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Original article
2021
:14;
202108
doi:
10.1016/j.arabjc.2021.103265

Viscometric and FTIR studies of chloroquine phosphate, acefylline piperazine and gentamicin sulfate in aqueous-polyethylene glycol and aqueous-polyvinyl pyrrolidone at different temperatures

Department of Chemistry, University of Karachi, Karachi 75270, Pakistan
Department of Materials and Metallurgical Engineering, NED University of Engineering and Technology, Karachi 75270, Pakistan
Department of Chemistry, Federal Urdu University of Science, Arts &Technology, Gulshan-e-Iqbal, Karachi, Pakistan
Department of Chemistry, Shaheed Benazir Bhutto Women University, Peshawar, Pakistan
Department of Chemistry, University of Malakand, Chakdara Dir Lower, Pakistan

⁎Corresponding authors at: Department of Chemistry, University of Karachi, 75270 Karachi, Pakistan. warda28rehman@yahoo.com (Warda Rehman), smasood@uok.edu.pk (Summyia Masood)

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Abstract

This paper aimed to study the effect of aqueous, aqueous polyethylene glycol (1.0 %w/v) and aqueous polyvinyl pyrrolidone (1.0 %w/v) on the physicochemical behaviour of three pharmaceuticals substantial drugs by viscosity method. Viscosity measurements of the drugs (chloroquine phosphate, acefylline piperazine and gentamicin sulfate) solutions were performed within concentration ranges from 2.0 × 10−2 to 10.0 × 10−2 ± 0.001 mol.dm−3 at varying temperatures (293.15, 298.15, 303.15, 308.15, 313.15 and 318.15 ± 0.01 K). The viscosity data used to interpret the interactions (drug-drug and drug-solvent) existing in the solutions of drugs in terms of ‘A’ and ‘B’ coefficients of Jones–Dole equation respectively. Temperature derivatives of the B-coefficient (dB/dT) were also calculated which help to establish the relation between the nature of the solute and the structural modifications in the solution. Hence, the structure promoting ability of the AP in aqueous system and structure destroying effect of CP, AP and GS in the aqueous-polymeric system was observed. The FTIR studies of CP, AP and GS show that the chemical identity of the drug was not affected by the polymers and no binding of the new forming compound was detected.

Keywords

Viscosity B-coefficient
FTIR
Chloroquine phosphate
Acefylline piperazine
Gentamicin sulfate
Structure promoting/destroying effect
1

1 Introduction

Physicochemical properties have great importance in physical chemistry, geochemistry, pharmaceutical chemistry and medicinal chemistry. The physicochemical behaviour of a drug in an aqueous solution is considered to be not only significant in understanding the pattern of molecular aggregation, complication but also describes the drug mechanism that followed by a drug to reach and interact with the biological system at targeted sites. The absorption, transport, distribution and biological response of a drug at active sites can also be anticipated by an understanding of the interactions at molecular levels. These molecular interactions (solute–solute and solute–solvent) include charge transfer, ionic or covalent, ion–dipole interactions, hydrogen bonding, and electrostatic (due to the presence of hydrophobic or hydrophilic moieties) interactions. Since the biological activity of drug molecules depends on the type and strength of the intermolecular interactions, so the knowledge about these interactions between drug and solvent and their temperature dependence play a significant role in elaborating the physiological action of drug solutions in five (Saeed et al., 2007)(Masood et al., 2020a)(Masood et al., 2020b). Transport property measurements are conducive to elucidate the physiological action of the drug by providing systematic knowledge about the drug's behaviour in the solution. The transport properties such as viscosity provide understanding about the solute–solvent, solute–solute and solvent–solvent interactions in the solution phase, which also correlate with the structure, promoter (kosmotropes) and breaker (chaotropes) of the solute and solvent. The effectiveness, absorption and pharmacological activities of the drug in the human anatomy will directly relate to the viscosity measurements of the drug solutions leading to its metabolic and physical activities across biological membranes. For understanding the nature of different component of their physicochemical interaction viscometric technique can be considered as the most steadfast one. Many articles reported (Attiya et al., 2019) (Rajagopal et al., 2017) (Li et al., 2013) (Iqbal and Chaudhry, 2009) (Munir, 2014) the viscometric studies of the drug in aqueous and aqueous-mixed solvent systems.

The present study is aimed to elaborate the physicochemical properties of three pharmaceutical significant drugs having varied physiological effect chloroquine phosphate (antimalarial), acefylline piperazine (anti-asthmatic) and gentamicin sulfate (antimicrobial). Chloroquine phosphate is the most widely used drugs for a long time and now researchers are concerned to use it against a pandemic novel COVID-19 due to its effectiveness in inhibiting the replication process of virus (Gao et al., 2020) (Philippe Colson et al., 2020). Acefylline piperazine (AP) is a methylated xanthine drug it is the derivative and use to combat different lung’s issues and serves as an anti-asthmatic, cardiac stimulant, bronchodilator and also a diuretic. (Masood et al., 2018). Gentamicin sulfate (GS) is an antibiotic that is broad-spectrum and belongs to an aminoglycoside based class of drugs that is used to control bacterial infections. (Grahek and Zupančič-Kralj, 2009) The literature data for GS in aqueous system are summarized in Table 1, (Gupta and Nain, 2019) but to the best of our knowledge, no viscosity data have been reported for GS in aqueous-PEG and aqueous-PVP. Therefore, a precise and reliable experimental data of viscosity of drug solutions in aqueous, aqueous-PEG (1.0 %w/v) and aqueous-PVP (1.0 %w/v) within the concentration range from 0.02 to 0.1 ± 0.001 mol dm−3 over the range of temperatures (293.15 to 318.15 K) with the difference of 5 K is of main interest. Polyethylene glycol and polyvinyl pyrrolidone are widely used synthetic polymers which are mainly recognized as a biocompatible polymer material (Zhi et al., 2013). Vast commercial applications of these two polymers, specifically biomedical applications subjected them to a variety of investigations to examine their properties. PEG has a high solubility in aqueous media, good tolerance, and biocompatibility which make it more appropriate for different biomedical applications such as bio-conjugation, imaging, biosensing, drug-polymer delivery and tissue engineering (Veronese et al., 2009). Polyvinyl pyrrolidone (PVP) is considered as the potential candidate, which is suitable to achieve the controlled release of therapeutic agents in constant doses over long periods. Also, it is used as a binder in many tablets due to its chemical stability, non-toxicity, affinity for complex, both hydrophobic and hydrophilic substances and high solubility in water (Teodorescu and Bercea, 2015). The Jones-Dole equation interprets the relation between the viscosities of solution and the concentration of solute. The effect of drug concentration, solvent nature and experimental thermal conditions of the flow process of drug can be explained in term of Jones-Dole Coefficients A and B which represent drug-drug and drug-solvent interactions in studying solutions. Jone-Doles viscosity B-coefficient also used to evaluate the temperature derivative of the B-coefficient (dB/dT) and hydration number and provide information insight into solution structure.

Table 1 Comparison on the viscosities of GS in aqueous.
m/mol kg−1 293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Viscosities of GS in water as reported in literature [13]
0.0202 1.0308 0.9148 0.8182 0.7370 0.6681 0.6106
Viscosities of GS in water as obtained experimentally through our data
0.0203 1.0585 0.9402 0.8423 0.7611 0.6917 0.6319

1.1

1.1 FTIR spectrum studies

The principle of the IR spectroscopy technique based on the estimation of the extent of absorbed IR radiation by a sample as a function of the wavelength. FTIR spectroscopy is a classical analytical process that offers several advantages covering rapid speed, ease of operation, cost-effectiveness, low noise and so on. This technique has a great potential for the interpretation of molecular structures in polyatomic molecular systems through the measurement of molecular vibrations in the infrared region. It provides a better insight into the IR absorption pattern of the organic compound which can be easily distinguished from other compounds, including isomers, that’s why it is considered as a fingerprint scheme for the identification of organic compound (Bunaciu et al., 2010).

Design and development in the formulation of any drug must be followed by the pre-formulation studies which provide interactions of active and inactive pharmaceutical ingredients. As drug excipient compatibility can alter the stability profile of drugs, chemical nature, bioavailability, their therapeutic effectiveness, and safety. It helps in the selection of appropriate excipient to develop the stable, effective and safe formulation. One of the important tools to evaluate the compatibility of the drug and excipient in pre-formulation studies is done by the fourier transform infrared spectroscopy. It is considered the most useful technique in pharmaceutical sciences and widely used in the formulation of any drug delivery system. The ability to distinguish between different molecules is provided by the different characteristics, IR bands which depend on the functional groups of the structural components. Few researchers also investigated the compatibility of the drug with polymers by using the FTIR technique (Choudhury, 2012) (Khan et al., 2015) (Mohamed et al., 2017)

2

2 Experimental

2.1

2.1 Materials

Nabi Qasim pharmaceutical industry granted drugs i-e., chloroquine phosphate, acefylline piperazine and gentamicin sulfate. Water-soluble polymers, i.e., Polyethylene glycol of BDH and Polyvinyl pyrrolidone of Sigma-Aldrich were used as the solvents. Table 2, represents the description of all chemicals used for experimental purposes. The preparation of the solutions was done by using de-ionized water (specific conductivity < 10−6 S. cm−1). Glassware was used to prepare standard solutions for experimental purposes that are all of Pyrex ‘A’ grade quality.

Table 2 Sample table.
Chemical Name Molecular weight Sources Fraction Purity Purificationmethod
Polyethylene Glycol 03513 Da BDH 0.999 None
Polyvinyl Pyrroliodne 40476 Da Sigma-Aldrich 0.999 None
Chloroquine phosphate 515.87 g mol−1 Nabi Qasim 0.990 None
Acefylline piperazine 324.30 g mol−1 Nabi Qasim 0.990 None
Gentamicin sulfate 575.67 g mol−1 Nabi Qasim 0.990 None

2.2

2.2 Solution preparation

Stock solutions of each polymer (1.0% w/v) were prepared, by taking a required amount of polymer and dissolved in a known volume of deionized water with constant stirring by using a magnetic stirrer. Stock solutions of 0.1 mol.dm−3 concentration of drugs chloroquine phosphate, acefylline piperazine and gentamicin sulfate were prepared in aqueous, aqueous-PEG and aqueous-PVP. A Shimadzu, AUW220 weighing balance was used for the measurement of chemicals for stock solutions preparation with the uncertainty ± 0.0001 g. Dilutions of required concentration ranges from 2.0 to 10.0 × 10−2 ± 0.001 mol.dm−3 in aqueous, aqueous-PEG (1.0 %w/v) and aqueous-PVP (1.0 %w/v) solvent systems were prepared from stock solutions.

2.3

2.3 Instrumentation and procedure

To generate reliable and accurate experimental values of the viscosity of drugs’ solutions an Ostwald U-tube glass Viscometer type Techniconominal constant 0.1 Cs s−1 capillary ASTMD, 445 was used. U-tube glass viscometer containing test solutions was suspended in a thermostatic water bath for 30 min to minimize any possible thermal fluctuations. A thermostatic water bath (type VWP Scientific, model 1120, SER 9143791) was used to measure experimental viscosities at different temperature range from 293.15 to 318.15 K with (5 K intervals ± 0.01 K). The time of flow was measured with a stopwatch Japan CBM Corp, QsQ capable of recording ± 0.01 s. The calibration of the viscometer was done with distilled water at temperatures (293.15, 298.15, 303.15, 308.15, 313.15 and 318.15 K). The values of densities and viscosities of pure water at various temperature are reported in Table 3, were taken from Lange’s handbook of chemistry (Dean, 1996). The uncertainty in the viscosity data was found ± 0.02 mPa s. The reproducibility of the results will be ensured by performing all measurements three times.

Table 3 Viscosities and densities values of aqueous, aqueous-PEG and aqueous-PVP at different temperatures.
Temperature (K) Viscosities (ƞ°/mPa s) Densities (ρ°/kg m−3)
Aqueous system 1% (w/v) aqueous-PEG System 1% (w/v) aqueous-PVP System Aqueous system 1% (w/v) aqueous-PEG System 1% (w/v) aqueous-PVP System
293.15 1.0016 ± 0.0001f 1.1832 ± 0.0000f 1.2973 ± 0.0000f 0.9982 ± 0.0000f 0.9994 ± 0.0000f 0.9999 ± 0.0001f
298.15 0.8901 ± 0.0002e 1.0177 ± 0.0000e 1.1169 ± 0.0012e 0.9970 ± 0.0000e 0.9988 ± 0.0011e 0.9991 ± 0.0000e
303.15 0.7973 ± 0.0000d 0.8235 ± 0.0003d 0.9471 ± 0.0000d 0.9957 ± 0.0001d 0.9985 ± 0.0001d 0.9983 ± 0.0002d
308.15 0.7193 ± 0.0000c 0.7225 ± 0.0002c 0.8614 ± 0.0001c 0.9940 ± 0.0000c 0.9957 ± 0.0000c 0.9974 ± 0.0003c
313.15 0.6529 ± 0.0001b 0.6500 ± 0.0000e 0.7889 ± 0.0002b 0.9922 ± 0.0012b 0.9942 ± 0.0000b 0.9960 ± 0.0000b
318.15 0.5961 ± 0.0012a 0.5807 ± 0.0014a 0.6810 ± 0.0000a 0.9902 ± 0.0003a 0.9932 ± 0.0014a 0.9942 ± 0.0002a

Values are the mean of three difference replications. Different alphabets (a-f) within each column are significantly different at p < 0.05.

2.4

2.4 FTIR spectrum studies

FTIR spectrometer (Shimadzu, IR Prestige-21, Japan) was used for FTIR Spectrum studies of the solution of CP, AP and GS in aqueous, aqueous-PEG (1.0 %w/v) and aqueous-PVP (1.0 %w/v). KBr disk technique was applied here to conduct FTIR spectroscopy. A disk of finely powdered IR grade dry KBr along with a sample was prepared for each mockup by applying the pressure technique and compressed under a hydraulic press to get a film. To avoid any moisture intervention, formerly all samples were dried in the oven and then use for sample disk preparation for FTIR spectroscopy. The spectrum of these samples was taken 4000 to 400 cm−1 at the resolution of 8 cm−1.

3

3 Results and discussion

3.1

3.1 Viscometric analysis

The data of viscosities of the solutions for different concentration ranges from 2.0 to 10.0 x10−2 mol.dm−3 of CP, AP and GS drugs at the temperature range from the 293.15 to 318.15 K with the difference of 5 K in aqueous, aqueous-PEG (1.0 %w/v) and aqueous-PVP (1.0 %w/v) solvent systems are given in the Tables 4–6, were calculated by Eq (1):

(1)
η = d s t s d o t o × η 0 where η0 and η is the viscosity of solvent and solution, d o and d s the density of solvent and solution and t o and t s are the times of flow of solvent and solution. The values obtained from the above relation show the variation with the change in experimental conditions such as concentration, temperature and solvent. The viscosity data for drugs in aqueous, aqueous-PEG (1.0 %w/v) and aqueous-PVP (1.0 %w/v) solvent systems increased rapidly with the increase in concentration which may lead to hydrophobic-hydrophobic and hydrophilic-ionic interactions. The increased in viscosity is due to the fact that with the variation of solute concentration, the number of collisions between the molecules ultimately increases, thus molecules tend to stick with each other and increasing viscosity of solutions (Saeed et al., 2009). Furthermore, when a solute is dissolved in a solvent, the solute–solvent interactions are originated due to the attraction of some solvent molecules towards solute and hence solution viscosity increases (Rajagopal and Jayabalakrishnan, 2010). The non-rupturing of the drug molecules in the polymeric system also supported by the increase in viscosity with the increasing concentration of drugs. The viscosity of drug solution in aqueous, aqueous-PEG (1.0 %w/v) and aqueous-PVP (1.0 %w/v) solvent systems decreased with the increase in temperature. The decreasing behaviour of solution viscosity may come from the increase in kinetic energy of molecules which increases the fluidity of solutions (Saeed et al., 2009) and also indicate the intermolecular forces of solvent weakens due to the thermal vibration at high-temperature. This trend of viscosity also relates to the breaking-down in solvent structure at high-temperature conditions. As the distortion of intermolecular forces and rupturing in solvent structure result in a decrease in viscosity (Solanki et al., 2010) (Saeed et al., 2005). At higher temperature, the molecules move randomly and decrease the attraction forces, which are responsible for the movement of solute and solvent molecules and ions, which causes prompt movement of molecules and ions into the vacant sites. So the reduction in interactions is mainly responsible for the decrease in viscosity with the rise in temperature (Zafarani-Moattar and Sarmad, 2012). The values of viscosities were found to be relatively higher in polymer–solvent systems as compared to the aqueous system that indicates the viscosity of drugs in polymer–solvent systems influenced by inter or intramolecular forces. The expected intermolecular interactions between drug and solvent in the solution can be designed by considering drug as a Lewis acid (–OH and –NH2 groups) and Lewis base (–OH, –O– and >C=O groups) that are forming hydrogen bonds with proton-acceptor or donor functional groups of the solvent.
Table 4 Viscosity ( η ) of drug in aqueous system at different temperatures.
m (mol kg−1) η /mPa s
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
0.0203 1.0289 ± 0.0012f 0.9154 ± 0.0000e 0.8212 ± 0.0003d 0.7428 ± 0.0001c 0.6764 ± 0.0002b 0.6191 ± 0.0001a
0.0408 1.0473 ± 0.0020f 0.9314 ± 0.0001e 0.8376 ± 0.0001d 0.7588 ± 0.0020c 0.6911 ± 0.0001b 0.6346 ± 0.0005a
0.0616 1.0666 ± 0.0001f 0.9519 ± 0.0013e 0.8564 ± 0.0000d 0.7769 ± 0.0003c 0.7074 ± 0.0003b 0.6503 ± 0.0031a
0.0827 1.0996 ± 0.0001f 0.9845 ± 0.0002e 0.8892 ± 0.0004d 0.8084 ± 0.0001c 0.7385 ± 0.0014b 0.6798 ± 0.0004a
0.1042 1.1401 ± 0.0020f 1.0207 ± 0.0012e 0.9203 ± 0.0021d 0.8403 ± 0.0011c 0.7727 ± 0.0002b 0.7141 ± 0.0003a
Acefylline piperazine
0.0202 1.0336 ± 0.0003f 0.9236 ± 0.0000e 0.8312 ± 0.0002d 0.7522 ± 0.0000c 0.6839 ± 0.0002b 0.6260 ± 0.0001a
0.0406 1.0620 ± 0.0001f 0.9490 ± 0.0001e 0.8579 ± 0.0010d 0.7791 ± 0.0004c 0.7079 ± 0.0000b 0.6495 ± 0.0002a
0.0612 1.0969 ± 0.0001f 0.9807 ± 0.0000e 0.8846 ± 0.0000d 0.8025 ± 0.0000c 0.7289 ± 0.0021b 0.6671 ± 0.0000a
0.0821 1.1439 ± 0.0010f 1.0256 ± 0.0002e 0.9246 ± 0.0002d 0.8386 ± 0.0001c 0.7628 ± 0.0001b 0.6968 ± 0.0010a
0.1032 1.1956 ± 0.0002f 1.0704 ± 0.0004e 0.9694 ± 0.0001d 0.8809 ± 0.0012c 0.8018 ± 0.0001b 0.7348 ± 0.0020a
Gentamicin sulfate
0.0203 1.0585 ± 0.0001f 0.9402 ± 0.0000e 0.8423 ± 0.0014d 0.7611 ± 0.0002c 0.6917 ± 0.0001b 0.6319 ± 0.0001a
0.0408 1.0876 ± 0.0001f 0.9689 ± 0.0001e 0.8711 ± 0.0001d 0.7879 ± 0.0001c 0.7156 ± 0.0011b 0.6557 ± 0.0003a
0.0616 1.1124 ± 0.0000f 0.9932 ± 0.0000e 0.8929 ± 0.0002d 0.8074 ± 0.0001c 0.7336 ± 0.0000b 0.6715 ± 0.0000a
0.0827 1.1354 ± 0.0003f 1.0143 ± 0.0002e 0.9110 ± 0.0000d 0.8246 ± 0.0000c 0.7499 ± 0.0001b 0.6857 ± 0.0002a
0.1039 1.1584 ± 0.0000f 1.0346 ± 0.0002e 0.9337 ± 0.0002d 0.8464 ± 0.0002c 0.7707 ± 0.0000b 0.7072 ± 0.0002a

Values are the mean of three difference replications. Different alphabets (a-f) within each column are significantly different at p < 0.05.

Table 5 Viscosity ( η ) of drug in aqueous-PEG solvent system at different temperatures.
m (mol kg−1) η / mPa s
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
0.0203 1.2059 ± 0.0002f 1.0392 ± 0.0001e 0.8426 ± 0.0001d 0.7409 ± 0.0001c 0.6687 ± 0.0000b 0.5985 ± 0.0002a
0.0408 1.2181 ± 0.0000f 1.0527 ± 0.0010e 0.8551 ± 0.0000d 0.7543 ± 0.0000c 0.6801 ± 0.0001b 0.6114 ± 0.0011a
0.0616 1.2349 ± 0.0001f 1.0643 ± 0.0001e 0.8668 ± 0.0000d 0.7662 ± 0.0001c 0.6916 ± 0.0001b 0.6233 ± 0.0000a
0.0827 1.2749 ± 0.0002f 1.1043 ± 0.0000e 0.8976 ± 0.0002d 0.7947 ± 0.0012c 0.7236 ± 0.0012b 0.6530 ± 0.0001a
0.1042 1.3029 ± 0.0000f 1.1312 ± 0.0011e 0.9268 ± 0.0000d 0.8225 ± 0.0003c 0.7463 ± 0.0001b 0.6742 ± 0.0001a
Acefylline piperazine
0.0202 1.2009 ± 0.0001f 1.0351 ± 0.0001e 0.8407 ± 0.0001d 0.7400 ± 0.0000c 0.6687 ± 0.0000b 0.6000 ± 0.0010a
0.0406 1.2159 ± 0.0003f 1.0495 ± 0.0000e 0.8533 ± 0.0010d 0.7544 ± 0.0001c 0.6839 ± 0.0010b 0.6160 ± 0.0004a
0.0612 1.2328 ± 0.0001f 1.0651 ± 0.0000e 0.8666 ± 0.0000d 0.7674 ± 0.0002c 0.6982 ± 0.0010b 0.6302 ± 0.000a
0.0821 1.2621 ± 0.0001f 1.0935 ± 0.0001e 0.8960 ± 0.0004d 0.7949 ± 0.0000c 0.7238 ± 0.0000b 0.6524 ± 0.0001a
0.1032 1.2925 ± 0.0000f 1.1245 ± 0.0002e 0.9231 ± 0.0010d 0.8168 ± 0.0000c 0.7419 ± 0.0002b 0.6701 ± 0.0002a
Gentamicin sulfate
0.0203 1.2766 ± 0.0000f 1.1017 ± 0.0010e 0.8931 ± 0.0001d 0.7839 ± 0.0000c 0.7069 ± 0.0003b 0.6316 ± 0.0011a
0.0408 1.3163 ± 0.0001f 1.1393 ± 0.0002e 0.9284 ± 0.0000d 0.8163 ± 0.0001c 0.7358 ± 0.0014b 0.6594 ± 0.0001a
0.0616 1.3481 ± 0.0010f 1.1692 ± 0.0003e 0.9535 ± 0.0002d 0.8378 ± 0.0002c 0.7579 ± 0.0002b 0.6795 ± 0.0002a
0.0827 1.3743 ± 0.0010f 1.1980 ± 0.0001e 0.9762 ± 0.0010d 0.8591 ± 0.0001c 0.7768 ± 0.0001b 0.6983 ± 0.0001a
0.1039 1.3983 ± 0.0000f 1.2211 ± 0.0011e 0.9978 ± 0.0001d 0.8762 ± 0.0003c 0.7939 ± 0.0021b 0.7149 ± 0.0002a
Table 6 Viscosity ( η ) of drug in aqueous-PVP solvent system at different temperatures.
m (mol kg−1) η /mPa s
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
0.0203 1.3883 ± 0.0000f 1.2005 ± 0.0012e 1.0209 ± 0.0002d 0.9331 ± 0.0001c 0.8574 ± 0.000b 0.7427 ± 0.0011a
0.0408 1.4285 ± 0.0010f 1.2397 ± 0.0011e 1.0569 ± 0.0004d 0.9659 ± 0.0010c 0.8881 ± 0.0011b 0.7711 ± 0.000a
0.0616 1.4692 ± 0.0002f 1.2674 ± 0.0004e 1.0827 ± 0.0001d 0.9901 ± 0.0012c 0.9123 ± 0.0010b 0.7943 ± 0.0001a
0.0827 1.5205 ± 0.0002f 1.3201 ± 0.0000e 1.1261 ± 0.0001d 1.0296 ± 0.0010c 0.9464 ± 0.0020b 0.8246 ± 0.0000a
0.1042 1.5703 ± 0.0003f 1.3669 ± 0.0003e 1.1702 ± 0.0001d 1.0765 ± 0.0001c 0.9948 ± 0.0000b 0.8649 ± 0.0000a
Acefylline piperazine
0.0202 1.3271 ± 0.0001f 1.1434 ± 0.000e 0.9710 ± 0.0000d 0.8847 ± 0.000c 0.8122 ± 0.0011b 0.7016 ± 0.0004a
0.0406 1.3498 ± 0.0000f 1.1699 ± 0.0011e 0.9974 ± 0.0000d 0.9131 ± 0.0010c 0.8419 ± 0.000b 0.7296 ± 0.000a
0.0612 1.3832 ± 0.0010f 1.1973 ± 0.0001e 1.0191 ± 0.0010d 0.9327 ± 0.0002c 0.8603 ± 0.0010b 0.7471 ± 0.0012a
0.0821 1.4217 ± 0.0010f 1.2317 ± 0.0002e 1.0531 ± 0.0002d 0.9651 ± 0.0003c 0.8927 ± 0.0012b 0.7731 ± 0.0001a
0.1032 1.4581 ± 0.0012f 1.2693 ± 0.0000e 1.0855 ± 0.0004d 0.9997 ± 0.0010c 0.9267 ± 0.000b 0.8067 ± 0.0010a
Gentamicin sulfate
0.0203 1.3506 ± 0.0000f 1.1689 ± 0.000e 0.9942 ± 0.0001d 0.9084 ± 0.0010c 0.8357 ± 0.0000b 0.7232 ± 0.0001a
0.0408 1.3835 ± 0.0001f 1.1992 ± 0.0002e 1.0231 ± 0.0000d 0.9391 ± 0.0002c 0.8651 ± 0.0010b 0.7484 ± 0.0000a
0.0616 1.4151 ± 0.0002f 1.2257 ± 0.0010e 1.0511 ± 0.0002d 0.9627 ± 0.0001c 0.8889 ± 0.0012b 0.7703 ± 0.0012a
0.0827 1.4392 ± 0.0002f 1.2474 ± 0.0000e 1.0711 ± 0.0001d 0.9850 ± 0.0000c 0.9092 ± 0.0004b 0.7888 ± 0.0002a
0.1039 1.4534 ± 0.0003f 1.2742 ± 0.0010e 1.0914 ± 0.000d 1.0031 ± 0.0000c 0.9275 ± 0.0001b 0.8052 ± 0.0001a

Data shows the increased in viscosities of drugs in polymer system is due to the electrostatic (hydrophobic/hydrophilic) interactions, Vander Waals forces and hydrogen bonding which is mainly responsible for the formation of an association. In the aqueous-PEG system, the hydroxyl group of PEG and similar in the case of the aqueous-PVP system carbonyl group of PVP is involved in the formation of hydrogen bonding with water molecules which enhance the resistance to flow. The electrostatic interactions due to hydrophobic moiety (–CH3) and hydrophilic moiety (–OH, >C=O and –NH2 groups) of the drug and polymer (–CH3, –O–, –OH and –NH2 groups) are also comprised here as exemplified in Fig. 1(a-f).

Structural description of interionic interactions existing in drug-aq-polymeric system (a) CP in aq-PEG (b) CP in aq-PVP (c) AP in aq-PEG (d) AP in aq-PVP (e) GS in aq-PEG (f) GS in aq-PVP.
Fig. 1
Structural description of interionic interactions existing in drug-aq-polymeric system (a) CP in aq-PEG (b) CP in aq-PVP (c) AP in aq-PEG (d) AP in aq-PVP (e) GS in aq-PEG (f) GS in aq-PVP.

The relative viscosity ( η rel ) is the ratio between the viscosities of solution and solvent. Relative viscosities of solutions were calculated from the viscosity data of solvent and solutions by using Eq (2),

(2)
η rel = η η °

The data are tabulated in Tables 7–9, shows the increased in relative viscosities with the increase in concentration and temperature of CP, AP and GS in aqueous, aqueous-PEG (1.0 %w/v) and aqueous-PVP (1.0 %w/v) solvent systems.

Table 7 Relative Viscosity ƞrel of drug in aqueous system at different temperatures.
m (mol kg−1) ƞrel
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
0.0203 1.027 ± 0.001a 1.028 ± 0.001b 1.029 ± 0.014c 1.033 ± 0.002d 1.036 ± 0.000e 1.038 ± 0.001f
0.0408 1.046 ± 0.000a 1.046 ± 0.021b 1.051 ± 0.001c 1.055 ± 0.012d 1.058 ± 0.010e 1.065 ± 0.000f
0.0616 1.065 ± 0.001a 1.069 ± 0.002b 1.074 ± 0.0020c 1.081 ± 0.002d 1.083 ± 0.011e 1.09 ± 0.010f
0.0827 1.098 ± 0.002a 1.106 ± 0.000b 1.115 ± 0.001c 1.124 ± 0.001d 1.131 ± 0.001e 1.141 ± 0.011f
0.1042 1.138 ± 0.002a 1.147 ± 0.011b 1.154 ± 0.012c 1.168 ± 0.001d 1.183 ± 0.002e 1.198 ± 0.003f
Acefylline piperazine
0.0202 1.032 ± 0.010a 1.038 ± 0.002b 1.042 ± 0.000c 1.046 ± 0.001d 1.047 ± 0.002e 1.051 ± 0.001f
0.0406 1.061 ± 0.012a 1.066 ± 0.001b 1.076 ± 0.002c 1.083 ± 0.001d 1.084 ± 0.003e 1.089 ± 0.014f
0.0612 1.095 ± 0.021a 1.102 ± 0.001b 1.109 ± 0.001c 1.116 ± 0.000d 1.116 ± 0.001e 1.119 ± 0.000f
0.0821 1.142 ± 0.001a 1.152 ± 0.004b 1.159 ± 0.001c 1.166 ± 0.013d 1.168 ± 0.011e 1.169 ± 0.012f
0.1032 1.194 ± 0.000a 1.202 ± 0.000b 1.216 ± 0.000c 1.225 ± 0.014d 1.228 ± 0.010e 1.232 ± 0.011f
Gentamicin sulfate
0.0203 1.057 ± 0.011a 1.056 ± 0.000b 1.056 ± 0.014c 1.058 ± 0.001d 1.059 ± 0.010e 1.059 ± 0.001f
0.0408 1.087 ± 0.012a 1.089 ± 0.002b 1.092 ± 0.001c 1.095 ± 0.011d 1.096 ± 0.011e 1.101 ± 0.001f
0.0616 1.111 ± 0.001a 1.116 ± 0.001b 1.119 ± 0.004c 1.122 ± 0.021d 1.123 ± 0.012e 1.127 ± 0.021f
0.0827 1.134 ± 0.014a 1.139 ± 0.010b 1.142 ± 0.002c 1.146 ± 0.001d 1.148 ± 0.013e 1.151 ± 0.001f
0.1039 1.156 ± 0.011a 1.162 ± 0.012b 1.171 ± 0.000c 1.177 ± 0.011d 1.181 ± 0.001e 1.186 ± 0.001f
Table 8 Relative Viscosity (ƞrel) of drug in aqueous-PEG solvent system at different temperatures.
m (mol kg−1) ƞrel
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
0.0203 1.019 ± 0.012a 1.021 ± 0.002b 1.023 ± 0.010c 1.025 ± 0.010d 1.029 ± 0.010e 1.031 ± 0.000f
0.0408 1.029 ± 0.000a 1.034 ± 0.021b 1.038 ± 0.011c 1.044 ± 0.011d 1.046 ± 0.011e 1.053 ± 0.002f
0.0616 1.044 ± 0.001a 1.046 ± 0.000b 1.053 ± 0.021c 1.061 ± 0.002d 1.064 ± 0.002e 1.074 ± 0.001f
0.0827 1.077 ± 0.014a 1.085 ± 0.001b 1.090 ± 0.001c 1.099 ± 0.012d 1.113 ± 0.002e 1.125 ± 0.011f
0.1042 1.101 ± 0.001a 1.112 ± 0.011b 1.126 ± 0.002c 1.138 ± 0.000d 1.148 ± 0.003e 1.161 ± 0.010f
Acefylline piperazine
0.0202 1.015 ± 0.020a 1.017 ± 0.010b 1.021 ± 0.001c 1.024 ± 0.000d 1.029 ± 0.004e 1.033 ± 0.000f
0.0406 1.028 ± 0.001a 1.031 ± 0.002b 1.036 ± 0.004c 1.044 ± 0.001d 1.052 ± 0.001e 1.061 ± 0.011f
0.0612 1.042 ± 0.014a 1.046 ± 0.002b 1.052 ± 0.001c 1.062 ± 0.020d 1.074 ± 0.013e 1.085 ± 0.020f
0.0821 1.067 ± 0.001a 1.074 ± 0.003b 1.088 ± 0.002c 1.101 ± 0.010d 1.114 ± 0.011e 1.123 ± 0.010f
0.1032 1.092 ± 0.004a 1.105 ± 0.001b 1.121 ± 0.011c 1.131 ± 0.012d 1.142 ± 0.000e 1.154+±0.004f
Gentamicin sulfate
0.0203 1.079 ± 0.010a 1.082 ± 0.004b 1.086 ± 0.011c 1.085 ± 0.002d 1.087 ± 0.010e 1.088 ± 0.004f
0.0408 1.113 ± 0.020a 1.119 ± 0.003b 1.127 ± 0.001c 1.129 ± 0.001d 1.132 ± 0.000e 1.135 ± 0.001f
0.0616 1.139 ± 0.001a 1.149 ± 0.021b 1.158 ± 0.003c 1.159 ± 0.011d 1.166 ± 0.014e 1.171 ± 0.000f
0.0827 1.161 ± 0.000a 1.177 ± 0.001b 1.185 ± 0.002c 1.189 ± 0.001d 1.195 ± 0.012e 1.203 ± 0.012f
0.1039 1.182 ± 0.011a 1.199 ± 0.014b 1.212 ± 0.000c 1.213 ± 0.012d 1.221 ± 0.021e 1.231 ± 0.000f
Table 9 Relative Viscosity (ƞrel) of drug in aqueous-PVP solvent system at different temperatures.
m (mol kg−1) ƞrel
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
0.0203 1.070 ± 0.001a 1.075 ± 0.012b 1.078 ± 0.001c 1.083 ± 0.011d 1.087 ± 0.001e 1.091 ± 0.003f
0.0408 1.101 ± 0.001a 1.110 ± 0.000b 1.116 ± 0.004c 1.121 ± 0.010d 1.126 ± 0.004e 1.132 ± 0.013f
0.0616 1.132 ± 0.003a 1.135 ± 0.011b 1.143 ± 0.002c 1.149 ± 0.000d 1.156 ± 0.014e 1.166 ± 0.001f
0.0827 1.172 ± 0.011a 1.182 ± 0.000b 1.189 ± 0.001c 1.195 ± 0.002d 1.199 ± 0.001e 1.211 ± 0.000f
0.1042 1.211 ± 0.000a 1.224 ± 0.010b 1.235 ± 0.014c 1.249 ± 0.011d 1.261 ± 0.013e 1.271 ± 0.001f
Acefylline piperazine
0.0202 1.023 ± 0.010a 1.024 ± 0.000b 1.025 ± 0.002c 1.027 ± 0.013d 1.029 ± 0.021e 1.030 ± 0.001f
0.0406 1.041 ± 0.001a 1.047 ± 0.013b 1.053 ± 0.001c 1.060 ± 0.001d 1.067 ± 0.011e 1.071 ± 0.000f
0.0612 1.066 ± 0.002a 1.072 ± 0.001b 1.076 ± 0.003c 1.083 ± 0.014d 1.090 ± 0.013e 1.097 ± 0.011f
0.0821 1.096 ± 0.001a 1.103 ± 0.001b 1.112 ± 0.002c 1.121 ± 0.001d 1.131 ± 0.001e 1.135 ± 0.010f
0.1032 1.124 ± 0.000a 1.137 ± 0.021b 1.146 ± 0.001c 1.161 ± 0.002d 1.174 ± 0.014e 1.185 ± 0.001f
Gentamicin sulfate
0.0203 1.041 ± 0.010a 1.047 ± 0.021b 1.049 ± 0.004c 1.055 ± 0.010d 1.059 ± 0.000e 1.061 ± 0.013f
0.0408 1.067 ± 0.011a 1.074 ± 0.001b 1.081 ± 0.003c 1.090 ± 0.011d 1.096 ± 0.012e 1.099 ± 0.001f
0.0616 1.091 ± 0.001a 1.097 ± 0.011b 1.109 ± 0.014c 1.118 ± 0.012d 1.127 ± 0.010e 1.131 ± 0.020f
0.0827 1.109 ± 0.013a 1.117 ± 0.001b 1.131 ± 0.001c 1.143 ± 0.011d 1.152 ± 0.001e 1.158 ± 0.012f
0.1039 1.120 ± 0.001a 1.141 ± 0.003b 1.152 ± 0.011c 1.164 ± 0.000d 1.176 ± 0.014e 1.182 ± 0.001f

The increase in the relative viscosity in concentration is due to an increase in the amount of drug that causes more solute–solvent interactions, which ultimately enhance the viscous property of the studied systems. This indicates that the high amount of solute decreased absorption and transmission of a drug, hence drug efficiency and activity would be lesser at high concentration.

The relative changes in viscosities of CP, AP and GS in aqueous, aqueous-PEG and aqueous-PVP solvent systems can be expressed by the following equation:

(3)
η sp = η rel - 1

The specific viscosity data of the drugs solutions in aqueous-polymer solvent systems are given in Tables 10 and 12, show an increase in values with the increases in drug concentrations, indicating drug-solvent interaction enhanced with the increasing molarities of drugs (Li et al., 2013). The specific viscosities of solutions in the studied solvent systems increased with the increase in temperature showing solute–solvent interaction is weakened at high temperature due to an increase in thermal motion of the system H-bond (Li et al., 2013).

Table 10 Specific Viscosity (ƞsp) of drug in aqueous system at different temperatures.
m (mol kg−1) ƞsp
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
0.0203 0.0272 ± 0.0015a 0.0284 ± 0.0010b 0.0297 ± 0.0001c 0.0327 ± 0.011d 0.0360 ± 0.0013e 0.0385 ± 0.0010f
0.0408 0.0457 ± 0.0011a 0.0464 ± 0.0012b 0.0505 ± 0.0011c 0.0549 ± 0.0001d 0.0585 ± 0.0012e 0.0647 ± 0.0012f
0.0616 0.0649 ± 0.0001a 0.0694 ± 0.0001b 0.0741 ± 0.0010c 0.0802 ± 0.0004d 0.0834 ± 0.0003e 0.0911 ± 0.0013f
0.0827 0.0978 ± 0.0002a 0.1061 ± 0.0002b 0.1152 ± 0.0014c 0.1239 ± 0.0021d 0.1311 ± 0.0001e 0.1406 ± 0.0014f
0.1042 0.1383 ± 0.0010a 0.1467 ± 0.0001b 0.1542 ± 0.0010c 0.1683 ± 0.0001d 0.1835 ± 0.0011e 0.1981 ± 0.0004f
Acefylline piperazine
0.0202 0.0319 ± 0.0020a 0.0377 ± 0.0002b 0.0424 ± 0.0010c 0.0458 ± 0.0003d 0.0475 ± 0.0011e 0.0502 ± 0.0001f
0.0406 0.0603 ± 0.0010a 0.0662 ± 0.0001b 0.0759 ± 0.011c 0.0831 ± 0.0014d 0.0843 ± 0.0012e 0.0897 ± 0.0011f
0.0612 0.0951 ± 0.0011a 0.1019 ± 0.0013b 0.1095 ± 0.0012c 0.1157 ± 0.0011d 0.1164 ± 0.0012e 0.1192 ± 0.0012f
0.0821 0.1421 ± 0.0001a 0.1523 ± 0.0003b 0.1596 ± 0.0020c 0.1659 ± 0.0013d 0.1684 ± 0.0010e 0.1691 ± 0.0014f
0.1032 0.1937 ± 0.0004a 0.2026 ± 0.0013b 0.2159 ± 0.0004c 0.2247 ± 0.0020d 0.2279 ± 0.0020e 0.2327 ± 0.0002f
Gentamicin sulfate
0.0203 0.0554 ± 0.0010a 0.0563 ± 0.0002b 0.0564 ± 0.0001c 0.0580 ± 0.001d 0.0593 ± 0.0013e 0.0599 ± 0.0002f
0.0408 0.0859 ± 0.0020a 0.0887 ± 0.0001b 0.0924 ± 0.0011c 0.0954 ± 0.0011d 0.0960 ± 0.0012e 0.1001 ± 0.0001f
0.0616 0.1106 ± 0.0012a 0.1159 ± 0.0012b 0.1198 ± 0.0012c 0.1224 ± 0.0003d 0.1236 ± 0.0001e 0.1266 ± 0.0001f
0.0827 0.1336 ± 0.0001a 0.1396 ± 0.0010b 0.1425 ± 0.0010c 0.1464 ± 0.0001d 0.1486 ± 0.0011e 0.1505 ± 0.0013f
0.1039 0.1565 ± 0.0014a 0.1624 ± 0.0010b 0.1711 ± 0.0001c 0.1767 ± 0.0002d 0.1804 ± 0.0010e 0.1864 ± 0.0003f
Table 11 Specific Viscosity (ƞsp) of drug in aqueous-PEG solvent system at different temperatures.
m (mol kg−1) ƞsp
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
0.0203 0.0192 ± 0.0012a 0.0211 ± 0.0021b 0.0232 ± 0.0020c 0.0255 ± 0.0001d 0.0287 ± 0.0010e 0.0307 ± 0.0001f
0.0408 0.0295 ± 0.0010a 0.0343 ± 0.0010b 0.0384 ± 0.0001c 0.0439 ± 0.0011d 0.0461 ± 0.0021e 0.0528 ± 0.0002f
0.0616 0.0437 ± 0.0003a 0.0458 ± 0.0011b 0.0526 ± 0.0004c 0.0604 ± 0.0014d 0.0639 ± 0.0021e 0.0734 ± 0.0003f
0.0827 0.0775 ± 0.0004a 0.0851 ± 0.0001b 0.0901 ± 0.0003c 0.0999 ± 0.0004d 0.1131 ± 0.0014e 0.1245 ± 0.0001f
0.1042 0.1012 ± 0.0001a 0.1116 ± 0.0014b 0.1256 ± 0.0001c 0.1383 ± 0.0002d 0.1481 ± 0.00012e 0.1610 ± 0.0010f
Acefylline piperazine
0.0202 0.0149 ± 0.0000a 0.0171 ± 0.0010b 0.0209 ± 0.0000c 0.0242 ± 0.0010d 0.0287 ± 0.0001e 0.0332 ± 0.0000f
0.0406 0.0277 ± 0.0001a 0.0312 ± 0.0000b 0.0362 ± 0.0001c 0.0441 ± 0.0003d 0.0521 ± 0.0041e 0.0608 ± 0.0010f
0.0612 0.0419 ± 0.0011a 0.0465 ± 0.0012b 0.0524 ± 0.0014c 0.0621 ± 0.0014d 0.0741 ± 0.0001e 0.0852 ± 0.0012f
0.0821 0.0667 ± 0.0014a 0.0744 ± 0.0014b 0.0881 ± 0.0011c 0.1002 ± 0.0010d 0.1135 ± 0.0014e 0.1234 ± 0.0001f
0.1032 0.0924 ± 0.0001a 0.1049 ± 0.0010b 0.1209 ± 0.0001c 0.1304 ± 0.0020d 0.1413 ± 0.0010e 0.1539 ± 0.0004f
Gentamicin sulfate
0.0203 0.0789 ± 0.0000a 0.0825 ± 0.0001b 0.0846 ± 0.0001c 0.0851 ± 0.0012d 0.0875 ± 0.0010e 0.0877 ± 0.0011f
0.0408 0.1125 ± 0.0010a 0.1194 ± 0.0011b 0.1274 ± 0.0010c 0.1298 ± 0.0012d 0.1319 ± 0.0012e 0.1356 ± 0.0001f
0.0616 0.1394 ± 0.0014a 0.1488 ± 0.0020b 0.1579 ± 0.0014c 0.1595 ± 0.0001d 0.1660 ± 0.0003e 0.1701 ± 0.0003f
0.0827 0.1615 ± 0.0001a 0.1772 ± 0.0010b 0.1855 ± 0.0011c 0.1890 ± 0.0004d 0.1949 ± 0.0001e 0.2025 ± 0.0004f
0.1039 0.1819 ± 0.0011a 0.1998 ± 0.0000b 0.2118 ± 0.0010c 0.2126 ± 0.0002d 0.2214 ± 0.0013e 0.2311 ± 0.0010f
Table 12 Specific Viscosity (ƞsp) of drug in aqueous-PVP solvent system at different temperatures.
m (mol kg−1) ƞsp
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
0.0203 0.0701 ± 0.0020a 0.0749 ± 0.0011b 0.0779 ± 0.0001c 0.0834 ± 0.0011d 0.0867 ± 0.0001e 0.0906 ± 0.0012f
0.0408 0.1011 ± 0.0012a 0.1100 ± 0.0013b 0.1159 ± 0.0010c 0.1214 ± 0.0021d 0.1256 ± 0.0012e 0.1323 ± 0.0001f
0.0616 0.1325 ± 0.0001a 0.1348 ± 0.0010b 0.1432 ± 0.0020c 0.1495 ± 0.0012d 0.1563 ± 0.0011e 0.1664 ± 0.0002f
0.0827 0.1720 ± 0.0014a 0.1821 ± 0.0012b 0.1891 ± 0.0003c 0.1953 ± 0.0011d 0.1995 ± 0.0001e 0.2108 ± 0.0003f
0.1042 0.2104 ± 0.0001a 0.2239 ± 0.0011b 0.2355 ± 0.0011c 0.2497 ± 0.0001d 0.2609 ± 0.0001e 0.2701 ± 0.0010f
Acefylline piperazine
0.0202 0.0229 ± 0.0020a 0.0237 ± 0.0012b 0.0253 ± 0.0000c 0.0271 ± 0.0014d 0.0294 ± 0.0010e 0.03013 ± 0.0001f
0.0406 0.0405 ± 0.0003a 0.0475 ± 0.0001b 0.0531 ± 0.0000c 0.0601 ± 0.0001d 0.0670 ± 0.0020e 0.07125 ± 0.0012f
0.0612 0.0662 ± 0.0001a 0.0719 ± 0.0014b 0.0759 ± 0.0010c 0.0828 ± 0.0002d 0.0904 ± 0.0012e 0.09697 ± 0.0002f
0.0821 0.0959 ± 0.0013a 0.1028 ± 0.0003b 0.1119 ± 0.0030c 0.1204 ± 0.0003d 0.1315 ± 0.0010e 0.13519 ± 0.0012f
0.1032 0.1239 ± 0.0013a 0.1366 ± 0.0004b 0.1461 ± 0.0011c 0.1607 ± 0.0011d 0.1745 ± 0.0011e 0.18450 ± 0.0010f
Gentamicin sulfate
0.0203 0.0411 ± 0.0020a 0.0467 ± 0.0014b 0.0497 ± 0.0004c 0.0546 ± 0.0001d 0.0592 ± 0.0002e 0.0619 ± 0.0000f
0.0408 0.0665 ± 0.0012a 0.0737 ± 0.0001b 0.0803 ± 0.0001c 0.0902 ± 0.0012d 0.0965 ± 0.0001e 0.0989 ± 0.0001f
0.0616 0.0907 ± 0.0001a 0.0974 ± 0.0013b 0.1097 ± 0.0001c 0.1176 ± 0.0013d 0.1267 ± 0.0021e 0.1310 ± 0.0012f
0.0827 0.1094 ± 0.0003a 0.1169 ± 0.0001b 0.1309 ± 0.0012c 0.1435 ± 0.0010d 0.1523 ± 0.0014e 0.1582 ± 0.0011f
0.1039 0.1203 ± 0.0002a 0.1409 ± 0.0012b 0.1524 ± 0.0010c 0.1645 ± 0.0011d 0.1756 ± 0.000e 0.1823 ± 0.0001f

The B-coefficient is an empirical term that represents the solvation effect, size and shape effect of solute or Einstein effect, structural effect and coulombic interactions induced by solute–solvent interaction. The information obtained from the data of viscosity B-coefficient determined the solvation behaviour of solutes and its effects on the solvent’s structure in the surrounding solute molecules.

(4)
η rel = η η ° = 1 + AC 1 / 2 + BC where C is the concentration of the drugs (CP, AP and GS) in mol dm−3.

The dependencies of relative changes in the viscosities of the solutions on drug concentration in aqueous, aqueous-PEG and aqueous-PVP are shown in Figs. 2 and 3. The data of the B-coefficient and A-coefficient were obtained through the slope and intercept by plotting ƞsp/C1/2 against C1/2 according to the Jones-Dole equation and given in Table 13. It can be seen from tabulated data that the viscosity B-coefficients of CP, AP and GS in aqueous, aqueous-PEG and aqueous-PVP solvent systems are positive, suggesting the presence of strong drug-solvent interactions. Smaller values of the B-coefficient also show the strong H bonding between the drug and water molecules.

Plot of Ƞsp/√C v/s C1/2 for AP in aq system at different temperature K.
Fig. 2
Plot of Ƞsp/√C v/s C1/2 for AP in aq system at different temperature K.
Table 13 Jone-Doles coefficient B and coefficient A of drugs in aqueous, aqueous-PEG and aqueous-PVP system at different temperatures.
Solvent 1% (w/v) B (dm3 mol−1) coefficient
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
Aqueous 1.35 ± 0.02c 1.49 ± 0.02c 1.58 ± 0.02c 1.71 ± 0.02c 1.82 ± 0.0025c 1.96 ± 0.0025c
PEG 1.09 ± 0.06b 1.19 ± 0.06b 1.31 ± 0.06b 1.44 ± 0.06b 1.55 ± 0.0006b 1.70 ± 0.0006b
PVP 0.98 ± 0.01a 0.99 ± 0.01a 1.05 ± 0.01a 1.05 ± 0.01a 1.09 ± 0.0100a 1.12 ± 0.0100a
Acefylline piperazine
Aqueous 2.20 ± 0.05c 2.15 ± 0.05c 2.141 ± 0.05c 2.13 ± 0.05c 2.12 ± 0.05c 2.05 ± 0.05c
PEG 1.05 ± 0.01a 1.18 ± 0.01a 1.34 ± 0.01a 1.38 ± 0.01a 1.42 ± 0.01a 1.45 ± 0.01a
PVP 1.37 ± 0.01b 1.49 ± 0.01b 1.59 ± 0.01b 1.73 ± 0.01b 1.87 ± 0.01b 1.98 ± 0.01b
Gentamicin sulfate
Aqueous 0.58 ± 0.01c 0.65 ± 0.01c 0.76 ± 0.01c 0.78 ± 0.01c 0.80 ± 0.01c 0.84 ± 0.01c
PEG 0.09 ± 0.03a 0.29 ± 0.03a 0.38 ± 0.03a 0.38 ± 0.03a 0.45 ± 0.03a 0.61 ± 0.03a
PVP 0.56 ± 0.03b 0.64 ± 0.03b 0.76 ± 0.03b 0.76 ± 0.03b 0.77 ± 0.03b 0.80 ± 0.03b
A (dm3mol)½ coefficient
Chloroquine phosphate
Aqueous −0.03 ± 0.02b −0.04 ± 0.02b −0.04 ± 0.02b −0.04 ± 0.02b −0.05 ± 0.02b −0.05 ± 0.02b
PEG −0.06 ± 0.01c −0.05 ± 0.01c −0.05 ± 0.01c −0.05 ± 0.01c −0.06 ± 0.01c −0.06 ± 0.01c
PVP 0.33 ± 0.01a 0.36 ± 0.01c 0.38 ± 0.01a 0.41 ± 0.01a 0.42 ± 0.01a 0.45 ± 0.01a
Acefylline piperazine
Aqueous −0.12 ± 0.05c −0.07 ± 0.05c −0.03 ± 0.05c −0.01 ± 0.05c −0.05 ± 0.05b 0.04 ± 0.05b
PEG −0.06 ± 0.01a −0.07 ± 0.01a −0.07 ± 0.01a −0.05 ± 0.01a −0.02 ± 0.01a −0.02 ± 0.01a
PVP −0.05 ± 0.00b −0.05 ± 0.00b −0.05 ± 0.00b −0.06 ± 0.00b −0.06 ± 0.00c −0.06 ± 0.00c
Gentamicin sulfate
Aqueous 0.31 ± 0.00c 0.31 ± 0.00c 0.29 ± 0.00c 0.31 ± 0.00c 0.31 ± 0.00c 0.32 ± 0.00c
PEG 0.54 ± 0.01a 0.54 ± 0.01a 0.55 ± 0.01a 0.56 ± 0.01a 0.56 ± 0.01a 0.54 ± 0.01a
PVP 0.22 ± 0.03b 0.24 ± 0.03b 0.25 ± 0.03b 0.29 ± 0.03b 0.32 ± 0.03b 0.33 ± 0.03b

Results are tabulated in Table 13, shows a drop in the values of B-coefficient for AP in the aqueous system with the increase in temperature represent the structure promoting effect this is due to enforcement and ordering of hydrogen-bonded structure around the drug molecules. At higher temperatures, the shield of solvent molecules that surround the drug is broken and the probability of drug-drug interactions may increase results the weaker drug-solvent interactions. The B-coefficient values for AP in aqueous-polymer systems and for CP and GS in aqueous and aqueous-polymer systems decreased with the temperature rise represent the structure breaking effect due to dipole interaction of solvent molecules with a solute which causes a regular arrangement of solvent molecules around the solute (Masood et al., 2013). These interactions have been reported in our research article (Masood et al., 2020b).

A (Falkenhagen coefficient) is the representation of the ion-ion (solute–solute) interactions, which are associated with the size and shape of the solute. The ion-ion interactions are based on the hypothetical model according to this model ions are associated with the ion cloud which has spherical symmetry of the ion cloud of opposite charge sharing forces in the solutions. These forces are originated due to the influence of an applied linear velocity gradient and alter the spherical form to an ellipsoidal form. These opposite forces of electrostatic interaction and thermal agitation collectively restore the stable equilibrium distribution for finite time of relaxation.

A-coefficient values are negative for AP in aqueous, aqueous-PEG and aqueous-PVP systems and for CP in aqueous and aqueous-PEG, while for GS positive values in aqueous, aqueous-PEG and aqueous-PVP systems were obtained over the temperature range. The positive values of the A-coefficient for drugs show the stronger water and polymer (solvent–solvent) association as compare to solvent interactions with ions. Negative values indicate the association between the water and polymer is weak in comparison with the solvent interactions with the solute.

The temperature derivative of the B-coefficient (dB/dT) is evaluating the variation in B-coefficient as a function of temperature as exemplified in Figs. 4 and 5. It is considered as a better criterion for determining the structure making/breaking effect of the solute in the studied solvent systems. In general, the negative values of dB/dT associated with the structure promoting property of the solute and positive data related to the structure breaking criteria. The values of dB/dT have also been calculated and collected in Table 14, to represent the structure making nature of AP in aqueous systems, while in aqueous-PEG and aqueous-PVP solvent systems it shows the structure destroying ability. AP behaviour in an aqueous system is the clear indication of the formation of solvent structure through hydrophobic hydration which may be due to electrostatic influenced by the charged groups of AP on the water molecules present in the near environment (Rajagopal and Jayabalakrishnan, 2011). Data obtained for CP and GS in aqueous, aqueous-PEG and aqueous-PVP solvent systems evident the structure breaking nature of these drugs in studied solvent systems.

Plot of Ƞsp/√C v/s C1/2 for GS in aq-PVP system at different temperature K.
Fig. 3
Plot of Ƞsp/√C v/s C1/2 for GS in aq-PVP system at different temperature K.
Plot of B-coeff v/s T for CP in aq, aq-PEG and aq-PVP systems.
Fig. 4
Plot of B-coeff v/s T for CP in aq, aq-PEG and aq-PVP systems.
Table 14 Temperature derivatives of the B-coefficient (dB/dT) of drugs in aqueous, aqueous-PEG and aqueous-PVP.
Solvents dB/dT
Drugs
Chloroquine phosphate Acefylline piperazine Gentamicin sulfate
Aqueous 0.0238 −0.005 0.0103
PEG 0.0243 0.0157 0.0176
PVP 0.0057 0.0248 0.0095

The transfer behaviour of the B-coefficient can be determined by taking the difference in B-coefficient values as in Eqs. (5) and (6) and placed in Table 15,

(5)
Δ B ( t r ) = B ( aq ) - - B ( aq - PEG )
(6)
Δ B ( tr ) = B ( aq ) - - B ( aq - PVP )
ΔB(tr) values were negative, which confirms that hydrophobic-hydrophobic interactions are dominant over hydrophilic-hydrophilic interactions. As interactions between the non-polar group and a hydrophobic group of polymer and drug (R - CH2) are strong enough to mask the interactions between polar groups of drug ( - N H 2 , - C l , - N H a n d - C H 3 ) and a polar group of the polymer (–OH).
Table 15 Transfer behavior of B coefficient of drugs in aqueous, aqueous-PEG and aqueous-PVP system at different temperatures.
Solvent 1% (w/v) ΔB(tr) (dm3 mol−1)
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
PEG −0.2576 ± 0.006c −0.3057 ± 0.006c −0.2746 ± 0.006c −0.2689 ± 0.006c −0.2713 ± 0.006c −0.2617 ± 0.006c
PVP −0.3747 ± 0.170a −0.5031 ± 0.170c −0.5358 ± 0.170a −0.6579 ± 0.170a −0.7373 ± 0.170a −0.8446 ± 0.170a
Acefylline piperazine
PEG −1.1478 ± 0.016a −0.9722 ± 0.016a −0.8022 ± 0.016a −0.7452 ± 0.016a −0.7022 ± 0.016a −0.5981 ± 0.016a
PVP −0.8294 ± 0.012b −0.6649 ± 0.012b −0.5485 ± 0.012b −0.3984 ± 0.012b −0.2527 ± 0.012c −0.0645 ± 0.012c
Gentamicin sulfate
PEG −0.4788 ± 0.034a −0.3664 ± 0.034a −0.3797 ± 0.034a −0.3999 ± 0.034a −0.3491 ± 0.034a −0.2305 ± 0.034a
PVP −0.0178 ± 0.043b −0.0177 ± 0.043b −0.0051 ± 0.043b −0.0201 ± 0.043b −0.0274 ± 0.043b −0.0380 ± 0.043b

Solvation or hydration numbers for CP, AP and GS were also calculated by using the Eq (7):

(7)
Sn = B ϕ v ° where ϕ v ° is limiting the apparent molar volume and its data is reported in our previous published article (Masood et al., 2020b).

Sn determined the formation of the primary solvation shell that surrounds the solute. Sn data can be considered as an imperative indicator of solvated and unsolvated drug molecules. The range of Sn values lies between (0 and 2.5) represents unsolvated molecules, while higher values than 2.5 confirm the presence of solvated spherical species. The values of Sn given in Table 16, show that CP in aqueous and aqueous-PEG and AP in aqueous, aqueous-PEG and aqueous-PVP solvent systems exhibited solvated behaviour. Whereas, GS shows unsolvated nature in all studied solvent systems which may be due to the higher hydrophobicity of GS which arises from the enrichment of hydrophobic groups (CH3), aromatic rings and hydroxyl groups of drugs. Sn values found to be highest for AP, whereas, lowest for GS. It indicates that the molecules of AP are more solvated in aqueous and aqueous-polymer systems as compared to the GS and CP and follow the below trend concerning their solvation behaviour. AP > CP > GS

Table 16 Solvation number of drugs in aqueous, aqueous-PEG and aqueous-PVP system at different temperatures.
Solvent 1% (w/v) Sn
293.15 K 298.15 K 303.15 K 308.15 K 313.15 K 318.15 K
Chloroquine phosphate
Aqueous 3.4428 ± 0.025b 3.2315 ± 0.025b 3.3843 ± 0.025b 3.6281 ± 0.025b 3.8227 ± 0.025b 4.0467 ± 0.025b
PEG 3.2036 ± 0.006c 3.2072 ± 0.006c 3.5193 ± 0.006c 3.7270 ± 0.006c 3.9820 ± 0.006c 4.0960 ± 0.006c
PVP 0.3109 ± 0.170a 0.3292 ± 0.170c 0.3514 ± 0.170a 0.3590 ± 0.170a 0.3755 ± 0.170a 0.3900 ± 0.170a
Acefylline piperazine
Aqueous 7.0464 ± 0.055c 7.5648 ± 0.055c 7.6711 ± 0.055c 8.4954 ± 0.055c 7.9585 ± 0.055b 7.6789 ± 0.055b
PEG 7.7841 ± 0.016a 6.7930 ± 0.016a 6.7705 ± 0.016a 6.2055 ± 0.016a 5.9619 ± 0.016a 5.6504 ± 0.016a
PVP 6.7357 ± 0.012b 6.8262 ± 0.012b 6.6626 ± 0.012b 6.7420 ± 0.012b 6.8590 ± 0.012c 6.8937 ± 0.012c
Gentamicin sulfate
Aqueous 1.4432 ± 0.008c 1.4938 ± 0.008c 1.5818 ± 0.008c 1.5474 ± 0.008c 1.5551 ± 0.008c 1.5386 ± 0.008c
PEG 0.0331 ± 0.034a 0.0987 ± 0.034a 0.1324 ± 0.034a 0.1346 ± 0.034a 0.1595 ± 0.034a 0.2153 ± 0.034a
PVP 0.5803 ± 0.043b 0.6496 ± 0.043b 0.7592 ± 0.043b 0.7417 ± 0.043b 0.7394 ± 0.043b 0.7503 ± 0.043b

The values of Sn increase with the increase in temperature for CP, AP and GS in the aqueous-polymer system indicates that extend of co-sphere water around the drug increases at high temperature.

3.2

3.2 FTIR spectrum studies

The chemical interactions of drugs (i-e., CP, AP and GS) with polymer were measured by FTIR studies of these drugs in aqueous, aqueous-PEG (1.0% w/v) and aqueous-PVP (1.0% w/v) solvent systems. FTIR spectral analysis is the technique that is used to measure the changes that occur in the frequency and bandwidth of interacting groups in the spectrum of the drug and polymer when these drugs mixed with a polymer, based on the oscillation of the molecular dipoles causes changes in molecular-level.

The spectra of CP in aqueous (Fig. 8 a) shows broadband in a relatively interference-free region at 3651 cm−1 due to absorption of electromagnetic radiation through stretching vibration by N-H. Moreover, a sharp peak at 1614 cm−1 for bending vibration of the amide group (N-H) was obtained. The IR region from 35000 to 3100 cm−1 is identified in the absorption spectra of primary aliphatic amines and amides. A band of medium intensity for secondary aromatic amines was observed at 3400–3300 cm−1. The bands at 2941.44 cm−1 for C-H (methyl and methylene group stretching, vibration) and at 3099 cm−1 indicate the presence of an aromatic ring (stretching vibration). The bands at 1554 cm−1 (C-N stretching vibration) 1365 cm−1 (C-C stretching and C = N ring stretching). Peaks of lower intensities also observed between 532 and 659 cm−1 may specify the presence of chloride group. For phosphate ion at 1215 cm−1 moderate-intensity peak was detected (Usman and Akhyar Farrukh, 2018). The spectra for pure PEG and PVP show (Figs. 6 and 7) the bands in the region 1500–1100 cm−1 generally associated with wagging, bending and twisting modes of CH2 groups. In spectra for PEG a broad and prominent band at 3442 cm−1point toward the presence of O-H (alcohol) group that is bonded with H. The band for stretching vibration at 2918 cm−1 for the methyl group has appeared. Spectra has given for CP in aqueous-PEG (Fig. 8.b) solvent system draws an illustration of shifting of the band for N-H group from 3651 to 3400 cm−1 and width of the band increases due to presence of OH group along with NH. For PVP at 1544 cm−1 a peak was observed specifies the C=O group stretching vibrational band. Few small peaks in the region of 1022–1292 cm−1 represent the amines (C-N). The width of the band increased in the spectra of CP in an aqueous-PVP (Fig. 8.c) system in the region between 3100 and 3650 cm−1 due to moisture content (Donald et al., 2001). The presence of drug molecules in aqueous polymer–solvent systems slightly increased the bandwidth of representative functional groups of polymers.

Plot of B-coeff v/s T for CP, AP and GS in aq-PEG system.
Fig. 5
Plot of B-coeff v/s T for CP, AP and GS in aq-PEG system.
FTIR spectra of pure PEG.
Fig. 6
FTIR spectra of pure PEG.
FTIR spectra of pure PVP.
Fig. 7
FTIR spectra of pure PVP.

The absorption band was obtained at 1664 cm−1 for the carbonyl group that is characteristics of the AP (Fig. 9.a) as it can be easily observed due to its high intensity. As C=O group gives its absorption band in the region of 1850–1550 cm−1 due to its stretching vibration. The vibrational band is broad and having low intensity was found at 3439 cm−1 for stretching mode of N-H. Peak obtained at 1641 cm−1 represent the existence of the C=C group and a sharp band for C–N stretching of the pyrimidine ring was observed at 1334 cm−1. A spectrum of AP-PEG shows (Fig. 9.b) that PEG gave its intense band on 1107 cm−1 for C-O-C stretching. Bands on 1240, 1319 and 1390 cm−1 indicate CH2 wagging and twisting. The FTIR spectrum of AP-PVP (Fig. 9.c) was taken having a band at 1645 cm−1 can be identified for the carbonyl stretch modes that show drug-polymer incompatibility, as polymer had maintained its identity in solution with the drug.

(a, b and c) FTIR spectras of CP in aq, aq-PEG and aq-PVP solvent systems.
Fig. 8
(a, b and c) FTIR spectras of CP in aq, aq-PEG and aq-PVP solvent systems.
(a, b and c) FTIR spectras of CP in aq, aq-PEG and aq-PVP solvent systems.
Fig. 8
(a, b and c) FTIR spectras of CP in aq, aq-PEG and aq-PVP solvent systems.

The typical absorption band at wavenumber 3442, 1643 and 1386 for GS (Fig. 10.a) can be assigned to the primary and secondary amides (stretching and bending vibrations). The peak observed at 657 cm−1 related to the SO2. While the presence of HSO4−1 functional group evidence of the band at 1107 cm−1 (Dwivedi et al., 2014). In the FTIR spectrums of GS in aqueous-polymer systems (Fig. 10b and c) broad absorption bands at about 3456 cm−1 (aqueous-PEG) and 3442 cm−1 (aqueous-PVP) were attained, which may be due to the N–H and OH-O stretching vibration and the intermolecular hydrogen bonding. The spectrums for CP, AP and GS in aqueous, aqueous-PEG and aqueous-PVP draw a conclusion that the characteristic peaks of drug retained in all solvent systems indicate that solvents did not change the chemical identity of the drug. Hence, there is no significant chemical interaction was observed between drug and polymer. The slight shifting of characteristic bands in the spectrum of CP, AP and GS in the polymeric system was also obtained, but no new band observed, which confirms that there is no formation of a new chemical bond (between drug and polymer) occur.

(a, b and c) FTIR spectras of AP in aq, aq-PEG and aq-PVP solvent systems.
Fig. 9
(a, b and c) FTIR spectras of AP in aq, aq-PEG and aq-PVP solvent systems.
(a, b and c) FTIR spectras of AP in aq, aq-PEG and aq-PVP solvent systems.
Fig. 9
(a, b and c) FTIR spectras of AP in aq, aq-PEG and aq-PVP solvent systems.
(a, b and c) FTIR spectras of GS in aq, aq-PEG and aq-PVP solvent systems.
Fig. 10
(a, b and c) FTIR spectras of GS in aq, aq-PEG and aq-PVP solvent systems.
(a, b and c) FTIR spectras of GS in aq, aq-PEG and aq-PVP solvent systems.
Fig. 10
(a, b and c) FTIR spectras of GS in aq, aq-PEG and aq-PVP solvent systems.

4

4 Conclusion

The experimental values of viscosity for CP, AP and GS drugs were determined over concentration ranges 2.0 × 10−2 to 10.0 × 10−2 ± 0.001 mol.dm−3 at different temperatures. The viscosity data were further used to evaluate Jones– Dole equation coefficients interactions A’ and ‘B’ to provide insight into the drug-drug and drug-solvent interactions.

The positive values of dB/dT manifest that AP behaves as structure maker in an aqueous system while in aqueous-polymer systems CP, AP and GS show their structure breaking tendency which indicates drug–solvent interactions destroy the structure of the solution. The transfer behaviour of the B-coefficient represents the dominancy of hydrophobic-hydrophobic interactions in comparison with hydrophilic-hydrophilic interactions. FTIR studies of CP, AP and GS represent that drug chemical identity remained unaffected by polymers and no new bond formation was proceeding between drug and solvent molecules.

Acknowledgement

Summyia Masood (author) is grateful for the research grant provided by the Dean Faculty of Science (DFS) and Azher Yar Khan for FTIR analysis, University of Karachi and Nabi Qasim pharmaceutical industry for the drug support.

Declaration of Competing Interest

The author declare that there is no conflict of interest.

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