Polymorphic properties of micronized carbamazepine produced by RESS.

Carbamazepine microparticles were produced by the rapid expansion of supercritical carbon dioxide solutions (RESS) method. The characteristics of the resulting particles were studied by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and image analysis. X-ray diffractograms and SEM photomicrographs revealed that the crystalline nature of the produced carbamazepine microparticles depended on operating pressure and temperature conditions. Different polymorphs were obtained under various operating conditions. Under certain temperature (below 40 degrees C) and pressure (below 240 bar) conditions, it was possible to form primarily the carbamazepine polymorph stipulated by US Pharmacopeia. A significant reduction was observed in the particle size and size distribution range of carbamazepine produced by RESS. The processed particles had a mean diameter smaller than 3 microm and a size distribution range between 0.5 and 2.5 microm compared to unprocessed starting material with a mean diameter of approximately 85 microm and a size distribution range between 15 and 336 microm. Thus, this study demonstrates that the polymorphic characteristics of carbamazepine microparticles produced by the RESS method can be controlled by varying operating pressure and temperature parameters.

Influence of surface properties at biodegradable microsphere surfaces: effects on plasma protein adsorption and phagocytosis.

OBJECTIVE: The objective of this work was to determine plasma protein adsorption and macrophage phagocytosis of biodegradable polyanhydride, polylactic acid and polylactic-co-glycolic acid microspheres prepared by both spray-drying and solvent evaporation techniques. METHODS: Microspheres were characterized by scanning electron microscopy (SEM), confocal laser microscopy, particle size distribution and zeta (zeta) potential determination. Plasma protein adsorption onto the microspheres was determined using a fluoroaldehyde reagent. Phagocytosis was evaluated by incubating microspheres containing the angiotensin II antagonist, L-158,809, with the macrophages in the presence or absence of the phagocytosis inhibitor cythochalasin D. The extent of phagocytosis was established by fluorescence determination of L-158,809 and by optical microscopy. The effect of amphiphilic poly(ethylene glycol) (PEG) derivatives on phagocytosis was determined using PEG-distearate incorporated into the microspheres. RESULTS: The average diameter of the microspheres, which depended on the polymer and the initial formulation, ranged from 0.9 to 3.2 micrometers. Zeta potential studies showed strong negative values irrespective of the polymer used for the spray-dried formulations. The zeta potential was masked by the incorporation of PEG 400- or PEG 1,400-distearate in the formulation. Confocal laser microscopy showed a homogenous dispersion of PEG (measured as PEG-fluorescein) in the microspheres. Protein adsorption was not observed for any of the microsphere formulations following incubation with bovine serum. Incubation of microspheres with murine macrophages showed that PEG-distearate inhibited phagocytosis at appropriate levels (0.1% w/w). Higher levels > 1% w/w of PEG-distearate) resulted in enhanced association with macrophages, despite the presence of the phagocytosis inhibitor cytochalasin D, indicating fusion between the microspheres and the plasma membrane. CONCLUSIONS: These results demonstrate that spray-dried PEG-containing microspheres can be manufactured and that an appropriate concentration of this excipient in microspheres results in decreased phagocytosis.

Improved activity of a new angiotensin receptor antagonist by an injectable spray-dried polymer microsphere preparation.

PURPOSE: To characterize and evaluate in vitro and in vivo the release mechanisms involved in spray-dried biodegradable microspheres having different Poly(D,L-lactide) blend formulations and containing an antihypertensive drug (L-158,809). METHODS: Microspheres and blended polymers were characterized by DSC, SEM, confocal laser microscopy and size analysis. In vitro release studies were evaluated by using microspheres made from various blends of high and low molecular weight polymer. In vivo studies were evaluated by L-158,809 antagonist AT1 function versus the shift of the normal dose-response curve of blood pressure induced by Angiotensine II. RESULTS: The average yield of L-158,809 microspheres (10% (w/w)) was 95% of the theoretical loading. The average diameter of the microspheres was from 1 to 3 micrometers. In all release experiments, a significant burst effect (< 15%) was observed followed by a near zero-order release kinetics. In vivo studies with two different formulations show a strong shift of angiotensin II dose-response curve. CONCLUSIONS: The release kinetics and photomicrographs suggest that the system is best described as a multi-parameter controlled released system in which the drug is molecularly dispersed. In vivo results demonstrating the controlled release of L-158,809.

Discharge criteria for ambulatory surgery: a review of the current literature.

Over the past two decades there has been an increasing trend toward ambulatory surgery. There has also been a corresponding emphasis in research in this area, with particular attention to perioperative management and preoperative selection of ambulatory patients. However, one area of limited information in the literature is postoperative management of the ambulatory surgery patient, in particular, discharge criteria from an ambulatory surgery unit. This paper will address the importance of this issue and provide an overview of the criteria considered in the current literature.

Solute release from a porous polymeric matrix: inwardly tapered disk with a central releasing hole.

Diffusional solute release from an inert porous polymeric matrix was evaluated using sodium salicylate released from fused, inwardly tapered, polyethylene disk matrices (1.27 cm in diameter) with a central releasing hole. Two types of matrix were made by compressing (175 MPa) a sodium salicylate-melt polyethylene mixture with two different sets of circular conical punches having angles of 20 degrees and 30 degrees, with an axis perpendicular to the cone. The matrix sodium salicylate loading was greater than its solubility limit in the release medium. The fused matrices were coated with wax and perforated in their center to create a surface available for solute release. Flat disks with a central cylindrical hole were also made to compare the release profiles. An approximate solution was developed for these inwardly tapered disks and tested against experimental results. The theoretical model and experimental results showed good agreement and indicated that this type of matrix geometry may be useful as a pharmaceutical dosage form to approximate zero-order release.

Pectin-gelatin complex coacervates II: Effect of microencapsulated sulfamerazine on size, morphology, recovery, and extraction of water-dispersible microglobules.

Spherical medicated microglobules were prepared by complex coacervation of Type A gelatin with pectin, having nominal diameters of 5, 10, and 25 micron and containing 37.3, 44.9, and 45.2% (w/w) sulfamerazine, respectively. They were recovered as water-insoluble powders and were spontaneously revertible to highly disperse systems when reconstituted in water or physiological electrolyte solution. The conditions affecting microglobule formation were studied. For complete formation, the crystals must be dispersed at greater than or equal to pH 5. The effect of the sulfamerazine mass added on microglobule morphology, yield, and contents were investigated. As much as 37.3, 44.5, and 69.1% (w/w) sulfamerazine in 5-, 10- and 25-micron microglobules could be formed without loss of spherical shape. The microglobule yield versus drug-to-colloid ratio curves were nonlinear below the critical drug-to-colloid ratio for loss of sphericity. Addition of sulfamerazine suppressed coacervation by 10-15% but it had no significant effect on microglobule size. The extraction of medicated microglobules in various media demonstrated the existence of a porous matrix that required hydration to facilitate extraction of the microglobular drug. Fifteen percent of the encapsulated sulfamerazine was extracted from 25-micron microglobules as opposed to 9% from 10-micron microglobules after equilibration for 24 h in replacement electrolyte solution.

Pectin-gelatin complex coacervates I: Determinants of microglobule size, morphology, and recovery as water-dispersible powders.

The pectin-gelatin complex coacervate system was evaluated and characterized. The effects of final pH, mixing pH, colloid ratio, and solution concentration were investigated. A recovery procedure yielding microglobules of a controlled and uniform size in dry powder form which were readily revertible in water to a polydispersed suspension was developed. The effect of various conditions and additives on the recovery morphology and size of the microglobules was evaluated.

Characteristics of medicated and unmedicated microglobules recovered from complex coacervates of gelatin-acacia.

Medicated and unmedicated microglobules prepared from complex coacervates of Type A gelatin and acacia were recovered as water-insoluble powders consisting of discrete units, which were spontaneously revertible to highly disperse systems when suspended in water or physiological electrolyte solutions. Spherical microglobules containing up to 15% (w/w) sulfamerazine had a nominal diameter of 30 micron in aqueous suspension. Larger but irregularly shaped products containing up to 45% (w/w) sulfamerazine were also recovered. The relationships of the weight of sulfamerazine added per coacervate batch to weight yield and percent (w/w) included sulfamerazine of the microglobules were both linear.