Formulation and process considerations for beads containing Carbopol 974P, NF resin made by extrusion-spheronization.

Preliminary studies revealed that Carbopol 974P, NF resin could be incorporated into beads manufactured by extrusion and spheronization, and can slow the release of a highly water soluble drug if calcium chloride was included in the granulating fluid to reduce the tack of the wetted polymer. In this study, the same approach was used to produce high quality chlorpheniramine maleate beads with a prolonged release duration. Because of the complex nature of the extrusion and spheronization process and the various components in the bead formulations, a statistically sound factorial experiment was considered for this study. A one-half fraction of a two level factorial design with three center points was employed to estimate the effects of simultaneously modifying multiple process and formulation variables, including the Carbopol concentration, calcium chloride concentration, water content, and the spheronization speed and time. Product yield, average bead roundness, and the drug release profile were selected as responses. Increasing the Carbopol content across the experimental range resulted in a significant (P<0.05) reduction in the percentage drug released at 25, 40, and 60 min. Results suggest that combining the conditions of high Carbopol, high water, and low calcium chloride levels with low spheronization speeds at long spheronization times produce the highest quality bead with the longest drug release duration.

Drug solubility effects on predicting optimum conditions for extrusion and spheronization of pellets.

This paper explores the utility of aqueous solubility of structurally similar drugs in predicting optimum conditions for extrusion and spheronization of pellets using response surface methodology. Pharmacologically active xanthine derivatives exhibiting widely varying aqueous solubility were used to determine optimum conditions for pelletization. The amount of water added to the formulation, wet mixing time, and spheronizing time were explored in a series of central composite experimental designs to exhaustively explore and mathematically model the response surfaces for each drug. Using a marketed microcrystalline cellulose excipient, optimum extrusion and spheronization conditions for less soluble drugs required more water, a longer wet mixing time, and prolonged spheronizing times. Results were similar when a new microcrystalline cellulose was substituted, except that more water was required. When comparing results for different drugs, a strong linear relationship was observed between the aqueous solubility of the drug and the water content required for optimum pellet production. The water content range over which quality pellets could be produced was much broader for poorly soluble drugs. Aqueous solubility of the active component appears to be a good predictor for the water requirements for optimum extrusion and spheronization of pellets for pharmaceutical applications.

A limited sampling method for the estimation of vigabatrin maximum plasma concentration and area under the curve.

A limited sampling model (LSM) was developed to estimate the area under the curve (AUC) and maximum plasma concentration (Cmax) for a 1-g oral dose of vigabatrin. The model was developed using the data from 10 healthy subjects and one time point. The following equations describe the model for AUC and Cmax: AUC(predicted) = 5.4 x C3h + 70 and Cmax(predicted) = 0.18 x AUC(0-infinity) + 9.4. The model was validated in 49 subjects who orally received 1-g vigabatrin. This LSM was also used to predict AUC and Cmax volunteers who received 2- and 4-g vigabatrin doses and in renal failure patients who were given a 0.75-g dose. The model provided good estimates of both AUC and Cmax in all groups of subjects except renal dysfunction patients. The method described here may be used to estimate AUC and Cmax of vigabatrin without detailed pharmacokinetic studies.