High-amylose sodium carboxymethyl starch matrices for oral, sustained drug release: development of a spray-drying manufacturing process.

CONTEXT: High-amylose sodium carboxymethyl starch (HASCA) was recently proposed as a material for oral, sustained drug-release tablets prepared by direct compression. It was produced on a pilot scale, but appeared to be unsuitable for tableting and sustained drug release. Pilot-scale dry powder HASCA was dispersed in hot water and then precipitated with ethanol to give a dry powder presenting the required properties, but very high volumes of ethanol were used to recover the product. OBJECTIVE: A process was therefore designed to transform totally amorphous pregelatinized HASCA by spray-drying into a suitable sustained drug-release excipient for matrix tablets while decreasing ethanol quantities. RESULTS AND DISCUSSION: During the first manufacturing step, that is, heating of the initial hydro-alcoholic suspension, powder and water concentrations are key parameters for the acquisition of excellent binding properties. Hence, a variable ratio of amylose Vh, a crystalline polymorph of amylose, to the amorphous form, is observed depending on the key parameter values. As the most crystalline samples give the weakest tablets, binding properties do not appear to be linked to the presence of a Vh form of amylose. On the other hand, a high water concentration results in excessive tablet strength, that is, inverse conditions leading to the appearance of a Vh form of amylose. Finally, variations in hydro-alcoholic composition appear to affect only tableting properties and do not influence the drug-release rate. CONCLUSION: A process designed to transform totally amorphous pregelatinized HASCA by spray-drying is proposed for easier, economical industrial HASCA production.

The focused ion beam technique: a useful tool for pharmaceutical characterization.

Focused ion beam (FIB) instrumentation, a hybrid of the scanning electron micrsocope, ion milling and computer-aided design systems, has special uses in the electronic and semiconductor industries as a tool for failure analysis and device development. This paper examines the pharmaceutical applications of the FIB, particularly microscopic analysis of microspheres. With the FIB, microsphere structures were peeled off, layer by layer, and the structure of each layer was simultaneously observed under scanning microscopy. The particles had a wrinkled but non-porous surface. Going deeper, some holes appeared, with size and numbers increasing toward the particle center. This unique method precisely investigated the inner structure of particles, layer by layer. Then, by FIB milling, samples were extracted with an accuracy of localization of 50nm from specific parts of the microspheres and prepared to a 200nm uniform thickness film for examination under transmission electron microscopy. The FIB method also has the potential for a wide range of other quantitative and qualitative analysis of dosage forms and materials.

Agglomeration tendency in dry pharmaceutical granular systems.

The agglomeration tendency of dry pharmaceutical mixtures containing various concentrations of Xylitab 100 (Xylitol), calcium carbonate precipitated (CCP) and magnesium stearate (MgSt) was evaluated statistically as a function of mixing time. A Ro-Tap tester was employed to mix the three pharmaceutical components, and the agglomerates formed were measured with respect to their weight and size. An experimental design was devised and applied to structure and then statistically analyze the results. Xylitab was found not to be influential in the formation of agglomerates, but aided in deagglomeration when mixed with other components. CCP and MgSt formed agglomerates over time and showed positive interactions favouring agglomeration. The agglomerates started to fracture when they reached a critical size, at which stage the particles' attraction forces (cohesion forces) were weaker than both gravity and inertia. It has been shown and quantitatively demonstrated that the mixing time and ingredient concentrations of a three-component pharmaceutical mixture can affect agglomeration tendency.

Insights into the role of electrostatic forces on the behavior of dry pharmaceutical particulate systems.

PURPOSE: Under different charging conditions, particles can be either attracted or repulsed by each other, causing powder agglomeration or segregation. Such behavior can be detrimental in many processes aimed at achieving particulate mixture homogeneity. Consequently, the effects of electrostatic charges on mixing kinetics must be well understood to insure a high level of process control, product quality, and reproducibility. METHODS: In Part 1, an electrostatic charger is used to evaluate the ability of the studied particles to develop and retain an induced charge at the surface for a fixed period of time. Part 2 assesses the natural electrostatic charge developed by powders sliding across a stainless steel, plastic, or Tyvek chute. In Part 3, 2 binary systems were formed according to an experimental design under different charging conditions, and their behavior was quantified by measuring the degree of agglomeration attained. RESULTS: This work has shown that each raw material develops a different charge according to its physico-chemical properties and the type of contact surface. Electrostatic charges influence the creation of agglomerates under certain conditions. CONCLUSIONS: The presence of electrostatic charges must be accounted for in any effort to maximize mixing efficiency.

New methods characterizing avalanche behavior to determine powder flow.

PURPOSE: To characterize the avalanche behavior of different powders and to compare the results of the strange-attractor and novel characterization approaches. METHODS: The following nine different materials were tested: three lactoses, maltodextrin, two microcrystalline celluloses, sodium chloride, sucrose, and glass beads. Morphology, size, and size distribution, true density, bulk and tap density, angle of repose, flow index, and avalanching behavior were quantified for each excipient by scanning electron microscopy, laser time-of-flight analysis, helium pycnometer, graduated cylinder, fixed-height funnel, Flodex (Hanson Research Corp., Chatsworth, California) method, and AeroFlow (TSI, Inc., St. Paul, Minnesota), respectively. Environmental factors were controlled, and the avalanches were studied at various speeds. RESULTS: The strange-attractor graph obtained at 1 rotation per 120 s showed that it was difficult to appreciate the flowability differences among 3-mm glass beads, lactose 100, and lactose 325. However, plotting the raw data as a relationship of the time between each avalanche and the inverse of speed revealed a characteristic linear slope for each sample. Furthermore, a new flowability index based on the SD calculated from the raw data gave results that were consistent with Carr's index. A cohesive index also can be determined by avalanche behavior, and it reflects the stability of the rapid particular rearrangements of powder. CONCLUSION: A novel method of evaluating avalanche measurements makes it possible to better characterize powder flowability and to predict powder behavior under working conditions.