Yasser El-Malah

D-Optimal Mixture Design: Optimization of Ternary Matrix Blends for Controlled Zero-Order Drug Release From Oral Dosage Forms

ABSTRACT 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.

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.

Hard Gelatin and Hypromellose (HPMC) Capsules: Estimation of Rupture Time by Real-time Dissolution Spectroscopy

ABSTRACT 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.

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.

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

Abstract 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.

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.