Preformulation Studies of Zidovudine Derivatives: Acid Dissociation Constants, Differential Scanning Calorimetry, Thermogravimetry, X-Ray Powder Diffractometry and Aqueous Stability Studies

Mónica A Raviolo

doi:10.3797/scipharm.1105-04

Abstract

As part as of the preformulation studies of new 5′-OH derivatives of zidovudine, compounds 2–6, their acid dissociation constants, Differential Scanning Calorimetry (DSC) and Thermogravimetry (TG) curves, X-Ray Powder diffractograms and aqueous stability are reported. A sensitive technique such as differential scanning potentiometry was used to determine the pKa constants of the above mentioned compounds. In addition, pKa values were calculated from theoretical methods, and no significant differences with those of experimental ones were observed. X-Ray Powder Diffractometry data demonstrated that compounds 2–4 were crystalline while 5 and 6 were amorphous. DSC analysis indicated that all of them presented an exothermic decomposition peak above 150 °C which is accompanied by a weight loss in the respective TG curves. The stability of these compounds in aqueous medium at different pH values was investigated, using a validated High Performance Liquid Chromatography (HPLC) method, which demonstrated to be rapid, selective, sensitive, accurate and stability-indicating. Good recovery, linearity and precision were also achieved. For all compounds the aqueous hydrolysis followed a pseudo-first-order kinetics, depending on pH and the union existing between AZT and the associate moiety. The hydrolysis was catalyzed by hydroxide ion in the 7.4–13.2 pH range, while all compounds exhibited pH-independent stability from acidic to neutral media (pHs 1.0–7.4).

Highlights

Acquired immunodeficiency syndrome (AIDS) results from infection by the retrovirus, human immunodeficiency virus (HIV-1) [1]. 3’-Azido-3’-deoxythymidine, the first clinically successful nucleoside analog for the treatment of AIDS, is a potent nucleoside reverse transcriptase inhibitor (NRTI) of HIV-1 replication [2], when used in combination with other drugs, such as other NRTIs, non-nucleoside reverse transcriptase and protease inhibitors [3]
Nucleoside analogues continue to play a prominent role as antiviral agents [4], their therapeutic potential is often hampered by their poor biopharmaceutical properties [5]
As part of our ongoing efforts to search for novel antiviral agents, we developed AZT derivatives with anti HIV activity, modifying the 5’-OH position of AZT which could form a reservoir of the drug in different human tissues, requiring less frequent dosing [6,7,8,9,10,11]

Summary

Introduction

Acquired immunodeficiency syndrome (AIDS) results from infection by the retrovirus, human immunodeficiency virus (HIV-1) [1]. 3’-Azido-3’-deoxythymidine (zidovudine, AZT, 1), the first clinically successful nucleoside analog for the treatment of AIDS, is a potent nucleoside reverse transcriptase inhibitor (NRTI) of HIV-1 replication [2], when used in combination with other drugs, such as other NRTIs, non-nucleoside reverse transcriptase and protease inhibitors [3]. As part of our ongoing efforts to search for novel antiviral agents, we developed AZT derivatives with anti HIV activity, modifying the 5’-OH position of AZT which could form a reservoir of the drug in different human tissues, requiring less frequent dosing [6,7,8,9,10,11]. Parameters obtained from preformulation studies are essential to understand the biological activity of drugs, by depicting a more accurate picture of the macromolecule-ligand binding interaction. Through these studies, it is possible to derive valuable information on different properties of drugs [12,13,14]. Differential Scanning Potentiometry (DSP) yields areas as analytical responses, thereby enhancing its sensitivity for determining weak acids and bases in aqueous systems [16, 17]

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