STUDY OF IN-VITRO BIOTRANSFORMATION OF PRODRUGS OF ESTER AND AMIDE LINKAGES OF IBUPROFEN, DICLOFENAC SODIUM AND PARACETAMOL IN ACIDIC AND ALKALINE MEDIUM

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ABOUT AUTHOR
Dhrubo Jyoti Sen
Department of Pharmaceutical Chemistry,
Shri Sarvajanik Pharmacy College,
Mehsana, Gujarat, India
dhrubosen69@yahoo.com

ABSTRACT: Our goal is to perform in-vitro biotransformation of Prodrugs of ibuprofen+paracetamol, diclofenac sodium+paracetamol and ibuprofen+diclofenac sodium by acidic and alkaline hydrolysis of both ester (–COO–) and amide (–CONH–) linkages into free drugs and chromatographically separation of their Rt in HPLC. Since both ester (–COO–) and amide (–CONH–) linkages are susceptible for hydrolysis in both acidic pH (gastric pH) and basic pH (intestinal pH) to produce parent drug ibuprofen, diclofenac and paracetamol by biotransformation in in-vivo; so it will be implemented as a Prodrug which can show prolong action on pain and fever after getting release into free parent drug by biotransformation. The HPLC (High Performance Liquid Chromatography) study reports the retention time (Rt) and release kinetics of three Prodrugs by taking HPLC degradation datas of three samples of Prodrugs and individual HPLC datas of parent drugs separately to compare the Rt value of release of three drugs from Prodrugs in both acidic and alkaline pH. Prodrug–A (logP=4.56) releases Ibuprofen & Paracetamol, Prodrug–B (logP=4.90) releases Diclofenac & Paracetamol and Prodrug–C (logP=6.13) releases Ibuprofen & Diclofenac. This is a comparison study of drug release in in-vitro gastric as well as intestinal pH focusing on in-vivo biotransformation.  Keywords: Prodrug-A/Prodrug-B/Prodrug-C, Ibuprofen, Paracetamol, Diclofenac sodium, Molecular weight, logP, UV λmax, IR, Mobile phase, TLC-Rf value, HPLC-Rt value, LOD, LOC

REFERENCE ID: PHARMATUTOR-ART-2522

PharmaTutor (Print-ISSN: 2394 - 6679; e-ISSN: 2347 - 7881)

Volume 5, Issue 8

Received On: 23/05/2017; Accepted On: 23/05/2017; Published On: 01/08/2017

How to cite this article: Sen DJ;Study of in-vitro biotransformation of prodrugs of Ester and Amide linkages of Ibuprofen, Diclofenac Sodium and Paracetamol in acidic and alkaline medium; PharmaTutor; 2017; 5(8); 49-65

INTRODUCTION: 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 indicates the authenticity of fulfillment of Prodrug synthesis. [Jalpa G. Patel and Prof. Dr. Dhrubo Jyoti Sen; Synthesis of Prodrug of ester and amide linkages of NSAID having carboxylic acid, phenolic and imino groups: World Journal of Pharmacy and Pharmaceutical Sciences: 5(11), 897-908, 2016. (ISSN: 2278-4357, Impact Factor: 6.647, Index Copernicus Value: 52.51); Dhrubo Jyoti Sen and Jalpa G. Patel; Logarithmic partition coefficient comparison study and molecular weight of synthesized Prodrugs of ibuprofen+paracetamol, diclofenac sodium+paracetamol and ibuprofen+diclofenac sodium: American Journal of Advanced Drug Delivery: 4(05), 064-068, 2016. (ISSN: 2321-547X, Impact Factor: 0.786)].[1,2]

Figure-1: Prodrugs

The synthesized Prodrugs were characterized by m.p., logP values and IR (Infra Red) spectrum for structural identification. 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.[3-5]

 

Ibuprofen [C13H18O2; 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).
Diclofenac sodium [NaC14H10Cl2NO; 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 [C8H9NO2; 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).

Experimental part:
Mobile phase of TLC values has been selected after trial and error for all individual NSAID (ibuprofen, diclofenac sodium  and paracetamol) according to their logP and Rf values have been determined and after that Rf values have been obtained for all three Prodrugs (Prodrug-A, Prodrug-B, Prodrug-C). Mobile phase solvent ratio of TLC helped to select the mobile phase selection for HPLC.[6-8] The values are as follows:


 

UV maximum Absorbance (Prodrug-A)

UV maximum Absorbance (Prodrug-B)

UV maximum Absorbance (Prodrug-C)
 

Figure-2: λmax of Prodrugs


Samples


Molecular Formula


% yield


Melting Point (°C)


Molecular Weight


λmax (nm)


logP


Prodrug-A


C21H25NO3


83.67


152–155°C


339


275


4.56


Prodrug-B


C22H18Cl2N2O3


88.65


220–222°C


429


262


4.90


Prodrug-C


C27H27Cl2NO3


91.32


100–105°C


484


276


6.13

Table-1: Physicochemical parameters of Prodrugs

Solubility study of Prodrug-A, Prodrug-B and Prodrug-C:
The solubility of Prodrug-A, Prodrug-B and Prodrug-C were practically determined. Solubility was determined by taking 100mg of Prodrug-A, Prodrug-B and Prodrug-C respectively in 10ml volumetric flask, adding required quantity of solvent at room temperature and shaken for few minutes.[9-11] Solubility data for each study was observed and recorded in Table-2.

Solvent

Solubility

Water

Prodrug-A: Soluble, Prodrug-B: Insoluble, Prodrug-C: Slightly soluble

Methanol

Freely soluble

Acetone

Freely soluble

Table-2: Solubility parameters of Prodrugs

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