Drug release from Kollicoat SR 30D-coated nonpareil beads: evaluation of coating level, plasticizer type, and curing condition.

A newly available polyvinylacetate aqueous dispersion, Kollicoat SR 30D, was evaluated with respect to its ability to modulate the in vitro release of a highly water-soluble model compound (diphenhydramine hydrochloride) from nonpareil-based systems. Kollicoat SR 30D premixed with a selected plasticizer (10% wt/wt propylene glycol, 2.5% triethyl citrate, or 2.5% dibutyl sebacate), talc, and red #30 lake dye was coated onto the drug beads in an Aeromatic Strea I fluid-bed drier with a Wurster insert using bottom spray. With propylene glycol as the plasticizer, increases in polymer coating level retarded drug release from beads in a stepwise fashion along with apparent permeability, indicating a consistent release mechanism. Stability studies at 40 degrees C/75% RH revealed gradual decreases in dissolution rate, and additional curing studies further confirmed the dependence of release kinetics on curing condition. Furthermore, the type of plasticizer was found to play a key role. Unplasticized formulations exhibited the fastest dissolution, followed by formulations plasticized with triethyl citrate, propylene glycol, and dibutyl sebacate. All 4 formulations (unplasticized and plasticized), nevertheless, revealed a marked difference between uncured and cured dissolution profiles. Kollicoat SR 30D has, thereby, been demonstrated to effectively retard drug release from nonpareil-based systems. However, selected plasticizer type and subsequent curing condition play important roles in controlling drug release from such a system.

A novel method for estimating solid fraction of roller-compacted ribbons.

A simple method has been developed to estimate solid fraction or relative density of compacts using the weight of ribbons produced during roller compaction. The method provides an alternative to the commonly used dimensional measurement, especially for formulations not amenable to forming quality ribbons. Surface texture of the compaction rolls has been taken into consideration in our mathematical treatment along with correction for ribbon relaxation. Ribbon relaxation occurring upon ribbon exiting the compaction zone is estimated using roll geometry, roll gap, and ribbon thickness. Detailed experimental runs have been carried out to confirm the validity of the proposed theory. The predicted solid fraction was found comparable to that from actual dimensional measurement by caliper. In the case of the microcrystalline cellulose/dicalcium phosphate one:one formulation, the predicted solid fraction had an error sum of squares (SSE) of 2.64E-03 when compared to the dimensional method. When relaxation was included, the SSE decreased by four folds. Similarly, for the microcrystalline cellulose/lactose monohydrate 2:1 formulation, the SSE decreased twelfth folds when relaxation was taken into consideration. These results further confirm the utility of the proposed throughput method for estimating the solid fraction of ribbons.

Characterization of poly(ethylene oxide) as a drug carrier in hot-melt extrusion.

Poly(ethylene oxide) (PEO) as a drug carrier in hot-melt extrusion was studied by using a model drug, nifedipine, in a twin-screw extruder. Binary mixtures of PEO and nifedipine have been shown to be amenable to hot-melting at a temperature as low as 70 degrees C, well below nifedipine's melting point (172 degrees C). Hot-stage microscopy provided visual evidence that nifedipine can form a miscible dispersion with PEO at 120 degrees C. Complete loss of nifedipine crystallinity when extrudated at and above 120 degrees C with a drug loading of 20% (w/w) was further confirmed by differential scanning calorimetry (DSC) and X-ray diffraction. Cross-sectional imaging of the extrudates using scanning electron microscopy indicated homogeneous drug distribution inside PEO when the processing temperature was above 120 degrees C. Raman spectroscopy confirmed drug-PEO interactions at a molecular level. Cryo-milled extrudates showed significant improvement in dissolution rate compared to either pure nifedipine or the physical mixture of PEO and nifedipine. A state of supersaturation was achieved after 10-minute release in pH 6.8 phosphate buffer. Finally, stability study demonstrated that the solid dispersion system is chemically stable for at least 3 months under the conditions of both 25 degrees C/60% RH and 40 degrees C/75% RH. Overall, PEO appears to be a promising aid/carrier to solublize poorly soluble drugs through the formation of solid dispersion via hot-melt extrusion, thereby improving dissolution and absorption.

Cocrystal formation during cogrinding and storage is mediated by amorphous phase.

PURPOSE: The purpose of this work was to investigate the mechanisms of cocrystal formation during cogrinding and storage of solid reactants, and to establish the effects of water by cogrinding with hydrated form of reactants and varying RH conditions during storage. METHODS: The hydrogen bonded 1:1 carbamazepine-saccharin cocrystal (CBZ-SAC) was used as a model compound. Cogrinding of solid reactants was studied under ambient and cryogenic conditions. The anhydrous, CBZ (III), and dihydrate forms of CBZ were studied. Coground samples were stored at room temperature at 0% and 75% RH. Samples were analyzed by XRPD, FTIR and DSC. RESULTS: Cocrystals prepared by cogrinding and during storage were similar to those prepared by solvent methods. The rate of cocrystallization was increased by cogrinding the hydrated form of CBZ and by increasing RH during storage. Cryogenic cogrinding led to higher levels of amorphization than room temperature cogrinding. The amorphous phase exhibited a T (g) around 41 degrees C and transformed to cocrystal during storage. CONCLUSIONS: Amorphous phases generated by pharmaceutical processes lead to cocrystal formation under conditions where there is increased molecular mobility and complementarity. Water, a potent plasticizer, enhances the rate of cocrystallization. This has powerful implications to control process induced transformations.

Temperature/Humidity sensitivity of sustained-release formulations containing Kollidon SR.

The effects of temperature and humidity on tablets containing Kollidon SR have been evaluated using diphenhydramine HCl as a model drug. Exposure of tablets to ICH accelerated stability condition (40 degrees C/75%RH) in an open dish resulted in rapid increases in tablet hardness, accompahied by step-wise decreases in dissolution rate. Such a change can be observed as fast as an hour upon exposure. The tablet matrix appears to rapidly absorb atmospheric moisture, as demonstrated by tablet weight gain and moisture adsorption isotherms. Exposure to 25 degrees C/60%RH similarly resulted in increases in tablet hardness, although with minimal impact on dissolution. Potential implications of such rapid moisture uptake during aqueous film-coating were further evaluated by spraying either water or an Opadry solution in a coating pan. Exposure of Kollidon SR tablets to the aqueous coating process indeed resulted in noticeable changes in both hardness and dissolution. Application of the Opadry solution appears to affect tablet behavior to a lesser degree, compared to water, most likely due to protection via formed barrier film. Attention needs to be paid to the extreme sensitivity of Kollidon SR matrix tablets to temperature and moisture during product development.