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Potentiometric investigation of sparingly soluble metal-ligand systems using metal-ion buffers
Mybcdmn Vol. 1, No. 2. pp. ISfl55.1982 Printedin Great Britain.
02n-5387182/02015M3W)3.0010 PergamonPress Ltd.
POTENTIOMETRIC INVESTIGATION OF SPARINGLY SOLUBLE METAL-LIGAND SYSTEMS USING METAL-ION BUFFERS Z-X. HUANG,t
H. S. AL-FALAHI, A. COLE, J. R. DUFFIELD, C. FURNIVAL, D. C. JONES, P. M. MAY, G. L. SMITH and D. R. WILLIAMS* Departmentof Chemistry,University of WalesInstitute of Science and Technology, Cardiff CFI 3NU, Wales (Received 8 Iu/y 1981)
Ah&act--A novel approach based on metal-ion buffers has been used to determine metal-ligand formation constants for a variety of sparingly soluble systems. It is suggested that the approach will be particularly useful in the study of metal binding by pharmaceuticals.
The passive diffusion of molecules through biochemical membranes depends on their charge density and so the distribution of administered agents throughout the body is often determined by the polarity and formal electrical charge of the species which they form in uiuo.’ Molecules having a low charge density tend to be readily absorbed through the gastrointestinal tract and are subsequently dispersed into a wide variety of tissues whereas more highly charged species are poorly absorbed and, when injected intravenously, are confined to extracellular space. Thus, the properties of therapeuticals which enable them to reach their site of action by passing through cell walls, are inherently apt to make them insoluble in water. On the other hand, highly water-insoluble substances would be at a disadvantage because, in addition to the transport through membranes, drug species must also move through aqueous biofluids such as blood plasma. This dichotomy is resolved by agents which can change their stoichiometry (and thus also their electrical charge) according to the composition of the medium. Most commonly, the protonation of drug anions produces lower charged species. However, even neutral molecules must be relatively nonpolar in order to cross the lipid bilayer of cell membranes. So it is not surprising that many therapeutic agents are found to be only sparingly soluble in water. This limits potentiometric analysis of these systems because the protonated species tend to precipitate as soon as they begin to form in the solution. The difficulty is even more pronounced when metal-ion interactions with the drug are being investigated. With most anionic ligands, complexation will reduce the charge on the species so insolubility often becomes a problem as the pH is raised and the free concentration of the ligand increases. This paper outlines a technique which has proved very useful in avoiding such precipitation during potentiometric titrations. Although straightforward in principle, it has not previously been described in the literature. It appears to have considerable potential in many areas of inorganic solution chemistry but particularly in the field of metal binding by pharmaceuticals. *Authorto whom correspondence should be addressed. ton leave from the Chemistry Department, Fudan University, Shanghai, People’s Republic of China.
THE TECENIQUE It has long been established that the problem of
measuring very large formation constants can sometimes be overcome using the principle of ligand-ligand competition.2*3A secondary chelating agent is introduced to lower the free metal ion concentration in the solution and thus bring about some conditions under which the species being investigated can dissociate. This is tantamount to using a metal ion buffer.4 We have found that this kind of competition can also be used successfully to supress precipitation during potentiometric investigations of sparingly soluble systems where the solubility product of the metal-hydroxide or the metal-ligand species is exceeded. The reason why this approach is effective is illustrated in Figs. 1 and 2 using the cadmium(II)-cystine system. Figure 1 shows the concentration of the binary species over a wide range of pH (i.e. including calculated extensions as they would have been obtained had they not been precluded by insolubility). Figure 2 shows the distribution for the real ternary system. The introduction of the secondary ligand (NTA) sufficiently lowers the free cadmium ion concentration to permit limited formation of the mono cadmium-cystine complex in a pH range where the species does not precipitate.
Fig. 1. Theoretical distribution of cadmium in the presence of cystine (Cd: Cystine = 1: 2). The point at which the titration was prevented by precipitation is shown by the arrow. 153
Z-X. HUANG et al.
154
-toGrH+l
Fig. 2. Actual distribution of cadmium in the presence of cystine and nitrilotriacetate as buffering ligand (Cd: Cystine: NTA = I :2: 1). Note that the CdNTA complex suppresses [Cd”+] and allows the titration to be completed. RESULTSAND DISCUSSION
Table 1 gives some examples of formation constants for poorly soluble systems which have been obtained using this buffering method. The mathematics for treat-
ing such competition has been available for many decades but the introduction of computer programs such as SCOGS4 and MINIQUAD has greatly facilitated potentiometric data assessment and treatment. Ideally, the same value for the ML constant ought to be obtained by using two or more buffering ligands. We have several examples of this check procedure, one of which, /?roll for Cu-guanosine, is shown in the Table. The buffering ligands were chosen according to the following criteria. If the formation constant for &_ is required and if B is the buffering ligand, I. The complexing ability of B ought not to be much greater than that of L, otherwise MB and MB2 complexes will be formed (and vice versa in that only ML2 complexes will be formed if B is considerably weaker than L as a complexing ligand this leads to precipitation of ML). 2. Preferably mixed ligand ternary complexes should be avoided. This may be achieved by having the sum of the number of donor groups for both ligands considerably in excess of the coordination number of the central metal ion. 3. Unfortunately, polydentate groups as defined under 2, because of the chelate effect, often bring about very
Table 1. Formation constants (at 37”and I = I50 mmol dmm3NaCI) for the general reaction.
Complexes underlied are those determinedby the new approach Ligsnd,L
Metal
ion
Complex Pqrs
log
1001 2003 1003 1004
8.602 16.356 18.407 20.043
1010
8.22
6
Binary complexes
log
6
= Cd*+
Cystinate
Cystinate
as
9.020 11.449 13.357 8.253 12.238
EDDA
0101 0102 0103 0104 01:o 0210
9.541 16.025 18.327 19.602 8.629 12.991
Penicillaminate
0101 0102 0103
10.244 17.921 19.827
0110 0210 0211
10.742 17.684 24.671
EDTA
0101 0102 0103 0104 0110 0111
9.120 15.033 17.66 19.66 13.790 16.515
Thiazolidine carboxylate
0101 0102 0110 0210
6.104 7.029 3.19 5.75
above
w
5.41
Cystinate as
0101 0102 0103 0110 0210
1.07
Cystinate
as
NTA
above
111-l
above
111-l
Metal
Buffer,B
24.47
ion = Zn2+
Aminothiazoline
1001
8.483
potentiometric
Ligand
Complex Pqrs
,L
Metal
ion
investigation
:
Zn
2+
Aminothiazoline
of sparingly
log
6
soluble
metal-ligand
Buffer,B
Binary
ion
: Cu
f3
(contd) Alanine
0101 0102 0110 011-l
9.368 11.699 4.44 -3.18
1110
1.25
1002 1002 1003 1004
8.602 16.356 la.407 20.043
Histidinate
0101 0102 0103 0110 0210
a .777 14.601 16.287 6.30 11.45
0111 0211
16.67 lo.38
Ethylenediamine
0101 0102 0110 0210 021-l
9.6 16.43 10.14 la.84 7.4
Ethambutol
0101 0102 0110 011-l 01-l-2
9.05 15.10 9.9 3.26 -5.05
Nalidixate
0101 0110 0210
5.94 6.0 11.64
2+
Nalidixate
Guanosine
1001 1.010
1001
1002
5.94 6.0
a.91 10.97
20.77 m Guanosine
as above 1011
x
log
Pqrs
+@ Metal
I55
complexes
as above
Cystinate
systems
Full details published in
1x
of data treatment, full papers in
due
powerful complexing and this contravenes criterion number 1. Competition between two ligands for a central metal ion has been used since the early days of solution coordination chemistry. However, the application described in this letter to sparing solubility is a new concept that has a widespread potential to the field of pharmaceutical metal-ion studies.
standard course
deviations
etc.,
will
be
REFBRENCES
‘A. M. Fiabane and D. R. Williams, The Principles of Bioinorganic Chemislry.Royal Societyof Chemistry,1977. *J.Bjerrum,Dissertation,Copenhagen,1941. ‘I. Leden, Dissertation,Lund, 1943. ‘D. D. Perrin and B. Dempsey, Buffers for pH and Mefnl Ion Confrol, Chapmanand Hall, London, 1974. ‘A. Sabatini,A. Vaccaand P. Cans, Tnlnnfa 1974,21,53.
02n-5387182/02015M3W)3.0010 PergamonPress Ltd.
POTENTIOMETRIC INVESTIGATION OF SPARINGLY SOLUBLE METAL-LIGAND SYSTEMS USING METAL-ION BUFFERS Z-X. HUANG,t
H. S. AL-FALAHI, A. COLE, J. R. DUFFIELD, C. FURNIVAL, D. C. JONES, P. M. MAY, G. L. SMITH and D. R. WILLIAMS* Departmentof Chemistry,University of WalesInstitute of Science and Technology, Cardiff CFI 3NU, Wales (Received 8 Iu/y 1981)
Ah&act--A novel approach based on metal-ion buffers has been used to determine metal-ligand formation constants for a variety of sparingly soluble systems. It is suggested that the approach will be particularly useful in the study of metal binding by pharmaceuticals.
The passive diffusion of molecules through biochemical membranes depends on their charge density and so the distribution of administered agents throughout the body is often determined by the polarity and formal electrical charge of the species which they form in uiuo.’ Molecules having a low charge density tend to be readily absorbed through the gastrointestinal tract and are subsequently dispersed into a wide variety of tissues whereas more highly charged species are poorly absorbed and, when injected intravenously, are confined to extracellular space. Thus, the properties of therapeuticals which enable them to reach their site of action by passing through cell walls, are inherently apt to make them insoluble in water. On the other hand, highly water-insoluble substances would be at a disadvantage because, in addition to the transport through membranes, drug species must also move through aqueous biofluids such as blood plasma. This dichotomy is resolved by agents which can change their stoichiometry (and thus also their electrical charge) according to the composition of the medium. Most commonly, the protonation of drug anions produces lower charged species. However, even neutral molecules must be relatively nonpolar in order to cross the lipid bilayer of cell membranes. So it is not surprising that many therapeutic agents are found to be only sparingly soluble in water. This limits potentiometric analysis of these systems because the protonated species tend to precipitate as soon as they begin to form in the solution. The difficulty is even more pronounced when metal-ion interactions with the drug are being investigated. With most anionic ligands, complexation will reduce the charge on the species so insolubility often becomes a problem as the pH is raised and the free concentration of the ligand increases. This paper outlines a technique which has proved very useful in avoiding such precipitation during potentiometric titrations. Although straightforward in principle, it has not previously been described in the literature. It appears to have considerable potential in many areas of inorganic solution chemistry but particularly in the field of metal binding by pharmaceuticals. *Authorto whom correspondence should be addressed. ton leave from the Chemistry Department, Fudan University, Shanghai, People’s Republic of China.
THE TECENIQUE It has long been established that the problem of
measuring very large formation constants can sometimes be overcome using the principle of ligand-ligand competition.2*3A secondary chelating agent is introduced to lower the free metal ion concentration in the solution and thus bring about some conditions under which the species being investigated can dissociate. This is tantamount to using a metal ion buffer.4 We have found that this kind of competition can also be used successfully to supress precipitation during potentiometric investigations of sparingly soluble systems where the solubility product of the metal-hydroxide or the metal-ligand species is exceeded. The reason why this approach is effective is illustrated in Figs. 1 and 2 using the cadmium(II)-cystine system. Figure 1 shows the concentration of the binary species over a wide range of pH (i.e. including calculated extensions as they would have been obtained had they not been precluded by insolubility). Figure 2 shows the distribution for the real ternary system. The introduction of the secondary ligand (NTA) sufficiently lowers the free cadmium ion concentration to permit limited formation of the mono cadmium-cystine complex in a pH range where the species does not precipitate.
Fig. 1. Theoretical distribution of cadmium in the presence of cystine (Cd: Cystine = 1: 2). The point at which the titration was prevented by precipitation is shown by the arrow. 153
Z-X. HUANG et al.
154
-toGrH+l
Fig. 2. Actual distribution of cadmium in the presence of cystine and nitrilotriacetate as buffering ligand (Cd: Cystine: NTA = I :2: 1). Note that the CdNTA complex suppresses [Cd”+] and allows the titration to be completed. RESULTSAND DISCUSSION
Table 1 gives some examples of formation constants for poorly soluble systems which have been obtained using this buffering method. The mathematics for treat-
ing such competition has been available for many decades but the introduction of computer programs such as SCOGS4 and MINIQUAD has greatly facilitated potentiometric data assessment and treatment. Ideally, the same value for the ML constant ought to be obtained by using two or more buffering ligands. We have several examples of this check procedure, one of which, /?roll for Cu-guanosine, is shown in the Table. The buffering ligands were chosen according to the following criteria. If the formation constant for &_ is required and if B is the buffering ligand, I. The complexing ability of B ought not to be much greater than that of L, otherwise MB and MB2 complexes will be formed (and vice versa in that only ML2 complexes will be formed if B is considerably weaker than L as a complexing ligand this leads to precipitation of ML). 2. Preferably mixed ligand ternary complexes should be avoided. This may be achieved by having the sum of the number of donor groups for both ligands considerably in excess of the coordination number of the central metal ion. 3. Unfortunately, polydentate groups as defined under 2, because of the chelate effect, often bring about very
Table 1. Formation constants (at 37”and I = I50 mmol dmm3NaCI) for the general reaction.
Complexes underlied are those determinedby the new approach Ligsnd,L
Metal
ion
Complex Pqrs
log
1001 2003 1003 1004
8.602 16.356 18.407 20.043
1010
8.22
6
Binary complexes
log
6
= Cd*+
Cystinate
Cystinate
as
9.020 11.449 13.357 8.253 12.238
EDDA
0101 0102 0103 0104 01:o 0210
9.541 16.025 18.327 19.602 8.629 12.991
Penicillaminate
0101 0102 0103
10.244 17.921 19.827
0110 0210 0211
10.742 17.684 24.671
EDTA
0101 0102 0103 0104 0110 0111
9.120 15.033 17.66 19.66 13.790 16.515
Thiazolidine carboxylate
0101 0102 0110 0210
6.104 7.029 3.19 5.75
above
w
5.41
Cystinate as
0101 0102 0103 0110 0210
1.07
Cystinate
as
NTA
above
111-l
above
111-l
Metal
Buffer,B
24.47
ion = Zn2+
Aminothiazoline
1001
8.483
potentiometric
Ligand
Complex Pqrs
,L
Metal
ion
investigation
:
Zn
2+
Aminothiazoline
of sparingly
log
6
soluble
metal-ligand
Buffer,B
Binary
ion
: Cu
f3
(contd) Alanine
0101 0102 0110 011-l
9.368 11.699 4.44 -3.18
1110
1.25
1002 1002 1003 1004
8.602 16.356 la.407 20.043
Histidinate
0101 0102 0103 0110 0210
a .777 14.601 16.287 6.30 11.45
0111 0211
16.67 lo.38
Ethylenediamine
0101 0102 0110 0210 021-l
9.6 16.43 10.14 la.84 7.4
Ethambutol
0101 0102 0110 011-l 01-l-2
9.05 15.10 9.9 3.26 -5.05
Nalidixate
0101 0110 0210
5.94 6.0 11.64
2+
Nalidixate
Guanosine
1001 1.010
1001
1002
5.94 6.0
a.91 10.97
20.77 m Guanosine
as above 1011
x
log
Pqrs
+@ Metal
I55
complexes
as above
Cystinate
systems
Full details published in
1x
of data treatment, full papers in
due
powerful complexing and this contravenes criterion number 1. Competition between two ligands for a central metal ion has been used since the early days of solution coordination chemistry. However, the application described in this letter to sparing solubility is a new concept that has a widespread potential to the field of pharmaceutical metal-ion studies.
standard course
deviations
etc.,
will
be
REFBRENCES
‘A. M. Fiabane and D. R. Williams, The Principles of Bioinorganic Chemislry.Royal Societyof Chemistry,1977. *J.Bjerrum,Dissertation,Copenhagen,1941. ‘I. Leden, Dissertation,Lund, 1943. ‘D. D. Perrin and B. Dempsey, Buffers for pH and Mefnl Ion Confrol, Chapmanand Hall, London, 1974. ‘A. Sabatini,A. Vaccaand P. Cans, Tnlnnfa 1974,21,53.