Equilibrium Solubility Values Research Articles

A novel simulated media system for in vitro evaluation of bioequivalent intestinal drug solubility

Orally administered solid drug must dissolve in the gastrointestinal tract before absorption to provide a systemic response. Intestinal solubility is therefore crucial but difficult to measure since human intestinal fluid (HIF) is challenging to obtain, varies between fasted (Fa) and fed (Fe) states and exhibits inter and intra subject variability. A single simulated intestinal fluid (SIF) cannot reflect HIF variability, therefore current approaches are not optimal. In this study we have compared literature Fa/FeHIF drug solubilities to values measured in a novel in vitro simulated nine media system for either the fasted (Fa9SIF) or fed (Fe9SIF) state. The manuscript contains 129 literature sampled human intestinal fluid equilibrium solubility values and 387 simulated intestinal fluid equilibrium solubility values. Statistical comparison does not detect a difference (Fa/Fe9SIF vs Fa/FeHIF), a novel solubility correlation window enclosed 95% of an additional literature Fa/FeHIF data set and solubility behaviour is consistent with previous physicochemical studies. The Fa/Fe9SIF system therefore represents a novel in vitro methodology for bioequivalent intestinal solubility determination. Combined with intestinal permeability this provides an improved, population based, biopharmaceutical assessment that guides formulation development and indicates the presence of food based solubility effects. This transforms predictive ability during drug discovery and development and may represent a methodology applicable to other multicomponent fluids where no single component is responsible for performance.

Solubility of cinnarizine in natural deep eutectic solvent (camphor + menthol) and correlation with different solubility models

The objectives of the current investigation are (1) to determine the cinnarizine's equilibrium solubility values in four-different molar ratios of camphor and menthol-based natural deep eutectic solvents (NADES) (1:0.65, 1:0.97, 1:1.47 & 1:2.25) at 0.1 MPa atmospheric pressure and five-diverse temperature conditions [T = (298.15, 300.65, 303.15, 305.65 & 308.15) K], (2) to validate the experimentally obtained cinnarizine's solubility values with various empirical and local composition models and (3) to determine the thermodynamic properties of cinnarizine solubility in camphor and menthol-based NADES. In a preliminary pilot study, the solubility of cinnarizine was checked in different NADES-forming excipients such as camphor, capric acid, lauric acid, menthol and thymol at various molar ratios. At 1:0.97 molar ratio of camphor and menthol, the mole fraction solubility value of drug was augmented up to 4.6847 × 10−3 at 298.15 K in comparison to the other tested NADES-forming excipients. The highest cinnarizine's mole fraction solubility was obtained in 1:0.97 molar ratio of camphor and menthol NADES at 308.15 K with a value of 19.5207 × 10−3, while the lowest value (1.8 × 10−3) was obtained in 1:0.67 ratio of camphor and menthol NADES at 298.15 K. Solubility correlation results show that the modified Jouyban-Acree model was best-fitted as it was obtained with the lowest absolute average deviation percent and absolute relative deviation percent values. The findings of dissolution thermodynamic of cinnarizine in NADESs composed of camphor and menthol indicate that the cinnarizine dissolution in camphor and menthol-based NADESs is enthalpy-driven. Eutecticity could be of an effective strategy to overcome cinnarizine's obstacle during drug delivery system development.

Fasted intestinal solubility limits and distributions applied to the biopharmaceutics and developability classification systems

After oral administration, a drug’s solubility in intestinal fluid is an important parameter influencing bioavailability and if the value is known it can be applied to estimate multiple biopharmaceutical parameters including the solubility limited absorbable dose. Current in vitro measurements may utilise fasted human intestinal fluid (HIF) or simulated intestinal fluid (SIF) to provide an intestinal solubility value. This single point value is limited since its position in relation to the fasted intestinal solubility envelope is unknown. In this study we have applied a nine point fasted equilibrium solubility determination in SIF, based on a multi-dimensional analysis of fasted human intestinal fluid composition, to seven drugs that were previously utilised to investigate the developability classification system (ibuprofen, mefenamic acid, furosemide, dipyridamole, griseofulvin, paracetamol and acyclovir). The resulting fasted equilibrium solubility envelope encompasses literature solubility values in both HIF and SIF indicating that it measures the same solubility space as current approaches with solubility behaviour consistent with previous SIF design of experiment studies. In addition, it identifies that three drugs (griseofulvin, paracetamol and acyclovir) have a very narrow solubility range, a feature that single point solubility approaches would miss. The measured mid-point solubility value is statistically equivalent to the value determined with the original fasted simulated intestinal fluid recipe, further indicating similarity and that existing literature results could be utilised as a direct comparison. Since the multi-dimensional approach covered greater than ninety percent of the variability in fasted intestinal fluid composition, the measured maximum and minimum equilibrium solubility values should represent the extremes of fasted intestinal solubility and provide a range. The seven drugs all display different solubility ranges and behaviours, a result also consistent with previous studies. The dose/solubility ratio for each measurement point can be plotted using the developability classification system to highlight individual drug behaviours. The lowest solubility represents a worst-case scenario which may be useful in risk-based quality by design biopharmaceutical calculations than the mid-point value. The method also permits a dose/solubility ratio frequency distribution determination for the solubility envelope which permits further risk-based refinement, especially where the drug crosses a classification boundary. This novel approach therefore provides greater in vitro detail with respect to possible biopharmaceutical performance in vivo and an improved ability to apply risk-based analysis to biopharmaceutical performance. Further studies will be required to expand the number of drugs measured and link the in vitro measurements to in vivo results.

Equilibrium solubility determination, Hansen solubility parameters and solution thermodynamics of cabozantinib malate in different monosolvents of pharmaceutical importance

This research work reports new equilibrium solubility data for a novel weakly soluble tyrosine kinase inhibitor cabozantinib malate (CBZM) (a novel antitumor drug) in twelve different monosolvents (MS) of pharmaceutical importance including “water, methanol (MeOH), ethanol (EtOH), isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), ethyl acetate (EA), Transcutol-HP (THP) and dimethyl sulfoxide (DMSO)” within the temperature range “T = 298.2-318.2 K" under p = 101.1 kPa. The experimental equilibrium solubility values of CBZM were correlated well with “van't Hoff and the modified Apelblat models” with an error values of less than 3.0%. Different Hansen solubility parameters (HSPs) for CBZM and different MS of pharmaceutical importance were also predicted using HSPiP software and various mathematical equations. The maximum value of CBZM solubility was 4.35 × 10−2 in mole fraction in DMSO at T = 318.2 K, but the least data was found in water. The equilibrium solubility of CBZM increased with the rising temperature and the order followed in the twelve MS of pharmaceutical importance was DMSO (4.35 × 10−2) > PEG-400 (1.42 × 10−2) > THP (5.45 × 10−3) > PG (2.38 × 10−3) > 2-BuOH (2.21 × 10−3) > 1-BuOH (2.15 × 10−3) > IPA (1.69 × 10−3) > EG (1.38 × 10−3) > EtOH (1.27 × 10−3) > MeOH (7.05 × 10−4) > EA (4.15 × 10−4) > water (8.50 × 10−7) at T = 318.2 K. Similar trends were also found in other temperatures investigated. Most of the solubility parameters of CBZM were found to be closed with that of DMSO. Thermal analysis showed no existence of processes such as solvation, hydration or polymorphic transformation of CBZM during the entire experiment. The maximum solute-solvent interactions were recorded in CBZM-DMSO, CBZM-PEG-400 and CBZM-THP compared to other combination of drug and MS. “Apparent thermodynamic analysis” suggested an “endothermic and entropy-driven dissolution” of CBZM in all studies MS of pharmaceutical importance. Based on these results, DMSO has been considered as the best co-solvent for the solubilization of CBZM.

Buclizine crystal forms: First Structural Determinations, counter-ion stoichiometry, hydration, and physicochemical properties of pharmaceutical relevance.

Buclizine (BCZ) is a chiral synthetic piperazine derivative which has antihistaminic, anti-muscarinic and antiemetic properties, and has been reintroduced as an appetite stimulant, especially for pediatric patients. Structural information about this drug, as well as other buclizine crystalline forms (solvates, salts and co-crystals) including the BCZ free-base (BCZ-FB), is non-existent. Here, we present for the first time the crystal structure of the monohydrochloride monohydrate salt of BCZ (BCZHCl·H2O), and of its anhydrous form, BCZHCl. Interestingly, BCZHCl·H2O was obtained by recrystallization from the raw material (BCZH2Cl2) in ethanol:water solution showing that BCZ anhydrous dihydrochloride salt changes easily to a monohydrochloride monohydrate salt modification, which raise concerns about formulation quality control. BCZHCl·H2O and BCZHCl crystallize in the orthorhombic space groups (Pna21 and Pca21) belonging to the mm2 point group and are thus classified as non-centrosymmetric achiral structures (NA). Intuitively, we expect these salts to crystallize in a space group with a center of symmetry, since less than 5% of the known racemic compounds crystallize in the NA type. The crystal structures of BCZH2Cl2 and BCZ-FB were not determined, but their existence was verified by other techniques (chloride ion analysis, PXRD, HPLC, FT-IR, DSC, TGA) and by comparison of the obtained results with those found for BCZHCl. Additionally, we have also performed an evaluation of the equilibrium solubility (at six different aqueous media) and the dissolution profile of the BCZHCl salt compared to the raw material and BCZ-FB. Different equilibrium solubility values were found comparing the three forms in acidic and neutral pH ranges and all of them were insoluble at pH>7.0. Moreover, tablets prepared with BCZH2Cl2, BCZHCl or BCZ-FB show significant differences in terms of dissolution profile.

Revisit of solubility of oxytetracycline polymorphs. An old story in the light of new results

In the literature the therapeutic nonequivalence of oxytetracycline hydrochloride (OTCH) capsules and tablets was attributed to the different aqueous solubility of polymorphs without their comprehensive study. Our aim was to reveal the effects of polymorphism on equilibrium solubility, dissolution kinetics and the supersaturation of two OTCH polymorphs (stable Form A and metastable Form B).The equilibrium solubility was measured in biorelevant pH range 4–7.4 by the standardized saturation shake-flask method. We also studied the solubility in SGF at pH 1.2 and the effect of the pH change from 1.2 to 5.0 on solubility. The dissolution was studied using real-time concentration monitoring with an ATR probe attached to a UV spectrophotometer (µDISS Profiler). A wide spectrum of solid phase analysis methods (SEM, IR, XRPD, Raman) was applied for characterization of polymorphs and to identify which form is present at the equilibrium solubility. Identical equilibrium solubility values were obtained at the same pHs in region 4.0–7.4 using the two polymorphs as starting materials. The XRPD analysis of the isolated solid phases proved that both polymorphic forms were converted to dihydrate form. In situ monitoring of the dissolution at pH 5.0 showed immediate dissolution, no difference in supersaturation, and short equilibration time for both forms indicating the immediate conversion. In SGF (pH 1.2) Form B dissolved better than Form A and showed significantly different dissolution kinetic and stability. A long-lasting, false chain-citation stating that Form B dissolves 28x better in water than Form A, was cut by the present study (i) revealing that the cited data was measured in IPA not in water, and (ii) proving that only the intrinsic solubility of OTC dihydrate can be measured in water due to conversion of polymorphs under the experimental conditions of solubility measurement. However this conversion is inhibited below pH 1.5, so the differences in solubility and dissolution kinetic found at pH 1.2 may contribute to the interpretation of the different serum-levels reported at solid formulations.

The role of solid state properties on the dissolution performance of flufenamic acid

Flufenamic acid is a nonsteroidal anti-inflammatory drug characterized by a low solubility and a variable oral bioavailability. Flufenamic acid is present in the commercial products in two polymorphic enantiotropic forms (Form I and III). Bioinequivalence was observed for commercial solid dosage forms due to the different dissolution rate of batches. Aim of this work is the full characterization of the solid state properties of flufenamic acid in order to evidence reasons of its variable dissolution properties. Two different batches of pure drug obtained by different suppliers were fully characterized. In order to evaluate the effect of the technological processes used for tablet production, the powders were submitted to grinding, kneading, and compression. Thermal analysis and X-ray diffraction studies proved that the drug was provided by both suppliers as Form I, Form III is obtained by recrystallization from ethanol or ethanol/water of both batches and no changes were observed after the different mechanical treatments. No difference was observed between the two forms in terms of equilibrium solubility values. Dissolution rate studies evidenced a difference between the two batches due to their different particle size, which disappeared after sieving. Interestingly, a significant difference in terms of intrinsic dissolution rate and surface wettability of the two compacted powders was observed, even after sieving, probably related to a different behavior of the two powder samples under compaction. These results should be taken into account, during a tablet formulation, in order to obtain a reproducible dissolution performance of the drug, regardless of its original supplier.

Right filter-selection for phase separation in equilibrium solubility measurement

The phase separation is a crucial step in equilibrium solubility measurements. In the standardized protocol of saturation shake-flask method, sedimentation is proposed as the safest technique. However filtration is widely used in pharma practice. In this paper the effect of the filtration on the measured equilibrium solubility results is presented. The equilibrium solubility values of four model compounds, namely diclofenac sodium, hydrochlorothiazide, papaverine hydrochloride and progesterone were determined at various pH values using the saturation shake-flask method. Two phase separation techniques (sedimentation and filtration) were applied for the separation of the solid from the saturated solution. Four membrane filters, polyvinylidene fluoride (PVDF), polyether sulfone (PES), polytetrafluoroethylene (PTFE) and nylon, as well as an analytical filter paper were investigated. The results obtained by filtration were compared with those measured by sedimentation and the distortion effect of the filter (DEF) on solubility results was expressed in %. The results showed that the filter material type is able to remarkably influence the results in solubility measurements. In several cases, the significant adsorption to the filter caused high inaccuracy in the measured concentration value, more over in some cases failed to work at all. As a main conclusion of this work, if the step of filtration is inevitable, the adsorption to the filter can be mitigated with the appropriate filter type selection what needs some experiences and knowledge about the acid-base chemistry and polar/apolar nature of the sample.

Depletion of amyloid-β peptides from solution by sequestration within fibril-seeded hydrogels.

Aggregation of amyloid-β (Aβ) peptides in brain tissue leads to neurodegeneration in Alzheimer's disease (AD). Regardless of the kinetics or detailed mechanisms of Aβ aggregation, aggregation can only occur if Aβ concentrations exceed their local equilibrium solubility values. We propose that excess Aβ peptides can be removed from supersaturated solutions, including solutions in biological fluids, by the addition of hydrogels that are seeded with Aβ fibril fragments. Fibril growth within the hydrogels then sequesters excess peptides until equilibrium concentrations are reached. Experiments with 40- and 42-residue Aβ peptides (Aβ40 and Aβ42) in phosphate buffer at 24°C and in filtered fetal bovine serum at 37°C, using crosslinked polyacrylamide hydrogels, demonstrate the validity of this concept. Aβ sequestration in fibril-seeded hydrogels (or other porous media) may prove to be a useful technique in experiments with animal models of AD and may represent a possible approach to preventing or slowing the progression of AD in humans.

Statistical investigation of the full concentration range of fasted and fed simulated intestinal fluid on the equilibrium solubility of oral drugs

Upon oral administration the solubility of a drug in intestinal fluid is a key property influencing bioavailability. It is also recognised that simple aqueous solubility does not reflect intestinal solubility and to optimise in vitro investigations simulated intestinal media systems have been developed. Simulated intestinal media which can mimic either the fasted or fed state consists of multiple components each of which either singly or in combination may influence drug solubility, a property that can be investigated by a statistical design of experiment technique. In this study a design of experiment covering the full range from the lower limit of fasted to the upper limit of fed parameters and using a small number of experiments has been performed. The measured equilibrium solubility values are comparable with literature values for simulated fasted and fed intestinal fluids as well as human fasted and fed intestinal fluids. The equilibrium solubility data range is statistically equivalent to a combination of published fasted and fed design of experiment data in six (indomethacin, phenytoin, zafirlukast, carvedilol, fenofibrate and probucol) drugs with three (aprepitant, tadalafil and felodipine) drugs not equivalent. In addition the measured equilibrium solubility data sets were not normally distributed. Further studies will be required to determine the reasons for these results however it implies that a single solubility measurement without knowledge of the solubility distribution will be of limited value. The statistically significant media factors which promote equilibrium solubility (pH, sodium oleate and bile salt) were in agreement with published results but the number of determined significant factors and factor interactions was fewer in this study, lecithin for example did not influence solubility. This may be due to the reduction in statistical sensitivity from the lower number of experimental data points or the fact that using the full range will examine media parameters ratios that are not biorelevant. Overall the approach will provide an estimate of the solubility range and the most important media factors but will not be equivalent to larger scale focussed studies. Further investigations will be required to determine why some drugs do not produce equivalent DoE solubility distributions, for example combined fasted and fed DoE, but this simply may be due to the complexity and individuality of the interactions between a drug and the media components.

Statistical investigation of simulated fed intestinal media composition on the equilibrium solubility of oral drugs

Gastrointestinal fluid is a complex milieu and it is recognised that gut drug solubility is different to that observed in simple aqueous buffers. Simulated gastrointestinal media have been developed covering fasted and fed states to facilitate in vitro prediction of gut solubility and product dissolution. However, the combination of bile salts, phospholipids, fatty acids and proteins in an aqueous buffered system creates multiple phases and drug solubility is therefore a complex interaction between these components, which may create unique environments for each API. The impact on solubility can be assessed through a statistical design of experiment (DoE) approach, to determine the influence and relationships between factors. In this paper DoE has been applied to fed simulated gastrointestinal media consisting of eight components (pH, bile salt, lecithin, sodium oleate, monoglyceride, buffer, salt and pancreatin) using a two level D-optimal design with forty-four duplicate measurements and four centre points. The equilibrium solubility of a range of poorly soluble acidic (indomethacin, ibuprofen, phenytoin, valsartan, zafirlukast), basic (aprepitant, carvedilol, tadalafil, bromocriptine) and neutral (fenofibrate, felodipine, probucol, itraconazole) drugs was investigated. Results indicate that the DoE provides equilibrium solubility values that are comparable to literature results for other simulated fed gastrointestinal media systems or human intestinal fluid samples. For acidic drugs the influence of pH predominates but other significant factors related to oleate and bile salt or interactions between them are present. For basic drugs pH, oleate and bile salt have equal significance along with interactions between pH and oleate and lecithin and oleate. Neutral drugs show diverse effects of the media components particularly with regard to oleate, bile salt, pH and lecithin but the presence of monoglyceride, pancreatin and buffer have significant but smaller effects on solubility. There are fourteen significant interactions between factors mainly related to the surfactant components and pH, indicating that the solubility of neutral drugs in fed simulated media is complex. The results also indicate that the equilibrium solubility of each drug can exhibit individualistic behaviour associated with the drug's chemical structure, physicochemical properties and interaction with media components. The utility of DoE for fed simulated media has been demonstrated providing equilibrium solubility values comparable with similar in vitro systems whilst also providing greater information on the influence of media factors and their interactions. The determination of a drug's gastrointestinal solubility envelope provides useful limits that can potentially be applied to in silico modelling and in vivo experiments.

On the calculation of solubilities via direct coexistence simulations: Investigation of NaCl aqueous solutions and Lennard-Jones binary mixtures.

Direct coexistence molecular dynamics simulations of NaCl solutions and Lennard-Jones binary mixtures were performed to explore the origin of reported discrepancies between solubilities obtained by direct interfacial simulations and values obtained from the chemical potentials of the crystal and solution phases. We find that the key cause of these discrepancies is the use of crystal slabs of insufficient width to eliminate finite-size effects. We observe that for NaCl crystal slabs thicker than 4 nm (in the direction perpendicular to the interface), the same solubility values are obtained from the direct coexistence and chemical potential routes, namely, 3.7 ± 0.2 molal at T = 298.15 K and p = 1 bar for the JC-SPC/E model. Such finite-size effects are absent in the Lennard-Jones system and are likely caused by surface dipoles present in the salt crystals. We confirmed that μs-long molecular dynamics runs are required to obtain reliable solubility values from direct coexistence calculations, provided that the initial solution conditions are near the equilibrium solubility values; even longer runs are needed for equilibration of significantly different concentrations. We do not observe any effects of the exposed crystal face on the solubility values or equilibration times. For both the NaCl and Lennard-Jones systems, the use of a spherical crystallite embedded in the solution leads to significantly higher apparent solubility values relative to the flat-interface direct coexistence calculations and the chemical potential values. Our results have broad implications for the determination of solubilities of molecular models of ionic systems.

Effect of compositional heterogeneity on dissolution of non-ideal LNAPL mixtures

The extent of dissolution of petroleum hydrocarbon fuels into groundwater depends greatly on fuel composition. Petroleum fuels can consist of thousands of compounds creating different interactions within the non-aqueous phase liquid (NAPL), thereby affecting the relative dissolution of the components and hence a groundwater plume's composition over long periods. Laboratory experiments were conducted to study the variability in the effective solubilities and activity coefficients for common constituents of gasoline fuels (benzene, toluene, p-xylene and 1,2,4-trimethylbenzene) (BTX) in matrices with an extreme range of molar volumes and chemical affinities. Four synthetic mixtures were investigated comprising BTX with the bulk of the NAPL mixtures made up of either, ethylbenzene (an aromatic like BTX with similar molar volume); 1,3,5-trimethylbenzene (an aromatic with a greater molar volume); n-hexane (an aliphatic with a low molar volume); and n-decane (an aliphatic with a high molar volume). Equilibrium solubility values for the constituents were under-predicted by Raoult's law by up to 30% (higher experimental concentrations) for the mixture with n-hexane as a filler and over-predicted by up to 12% (lower experimental concentrations) for the aromatic mixtures with ethylbenzene and 1,3,5-trimethylbenzene as fillers. Application of PP-LFER (poly-parameter linear free energy relationship) model for non-ideal mixtures also resulted in poor correlation between experimentally measured and predicted concentrations, indicating that differences in chemical affinities can be the major cause of deviation from ideal behavior. Synthetic mixtures were compared with the dissolution behavior of fresh and naturally weathered unleaded gasoline. The presence of lighter aliphatic components in the gasoline had a profound effect on estimating effective solubility due to chemical affinity differences (estimated at 0.0055 per percentage increase in the molar proportion of aliphatic) as well as reduced molar volumes (estimated at −0.0091 in the activity coefficient per unit increase in molar volume, mL/mol). Previously measured changes in activity coefficients due to natural weathering of 0.25 compares well to 0.27 calculated here based on changes in the chemical affinity and molar volumes. The study suggests that the initial estimation of the composition of a fuel is crucial in evaluating dissolution processes due to ideal and non-ideal dissolution, and in predicting long term dissolution trends and the longevity of NAPL petroleum plume risks.

Simulated rat intestinal fluid improves oral exposure prediction for poorly soluble compounds over a wide dose range

<p class="ADMETabstracttext">Solubility can be the absorption limiting factor for drug candidates and is therefore a very important input parameter for oral exposure prediction of compounds with limited solubility. Biorelevant media of the fasted and fed state have been published for humans, as well as for dogs in the fasted state. In a drug discovery environment, rodents are the most common animal model to assess the oral exposure of drug candidates. In this study a rat simulated intestinal fluid (rSIF) is proposed as a more physiologically relevant media to describe drug solubility in rats. Equilibrium solubility in this medium was tested as input parameter for physiologically-based pharmacokinetics (PBPK) simulations of oral pharmacokinetics in the rat. Simulations were compared to those obtained using other solubility values as input parameters, like buffer at pH 6.8, human simulated intestinal fluid and a comprehensive dissolution assay based on rSIF. Our study on nine different compounds demonstrates that the incorporation of rSIF equilibrium solubility values into PBPK models of oral drug exposure can significantly improve the reliability of simulations in rats for doses up to 300 mg/kg compared to other media. The comprehensive dissolution assay may help to improve further simulation outcome, but the greater experimental effort as compared to equilibrium solubility may limit its use in a drug discovery environment. Overall, PBPK simulations based on solubility in the proposed rSIF medium can improve prioritizing compounds in drug discovery as well as planning dose escalation studies, e.g. during toxicological investigations.</p>

High-Speed Intrinsic Dissolution Rate in One Minute Using the Single-Particle Intrinsic Dissolution Rate Method.

Intrinsic dissolution rate (IDR) has traditionally been determined from a constant surface area of a substance. Here we present an optofluidic single-particle intrinsic dissolution rate (SIDR) method, by means of which real-time determination of IDR from continuously changing effective surface areas of dissolving individual microparticles, is possible. The changing surface area of the individual microparticles is characterized through continuous random orientation 3D particle morphology characterization during the dissolution process. Using noninvasive optical monitoring and nonspecific image analysis, we determined IDRs of a diverse set of substances from individual pure-substance microparticles (14-747 μg) with an average relative standard deviation of 9.4%. A linear fit between SIDR and literature equilibrium solubility values (R(2) = 0.999) was achieved and kinetic solubility equivalent SIDRs were obtained, for all substances, in as little as 1 min. Such miniaturized methods could become valuable tools in drug discovery, by providing resource sparing higher quality data acquisition means to replace current high-throughput solubility methods.

Preparation and crystallographic analysis of gliclazide polymorphs.

Since the introduction of gliclazide in the pharmaceutical industry, a large number of research groups have been engaged in various investigations aiming to enhance its biomedical application. But, very limited efforts have been made to study polymorphism of gliclazide. Therefore, this study focuses on solvent-induced polymorphism of gliclazide and its characterization by thermal methods. Three polymorphs namely, Form-I, II and III and an amorphous powder were produced from different solvents and solvent mixtures. Crystals were analyzed using infrared spectroscopy, differential scanning calorimetry, X-ray powder diffraction and single crystal x-ray diffraction. Polymorph Form-I is found to exist in centro-symmetric triclinic P-1 space group and has endothermic peak at 162.93°. Form-II has endothermic peak from 171.2° to 172.35° and exists in centro-symmetric monoclinic P21/a space group while Form-III has endothermic peak from 168.93° to 169.86° and exists in centro-symmetric monoclinic P21/n space group. The equilibrium solubility values of Form-I, II, III and the amorphous form were 0.4825±0.025, 0.2341±0.042, 0.2581±0.038 and 0.5213±0.072 mg/ml, respectively. The Form-I has relatively higher solubility and similar to that of amorphous gliclazide. Form-II and Form-III are relatively most stable and least soluble. However, there was no remarkable difference in their aqueous solubility under the conditions in which study was conducted.

Study of pH-dependent drugs solubility in water

The solubilities of five sparingly soluble drug-compounds in water have been measured at constant temperatures (298.1K and 310.1K) by the classical saturation shake-flask method. All substances presented in this work are derivatives of anthranilic acid: flufenamic acid, (FLU), mefenamic acid, (MEF), niflumic acid, (NIF), diclofenac sodium, (DIC), and meclofenamic sodium, (MEC). All of them have anti-inflammatory action. Since the aqueous solubility of the ionized drug is significantly higher than the unionized, the experimental conditions that affect equilibrium solubility values such as composition of aqueous buffer have been examined. The Henderson-Hasselbalch (HH) relationship has been used to predict the pH-dependent solubility profiles of chosen drugs at two temperatures. For this purpose the pKa values of the investigated drugs have been determined with Bates-Schwarzenbach spectrophotometric method at temperature 310.1 K. At temperature 298.1K these values were reported earlier. Similar values of pKa were obtained from the solubility measurements.

Comparison of the Solubility and Dissolution of Drugs in FastedState Biorelevant Media (FaSSIF and FaSSIF-V2)

The equilibrium solubility values and dissolution profiles in each of the media (FaSSIF or FaSSIF-V2) produced using methylene chloride and the corresponding SIF Powder are equivalent for the drugs tested representing acid, basic, and neutral compounds. Therefore, it is practical to switch from the more labor-intensive solvent-evaporation method to the use of standardized instant powders for preparing biorelevant media without affecting the solubility and dissolution results. Testing in the two versions of FaSSIF media with different bile salt/lecithin ratios will give an indication on how the drug and formulation could be affected in vivo by the variations in bile salt/lecithin ratio within the range found in human small intestinal fluids. INTRODUCTION Biorelevant media are artificial in vitro media designed to share physicochemical properties with their corresponding fluids found in vivo in terms of osmolarity, pH, buffer capacity, and surfactant content, for example. Specifically, intestinal biorelevant media are widely used to mimic the properties of gastrointestinal fluids for in vitro solubility and dissolution studies. These media can also be used to simulate gastrointestinal stability and to perform permeability studies (1). Biorelevant media simulate the gastrointestinal fluids by containing the physiological surfactants, bile salt and lecithin. These media are particularly important for the development of poorly soluble drugs, because these surfactants significantly increase solubility. Biorelevant intestinal media were first proposed by Dressman et al. (2) at the University of Frankfurt in collaboration with Reppas from the University of Athens who identified the deficiencies of standard pharmacopeial media. These two groups also demonstrated the clear advantage of biorelevant media over standard conventional media for studying the solubility and dissolution of poorly soluble compounds. Biorelevant intestinal media simulate intestinal fluids secreted under fasted(FaSSIF) or fed-state conditions (FeSSIF). Food intake alters the physiochemical properties and composition of intestinal fluids for digestion. That is why separate intestinal media are defined for fastedand fed-state conditions. The two states of media enable formulation scientists to obtain solubility values and dissolution profiles of drugs and their formulations in vitro under both fasted and fed states. This can help detect food effects and optimize formulation performance using standard pharmacopeial dissolution test apparatus (e.g., USP Apparatus 2 and 4). There are biorelevant media representing fluids found along all regions in the gastrointestinal tract. However, simulated upper small intestinal media are the most commonly used, particularly for immediate-release drugs, because they simulate the fluids in the intestinal region from which most drugs are absorbed. FaSSIF and FaSSIF-V2 are the two most frequently used compositions for biorelevant intestinal media reflecting fasted-state conditions. The main difference between FaSSIF and FaSSIF-V2 is the reduced amount of lecithin in FaSSIF-V2 (Table 1) as compared with FaSSIF. The level of lecithin in both versions falls within the range typically found in aspirates sampled from healthy human volunteers. The purpose of this study was to evaluate the equilibrium solubility of four poorly water soluble drug substances (danazol, dipyridamole, ketoconazole, miconazole) and the drug dissolution from five drug products containing drugs with various pKa values under fasted-state conditions (i.e., without food interference) using the FaSSIF and FaSSIF-V2 media. The drug products contained acidic (mefenamic acid), basic (ketoconozole), or neutral (danazol, metoprolol, paracetamol) compounds. In addition, the solubility and drug dissolution behaviors were compared in media made from commercially available instant powders (SIF Powder Original and SIF Powder FaSSIF-V2 from biorelevant.com, UK) and prepared from methylene chloride as described by Marques (3). MATERIALS AND METHODS Materials Drugs Used for Solubility Testing Danazol was purchased from Jai Radhe (Ahmedabad, India). Dipyridamole was from Sigma Aldrich Chemie GmbH *Corresponding author. Contact: www.biorelevant.com/contact dx.doi.org/10.14227/DT200313P44

Laboratory‐scale experiments and numerical modeling of cosolvent flushing of multi-component NAPLs in saturated porous media

This study examines the mechanistic processes governing multiphase flow of a water–cosolvent–NAPL system in saturated porous media. Laboratory batch and column flushing experiments were conducted to determine the equilibrium properties of pure NAPL and synthetically prepared NAPL mixtures as well as NAPL recovery mechanisms for different water–ethanol contents. The effect of contact time was investigated by considering different steady and intermittent flow velocities. A modified version of multiphase flow simulator (UTCHEM) was used to compare the multiphase model simulations with the column experiment results. The effect of employing different grid geometries (1D, 2D, 3D), heterogeneity and different initial NAPL saturation configurations was also examined in the model. It is shown that the change in velocity affects the mass transfer rate between phases as well as the ultimate NAPL recovery percentage. The experiments with low flow rate flushing of pure NAPL and the 3D UTCHEM simulations gave similar effluent concentrations and NAPL cumulative recoveries. Model simulations over-estimated NAPL recovery for high specific discharges and rate-limited mass transfer, suggesting a constant mass transfer coefficient for the entire flushing experiment may not be valid. When multi-component NAPLs are present, the dissolution rate of individual organic compounds (namely, toluene and benzene) into the ethanol–water flushing solution is found not to correlate with their equilibrium solubility values.

THERMODYNAMICS OF THE MIXING PROCESS OF SEVERAL SODIUM SULFONAMIDES IN ETHANOL + WATER COSOLVENT MIXTURES

Sodium sulfonamides have been extensively used for the treatment of certain infections caused by several types of microorganisms. Although sulfonamides are still widely used in therapeutics, the physicochemical information about their aqueous solutions has not been completed. In this context, the thermodynamic functions of mixing three structurally related sodium sulfonamides were evaluated: Gibbs energy, enthalpy, and entropy. The quantities of mixing were calculated based on the fusion calorimetric values obtained from differential scanning calorimetry measurements and equilibrium solubility values reported in the literature for all the drugs with ethanol + water mixtures. By means of an enthalpy-entropy compensation analysis, non-linear ΔH0mix vs. ΔG0mix plots with negative slopes from neat ethanol to a 0.60 ethanol mass fraction, and positive slopes from the latter composition to neat water were obtained. From these results, it was concluded that the dissolution process of these drugs in ethanol-rich mixtures was entropy-driven; whereas, in water-rich mixtures the process was enthalpy-driven. Nevertheless, the molecular and ionic events involved in the dissolution of these drugs in this cosolvent system remain unclear.