Modeling the effect of sonication parameters on size and dispersion temperature of solid lipid nanoparticles (SLNs) by response surface methodology (RSM).

The objective of this study was to evaluate the effect of sonication time and pulse frequency on average dispersion temperature (ART), particle size and zeta potential of solid lipid nanoparticles (SLNs). A two-factor, three-level response surface methodology (RSM) was used to optimize sonication time between 5 and 15 min and pulse frequency from 30 to 90%. SLNs made from stearyl alcohol (SA) and cetyl trimethylammonium bromide (CTAB) blend at 1:3 ratio were prepared by applying high-shear homogenization and sonication. Pulse frequency and time were found to have a significant effect on particle size and ART. The effect of sonication parameters on zeta potential, however, was insignificant. The optimal sonication parameters for preparing 100 nm SLNs made from a SA/CTAB blend was 60% pulse frequency at 40% power for 10 min. Optimized sonication parameters were then used to investigate the effect of lipid type on SLN size and zeta potential. The mean particle sizes of SLNs made with SA, cetyl palmitate, Precirol®, Dynasan118® and Compritol® were 98, 190, 350, 350 and 280 nm, respectively. In conclusion, pulse frequency and time were found to be critical for obtaining SLNs with desirable size, whereas the stability of the SLNs was dependent on their lipid content.

"Real-time" disintegration analysis and D-optimal experimental design for the optimization of diclofenac sodium fast-dissolving films.

The objective of this work was to study the dissolution and mechanical properties of fast-dissolving films prepared from a tertiary mixture of pullulan, polyvinylpyrrolidone and hypromellose. Disintegration studies were performed in real-time by probe spectroscopy to detect the onset of film disintegration. Tensile strength and elastic modulus of the films were measured by texture analysis. Disintegration time of the films ranged from 21 to 105 seconds whereas their mechanical properties ranged from approximately 2 to 49 MPa for tensile strength and 1 to 21 MPa% for young's modulus. After generating polynomial models correlating the variables using a D-Optimal mixture design, an optimal formulation with desired responses was proposed by the statistical package. For validation, a new film formulation loaded with diclofenac sodium based on the optimized composition was prepared and tested for dissolution and tensile strength. Dissolution of the optimized film was found to commence almost immediately with 50% of the drug released within one minute. Tensile strength and young's modulus of the film were 11.21 MPa and 6, 78 MPa%, respectively. Real-time spectroscopy in conjunction with statistical design were shown to be very efficient for the optimization and development of non-conventional intraoral delivery system such as fast dissolving films.

Effect of gel composition and phonophoresis on the transdermal delivery of ibuprofen: in vitro and in vivo evaluation.

The objective of this study was to evaluate the effect of formulation composition and continuous ultrasound at 1.5 W/Cm² intensity on the permeation of ibuprofen across polymeric and biological barriers. In vitro studies were performed using cellulose membrane and rabbit skin, whereas in vivo studies were performed on rabbits. Overall, higher transport data were obtained with the cellulose membrane. Nonetheless, with both barriers, transport was higher with the gel formulation than oleaginous or emulsion based preparations, which was also dependent on the viscosity of the gel and the concentration of the formulation additives. Transport increased with the increase in alcohol concentration and decreased with the addition of propylene glycol. Ultrasound had a significant effect on ibuprofen transport. For example, an 11-fold increase in drug permeation across cellulose membrane was observed after the application of ultrasound. Similar effect was observed in animal studies. Ibuprofen plasma concentration increased with the concentration of the drug in the gel, which significantly increased after the application of ultrasound. It was concluded that aqueous gel formulations act as ideal coupling agents for topical application of drugs. Nonetheless, in addition to ultrasound, the composition of the gel is expected to have a significant effect on the transdermal delivery of drugs.

Preparation of delayed release tablet dosage forms by compression coating: effect of coating material on theophylline release.

In this study, compression-coated tablets were prepared and examined by real-time swelling/erosion analysis and dissolution studies. Of the coating materials, PVP showed no swelling behavior and had no impact on theophylline release. Polyox(®) exhibited swelling behavior of an entangled polymer, which was reflected in its > 14-hour delayed-release profile. Hydroxypropyl methylcellulose (HPMC), which revealed the characteristics of a disentangled polymer, caused a 2-h delay in theophylline release. Based on preliminary texture analysis data, Polyox(®)/PVP blends were used as coating materials to manipulate the onset of drug release from the compression-coated tablets. Of the blends, at a 1:1 ratio, for example, resulted in a burst release after 10 h, which demonstrated the feasibility of preparing delayed release dosage forms by compression coating. Furthermore, it was feasible to predict the dissolution behavior of polymers from their swelling/erosion data, which were generated from texture analysis.

Effect of Eudragit RS 30D and talc powder on verapamil hydrochloride release from beads coated with drug layered matrices.

The aim of this study was to investigate the effect of Eudragit RS 30D, talc, and verapamil hydrochloride on dissolution and mechanical properties of beads coated with "drug-layered matrices". This was accomplished with the aid of a three-factor multiple-level factorial design using percent drug release in 1 and 2 h, T(50), tensile strength, brittleness, stiffness and toughness as the responses. Beads were coated in a fluidized-bed coating unit. Surface morphology and mechanical properties were evaluated by surface profilometry and texture analysis, respectively. No cracks, flaws and fissures were observed on the surfaces. The mechanical properties were dependent on the talc/polymer ratio. The release of verapamil from the beads was influenced by matrix components. Increasing the level of both talc and Eudragit decreased the percent drug released from 67% to 4.8% and from 80.7% to 6.7% in 1 and 2 h, respectively, and increased T(50) from 0.8 to 25.7 h. It was concluded that beads could be efficiently coated with "drug-layered matrices". The release of drug, however, depends on a balance between the levels of drug, talc, and polymer, whereby desired dissolution and mechanical properties could be controlled by the talc/polymer ratio and the level of drug loading.

Novel use of Eudragit NE 30D/Eudragit L 30D-55 blends as functional coating materials in time-delayed drug release applications.

The objectives of this study were to evaluate the mechanical and thermal properties of films prepared from Eudragit NE 30D/Eudragit L 30D-55 blends and to examine the dissolution behavior of beads coated with the polymer blends up to 120% weight gain. Eudragit NE 30D and L 30D-55 dispersions were blended at 50:50, 67:33, 75:25, and 80:20 ratios. Cast films were evaluated by texture analysis and differential scanning calorimetry. Increasing Eudragit NE 30D concentration increased miscibility, softness, and decreased stiffness of the films. At 80:20 ratio, the polymer blend was completely miscible whereby Eudragit L 30D-55 was molecularly distributed in the mixture. This was confirmed by SEM analysis. The surface morphology of films and beads was evaluated before and after dissolution by scanning electron microscopy. SEM analysis demonstrated that the size of the pores formed after the dissolution of Eudragit L 30D-55 at pH 6.8 was dependent on the miscibility of the Eudragit blend. The implications of this effect were apparent in dissolution studies. For the 75:25 and 80:20 blends, a linear increase in lag time up to 7 h was observed with an increase in coat weight gain from 15 to 120%. At 60% weight gain, the 80:20 blend delayed drug release by approximately 7 h whereas the less miscible 75:25 blend delayed drug release by only 3.5 h. A lag time could therefore be controlled by manipulating both the theoretical weight gain of the beads and the concentration of Eudragit NE 30D in the blend.

Fluid bed coating: the utility of dual programmable pumps for controlled gradient drug deposition on pellets.

The objective of this study was to demonstrate the potential use of dual programmable pumps in a fluid bed coating process to manufacture pellets coated with gradient layers of a drug. To achieve this goal, two matrix forming dispersions with an equivalent amount of solids, one containing verapamil HCl as a model drug, and the other without the drug, were forced in a gradient pattern into a fluid bed coater using two pumps joined at Y junction. The two pumps were operated at opposing flow rates via a computer guided program to maximize drug concentration in the inner layers around the core. The difference between gradient and non-gradient drug coating was demonstrated by dissolution studied. Depending on the drug to polymer ratio, verapamil HCl release from gradient layered pellets was delayed over an extended period of time and was significantly different from the non-gradient coated pellets.

A novel texture-probe for the simultaneous and real-time measurement of swelling and erosion rates of matrix tablets.

In this note, a novel probe fitted to a texture analyzer was described. This probe has the ability to simultaneously measure, in real-time, dimensional changes in the swollen layer and the glassy core of hydrophilic matrices when exposed to aqueous dissolution media. The utility of this probe was demonstrated on directly compressed tablets containing polymer blends, a water soluble additive, and theophylline as a model drug. Both the erosion and swelling fronts were measured for the same tablet every hour for 12 h. The probe provided accurate thickness data of the swollen region and the glassy core, and was able to demonstrate the swelling and subsequent erosion of the tablet with time. With this method, it is possible to simultaneously measure the swelling rate of the rubbery region and the erosion rate of the glassy core without operator intervention, which provides many advantages over the conventional approaches frequently reported in the literature.

Hard gelatin and hypromellose (HPMC) capsules: estimation of rupture time by real-time dissolution spectroscopy.

The objective of this study was to measure rupture time of gelatin and hypromellose (hydroxypropyl methylcellulose or HPMC) capsules using a novel approach based on real-time dissolution spectroscopy. Rupture time was measured in standard dissolution apparatus at a constant temperature using a dip-type fiber-optic probe. Labrasol released from the capsules was treated as the marker of the rupture process. Light scatter generated by the emulsified labrasol was detected by an ultrafast monochromator at scan rates approximating 24,000 nm/min. This technique was validated by measuring the dissolution time of gelatin capsules. Rupture times of hypromellose capsules were studied as a function of capsule size, capsule grade, and dissolution medium. Statistical correlations were analyzed by ANOVA. Rupture time of hypromellose capsules was dependent on both the medium and the grade of the capsule, and was independent of capsule size. The composition of the dissolution medium contributes to the rupture time of the capsules and should be considered when fast release and quick biological response is desired. Release delay, however, may not manifest itself in vivo and the time to maximum plasma concentration may not be significant.

D-optimal mixture design: optimization of ternary matrix blends for controlled zero-order drug release from oral dosage forms.

The objective of the present study was to develop a tablet formulation with a zero-order drug release profile based on a balanced blend of three matrix ingredients. To accomplish this goal, a 17-run, three-factor, two-level D-Optimal mixture design was employed to evaluate the effect of Polyox (X1), Carbopol (X2), and lactose (X3) concentrations on the release rate of theophylline from the matrices. Tablets were prepared by direct compression and were subjected to an in vitro dissolution study in phosphate buffer at pH 7.2. Polynomial models were generated for the responses Y4 (percent released in 8 h) and Y6 (similarity factor or f2). Fitted models were used to predict the composition of a formulation that would have a similar dissolution profile to an ideal zero-order release at a rate of 8.33% per hour. When tested, dissolution profile of the optimized formulation was comparable to the reference profile (f2 was 74.2, and n [release exponent] was 0.9). This study demonstrated that a balanced blend of matrix ingredients could be used to attain a zero-order release profile. Optimization was feasible by the application of response surface methodology, which proved efficient in designing controlled-release dosage forms.

Hydrophilic matrices: application of Placket-Burman screening design to model the effect of POLYOX-carbopol blends on drug release.

The aim of the present study was to screen the effect of seven factors--POLYOX molecular weight (X(1)) and amount (X(2)); carbopol (X(3)), lactose (X(4)), sodium chloride (X(5)), citric acid (X(6)); compression pressure (X(7))--on (1) the release of theophylline from hydrophilic matrices, demonstrated by changes in dissolution rate, and (2) their impact on the release exponent [n] indicative of the drug transport mechanism through the diffusion matrix. This objective was accomplished utilizing the Placket-Burman screening design. Theophylline tablets were prepared according to a 7-factor-12-run statistical model and subjected to a 24-h dissolution study in phosphate buffer at pH 7.2. The primary response variable, Y(4), was the cumulative percent of theophylline dissolved in 12h. The regression equation for the response was Y(4)=66.2167 - 17.5833X(1) - 3.3833X(2) - 9.366X(3) - 1.1166X(4) - 0.6166X(5) + 2.6X(6) - 2.783X(7). This polynomial model was validated by the ANOVA and residual analysis. The results showed that only two factors (X(2) and X(3)) had significant effect (p-value<0.10) on theophylline release from the hydrophilic polymer matrix. Factors (X(2) and X(7)) had significant effect (p-value<0.10) on [n], the exponent.