Ind. Eng. Chem. Prod. Res. Dev. 1983, 22,665-671
665
Pharmaceutical Aspects of Clay-Organic Interactions Joe L. Whlte and Stanley L. Hem" Department of Agronomy and Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, Indiana 47907
The structure and properties of clays used in pharmaceuticals are discussed and related to desirable and undesirable
clay-drug interactions. Clay-drug interactions are classed as arising from adsorption or because the environment at the clay surface is different from that in the bulk. X-ray diffraction, infrared absorption, and acid-base tirations may be used to provide information about the mechanism of adsorption. The importance of the desorption of the drug in the gastrointestinal tract in order to achieve drug action is emphasized. Surface modification by saturating the clay with an organic exchangeable cation can enlarge the pH range of adsorption of weak bases. The environment at the clay surface may contain a greater concentration of protons than the bulk solution leading to accelerated acid-catalyzed hydrolysis. Surface ferric iron may catalyze the oxidative degradation of drugs. Divalent exchangeable cations may form nonabsorbable clay-drug complexes.
Clay-drug interactions affect drug action in a number of ways to produce either desirable or undesirable effects. Interactions may be used to produce drug products with a desired drug release pattern following administration (McGinity and Lach, 1977), an improved palatability (Zentner, 1967a,b) or an accelerated dissolution of the drug (McGinity and Harris, 1980a,b). However, clay-drug interactions may produce undesired changes in the bioavailability of drugs or cause accelerated decomposition of the drug due to reactions occurring at the clay surface. The undesirable interactions usually occur when a clay is included in a drug product for its effect on the physical properties of the dosage form, Le., viscosity, tablet disintegration, and the potential for a clay-drug interaction is overlooked (Munzel, 1971) or when a clay-containing drug product is coadministered with a drug product and the clay-drug interaction occurs in the patient's gastrointestinal tract (Wagner, 1966, 1968). The purpose of this review is to show how most clay-drug interactions can be predicted based on an understanding of clay structure and properties, to describe experimental techniques which may be used to study clay-drug interactions, and to give examples of both desirable and undesirable interactions. Physiological Conditions Encountered in the Gastrointestinal Tract Oral administration of clay-containing pharmaceuticals results in the exposure of the clay to the acid environment of the stomach (approximately pH 2) for a 15-60 min period known as the gastric residence time. The pH of the intestine gradually increases to pH 6. Therefore, in vitro experiments to examine clay-drug interactions were conducted in similar environments. It has been shown that montmorilloniteand other clays are unstable in very acidic conditions (Low, 1955; Kerret al., 1956; Coleman and Craig, 1961; Schwertmann and Jackson, 1963). Protons attack the structure of the montmorillonite, resulting in dissolution of aluminum and magnesium cations; these ions may occupy exchange sites on the clay surface. We assume that exposure to an acid environment similar to that of the stomach for a time analogous to the gastric residence time would not greatly perturb the clay-drug interactions for the following reasons: (1)the montmorillonitewas initially sodium- and/or calcium-saturated and the experimental conditions could not produce hydrogen saturation; (2) the concentration of acid used in our studies was 10 to 100 times smaller than that in the studies cited above; and (3) the time period of exposure of the clay to an environment
of pH 2 or below was less than 1%of the half-time values for loss of exchangeablehydrogen predicted from the data of Coleman and Craig (1961). Our assumption is supported by comparison of the spectrophotometric titration curves for prometrpe in the presence of Ca-montmorilloniteand Al-montmorillonite (Feldkamp and White, 1979).
Structure and Properties of Clays The basic structure of clays consists of octahedra of aluminum and magnesium in combination with silica tetrahedra which are uniquely arranged to produce the surface charge, morphology, and surface area characteristic of each type of clay. A surface charge may arise from either isomorphous substitution, i.e., aluminum in place of silicon, magnesium in place of aluminum, etc., or broken bonds at the edges of the clay. The surface charge arising from isomorphous substitution is negative and is characterized by the cation-exchange capacity. Clays can be classified morphologically as platy or fibrous. A platy morphology is seen in the clays which have a layer-like structure. The kaolin group consists of sheets of silica tetrahedra and aluminum octahedra shared in a 1:l ratio. These minerals have little or no isomorphous substitution and normally are nonswelling in aqueous solutions. Smectites belong to the 2:l (ratio of silica tetrahedra to aluminum and/or magnesium octahedra) structural group of clays and include montmorillonite, hectorite, and saponite. In these clays an aluminum or magnesium octahedral sheet is sandwiched between two silica tetrahedral sheets. Isomorphous substitution occurs in both the tetrahedral and octahedral sheets of the 2:l minerals and gives rise to moderate to high cation-exchange capacities. The viscosity-enhancing properties of the 2:l platy clays is related to the ability of the clay to swell and immobilize large quantities of water between the layers. Likewise the 2:l minerals are useful as tablet disintegrating agents because of their swelling properties. The fibrous clays such as sepiolite and attapulgite are 2:l-type minerals but the laths are elongate along the x axis, resulting in ribbons of the 2:l layer attached at their longitudinal edges. A cross section of the fiber reveals a checkerboard arrangement of 2:l ribbons and channels with no possibility of expansion. The fibrous clays are effective viscosity-enhancing agents because the fibers become entangled in brush heap-like arrangements. The morphology of the clay also influences the adsorptive properties of the clays. The 2:l platy clays, which can swell, are able to accommodate solute molecules in the
Q196-4321/83/1222-Q665$01.5Q/Q 0 1983 American Chemical Society
666
Ind. Eng. Chem. Prod. Res. Dev., Vol. 22, No. 4, 1983
Table I. Surface Area and Charge of Classes of Clays
class
example
m'k
cat. exchange capacity, mequiv/ 100 g
1:1 platy fibrous 2 : l platy
kaolinite attapulgite montmorillonite
3-1 5 200-400 600-800
1-5 (5 80-150
surface area,
extensive interlayer space. The channels of the fibrous clays have a fixed geometry which is too small to accept molecules larger than water, ammonia, or perhaps primary alcohols. The clays fall into three groups in terms of surface area (Table I). The platy 1:l clays such as kaolin are nonswelling and have a surface area of 3-15 m2/g which only comprises the external surface. The fibrous clays have a moderately high surface because of the very thin nature of the ribbons. This surface area is all external and is on the order of 300 m2/g. The swelling, 2:l platy clays have the greatest surface area, reaching 600-800 m2/g because of the extensive internal surface area.
Classification of Clay-Drug Interactions In view of the surface properties of clays, interactions with drugs can be broadly classified as those due to adsorption in which the amount of drug in solution is decreased due to the clay's ability to concentrate drug at the clay surface, and those which arise because the environment which the drug encounters at the surface following adsorption differs from the bulk solution. A drug may be exposed to: (1)a high concentration of protons at the clay surface due to the electrostatic attraction of protons by the negative clay surface; (2) cations such as ferric iron which may be present in the clay structure due to isomorphous substitution; or (3) exchangeable cations such as calcium which neutralize the negative charge arising from isomorphous substitution. The presence of these extraneous cations may catalyze degradation reactions of the drug or may lead to the formation of drug-cation complexes. Techniques to Study Clay-Drug Interactions Clay-drug interactions have been traditionally studied by use of adsorption isotherms. This classical approach indicates the quantity of drug adsorbed but provides only indirect evidence of the adsorption mechanism. The interaction of drugs with swelling clays can be studied by X-ray diffraction because the c axis spacing adapts to the intercalated molecule when adsorption occurs in the interlamellar space. Thus the increase in interlayer spacing due to adsorption can be compared to the molecular dimensions of the drug in order to elucidate the orientation of the adsorbed drug and the number of adsorbed drug layers. In order to draw definite conclusions about the presence and size of the drug molecule in the interlayer space, water must be excluded from the clay-drug system when recording X-ray diffractograms so that the increase in basal spacing compared to the dehydrated clay will be due only to the dimensions of the adsorbed drug (Porubcan et al., 1978). Examination of the arrangement of the silica tetrahedra in the silica tetrahedral sheets of 2:l platy clays shows regular cavities in the oxygen surface which can accept a portion of an adsorbed drug molecule. Thus, the increase in interlayer space could be smaller than the dimension of the adsorbed drug by as much as 1 A (Green-Kelley, 1955). This effect is termed keying and was observed when
v
3420
3620 3000 2000 WAVENUMBER ( c m - ' )
1600
Figure 1. IR spectra of digoxin adsorbed by montmorillonite at pH 2.0 and 6.0, 37 "C. Key: a and d, one washing; b and e, five washings; c and f, 10 washings; and g, digoxin in potassium bromide. From Porubcan et al. (1979).
clindamycin was adsorbed by montmorillonite at pH 2 (Porubcan et al., 1978). X-ray diffraction showed that the basal spacing of the clay increased from 9.5 to 13.4 A, a difference of 3.9 A, due to the interlamellar adsorption of clindamycin. This interlayer spacing is 0.9 A smaller than the 4.8 A minimum dimension of clindamycin as determined by a Corey-Pauling-Kolton molecular scale model. It was concluded that a portion of the clindamycin molecule extended into the surface cavity and that a single layer of clindamycin was adsorbed in an orientation parallel to the planar surface. The interlayer spacing of montmorillonite increased by 4.6 A following interaction with digoxin (Porubcan et al., 1979). As the minimum dimension of digoxin is 5.6 A, a monomolecular layer of digoxin in parallel orientation was believed to be adsorbed in the interlamellar space. In contrast, the interlamellar space of montmorillonite increased by 6.8 A when tetracycline was adsorbed at pH 1.5 (Porubcan et al., 1978). As the smallest dimension of tetracycline is 6.3 A, it was concluded that a monomolecular layer of tetracycline was adsorbed in a slightly tilted orientation. This assumption was supported by the adsorption isotherm which showed that the adsorptive capacity exceeded that calculated for monomolecular adsorption in parallel orientation but was less than calculated based on bilayer adsorption. Infrared spectroscopy can provide information on the adsorption mechanism as perturbations of functional groups in adsorbed drug molecules can be observed. The IR spectrophotometer may be interfaced with a computer so that the IR spectrum of the clay can be subtracted from the IR spectrum of the clay-drug complex. Thus, the IR spectrum of the adsorbed drug can be obtained and compared to the pure drug. The observed shift in the digoxin carbonyl stretching frequency from 1745 to 1715 cm-l as a result of interaction with montmorillonite at both pH 2 and 6 may be attributed to hydrogen bonding and iondipole interaction (Figure 1) (Porubcan et al., 1979). The
Ind. Eng. Chem. Prod. Res. Dev., Vol. 22, No. 4, 1983 667
A
0.50
0.45
/-
I -
2
a m K
2 8 0.40 -
0'35
I I
I
I 4
2
I
I
6
8
3
pHb
mechanism of adsorption of clindamycin, a weak base, by montmorillonite at pH 2 was attributed to cation exchange as no substantial change in the IR spectrum of clindamycin was observed following adsorption (Poruban et al., 1978). There may be differences between the IR spectrum of a drug prepared as a potassium bromide pellet and a clay-drug adsorbate which are not related to clay-drug bonds and are seen even following physical adsorption. These shifts are to higher frequencies and occur because the adsorbed drug is isolated from other drug molecules. Therefore, intermolecular bonding between drug molecules which is present when the drug is prepared as a potassium bromide pellet is absent. The higher frequencies observed in the IR spectrum of s-triazines adsorbed on montmorillonite in comparison to preparation as a potassium bromide pellet indicate that there is less intermolecular bonding in the adsorbed state (Ledoux and White, 1966; Cruz and White, 1972; Hermosin et al., 1982). The effect of a clay on the acid-base equilibrium of a drug which is a weak acid or base provides a convenient method for determining the relative interaction of the charged and neutral form of the drug with the clay. The pK of the drug will be displaced if the clay preferentially interacts with one species of the drug. This is especially likely to occur with weak bases as a negative clay surface will interact more strongly with the protonated form of the base, HB+, than with the neutral base, B (Feldkamp and White, 1979). Tetracycline contains 1basic group and 2 acidic groups and undergoes the following equilibria K
+ H,TO HT- + H+ HT- S~ 2 +- H+
H2T0 H+
+
9
12
pHb
Figure 2. Effect of montmorillonite (20 mg/100 mL) on the first acid-base equilibrium of tetracycline (2 mg/100 mL). Key: (0) aqueous solution; (0) montmorillonite suspension. From Browne et al. (1980a).
H3T+
6
(1) (2)
(3) As seen in Figure 2, the first pK was shifted from 3.34 to 6.23 by the presence of montmorillonite indicating a much stronger interaction of the clay with the protonated species, H3T+,than the neutral species, H2T0. The second pK of
Figure 3. Distribution of the species of tetracycline. Key: (A) in aqueous solution; (B)in montmorillonite suspension. From Browne et al. (1980a).
tetracycline was only shifted from 7.86 to 8.01 by the presence of montmorillonite, indicating a slight preference for adsorption of the neutral species, H 2 P ,rather than the anionic species, HT-.Montmorillonite had no effect on the third ionization of tetracycline, indicating that the negative clay does not show a preference for adsorption of either of the anionic species (Browne et al., 1980a). The preferential adsorption of one species of an acidbase equilibrium has important effects on the distribution of drug species in a clay suspension. As seen in Figure 3, the preferential adsorption of the H3T+species caused the H3T+species to predominate up to pH 6. Thus, the HzTO species, which is the most readily absorbable form of tetracycline (Colaizzi and Klink, 1969),will be present over a smaller region of the gastrointestinal tract if a clay is also present. Desorption Mechanisms Adsorption of a drug by a clay may lead to a number of desirable effects such as enhanced palatability, improved dissolution, or controlled drug release. In every instance, the drug must be released from the clay to exert its pharmacological action. Thus, the desorption process is frequently the controlling parameter. Following oral administration, a clay-drug complex will encounter a pH gradient in the absorption region of the gastrointestinal tract ranging from pH 2 in the stomach to pH 6 in the small intestine. In addition, dilution will occur in the aqueous gastric fluid and an increase in ionic strength will be encountered in the intestinal fluid. Thus, a clay must be selected which will adsorb the drug by an appropriate mechanism in order for the drug to be desorbed as desired in the gastrointestinal tract in response to a pH change, dilution, or an increase in ionic strength. The fact that smectites adsorb the protonated species of weak bases by cation exchange and the neutral species by physical adsorption has been used to produce clay-drug complexes which prolong the systemic absorption of drugs such as amphetamine sulfate (Figure 4) (McGinity and Lach, 1977). The desorption of clindamycin, a weak base whose pK is 7.6, illustrates the principle. As seen in Figure 5, clindamycin was not desorbed by washing a montmo-
668
Ind. Eng. Chem. Prod. Res. Dev., Vol. 22, No. 4, 1983 Table 11. Effect of Smectite-Type Clays o n t h e Acid-Base Equilibrium of Atrazinea A?&+,
sample aqueous solution sodium-saturated montmorillonite suspension 3-hydroxypropylammonium-saturated montmorillonite suspension a
0
2
6
4
8 HOURS
10
12
14
Figure 4. Urinary amphetamine levels following a single oral dose 15 mg amphetamine sulfate; (*) of amphetamine sulfate. Key: (0) 7.5 mg amphetamine sulfate and 7.5 mg of a 1:20 amphetamine sulfate-montmorillonite adsorbate; (0)15 mg of a 1:20 amphetamine sulfate-montmorillonite adsorbate. From McGinity and Lach (1977).
rilloniteclindamycin complex with deionized water at pH 2 but clindamycin was readily desorbed by washing with deionized water at pH 11. Thus, a weak base which exists in its protonated form at pH 2 will be strongly adsorbed by a smectite-type clay in the stomach and absorption will be reduced. However, when the clay-drug complex leaves the stomach, the higher pH of the small intestine will cause the acid-base equilibrium of the drug to shift toward the neutral base. Because the neutral species is adsorbed by physical adsorption, desorption of the drug will occur as the clay-drug complex encounters the higher ionic strength of the intestinal fluid. The desorbed drug is therefore available for absorption for a prolonged period. A neutral drug such as digoxin, which is adsorbed by montmorillonite by hydrogen bonding, is readily desorbed
A?&,
apparent pK
kcall mol
kcall mol
1.64 4.40
-3.61
-0
6.90
-7.21
-0
From Erowne et al. (1980b).
by washing with water at either pH 2 or 6 (Figure 1). As will be discussed in a following section, the accelerated degradation of digoxin in the presence of a clay surface prevents the development of a useful clay-digoxin complex. However, a clay complex of a neutral drug which is chemically stable is expected to desorb the drug in both the stomach and intestine and provide prolonged absorption. It may be possible to further refine the release of a weak base from a clay complex by adsorbing a portion of the drug on a smectite-type clay where adsorption occurs by cation exchange and a portion on a fibrous clay where only physical adsorption occurs. The oral administration of a mixture of both clay-drug complexes should produce a systemic absorption pattern resulting from the desorption of the drug from the fibrous clay in the stomach and desorption from both the fibrous and smectitetype clays in the small intestine.
Surface Modification The nature of the exchangeable cation in smectite-type clays affects the preferential adsorption of the protonated form of a weak base (Browne et al., 1980b). As seen in Table 11, the apparent dissociation constant of atrazine, a weak base, increased from 1.64 to 4.40 in the presence p H 11.0
1680 I
1700
1500
1300 1700 W A V E NUMBER, cm-'
1500
1300
Figure 5. IR spectra of montmorillonite-clindamycin complex after 5 washes. Key: (A) montmorillonite; (B)montmorillonite-clindamycin complex at pH 2; (C) clindamycin at pH 2; (D) montmorillonite-clindamycin complex at pH 11 (one washing); and ( E )clindamycin at pH 11. From Porubcan et al. (1978).
Ind. Eng. Chem. Prod. Res. Dev., Vol. 22, No. 4, 1983 669 A
'"K
AIRAZINE- H'
f
=
'.
.
E 50i2LATRAZINE
Ew
v,
2
4
6
S
3-HAM
10
I
3
7
5
9
I1
pHb
2
4
6
8
10
D H ~
Figure 7. Fraction of atrazine adsorbed in clay suspensions containing 0.5 mg of atrazine and 20 mg of clay/ 100 mL. Key: (NaM) sodium-saturated montmorillonite; (3-HAM) 3-hydroxypropylammonium-saturated montmorillonite. From Browne et al. (1980b).
Figure 6. Distribution of species of atrazine. Key: (A) aqueous solution; (3-HAM)atrazine in 3-hydroxypropylammonium-saturated montmorillonite suspension. From Browne et al. (1980b).
of montmorillonite which was treated so that all of the exchangeable cations were sodium (sodium-saturated montmorillonite). The change in the partial molar Gibbs free energy of the protonated form of atrazine, AOBH+,was -3.61 kcal/mol, indicating that this species of atrazine interacted with the clay. In contrast, virtually no interaction occurred between the neutral atrazine molecule and the clay since AGE was approximately zero. The acid-base equilibrium of atrazine was affected more strongly when an organic cation, 3-hydroxylpropylammonium,was the exchangeable cation. A shift in the apparent pK of more than 5 units was caused by the strong interaction of the protonated species of atrazine with the 3-hydroxylpropylammonium-saturated montmorillonite. Thus, the protonated forms of weak bases are more strongly adsorbed when a smectite-type clay is modified by organic cation saturation. The shift of the acid-base equilibrium of atrazine in the organic cation-saturated clay suspension resulted in an altered distribution of protonated and neutral species of atrazine (Figure 6). The predominance of the protonated species of atrazine up to pH 5 in an organic cation-saturated montmorillonite suspension was confirmed by the adsorption of atrazine through pH 5 by the 3-hydroxylpropylammonium-saturatedmontmorillonite (Figure 7). The curves shown in Figure 7 are typical of fraction bound curves of weak bases on smectite-type clays. At low pH conditions, both protons and the protonated base compete for the negatively charged sites on the clay surface. The pH of maximum adsorption occurs when the interaction of the protonated base predominates. Adsorption decreases at pH conditions favoring the formation of the neutral base. The pH values for maximum adsorption of atrazine in Figure 7 reflect the apparent pK of atrazine in the presence of each clay. Surface modification of montmorillonitethrough organic cation saturation may be useful in causing the adsorption of weak bases at high pH conditions. One therapeutic application of organic cation-saturated montmorillonite may be in the treatment of poisoning by weak bases. For weak bases with low pK values, the neutral base should exist throughout the small intestine. This will lead to absorption of the toxic weak base. Conventional clay adsorbents do not strongly interact with neutral molecules and, therefore, are not effective in the emergency treat-
V 0
I
4
8
12 1 I M E (minl
16
20
Figure 8. Dissolution profiles of griseofulvin in 0.02% aqueous polysorbate at 37 "C. Key: ( 0 )griseofulvin; (0)1:l griseofulvinmontmorillonite complex; (0) 1:4 griseofulvin-montmorillonite complex; (M) 1:9 griseofulvin-montmorillonite complex. From McGinity and Harris (1980a).
ment of poisoning by weak bases. However, when montmorillonite is modified by saturation with an organic cation, the pH range over which adsorption occurs is greatly increased. Therefore, the toxic weak base will be adsorbed throughout the gastrointestinal tract and systemic effects will be avoided.
Environment at the Clay Surface A drug molecule which is adsorbed on a clay surface experiences an environment which is different from the bulk solution. The dissolution rate of a drug may be enhanced by adsorption to a clay if the adsorption forces are weaker than the attractive intermolecular forces within the crystal lattice of the drug. Thus, desorption from the clay occurs more readily than release from the crystal lattice. Enhanced dissolution rates have been observed for griseofulvin (Figure B), indomethacin and prednisone (McGinity and Harris, 1980a,b). It is believed that the same mechanism is responsible for the more rapid loss by volatilization of pesticide following field application than is anticipated based on the vapor pressure of the pesticide. A negatively charged clay surface will adsorb protons and, therefore, an adsorbed drug will encounter a greater concentration of protons than found in the bulk solution. Digoxin, which degrades by acid-catalyzed hydrolysis, was
870
Ind. Eng. Chem. Prod. Res. Dev., Vol. 22, No. 4, 1983
280 635 3.7 X 6.4
internal surface area, m Z / g 500 channel dimensions A 3.7 X 10.6 a
From Hermosin e t al. (1981).
"
\
0
-31
,
,
,
,
,
,
1
2
3
4
5
6
OH
Figure 9. Degradation of digoxin (0.2 mg/100 mL) at 37 "C. Key: (0) solution; (0) montmorillonite suspension (1g/100 mL). From Porubcan et al. (1979).
found to degrade much more rapidly than expected when in an aqueous montmorillonite suspension. As seen in Figure 9, the apparent rate constant for degradation in a montmorillonite suspension at pH 3.5 was equivalent to the rate constant in an aqueous solution at pH 2. The effective pH at the montmorillonite surface appears to be 1.5 units lower than the bulk. The catalytic effect of a negative surface should be considered whenever a drug which degrades by acid-catalyzed hydrolysis is combined with a clay. It should be remembered that this adsorption and subsequent accelerated degradation can occur in the stomach if a drug which degrades by acid-catalyzed hydrolysis is coadministered with a clay-containing product. Figure 10 shows that approximately 80% of the digoxin was intact and available for absorption after exposure to a pH 2 solution at 37 "C for 1h, Le., the estimated gastric residence time. However, virtually no digoxin remained after 1 h at pH 2, 37 OC in a montmorillonite suspension at pH 2. An adsorbed drug molecule may come into contact with ferric iron on the mineral surface which promotes the oxidative degradation of drugs. Surface ferric iron may exist as surface-adsorbed iron oxides or hydroxides, or as structural ferric iron which is located mainly in the octahedral sites of the clay (Cornejo et al., 1983). Hydrocortisone is a neutral steroid which degrades by oxidative degradation and is used topically to treat dermal inflammation. Hydrocortisone lotions often contain a clay as a viscosity-enhancing agent. Adsorption studies indicated that hydrocortisone is weakly adsorbed by attapulgite, a fibrous clay (Cornejo et al., 1980). As seen in Figure 11, adsorption by attapulgite accelerated the rate of oxidative degradation of hydrocortisone. Degradation in the presence of attap&@ appears to be composed of two apparent first-order reactions rather than the single apparent first-order reaction observed for hydrocortisone solutions. However, the same degradation products were obtained in both solutions and attapulgite suspensions, indicating that interaction with attapulgite did not alter the degradation pathway. Electron spin resonance studies showed that both structural ferric iron and surface-adsorbed iron oxides are present in attapulgite (Cornejo et al. 1983). The two types of ferric iron may be responsible for the apparent
1
2
3
4
5
HOURS
Figure 10. Degradation of digoxin (0.2 mg/100 mL) at 37 "C. Key: ( 0 )solution at pH 2; (0) montmorillonite suspension (1 g/100 mL) at pH 2; (m) solution a t pH 3; (0)montmorillonite suspension (1 g/100 mL) at pH 3. From Porubcan et al. (1979).
HOURS
Figure 11. Degradation of hydrocortisone (20 mg/100 mL). Key: (0) aqueous solution at pH 8.4,50 "C; (0) solution in supernate from attapulgite suspension (1.2 g/ attapulgite suspension at 38 "C; (0) 100 mL) at pH 8.4, 23 "C. From Cornejo et al. (1980).
two-phase degradation reaction because the rate of degradation will decrease as the oxidizing potential of the more accessible site is exhausted. Stability problems of this type may be avoided by selecting a clay which is free of surface iron. Sepiolite is a clay which also belongs to the fibrous group and has an ideal formula, external surface area, internal surface, and channel dimensions that are very similar to attapulgite (Table 111). However, there is a striking difference in the ferric iron content of these clays: sepiolite contains much less ferric iron than attapulgite. Infrared analysis showed that hydrocortisone was adsorbed by sepiolite but no increase in the rate of degradation occurred in sepiolite suspensions (Hermosin et al., 1981). Thus, desirable effects of clays can be obtained and undesirable effects avoided by selecting a clay of the proper type and composition. It must also be remembered that the exchangeable cations in smectite-type clays are available for interaction with drug molecules and that complexation with divalent interlayer cations may affect drug absorption. Tetracycline was adsorbed by montmorillonite by cation exchange at
Ind. Eng. Chem. Prod. Res. Dev., Vol. 22,
No. 4, 1983
671
the reason that patients are warned not to take tetracycline with milk.
Conclusions Clays may impart many desirable and unique properties to pharmaceutical dosage forms. However, careful examination of the clay structure as well as the drug structure is necessary in order to achieve the desired results while avoiding undesired reactions. Acknowledgment
J
Y
"V
This report is Journal Paper 9384, Purdue University Agriculture Experiment Station, West Lafayette, IN 47907. The authors gratefully acknowledge the contributions of the following former graduate students and research associates; J. E. Browne, J. Cornejo, J. R. Feldkamp, M. C. Hermosin, L. S. Porubcan, and C. J. Serna. The paper was presented at the ACS Symposium on Colloidal Particles: Colloidal Properties of Clays, March 29, 1982, in Las Vegas, NV.
Literature Cited
\G'
1440
1616 \
1595 I
I 1600
I
I
I
1400
W A V E NUMBER, cm-' Figure 12. Role of complexation when tetracycline interacts with montmorillonite. Key: (A) calcium-tetracycline complex at pH 11; (B) tetracycline interacted with montmorillonite at pH 11. From Porubcan et al. (1978).
low pH values where the cationic form of tetracycline predominates (Porubcan et al., 1978). However, metal-ion analysis of the sample of montmorilloniteshowed that 10% of the exchange capacity was satisfied by divalent cations (7.1% Ca2+, 2.7% Mg2+). Complexation with divalent interlayer cations was found to contribute significantly to the montmorillonite-tetracycline interaction at higher pH conditions where the zwitterionic and anionic species of tetracycline exist. Figure 12 shows that the infrared spectrum of tetracycline interacted with montmorillonite at pH 11 is identical with calcium tetracycline. This type of complexation may have important therapeutic consequences as calcium tetracycline is nonabsorbable and is
Browne, J. E.; Feldkamp, J. R.; White, J. L.; Hem, S. L. J. Pharm. Sci. l98Oa, 69, 811. Browne, J. E.; Feidkamp, J. R.; White, J. L.; Hem, S. L. J. Pharm. Sci. 1980b, 69, 1393. Coleman, N. T.; Craig, D. Soil Sci. 1981, 9 1 , 14. Coiiaizzi, J. L.; Kiink, P. R. J. Pharm. Sci. 1989, 58, 1184. Cornejo, J.; Hermosin, M. C.; White, J. L.; Peck, G. E.; Hem, S. L. J. Pharm. Scl. 1980, 69, 945. Cornejo, J.; Hermosin, M. C.; White, J. L.; Barnes, J. R.; Hem, S. L. Clays Clay Min. 1983, 31, 109. Cruz, M.; White, J. L. I n "Environmental Quality and Safety"; Couiston, F.; Korte, F., Ed.; Academic: New York, 1972; pp 221-229. Feldkamp, J. R.; White, J. L. J. CONOMInterface Sci. 1979, 69, 97. Green-Keiiey, R. Trans. Faraday SOC. 1955, 5 1 , 412. Hermosin, M. C.; Cornejo, J.; White, J. L.; Hem, S. L. J. Pharm. Sci. 1981, 70, 189. Hermosin, M. C.; Cornejo, J.; White, J. L.; Hess, F. D. J. Agric. Food Chem. 1982, 30, 728. Kerr, G. T.; Zimmerman, R. H.; Fox, H. A,, Jr.; Wells, F. H. Pub. 456, Nati. Acad. Sci. Nati. Research Council, Washington, DC, 1956; p 322. Ledoux, R. L.; White, J. L. J. ColloM Interface Sci. 1988, 27, 127. Low, P. F. SoilSci. SOC. Am. Proc. 1955, 79, 135. McGinity, J. W.; Harris, M. R. Drug Devel. Indust. Pharm. I98Oa, 6, 35. McGinity, J. W.; Harris, M. R. Drug Devel. Indust. Pharm. 1980b, 6 . 49. McGinRy, J. W.; Lach, J. L. J. Pharm. Sci. 1977, 66. 63. Munzei, K. Acta Pharmacol. Toxicol. Suppl. 1971, 29, 81. Porubcan, L. S.; Born, G. S.; White, J. L.; Hem, S. L. J. Pharm. Sci. 1979, 68,358. Porubcan, L. S.; Serna, C . J.; White, J. L.; Hem, S.L. J. Pharm. Sci. 1978, 67, 1081. Schwertmann, U.; Jackson, M. L. Science 1983, 139, 1052. Wagner, J. G. Can. J. Pharm. Sci. 1986, 1, 55. Wagner, J. G. Drug Intel. 1988, 2 , 38. Zentner, M. R. US. Patent 3337402, 1967a. Zentner, M. R. US. Patent 3337403, 1967b.
Received for review February 18, 1983 Accepted July 5, 1983
