Continuous Mixing Technology: Characterization of a Vertical Mixer Using Residence Time Distribution.

Continuous powder mixing technology (CMT) application during continuous direct compression has emerged as a leading technology used in the development and manufacture of solid oral dosage forms. The critical quality attributes of the final product are heavily dependent on the performance of the mixing step as the quality of mixing directly influences the drug product quality attributes. This study investigates the impact of blend material properties (bulk density, API particle size distribution) and process parameters (process throughput, hold up mass and impeller speed) on the mixing performance. Mixing of the blend was characterized using the Residence Time Distribution (RTD) of the process by trending the outlet stream of the mixer using a near-infrared (NIR) probe after the injection of a small mass of tracer at the inlet stream. The outcomes of this study show that the RTDs of the mixer with throughput ranging between 15 and 30 kg/h; impeller speed ranging between 400 and 600 rpm and hold up mass (HUM) ranging between 500 and 850 g can be described by a series of two ideal Continuous Stirred Tank Reactors (CSTRs) with different volumes, and correspondingly, different mean residence times. It is also observed that the mixing is mainly occurring in the lower chamber of the CMT and the normalized RTDs of the mixer are similar across the range of process conditions and material attributes studied. The results also showed that the formulation blend with different API particle sizes and bulk properties, like bulk density and flowability, provide insignificant impact on the mixing performance. The CMT allows independent selection of target set points for HUM, impeller rotational speed and line throughput and it shows great robustness and flexibility for continuous blending in solid oral dose manufacturing.

Development and in vivo evaluation of buccal tablets prepared using danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complexes.

The aim of the present work was to develop a mucoadhesive controlled-release formulation of danazol-sulfobutylether 7 beta-cyclodextrin (SBE 7) complex and to evaluate the feasibility of improving the bioavailability of danazol via the buccal route. Different types of polymers, polycarbophil (PC) and hydroxypropylmethyl cellulose (HPMC) were mixed with danazol-SBE 7 complex and compressed into tablets. These tablets were evaluated for their dissolution and mucoadhesion properties and for drug absorption in female beagle dogs. Increased mucoadhesion was observed for PC-containing tablets compared with HPMC tablets. As the concentration of polymer increased, drug release decreased, and PC-containing tablets gave slower release compared to HPMC tablets. In vivo bioavailability performed in dogs showed that the perorally administered danazol-SBE 7 complex and the danazol-SBE 7 (in PC matrix) buccal tablets had absolute bioavailabilities of 64% and 25%, respectively, that are significantly greater than 1.8% observed for the commercial formulation Danocrine. The increased bioavailability was attributed to the enhanced solubility consequent to complexation, and the possible avoidance of first-pass metabolism upon buccal administration.

Viscoelastic evaluation of topical creams containing microcrystalline cellulose/sodium carboxymethyl cellulose as stabilizer.

The purpose of this study was to examine the viscoelastic properties of topical creams containing various concentrations of microcrystalline cellulose and sodium carboxymethyl cellulose (Avicel(R) CL-611) as a stabilizer. Avicel CL-611 was used at 4 different levels (1%, 2%, 4%, and 6% dispersion) to prepare topical creams, and hydrocortisone acetate was used as a model drug. The viscoelastic properties such as loss modulus (G"), storage modulus (G'), and loss tangent (tan delta) of these creams were measured using a TA Instruments AR 1000 Rheometer and compared to a commercially available formulation. Continuous flow test to determine the yield stress and thixotropic behavior, and dynamic mechanical tests for determining the linear viscosity time sweep data, were performed. Drug release from the various formulations was studied using an Enhancer TM Cell assembly. Formulations containing 1% and 2% Avicel CL-611 had relative viscosity, yield stress, and thixotropic values that were similar to those of the commercial formulation. The elastic modulus (G') of the 1% and 2% formulation was relatively high and did not cross the loss modulus (G"), indicating that the gels were strong. In the commercial formulation, G' increased after preshearing and broke down after 600 seconds. The strain sweep tests showed that for all formulations containing Avicel CL-611, the G' was above G" with a good distance between them. The gel strength and the predominance of G' can be ranked 6% > 4% > 2%. The strain profiles for the 1% and 2% formulations were similar to those of the commercial formulation. The delta values for the 1% and 2% formulations were similar, and the formulations containing 4% Avicel CL-611 had lower delta values, indicating greater elasticity. Drug release from the commercial preparation was fastest compared to the formulations prepared using Avicel CL-611, a correlation with the viscoelastic properties. It was found that viscoelastic data, especially the strain sweep profiles of products containing Avicel CL-611 1% and 2%, correlated with the commercial formulation. Rheological tests that measure the viscosity, yield stress, thixotropic behavior, other oscillatory parameters such as G' and G" are necessary tools in predicting performance of semisolids.