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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 7  |  Issue : 3  |  Page : 80-86  

Conductometric and volumetric studies of atorvastatin in aqueous solution of arginine from 298.15 to 313.15 K


1 Laboratory Fundamental of Pharmaceutics, Faculty of Pharmacy; Pharmaceutical and Life Sciences Core, Universiti Teknologi MARA, Shah Alam, Selangor Darul Ehsan, Malaysia
2 Pharmaceutical and Life Sciences Core, Universiti Teknologi MARA, Shah Alam, Selangor Darul Ehsan, Malaysia

Date of Web Publication23-Jun-2016

Correspondence Address:
Minaketan Tripathy
Laboratory Fundamental of Pharmaceutics, Faculty of Pharmacy, Universiti Teknologi MARA, 42300 Bandar Puncak Alam, Selangor
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-4040.184589

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  Abstract 

Categorized as a Biopharmaceutics Classification System Class II drugs, atorvastatin (ATV) exhibits low aqueous solubility and bioavailability thus presenting an obstacle and great challenge to formulation researchers. Numerous studies are available in regard to the solubility enhancement of ATV, but very few actually describe this phenomenon in terms of thermodynamics and the solute-solvent interaction. Arginine (ARG) is an amino acid that has been reported to enhance the solubility of the highly insoluble wheat protein gluten through hydrogen bonding and π electron-cation interaction. To our knowledge, ARG has never been investigated as a solubility enhancement agent of aqueous insoluble drugs. Thus, this study aimed to elucidate the solute-solvent and solute-cosolute interactions and derive thermodynamic parameters that bolstered the solubility of ATV in the presence of ARG. We examined the electrolytic conductance and densities of ATV-ARG binary system covering the temperature ranging from 298.15 K to 313.15 K. Conductometric and volumetric parameters such as limiting molar conductance, association constants, limiting partial molar volumes, and expansibility values were calculated. Additionally, thermodynamic parameters (ΔG0, ΔH0, ΔS0, and Es) involved in the association process of the solute in the aqueous solution of ARG were also determined.

Keywords: Atorvastatin-arginine, binary system, conductometric, volumetric


How to cite this article:
Affandi MM, Tripathy M, Majeed A. Conductometric and volumetric studies of atorvastatin in aqueous solution of arginine from 298.15 to 313.15 K. J Adv Pharm Technol Res 2016;7:80-6

How to cite this URL:
Affandi MM, Tripathy M, Majeed A. Conductometric and volumetric studies of atorvastatin in aqueous solution of arginine from 298.15 to 313.15 K. J Adv Pharm Technol Res [serial online] 2016 [cited 2020 Aug 15];7:80-6. Available from: http://www.japtr.org/text.asp?2016/7/3/80/184589


  Introduction Top


Drugs with poor aqueous solubility characteristics have become one of the main technical issues highly discussed among pharmaceutical scientists. More than 70% of drug candidates and 40% of new chemical entities are poorly soluble or insoluble in water.[1],[2] Atorvastatin (ATV), an inhibitor of 3-hydroxy-3-methlyglutaryl coenzyme A reductase is a member of statins, which are lipid lowering agents that have been widely used in the treatment of hypercholesterolemia. ATV has very good intestinal permeability but poor bioavailability due to its low aqueous solubility, crystalline nature, and exposure to hepatic first pass metabolism.[3] There are various approaches in which solubility of ATV can be enhanced. These include solid dispersion,[4],[5],[6] size reduction,[7] and use of surfactants.[8]

Arginine (ARG) (2-amino-5-guanidinopentanoic acid) is a conditional essential or semi-essential amino acid which plays an important role in several metabolic pathways in the human.[9] It has been reported to have a positive impact on hypertension,[10],[11] reproductive physiology [12] muscle strength and mass,[13] renal and immune function,[14],[15] and the release of growth hormone.[16] The role of ARG in solubility enhancement of proteins has been expansively reported by several researchers.[17],[18] It is thought to increase the solubility of protein by disrupting the protein–protein and protein-surface interaction.[18]

The usage of ARG as a solubility enhancer for aqueous insoluble compounds and small molecules had been previously reported [18],[19] which revealed that ARG was bound to the aromatic group of the drug through a π electron-cation interaction.[18],[19] Although the role of ARG as a solubility enhancer has been described in detail by these authors, however, the fundamentals of the molecular interaction and thermodynamics involved in the binary mixture are still rather scarce in the current literature. Fundamental properties such as conductometric and volumetric studies at different temperature provide insight into the molecular interactions that occur in the binary mixture. In addition, this information contributes to a better understanding of the behavior of each component in the binary mixture. In this study, we investigated the conductometry and volumetry of several concentrations of ATV-ARG binary solution mixture at temperature of 298.15, 303.15, 308.15, and 313.15 K. Parameters related to this study such as association constants (KA), limiting molar conductance (Λ0), molar volume (Φv0), molar expansibility (ΦE0), and related thermodynamic parameters (ΔG 0, ΔH 0, ΔS 0 and Es) were computed. These parameters were used to deliberate the possible solute-solvent, solute-cosolute, and solvent-solvent interaction, the behavior of liquid systems, structure making, and structure breaking phenomena and related structural changes.[20],[21]


  Materials and Methods Top


Materials

ATV calcium was a gift from Hovid Berhad (Ipoh, Perak, Malaysia). ARG was purchased from Sigma Aldrich (St. Louis, MO, USA) while ethanol and methanol were purchased from HMBg Chemical (Germany). The water used was obtained from Select Bio O Purite (Oxfordshire, United Kingdom) water system. All other chemicals and reagents used in this study were of analytical grade unless otherwise stated.

Methods

Conductometric study

The electrical conductivity of each sample was measured with a cyber-scan conductivity meter with an accuracy of ± 0.5% and a conductivity cell (Model PC-510 – Eutech Instruments). The conductance cell was equipped with water circulating jacket, and the temperature was controlled within ± 0.02 K with a low-temperature thermostat. The cell constant is 1.01/cm, which was calculated by repeated measurements of KCl solutions. All data were corrected with specific conductivity of pure water at the experimental temperatures of 298.15 and 313.15 K. Six data points were recorded for each sample and results reported were mean values. Further, these data were used to define the equivalent conductance of the samples.

Volumetric study

The solution density of the blank, as well as solutions containing saturated concentrations of ATV at 4 different temperature ranging from 298.15- to 313.15 K, was determined with an Anton Paar digital density meter (Model DMA 60/602). An efficient constant temperature bath with stability within ± 0.02 K was used to regulate the temperature of water around the density meter cell. The density meter was calibrated daily at 298.15 K using dry air and water with conductivity of <1.0/μΩ/cm. All density measurements of the solutions were made relative to pure water. Densities of pure water at the experimental temperatures were taken from the literature.[22]


  Results and Discussion Top


Conductometric studies

The experimental value of specific conductance (Κ, µSm/cm) of ARG system in different molar concentrations, i.e., 0.1–7.34 mol/dm 3 saturated with ATV and the blank at 298.15, 303.15, 308.15, and 313.15 K was measured and presented in [Table 1] and [Table 2]. The molar conductance (Λ, Sm/cm) for all studied systems was evaluated using the following Equation 1:
Table 1: Specific conductance (κ), molar conductance (Λ), limiting molar conductance (Λ0) and activation energy for each system (Es) of arginine at different concentration and temperature

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Table 2: Specific conductance (κ), molar conductance (Λ), limiting molar conductance (Λ0) and activation energy for each system (Es) of arginine solution system with saturated presence of atorvastatin

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Λ =1000 Κ/C(1)

where C is the molar concentration and Κ is the measured specific conductance of the studied systems after solvent correction.

The limiting molar conductance (Λ0) of the ARG system in the presence of ATV was derived from Equation 2 which is based on the Kohlrausch expression.[23]

Λ0= Λ + b(2)

where b is a constant.

Values of molar conductance and limiting molar conductance are summarized in [Table 1] and [Table 2]. Further, these values were used to determine the degree of dissociation (α), which was assimilated into the mass action law for the ion association (KA) in the form of Equation 3.[24]

KA = 1−α/α2 c f±2(3)

where f ± is the mean activity coefficient. The values of KA of ARG system in the presence and absence of ATV at 298.15 K are presented in [Table 3] and [Table 4].
Table 3: Ion association (KA) of arginine at different concentrations and temperatures

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Table 4: Ion association (KA) of arginine solution system with saturated presence of atorvastatin at different concentration and temperature

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Results presented in [Table 1]and [Table 2] illustrate that the calculated molar conductance Λ of aqueous molar solutions of ARG in the absence and saturated presence of ATV decrease with the increase of ARG concentration. The increase in ARG concentration was due to the formation of ion pairs which promote stronger ion association thus decreasing molar conductivity. Further, the increase in ARG concentration resulted in a strong interaction between water molecule ions and −NH2 charged end group of ARG. In addition, in saturated presence of ATV the molar conductivity values increased as compared to their counterparts without ATV. The above observation can be ascribed to the fact that reduced microscopic viscosity decreases the frictional coefficient of the medium and increases the species mobility. This phenomenon was due to a preferential interaction between the solute ATV and cosolute ARG in water hence increasing the solubility of the former. Additionally, the preferential affinity of ARG to ATV reduces the attraction between ARG ions and water molecules causing a decrease in hydrodynamic radii of these ions and an increase in their mobility.

[Table 1] and [Table 2] show that the values of Λ0 of ATV are high in the aqueous solution of ARG. The higher Λ0 value of ATV can be attributed to the similar point of analogy as in the case of the molar conductance.[25] It can be seen from [Table 1] and [Table 2] that Λ0 of ATV and aqueous ARG solution increases with a rise in temperature which indicates less solvation or higher mobility of ions. In addition, an increased in thermal energy results in greater bond breaking and variation in vibrational, rotational, and translational energy of the molecules that leads to higher frequency and higher mobility of the ions.[26],[27]

[Table 3] and [Table 4] show that the association constant (KA) of ARG increases with a concentration in the presence or absence of ATV. This was in line with the earlier claim which stated that the increase in ARG concentration resulted on the formation of ion pairs in the dilute region and possibly led to an increase in ion association. Additionally, it is interesting to note that at higher concentrations of ARG with saturated presence of ATV (S5 and S6) the KA value decreases with the increased concentration of ARG. This phenomenon can be explained by the fact that at higher concentration of ARG more and more ATV will be bound with ARG resulting in the reduced attraction between the ions of the ARG and water molecules.[28]

Since the conductance measurements of an ion depend upon mobility,[29] it is quite reasonable to treat the conductance data similar to the one employed for the rate process taking place with the change of temperature (Equation 4):

Λ0 = A e − Es/RT (or) logΛ0 = log A − Es/2.303RT(4)

where A is the frequency factor, R is the gas constant, and Es is the Arrhenius activation energy of the transport process. The Es values were computed from the slope (=−Es/2.303R) of logΛ0 vs. 1/T plot and recorded in [Table 1] and [Table 2].

The free energy change, ΔG 0 for the association process is derived from Equation 5:

ΔG 0 = −RT ln KA(5)

The heat of association Δ H 0 is determined from the slope of the plot of ln KA versus 1/T and the entropy change, ΔS 0 from Gibbs–Helmholtz Equation 6:

ΔG 0 = ΔH 0 − T ΔS 0(6)

The values of ΔG 0, ΔH 0, and ΔS 0 at 298.15 K–313.15 K are presented in [Table 5] and [Table 6].
Table 5: Gibbs free energy (ΔG0), entrophy (ΔS0), and entalphy (ΔH0) of arginine at different concentrations and temperatures

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Table 6: Gibbs free energy (ΔG0), entrophy (ΔS0), and entalphy ΔH0 of arginine solution system with saturated presence of atorvastatin

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As presented in [Table 1] and [Table 2], the values of ES are positive at all experimental concentration of ARG either in the absence or saturated presence of ATV. The negative ΔG 0 values for the systems of ARG with and without ATV indicate that the association process predominates over the dissociation process. It is interesting to note that for the system of ARG, the association is endothermic for all concentrations whereas there is no specific trend observed in the ARG system saturated with ATV. Depending on the concentration of ARG in the system, the association process is either endothermic or exothermic. Values of ΔS 0 are found to be positive indicating the disorderedness of the solubilized species and its highly hydrated nature.

Volumetric studies

Density value along with limiting apparent molar volume (Φv0) and limiting apparent molar expansibility (ΦE0) value of the ARG solution system in the absence and saturated presence of ATV in water at T= (298.15, 303.15, 308.15, 313.15) K are given in [Table 7]. Values of Φv0 and ΦE0 were obtained from the intercept of the plot of Φv versus C ½ and of ΦE versus C − 1, respectively, which was in turn derived from the experimentally measured densities (Equations 7 and 8).
Table 7: Limiting apparent molar volume (ΦV0), limiting apparent molar expansibility (ΦE0), SV and SE constance of arginine, arginine solution system with saturated presence of atorvastatin (ATV-ARG)

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Φv = 1000(Cd0)−1 (d0–d) + M2/d0(7)

and

ΦE= αΦv0+ (α–α0) 1000C −1(8)

where C is the molar concentration of the solute, d0 is the density of pure water, d is the density of the solution, M2 is the molecular mass of the solute and α0 and α are the coefficients of expansion of the solvent and solution (with or without drug), respectively, and determined by means of the relation available in the literature.[30]

The Φv and ΦE showed linear dependence with square root of concentration and were found to obey the linear equation, Equations 9 and 10:

Φv= Φv0 + Svc 1/2(9)

and

ΦE= ΦE0 + SEc −1(10)

Values of SV and SE obtained from slopes of the corresponding plots are also given in [Table 7]. Results presented in [Table 7] illustrate that at the experimental temperature the values of Φv0 are positive for the ARG systems in the absence and presence of ATV. The positive values of Φv0 indicate strong drug-solvent interactions. Furthermore, a rise in temperature resulted in an increase in the ion-solvent and the solute-solvent interactions except at 311.15 K. This phenomenon promotes the structure making the effect of the ATV in aqueous ARG systems.

As observed, SV values are positive at the lower temperature except for ARG systems in the presence of ATV at 298.15 and ARG system at 303.15 K. The negative values of Sv at the higher temperature in all cases of ARG and ATV-ARG recommend the absence of ion-ion or solute-solute interaction in the system. Moreover, it is seen that values of SV for the system in the presence of ATV are higher as compared to those ARG only systems which indicate that the solvent structure is not too much enhanced in the presence of the drug.

The standard partial molar volume of transfer, ΔtΦv0 at infinite dilution of ATV from water to aqueous ARG was determined from Equation 11:

ΔtΦv0 = Φv0 (in aqueous ARG solutions) − Φv0 (in water) (11)

It is seen that at the experimental temperature the values of ΔtΦv0 are positive for all systems and decrease with a rise in temperature. This is because the dehydration of ions (the cation and anion of the ARG) and drug (ATV) molecules have taken place in the system. Moreover, the destructive overlap of cospheres resulting in a net decrease in salvation thereby increasing the solute (drug) volume, and because of the strong interactions between the drug and the ARG the latter loses its effect on the water structure.[27]

Values of ΦE0 are low but positive for all the systems at all temperature except in the case of ARG at 298.15 K and vary irregularly with the increase in temperature. However, values of ΦE0 in the presence of ATV indicate the presence of a caging or packing effect [31] supporting the earlier argument that the solvent structure is not too much enhanced.


  Conclusion Top


An extensive study of conductometry and volumetry of ATV-ARG binary solution system at different temperature has been conducted. It can be seen that the molar conductance, Λ, of an aqueous solution of ARG in the absence and saturated presence of ATV decreases with the increase of ARG concentration. Conversely, the molar conductivity is enhanced in ARG systems saturated with ATV as compared to their counterparts without ATV. It is also interesting to note that the values of limiting apparent molar volume (Φv0) are positive for the ARG systems in the absence and presence of ATV at the experimental temperature. Based on the various evaluated volumetric and conductometric parameters, it is concluded that there is a strong solute-solvent, solute-cosolute, and solute-solute interaction taking place in the ATV-ARG binary solution system.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]


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