Synthesis, Physico Chemical and Spectral Studies of Mercury Complex of Glibenclamide; An Oral Antidiabetic Drug

Introduction

Man has been in continued search for chemotherapeutic agents right from the earliest times, about 2000 B.C. or even earlier. As a result of this research several naturally occurring substances, plant materials and minerals including Arsenic, Mercury, Bismuth, Gold and Silver as metals or as their salts have been used for several thousand years, especially in Ayurveda and Unani system of medicines. In the early part of the twentieth century, organo-metallic compounds emerged as important agents in the treatment of syphilis, tropical diseases etc^1-3. Chemically arsenic, antimony and bismuth belong to the same family and have some common pharmacological actions. Mercurials comparatively, still hold importance in medicine and organic mercurials are used as divretics⁴. The discovery of vitamin B₁₂ and copper phthalocyanine has given impetus to the development of metal complexes with organic ligands. A survey of literature reveals that metal complexes of some drugs have been found to be more potent than the drug alone therefore in continuation of our previous work 5-10 on metal complexes of oral antidiabetic agents of hypoglycemic activity, the synthesis and structural studies of glibenclamide-Hg complex is described here. Glibenclamide (Euglucon, 1-(4-(2(chloro-2-methoxybenzamide⁰) ethyl) – benzene sulphonyl)-3-cyclo hexyl urea, is a sulphonyl urea derivative having melting point 169-174⁰C is a white or almost white crystalline orderless powder, practically without taste, insoluble in water and soluble in ethanol, methanol and in alkalisolution. It dissolves in diethyl ether also. Glibenclamide is a second generation oral hypoglycemic agent which is more potent than those of first group¹¹ and is used to assist in the control of mild to moderately severe type (II) diabetes mellitus. Complexation of sulphonyl urea with lighter transition metals has been studied in detail^12-13. A perusal of available literature shows that many drugs possessed modified pharmacological and toxicological properties when administered in the form of metallic complexes.

Experimental Ligand-Metal ratio

Pure glibenclamide (1) Trade name, Euglucon a sulphonyl urea derivative is supplied by Aventis pharma Ltd; Goa in powdered form. 0.005 M drug and mercuric (II) chloride (HgCl₂) 0.01M (Analar grade) were prepared in purified 80% ethanol. Glibenclamide (20ml) was diluted to 200ml and titrated conductometrically against mercuric chloride at 27 1⁰C.

Formation of 2:1 (L₂M) ratio was also confirmed by Job’s method¹⁴ of continuous variation as modified by Turner and Anderson¹⁵ using conductance as index property. Form these value, the stability constant (logk) and free energy change (- F) were also calculated^16-17. (Table 1 and 2., Fig I & II).

Synthesis of Complex

The chemicals used in this synthesis were all of analytical grade. A weighed quantity of glibenclamide (2 mol) was dissolved in minimum quantity of 80% ethanol. The mercuric (II) chloride solution was prepared by dissolving it separately in the same solvent. Lignd solution was added slowly with constant stirring into the solution of metallic salt at room temprature maintaining the pH between 6.2 to 6.9 by adding dilute NaOH solution. On refluxing the mixture for  3h at 80⁰C on cooling, the complex separated out which was filtered off, washed well with ethanol (80%) and finally dried in vacuum and weighed. The elemental analysis of the isolated complex was carried out using the reported methods^18-19. In the comlex, mercury was estimated gravimetrically as sulphide, nitrogen by kjeldhal method and sulphur by massenger’s method, using modified digestion mixture^20-21. The IR spectrum of the ligand as well as of the complex was recorded on Perkin Elmer spectrophotometer RX1(4000-450 cm^-1) CDRI Lucknow.

Glibenclamide With Mercuric Chloride

(JOB’S METHOD)

Glibenclamide – 0.005 M   HgCl₂ – 0.005 M

Solvent – 90% Ethanol  Temperature 27.5 1⁰C

Mole metal ligand ratio	Conductance X10-4Mhos M:S  S:L M:L C1 C2 C3			Conductance X10-4Mhos C1+C2-C3	Corrected Δconductance X10-4Mhos
0:12	0.22	1.66	1.84	0.04	0.00
1:11	0.26	1.55	1.69	0.12	0.08
2:10	0.35	1.51	1.65	0.21	0.17
3:9	0.39	1.42	1.56	0.25	0.21
4:8	0.43	1.30	1.40	0.33	0.29
5:7	0.47	1.19	1.36	0.30	0.26
6:6	0.50	1.40	1.30	0.24	0.20
7:5	0.53	0.89	1.21	0.21	0.17
8:4	0.56	0.79	1.16	0.19	0.15
9:3	0.60	0.64	1.10	0.14	0.10
10:2	0.64	0.50	1.04	0.10	0.05
11:1	0.69	0.36	0.97	0.08	0.03
12:0	0.73	0.20	0.88	0.05	0.00

 

Glibenclamide With Mercuric Chloride

(JOB’S METHOD)

Glibenclamide – 0.002 M    HgCl₂ – 0.002 M

Solvent – 90% Ethanol    Temperature 27.5 1⁰C

Mole metal ligand  ratio	Conductance X10-4Mhos M:S S:L M:L C1 C2 C3			Conductance X10-4Mhos C1+C2-C3	Corrected Δconductance  X10-4Mhos
0:12	0.24	1.32	1.53	0.03	0.00
1:11	0.28	1.25	1.43	0.10	0.07
2:10	0.31	1.19	1.36	0.14	0.11
3:9	0.34	1.15	1.28	0.21	0.18
4:8	0.37	1.07	1.18	0.26	0.23
5:7	0.40	0.98	1.16	0.22	0.19
6:6	0.43	0.89	1.12	0.20	0.17
7:5	0.47	0.75	1.07	0.15	0.12
8:4	0.50	0.63	1.00	0.13	0.10
9:3	0.54	0.50	0.93	0.11	0.08
10:2	0.57	0.39	0.86	0.10	0.07
11:1	0.61	0.29	0.84	0.06	0.04
12:0	0.65	0.14	0.76	0.03	0.00

 

 

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