Oral Bioavailability Enhancement of Acyclovir by Self-Microemulsifying Drug Delivery Systems (SMEDDS)

Acyclovir is a potent anti-viral agent useful in the treatment of Herpes Simplex Virus (HSV) infections. Acyclovir exerts its antiviral activity by competitive inhibition of viral DNA through selective binding of acyclovir to HSV-thymidine kinase. The main purpose of this work was to develop self-microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of acyclovir. Solubility of acyclovir was determined in various vehicles. SMEDDS is mixture of oils, surfactants, and co-surfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal (GI) tract. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region dilution study was also performed for optimization of formulation. SMEDDS was evaluated for its percentage transmittance, Assay of SMEDDS, phase separation study, droplet size analysis, zeta potential, electrophoretic mobility, and viscosity. The developed SMEDDS formulation contained acyclovir (50 mg), Tween 60 (60%), glycerol (30%) and sunflower oil (9%) was compared with the pure drug solution by oral administrating to male albino rats. The absorption of acyclovir from SMEDDS form resulted about 3.5 fold increase in bioavailability compared with the pure drug solution. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds such as acyclovir by oral route.     

Formulation and Pharmacokinetic Studies of Acyclovir Controlled-Release Capsules

Acyclovir controlled-release capsules (CRCs) were prepared by a three-step process: [1] melt granulation of acyclovir; [2] coating of granules with ethylcellulose; [3] incorporation of coated granules into hard gelatin capsules. In vitro release experiments showed that the main factors affecting the release rate were the mean particle size of the acyclovir raw material and the amount of coating material applied. Release of acyclovir from the capsules was in accordance with the Higuchi equation. Pharmacokinetic studies in dogs after oral administration of acyclovir controlled-release capsules showed that the formulation was successful in providing slow release of acyclovir and was superior to a commercially available controlled-release formulation.     

Evaluation of microporous polycaprolactone matrices for controlled delivery of antiviral microbicides to the female genital tract

Acyclovir (ACV) as a model antiviral microbicide, was incorporated in controlled-release polycaprolactone (PCL) matrices designed for application as intra-vaginal ring inserts (IVRs). Microporous materials incorporating acyclovir up to a level of ~10 % w/w were produced by rapidly cooling suspensions of drug powder in PCL solution followed by solvent extraction from the hardened matrices. Around 21, 50 and 78 % of the drug content was gradually released from matrices over 30 days in simulated vaginal fluid at 37 °C, corresponding to drug loadings of 5.9, 7.0 and 9.6 % w/w. The release behaviour of matrices having the lowest drug loading followed a zero order model, whereas, the release kinetics of 7.0 and 9.6 % ACV-loaded PCL matrices could be described effectively by the Higuchi model, suggesting that Fickian diffusion is controlling drug release. Corresponding values of the diffusion co-efficient for ACV in the PCL matrices of 3.16 × 10^?9 and 1.07 × 10^?8 cm²/s were calculated. Plaque reduction assays provided an IC₅₀ value of 1.09 μg/mL for acyclovir against HSV-2 and confirmed the antiviral activity of released acyclovir against HSV-2 replication in primate kidney cells (Vero) at levels ~70 % that of non-formulated acyclovir at day 30. Estimated minimum in vivo acyclovir concentrations produced by a PCL IVR (19 μg/mL) exceeded by a factor of 20 the IC₅₀ value against HSV-2 and the reported ACV vaginal concentrations in women (0.5–1.0 μg/mL) following oral administration. These findings recommend further investigations of PCL matrices for vaginal delivery of antiviral agents in the treatment and prevention of sexually transmitted infections such as AIDS.     

Studies on acyclovir-dextran conjugate: synthesis and pharmacokinetics

Acyclovir is an antivirus drug which has a good in vitro activity against hepatitis B virus. But because of the low solubility and low distribution in liver, the clinical application of acyclovir in hepatitis B was limited. To increase the solubility and the distribution in liver, acyclovir-dextran conjugate was synthesized by formation of Schiff's base. The solubility of obtained conjugate was 12 times greater than free acyclovir. Acyclovir will be slowly released from the obtained conjugate in pH 7.4 phosphate buffer solution (PBS) at 37°C with a rate constant of 0.0035 hr^- 1. Pharmacokinetic studies of acyclovir and acyclovir-dextran conjugate were conducted in mice by i. v. administration. Acyclovir concentrations in plasma, liver and kidney were determined by HPLC method. Relatively higher distribution of acyclovir in liver was observed when i. v. acyclovir-dextran conjugate as compared with i.v. free acyclovir. The results of pharmacokinetic studies indicated that acyclovir-dextran conjugate will be a good candidate to treat hepatitis B.     

Oral bioavailability enhancement of acyclovir by self-microemulsifying drug delivery systems (SMEDDS)

Acyclovir is a potent anti-viral agent useful in the treatment of Herpes Simplex Virus (HSV) infections. Acyclovir exerts its antiviral activity by competitive inhibition of viral DNA through selective binding of acyclovir to HSV-thymidine kinase. The main purpose of this work was to develop self-microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of acyclovir. Solubility of acyclovir was determined in various vehicles. SMEDDS is mixture of oils, surfactants, and co-surfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal (GI) tract. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region dilution study was also performed for optimization of formulation. SMEDDS was evaluated for its percentage transmittance, Assay of SMEDDS, phase separation study, droplet size analysis, zeta potential, electrophoretic mobility, and viscosity. The developed SMEDDS formulation contained acyclovir (50 mg), Tween 60 (60%), glycerol (30%) and sunflower oil (9%) was compared with the pure drug solution by oral administrating to male albino rats. The absorption of acyclovir from SMEDDS form resulted about 3.5 fold increase in bioavailability compared with the pure drug solution. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds such as acyclovir by oral route.     

Design and development of multiple emulsion for enhancement of oral bioavailability of acyclovir

The objective of this investigation was to design and develop water-in-oil-in-water type multiple emulsions (w/o/w emulsions) entrapping acyclovir for improving its oral bioavailability. Multiple emulsions (MEs) were prepared and optimized using Span-80 and Span-83 as lipophilic surfactant and Brij-35 as hydrophilic surfactant. The physio-chemical properties of the w/o/w emulsions - particle size, viscosity, phase separation (centrifugation test) and entrapment efficiency were measured and evaluated along with macroscopic and microscopic observations to confirm multiple nature, homogeneity and globule size. Stability study, in vitro and ex vivo release studies were performed followed by in vivo studies in rats. Stable w/o/w emulsions with a particle size of 33.098 ± 2.985 µm and 85.25 ± 4.865% entrapment efficiency were obtained. Stability studies showed that the concentration of lipophilic surfactant was very important for stability of MEs. Drug release from the prepared formulations showed initial rapid release followed by a much slower release. In vivo studies in rats indicated prolonged release and better oral bioavailability as compared to drug solution. The overall results of this study show the potential of the w/o/w emulsions as promising drug delivery systems for acyclovir.     

Effect of nerodilol and carvone on in vitro permeation of nicorandil across rat epidermal membrane

The objective of the study was to investigate the effect of nerodilol and carvone on the in vitro transdermal delivery of nicorandil so as to fabricate a membrane-moderated transdermal therapeutic system. The in vitro permeation studies were carried across the rat epidermal membrane from the hydroxypropyl methylcellulose (HPMC) gels (prepared with 70:30 v/v ethanol-water) containing selected concentrations of a terpene such as nerodilol (0% w/w, 4% w/w, 8% w/w, 10% w/w, or 12% w/w) or carvone (0% w/w, 4% w/w, 8% w/w, 12% w/w, or 16% w/w). The amount of nicorandil permeated (Q₂₄) from HPMC gel drug reservoir without a terpene was 3424.6 ± 51.4 μg/cm², and the corresponding flux of the drug was 145.5 ± 2.2 μg/cm²· h. The flux of nicorandil increased with an increase in terpene concentration in HPMC gel. It was increased ranging from 254.9 ± 3.1 to 375.7 ± 3.2 μg/cm²·h or 207.6 ± 4.7 to 356.7 ± 15.3 μg/cm²· h from HPMC gels containing nerodilol (4% w/w to 12% w/w) or carvone (4% w/w to 16% w/w), respectively. Nerodilol increased the flux of nicorandil by about 2.62-folds whereas carvone increased the flux of the drug by about 2.49-folds across the rat epidermal membrane. The results of the Fourier Transform Infrared (FT-IR) study indicated that the enhanced in vitro transdermal delivery of nicorandil might be due to the partial extraction of stratum corneum lipids by nerodilol or carvone. It was concluded that the terpenes, nerodilol and carvone, produced a marked penetration enhancing effect on the transdermal delivery of nicorandil that could be used in the fabrication of membrane-moderated transdermal therapeutic systems.     

Design and in vitro evaluation of polymeric formulae of simvastatin for local bone induction

Simvastatin (SVS), a cholesterol-lowering drug, has been shown to stimulate bone formation. This study deals with the design and in vitro evaluation of local delivery systems for simvastatin. They are intended to treat bony defects resulting from periodontitis or to induce osteogenesis around the titanium implants. Granules and gels were formulated using bioerodible/biocompatible polymers, namely hydroxypropylmethyl cellulose (H), sodium carboxymethyl cellulose (C), and chitosan (Ch). The in vitro release profiles and kinetics were evaluated and the swelling and/or erosion was monitored. Differential scanning calorimetry (DSC) and infrared (IR) were used to detect any SVS/polymer interactions that may affect drug release. The results revealed variable extents of controlled drug release from the designed formulae depending on the polymer nature. About 50% cumulative SVS was released from both H granules and gel formulae within 24 h and ∼66% and ∼88% from C granules and gel, respectively. Ch formulae exhibited ∼50% release from granules and ∼30% from gel.     

Eudragit coating of chitosan-prednisolone conjugate microspheres and in vitro evaluation of coated microspheres

Chitosan-prednisolone conjugate microspheres (Ch-SP-MS) were prepared, and Eudragit coating was applied in order to efficiently deliver the microspheres and drug to the intestinal disease sites. The Eudragit L100-coated microspheres (Ch-SP-MS/EuL100) were examined for particle characteristics and the release of drug and Ch-SP-MS in different pH media at 37°C. Ch-SP-MS were spherical, with a mean size of 4.5 μm and prednisolone content of 3.3% (w/w). Ch-SP-MS/EuL100 were fairly spherical, with a mean size of 22. 5 μm and drug content of 0.32% (w/w). At pH 1.2, the release extent was less than 5% even at 48 h, and Eudragit coating tended to suppress the release. In contrast, at pH 6.8 and 7.4, Ch-SP-MS/EuL100 tended to show somewhat faster drug release than Ch-SP-MS. Ch-SP-MS/EuL100 displayed a release extent of 23 and 27% at pH 6.8 and 7.4, respectively. Ch-SP-MS aggregated at pH 1.2, but almost kept their initial size and shape at pH 6.8 and 7.4. Ch-SP-MS/EuL100 almost maintained their original shape and size at pH 1.2, and gradually released Ch-SP-MS at pH 6.8 and 7.4 due to dissolution of the Eudragit layer. Eudragit coating is suggested to be useful to efficiently deliver Ch-SP-MS to the intestinal disease sites.     

Enhanced oral bioavailability of a poorly water soluble drug PNU-91325 by supersaturatable formulations

Supersaturatable cosolvent (S-cosolvent) and supersaturatable self-emulsifying drug delivery systems (S-SEDDS) are designed to incorporate water soluble cellulosic polymers such as hydroxypropyl methylcellulose (HPMC), which may inhibit or retard drug precipitation in vivo. A poorly soluble drug, PNU-91325, was used as a model drug in this study to illustrate this formulation approach. The comparative in vitro studies indicated that the presence of a small amount HPMC in the formulation was critical to achieve a stabilized supersaturated state of PNU-91325 upon mixing with water. An in vivo study was conducted in dogs for assessment of the oral bioavailability of four formulations of PNU-91325. A five-fold higher bioavailability (∼ 60%) was observed from a S-cosolvent formulation containing propylene glycol (PG) + 20 mg/g HPMC as compared to that (∼ 12%) of a neat polyethylene glycol (PEG) 400 formulation. The low bioavailability of the PEG 400 formulation is attributed to the uncontrolled precipitation of PNU-91325 upon dosing, a commonly observed phenomenon with the cosolvent approach. A S-SEDDS formulation composed of 30% w/w Cremophor (surfactant), 9% PEG 400, 5% DMA, 18% Pluronic L44, 20% HPMC, and other minor components showed an oral bioavailability of ∼ 76%, comparable to that of a neat tween formulation (bioavailability: ∼ 68%). The significant improvement of the oral bioavailability of the supersaturatable S-cosolvent and S-SEDDS formulations is attributed to a high free drug concentration in vivo as a result of the generation and stabilization of the supersaturated state due to the incorporation of polymeric precipitation inhibitor.     

CdSe band-splitting on thermal annealed films

Semiconducting polycrystalline CdSe thin films were prepared on glass substrates by chemical bath at 65 °C. As-deposited films grew in the metastable cubic sphalerite (S) crystalline structure with good stoichiometry. Upon thermal annealing (TA) in Ar+Se₂ atmosphere at different temperatures in the range 200–500 °C, the gradual phase transformation from cubic modification to hexagonal wurtzite (W) stable phase could be observed. From optical absorption measurements the fundamental energy band gap (E_g) and the second electronic transition (E_g+ΔE_g) were calculated for as-deposited and thermal annealed films. For TA350 °C, S-phase dominates the crystalline structure and only the spin orbit (ΔE_so) contribution to ΔE_g is present. Above 350 °C, the W-phase dominates and the energy splitting (ΔE_cf), owed to crystal field contribution and originated by the loss of lattice symmetry, should be added to ΔE_so in order to complete ΔE_g in the W-phase. The values ΔE_so=0.389±0.011 eV and ΔE_cf=0.048±0.018 eV were found from our analysis, and T_c=350 °C was here defined as the critical point of the phase transformation.     

Nifedipine molecular dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blends for controlled drug delivery: effect of matrix composition

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.     

The effect of storage temperatures on the in vitro properties of a polyanhydride implant containing gentamicin

Septacin® is a biodegradable sustained-release implant containing 20% (w/w) gentamicin sulfate. The matrix of the implant is a polyanhydride copolymer composed of erucic acid dimer (EAD) and sebacic acid (SA) in a one-to-one weight ratio. The effect of storage temperatures (-15°C and 25°C) on the stability of Septacin® was evaluated with respect to gentamicin potency, copolymer molecular weight, and in vitro drug release. The drug in polymer matrix was stable for at least 12 months when stored at 25°C, but the molecular weight of the copolymer declined rapidly at this temperature. At -15°C, there was no change in the molecular weight of the copolymer. However, the placebo (copolymer without gentamicin) exhibited a significant drop in copolymer molecular weight at both temperatures. The drug release profiles showed no change for samples stored at -15°C for the duration of this study, while the release of drug slowed down significantly for samples stored at 25°C for longer than one month. A pronounced difference in the morphology of the -15°C samples and the 25°C samples was observed during the in vitro dissolution test; cracking of the -15°C samples was evident, but the 25°C samples remained intact.     

Emulsion Spray-Drying for the Preparation of Albumin-Loaded PLGA Microspheres

The purpose of this work was to study the encapsulation of bovine serum albumin (BSA) in polylactide-co-glycolide (PLGA) microspheres using an emulsion/spray-drying method. Albumin was dissolved in an aqueous phase (w) in the presence of surfactant and emulsified in an organic phase containing the polymer (o). To stabilize the emulsion, different types of surfactant (Pluronic® F68, Pluronic F127, sodium oleate, dioctylsulfosuccinate) were added to the aqueous phase. The w/o emulsion was spray-dried to obtain BSA-loaded PLGA microspheres. The effect of type of surfactant on microsphere characteristics was evaluated. The microspheres were characterized for their morphology by scanning electron microscopy (SEM) and granulometric analysis; drug content determination and in vitro dissolution tests were performed. Results showed that the emulsion/spray-drying method is suitable for obtaining small microparticles (2-5 μm) characterized by high drug payloads (70%-80% encapsulation efficiency). The type of surfactant affects the microsphere shape and BSA release behavior.     

Preparation, evaluation, and NMR characterization of vinpocetine microemulsion for transdermal delivery

A novel microemulsion was prepared to increase the solubility and the in vitro transdermal delivery of poorly water-soluble vinpocetine. The correlation between the transdermal permeation rate and structural characteristics of vinpocetine microemulsion was investigated by pulsed field gradient nuclear magnetic resonance (PFG-NMR). For the microemulsions, oleic acid was chosen as oil phase, PEG-8 glyceryl caprylate/caprate (Labrasol®) as surfactant (S), purified diethylene glycol monoethyl ether (Transcutol P®) as cosurfactant (CoS), and the double-distilled water as water phase. Pseudo-ternary phase diagrams were constructed to obtain the concentration range of each component for the microemulsion formation. The effects of various oils and different weight ratios of surfactant to cosurfactant (S/CoS) on the solubility and permeation rate of vinpocetine were investigated. Self-diffusion coefficients were determined by PFG-NMR in order to investigate the influence of microemulsion composition with the equal drug concentration on their transdermal delivery. Finally, the microemulsion containing 1% vinpocetine was optimized with 4% oleic acid, 20.5% Labrasol, 20.5% Transcutol P, and 55% double-distilled water (w/w), in which drug solubility was about 3160-fold higher compared to that in water and the apparent permeation rate across the excised rat skin was 36.4 ± 2.1 µg/cm²/h. The physicochemical properties of the optimized microemulsion were examined for the pH, viscosity, refractive index, conductivity, and particle size distribution. The microemulsion was stable after storing more than 12 months at 25°C. The irritation study showed that the optimized microemulsion was a nonirritant transdermal delivery system.     

Development of a Transdermal Delivery Device for Melatonin In Vitro Study

The present study was undertaken to develop a transdermal delivery device for melatonin and to determine the effects of system design on the release of melatonin. Melatonin(MT) diffusion characteristics from 2 solvents through a series of ethylene vinyl acetate membranes with 4.5%, 9%, 19%, 28% vinyl acetate were characterized using vertical Franz® diffusion cells. The solvent used were 40% (v/v) propylene glycol (PG) and 40%(v/v) propylene glycol with 30%(w/v) 2-hydroxypropyl-β-cytrodextrin. The best release rate (Jss = 0.795 μg/h/cm²) was obtained from the 40% PG vehicle through the 28% vinyl acetate membrane. Melatonin diffusion through this membrane with an acrylate pressure sensitive adhesive (PSA) with and without MT loading was also studied. The data revealed an interaction between MT and the PSA in the systems with MT-loaded adhesive. A MT transdermal delivery device was constructed based on the above data. Effect of storage time (1 day, 2 days, and 3 days) on the developed device was also investigated. Steady state flux values of MT did not vary significantly with storage time (p-value = 0.14). The steady state flux was 1.88 ± 0.6 μg/hr/cm²(n = 9). However, storage time did affect the burst effect of MT. Total amount of MT released in the first hour was 137.4 ± 25.7 μg after 3 days, 61.5 ± 8.9 μg after 2 days, and 43.8 ± 20.9 μg after 1 day.     

Transdermal delivery of ketorolac tromethamine: effects of vehicles and penetration enhancers

The effects of vehicles and penetration enhancers on the in vitro permeation of ketorolac tromethamine (KT) across excised hairless mouse skins were investigated. Among pure vehicles examined, propylene glycol monolaurate (PGML) showed the highest permeation flux, which was 94.3 ± 17.3 µg/cm²/h. Even though propylene glycol monocaprylate (PGMC) alone did not show high permeation rate, the skin permeability of KT was markedly increased by the addition of diethylene glycol monoethyl ether (DGME); the enhancement factors were 19.0 and 17.1 at 20% and 40% of DGME, respectively. When DGME was added to PGML, the permeation fluxes were almost two times at 20-60% of DGME compared to PGML alone. In the cosolvent system consisting of propylene glycol (PG)-oleyl alcohol, the permeation rate increased as the ratio of PG increased. In the study to investigate the effect of drug concentration on the permeation rate of KT, the permeation rates increased as the drug concentration increased in all vehicles used, and the dramatic increase in permeation rate was obtained when the drug concentration was higher than its solubility. For the effects of fatty acids on the permeation of KT, five fatty acids were added to PG at concentrations of 1%-, 3%-, 5%- and 10%-caprylic acid, capric acid, lauric acid, oleic acid, and linoleic acid. The enhancing effects of fatty acids were different, depending on the concentration as well as the sort of fatty acids. The highest enhancing effect was attained with 10% caprylic acid in PG; the permeation flux was 113.6 ± 17.5 µg/cm²/h. The lag time of KT was reduced as the concentration of fatty acids increased except for caprylic acid.     

Mucoadhesive Polymeric Hydrogels for Nasal Delivery of Acyclovir

The study evaluated different mucoadhesive polymeric hydrogels for nasal delivery of acyclovir. Gels containing poly-N-vinyl-2-pyrrolidone (PVP) were prepared with crosslinking achieved by irradiation with a radiation dose of 15 kGy being as efficient as 20 kGy. Gels containing chitosan and carbopol were also evaluated. The mucoadhesive properties of gels were measured by a modification of a classical tensile experiment, employing a tensile tester and using freshly excised sheep nasal mucosa. Considering the mucoadhesive force, chitosan gel and gel prepared with 3% PVP in presence of polyethylene glycol (PEG) 600 were the most efficient. The in vitro drug release depended on the gel composition. Higher release rates were obtained from PVP gels compared to chitosan or carbopol gels. The release rate of drug from PVP gels was increased further in presence of PEG or glycerol. Histopathological investigations proved that the PVP was a safe hydrogel to be used for mucosal delivery. The PEG in gel formulations caused less damages to the nasal mucosal compared to formulation containing glycerol.     

Preparation, Characterization and In-Vitro Release Kinetics of Salbutamol Sulphate Loaded Albumin Microspheres

Salbutamol sulphate loaded Bovine serum albumin microspheres were prepared by heat denaturation method. The effects of such preparation conditions as denaturation temperature, denaturation time, protein concentration and phase volume ratio on the extent of drug loading, size and size distribution and drug release were studied. An increase in protein concentration from 5% w/v to 15% w/v increased the mean particle size from 8.5 μm to 16.6 μm and decreased the drug loading from 46% w/w to 18% w/w. A decrease in the phase volume ratio substantially lowered mean particle size and size distribution. An increase in the severity of denaturaion conditions lowered both the drug incorporated and drug released. The kinetics of drug release from microspheres were compared to the theoretical models of Higuchi diffusional release and first order release. Both the models gave an adequate fit to the data. Scanning electron microscopy revealed that the dummy microspheres are spherical with smooth surfaces. As the drug-protein ratio increased, the microspheres exhibited rough surfaces showing the presence of drug crystals.     

Sintering kinetics of 8Y–cubic zirconia: Cation diffusion coefficient

Zirconia ceramics, mainly of cubic phase, are used in different applications because of their particular electrical and structural properties.

After the forming stage, sintering leads to a material with suitable microstructural characteristics. The sintering process mainly depends on thermal cycle and on starting particle size and its distribution; it also depends on density and the microstructure of green material. Cubic zirconia has a high (2680 °C) melting temperature; however, effective sintering could be observed for temperatures higher than 900 °C (nanoparticles), and it may reach a final density of 96–98% the theoretical value at relative low temperatures.

The objective of this paper is to study the sintering kinetics of stabilized zirconia in its cubic phase with 8% molar of Y₂O₃ under fast firing rates up to nearly isothermal conditions. Samples were shaped from suspensions dispersed with ammonium polyacrylate by slip casting. Sintering was performed in the temperature range between 1200 °C and 1400 °C. The sintering kinetic process was followed by measuring density as a function of time. A sintering model was applied to fit the experimental data of the first steps of densification. It was observed that sintering obeys the same mechanism in the temperature and time ranges under study, which results in an activation energy of 170 kJ mol⁻¹. Sintering is controlled by Zr cation diffusion, for which a lattice diffusion coefficient of D_l = 8 × 10⁻¹² cm² s⁻¹ at 1400 °C was found, and the activation energy of the diffusion process was 223 kJ mol⁻¹.