Nifedipine Molecular Dispersion in Microparticles of Ammonio Methacrylate Copolymer and Ethylcellulose Binary Blends for Controlled Drug Delivery: Effect of Matrix Composition

ABSTRACT

The objective of this study is to explore matrix-type microparticles, comprising a solid dispersion of drug with an ammonio methacrylate copolymer and ethylcellulose binary blend, for use in the controlled release of a poorly water-soluble drug, nifedipine. Microparticles consisting of an ethylcellulose N7 (N7) and Eudragit RL® (RL) binary blend at different ratios were prepared using phase-separation methodology. The effects of matrix composition on microparticle properties were evaluated by polarized light microscopy, differential scanning calorimetry (DSC), FT-infrared and UV-visible spectroscopy, stability, and drug release studies. Study results indicate that the particle size distribution, particle morphology, and drug release rate from the microparticles were influenced by the ratio of RL to N7. Discrete spherical microparticles with a narrow size distribution and a controlled release profile were obtained when the ratio of RL to N7 was in the range from 1:1 to 2:1 w/w. Solid-state characterization and release kinetic studies on these microparticles confirmed that the nifedipine release from the microparticles followed the Baker and Lonsdale's matrix diffusion model (1974) for microspheres containing dissolved drug, and the nifedipine diffusion in the microparticle matrix was the rate-limiting step. As the ratio of RL to N7 was changed from 0:1 to 4:1 w/w, the effective drug diffusion coefficient in the micro-matrix increased from 5.8?×?10^?10 to 8.6?×?10^?9 (cm²/h). In addition, probably due to formation of a stable molecular dispersion promoted by hydrogen bonding between nifedipine and the polymers, no significant changes in the nifedipine physical form or release kinetics were observed after 1-year storage at ambient room temperature followed by 3-month accelerated stability at 40°C/75% RH in a closed container.     

New Ultraviolet spectrophotometric method for the estimation of nimesulide

Two simple and accurate ultraviolet (UV) spectrophotometric methods with better detection range for estimation of nimesulide in pure form and in solid dosage form were developed in the present studies using 50% v/v and 100% v/v acetonitrile as the solvent system. The linearity range of nimesulide in both the methods was found to be 10-50 μg/ml at a λ_max of 300 nm. The linear regression equations obtained by the least-square regression method are Abs = 1.33 × 10^-1. Conc + 1.89 × 10^-1 in 50% v/v acetonitrile and Abs = 1.05 × 10^-1. Conc + 1.14 × 10^-1 in 100% v/v acetonitrile. The detection limit as per the error propagation theory was found to be 0.46 μg/ml and 1.04 μg/ml, respectively, in 50% v/v and 100% v/v acetonitrile. The developed methods were employed with high degree of precision and accuracy for the estimation of total drug content in three commercial tablet formulations of nimesulide. The results of the analysis were validated statistically and by recovery studies.     

Photodegradation study of sodium usnate solution: influence of pH

Photodegradation of 2.6 × 10^-5 M aqueous solutions of sodium usnate at various pH was studied. Photodegradation appeared to follow first-order kinetics and was found to be pH dependent. The degradation rate constant was calculated to be 9.20 × 10^-4 min^-1, 5.93 × 10^-4 min^-1, 9.69 × 10^-4 min^-1, and 9.88 × 10^-4 min^-1 at pH 6, pH 7, pH 8, and pH 9, respectively.     

GLC and Radiometric Determination of Hydrolysis Rate Constants of [[2-[4-(Methoxycarbonyl) 1) Benzamido]Diethyl]Triamino] Methylated Polystyrene

The rate constants of the hydrolysis of the methyl ester in 3N HC1 as function of temperature was determined and found to be in the range of 1.3 × 10^-2 to 1.2 × 10^-1 h^-1 at 40 and 60 C respectively. The rate constants were determined by GLC on Pola-pack-Q and by a radiotracer technique.     

An electron diffraction study of the ZnIn2Se4 crystal structure: A novel phase

A novel layered-structure ZnIn₂Se₄ phase has been obtained. Texture electron diffraction patterns aid in the identification of a crystal structure with lattice parameters a = 4.045 Å and c = 52.29 Å, space group R m, and z = 4.5. Crystal electron diffraction patterns displayed superstructural reflection, thus indicating a √3-fold increase in the a parameter. The similirity of reflection locations and intensities both on the crystal rotation electron diffraction pattern and on texture electron diffraction patterns showed that no phase transition occurred on specimen pounding. Electrophysical and optical parameters (E_g = 1.68 eV; N = 8 × 10²² m^-3; = 0.1Ωm) are studied at 300 K. The Hall coefficient is constant (R_H = 7.2 × 10^-5m³C^-1, mobility μ = 8 × 10^-3m²V^-1s^-1 at 200–300 K.     

Influence of the cohesive behaviour of small particles on the solid-state photolytic degradation of furosemide

The effect of the cohesive behaviour of small particles on the solid-state photochemical degradation of furosemide is reported. Samples of agglomerated and recrystallised separated particles were exposed to direct sunlight for up to 240 hours, and the furosemide content measured with time. The solid-state photolytic degradation of furosemide proceeds from a nucleation period, through a growth period and eventual deceleration of the reaction. The kinetic process was best described by a power law dependence of the fraction degraded on time for the nucleation period and first order kinetics with asymptote, Prout-Tompkins equation, for the growth of the nuclei. The first order rate constants for the degradation of the agglomerated and the separated particles were 1.20 × 10^-2 hour^-1 and 1.48 × 10^-2 hour^-1 respectively for the nucleation period and 2.85 × 10² hour^-1 and 2.45 × 10^-2 hour^-1 for the growth period. Although the mean particle size of the particles which made up the agglomerates was significantly smaller (2.5 μm) than the separated particles (22 μm), the separated particles degraded more than the agglomerates. The maximum, infinite, fraction degraded ($aL∞,) was 0.450 for the agglomerates and 0.660 for the separated particles. It seemed as though nucleation depended on the surface area exposed to irradiation. Agglomeration decreased the surface area available and therefore nucleation was less. Degradation during the growth period appeared to occur inside the particles and was limited by the extent of nucleation.     

RADIATION CHEMICAL AND PHOTOPHYSICAL PROPERTIES OF C60(C4H8SO3Na)n IN AQUEOUS SOLUTION: A LASER FLASH PHOTOLYSIS AND PULSE RADIOLYSIS STUDY

Optical absorption studies on aqueous solutions of C₆₀(C₄H₈SO₃Na)_n (n = 4-6) revealed deviation from the Beer-Lambert law in the 250-350 nm region, which is assigned to the formation of solute aggregates at concentrations higher than 1 × 10^-3 mol dm^-3. Dynamic light scattering experiments showed aggregates with an average size of ∼100 nm. The solute has a broad weak fluorescence emission (ϕ_f = 1.8 × 10^-3) in the 450-650 nm region, which remained independent of solute concentration. The broad transient absorption band in the 450-900 nm region (ε₆₆₀ = 2170 dm³ mol^-1 cm^-1), which formed immediately on laser flash photolysis (λ_ex = 355 nm, 35 ps), is assigned to singlet-singlet transition. It decays to a triplet excited state whose absorption is observed to depend strongly on solute concentration. In dilute solutions, an absorption band with λ_max = 590 nm is seen, and at high solute concentration a broad absorption in the 500-900 nm region is observed. The e_aq^- reacts with the solute with a bimolecular rate constant of 1.7 × 10⁸ dm³ mol^-1 s^-1 and forms weak broad absorption bands at 440, 540, 620, 870, 940, and 1020 nm. Isopropanol radicals also react with the solute with a bimolecular rate constant of 2.3 × 10⁸ dm³ mol^-1 s^-1 with the formation of a transient optical absorption spectrum similar to that observed on reaction with e_aq^- and assigned to a solute radical anion. The ^•H and ^-OH radicals react with bimolecular rate constants of 3.2 × 10⁹ and 4.4 × 10⁹ dm³ mol^-1 s^-1, respectively, and form transient absorption bands at 440, 510, and 660 nm. Based on electron transfer studies with suitable electron donor/acceptor substrates, the ranges of the reduction and oxidation potentials of the solute an estimated.     

Reactions in Au/Nb bilayer thin films

The interdiffusion and intermetallic compound formation of Au/Nb bilayer thin films annealed at 200–400 °C have been investigated. The bilayer thin films were prepared by electron beam deposition. The Nb film was 50 nm thick and the Au film was 50–200 nm thick. The interdiffusion of annealed specimens was examined by measuring the electrical resistance and depth-composition profile and by transmission electron microscopy. Interdiffusion between the thin films was detected at temperatures above 325 °C in a vacuum of 10^-4 Pa. The intermetallic compound Au₂Nb₃ and other unknown phases form during annealing at over 400 °C. The apparent diffusion constants, determined from the penetration depth for annealing at 350 °C, are 3.5 × 10⁻¹⁵ m² s⁻¹ for Nb in Au and 8.6 × 110^7minus;15 m² s⁻¹ for Au in Nb. The Au surface of the bilayer films becomes uneven after annealing at over 400 °C due to the reaction.     

Determinatiom of the Rydrolysis of Quinolinium-I-Methyliocide-6-Carboxt-Methyl Ester by Glc

A CLC method for the determination of the hydrolysis of quiolinlues I-methyliodide-6-carboxy-mathylester is dascribed. GLC is parforsud on porous polymer composed of ethylvinylbenzena crose-linked with divinyl-bensen (Polapak-Q). The retention times of methyl alcohol and the internal standare (tertiary butanol) are 2.8 and 6.3 min., respectively. The- apparent pseudo-first order rate constants as a function of taparature (37.C and 50°C) in the presence of 6N HCl were calculated and found to be 2.6 × 10^-2 min^-1 and 2.7 × 10^-2 win-1 respactively.     

Degradation of tobramycin in aqueous solution

The kinetics of degradation of tobramycin (Ne-De-Ka) in aqueous solution was studied as a function of pH. Tobramycin hydrolyzes in acidic solution to yield kanosamine (Ka-OH) and nebramine (Ne-De-OH) with a pseudo first-order rate constant of 2.7 × 10^-6 s^-1 in 1 N HCl at 80°C. The activation energy for the acid catalyzed hydrolysis is 32 kcal mol^-1. In basic solution, the hydrolysis products are deoxystreptamine (De-OH), nebramine (Ne-De-OH) and deoxystreptamine-kanosaminide (HO-De-Ka). The pseudo first-order rate constant for the hydrolysis in 1 N KOH is 1 × 10^-8 s^-1 at 80°C. The activation energy for the base catalyzed hydrolysis is 15 kcal mol^-1. Tobramycin is very stable towards hydrolysis at neutral pH; however, it rapidly oxidizes giving several products including De-OH, Ne-De-OH, and HO-De-Ka. In pH 7 phosphate buffer (0.01 M), the t₉₀ value is 70 hr at 80°C.     

Study of Nitrogen Implanted in Aluminum at Various Doses

Experimental and theoretical studies are carried out to understand transport of nitrogen in aluminum during implantation process. 60 keV and 120 keV N₂⁺ ion are implanted in pure Al substrates at doses ranging from l×l0¹⁷ to 9×l0¹⁷ N-atoms per cm². RBS and Glancing angle XRD studies are carried out. RBS studies show that the depth profiles are gaussian in nature at low doses and gradually become rectangular in shape as the dose increases. XRD analysis reveals that AlN is formed even at low doses. Theoretical simulations of depth profiles at low dose, include displacement mixing and radiation enhanced diffusion, which are modelled to be described by a diffusion like process. Effective diffusion coefficient in radiation environment is found to be equal to 8×l0^-16 cm².sec^-1. At high doses, when new N-atoms are added during implantation their transport gets linked with the already formed AlN. This leads to a rectangular shape of depth profiles observed at high doses.     

Corrosion resistant coatings (Al2O3) produced by metal organic chemical vapour deposition using aluminium-tri-sec-butoxide

The metal organic chemical vapour deposition (MOCVD) of amorphous alumina films on steel was performed in nitrogen at atmospheric pressure. This MOCVD process is based on the thermal decomposition of aluminium-tri-sec-butoxide (ATSB). The effect of the deposition temperature (within the range 290–420 °C), the precursor vapour pressure (5.33×10^-3−2.67×10^-2 kPa), and the gas flow (6.5−12.5 1 min^-1) of the MOCVD process have been studied in relation to corrosion properties at high temperatures. The corrosion experiments were performed at 450 °C in a gas atmosphere containing 1% H₂S, 1% H₂O, 19% H₂, and balanced Ar.

It was found that the amount of corrosion products on an alumina film (0.20±0.05 mg cm^-2)-AISI 304 combination decreased with increasing deposition temperature of the coating. This was more pronounced for the products formed through the coating owing to a certain porosity. The crack density, where products were also formed, was almost unaffected.     

INHIBITORY EFFECTS OF FULLERENE C60 DERIVATIVES ON ENDOTHELIUM-DERIVED RELAXATION IN RABBIT THORACIC AORTA

Inhibitory effects of newly synthesized fullerene C₆₀ derivatives 1 (C₆₀-bis(N,N-dimethylpyrrolidinium iodide)), 2 (C₆₀-proline-N-acetic acid) and 3 (C₆₀-ethylenediamine-N, N'-diacetic acid) on acetylcholine-induced relaxation in endothelium-intact rabbit thoracic aorta precontracted by phenylephrine (10^-6 M) were studied. Fullerene C₆₀ derivative 1 (3 × 10^-6 M), 2 (10^-5 M) and 3 (10^-5 M) reduced the maximum amplitude of the acetylcholine-induced relaxation without significantly changing the pD₂ values obtained from the concentration - response curves. In the presence of fullerene C₆₀ derivative 1 (10^-5 M) the acetylcholine-induced relaxation was eliminated and an acetylcholine-induced contraction was observed. These results suggest that fullerene C₆₀ derivative 1 strongly inhibits endothelium (nitric oxide)-dependent acetylcholine-induced relaxation in thoracic aorta of rabbit.     

Liquid-Liquid Extraction, Separation, Preconcentration, and ICP-AES Determination of Lanthanum and Cerium with N-Phenyl-(1,2-methanofullerene C60)61-formohydroxamic Acid

A novel method for liquid-liquid extraction, separation, preconcentration, and simultaneous trace determination of cerium(IV) and lanthanum(III) with N-phenyl-(1,2-methanofullerene C₆₀)61-formohydroxamic acid (PMFFA) is reported. Lanthanum and cerium are extracted at pH 8.5 and 9.5, respectively in chloroform and recovered from monazite sands in the presence of thorium, uranium, and large number of cations and anions in high purity (99.98%). The extraction mechanism is investigated. The influence of PMFFA, pH, diverse ions, and temperature on the distribution constants of lanthanum and cerium was examined. The overall stability constants (log β₂K_e) and extraction constants (K_ex) for lanthanum(III) are 22.50 and 5.0 × 10^-9, respectively and for cerium(IV) are 21.51 and 3.9 × 10^-9, respectively. Lanthanum(III) gives a colourless complex with PMFFA which is extracted into chloroform having molar absorptivity 5.5 × 10⁴ L mol^-1 cm^-1 at 395 nm, and Beer's law 0.12-2.52 µg mL^-1, while cerium(IV) forms a red coloured complex, λ_max 460 nm, molar absorptivity 1.5 × 10⁴ L mol^-1 cm^-1, and Beer's law 0.46-9.26 µg mL^-1. For trace determination the extracts were directly inserted into the plasma for inductively coupled plasma atomic emission spectrometry ICP-AES measurements of lanthanum and cerium which increases the sensitivity 60 folds and obey Beer's law in the range, 2.1-37.5 ng mL^-1 for lanthanum and 9.2-186.4 ng mL^-1 for cerium. The method is applied for the determination of lanthanum and cerium in real and standard samples, sea water, and environmental samples.     

Transport of insulin in modified Valia-Chien chambers and Caco-2 cell monolayers

The transport characteristics of insulin were investigated using two different absorption models. Using the modified Valia-Chien chambers, permeability coefficients of insulin in the duodenum, jejunum, and ileum were 0.71 × 10^-7, 7.11 × 10^-7 and 9.45 × 10^-7 cm/s, respectively. In the Caco-2 cell monolayers, the bidirectional transepithelial fluxes of insulin across Caco-2 cell line showed symmetry. Confocal laser scanning microscopy visualized that FD-4 and FITC-insulin were mainly located in the paracellular route. It is evident that the lower intestine might be an advantageous region, and absorption enhancer that helps open tight junctions between cells should be used for oral delivery of insulin.     

Second harmonic generation in alternate non-linear Langmuir-Blodgett films

Second harmonic generation experiments are performed in alternate multilayers of two non-linear molecules, the hydrophobic chain being grafted onto the acceptor group of the first species A and onto the donor group of the second species B. Two families of non-linear molecules are studied: p-aminobenzoic acid derivatives and diazostilbene derivatives. High χ⁽²⁾ values (around 5×10^-10 SI) and β values (around 10^-37 SI) are obtained for the diazostilbenes. The variation in the second harmonic intensity with respect to the number N of active layers is interpreted in terms of the disorder appearing in the upper monolayer of the Langmuir-Blodgett film.     

Excited-state absorption at 1.57 μm in U:CaF2 and Co:ZnSe saturable absorbers

Appreciable excited-state absorption (ESA) in U²⁺:CaF₂ and Co²⁺:ZnSe saturable absorbers was measured at λ=1.573 μm by optical transmission versus light fluence curves of 30–40 ns long pulses. The ground- and excited-state absorption cross-sections obtained were (9.15±0.3)×10⁻²⁰ and (3.6±0.2)×10⁻²⁰ cm², respectively, for U²⁺:CaF₂, and (57±4)×10⁻²⁰ and (12.5±1)×10⁻²⁰ cm² for Co²⁺:ZnSe. Thus, ESA is not negligible in U²⁺:CaF₂ and Co²⁺:ZnSe, as previously estimated.     

Preparation and pharmacokinetics in rabbits of breviscapine unilamellar vesicles

The purpose of the study was to prepare the unilamellar liposomal vesicles of breviscapine (Breviscapine-LUVs) and investigate the pharmacokinetics of Breviscapine-LUVs in rabbits. Breviscapine-LUVs were prepared by the film dispersion method and treated further by extrusion. Its size distribution and zeta potential were determined by photon correlation spectroscopy. The encapsulation efficiency (EE) and cumulative release of Breviscapine-LUVs were assayed by the dialysis method. The crossover design (two periods) was used in six rabbits, which were administered Breviscapine-LUVs and reference preparation. Results showed that the particle size of Breviscapine-LUVs was 50.8 nm, and the polydispersity index was 0.287. The zata potential was -24 mV ± 9 mV(n = 3), and the EE% was 81.1 ± 1.1% (n = 3). The cumulative release of vesicles in 0.9% NaCl was 17.2 ± 0.78%, 26.1 ± 0.68%, and 29.9 ± 0.81% in 2, 8, and 24 h, respectively. The mean concentration-time curves of breviscapine liposomes and reference preparation were both fitted to a two-compartment model with the main pharmacokinetic parameters as follows: t_1/2β of Breviscapine-LUVs and reference preparation were (42.5 ± 28.6) min and (6.01 ± 4.64) min, respectively; CL_(s) were (15.3 ± 9.03) mL × min^-1 and (84.6 ± 40.6) mL × min^-1, respectively; AUC_0-300 were (1267 ± 1083) μg × min × mL^-1 and (196 ± 107) μg × min × mL^-1, respectively. Compared with the reference preparation, breviscapine liposomes had a much higher concentration in plasma and contained characteristic of sustained-release, which ameliorated the pharmacokinetic properties of scutellarin.     

Release Kinetics of Indomethacin from Polymeric Matrices

Polymeric matrices containing three different concentrations of indomethacin 1, 2 and 4% preparations were prepared. The release kinetics of indomethacin from matrices followed Higuchi equation. The effective diffusivity of indomethacin (D_m) was 1.32 × 10^-7 +7.4% cm²/sec. The amount released in 24 hours 2 from 10 cm² matrices with three different concentrations of indomethacin, were 12.0, 18.6 and 25.0 mg respectively. These matrices may potentially be developed as a transdermal therapeutic system.     

Determination of the Acidic Degradation Products, Acetic, Propionic, Butyric, and Phthalic Acid in Aqueous Pseudolatexes of Cellulosic Esters by High Performance Liquid Chromatography

An isocratic, reversed-phase HPLC method was developed to quantify the organic acids, acetic, propionic, butyric, and phthalic acid, formed as a result of ester hydrolysis, in pseudolatexes of cellulosic esters. Colloidal dispersions of cellulose acetate, cellulose acetate butyrate, and cellulose acetate propionate were prepared by a microfluidization-solvent evaporation method. Dispersions of cellulose acetate phthalate were prepared by redispersion of a spraydried commercial pseudolatex. The acids were detected at 210 nm, the mobile phase being 0.025 M phosphate buffer: methanol (80:20 v/v%, pH 3.0). The peak height response was linear over the studied concentration range of 2 - 10 mM/L for the aliphatic acids and 20-100 μM/L for phthalic acid. The minimum detectable quantities for acetic, propionic, butyric, and phthalic acid were 0.02 mM/L, 0.05 mM/L, 0.1 mM/L, and 0.0005 mM/L, corresponding to a % change in acetyl, propionyl, butyryl, and phthalyl content of 4.0 × 10⁴, 1.2 × 10³, 2.9 × 10³, and 2.8 × 10^-5 for a 30% w/v pseudolatex. The colloidal polymer particles were separated by ultracentrifugation, filtration, or flocculation with aluminum chloride solution before analysis of the aqueous phase. Similar acid concentrations were obtained for the three separation methods. The recovery from spiked samples was almost complete for acetic, approximately 90% for propionic acid, and less than 80% for butyric acid.