Adsorption of fluoxetine HCl by activated charcoal.

We studied the adsorption of fluoxetine HCl (Prozac) by Norit USP XXIII activated charcoal in vitro, in simulated gastric fluid (USP; pH 1.2), and in simulated intestinal fluid (USP; pH 7.5). The data were fitted to both Langmuir and Freundlich equations. The Langmuir Qm values (maximal adsorption capacities) for pH 1.2 and 7.5 were 0.258 and 0.330 g drug/g charcoal, respectively. These excellent capacities suggest that oral charcoal therapy would be effective for fluoxetine overdose.

Minimal water requirements for suspending powdered antidotal charcoals.

The minimal amounts of water needed to assure complete suspension of 50 g of 4 different antidotal charcoals were determined. The water volumes ranged from 170-192 ml. The total suspension volumes (water + charcoal) ranged from 201-221 ml. Since manufacturers package 50 g charcoal formulations with a total volume of 8 fluid ounces (237 ml) there is only 16-36 ml of water beyond the minimal amounts needed for suspension. It is recommended that water in an amount of 10% or more of the total volume (ie 24 ml or more) be added by manufacturers to help prevent compaction during storage, or be added by users to aid in resuspension and to increase the suspension flow rate during delivery through tubes.

Evaluation of the US pharmacopeia adsorption tests for activated charcoals and proposals for changes.

The current USP adsorption tests for activated charcoals, involving methylene blue (MB) and strychnine sulfate (SS), were conducted for 6 activated charcoals having surface areas ranging from 600 to 2000 m2/g. The MB test is relatively complex and tedious, and uses a pass/fail criterion which is of such small magnitude that substantial uncertainties are likely. The SS test is only qualitative. Modification, using quantification of the turbidities, permitted quantitative interpretation. The test was failed by 2 charcoals of surface area 660 m2/g or less, and was passed by 4 charcoals of 720 m2/g surface area or higher. Neither test was able to reflect the substantial drug adsorption differences which exist for charcoals of average, above average, and high surface areas. Alternative tests for MB and SS were developed and evaluated using 6 charcoals. These tests, which are proposed for consideration by the US Pharmacopeial Convention, are simpler and faster than the current tests and yield precise values for the percentages of the 2 compounds adsorbed. Moreover, they clearly reflect the wide differences in adsorption performance of charcoals having widely different surface areas. Minimum percent adsorption values that must be attained for a charcoal to qualify as "USP grade" are proposed for both alternative tests (these would not exclude any current USP grade charcoal). Performance classifications of charcoals into categories of Low, Average, Above Average, and High are also proposed for both tests. These are shown to correspond to surface area ranges of < 700, 700-950, 950-1200, and > 1200 m2/g, respectively.

In vitro adsorption of phenobarbital, chlorpheniramine maleate, and theophylline by four commercially available activated charcoal suspensions.

Four commercially available antidotal activated charcoal suspensions (Actidose Aqua, InstaChar, LiquiChar, and CharcoAid 2000) were evaluated with respect to their abilities to adsorb three test drugs in vitro from simulated gastric fluid. Different volumes of each suspension were added to glass vials containing 20 mL of stock solutions of each drug. The vials were shaken for a time more than sufficient to ensure adsorption equilibrium, then the charcoal was removed from the samples by filtration. The filtrates were analyzed by ultraviolet spectroscopy to determine the residual drug concentrations. The product containing a 2000 m2/g charcoal (CharcoAid 2000) adsorbed more drug per unit volume of suspension than did the other three products, which contained 900 m2/g charcoal and which were all similar in performance.

Effect of magnesium citrate on the adsorptive capacity of activated charcoal for sodium salicylate.

The effects of an added saline cathartic (magnesium citrate) on the in vitro adsorption of sodium salicylate by activated charcoal were determined at different pH levels. At low pH added magnesium citrate reduced salicylate adsorption. However, at high pH added magnesium citrate enhanced adsorption. These results indicate that magnesium citrate should have no detrimental effect on the action of activated charcoal in vivo. Indeed, a slight beneficial effect is suggested by this and other studies.

The thin-film adsorber hemoperfusion device: detailed mass transfer and flow characteristics.

Further testing and evaluation of the thin-film adsorber (TFA) type of hemoperfusion device is reported here to complement an earlier paper describing the development of these devices and clearance tests performed with them. The present paper describes the results of pressure drop tests, flow uniformity tests, and detailed studies of the mass transfer characteristics of the components of the TFA units. The TFA units consist of powdered activated charcoal embedded in thin films of cellulose nitrate. These films are sprinkled with small particles of granular charcoal and then wound into spools, which are then placed in a plastic housing. The use of powdered charcoal exploits the enormous rate-of-uptake advantage of powdered charcoal over the granular sorbents used in other hemoperfusion devices. The present tests showed that the pressure drops in the TFA devices are intrinsically low, but that their priming volumes are only marginally acceptable. Significant flow nonuniformities also exist. Despite this, the overall mass transfer resistance values for the TFA devices are lower than those for available commercial hemoperfusion units. Measurements of diffusion coefficients in the carbon and in the carbon-loaded polymer film showed that in the carbon-loaded film, the slowest diffusion step involves the carbon particles themselves. Other tests disclosed that the liquid external to the film (i.e., in the flow spaces) offers even greater mass transfer resistance than does the carbon-loaded film. Further evaluations of the TFA type of device are suggested, particularly concerning its thrombogenic properties.

Effect of type and amount of carboxymethylcellulose on in vitro salicylate adsorption by activated charcoal.

The effect of the type of carboxymethylcellulose (CMC) and amount of CMC used in preparing antidotal charcoal formulations on the in vitro kinetics of sodium salicylate adsorption from simulated gastric fluid was assessed in agitated vessels of two designs. Mixtures made with low, medium, and high viscosity CMC were tested. Additionally, the effects of the charcoal and water contents of these mixtures on adsorption kinetics were considered. The results suggest that charcoal mixtures which are fluid enough to be pourable (hence, drinkable) are strongly to be preferred from the standpoint of rate of adsorption. More particularly, gel-like formulations should be avoided because they disperse poorly and result in rather slow rates of drug uptake.

The thin-film adsorber hemoperfusion device: development and evaluation of clearance characteristics.

A novel hemoperfusion device was developed by embedding powered activated charcoal in thin (150 micrometer) films of cellulose nitrate. These films were sprinkled with small particles of granular charcoal and wound into spools, which were then placed in a plastic housing. The use of powdered charcoal exploits the enormous rate-of-uptake advantage of powered charcoal over the granular sorbents found in other hemoperfusion devices. The granular carbon sprinkled on the films was primarily to provide spacing between adjacent film layers for adequate fluid flow; the granules did enhance long-term uptake in addition. Clearance tests with this novel "thin-film adsorber," using sodium salicylate, sodium barbital, and creatinine, showed that its rate of solute adsorption, particularly at early times, was consistently very high. This type of hemoperfusion device is a promising alternative to the granular-sorbent types of devices currently available, especially when maximal solute removal during the early stages of treatment is mandated.

"Superactive" charcoal adsorbs drugs as fast as standard antidotal charcoal.

Experimental data on the uptake of two test drugs by powdered Amoco PX-21 and Norit A activated charcoals in stirred-batch tests indicate that the rate of uptake by the Amoco charcoal is equal to, or higher than, the uptake rate by Norit A. In contrast to the conjecture of Medema [1], the superactive Amoco charcoal is not kinetically inferior to Norit A. The superactive charcoal remains highly recommended for antidotal uses.

Palatability of sucrose-, sorbitol-, and saccharin-sweetened activated charcoal formulations.

The palatabilities of thickened activated charcoal formulations flavored with sucrose, sorbitol or saccharin sodium were compared. Three flavored activated charcoal formulations were prepared from a base of 25 g of activated charcoal, 1.5 g of carboxymethylcellulose, and 75 g of distilled water. The ratios of sweetener to activated charcoal were 1:1 for sucrose and sorbitol, and 1:20 for saccharin sodium. The palatabilities of the three flavored and one unflavored formulation were rated by 16 adults for taste, texture, ease of swallowing, and overall impression. No significant palatability differences were noted among the flavored mixtures, but all three flavored formulations were significantly more acceptable than the unflavored mixture (p less than 0.005). Saccharin sodium, sucrose, and sorbitol are suitable flavoring agents for activated charcoal slurries. Because saccharin sodium requires the smallest total volume to deliver a given quantity of activated charcoal, it has a distinct advantage over sucrose and sorbitol.

Rates of heparin adsorption in hemoperfusion devices.

In vitro studies have shown that the rates of adsorption of heparin from saline in commercially available hemoperfusion devices at 100 to 200 ml/min flow rates are intrinsically quite low. Thus the potential for significant heparin removal from blood (and thus a rise in the possibility of clotting problems) in clinical applications seems remote.

Mass transfer characteristics of hollow-fiber dialyzers and hemoperfusion devices.

Clearance versus time tests were carried out on three charcoal-based hemoperfusion devices (Sandev, Becton-Dickinson and Gambro) using solutions of 1 gm/L sodium salicylate in a pH 7.4 buffer and in bovine blood at flow rates of 200 ml/min. Similar tests were performed on a Cordis Dow 2.5 m2 hollow-fiber dialyzer at a tube side flow rate (QB) of 200 ml/min. Buffer was pumped through the dialysate side at a flow rate (QD) of 400 ml/min. Two dialyzers were run in series at QB = 200 ml/min and QD = 500 or 1000 ml/min. Mass transfer resistances were computed from the test results. These values are useful in that they constitute an index of the intrinsic initial kinetics of solute transfer in each device. However, the clearance versus time curves indicate that these initial kinetics decrease at different rates for each hemoperfusion unit as sorption capacity begins to be depleted. In contrast, the initial clearances for the dialyzers remain at their initial values. These data reveal much about the relative mass transfer characteristics of these devices.

Sucrose as a sweetener for activated charcoal.

The efficacy of sucrose as a flavor for activated charcoal was studied. In vitro adsorption of sucrose (in Simulated Gastric Fluid, USP, without pepsin) to activated charcoal, and of a 1-g/liter sodium salicylate solution to a 1:1 mixture of sucrose and activated charcoal and to plain activated charcoal, was measured spectrophotometrically. In vitro adsorption of sucroses to activated charcoal was minimal. Sucrose reduced in vitro adsorption of sodium salicylate to activated charcoal by only small amounts. For example, at a ratio of 4 g activated charcoal to 1 g sodium salicylate, sucrose reduced salicylate adsorption to activated charcoal from 99% to 95%. A 1:1 sucrose-activated charcoal preparation provides sufficient flavor without substantial loss of adsorbance.

Comparative studies of hemoperfusion devices. II. Pressure drop and flow uniformity tests.

One resin-based hemoperfusion device and three charcoal-based hemoperfusion devices were tested to determine their pressure drop and flow uniformity characteristics. Measurements were made on pressure drop versus flow rate using distilled water and on pressure drop versus time using bovine blood. Effluent concentration curves obtained after the step-change introduction of a high molecular weight dye solution to each unit were used to determine the priming volumes of the devices and were interpreted to yield information regarding the uniformities of flow in each device. The pressure drop and priming volume values for the resin-based device were significantly higher than the corresponding values for the charcoal-based units.

Omission of pepsin from simulated gastric fluid in evaluating activated charcoals as antidotes.

Although simulated gastric fluid USP calls for 3.2 g of pepsin/liter, most researchers omit pepsin when evaluating adsorbents. The present results show that, although pepsin adsorbs strongly to activated charcoal, it does not interfere significantly with the adsorption of a typical drug like sodium salicylate. Therefore, its omission is justified. Gastric mucin also had almost no effect on salicylate adsorption.

In vitro evidence for ipecac inactivation by activated charcoal.

The in vitro adsorption of the alkaloid emetine, a primary constituent of ipecac, on activated charcoal was studied. The results support the supposition that syrup of ipecac should not be given to counteract poisonings if activated charcoal is also to be administered.

Comparative studies of hemoperfusion devices. I. In vitro clearance characteristics.

Drug adsorption studies were carried out using three charcoal-based and one resin-based hemoperfusion devices. They were the Sandev Hemocol unit, the Gambro Adsorba 300C unit unit, the Becton-Dickinson Hemodetoxifier, and the Extracorporeal Medical Specialties XR-010 Hemoperfusion column, respectively. Clearance versus time tests of up to six hours duration were performed using solutions of sodium salicylate, sodium barbital, and creatinine in a pH 7.4 buffer which were pumped through the columns at flow rates of either 100 or 200 ml/minute. Short term clearance tests were performed at various other flow rates to determine overall mass transfer resistances for the devices. Further analysis yielded values for the individual fluid-phase and solid-phase resistances. Studies were also done using sodium salicylate in bovine blood. The results provide information on typical adsorption capacities and drug removal rates for the four devices, and indicate the relative extents to which the solid and fluid phases control the drug uptake rates.

Interference by tannic acid with the effectiveness of activated charcoal in "universal antidote".

Evidence is presented to show that tannic acid is responsible for the reduced effectiveness of "universal antidote" as compared with activated charcoal alone. Adsorption isotherm data indicate that tannic acid binds strongly to charcoal and hence uses up part of the adsorption capacity that would otherwise be available for binding of a drug or poison. Data on sodium salicylate adsorption from simulated gastric fluid, both with and without the presence of tannic acid, are presented that illustrate clearly that tannic acid interferes significantly with the adsorption of salicylate. Magnesium oxide, another component of "universal antidote," was found to offer no interference to salicylate adsorption, presumably because it does not adsorb to charcoal to any significant extent.

Heparin adsorption on activated charcoal.

By vitro studies have shown that sodium heparin adsorbs significantly at pH 7.4 conditions onto a typical activated charcoal. These results imply that enhanced heparin removal from blood should be anticipated in hemoperfusion systems that utilize uncoated charcoals.

Saccharin sodium as a potential sweetener for antidotal charcoal.

This study explored if saccharin sodium, as a sweetener in activated charcoal formulations, would be sufficiently available to provide sweetness while not severely reducing charcoal's adsorption capacity. In vitro tests showed that charcoal takes up 40wt% of saccharin at a 1 g/liter concentration of saccharin in the residual fluid; 29.3wt% at 0.1 g/liter. A saccharin level of 0.1 g/g of charcoal in a carboxymethylcellulose formulation gave enough residual flavor to be appealing. Sodium salicylate, 1 g/liter and 10 g/liter, was used to test whether the 0.1 g/g level of saccharin would interfere with charcoal's ability to adsorb a typical drug. By use of colorimetric assay, it was shown that a 2 g charcoal per gram of salicylate (initial salicylate concentration of 1 g/liter), the extent of drug adsorption was reduced from 70% to 64%, at a 10 g/liter initial concentration, the reduction was 87% to 82%. Under the conditions tested, the antidotal mixture should be pleasantly sweet at a saccharin level of 1 g/10g charcoal, and little effect would be produced on the adsorption of sodium salicylate and other drugs that are well adsorbed by charcoal.