WRLD JURNAL F PHARMACY AND PHARMACEUTICAL SCIENCES Sen et al. SJIF Impact Factor 6.041 Volume 5, Issue 11, 897-908 Research Article ISSN 2278 4357 SYNTHESIS F PRDRUG F ESTERS AND AMIDE LINKAGES F NSAID HAVING CARBXYLIC ACID, PHENLIC AND IMIN GRUPS Jalpa G. Patel and Prof. Dr. Dhrubo Jyoti Sen* Department of Pharmaceutical Quality Assurance and Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana 384001, Gujarat, India. Article Received on 12 Sept. 2016, Revised on 02 ct 2016, Accepted on 23 ct 2016 DI: 10.20959/wjpps201611-7945 *Corresponding Author Prof. Dr. Dhrubo Jyoti Sen Department of Pharmaceutical Quality Assurance and Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana 384001, Gujarat, India. ABSTRACT Ibuprofen, Diclofenac & Paracetamol have been taken as NSAID and three prodrugs have been synthesized by reacting of acid chloride of ibuprofen & diclofenac with paracetamol to get prodrug of ester linkage and acid chloride of ibuprofen has been reacted with diclofenac to get prodrug of amide linkage. These have been characterized by IR and authenticated by m.p. and logp values. KEYWRDS: Ibuprofen, Diclofenac sodium, Paracetamol, Thionyl chloride, Peptoid, logp, pka, Melting Point, Prodrug. INTRDUCTIN Ibuprofen [C 13 H 18 2 ; MW=206] (2 [4 (2 methylpropyl)phenyl] propanoic acid), from isobutylphenylpropanoic acid, is a drug in the nonsteroidal anti inflammatory drug (NSAID) class used for treating pain, fever, and inflammation. logp=3.97, pka=4.91. Ibuprofen m.p.=theoretical (76 C), practical (75 C). [1-3] Diclofenac sodium [NaC 14 H 10 2 N; MW=302] (Sodium {2 [(2,6 dichlorophenyl)amino] phenyl}acetic acetate) is a nonsteroidal anti inflammatory drug (NSAID) taken or applied to reduce inflammation and as an analgesic reducing pain in certain conditions. logp=4.51, pka=4.15. Diclofenac sodium m.p.=theoretical (283 285 C), practical (282 C) Paracetamol [C 8 H 9 N 2 ; MW=151] (N (4 hydroxyphenyl)acetamide), also known as acetaminophen or APAP, is a medication used to treat pain and fever. logp=0.46, pka=9.38. Paracetamol m.p.=theoretical (169 C), practical (170 C). www.wjpps.com Vol 5, Issue 11, 2016. 897
Ibuprofen, Diclofenac and Paracetamol all comes under NSAID and all three are acidic in nature. Ibuprofen and diclofenac both have free carboxylic acid ( CH) group and paracetamol has free phenolic group ( H). The idea of formation of prodrug by joining of free carboxylic acid ( CH) group of ibuprofen and diclofenac with phenolic group ( H) of paracetamol by converting free carboxylic acid ( CH) group into acid chloride ( C) and conjugated with free phenolic group ( H) by benzoylation reaction to get the three desired compounds [Prodrug A & Prodrug B having ester ( C ) linkage. Acid chloride ( C) of ibuprofen when reacts with imino group ( ) of diclofenac then it produces Prodrug C having amide ( C ) linkage. [4-6] H 3 C H 3 C S 2 H 2-[4-(2-methylpropyl)phenyl]propanoic acid 2-[4-(2-methylpropyl)phenyl]propanoyl chloride H 3 C 2-[4-(2-methylpropyl)phenyl]propanoyl chloride + H N-(4-hydroxyphenyl)acetamide H 3 C Prodrug-A Figure 1: Prodrug of Ibuprofen & Paracetamol. www.wjpps.com Vol 5, Issue 11, 2016. 898
Na S 2 sodium {2-[(2,6-dichlorophenyl)amino]phenyl}acetate {2-[(2,6-dichlorophenyl)amino]phenyl}acetyl chloride + {2-[(2,6-dichlorophenyl)amino]phenyl}acetyl chloride H N-(4-hydroxyphenyl)acetamide Prodrug-B Figure 2: Prodrug of Diclofenac sodium & Paracetamol. H 3 C H 3 C S 2 H 2-[4-(2-methylpropyl)phenyl]propanoic acid H 3 C 2-[4-(2-methylpropyl)phenyl]propanoyl chloride 2-[4-(2-methylpropyl)phenyl]propanoyl chloride + H {2-[(2,6-dichlorophenyl)amino]phenyl}acetic acid H 3 C N H Prodrug-C Figure 3: Prodrug of Ibuprofen & Diclofenac. www.wjpps.com Vol 5, Issue 11, 2016. 899
Chemistry: Ibuprofen (2g, 0.01m) has been reacted with 5ml thionyl chloride and refluxed for 30mins in moisture free environment until all ibuprofen has been dissolved. The reaction mixture was heated on water bath to remove excess thionyl chloride. It was then cooled in ice and paracetamol (1.5g, 0.01m) dissolved in methanol was added in it with shaking. ily droplets separates out which was then mixed with ice water and kept in ice to solidify the droplets into white solid of prodrug A. It was filtered and %yield and m.p. has been recorded for dried mass. Prodrug A is a combination of ibuprofen (logp=3.97, nonpolar) and paracetamol (logp=0.46, polar) produced a derivative of semipolar unit (logp=4.56). MP=162 164 C. %yield=83.67. Prodrug A [4 (acetylamino)phenyl (2S) 2 [4 (2 methylpropyl) phenyl] propanoate]. [Molecular Formula=C 21 H 25 N 3, Formula Weight=339.42]. (Solubility=0.1g soluble in 10ml methanol/10ml acetone). Figure 4: Histogram of logp of prodrugs. Diclofenac sodium (3g, 0.01m) has been reacted with 10ml thionyl chloride and refluxed for 30mins in moisture free environment until all diclofenac sodium has been dissolved. The reaction mixture was heated on water bath to remove excess thionyl chloride. It was then cooled in ice and paracetamol (1.5g, 0.01m) dissolved in methanol was added in it with shaking. ily droplets separates out which was then mixed with ice water and methanol and kept in ice to solidify the droplets into white solid of prodrug A. It was filtered and %yield and m.p. has been recorded for dried mass. Prodrug B is a combination of diclofenac sodium (logp=6.13, nonpolar) and paracetamol (logp=0.46, polar) produced a derivative of semipolar unit (logp=4.9). MP=162 165 C. %yield=88.65. The beauty of reaction shows that www.wjpps.com Vol 5, Issue 11, 2016. 900
diclofenac sodium which is sodium salt that releases free diclofenac during reaction between thionyl chloride in acid environment to get free CH group which then reacts with thionyl chloride to produce acid choride [ C] which then combines with phenolic group [ H] of paracetamol to give Prodrug B [4 (acetylamino)phenyl {2 [(2,6 dichlorophenyl) amino]phenyl}acetate]. [Molecular Formula=C 22 H 18 2 N 2 3, Formula Weight=429.29]. (Solubility=0.1g soluble in 10ml methanol/10ml acetone). [7-9] Figure 5: Histogram of molecular weights of prodrugs. Ibuprofen, diclofenac sodium and paracetamol all are white in colour. Prodrug A [Ibuprofen & Paracetamol] produces off white product. Prodrug B [Diclofenac & Paracetamol] produces dark brown product. Prodrug C [Ibuprofen & Diclofenac] produces light brown product after keeping in refrigerator overnight after addition of ethanol. Prodrug C [N (2,6 dichloro phenyl) [2 ({(2S) 2 [4 (2 methylpropyl)phenyl]propanoyl}amino)phenyl] acetic acid]. MP=162 165 C. %yield=91.32. (Solubility=0.1g soluble in 10ml methanol/10ml acetone). [Molecular Formula=C 27 H 27 2 N 3, Formula Weight =484.41]. This is due to formation of amide linkage ( C ) because ester linkage ( C ) produced the products prodrug A & prodrug B within an hour. The linkage ( C X ; X=/) shows the electronegativity (=3.44 and N=3.04); so ester ( C ) forms faster than amide ( C ) because =3.44 > N=3.04. (Vogel, 1956) www.wjpps.com Vol 5, Issue 11, 2016. 901
Figure 6: Ibuprofen spectral datas H 3 C H www.wjpps.com Vol 5, Issue 11, 2016. 902
IR (cm 1 ; ν): CH: 1725 1700 (1721) CH( ): 2970 2950/2880 2860 Methyl C..H asym./sym. stretch (2980), 1385 1380/1370 1365 gem Dimethyl or iso (doublet) (1380), 1470 1430/1380 1370 Methyl C..H asym./sym. bend (1420) C=C C 1615 1580 Aromatic ring stretch (1510) NMR (ppm): 11.78 (s, CH), 7.48 (s, Ar H), 3.83 (d, Ar CH ), 2.48 (d, Ar CH 2 ), 1.5 (d, CH( ) 2 ) Mass Spectrum: m/e=206 (M+) [fragments=44, 134] Figure 7: Diclofenac sodium spectral datas www.wjpps.com Vol 5, Issue 11, 2016. 903
Na IR (cm 1 ; ν): C 800 700 Aliphatic chloro compounds, (745), C stretch 1725 1700 Carboxylic acid (1720) 3450 Aromatic secondary amine, (3440), stretch C=C C 1615 1580 Aromatic ring stretch (1573) NMR (ppm): 7.58 (d, Ar) Mass Spectrum: m/e=296/298 (M+2) [318 for sodium salt] Figure 8: Paracetamol spectral datas www.wjpps.com Vol 5, Issue 11, 2016. 904
H IR (cm 1 ; ν): 1200 Phenol, C stretch (1200), 3640 3530 Phenols, H stretch (3630) 1680 1630 Amide (1680) 1725 1705 Ketone (1720) 2970 2950/2880 2860 Methyl C H asym./sym. stretch (2870) C=C C 1615 1580 Aromatic ring stretch (1580) NMR (ppm): 7.45 (d, Ar), 6.93 (Ar CH ), 9.43 ( H), 10.1 ( ), 2.04 ( ) Mass Spectrum: m/e=151 (M+) [fragments=109, 44] H 3 C Prodrug=A (MW=339) Prodrug=B (MW=429) www.wjpps.com Vol 5, Issue 11, 2016. 905
H 3 C N H Prodrug=C (MW=484) Figure 9: Prodrug and 3D structures CNCLUSIN Three prodrugs (Prodrug A, Prodrug B and Prodrug C) have been successfully synthesized and have shown different melting points from individual parent drugs (Ibuprofen, Diclofenac sodium and Paracetamol) which indicate the authenticity of fulfillment of prodrug synthesis. IR spectra of Prodrug-C proves the linkage of amide ( C ) formed by acid chloride ( C) of ibuprofen with imino ( ) of diclofenac. www.wjpps.com Vol 5, Issue 11, 2016. 906
H 3 C N Prodrug-C: IR (cm 1 ; ν): Amide ( C ): (standard=1630 1680, found=1735), Ketone (>C=): (standard=1705 1725, found=), Tertiary amino (Peptoid, =N ): (standard: 1150 1210, found=1192), Chlorine ( ): (standard=700-800, found=747, 778), Phenyl ( C6H5): (standard=1615 1580, found=1577), Carboxylic acid ( CH): (standard=1700 1725, found=1734), Methyl (CH3 ): (standard=2970 2950/2880 2860, found=2952) Methyl C H asym./sym. stretch standard=1470 1430/1380 1370, found=1447). Actually Prodrug-A and Prodrug-B both are peptide [ C ] in nature where as Prodrug-C is peptoid in nature [ CN (Ar) ] because amide group is free in Prodrug-A and Prodrug-B to make peptide but hydrogen of amide in Prodrug-C is replaced by aryl ring to make peptoid. H Their solubility parameters also found different from parent drugs. Prodrug is a substance having no medicinal importance but after biotransformation in GIT it releases the parent drug which is able to show the pharmacological activity. ur future goal is to perform in-vitro biotransformation of these prodrugs by acidic and alkaline hydrolysis of both ester ( C ) and amide ( C ) linkages into free drugs and chromatographically separation of their Rt in HPLC. Study of in-vitro biotransformation of prodrugs of ester and amide linkages of ibuprofen, diclofenac sodium and paracetamol in acidic and alkaline medium will be our next target after this project. REFERENCE 1. A.V. Bhosale, G.P. Agrawal and P.Mishra: Preparation and Evaluation of Directly Compressible Forms of Mutual Prodrugs of Ibuprofen Forms of Mutual Prodrugs of Ibuprofen. Indian Journal of Pharmaceutical Sciences, 2006; 68(4): 425-431. 2. B.C. Ghodeswar, R.N. Pophalikar, M.R. Bhojani, D. Nagpal and S. Dhaneshwar, Indian Journal of Pharmaceutical Sciences., 2004; 66: 773. 3. K. Koren, A.R. Mann, A.L. Colosimo, Z. Diaz, A. Nuclelman, I. Levovich, Y. Jing, S. Waxman and W.H. Miller, Jr., Mol. Cancer Res., 2003; 1: 903. www.wjpps.com Vol 5, Issue 11, 2016. 907
4. J.E. Slemmer, B.R. Martin and M.I. Damaj. Bupropion is a nicotinic antagonist. J. Pharm. Exp. Ther., 2000; 295: 321 327. 5. C. Wu, J. Quan, J. Xie, C Branford-White, L. Zhu, Y. Yu and Y. Wang. Preparation and controlled release of degradable polymeric ketoprofen-saccharide conjugates. Polym Bull., 2011; 67: 593 608. 6. M, Babazadeh and T. Mosanejhad, Vinyl ester type polymers containing ibuprofen pendents: synthesis, characterization and evaluation. Iran Polym J., 2009; 18: 179 186. 7. L. Shargel, Susanna Wu-Pong and B.C. Andrew, Applied Biopharmaceutics & Pharmacokinetics, 6 th Ed.McGraw-Hill Medical Publishing Division, US., 2012; 47-66, 129-154. 8. S. Shirke*, S. Shewale and M. Satpute, Prodrug design: an overview. International Journal of Pharmaceutical, Chemical and Biological Sciences., 2015; 5(1): 232-241 9. A.I. Vogel, A textbook of practical organic chemistry, 3 rd edition, Longmans, Green and Co, Ltd, London, 1956; 791: 361. www.wjpps.com Vol 5, Issue 11, 2016. 908