Dissolution Parameters Research Articles

Development and Validation of a Discriminatory Dissolution Method for Rifaximin Products

The commercial product of rifaximin (RFX) contains α form. The α form can change to β form on exposure to high humidity that can occur during manufacturing, stability, and in-use period. It is critical to maintain α form of the drug in a drug product to avoid variability in clinical response. U.S. Food and Drug Administration dissolution method was found to be nondiscriminatory for RFX formulations containing either 100% α or β form. The objective of this study was to develop a discriminatory dissolution method that can detect low levels of α to β transformation in RFX products. Formulations containing a variable fraction of α and β forms were prepared by using direct compression method. Dissolution parameters investigated were type of dissolution medium (water and phosphate buffer), volume (500, 900, and 1000 mL), and paddle speed (50, 75, and 150 rpm). Dissolution in water with 0.2% sodium lauryl sulfate was less than 80% and nondiscriminatory. However, dissolution tested in a phosphate buffer pH 7.4 with 0.2% sodium lauryl sulfate at 50 rpm was discriminatory with more than 17.5% difference in dissolution profile between formulations containing α and β forms. The developed method can detect polymorphic transformation if there is 25% or more β form conversion.

The effect of alkaline solution seepage on deformation appearances in the soil foundation of engineering structures

Aim. This study aims to analyze the influence of static loading and descending seepage of concentrated alkaline solution on deformation appearances in the soil foundation and forming the construction tilt using the example of an overhead crane. Methodology. The methodology of research included laboratory determination of the physico-mechanical and subsidence properties of soils focusing on alluvial-diluvial loam and groundwater chemical composition at the studied site, evaluation of leaching parameters of loam soil phase by an alkaline solution using the X-ray fluorescent spectrometer СЕР-01 ElvaX Plus, and variable-based calculations of soil subsidence based on the standard techniques applied in geotechnics taking into account partial dissolution of soil solid phase. Findings. This study examined the case of an overhead crane with the foundation affected by the leakages of strong alkaline solutions from technological basins on the ground. Laboratory studies have established the components of Al2O3, Fe2O3, CaO, K2O soluble with strong alkaline solution and their share of 13,3% in the solid phase of the alluvial-diluvial loam sampled at the site. These compounds can transform into more soluble salts in a concentrated alkaline medium, which creates the conditions for the development of soil collapse and subsidence, with the chemically induced deformations being more significant in comparison to those in soils filled with a neutral pore solution. Calculations of soil subsidence and collapse with and without taking into account the chemical impact on soils under the overhead crane foundation showed that the non-uniform critical deformations of 5...10 cm leading to an unacceptable tilt between the crane columns of 0.004 can be caused only by the long-term descending seepage of an alkaline solution and leaching the alluvial-diluvial loam. The calculated deformations and tilt correlate with the appeared deformations and the tilt between the crane columns that exceeded the maximum allowed value since 2016, which affected the operating conditions for this construction. Reducing the bearing capacity of soils due to the influence of alkaline solution occurred after engineering reclamation of soils performed prior to crane operation more than two decades ago. Scientific novelty. The effect of strong alkaline solution that seeps through the upper soil layer loaded by constructions has been evaluated; the share of dissolved solid phase in the affected soil is estimated at 1-1,5%, which is in agreement with the dissolution parameters of soil influenced by strong alkaline solutions evaluated in this study and other researchers. Practical value. The results obtained can be applied for long-term predicting the operational conditions and stability of buildings constructed on soils subjected to seepage of chemically aggressive solutions.

Novel extended in vitro-in vivo correlation model for the development of extended-release formulations for baclofen: From formulation composition to in vivo pharmacokinetics

In vitro-in vivo correlation (IVIVC), a predictive mathematical model between the in vitro dissolution and the in vivo pharmacokinetics has been utilized for the development of new extended release (ER) formulations. The aim of the present study was to extend the IVIVC approach, which correlates among the formulation composition, the in vitro dissolution, and the plasma drug concentration, to predict plasma drug concentrations from a given composition of the formulation, and vice versa, using baclofen as a model drug. Baclofen ER tablets with different dissolution rates were prepared by varying the composition of hydroxypropyl methylcellulose (HPMC). First, the HPMC compositions and the corresponding in vitro dissolutions parameters were correlated, and then the in vitro dissolution parameters were correlated with the in vivo dissolution parameters extracted from the pharmacokinetic profiles of the baclofen ER formulations via population pharmacokinetic modeling. The final extended IVIVC model linked the composition of the formulation, the in vitro dissolution, and the in vivo plasma concentration profile and was successfully applied for the prediction of in vivo pharmacokinetics from the amount of HPMC in baclofen ER formulations. The present approach holds great promise for designing optimal compositions of ER formulations to present desired plasma concentration profile.

Analytical solution of a mathematical model for rock salt dissolution in still water

In this study, an ordinary differential equation for dissolution of rock salt in still water is established, for the purpose of researching the dissolution mechanism of rock salt in still water, by calculating the concentration distribution of the boundary layer of the rock salt solution. On this basis, a dissolution model for rock salt in still water with different dissolution areas, solution concentrations, and solution temperatures is established. The corresponding analytical solutions are derived and solved, and parameter inversion is conducted with experimental data on rock salt dissolution, from which the dissolution parameter convective mass transfer coefficient k in still water is obtained. In addition, the results of previous dissolution tests are interpreted and discussed from a theoretical perspective using the derived dissolution model. It is found that the dissolution area has no obvious influence on the dissolution rate and the dissolution rate gradually decreases with increasing solution concentration when the solution volume is 5 L and the water is changed every 5 min. It is also proved that parameter a1 is relevant to the molar mass M and saturation concentration Cs, and parameter a2 is relevant to the convective mass transfer coefficient k. The model established in this paper may describe well the dissolution mechanism of rock salt in still water, and provides a basic theoretical foundation and analytical method for research on the dissolution characteristics of rock salt.

Influence of Discrete Pulse Energy Input at Absorption of Oxygen in the Liquid Medium

The article presents research results on the rates of dissolving oxygen of the air in water during its treatment in an aerator–oxidizer. Relationships between the oxygen dissolution rates and parameters of treatment and design of the aerator–oxidizer are esteblished.

Solubility enhancement of glimperide: Development of solid dispersion by solvent melt method, characterization and dosage form development

The aim of the present work was to develop immediate release dosage form of the solid dispersion of glimperide (GLIM) for potential enhancement in the bioavailability. The solid dispersions of GLIM were prepared with PEG6000, PVP K30 and Poloxamer 188, in 1:1, 1:3 and 1:5 %w/w ratio by using solvent wetting and solvent melt method. The in vitro dissolution parameters (%DE10min, %DE30min, %DE60min, T50% and DP30) were used to select the optimized solid dispersion that was characterized by IR, PXRD, DSC and SEM. The optimized solid dispersion of GLIM (GSDSM3) was used as drug component for immediate release (IR) tablets that were evaluated for physical and pharmacopoeial parameters. The in vitro drug release studies identified G4 as the optimized tablet with a cumulative drug release (CDR) of 99.34% in 30 min in phosphate buffer, pH 7.4. The CDR was higher than the marketed tablet (91.15%, Amaryl®, Sanofiaventis), However, the f1 and f2 were 10.6 and 52 respectively, which confirmed similarity of the dissolution profile(s). Accelerated stability studies confirmed stability up to 6 months at 40°C/75% condition in the HDPE bottle pack.

Effect of crystallization time on the structure of the Aluminosilicate glass-ceramic

All This study deals with the influence of the time of crystallization on the structure of an aluminosilicate glass-ceramic ceramized by a nucleation –crystallization treatment at 790°C for 2 h, and 900°C, for different periods of time ranging from 2 to 12 h. For the whole of the materials, Archimedes density is between 2441-2578 kg/m3. Both X-ray diffraction and scanning electron microscopy analyses reveal two main crystalline phases for the whole of the heating treatments, namely spodumen and leucite. These phases grow regularly with the crystallization time. In addition, aqueous stability testing was carried out using the standard MCC-2 static leach test method at 90 °C and V(ml) = 30 S(cm2) for a series of five test durations - 7, 14, 28, 35 and 42 days. The X-ray fluorescence analytical technique was used to determine the concentration of lanthanum (La) and molybdenum (Mo) leached in our material. The dissolution parameters, in this case the normalized elemental mass loss (NL) and the leaching rate (τ) of each element, were determined from these concentrations. The results demonstrate that The leaching tests showed that the material is stable and it stabilizes at low values (2.5 10−9Kg/m2) for La when the ceramization time does not exceed 4h beyond this, Leaching equilibrium and the passivation phase is broken. For Mo and for all glass ceramics at different times of crystallization, the equilibrium reaches (3.15 10-8 Kg/m2j) and the passivation layer is formed. The glass ceramics at different time of cristallization presently studied appears to have a good chemical durability.

Fabrication and statistical optimization of starch-κ-carrageenan cross-linked hydrogel composite for extended release pellets of zaltoprofen

The current study was aimed to develop extended release (ER) pellets formulations containing zaltoprofen as a model drug and cross-linked starch-κ-carrageenan (Sκ-C) hydrogel composite as a binder and extended release polymer. The Sκ-C cross-linked hydrogel composites were prepared using a 32 full factorial design approach and characterized by FTIR, DSC, XRD and SEM analysis. The matrix pellets were prepared by extrusion-spheronization technique and characterized production yield, FTIR, DSC, XRD, SEM, optical microscopy, flow characteristics, mucoadhesiveness, in-vitro dissolution and in-vivo pharmacokinetic parameter. The FTIR interpretation of Sκ-C cross-linked hydrogel composite provides the significant result as a formation of hemiacetal group and keton group of glyoxal is abolished; hence it could be satisfied that Sκ-C cross-linked hydrogel composite was formed. The optimized formulation (Sκ-C2) was contained 4:2 ratio of starch and κ-carrageenan of Sκ-C cross-linked hydrogel composite showed in-vitro drug release up to 99.15 ± 2.20% up to 12h, and mucoadhesion of 94.00 ± 2.00 up to 12 h, respectively and in-vivo parameter were showed decrease in C max and increase in t1/2 significantly and drug release >12 h. Hence it was concluded that optimized formulation (Sκ-C2) showed acceptable release pattern, hence would be the viable alternative to ER type formulations.

STUDY TO UNDERSTAND FACTORS GOVERNING DISSOLUTION OF PARACETAMOL TABLETS USING DESIGN EXPERT® SOFTWARE

In vitro testing is of paramount importance both in formulation development and in optimization of any pharmaceutical dosage form. Dissolution testing is a quality control test used to check batch to batch variability The main objective of this study was to determine the impact of various parameters like volume of the buffer used, the rotational speed of the paddle and temperature over the percentage drug release in a particular time frame. The collected data was analyzed using Design Of Experiments (DOE) software in order to optimize the dissolution parameters for the marketed paracetamol tablet formulation. A marketed batch of paracetamol tablets was used for the present study. The obtained results showed that the standard percent cumulative drug release was maintained even when the dissolution parameters were refashioned and thus provided a substantial waiver of exploitative use of water resources for the in vitro dissolution testing for paracetamol tablets making it a greener method.

Buccoadhesive gel of carvedilol nanoparticles for enhanced dissolution and bioavailability

The aim of the work was to improve carvedilol bioavailability through preparation of nanoparticles to be formulated as a buccoadhesive gel. Physicochemical compatibility of drug was studied. The ionic gelation technique was used for nanoparticles preparation based on 31 × 41 factorial design using Eudragit® RS100 as a complexing agent. Particle size, entrapment efficiency and dissolution parameters were measured and the formula of choice was prepared into two nanoparticles gel formulae to study the effect on bioavailability. The nanoparticles appearance was spherical and uniform. The tested formula variables significantly affected all the parameters (P value < 0.05). The particle size of the prepared formulae ranged from 150 to 225 nm and entrapment efficiency varied from 73.3 to 98.8%. The prepared gel formulae showed an acceptable bioadhesion force which is required for buccal application. Regarding pharmacokinetics parameters, both gel formulae shorten the Tmax from 1.5 h to 1 h compared to the market product. Carvedilol nanoparticles were successfully formulated using the ionic gelation technique with low particle size and high entrapment efficiency. The prepared nanoparticles gel contains both sodium carboxymethyl cellulose and hydroxypropyl methylcellulose K4M polymers showed two fold increase in relative bioavailability.

Development of a Dissolution Method for Gliclazide Modified-Release Tablets Using USP Apparatus 3 with in Vitro-in Vivo Correlation.

Gliclazide (GLZ) is a second generation hypoglycemic drug used for the treatment of Type 2 diabetes mellitus. The low solubility of GLZ has been described as the rate limiting step for drug dissolution and absorption, thus a prediction of its in vivo behavior based on a discriminative dissolution test should lead to a relevant in vitro-in vivo correlation (IVIVC). The aim of this study was to develop a dissolution method for GLZ modified-release (MR) tablets using an United States Pharmacopeia (USP) apparatus 3 through its evaluation by an IVIVC analysis. Various dissolution parameters were evaluated to establish an in vitro method for GLZ tablets. The final dissolution conditions, referred to as method 3, utilized a 400 µm mesh and 30 dips per minute over a total period of 10 h that included 1h in HCl media (pH 1.2), 2h in acetate buffer solution (pH 4.5), 1 h in phosphate buffer solution (PBS; pH 5.8), 5h in PBS (pH 6.8) and finally 1h in PBS (pH 7.2). The calculated point-to-point IVIVC (R2=0.9970) was significantly greater than other methods. The robustness of method 3 suggests it could be applied to pharmaceutical equivalence studies and for quality control analyses of GLZ.

Kinetics and thermodynamics of swelling and dissolution of PVA gels obtained by freeze-thaw technique

PVA hydrogels obtained by freeze-thaw technique find important applications in regenerative medicine and controlled drug delivery technologies. The novelty of this contribution is the establishment of the cross-dependency of kinetics and thermodynamics parameters of swelling and dissolution of PVA hydrogels with the freeze-thaw process main variables. The work also establishes cross-correlations between the freeze-thaw process conditions, the gel microstructure and the properties of obtained hydrogel/hydrosoluble PVA materials. The conditions of the freeze-thaw process were selected by following an experimental design. The time evolution of the water up-take of PVA hydrogels was measured and used as main raw data generator. A 4-D surface response of the swelling and dissolution parameters in the space of freeze-thaw process variables was obtained and analyzed in terms of the resulting hydrogel and hydrosoluble polymeric structures. The 4-D surface response in the space of freeze-thaw process variables can predict very precisely the swelling and dissolution of PVA systems and their conditions for developing fully crosslinked hydrogel networks to fully hydrosoluble polymeric bodies.

Real-time monitoring of the tablet-coating process by near-infrared spectroscopy - Effects of coating polymer concentrations on pharmaceutical properties of tablets

In order to establish a pharmaceutical manufacturing process control system based on a Quality-by-Design concept, the pharmaceutical properties of tablets during the tablet-coating process were monitored in real time and predicted using values recorded by in-line near-infrared (NIR) spectroscopy. Coating amount (C%), thickness (L), tablet hardness (HT), and tablet dissolution parameters with elution times (T0, T50, and T80) were measured using individual pharmaceutical tests. Tablet coating was performed by spraying F-A (25 w/w%) or F-B (17.8 w/w%) containing EUDRAGIT® L 30 D-55, and monitored using an in-line NIR spectroscopy instrument. Calibration models to predict tablet properties (C%, L, HT, T0, T50, and T80) were obtained based on NIR spectroscopy using a partial least-squares regression (PLS). Chemometric parameters were found to be sufficiently accurate. Correlations between the predicted and measured values of each tablet property showed satisfactory linear relationships. Therefore, the pharmaceutical properties (C%, L, HT, T0, T50, and T80) of tablets may be monitored in real time during the coating process with an in-line NIR spectroscopy method.

ENHANCING DISSOLUTION RATE OF INDOMETHACIN BY IN SITU CRYSTALIZATION; DEVELOPMENT OF ORALLY DISINTEGRATING TABLETS

Objective: The main objective of this study was to investigate the potential of in situ crystallization of indomethacin, in presence or absence of hydrophilic materials, to improve drug dissolution with the goal of developing fast disintegrating tablets.Methods: Indomethacin crystals were prepared by bottom up approach. Water containing hydrophilic additive (polymer or/and surfactant) was added to ethanolic solution of indomethacin while stirring. The selected polymers were hydroxylpropylmethyl cellulose E5 (HPMC E5), polyethylene glycol 6000 (PEG6000) and polyvinylpyrrolidone K40 (PVP K40). The surfactants used were Tween80 and Glucire 44/14. The precipitated particles were collected and air dried. Solid state characterization were performed in addition to in vitro release studies in both acidic (0.1 N HCL) and alkaline medium (phosphate buffer pH 6.8). Optimized formulation was selected to develop fast disintegrating tablets.Results: Thermal behavior suggested modulation in crystalline nature with reduction in particle size that was confirmed by X-ray diffraction results. Infrared spectroscopy excluded any interaction between drug and hydrophilic excipients. Drug dissolution in acid media showed slight improve in drug release, while marked increase was observed in the alkaline media. Combination between Tween80 and HPMC (F7) showed the best dissolution parameters with 5-folds enhancement in release efficiency (RE) compared to pure drug. Formula F7 was successively used to formulate fast disintegrating tablets with prompted release of 58% of the loaded dose and RE of 83%.Conclusion: In situ crystallization of indomethacin is a good approach for enhanced dissolution rate with the presence of hydrophilic additives during precipitation process improving the efficiency.

Micronized Zaleplon Delivery via Orodispersible Film and Orodispersible Tablets.

The following research study focuses on improving the solubility of zaleplon (BCS class II drug) via micronization technique in order to enhance its oral delivery in orodispersible formulations. Zaleplon along with a surfactant solution was micronized by ultrasonication. The micronization process reduced the particle size of the crystalline drug about six-fold from its original size of 155.5μm. The micronized zalepon dispersion was lyophilized to allow for a change in the state of matter (to a powder). The superior dissolution parameters (Q5, Q30, IDR, MDR, MDT, DE, and RDR) of zaleplon in microcrystalline form over the original crystalline form in in vitro dissolution studies had unraveled that micronization technique is an efficient tool in enhancing drug solubility. The micronized zaleplon solid dispersion (after lyophilization) was loaded into orodispersible tablet (ODT) and orodispersible film (ODF) formulations. The positive quality of ODT with adequate hardness and smooth texture was attributing to the presence of Pearlitol Flash® as a ready to use ODT platform. On the other hand, the ODF loaded with micronized zaleplon and prepared with Lycoat® RS 720 (as a film former) ensured adequate tensile strength. The disintegration time of ODT and ODF was 30 ± 5 and 35 ± 5s, respectively. Thus, the orodispersible formulations containing micronized zaleplon have a strong potential for rapid disintegration following superior absorption in solution state through oral cavity into the blood stream, envisaging better oral delivery.

Formulation and evaluation of Itraconazole mucoadhesive tablets for sustained release

The aim of this research was to prepare and evaluate sustain release mucoadhesive tablet ofitraconazole, in order to overcome its poor biopharmaceutical property and therapeutical efficacy. Itraconazole have low aqueous solubility and high permeability, hence in order to improve its solubility in both HCl and water it is formulated as solid dispersion by using solvent evaporation method. Solid dispersion was formulated using with itraconazole PEG 6000 in the ratio of 1: 2. Solid dispersion was then formulated in matrix of hydrophilic mucoadhesive polymers Carbopol 934P (CP) and HPMC E5LV into mucoadhesive sustained release tablet. Further, formulation were optimized for various amounts of CP and HPMC. Various amount of HPMC and Carbapol were taken as formulation variables for optimizing response variables i.e. dissolution parameters. Solid dispersion leads to enhancement in solubility of itraconazole in water up to 5.95% and in HCl it was 6.43%. In addition to enhancement of solubility in HCl and water they also lead to the slow release of drug up to 1.44% in 1 hour. Optimum combination of mucoadhesive polymers Carbopol 934P (CP) and HPMC E5LV provided adequate fairly regulated release profile. The experimental and predicted results for optimum formulations were found to be in close agreement. The formulation showed percentage drug release upto 86% for 9hour.

ENHANCEMENT OF SOLUBILITY OF RILPIVIRINE BY INCLUSION COMPLEXATION WITH CYCLODEXTRINS

Rilpivirine having lowest water solubility indicates class II drugs of BCS. These classes of drugs could potentially exhibit dissolution rate limited absorption. The objective of the present study is to improve the solubility and dissolution of Rilpivirine through inclusion complexation with βCD and HPβCD. Solid binary systems of Rilpivirine with βCD and HPβCD were prepared by solvent evaporation and kneading methods at 1:1 and 1:2 M ratios. The prepared solid binary systems were studied in solution state by phase solubility, in vitro dissolution rate and solid state by FTIR and XRD. The dissolution parameters were studied by using dissolution software PCP Disso V3. The drug content was uniform in all the solid binary systems with low SD and CV values. The apparent stability constant indicates there is a 1:1 stochiometric complex with βCD and HPβCD. The formation of inclusion complexes with βCD and HPβCD in the solid state were confirmed by FTIR, XRD. The dissolution data clearly suggest drug release was method dependent and type of cyclodextrin. The dissolution of solid binary systems obeyed first-order kinetics and model fitted with Hixon crowel. A true inclusion complex of Rilpivirine was observed with βCD and HPβCD. Dissolution properties of solid binary systems were superior then rilpivirine alone and its corresponding physical mixtures. Overall dissolution rate was solvent evaporation &gt; kneaded binary systems &gt; physical mixture &gt; pure drug. One-way ANOVA results suggest the DE30 and DE60 values were significantly higher (P&lt;0.05) in solid binary systems when compared to physical mixture and pure drug.

FORMULATION DEVELOPMENT AND EVALUATION OF GASTRO-RETENTIVE DOSAGE FORM OF ATAZANAVIR SULPHATE

Objective: To improve dissolution properties of atazanavir sulphate by preparing gastro-retentive granules by solid dispersion method and development of RP-HPLC method for estimation of this drug.Methods: Estimation of atazanavir sulphate was done using high performance liquid chromatography (HPLC) on inertsil column (5 µm, 250x4, 6 mm) with a mobile phase consists of methanol: water (91:9 v/v), at 0.5 ml/min flow rate and 249 nm UV detection. The method was validated as per ICH guidelines. Selection of the carrier for gastro-retentive formulation was based on phase solubility study of the drug. Solid dispersions of gastro-retentive granules of different composition of drug and carrier, were prepared by the kneading, heating and solvent evaporation. A 32factorial design was applied to optimize the gastro-retentive formulation. The amounts of polyethylene glycol 6000 (PEG 6000) (X1) and hydroxypropyl methyl cellulose (HPMC) (X2) were selected as independent variables and in vitro-release at 5, 9 h and total floating time was selected as dependent variables. Results: HPLC method was found to be linear in a concentration range of 10-60 μg/ml of the drug (r2= 0.999). The low value of % RSD in precision study indicates reproducibility of the method. The low value of LOD and LOQ suggests the sensitivity of the method. The solubility enhancement study of drug with various carriers followed descending order of solubility [Gelucire 44/14&gt;PEG 6000&gt;polyvinyl pyrrilidone (PVP)]. Highest % cumulative release was observed for the heating method at drug polymer (PEG 6000) ratio 1:5. Hence, this ratio has been selected for preparation of solid dispersion. From comparison of dissolution profile of formulated batches, formulation F4 [containing PEG6000 (1.6 g) and HPMC (200 mg)] showed promising dissolution parameters with desired floating properties.Conclusion: Results obtained by validation studies suggested that the developed HPLC method is simple, accurate, precise and can be used for routine analysis of atazanavir sulphate formulation. Results of evaluation of prepared batches indicate that batch F4 is a promising formulation for gastro-retentive dosage form of drug.

Dissolution and transport of insensitive munitions formulations IMX-101 and IMX-104 in saturated soil columns

Military training exercises can result in deposition of energetic residues on range soils, which ultimately can contaminate groundwater with munitions constituents. Column experiments followed by HYDRUS-1D modeling were conducted to evaluate dissolution and transport of energetic constituents from the new insensitive munitions (IM) formulations IMX-101, a mixture of 3-nitro-1,2,4-triazol-5-one (NTO), nitroguanidine (NQ), and 2, 4-dinitroanisole (DNAN), and IMX-104, a mixture of NTO, 1,3,5-hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and DNAN. NTO and DNAN are emerging contaminants associated with the development of insensitive munitions as replacements for traditional munitions. Flow interruption experiments were performed to investigate dissolution kinetics and sorption non-equilibrium between soil and solution phases. The results indicated that insensitive munitions compounds dissolved in order of their aqueous solubility, consistent with prior dissolution studies conducted in the absence of soil. Initial elution of the high concentration pulse of highly soluble NTO and NQ was followed by lower concentrations, while DNAN had generally lower and more constant concentrations in leachate. The sorption of NTO and NQ was low, while RDX, 1,3,5,7-octahydro-1,3,5,7-tetranitrotetrazocine (HMX, an impurity in technical grade RDX), and DNAN all exhibited appreciable sorption. DNAN transformation was observed, with formation of amino-reduction products 2-ANAN (2-amino-4-nitroanisole) and 4-ANAN (4-amino-2-nitroanisole). HYDRUS-1D model, incorporating one-dimensional advective-dispersive transport with particle dissolution and first-order solute transformation was used to simulate the measured breakthrough curves. Optimized dissolution parameters varied widely but were correlated between compounds in the same formulation. Determined adsorption coefficients generally agreed with values determined from batch and column studies conducted with pure NTO and DNAN, while mass-loss rate coefficients were in better agreement with ones from batch than column studies possibly due to suppression of microbial transformation during elution of high concentrations of explosives. Even in the low organic matter soils selected in this study DNAN experienced significant retardation and transformation, indicating potential for its natural attenuation.

Brain-targeted intranasal zaleplon solid dispersion in hydrophilic carrier system; 23 full-factorial design and in vivo determination of GABA neurotransmitter

Intranasal zaleplon solid dispersion was formulated to enhance the solubility, bioavailability and deliver an effective therapy. Zaleplon belongs to Class II drugs, and undergoes extensive first-pass metabolism after oral absorption exhibiting 30% bioavailability. A 23 full-factorial design was chosen for the investigation of solid dispersion formulations. The effects of different variables include drug to carrier ratio (1:1 and 1:2), carrier type (polyethylene glycol 4000 and poloxamer 407), and preparation method (solvent evaporation and freeze drying) on different dissolution parameters were studied. The dependent variables determined from the in vitro characterization and their constraints were set as follows: minimum mean dissolution time, maximum dissolution efficiency and maximum percentage release. Numerical optimization was performed according to the constraints set based on the utilization of desirability functions. Differential scanning calorimetry, infrared spectroscopy, X-ray diffraction and scanning electron microscopy were performed. Ex vivo estimation of nasal cytotoxicity and assessment of the γ-aminobutyric acid level in plasma and brain 1 h after nasal SD administration in rabbits compared to the oral market product were conducted. The selected ZP-SD, with a desirability 0.9, composed of poloxamer 407 at drug to carrier ratio 1:2 successfully enhanced the bioavailability showing 44% increase in GABA concentration than the marketed tablets.