Reversible Adsorption of Nicotinic Acid onto Charcoal In Vitro LEENA ROIVASAND
PERlTl J.
NEUVONEN'
Received April 9, 19q1, from the Department of Pharmacology, University of Turku, Kilnamyllynkatu 10, SF-20520 Turku, Finland. Accepted for publication November 1 1, 1991. Abotract 0 The effects of various factors on the adsorption of nicotinic acid onto and desorption from activated charcoal were investigated in
vitro. The affinity of nicotinic acid for charcoal was poor both in acidic and neutral media. Adsorption increased with increasing charcoa1:drug ratios and decreasing incubation vo1ume:charcoal ratios. Desorption of nicotinic acid from dried drug-charcoal complexes was investigated in a Sartorius dissolution apparatus. The rate of the rapid, initial desorption depended on the pH and the amounts of charcoal and drug. As equilibrium was reached in the dissolution chamber, the release rate of nicotinic acid decreased slowly, depending mainly on the flow of the medium.Thus, nicotinic acid preadsorbed onto charcoal was released in a sustained manner under "continuous flow" conditions. However, because of the poor affinity for nicotinic acid, charcoal may not be a suitable matrix for sustained release of nicotinic acid.
Activated charcoal has been used for pharmaceutical and medicinal purposes since ancient times,1.2 and the ability of charcoal to adsorb drugs and chemicals has been investigated both in vitro and in vivo.26 Recently, the use of charcoal as an antidote in the treatment of poisonings by various drug classes has been evaluated.6 The adsorption-desorption process is reversible, depending on amounts and properties of the adsorbent, the substrate, and the solvent.1.2 The drug is adsorbed from the solvent or desorbed from the charcoal until an equilibrium between the two compartments is reached. The adsorption of various drugs onto charcoal from aqueous solutions or buffers has been studied in vitro. The desorption, however, has been given much less attention. In previous studies, the desorption phenomenon has been demonstrated only either by diluting an equilibrated adsorption system with fresh solvents.7 or by transferring the separated drugcharcoal complex into fresh solvent.7.8 The aim of this study was to investigate the adsorption of nicotinic acid (NA) onto charcoal. After separation of NAcharcoal complexes, dissolution studies were conducted in vitro to determine the factors afFecting the rate of desorption. It was thought that, for certain drugs, activated charcoal could be used as a matrix for sustained release in the same manner that ion-exchange resins or porous silica are used.9
Experimental Section M a t e r i a l s N A (E.Merck, Darmstadt, Germany) was used as received. Activated charcoal (Norit A Supra; surface area, 2000 m2/g; particle size, 5%, >74 pn and 50%, < l o pm; Norit-Farma, Amersfoort, The Netherlands) was dried at 120 "Cfor 4 h before use in the adsorption studies. All reagents used were analytical grade. MethodeZn Vitro Adsorption4tudies were carried out at room temperature and at pH 1.2 (0.1 N HCl) and pH 7 (0.05 M phosphate buffer). The charcoa1:drug ratios were 1:1, 2.5:1, 5:1, l O : l , and 20:l. Activated charcoal (20 mg) and 20 mL of NA solution at different concentrations were placed in 100-mL stoppered glass bottles and equilibrated for 15 min with shaking. The solutions were then rapidly centrifuged for 12 min at 13 800 x g (model J2-21MIE;Beckman, Inc., Palo Alto, CA). The NA concentrations in the supernates were measured spectrophotometrically at 263 nm after suitable dilution (Perkin-Elmer Lambda 2 U V M S Spectrophotometer; Perkin-Elmer 0022-3!549/92'm9 1 7$O2.50/0
0 1992,American Pharmaceutical Association
Corporation, Uberlingen, Germany), and the fractions of unbound NA were calculated. Six measurements were made at each charcoal:drug ratio. The effect of incubation volume on adsorption was studied at the given charcoa1:drug ratios, with incubation volume (mL):chmal (g) ratios of 100:1,200:1,500:1, 1000:1,and 2500:l and at pH 1.2. These adsorption studies were performed in the same manner as described earlier, and four analogous measurements were made. Preparation OfNA-Charcd C o m p k s N A was preadsorbed onto charcoal from aqueous solutions to obtain complexes with charcoal: drug ratios of 3.6,5.1, and 25. Activated charcoal (10 g) and NA (3.0, 2.0, and 0.4 g, respectively) were shaken in distilled water (800 mL) for 15 min to equilibrate and then rapidly filtered through a 2.5-pn-pore-size filtration paper to separate the NA-charcoal complex. The NA concentration in the filtrate was determined, and the amount of adsorbed NA was calculated. The drug-charcoal complex was then dried at 120 "C until no further loss of weight was detected. NA was stable in the complex, as evidenced by the unchanged UV spectrum after the drying process. The complexes were used in the desorption studies as powders. In Vitro Desorptwn-Studies were conducted in a dissolution apparatus (Sartorius Solubility Simulator SM 16751; Sartorius GmbH, Gdttingen, Germany). The thermostated (37 "C)dissolution chambers contained glass beads in 100 mL of dissolution medium and were rotated around their horizontal axis to achieve good mixing during the experiment. After the drug was placed in the dissolution chambers, 5-mL samples were drawn from the chambers through filters every 2 min and were replaced with an equal volume of fresh medium. The same media were used for adsorption and desorption studies. When the effect of flow rate was studied, the sampling volumes were 2.5, 5, and 7.5 mL, giving flow rates of 2.5 m u 2 min, 5 mU2 min, and 7.5 mU2 min, respectively. The samples were then analyzed, and the cumulative amount of the desorbed drug was calculated. Triplicate runs were made in each desorption test. Studies of NA desorption at pH 1.2 and 7 from NA-charcoal complexes with chma1:drug ratios of 3.6, 5.1, and 25 (the amount of c h m a l in the complex being 1.0 g) were conducted. Also, the dissolution of plain NA powder was tested. The following desorption studies were conducted only at pH 7, with the NA-charcoal complex having a charcoa1:drug ratio of 3.6. Three doses of the complex (56, 140, and 280 mg of NA preadsorbed onto 200,500, and 1000 mg of charcoal, respectively) were tested to determine the effect of the incubation vo1ume:charcoal ratio, and three sampling volumes were tested to determine the effect of the flow rate on the desorption. StatisticeMeans 2 standard deviations (SD) are given for the in vitro adsorption and desorption results. The t test was applied to determine the significance of differences due to pHs or charcoa1:drug ratios.
ResuIts Adsorption Studies-The unadsorbed fraction of NA at different charcoa1:drug ratios is shown in Figure 1. At the charcoa1:drug ratio of 1,the unadsorbed fraction was 83 ? 1% a t pH 7 and 75 f 1% a t pH 1.2.At the charcoa1:drug ratio of 25,14 ? 1% and 15 * 1%of the NA remains unbound at pH 7 and pH 1.2,respectively. NA was significantly less adsorbed onto charcoal from the neutral medium than from the acidic medium up to a charcoa1:drug ratio of 20 (p < 0.001). The adsorption of NA onto charcoal is also strongly dependent on the incubation vo1ume:charcoal ratio (Figure 2).For Journal of Pharmaceutical Sciences / 917 Vol. 81, No. 9, September 7992
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20
25
0
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20
Charcoal : d r u g ratio Figure 1-Unadsorbed fraction of NA [mean f SD; number of observations (n) = 61 at different charcoa1:drug ratios at pH 1.2 (0)and pH 7 (0).The incubation vo1ume:charcoal ratio is lo00 mug. The unbound fraction of NA at pH 1.2was significantlydifferent from that at pH 7 (***,
p < 0.001).
example, at a constant charcoa1:drug ratio of 20, an increase in the incubation vo1ume:charcoal ratio from 100 mUg to 200, 500, 1000, and 2500 mUg resulted, respectively, in 2-, 5-, 7-, and 14-fold increases in the unadsorbed fraction of NA. The same trend also can be seen at the lower charcoa1:drug ratios. Desorption Studies-Figure 3 shows the dissolution curves of plain NA and NA preadsorbed onto activated charcoal. Plain NA powder was rapidly dissolved in a pH independent manner in the dissolution medium. The amounts of plain NA used were the same as those in the drug-charcoal complexes with charcoa1:drug ratios of 3.6 and 5.1 when the amount of charcoal is 1.0 g. The desorption of NA from charcoal at pH 1.2 and 7 was accelerated by decreasing the charcoa1:drug ratio from 25 to 5.1 and further to 3.6 (p < 0.01, Figure 3). The desorption of NA was also pH dependent. At charcoa1:drugratios of 3.6 and 5.1, the fraction of NA desorbed from charcoal was higher at pH 7 than at pH 1.2 (p < 0.01). At the charcoa1:drug ratio of 25, however, the desorbed fraction of NA was roughly the same at both pHs. The desorption studies were also performed with three amounts of the same drug-charcoal complex. The desorption of NA was accelerated by decreasing the amounts of the drug-charcoal complex in the dissolution chamber (i.e., with increasing incubation vo1ume:charcoal ratio; Figure 4). The flow rate had an effect on the rate of NA desorption from charcoal, but only after the initial rapid desorption of NA
E
0 0
1
2
3
4
Time ( h ) Figure 3-Cumulativedesorption of NA (means f SD; n = 3) from activated charcoal in the Sartorius dissolution apparatus at initial charcoakdrug ratios of 3.6 (0),5.1 (A), and 25 (0)at pH 1.2(open symbols) and pH 7 (filled symbols).The amount of charcoal in the complexes was 1 .O g. The differences between pH 1.2and 7 at the charcoa1:drug ratios of 3.6and 5.1 and the differences between the charcoa1:drugratios of 3.6 versus 5.1 and 5.1 versus 25 at both pHs were significant (p < 0.01)from 10 min to 4 h. The dotted line represents both 195 and 280 mg of plain NA at both pH 1.2and pH 7 (means 2 SD; n = 4). (Figure 5 ) . The change in the desorption rate was more apparent when the flow rate was decreased from 5 mU2 min to 2.5 mU2 min than when it was increased to 7.5 mU2 min.
Discussion The present results indicate that NA is adsorbed in vitro onto activated charcoal and that this phenomenon is clearly revemible. The f f i i t y of NA for charcoal is, however, considerably less than that of most other drugs studied to date.6 Accordingly, in an acute NA overdose, charcoal would not be effective in preventing the absorption of NA from the gastrointestinal tract even if given immediately after NA. Ionized drugs with low molecular weights are poorly adsorbed onto charcoal. Also, acids are best adsorbed at low pHs. The adsorption of NA [M,,123; pKa (K, is dissociation constant), 4.81 onto charcoal at acidic pH, however, was only slightly better than that a t neutral pH. When similar adsorption studies were made with distilled water (pH M),the unadsorbed fraction of NA at a charcoa1:drug ratio of 20 was only 4% (data not shown);that is, 14%more NA was adsorbed
100
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1
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2 5
20
;; 10 I! u
5
a 0
n c
3
2 1 ’
.
1 2.5
5
10
20
Charcoal : d r u g ratio Figure 2-Effect of incubation volume on unbound fraction of NA at differentcharcoakdrug ratios at pH 1.2 (mean f SD; n = 4). The 200 mug (2), 500 incubation vo1urne:charcoal ratios were 100 mug (l), mug (3), 1000 mug (4), and 2500 mug (5). 918 1 Journal of Pharmaceutical Sciences Vol. 81, No. 9, September 1992
0 0
1
2
Time [h) Figure 4-Cumulative desorption of NA (mean f SD; n = 3) from activated charcoal at the initial charcoa1:drug ratio of 3.6and at pH 7. The charcoal:NA ratios (w/w, mg) in 100 mL of dissolution medium were 20056 (O), 500:140 (A), and 1 000:280(0).
loo
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20
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0
1
2
Time (h)
Figure !%Cumulativedesorption of NA (mean 2 SD; n = 3) from activated charcoal at the initial charcoal:drug ratio of 3.6and at pH 7.The flow rates during the desorption studies were 7.5 mU2 min (0), 5 mU2 min (A), and 2.5 mU2 min (0).
from water than from HCl solution (pH 1.2).The HCl in the solvent seems to compete strongly with drugs for the adsorption sites on charcoal,* with the competitive adsorption becoming even stronger with decreasing concentrations of NA. The Sartorius dissolution apparatus was chosen for the in vitro desorption studies, because in conventional beaker methods, the desorption would have stopped when equilibrium is reached. Prolonged desorption is possible only when the system is constantly diluted by removing portions of the desorbed drug and adding fresh solvent. The Sartorius apparatus also correlates better with in vivo conditions in the gastrointestinal tract. The rotation of the chambers, in addition to preventing the blocking of filters, simulates the peristaltic and mechanical forces acting in the gastrointestinal tract, and the relatively small amount of medium matches the volume of the gastrointestinal fluids. Also, the time between samplings and the volume of sample can be adjusted to correlate with the absorption rate of the drug.
The desorption of NA from charcoal can be divided into two phases. The rapid initial increase in the amount of free NA at the beginning of the desorption studies reflects the equilibrium that first develops in the dissolution chamber. Then, the desorption of NA slowly continues according to the rate of dilution in the incubation medium. The initial equilibrium depends on the amounts of charcoal and NA and the properties of the medium. In conclusion, because of the reversible adsorption of drugs onto activated charcoal, activated charcoal may be used for sustained release of drugs with ideal adsorption and desorption profiles. Furthermore, because of the mucoadhesive properties of charcoal, the drug-charcoal complex may remain in the gastrointestinal tract for a longer period than would conventional sustained-release preparations; thus, gastrointestinal absorption of the drug would be prolonged. The adsorption and desorption properties of NA with respect to charcoal are, however, not suitable for such sustainedrelease formulations.
References and Notes 1. Holt, L. E.; Holz, P. H. J . Pediatr. 1963, 63, 30-14. 2. Cooney, D. 0. Activated Charcoal: Antidotal and Other Medical Uses; Dekker: New York, 1980; pp 24-120. 3. Tsuchiya, T.; Levy, G. J . Pharm. Sci. 1972,61, 58G-589. 4. Kannisto, H.; Neuvonen, P. J. J . Pharm. Sci. 1984, 73, 253-256. 5. Neuvonen, P. J.; Olkkola, K. T.; Alanen, T. Acta Pharmacol. Toxicol. 1984,54, 1-7. 6. Neuvonen, P. J.; Olkkola, K. T. Med. Toxicol. 1988,3, 33-58. 7 . Sorbv. D. L. J . Pharm. Sci. 1965. 54. 677-683. 8. Bainbridge, C. A.; Kelly, E. L.; Walkling, W. D. J . Pharm. Sci. 1977,66,480-483. 9. Ru precht, H.; Lee, G. In Encyclopedia of Pharmuceutical Techno&~; Swarbrick, J.; Boylan, J. C.; Eds.; Marcel Dekker: New York, 1988; pp 73-114.
Acknowledgments The stud was supported by the Technology Development Center, Helsinki, dnland.
Journal of Pharmaceutical Sciences I 919 Vol. 81, No. 9,September 1992
PERlTl J.
NEUVONEN'
Received April 9, 19q1, from the Department of Pharmacology, University of Turku, Kilnamyllynkatu 10, SF-20520 Turku, Finland. Accepted for publication November 1 1, 1991. Abotract 0 The effects of various factors on the adsorption of nicotinic acid onto and desorption from activated charcoal were investigated in
vitro. The affinity of nicotinic acid for charcoal was poor both in acidic and neutral media. Adsorption increased with increasing charcoa1:drug ratios and decreasing incubation vo1ume:charcoal ratios. Desorption of nicotinic acid from dried drug-charcoal complexes was investigated in a Sartorius dissolution apparatus. The rate of the rapid, initial desorption depended on the pH and the amounts of charcoal and drug. As equilibrium was reached in the dissolution chamber, the release rate of nicotinic acid decreased slowly, depending mainly on the flow of the medium.Thus, nicotinic acid preadsorbed onto charcoal was released in a sustained manner under "continuous flow" conditions. However, because of the poor affinity for nicotinic acid, charcoal may not be a suitable matrix for sustained release of nicotinic acid.
Activated charcoal has been used for pharmaceutical and medicinal purposes since ancient times,1.2 and the ability of charcoal to adsorb drugs and chemicals has been investigated both in vitro and in vivo.26 Recently, the use of charcoal as an antidote in the treatment of poisonings by various drug classes has been evaluated.6 The adsorption-desorption process is reversible, depending on amounts and properties of the adsorbent, the substrate, and the solvent.1.2 The drug is adsorbed from the solvent or desorbed from the charcoal until an equilibrium between the two compartments is reached. The adsorption of various drugs onto charcoal from aqueous solutions or buffers has been studied in vitro. The desorption, however, has been given much less attention. In previous studies, the desorption phenomenon has been demonstrated only either by diluting an equilibrated adsorption system with fresh solvents.7 or by transferring the separated drugcharcoal complex into fresh solvent.7.8 The aim of this study was to investigate the adsorption of nicotinic acid (NA) onto charcoal. After separation of NAcharcoal complexes, dissolution studies were conducted in vitro to determine the factors afFecting the rate of desorption. It was thought that, for certain drugs, activated charcoal could be used as a matrix for sustained release in the same manner that ion-exchange resins or porous silica are used.9
Experimental Section M a t e r i a l s N A (E.Merck, Darmstadt, Germany) was used as received. Activated charcoal (Norit A Supra; surface area, 2000 m2/g; particle size, 5%, >74 pn and 50%, < l o pm; Norit-Farma, Amersfoort, The Netherlands) was dried at 120 "Cfor 4 h before use in the adsorption studies. All reagents used were analytical grade. MethodeZn Vitro Adsorption4tudies were carried out at room temperature and at pH 1.2 (0.1 N HCl) and pH 7 (0.05 M phosphate buffer). The charcoa1:drug ratios were 1:1, 2.5:1, 5:1, l O : l , and 20:l. Activated charcoal (20 mg) and 20 mL of NA solution at different concentrations were placed in 100-mL stoppered glass bottles and equilibrated for 15 min with shaking. The solutions were then rapidly centrifuged for 12 min at 13 800 x g (model J2-21MIE;Beckman, Inc., Palo Alto, CA). The NA concentrations in the supernates were measured spectrophotometrically at 263 nm after suitable dilution (Perkin-Elmer Lambda 2 U V M S Spectrophotometer; Perkin-Elmer 0022-3!549/92'm9 1 7$O2.50/0
0 1992,American Pharmaceutical Association
Corporation, Uberlingen, Germany), and the fractions of unbound NA were calculated. Six measurements were made at each charcoal:drug ratio. The effect of incubation volume on adsorption was studied at the given charcoa1:drug ratios, with incubation volume (mL):chmal (g) ratios of 100:1,200:1,500:1, 1000:1,and 2500:l and at pH 1.2. These adsorption studies were performed in the same manner as described earlier, and four analogous measurements were made. Preparation OfNA-Charcd C o m p k s N A was preadsorbed onto charcoal from aqueous solutions to obtain complexes with charcoal: drug ratios of 3.6,5.1, and 25. Activated charcoal (10 g) and NA (3.0, 2.0, and 0.4 g, respectively) were shaken in distilled water (800 mL) for 15 min to equilibrate and then rapidly filtered through a 2.5-pn-pore-size filtration paper to separate the NA-charcoal complex. The NA concentration in the filtrate was determined, and the amount of adsorbed NA was calculated. The drug-charcoal complex was then dried at 120 "C until no further loss of weight was detected. NA was stable in the complex, as evidenced by the unchanged UV spectrum after the drying process. The complexes were used in the desorption studies as powders. In Vitro Desorptwn-Studies were conducted in a dissolution apparatus (Sartorius Solubility Simulator SM 16751; Sartorius GmbH, Gdttingen, Germany). The thermostated (37 "C)dissolution chambers contained glass beads in 100 mL of dissolution medium and were rotated around their horizontal axis to achieve good mixing during the experiment. After the drug was placed in the dissolution chambers, 5-mL samples were drawn from the chambers through filters every 2 min and were replaced with an equal volume of fresh medium. The same media were used for adsorption and desorption studies. When the effect of flow rate was studied, the sampling volumes were 2.5, 5, and 7.5 mL, giving flow rates of 2.5 m u 2 min, 5 mU2 min, and 7.5 mU2 min, respectively. The samples were then analyzed, and the cumulative amount of the desorbed drug was calculated. Triplicate runs were made in each desorption test. Studies of NA desorption at pH 1.2 and 7 from NA-charcoal complexes with chma1:drug ratios of 3.6, 5.1, and 25 (the amount of c h m a l in the complex being 1.0 g) were conducted. Also, the dissolution of plain NA powder was tested. The following desorption studies were conducted only at pH 7, with the NA-charcoal complex having a charcoa1:drug ratio of 3.6. Three doses of the complex (56, 140, and 280 mg of NA preadsorbed onto 200,500, and 1000 mg of charcoal, respectively) were tested to determine the effect of the incubation vo1ume:charcoal ratio, and three sampling volumes were tested to determine the effect of the flow rate on the desorption. StatisticeMeans 2 standard deviations (SD) are given for the in vitro adsorption and desorption results. The t test was applied to determine the significance of differences due to pHs or charcoa1:drug ratios.
ResuIts Adsorption Studies-The unadsorbed fraction of NA at different charcoa1:drug ratios is shown in Figure 1. At the charcoa1:drug ratio of 1,the unadsorbed fraction was 83 ? 1% a t pH 7 and 75 f 1% a t pH 1.2.At the charcoa1:drug ratio of 25,14 ? 1% and 15 * 1%of the NA remains unbound at pH 7 and pH 1.2,respectively. NA was significantly less adsorbed onto charcoal from the neutral medium than from the acidic medium up to a charcoa1:drug ratio of 20 (p < 0.001). The adsorption of NA onto charcoal is also strongly dependent on the incubation vo1ume:charcoal ratio (Figure 2).For Journal of Pharmaceutical Sciences / 917 Vol. 81, No. 9, September 7992
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Charcoal : d r u g ratio Figure 1-Unadsorbed fraction of NA [mean f SD; number of observations (n) = 61 at different charcoa1:drug ratios at pH 1.2 (0)and pH 7 (0).The incubation vo1ume:charcoal ratio is lo00 mug. The unbound fraction of NA at pH 1.2was significantlydifferent from that at pH 7 (***,
p < 0.001).
example, at a constant charcoa1:drug ratio of 20, an increase in the incubation vo1ume:charcoal ratio from 100 mUg to 200, 500, 1000, and 2500 mUg resulted, respectively, in 2-, 5-, 7-, and 14-fold increases in the unadsorbed fraction of NA. The same trend also can be seen at the lower charcoa1:drug ratios. Desorption Studies-Figure 3 shows the dissolution curves of plain NA and NA preadsorbed onto activated charcoal. Plain NA powder was rapidly dissolved in a pH independent manner in the dissolution medium. The amounts of plain NA used were the same as those in the drug-charcoal complexes with charcoa1:drug ratios of 3.6 and 5.1 when the amount of charcoal is 1.0 g. The desorption of NA from charcoal at pH 1.2 and 7 was accelerated by decreasing the charcoa1:drug ratio from 25 to 5.1 and further to 3.6 (p < 0.01, Figure 3). The desorption of NA was also pH dependent. At charcoa1:drugratios of 3.6 and 5.1, the fraction of NA desorbed from charcoal was higher at pH 7 than at pH 1.2 (p < 0.01). At the charcoa1:drug ratio of 25, however, the desorbed fraction of NA was roughly the same at both pHs. The desorption studies were also performed with three amounts of the same drug-charcoal complex. The desorption of NA was accelerated by decreasing the amounts of the drug-charcoal complex in the dissolution chamber (i.e., with increasing incubation vo1ume:charcoal ratio; Figure 4). The flow rate had an effect on the rate of NA desorption from charcoal, but only after the initial rapid desorption of NA
E
0 0
1
2
3
4
Time ( h ) Figure 3-Cumulativedesorption of NA (means f SD; n = 3) from activated charcoal in the Sartorius dissolution apparatus at initial charcoakdrug ratios of 3.6 (0),5.1 (A), and 25 (0)at pH 1.2(open symbols) and pH 7 (filled symbols).The amount of charcoal in the complexes was 1 .O g. The differences between pH 1.2and 7 at the charcoa1:drug ratios of 3.6and 5.1 and the differences between the charcoa1:drugratios of 3.6 versus 5.1 and 5.1 versus 25 at both pHs were significant (p < 0.01)from 10 min to 4 h. The dotted line represents both 195 and 280 mg of plain NA at both pH 1.2and pH 7 (means 2 SD; n = 4). (Figure 5 ) . The change in the desorption rate was more apparent when the flow rate was decreased from 5 mU2 min to 2.5 mU2 min than when it was increased to 7.5 mU2 min.
Discussion The present results indicate that NA is adsorbed in vitro onto activated charcoal and that this phenomenon is clearly revemible. The f f i i t y of NA for charcoal is, however, considerably less than that of most other drugs studied to date.6 Accordingly, in an acute NA overdose, charcoal would not be effective in preventing the absorption of NA from the gastrointestinal tract even if given immediately after NA. Ionized drugs with low molecular weights are poorly adsorbed onto charcoal. Also, acids are best adsorbed at low pHs. The adsorption of NA [M,,123; pKa (K, is dissociation constant), 4.81 onto charcoal at acidic pH, however, was only slightly better than that a t neutral pH. When similar adsorption studies were made with distilled water (pH M),the unadsorbed fraction of NA at a charcoa1:drug ratio of 20 was only 4% (data not shown);that is, 14%more NA was adsorbed
100
loo
1
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2 5
20
;; 10 I! u
5
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n c
3
2 1 ’
.
1 2.5
5
10
20
Charcoal : d r u g ratio Figure 2-Effect of incubation volume on unbound fraction of NA at differentcharcoakdrug ratios at pH 1.2 (mean f SD; n = 4). The 200 mug (2), 500 incubation vo1urne:charcoal ratios were 100 mug (l), mug (3), 1000 mug (4), and 2500 mug (5). 918 1 Journal of Pharmaceutical Sciences Vol. 81, No. 9, September 1992
0 0
1
2
Time [h) Figure 4-Cumulative desorption of NA (mean f SD; n = 3) from activated charcoal at the initial charcoa1:drug ratio of 3.6and at pH 7. The charcoal:NA ratios (w/w, mg) in 100 mL of dissolution medium were 20056 (O), 500:140 (A), and 1 000:280(0).
loo
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20
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-
0
1
2
Time (h)
Figure !%Cumulativedesorption of NA (mean 2 SD; n = 3) from activated charcoal at the initial charcoal:drug ratio of 3.6and at pH 7.The flow rates during the desorption studies were 7.5 mU2 min (0), 5 mU2 min (A), and 2.5 mU2 min (0).
from water than from HCl solution (pH 1.2).The HCl in the solvent seems to compete strongly with drugs for the adsorption sites on charcoal,* with the competitive adsorption becoming even stronger with decreasing concentrations of NA. The Sartorius dissolution apparatus was chosen for the in vitro desorption studies, because in conventional beaker methods, the desorption would have stopped when equilibrium is reached. Prolonged desorption is possible only when the system is constantly diluted by removing portions of the desorbed drug and adding fresh solvent. The Sartorius apparatus also correlates better with in vivo conditions in the gastrointestinal tract. The rotation of the chambers, in addition to preventing the blocking of filters, simulates the peristaltic and mechanical forces acting in the gastrointestinal tract, and the relatively small amount of medium matches the volume of the gastrointestinal fluids. Also, the time between samplings and the volume of sample can be adjusted to correlate with the absorption rate of the drug.
The desorption of NA from charcoal can be divided into two phases. The rapid initial increase in the amount of free NA at the beginning of the desorption studies reflects the equilibrium that first develops in the dissolution chamber. Then, the desorption of NA slowly continues according to the rate of dilution in the incubation medium. The initial equilibrium depends on the amounts of charcoal and NA and the properties of the medium. In conclusion, because of the reversible adsorption of drugs onto activated charcoal, activated charcoal may be used for sustained release of drugs with ideal adsorption and desorption profiles. Furthermore, because of the mucoadhesive properties of charcoal, the drug-charcoal complex may remain in the gastrointestinal tract for a longer period than would conventional sustained-release preparations; thus, gastrointestinal absorption of the drug would be prolonged. The adsorption and desorption properties of NA with respect to charcoal are, however, not suitable for such sustainedrelease formulations.
References and Notes 1. Holt, L. E.; Holz, P. H. J . Pediatr. 1963, 63, 30-14. 2. Cooney, D. 0. Activated Charcoal: Antidotal and Other Medical Uses; Dekker: New York, 1980; pp 24-120. 3. Tsuchiya, T.; Levy, G. J . Pharm. Sci. 1972,61, 58G-589. 4. Kannisto, H.; Neuvonen, P. J. J . Pharm. Sci. 1984, 73, 253-256. 5. Neuvonen, P. J.; Olkkola, K. T.; Alanen, T. Acta Pharmacol. Toxicol. 1984,54, 1-7. 6. Neuvonen, P. J.; Olkkola, K. T. Med. Toxicol. 1988,3, 33-58. 7 . Sorbv. D. L. J . Pharm. Sci. 1965. 54. 677-683. 8. Bainbridge, C. A.; Kelly, E. L.; Walkling, W. D. J . Pharm. Sci. 1977,66,480-483. 9. Ru precht, H.; Lee, G. In Encyclopedia of Pharmuceutical Techno&~; Swarbrick, J.; Boylan, J. C.; Eds.; Marcel Dekker: New York, 1988; pp 73-114.
Acknowledgments The stud was supported by the Technology Development Center, Helsinki, dnland.
Journal of Pharmaceutical Sciences I 919 Vol. 81, No. 9,September 1992
