variation of corrosion potential of iron in the test solution (17.3 mol kg-1 LiBr + 0.1 mol kg-1 LiOH+ 3.0×10-3 mol kg-1 Li2MoO4) at 155 ºC indicated that passivation of iron was delayed somehow by the addition of 1.0×10-2 mol kg-1 disulfite: it took about 10 h to reach passive region, while 5 h was needed in the absence of disulfite. But the delay was made up for by the further addition of nitrate passivator: the corrosion potential shifted into passive region soon after temperature reached 155 ºC irrespectively of the presence of disulfite. Polarization curves for iron also indicated harmlessness of disulfite against passivation behavior of iron. The results suggested usefulness of disufite salt as a precipitation inhibitor for Li2MoO4 with no harm in passivation of steel.

Enhanced oral delivery of celecoxib via the development of a supersaturable amorphous formulation utilising mesoporous silica and co-loaded HPMCAS

Stabilization of amorphous formulations via mesoporous silica has gained considerable attention for oral delivery of poorly soluble drugs. The release of the drug from the silica is expected to generate supersaturation which is often associated with subsequent precipitation. The aim of the study was hence to develop a novel supersaturable amorphous formulation through the co-loading of a BCS class II drug Celecoxib (CXB) with a precipitation inhibitor hydroxypropyl methylcellulose acetate succinate (HPMCAS) onto the silica. The addition of HPMCAS did not hamper the adsorption but on the contrary promoted the complete solid state conversion of the drug as proved by DSC analysis. In an in vitro pH shift assay, the CXB-HPMCAS co-loaded silica achieved a 5-fold solubility increase over the crystalline CXB and over the CXB-loaded silica blended with HPMCAS which did not show any enhancement. The drug co-loaded silica was then suspended in an aqueous vehicle facilitating the dosing to animals. The CXB-HPMCAS co-loaded silica suspension achieved 15-fold solubility increase in vitro over the crystalline counterpart which translated in 1.35-fold Cmax increase in vivo after oral dosing in rats. This approach represents a novel formulation strategy to maximize in vivo exposure of poorly soluble drugs critical for discovery studies.

Studying the Propensity of Compounds to Supersaturate: A Practical and Broadly Applicable Approach

Supersaturating drug delivery systems can enhance the oral bioavailability of poorly soluble drug compounds. Supersaturation of such compounds has been studied in many different ways; however, a more standardized method is required. The rationale of choosing suitable concentrations of supersaturation to study has previously been very inconsistent. This makes comparisons between studies and compounds difficult, as the propensity of compounds to supersaturate varies greatly. This study presents a standardized method to study the supersaturation of drug compounds. The method allows, both, for a ranking of compounds according to their supersaturation propensity and the effectiveness of precipitation inhibitors. The time–concentration profile of supersaturation and precipitation was studied in situ for 4 different concentrations for 6 model compounds (albendazole, aprepitant, danazol, felodipine, fenofibrate, and tadalafil) in the μDISS Profiler™ in fasted-state simulated intestinal fluid. A relation between the induction time of nucleation and the initial supersaturated concentration could be established based on classical nucleation theory. The model compounds had different propensities to upersaturate. The data show that a single degree of supersaturation or concentration would not have described the different systems adequately. The method could be used in early preformulation for characterization of supersaturation propensity of novel compounds or precipitation inhibitor effects.

Supersaturation of zafirlukast in fasted and fed state intestinal media with and without precipitation inhibitors

Poor water solubility is a bottle neck in the development of many new drug candidates, and understanding and circumventing this is essential for a more effective drug development. Zafirlukast (ZA) is a leukotriene antagonist marketed for the treatment of asthma (Accolate®). ZA is poorly water soluble, and is formulated in an amorphous form (aZA) to improve its solubility and oral bioavailability. It has been shown that upon dissolution of aZa, the concentration of ZA in solution is supersaturated with respect to its stable crystalline form (ZA monohydrate), and thus, in theory, the bioavailability increases upon amorphization of ZA. The polymers hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP), often used as stabilizers of the supersaturated state, are in the excipient list of Accolate®. It is not recommended to take Accolate® with food, as this reduces the bioavailability by 40%.The aim of this study was to investigate the effect of simulated fasted and fed state intestinal media as well as the effect of HPMC and PVP on the supersaturation and precipitation of ZA in vitro.Supersaturation of aZA was studied in vitro in a small scale setup using the μDiss Profiler™. Several media were used for this study: One medium simulating the fasted state intestinal fluids and three media simulating different fed state intestinal fluids. Solid state changes of the drug were investigated by small angle x-ray scattering. The duration wherein aZA was maintained at a supersaturated state was prolonged in the presence of HPMC and lasted more than 20h in the presence of PVP in a fasted state intestinal medium. The presence of PVP increased the concentration of drug dissolved in the supersaturated state. The duration of supersaturation was shorter in fed than in a fasted state simulated intestinal media, but the concentration during supersaturation was higher. It was thus not possible to predict any positive or negative food effects from the dissolution/precipitation curves from different media. Lipolysis products in the fed state simulated media seemed to cause both a negative effect on the duration of supersaturation, and an increased drug concentration during supersaturation. In contrast, when testing the effect of a fed state simulated medium compared to the fasted state medium, in the presence of PVP, a clear negative effect was seen on the dissolution/precipitation curved of the fed state medium. The drug concentration during supersaturation was marginally different in the two media, but a precipitation of ZA was seen in the fed state medium, which was not observed in the fasted state medium. Solid state transformation from aZA to ZA monohydrate (mhZA) upon precipitation of the supersaturated solutions was confirmed by small angle x-ray scattering. All of these results can explain the described in vivo behavior of ZA. For ZA simple dissolution experiments in vitro can be used to examine supersaturation, effectiveness of PI and potential food effects on these.

Development of Itraconazole Liquisolid Compact: Effect of Polyvinylpyrrolidone on the Dissolution Properties

The aim of this work was to utilize the liquisolid technique to enhance dissolution of itraconazole (ITZ). Liquisolid tablets of ITZ were formulated by using N-methyl-2-pyrrolidone as liquid vehicle, polyvinylpyrrolidone (PVP) as a precipitation inhibitor and magnesium aluminometasilicate Neusilin® as a carrier and coating material. The effect of PVP level on stability of liquid medication, physicomechnanical properties and dissolution rate of liquisolid compacts was studied in detail. The crystallinity of formulated drug and the interaction between excipients were examined by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). All the liquisolid tablets showed higher drug dissolution rates than the conventional, directly compressed tablets. The flowability of liquisolid powders was slightly improved as the proportion of PVP in ITZ-NMP mixture increased. Moreover, the stability of liquid medication and wetting ability of liquisolid tablets were improved by PVP. The presence of low amount of PVP (≤ 1%) in liquisolid formulation could enhance dissolution of ITZ liquisolid tablets, whereas the percentage of PVP over 5% decreased the dissolution of ITZ from liquisolid tablets. Both DSC and XRPD suggested reduction or loss of ITZ crystallinity upon liquisolid formulations indicating that the drug was almost solubilized and molecularly dispersed with excipients within the liquisolid matrix. It could be shown that increased solubility, wetting properties and surface area available for dissolution contributed to the improvement of the dissolution of ITZ from liquisolid tablets.

Effectiveness of supersaturation promoting excipients on albendazole concentrations in upper gastrointestinal lumen of fasted healthy adults

PurposeTo evaluate the impact of dosage form relevant levels of a polymeric precipitation inhibitor and of lipid excipients on supersaturation of upper gastrointestinal contents with albendazole, a lipophilic weak base. Materials and methodsAlbendazole concentrations in stomach and in duodenum were evaluated after administration of 1) a suspension in water (Susp-Control), 2) a suspension in water in which hydroxyprolylmethylcellulose E5 (HPMC E5) had been pre-dissolved (Susp-HPMC), and 3) and 4) two contrasting designs of lipid based suspensions dispersed in water (Susp-IIIA and Susp-IV), on a cross-over basis to fasted healthy adults. ResultsLimited, but statistically significant supersaturation of duodenal contents was observed after Susp-HPMC, Susp-IIIA, and Susp-IV; supersaturation was more consistent after Susp-HPMC administration. Based on total albendazole amount per volume, gastric secretions did not significantly alter volumes of bulk gastric contents during the first 40min post administration of a glass of non-caloric water-based fluid. Αlbendazole gastric concentrations were higher than in the administered suspensions, but similar for all four formulations. Gastric emptying of albendazole after administration of Susp-Control or Susp-HPMC was slower than after administration of Susp-IIIA or Susp-IV. ConclusionsSmall amounts of HPMC E5 were as effective as lipid excipients in achieving supersaturation of duodenal contents with albendazole, a fast precipitating weak base, in fasted adults. However, compared with the effect of HPMC E5 the effect of lipid excipients was delayed and variable.

Enhanced dissolution and oral absorption of tacrolimus by supersaturable self-emulsifying drug delivery system.

A new Soluplus (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer)-based supersaturable self-emulsifying drug delivery system (S-SEDDS) was formulated to enhance oral absorption of tacrolimus (FK506) with minimal use of oil, surfactant, and cosurfactant. A high payload supersaturable system (S-SEDDS) was prepared by incorporating Soluplus, as a precipitation inhibitor, to SEDDS consisting of Capmul MCM, Cremophor EL, and Transcutol (FK506:vehicle:Soluplus =1:15:1). In vitro dissolution profile and in vitro pharmacokinetic aspect of S-SEDDS in rats were comparatively evaluated with those of conventional SEDDS formulas containing four times greater content of vehicle components (FK506:vehicle =1:60). Both formulations formed spherical drug-loaded microemulsion <70 nm in size when in contact with aqueous medium. In an in vitro dissolution test in a nonsink condition, the amphiphilic polymer noticeably retarded drug precipitation and maintained >80% of accumulated dissolution rate for 24 hours, analogous to that from conventional SEDDS. Moreover, pharmacokinetic parameters of the maximum blood concentration and area under the curve from S-SEDDS formula in rats were not statistically different (P>0.05) than those of conventional SEDDS. The results suggest that the Soluplus-based supersaturable system can be an alternative to achieve a comparable in vitro dissolution profile and in vivo oral absorption with conventional SEDDS, with minimal use of vehicle ingredients.

The Effect of Additives on the High‐Temperature Stability of the Vanadium Redox Flow Battery Positive Electrolytes

AbstractSeveral inorganic additives are investigated as potential precipitation inhibitors for the positive half‐cell electrolyte of the vanadium redox flow battery (VRB) at elevated temperatures. Electrolyte stability tests on the more concentrated 2 m vanadium electrolyte show that of the additives tested, the best results are obtained with the addition of 1 % phosphoric acid that give induction times of 40, 22 and 18 days for 80, 90 and 95 % state of charge (SOC) solutions at 50 °C, compared with 5, 2 and 1 days respectively for the corresponding blank solution. Several additives are also evaluated at 45 °C in a vanadium redox flow cell operating with a 2 m vanadium electrolyte. In the case of the cell employing the blank solution, a sudden drop in capacity, followed by pump failure is observed after around 70 cycles, while the cells with the additives continue to cycle without failure for 120 and 150 cycles for ammonium sulphate and ammonium phosphate additives respectively. A similar stabilising effect has previously been observed with these additives at low temperatures in the negative half‐cell electrolyte of the VRB, confirming that these stabilising agents have the potential to extend the upper and lower operating temperature limits of a 2 m vanadium electrolyte in the VRB to 45 and 5 °C respectively, while also significantly enhancing its energy density without the need for potentially hazardous chloride additions.