Abstract: The aim of the present study is to enhance the solubility and stability of drugs in addition of water-soluble polymer and carbohydrate complexes. The data show that the polymer polyvinyl alcohol (PVA) interacts with the free Lamivudine and with the Lamivudine; β-cyclodextrin (β-CD) inclusion complex, in both cases with particular intermolecular interaction was studied using ultrasonic technique under different concentrations at a temperature 303 K. Consequently, the reason of this study was to improve the biological performance of the drug through enhancing its solubility and stability. The binary and ternary mixtures prepared inclusion complexes of Lamivudine in β-CD and PVA. The presence of PVA, changes the drug: β-CD interaction, a Lamivudine: β-CD: PVA complex was formed. In addition, the presence of PVA produces a strong increase in the binding constant at a particular concentration (1.25%). In the ternary complex, the Lamivudine is wrapped at both ends for the β-CD. In this complex, the polymer seems to act as a bridge between both β-CD molecules that bind the Lamivudine.
INTRODUCTION
Inclusion complexation with ß-cyclodextrins (ß-CD) has been widely exploited to improve solubility and stability, of various drug molecules (Uekama et al., 1998). Lamivudine (L-2`, 3`-Dideoxy-3`-thiacytidine) (Scheme 1) is a potent reverse transcriptase inhibitor of the class of Nucleoside Analogue Reverse Transcriptase Inhibitors (NARTI) (Sweetman, 2002). It has been used for the treatment of human immunodeficiency virus type 1 (HIV-1), which causes the acquired immunodeficiency syndrome (AIDS) (Siegfried et al., 2006) and of chronic (Manas Garcia et al., 2005) and acute (Torii et al., 2002) hepatitis B (HBV). However, the efficiency of complexation is often not very high and therefore, relatively large amounts of ß-CD must be used to obtain the desired effect (Loftsson and Brewster, 1996). On the other hand, for a series of reasons including cost, production capacity, possible toxicity, problems of formulation bulk, etc., pharmaceutical dosage forms should contain as small amounts of ß-CD as possible (Kagathara et al., 2000). When polyvinyl alcohol (PVA) (Scheme 2) was added, all the data clearly show that the effect of the polymer on the complexing ability of ß-CD (Scheme 3) depends on the nature of the ß-CD and the polymer interactions between both of them. The nature and the interactions of the components in the ternary complex, also change the chemical behavior of the drug. The addition of a third component such as water-soluble polymers enhances the efficiency of drug-cyclodextrine complexation. This solubilization enhancement is synergistic (Loftsson et al., 1994; Ganzerli et al., 1996).
| Scheme 3: |
The chemical structure of
ß-cyclodextrin (ß-CD) |
MATERIALS AND METHODS
Materials:
Lamivudine (Sigma, USA) a sparingly soluble drug
with the formula C8H11N3O3S,
molecular weight (229.26 g mol-1) Polyvinyl alcohol was obtained
from (Fluka AG Switzerland) with the formula-OH(-CH2-CH-)n-M.W
125000 g mol-1. ß-cyclodextrin (ß-CD) (M.W 1135.01 g mol-1)
was purchased from (E. Merck, Germany) stated by the manufacturers. These
reagents were considered sufficiently well characterized by the manufacturer
to be used without further purification. Conductivity water was used for
the preparation of all aqueous solutions.
Methods: Initially, three concentrated aqueous solutions were prepared: (1) Lamivudine/H2O: prepared as described above. (2) Lamivudine/PVA/H2O: prepared by weighing the required amount of PVA, using the aqueous drug solution (1) as solvent. (3) Lamivudine/ß-CD/PVA/H2O: prepared by weighing the required amount of ß-CD, using the aqueous drug/polymer solution (2) as solvent. Solutions with variable PVA concentrations were obtained by successive dilution of (2) with (1). Solutions with variable ß-CD concentrations and constant PVA content were obtained by successive dilution of (3) with (2). All measurements were carried out at room temperature of 303 K.
Ultrasonic measurements: The ultrasonic velocity, density and viscosity of these solutions were measured. Ultrasonic velocity was measured using single-crystal continuous wave interferometer (Mittal Enterprises, New Delhi) operating at 3 MHz with an accuracy of ±0.05%. The densities were measured using specific gravity bottle and viscosity is measured using Ostwald`s viscometer to an accuracy of ±0.2 parts in 104 and ±0.2%, respectively.
Using the measured date, the acoustical parameters such as adiabatic compressibility (ß) and internal pressure (pi), have been calculated using the following standard expressions given in our previous paper (Ramesh et al., 2006).
| • | Adiabatic compressibility |
| • | Intermolecular free length |
| • | Internal pressure |
| [K-Boltzman constant, b-Cubic packing factor, R-Gas constant, T-Absolute temperature, M-Effective molecular weight] | |
| • | Solvation number |
RESULTS AND DISCUSSION
Ultrasonic analysis: Using the measured values of ultrasonic velocity, density and viscosity of the solutions, other acoustical parameters viz., adiabatic compressibility, intermolecular free length, internal pressure and solvation number are calculated and are shown in Table 1 and 2. Ultrasonic velocity increases with increase in concentration of drug, carbohydrate and polymer in water. Density and viscosity increases with the concentration in carbohydrate and polymer in aqueous solutions. Adiabatic compressibility (ß) and intermolecular free length (Lf) decreases with increase in concentration of drug, carbohydrate and polymer mixture. Internal pressure (pi) decreases with increase in concentration of polymer. Solvation number decreases with increase in concentration of drug, carbohydrate and polymer.
In all the three systems studied, the velocity is gradually increasing
with concentration at room temperature shown in the Table
1 and 2. The variation in velocity is much higher
in the ß-cyclodextrin-water system and PVA-water it is due to the formation
of intermolecular hydrogen bonding between the molecules. This behaviour
may be explained as follows: the molecules of drug and polymer/carbohydrate
(Table 2) are randomly coiled in solution and the chains
have no overall tendency to adapt to any particular conformation (Geetha
and Rakkappan, 2003). Dissolved macromolecules
| Table 1: |
Ultrasonic velocity and related
acoustical parameters in the aqueous solution of lamivudine,
polyvinyl alcohol, ß-cyclodextrine at 303 K |
| Table 2: |
Ultrasonic velocity and related
acoustical parameters in the aqueous solution of lamivudine
(1 %) + polyvinyl alcohol, ß-cyclodextrine (1 %) + polyvinyl
alcohol, ß-cyclodextrine (1 %) + polyvinyl alcohol (1%) + lamivudine
at 303 K |
frequently find molecular association complexes either with species of low molecular weight solvent with other macromolecules. The Lamivudine-water, PVA-water and ß-CD-water interaction due to hydrogen bonding is a major source of ultrasonic relaxation. The mechanism should produce the increase in density and ultrasonic velocity with increase in concentration (Sundaresan and Srinivasa Rao, 1994; Geetha and Rakkappan, 2005a). These measurements suggested the formation of a more rigid structure as a function of concentration, possibly due to bonding of polymer and carbohydrate molecules to water at its carboxyl sites (Jin et al., 1995).
In the hydrogen bonded systems, the intermolecular free length, internal pressure decreases with increase of hydrogen bond strength. The decrease in the value of adiabatic compressibility and inter-molecular free length with increase in concentration at room temperature further supports the interaction between the solute and solvent. Density and viscosity increases with the concentration in drug, carbohydrate and polymer in aqueous solutions.
The positive value of Sn indicates the structure-forming tendency of the carbohydrate and polymer. The resultant value of the Sn depends upon solvent-solute and solute-solute interactions occurring in the solution (Kagathara et al., 2000; Geetha and Rakkappan, 2005b). Increase in Sn with concentration indicates predominant solvent-polymer interaction. Thus, dipole-dipole interaction of the opposite type profoundly favours the solvating tendency.
The above, mentioned results reveal that the ternary system Lamivudine-ß-CD-PVA improves significantly the therapeutic efficacy of the drug at 1.25% concentration.
ACKNOWLEDGMENTS
The authors are thankful to Dr. AN. Kannappan, Professor and Head, Department of Physics, Dr. C. Rakkappan, Professor, Wing Head (DDE) and Dr. P.S. Ramesh, Lecturer, DDE Physics, for encouraging them to take up these studies.