6.jcbps .49._179-187_

E- ISSN: 2249 –1929
Journal of Chemical, Biological and Physical Sciences
An International Peer Review E-3 Journal of Sciences
Available online at www.jcbsc.org
Section A: Chemical Science
Research Article
Equilibrium studies of calcium (II) complexes with
drug Furosemide and some amino acids
Bhimrao C. Khade1*, Pragati M. Deore2 and Sudhakar R. Ujagare1
1Department of Chemistry, Dnyanopasak College, Parbhani 431401, MS, India 2Department of Chemistry, Dr. B. A. M. University, Aurangabad, MS, India Received: 22 August 2011; Revised: 27 August; Accepted; 12 September 2011
The equilibrium studies of the mixed ligands complexes of calcium (II) ion with drug
Furosemide as primary ligand and the amino acids viz. leucine and phenylalanine as secondary
ligand were determined pH metrically at 270C and an ionic strength of 0.1 M NaClO4 in 80% (v/v)
ethanol-water medium. The calculations have been made using the stability constant of

generalized species computer programmed.
Key words: Equilibrium constant, ∆ Log K and mixed ligand complexes.
Furosemide is an example of high-ceiling diuretic1 and may be regarded as a derivative of anthranilic acid or o-aminobenzoic acid. Research on 5-sulfamoylanthranilic acid at the Hoechst laboratories in Germany showed them to be effective diuretics. The most active of a series of variously substituted derivative was furosemide. The chlorine and sulfonamide substitutions are features seen also in another diuretic such as thiazide. Because the molecule posses a free carboxyl group, furosemide is a stronger acid than the thiazide diuretics. A small amount of metabolism, however, can take place on the furan ring, which is substituted on the aromatic amino group. Furosemide has a saluretic effect2 ten times that of the thiazide diuretics; however, it has a shorter duration of action, about 6-8 hours. Furosemide causes and excretion of sodium, chloride, potassium, calcium, magnesium and bicarbonate ions. It is effective for the treatment of edemas connected with cardiac, hepatic and renal sites. Because it lowers the blood pressure similar to the thiazide derivatives, one of its uses is in the treatment of hypertension. Furosemide is orally effective but may be used parent rally when a more prompt diuretic effect is desired. The dosage of furosemide, 20-80 mg/day, may be given in the divided doses because of the J. Chem. Bio. Phy. Sci. 2011, Vol.1, N0.2, Sec.A, 179-187.
Equilibrium studies. Bhimrao C. Khade et al.
short duration of action of the drug and carefully increased up to maximum of 600 mg/day. Clinical toxicity of furosemide involves abnormalities134 of fluid and electrolyte balance. Hyperuricemia, ototoxicity and gastrointestinal side effects are also observed. Leucine3 is neutral essential ketogenic amino acid and forms an acetoacetate and acetate. It is branched chain amino acid and taken up by brain and muscle. In leucine metabolism, transamination gives α-keto isocaproic acid, which is converted into corresponding CoA, this is similar to oxidative decarboxylation of alfaketoglutarate and pyruvate. The enzyme complex is very important in the body of living organism. A deficiency of the enzyme causes maple syrup urine disease. In this disease the urine gives odor of maple syrup or burnt sugar, deterioration is rapid and results in mental retardation. Phenylalanine4 is aromatic essential glucogenic and ketogenic amino acid. In metabolism phenylalanine is converted into tyrosine. In metabolism homogenstic acid is formed which undergoes cleavage and form fumarate and acetoacetate. Several abnormalities observed in phenylalanine metabolism such as phenylketonaria and alkaptonaria. In phenylketonaria, there is a black in hydroxylation of phenylalanine to form tyrosine, this leads to mental retardation. Alkeptanaria, in this homogenstic acid is not further oxidised and excreted in urine, this leads to black urine. Calcium occurs in the body in large amount than any other mineral elements. About 99% of the body calcium is in the skeleton, where it is present as deposit of Ca3PO4 in a soft, fibrous matrix. It plays an important role in the body of a living organism because it is well suited for binding to irregularly shaped crevices in proteins because calcium ion can form asymmetric complexes having a large radius, and binding of calcium is highly selective. Another characteristic of Ca (II) that makes it a highly suitable intracellular messenger is that it can bind tightly to proteins. Negatively charged and uncharged oxygen’s bind well to Ca (II). A capacity of Ca (II) to be coordinated to multiple ligands six to eight oxygen atoms enables it to cross-link different segment of protein and induced large conformational changes. The intracellular level of Ca (II) is kept low because phosphate esters are highly abundant are calcium phosphate and quite insoluble. More than 99% of the total body of living organism, calcium is immobilized in bones and teeth as hydroxyl apatite Ca10 (PO4)6(OH)2. A very little portion of calcium is present in extra cellular and intracellular fluids5. Milk is rich source of calcium where calcium is present largely as calcium casein ate. Absorption of Ca (II) occurs mainly in the proximal small intestine and decrease in the more distal regions. Several calcium-binding proteins have been identified. The skeleton is a huge reservoir of insoluble complexes of calcium which are in dynamic equilibrium with physicochemically soluble forms of circulating calcium that are maintained at a remarkably constant level. During states of calcium deprivation, calcium homeostasis is maintained at the skeleton, even to the point of producing severe bone disease. When calcium rises above normal, the C cells of thyroid secrete a hormone, calcitonin, which blocks mobilization of calcium from bone and stimulate calcium excretion in kidney thus restoring calcium to normalcy. Mobilization and deposition of calcium in biological system is controlled by parathyroid hormone, vitamin D, Calsequestrin, calcitonin and osteocalcium. Calcium is stored in the sarcoplasmic reticulum membrane on calcium binding proteins. The contraction of muscle is associated with the release of Ca (II) ions from sarcoplasmic and binding of Ca (II) ions to different sites of muscle fibers. Calcium plays a vital role in various essential physiological and biochemical processes. Calcium serves as the principal component of skeletal tissue, imparting to it the structural integrity essential to support the increasing body size of the individual during growth. It is used in the construction of cell J. Chem. Bio. Phy. Sci. 2011, Vol.1, N0.2, Sec.A, 179-187.
Equilibrium studies. Bhimrao C. Khade et al.
walls, bones, teeth, some shells and other structural constituents. The biological functions include its influence on biological calcification, structural role, muscle contraction, nerve impulse transmission, release of hormone, and activation of blood clotting enzymes, rhythm of heartbeats and permeability of gap junctions. Survey of literature reveals that no work has been reported on complex tendencies of drug furosemide with transition metal ion ca (II) in ethanol-water solution. Therefore in order to understand the complex formation tendencies of Furosemide it was though worthwhile to determine the formation constant 1:1:1 ternary complexes of Furosemide with calcium (II) in the presence of amino acids in 80 % (v/v) ethanol-water medium at 270C at a fixed ionic strength 0.1 M NaClO4. EXPERIMENTAL
Drug sample of Furosemide in pure form were obtained from pharma industries and used as received. Ethanol was purified as described in literature6. Double distilled water was used for the preparation of ethanol-water mixture and stock solution of Furosemide. All chemicals used were AnalaR grade. NaClO4 (0.1M) and NaOH solution was prepared in carbon dioxide free double distilled water. Carbonate free NaOH was standardized by titrating with oxalic acid. HClO4 Reidal (Germany) was used for the preparation of the stock solutions of ca (II) to prevent hydrolysis and standardized by using standard EDTA solution7. The experimental procedure, in the study of ternary chelated by the potentiometric titration technique, involves the titration of carbonate free solution of Free HClO4 + Ligand Furosemide + Metal ion Free HClO4 + Ligand Amino acids + Metal Ion Free HClO4 + Ligand Drug + Ligand Amino acids + Metal Ion Against standard solution of sodium hydroxide, were drug Furosemide and amino acid are two ligands. The ionic strength of the solutions was maintained constant i.e. 0.1M by adding appropriate amount of 1M sodium per chlorate solution. The titrations were carried out at 270C in an inert atmosphere by bubbling oxygen free nitrogen gas through an assembly containing the electrode to expel out CO2. pH meter reading in 80 % ( v/v) ethanol-water were corrected by method of Vanuitert and Hass8. The formation constant of ternary complexes were determined by computational programme SCOGS9 to minimize the standard derivation. RESULTS AND DISCUSSION
(a) Binary metal complexes: The proton ligand constant and metal ligand stability constant of
Furosemide and amino acids with ca (II) determined in 80 %( v/v) ethanol-water mixture at 270C and
ionic strength µ = 0.1M NaClO4 are given in Table- 110

J. Chem. Bio. Phy. Sci. 2011, Vol.1, N0.2, Sec.A, 179-187.
Equilibrium studies. Bhimrao C. Khade et al.
Table 1: The proton ligand constant and metal ligand stability constant of furosemide and amino
acids with calcium (II) determined in 80 %( v/v) ethanol-water mixture at 270C and ionic strength µ =
0.1M NaClO4 are given in Table 111
Proton dissociation Scheme for free ligand Furosemide (80% Ethanol- Water medium)
Proposed structure of binary complex formation of furosemide
(b) Ternary metal complexes: In the ternary systems, the mixed ligand titration curve coincide
with acid + drug complex curve up to the pH ∼ 2.5 and after this pH, it deviates. Theoretical
composition curve remains toward left to the mixed ligand titration complex curve. After pH∼ 2.7, the
J. Chem. Bio. Phy. Sci. 2011, Vol.1, N0.2, Sec.A, 179-187.
Equilibrium studies. Bhimrao C. Khade et al.
mixed ligand curve drift towards X axis, indicating the formation of hydroxide species. Since the mixed ligand curve coincide with individual metal complex titration curves, the formation of 1:1:1 complex by involving stepwise equilibria. The primary ligand Furosemide form 1:1while secondary ligand amino acids such as leucine and phenylalanine form 1:1 and 1:2 complexes with Ca (II). It is evident from the figure of the percentage concentration species Ca (II) - Furosemide amino acids system that the percentage distribution curves of free metal decreases sharply with increasing pH. This indicates involvement of metal ion in the complex formation process. Percentage concentration of free ligand Furosemide and amino acids increases and this increase may be due to the dissociation of ligand present in the system, as a function of pH. Species distribution studies: To visualize the nature of the equilibria and to evaluate the calculated
stability constant of ternary complexes Ca(II) - Furosemide – amino acids, species distribution curves
have been plotted as a function of pH at temperature 270C and µ = 0.1 M NaClO4 using SCOG programme. It can be observed that the concentration of Ca (II) - Furosemide amino acids such as leucine increases from pH 2.9 where as phenylalanine from pH∼ 3.8. The concentration for the formation of D(drug) and HR (amino acid) represented by C1 and C2 show continuous decrease with increasing pH which indicates the formation of Ca (II) – Furosemide (D)- amino acid (R) such as leucine and phenylalanine, represented by C6. The concentration of this species continuously increases; confirm the formation of ternary complexes. Ca (II) – ciprofloxacin (D) – amino acid (R) such as leucine and phenylalanine represented by C6. The concentration of this species continuously increases; confirm the formation of ternary complexes. From the SCOG distribution curve it is concluded that the formation of ternary complex started only after the metal primary ligand complex has attained its maximum concentration. This indicate that metal primary ligand complex Ca(II)- Furosemide is formed first then the secondary ligands such as leucine & Phenylalanine coordinated to it, resulting the formation of ternary complex. According to this method in this system ternary complex of Furosemide with leucine and phenylalanine show the following types of the concentration species distribution. Moreover the maximum percentage of the formation of ternary complexes of Furosemide is more than that of the Ca (II) amino acids leucine and less than of Ca (II) furosemide. This indicate that ternary complex if Ca (II) is less stable as compare to Ca(II) furosemide binary complex and more stable J. Chem. Bio. Phy. Sci. 2011, Vol.1, N0.2, Sec.A, 179-187.
Equilibrium studies. Bhimrao C. Khade et al.
than Ca(II) amino acid leucine. Whereas the ternary complex of Ca (II) with furosemide and amino acid phenylalanine is less stable to these two. The stability constant of ternary complexes: The relative stabilities of the binary and ternary
complexes are quantitatively expressed in term of β11, β20, β02, KD, KR, Kr and ∆ Log K value which are represented in table 2. The stability constants of ternary systems are represented in table 2. The stability of ternary complexes is conveniently characterizes by two ways, one based on difference of stability constant ∆ Log K and second disproportion constant. The first equation mentioned above is similar to the reaction With respect to the availability of coordination sites for ligand D in MR or MD, generally KML1 > KML2 , because more coordination positions are normally available for bonding first ligand to a metal ion than the second ligand. Evidently KML1 > KML2 or ∆ Log K is negative. ∆ Log K can be calculated by the expression. The negative ∆ Log K for ternary systems indicates that the primary ligand anion and secondary ligand anions preferentially form ternary complexes to their binary ones. It follows from above expression that the difference, ∆ Log K results from the subtraction of two constants and therefore, a constant which corresponds to the equation, The positive value of ∆ Log K indicates the equilibrium is more on its right side. The other characterization is based on the disproportion reaction represented by the following equilibrium The disproportion reactions for the system containing the ligands which form 1:1 and 1:2 complexes individually with the metal ion are as J. Chem. Bio. Phy. Sci. 2011, Vol.1, N0.2, Sec.A, 179-187.
Equilibrium studies. Bhimrao C. Khade et al.
Above two reactions are for the system containing one ligand which form only 1:1 and other form both 1:1 and 1:2 binary complexes. The last reaction is for the system containing ligands which form only 1:1 binary complexes. The magnitude of the constant is the measure of stability of mixed ligand complexes. Watter and Kida calculated statistically expected value 0.6 log units by considering with probabilities for a variety of reason discussed by Sigel. ∆ Log K value can be calculated by using
first or second approach. The calculated ∆ Log K values for all systems are given in Table- 2
Table 2: Parameters based on some relationship between the formation of ternary complexes of
calcium (II) metal ion with furosemide in the presence of amino acids (1:1:1) system
Temp = 270C I = 0.1 M NaClO4 Medium = 80% (V/V) Ethanol-Water
7.2478 2.8400 5.9948 1.5870 1.7515 -1.2530 3.1611 2.8400 1.4103 1.0892 1.4165 -1.7508 In Ca (II)- Furosemide –amino acids, Primary ligand Furosemide form only 1:1 and secondary ligand form both 1:1 and 1:2 binary complexes. Therefore this system favours the following disproportion reactions. The Comparison of β11 with β20 and β02 of this system show that preferential formation of ternary complexes over binary complex of primary as well as secondary ligand. The considerably low value of KD and KR indicates less stability of ternary complexes with respect to that of primary as well as secondary ligands. The Kr value of this complex is positive but less which indicates lower stability of ternary complexes. Results of the present investigations show that the stability constant of ternary complexes formed are less stable. The negative ∆ Log K value of this system indicates that the ternary complex is less stable than the binary 1:1 metal – Furosemide and metal – amino acids complex. This is in accordance with statistical considerations. The negative value of ∆ Log K does not mean that the complex is not formed. The negative value may be due to the higher stability of its binary complexes, reduced number of coordination sites, steric hindrance11-14, electronic consideration15-16, difference in bond type, geometrical structure etc. Sigel concluded that in the case of bidentate ligand Furosemide & amino acid, there are twelve edges of a regular octahedron available to the first entering ligand and only five for the second. Then the statistical factor would be 5/12 and accordingly ∆ Log K= -0.4, -0.6 and -0.9 for square planer & distorted octahedral complexes. Hence the experimentally determined value ∆ Log K < -0.6 indicate less stabilization in ternary complexes. J. Chem. Bio. Phy. Sci. 2011, Vol.1, N0.2, Sec.A, 179-187.
Equilibrium studies. Bhimrao C. Khade et al.
The ∆ Log K value of this system is higher than the statistically expected value except leucine & phenylalanine, showing the stabilized nature of the ternary complex. The primary ligand Furosemide having smaller size. Therefore its ∆ Log K value is less negative. Thompson and Lorass pointed out that more negative ∆ Log K value of ternary complexes is due to the electrostatic repulsion between the negative charges on Furosemide & amino acids. Steric hindrance consideration is the most important factor because in the present studies of ternary complex, primary ligand Furosemide coordinates with the metal ion in the lower pH range and form 1:1 complex. In solution, ternary complex forms as the titration curve run below the Ca (II) – Furosemide titration curve. So, it is evident that the entry of the secondary ligand amino acids faces steric hindrance due to bigger size of the Ca (II) Furosemide complex as compared to aquo ion, which tries to restrict the entry of the secondary ligand in the coordination sphere of the Ca (II) metal ion and thus reduces the stability of ternary complexes. The order of stability of ternary complexes of Ca (II) with respect of secondary ligand for respective primary ligands is ACKNOWLEDGEMENT
The authors are very much thankful to the Dr. P. L. More, Principal, Dr. W. N. Jadhav, Department of Chemistry for providing necessary facilities and UGC (WRO) for financial assets under minor research project (47-529/08). REFERENCES
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