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Interaction of biocompatible polymers with amphiphilic phenothiazine drug chlorpromazine hydrochloride
Journal of Molecular Liquids 177 (2013) 283–287
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq
Interaction of biocompatible polymers with amphiphilic phenothiazine drug chlorpromazine hydrochloride Mohd. Sajid Ali ⁎, Hamad A. Al-Lohedan Department of Chemistry, College of Science, King Saud University, Riyadh 11541, Saudi Arabia
a r t i c l e
i n f o
Article history: Received 8 October 2012 Received in revised form 29 October 2012 Accepted 29 October 2012 Available online 13 November 2012 Keywords: Chlorpromazine Drug–polymer interaction Critical aggregation concentration Polymer saturation point
a b s t r a c t Interaction of chlorpromazine hydrochloride (CPZ), an amphiphilic drug of phenothiazine category, was investigated with several biocompatible polymers. The studies were carried out by using conductometry. Results were found to be in analogy with the surfactant–polymer interactions. The plots of specific conductivity versus concentration of drug were nonlinear with three different linear regions and with two clear breaks. First break point is regarded as the onset of aggregation, i.e., critical aggregation concentration (C1) and appeared well below the critical micelle concentration of pure drug. Second break (C2) is regarded as polymer saturation point which is akin to the critical micelle concentration. At C2 polymer domain saturated with the drug monomers which occurred at quite higher concentration suggestive of unavailability of drug monomers at lower concentrations due to the polymer–drug binding. Free energies of aggregation (ΔGagg) and micellization (ΔGmic) were calculated with the help of degrees of micelle ionization obtained from the specific conductivity–[CPZ] plots. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Polymers are ubiquitous materials which find their applications in almost every aspect of life, e.g., in household items and in several industries such as, pharmaceuticals, petrochemicals, cosmetics. Polymers have also proved themselves the promising agents in the drug delivery formulations [1–5]. The pioneers are cellulose derivatives and also some synthetic polymers like poly ethylene glycol (PEG) and polyvinylpyrrolidone (PVP). These polymers have the tendency to regulate the rheology of a system and to control the release of the drug. In addition, most of these polymers are amphiphilic in nature with mixed hydrophilic/hydrophobic segments that leads to an apparent surface activity. Several drug molecules display amphiphilic behavior and their example includes phenothiazine and benzodiazepine tranquilizers, analgesics, tricyclic antidepressants and non-steroidal anti-inflammatory drugs [6]. Due to their amphiphilic nature these drugs tend to self-associate beyond some concentration ranges; called as critical micelle concentration [6–13]. Though the micelles formed from these drugs are rather rigid and have small aggregation numbers, the knowledge of their self-association behavior under different conditions is necessary for drawing some conclusion of their delivery and physiological actions [14,15]. Nevertheless their therapeutic action might start well below the critical micelle concentration; it is a possibility that the aggregation of these drugs takes place as a result of accumulation and likely localized high concentration ⁎ Corresponding author. Tel.: +966 598878428; fax: +966 14679972. E-mail address: [email protected] (M.S. Ali). 0167-7322/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molliq.2012.10.037
inside the human body. Furthermore, the interaction of these drugs with carrying agents like polymers, nanomaterials, dendrimers, etc., is also of great interest as with these substances they may interact in a typical surfactant like manner. The interaction between polymers and surfactants in aqueous solution has engrossed huge attention throughout the several past decades, and the topic has systematically been reviewed [16]. It was found that all types of surfactants (cationic, anionic and nonionic) interacts with the polymers in a cooperative manner [17–19]. However, some reports exist which describe the interaction of several surface active drugs with various polymers [20–22]. Ibuprofen shows interactions with cellulose ethers, polyethylene glycol and polyvinylpyrrolidone [20,21]. Amitriptyline and other tricyclic antidepressants also interact with the polymers of Carrageenan family [22]. In our several previous reports we have studied the interaction of various drugs with some biocompatible polymers [21,23–25]. Cationic amphiphilic drug amitriptyline hydrochloride was found to decrease the hydrodynamic radii of PEG and PVP and that was concluded on the basis of strong interaction of drug and polymer owing to the attraction between cationic head group of the drug and partial negative charge bearing oxygen atom of the polymers which was further supported by the hydrophobic interactions between them. Very recently, it was found that non-steroidal anti-inflammatory drug ibuprofen interacts with polymers in a classical surfactant like fashion, i.e., the presence of two types of aggregation phenomenon (i) critical aggregation concentration (C1) at which the interaction of polymer and amphiphile initiates and (ii) polymer saturation point or apparent critical micelle concentration (C2) equivalent to the saturation of polymer
M.S. Ali, H.A. Al-Lohedan / Journal of Molecular Liquids 177 (2013) 283–287
domain with amphiphile and the beginning of formation of autonomous micelles [21]. The anionic drug interacted with cationic polymers more strongly as compared to the nonionic ones and anionic polymers had shown the least interaction. From the observed results it was concluded that hydrophobicity plays an important role in the interaction as it overcomes the likely repulsion between the anionic drug and anionic polymers. All these previous studies motivated us to study the effect of cationic drug with various polymers. In the succession of this we studied the interaction of cyclodextrin with these drugs [24,25]. Following these approaches, in this paper, we have studied the effect of chlorpromazine hydrochloride, CPZ (Scheme 1), with various polymers like hydroxypropylmethyl cellulose (HPMC), dextran sulfate (DxS), sodium carboxymethyl cellulose (NaCMC), poly ethylene glycol (PEG) and polyvinylpyrrolidone (PVP) is seen using conductometry.
4.0 3.5 3.0
10-2κ (Scm-1)
284
2.5 2.0 1.5
% HPMC (w/v)
1.0
0.1
2. Materials and methods
0.2
0.5
0.5
2.1. Materials The amphiphilic phenothiazine drug chlorpromazine hydrochloride (CPZ) (98%, Sigma, USA), neutral polymers, i.e., polyvinylpyrrolidone K 30 (Fluka, Switzerland), polyethylene glycol K 35 (Fluka, Germany), hydroxypropylmethyl cellulose (Sigma, USA), and anionic polymers, i.e., sodium carboxymethylcellulose (Sigma, USA), dextran sulfate (Merck, Germany), were used as received. Demineralized doubledistilled water of specific conductivity 1–2 × 10 −6 S cm −1 was used to prepare the stock solutions of the drug and polymers. 2.2. Conductivity measurements The conductivity measurements were executed on an ELICO (type CM 82T) bridge equipped with platinized electrodes (cell constant = 1.02 cm −1). The conductivity runs were carried out by adding gradually concentrated CPZ stock solution into the thermostated solvent or solvent including polymer at temperature 25 °C. The critical micellar concentration of the pure CPZ used was obtained from the plots of specific conductivity (κ) as a function of the drug concentration. The cmc values were taken from the intersection of the two straight lines drawn before and after the intersection point in the plots (figure not shown). As in case of the polymer–drug mixtures the plots of κ versus [drug] showed two breaks (Figs. 1–5), the C1 was determined by the intersection of first and second linear parts and the C2 in this case was the intersection point of the second and third linear parts.
1.0
0.0 0
10
20
30
40
[CPZ] (mM) Fig. 1. Plots of specific conductivity (κ) versus CPZ concentration at different concentrations of HPMC. The scale shown is for plot denoted as (●). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1×10−2 S cm−1), respectively.
obtained by data fitting in Eqs. (1)–(4). It was interesting to note that both polar and non-polar (hydrophobic) interactions play important role in the polymer–amphiphile chemistry. In all the polymer– drug's specific conductivity profiles, there seems a steep rise in the conductivity of the solution on adding the drug up to the C1. At C1 the cooperative interaction between the drug and polymers starts and the mobility of the drug ions diminished as a result of the complexation with the polymer domain. Up to the second transition (C2) when all the polymer sites are occupied by the monomers or small aggregates the rise in conductivity acquires a smooth change. But as the C2 approaches the formation of the normal micelles begins and as micelles further have low mobility as compared to the free monomers and ions the slope becomes less steeper [27,28].
4.0 3.5
For the titration of CPZ into pure water, the conductivity below the cmc is due to the contribution of drug's head-groups and counterions. Above the cmc, the rate of the conductivity is smaller because micelles have rather lower mobility and a fraction of counterions are ion-paired with the micelles [26]. The experimental cmc of pure drug was found to be 21 mM (data not shown) which is in good agreement with the observed values [1]. It is apparent from the figures that, in the presence of polymers, the first break-point (C1) appears well below the usual cmc of the drug which is an indication of the onset of the polymer–amphiphilic drug interaction. Tables 1–5 display the values of C1, C2 and various thermodynamic parameters
3.0
10-2κ (Scm-1)
3. Results and discussion
2.5 2.0 1.5
% PEG (w/v)
1.0
0.1 0.2
0.5
0.5 1.0
0.0 0
10
20
30
40
[CPZ] (mM)
Scheme 1. Structure of chlorpromazine hydrochloride.
Fig. 2. Plots of specific conductivity (κ) versus CPZ concentration at different concentrations of PEG. The scale shown is for plot denoted as (●). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1×10−2 S cm−1), respectively.
4.0
4.0
3.5
3.5
3.0
3.0
2.5
2.5
10-2κ (Scm-1)
10-2κ (Scm-1)
M.S. Ali, H.A. Al-Lohedan / Journal of Molecular Liquids 177 (2013) 283–287
2.0 1.5
% PVP (w/v)
1.0
285
2.0
1.5
% NaCMC (w/v)
1.0
0.1
0.1
0.2
0.5
0.2
0.5
0.5
0.5
1.0
1.0
0.0 0
10
20
30
0.0
40
0
[CPZ] (mM)
10
20
30
40
[CPZ] (mM)
Fig. 3. Plots of specific conductivity (κ) versus CPZ concentration at different concentrations of PVP. The scale shown is for plot denoted as (●). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1×10−2 S cm−1), respectively.
While comparing the C1 and C2 values of different concentrations of same polymers and respective concentration (Fig. 6 and Tables 1–5) of different polymers it was found that C1 decreases on increasing the polymer concentration suggesting that the interaction is cooperative and increases on increasing the polymer concentration [28,29]. PEG shows the least interaction among non-ionic polymers while HPMC interacts strongly as compared to both PVP and PEG. It is reported that PEG is less hydrophobic as compared to the PVP [29]. The other factor which seems to be responsible for the stronger interaction of PVP is its partial negatively charged oxygen which bears more charge as compared to the PEG [21]. HPMC, conversely, is found to interact with both anionic and cationic surfactants as compared to the other nonionic polymers, interaction of which generally depends on the conditions of the interacting environment [30–34]. HPMC has an amphiphilic
Fig. 5. Plots of specific conductivity (κ) versus CPZ concentration at different concentrations of NaCMC. The scale shown is for plot denoted as (●). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1×10−2 S cm−1), respectively.
behavior and show a considerable surface activity. Therefore, stronger interaction of HPMC is, probably, due to its strong amphiphilic and surface active nature. Due to the stronger interaction of anionic polymers and the cationic drug C1 was found to be low at even very low concentrations of NaCMC and DxS in comparison to the experimental concentrations and observed C1 of nonionic polymers which obviously is attributable to the involvement of the electrostatic interactions between oppositely charged entities (Tables 4 and 5). Nevertheless, it was difficult to discriminate between the relative interactions of NaCMC and DxS towards the drug owing to very close values of observed and analyzed parameters. Since we have used basic techniques, these may probably be insensitive to distinguish between the strong interactions of anionic polymers and cationic amphiphilic drug.
4.0 3.5
Table 1 Degrees of micelle ionizations (α1 and α2), Free energies (ΔGagg, ΔGmic, and ΔGt) associated with the solution properties of HPMC and CPZ at 25 °C evaluated on the basis of conductometric measurements.
10-2κ (Scm-1)
3.0 2.5 2.0 1.5
% DxS (w/v)
1.0
103C1 mol dm−3
103C2 mol dm−3
α1
α2
ΔGagg (J mol−1)
ΔGmic (J mol−1)
ΔGt (J mol−1)
0.1 0.2 0.5 1.0
7.6 6.9 6.7 6.2
26.0 26.8 27.4 28.2
0.66 0.63 0.57 0.54
0.59 0.63 0.73 0.69
−4138 −4656 −5353 −5755
−3638 −3330 −2434. −2810
−500 −1326 −2918 −2945
Table 2 Degrees of micelle ionizations (α1 and α2), Free energies (ΔGagg, ΔGmic, and ΔGt) associated with the solution properties of PEG and CPZ at 25 °C evaluated on the basis of conductometric measurements.
0.1 0.2
0.5
%HPMC (w/v)
0.5 1.0
0.0 0
10
20
30
40
[CPZ] (mM) Fig. 4. Plots of specific conductivity (κ) versus CPZ concentration at different concentrations of DxS. The scale shown is for plot denoted as (●). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1×10−2 S cm−1), respectively.
%PEG (w/v)
103C1 mol dm−3
103C2 mol dm−3
0.0 0.1 0.2 0.5 1.0
9.4 9.0 8.0 8.0
21.2 25.4 27.3 30.2 31.4
α1
α2
0.65 0.58 0.54 0.53
0.55 0.63 0.58 0.59 0.58
ΔGagg (J mol−1)
ΔGmic (J mol−1)
ΔGt (J mol−1)
−4037 −4817 −5491 −5585
−4314 −3412 −3852 −3781 −3836
−625 −964 −1709 −1748
286
M.S. Ali, H.A. Al-Lohedan / Journal of Molecular Liquids 177 (2013) 283–287
Table 3 Degrees of micelle ionizations (α1 and α2), Free energies (ΔGagg, ΔGmic, and ΔGt) associated with the solution properties of PVP and CPZ at 25 °C evaluated on the basis of conductometric measurements.
Table 5 Degrees of micelle ionizations (α1 and α2), Free energies (ΔGagg, ΔGmic, and ΔGt) associated with the solution properties of NaCMC and CPZ at 25 °C evaluated on the basis of conductometric measurements.
%PVP (w/v)
103C1 mol dm−3
103C2 mol dm−3
α1
α2
ΔGagg (J mol−1)
ΔGmic (J mol−1)
ΔGt (J mol−1)
%NaCMC 103C1 103C2 α1 (w/v) mol dm−3 mol dm−3
α2
ΔGagg ΔGmic ΔGt (J mol−1) (J mol−1) (J mol−1)
0.1 0.2 0.5 1.0
7.4 7.2 7.0 6.8
25.3 26.5 28.4 30.6
0.66 0.57 0.57 0.55
0.61 0.58 0.65 0.64
−4146 −5262 −5149 −5537
−3522 −3767 −3155 −3183
−623 −1494 −1994 −2353
0.1 0.2 0.5 1.0
0.56 0.58 0.62 0.65
−5409 −5285 −5689 −6292
For ionic amphiphiles, the Gibbs energy of micelle formation was calculated from the pseudophase separation model according to the following relation [35] ΔGmic ¼ RT ð1 þ βÞ lncmc
ð1Þ
6.1 5.5 5.3 4.7
27.0 29.0 29.4 31.0
0.57 0.59 0.56 0.51
−3912 −3689 −3393 −3049
−1497 −1596 −2295 −3242
concentrations. For same concentration of polymers the value of ΔGt follows the trend:
PEG
where β is the counterion binding degree which is related to the degree of micelle ionization in the following way: ð2Þ
where α was calculated by taking the ratio between the slopes of the linear portions above and below the cmc. In the presence of the polymer, two values α1 and α2 are obtained corresponding to C1 and C2 respectively. Therefore, free energy associated with the interaction between polymer and amphiphilic drug (ΔGagg) and the free energy of micellization (ΔGmic) can be written as: ΔGagg ¼ RT ð1 þ β1 Þ lnC1 and ΔGmic ¼ RT ð1 þ β2 Þ lnC2 :
ð3Þ
The free energy of transfer can be given as [36]: ( ) ΔGt ðC1 Þð1þβ1 Þ : ¼ ln RT ðC2 Þð1þβ2 Þ
ð4Þ
From the respective values of (ΔGagg) for various polymers and their different concentrations, it can be concluded that it decreases on increasing the polymer concentration owing to the increased interaction which makes the process energetically more favorable. Free energy of aggregation is much higher as compared to the free energy of micellization in polymer free solution. This suggests that the complexation of drug and polymer is a more favorable process as compared to the micellization of drug in the absence of polymer. It is supposed that ΔGmic will become less favorable on increasing the polymer concentrations but there is no considerable change in the case of nonionic polymers on doing so. However, anionic polymers face a small change in the value of ΔGmic. In the presence of anionic polymers a strong electrostatic interaction may lead to a delayed micellization of drugs due to which the micellization becomes more energetically unfavorable. Both qualitative and quantitative aspects of binding interactions between drug and polymers can easily be understood with the help of ΔGt values obtained for different polymers and at various
Table 4 Degrees of micelle ionizations (α1 and α2), Free energies (ΔGagg, ΔGmic, and ΔGt) associated with the solution properties of DxS and CPZ at 25 °C evaluated on the basis of conductometric measurements. %Dextran 103C1 103C2 α1 (w/v) mol dm−3 mol dm−3
α2
ΔGagg ΔGmic ΔGt (J mol−1) (J mol−1) (J mol−1)
0.1 0.2 0.5 1.0
0.53 0.59 0.67 0.68
−4928 −5226 −5851 −5961
6.2 5.6 5.3 4.5
26.7 27.5 29.2 31.9
0.59 0.58 0.55 0.55
−4208 −3617 −2922 −2832
−720 −1608 −2929 −3128
It was easy to compare the relative interactions of nonionic polymers with each other on the basis of observed and calculated values. However, in the case of anionic polymers (NaCMC and DxS) all the reported values and fitted parameters were close enough and it was difficult to distinguish which one is a strongly interacting anionic polymer.
4. Conclusions Interaction of amphiphilic drug chlorpromazine hydrochloride (CPZ) with several biocompatible polymers has been studied using conductometry. Being a cationic drug, CPZ interacts more strongly with anionic polymers as compared to the nonionic ones. The onset of interaction decreases on increasing the concentration of the polymer which also indicates that interaction between the drug and polymer was cooperative. Hydrophobicity plays an important role in the interaction as revealed by the comparative interaction of nonionic polymers with CPZ. Acknowledgment The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RGP-VPP-148.
10 HPMC PEG PVP
9
DxS NaCMC
8
c1(mM)
β ¼ ð1−α Þ
7
6
5
4 0.0
0.2
0.4
0.6
0.8
1.0
[polymer] (wt/vol) Fig. 6. Critical aggregation concentration as a function of concentrations of various polymers.
M.S. Ali, H.A. Al-Lohedan / Journal of Molecular Liquids 177 (2013) 283–287
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Contents lists available at SciVerse ScienceDirect
Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq
Interaction of biocompatible polymers with amphiphilic phenothiazine drug chlorpromazine hydrochloride Mohd. Sajid Ali ⁎, Hamad A. Al-Lohedan Department of Chemistry, College of Science, King Saud University, Riyadh 11541, Saudi Arabia
a r t i c l e
i n f o
Article history: Received 8 October 2012 Received in revised form 29 October 2012 Accepted 29 October 2012 Available online 13 November 2012 Keywords: Chlorpromazine Drug–polymer interaction Critical aggregation concentration Polymer saturation point
a b s t r a c t Interaction of chlorpromazine hydrochloride (CPZ), an amphiphilic drug of phenothiazine category, was investigated with several biocompatible polymers. The studies were carried out by using conductometry. Results were found to be in analogy with the surfactant–polymer interactions. The plots of specific conductivity versus concentration of drug were nonlinear with three different linear regions and with two clear breaks. First break point is regarded as the onset of aggregation, i.e., critical aggregation concentration (C1) and appeared well below the critical micelle concentration of pure drug. Second break (C2) is regarded as polymer saturation point which is akin to the critical micelle concentration. At C2 polymer domain saturated with the drug monomers which occurred at quite higher concentration suggestive of unavailability of drug monomers at lower concentrations due to the polymer–drug binding. Free energies of aggregation (ΔGagg) and micellization (ΔGmic) were calculated with the help of degrees of micelle ionization obtained from the specific conductivity–[CPZ] plots. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Polymers are ubiquitous materials which find their applications in almost every aspect of life, e.g., in household items and in several industries such as, pharmaceuticals, petrochemicals, cosmetics. Polymers have also proved themselves the promising agents in the drug delivery formulations [1–5]. The pioneers are cellulose derivatives and also some synthetic polymers like poly ethylene glycol (PEG) and polyvinylpyrrolidone (PVP). These polymers have the tendency to regulate the rheology of a system and to control the release of the drug. In addition, most of these polymers are amphiphilic in nature with mixed hydrophilic/hydrophobic segments that leads to an apparent surface activity. Several drug molecules display amphiphilic behavior and their example includes phenothiazine and benzodiazepine tranquilizers, analgesics, tricyclic antidepressants and non-steroidal anti-inflammatory drugs [6]. Due to their amphiphilic nature these drugs tend to self-associate beyond some concentration ranges; called as critical micelle concentration [6–13]. Though the micelles formed from these drugs are rather rigid and have small aggregation numbers, the knowledge of their self-association behavior under different conditions is necessary for drawing some conclusion of their delivery and physiological actions [14,15]. Nevertheless their therapeutic action might start well below the critical micelle concentration; it is a possibility that the aggregation of these drugs takes place as a result of accumulation and likely localized high concentration ⁎ Corresponding author. Tel.: +966 598878428; fax: +966 14679972. E-mail address: [email protected] (M.S. Ali). 0167-7322/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molliq.2012.10.037
inside the human body. Furthermore, the interaction of these drugs with carrying agents like polymers, nanomaterials, dendrimers, etc., is also of great interest as with these substances they may interact in a typical surfactant like manner. The interaction between polymers and surfactants in aqueous solution has engrossed huge attention throughout the several past decades, and the topic has systematically been reviewed [16]. It was found that all types of surfactants (cationic, anionic and nonionic) interacts with the polymers in a cooperative manner [17–19]. However, some reports exist which describe the interaction of several surface active drugs with various polymers [20–22]. Ibuprofen shows interactions with cellulose ethers, polyethylene glycol and polyvinylpyrrolidone [20,21]. Amitriptyline and other tricyclic antidepressants also interact with the polymers of Carrageenan family [22]. In our several previous reports we have studied the interaction of various drugs with some biocompatible polymers [21,23–25]. Cationic amphiphilic drug amitriptyline hydrochloride was found to decrease the hydrodynamic radii of PEG and PVP and that was concluded on the basis of strong interaction of drug and polymer owing to the attraction between cationic head group of the drug and partial negative charge bearing oxygen atom of the polymers which was further supported by the hydrophobic interactions between them. Very recently, it was found that non-steroidal anti-inflammatory drug ibuprofen interacts with polymers in a classical surfactant like fashion, i.e., the presence of two types of aggregation phenomenon (i) critical aggregation concentration (C1) at which the interaction of polymer and amphiphile initiates and (ii) polymer saturation point or apparent critical micelle concentration (C2) equivalent to the saturation of polymer
M.S. Ali, H.A. Al-Lohedan / Journal of Molecular Liquids 177 (2013) 283–287
domain with amphiphile and the beginning of formation of autonomous micelles [21]. The anionic drug interacted with cationic polymers more strongly as compared to the nonionic ones and anionic polymers had shown the least interaction. From the observed results it was concluded that hydrophobicity plays an important role in the interaction as it overcomes the likely repulsion between the anionic drug and anionic polymers. All these previous studies motivated us to study the effect of cationic drug with various polymers. In the succession of this we studied the interaction of cyclodextrin with these drugs [24,25]. Following these approaches, in this paper, we have studied the effect of chlorpromazine hydrochloride, CPZ (Scheme 1), with various polymers like hydroxypropylmethyl cellulose (HPMC), dextran sulfate (DxS), sodium carboxymethyl cellulose (NaCMC), poly ethylene glycol (PEG) and polyvinylpyrrolidone (PVP) is seen using conductometry.
4.0 3.5 3.0
10-2κ (Scm-1)
284
2.5 2.0 1.5
% HPMC (w/v)
1.0
0.1
2. Materials and methods
0.2
0.5
0.5
2.1. Materials The amphiphilic phenothiazine drug chlorpromazine hydrochloride (CPZ) (98%, Sigma, USA), neutral polymers, i.e., polyvinylpyrrolidone K 30 (Fluka, Switzerland), polyethylene glycol K 35 (Fluka, Germany), hydroxypropylmethyl cellulose (Sigma, USA), and anionic polymers, i.e., sodium carboxymethylcellulose (Sigma, USA), dextran sulfate (Merck, Germany), were used as received. Demineralized doubledistilled water of specific conductivity 1–2 × 10 −6 S cm −1 was used to prepare the stock solutions of the drug and polymers. 2.2. Conductivity measurements The conductivity measurements were executed on an ELICO (type CM 82T) bridge equipped with platinized electrodes (cell constant = 1.02 cm −1). The conductivity runs were carried out by adding gradually concentrated CPZ stock solution into the thermostated solvent or solvent including polymer at temperature 25 °C. The critical micellar concentration of the pure CPZ used was obtained from the plots of specific conductivity (κ) as a function of the drug concentration. The cmc values were taken from the intersection of the two straight lines drawn before and after the intersection point in the plots (figure not shown). As in case of the polymer–drug mixtures the plots of κ versus [drug] showed two breaks (Figs. 1–5), the C1 was determined by the intersection of first and second linear parts and the C2 in this case was the intersection point of the second and third linear parts.
1.0
0.0 0
10
20
30
40
[CPZ] (mM) Fig. 1. Plots of specific conductivity (κ) versus CPZ concentration at different concentrations of HPMC. The scale shown is for plot denoted as (●). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1×10−2 S cm−1), respectively.
obtained by data fitting in Eqs. (1)–(4). It was interesting to note that both polar and non-polar (hydrophobic) interactions play important role in the polymer–amphiphile chemistry. In all the polymer– drug's specific conductivity profiles, there seems a steep rise in the conductivity of the solution on adding the drug up to the C1. At C1 the cooperative interaction between the drug and polymers starts and the mobility of the drug ions diminished as a result of the complexation with the polymer domain. Up to the second transition (C2) when all the polymer sites are occupied by the monomers or small aggregates the rise in conductivity acquires a smooth change. But as the C2 approaches the formation of the normal micelles begins and as micelles further have low mobility as compared to the free monomers and ions the slope becomes less steeper [27,28].
4.0 3.5
For the titration of CPZ into pure water, the conductivity below the cmc is due to the contribution of drug's head-groups and counterions. Above the cmc, the rate of the conductivity is smaller because micelles have rather lower mobility and a fraction of counterions are ion-paired with the micelles [26]. The experimental cmc of pure drug was found to be 21 mM (data not shown) which is in good agreement with the observed values [1]. It is apparent from the figures that, in the presence of polymers, the first break-point (C1) appears well below the usual cmc of the drug which is an indication of the onset of the polymer–amphiphilic drug interaction. Tables 1–5 display the values of C1, C2 and various thermodynamic parameters
3.0
10-2κ (Scm-1)
3. Results and discussion
2.5 2.0 1.5
% PEG (w/v)
1.0
0.1 0.2
0.5
0.5 1.0
0.0 0
10
20
30
40
[CPZ] (mM)
Scheme 1. Structure of chlorpromazine hydrochloride.
Fig. 2. Plots of specific conductivity (κ) versus CPZ concentration at different concentrations of PEG. The scale shown is for plot denoted as (●). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1×10−2 S cm−1), respectively.
4.0
4.0
3.5
3.5
3.0
3.0
2.5
2.5
10-2κ (Scm-1)
10-2κ (Scm-1)
M.S. Ali, H.A. Al-Lohedan / Journal of Molecular Liquids 177 (2013) 283–287
2.0 1.5
% PVP (w/v)
1.0
285
2.0
1.5
% NaCMC (w/v)
1.0
0.1
0.1
0.2
0.5
0.2
0.5
0.5
0.5
1.0
1.0
0.0 0
10
20
30
0.0
40
0
[CPZ] (mM)
10
20
30
40
[CPZ] (mM)
Fig. 3. Plots of specific conductivity (κ) versus CPZ concentration at different concentrations of PVP. The scale shown is for plot denoted as (●). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1×10−2 S cm−1), respectively.
While comparing the C1 and C2 values of different concentrations of same polymers and respective concentration (Fig. 6 and Tables 1–5) of different polymers it was found that C1 decreases on increasing the polymer concentration suggesting that the interaction is cooperative and increases on increasing the polymer concentration [28,29]. PEG shows the least interaction among non-ionic polymers while HPMC interacts strongly as compared to both PVP and PEG. It is reported that PEG is less hydrophobic as compared to the PVP [29]. The other factor which seems to be responsible for the stronger interaction of PVP is its partial negatively charged oxygen which bears more charge as compared to the PEG [21]. HPMC, conversely, is found to interact with both anionic and cationic surfactants as compared to the other nonionic polymers, interaction of which generally depends on the conditions of the interacting environment [30–34]. HPMC has an amphiphilic
Fig. 5. Plots of specific conductivity (κ) versus CPZ concentration at different concentrations of NaCMC. The scale shown is for plot denoted as (●). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1×10−2 S cm−1), respectively.
behavior and show a considerable surface activity. Therefore, stronger interaction of HPMC is, probably, due to its strong amphiphilic and surface active nature. Due to the stronger interaction of anionic polymers and the cationic drug C1 was found to be low at even very low concentrations of NaCMC and DxS in comparison to the experimental concentrations and observed C1 of nonionic polymers which obviously is attributable to the involvement of the electrostatic interactions between oppositely charged entities (Tables 4 and 5). Nevertheless, it was difficult to discriminate between the relative interactions of NaCMC and DxS towards the drug owing to very close values of observed and analyzed parameters. Since we have used basic techniques, these may probably be insensitive to distinguish between the strong interactions of anionic polymers and cationic amphiphilic drug.
4.0 3.5
Table 1 Degrees of micelle ionizations (α1 and α2), Free energies (ΔGagg, ΔGmic, and ΔGt) associated with the solution properties of HPMC and CPZ at 25 °C evaluated on the basis of conductometric measurements.
10-2κ (Scm-1)
3.0 2.5 2.0 1.5
% DxS (w/v)
1.0
103C1 mol dm−3
103C2 mol dm−3
α1
α2
ΔGagg (J mol−1)
ΔGmic (J mol−1)
ΔGt (J mol−1)
0.1 0.2 0.5 1.0
7.6 6.9 6.7 6.2
26.0 26.8 27.4 28.2
0.66 0.63 0.57 0.54
0.59 0.63 0.73 0.69
−4138 −4656 −5353 −5755
−3638 −3330 −2434. −2810
−500 −1326 −2918 −2945
Table 2 Degrees of micelle ionizations (α1 and α2), Free energies (ΔGagg, ΔGmic, and ΔGt) associated with the solution properties of PEG and CPZ at 25 °C evaluated on the basis of conductometric measurements.
0.1 0.2
0.5
%HPMC (w/v)
0.5 1.0
0.0 0
10
20
30
40
[CPZ] (mM) Fig. 4. Plots of specific conductivity (κ) versus CPZ concentration at different concentrations of DxS. The scale shown is for plot denoted as (●). Other plots have been shifted upwards by 0.5, 1.0, and 1.5 scale units (1×10−2 S cm−1), respectively.
%PEG (w/v)
103C1 mol dm−3
103C2 mol dm−3
0.0 0.1 0.2 0.5 1.0
9.4 9.0 8.0 8.0
21.2 25.4 27.3 30.2 31.4
α1
α2
0.65 0.58 0.54 0.53
0.55 0.63 0.58 0.59 0.58
ΔGagg (J mol−1)
ΔGmic (J mol−1)
ΔGt (J mol−1)
−4037 −4817 −5491 −5585
−4314 −3412 −3852 −3781 −3836
−625 −964 −1709 −1748
286
M.S. Ali, H.A. Al-Lohedan / Journal of Molecular Liquids 177 (2013) 283–287
Table 3 Degrees of micelle ionizations (α1 and α2), Free energies (ΔGagg, ΔGmic, and ΔGt) associated with the solution properties of PVP and CPZ at 25 °C evaluated on the basis of conductometric measurements.
Table 5 Degrees of micelle ionizations (α1 and α2), Free energies (ΔGagg, ΔGmic, and ΔGt) associated with the solution properties of NaCMC and CPZ at 25 °C evaluated on the basis of conductometric measurements.
%PVP (w/v)
103C1 mol dm−3
103C2 mol dm−3
α1
α2
ΔGagg (J mol−1)
ΔGmic (J mol−1)
ΔGt (J mol−1)
%NaCMC 103C1 103C2 α1 (w/v) mol dm−3 mol dm−3
α2
ΔGagg ΔGmic ΔGt (J mol−1) (J mol−1) (J mol−1)
0.1 0.2 0.5 1.0
7.4 7.2 7.0 6.8
25.3 26.5 28.4 30.6
0.66 0.57 0.57 0.55
0.61 0.58 0.65 0.64
−4146 −5262 −5149 −5537
−3522 −3767 −3155 −3183
−623 −1494 −1994 −2353
0.1 0.2 0.5 1.0
0.56 0.58 0.62 0.65
−5409 −5285 −5689 −6292
For ionic amphiphiles, the Gibbs energy of micelle formation was calculated from the pseudophase separation model according to the following relation [35] ΔGmic ¼ RT ð1 þ βÞ lncmc
ð1Þ
6.1 5.5 5.3 4.7
27.0 29.0 29.4 31.0
0.57 0.59 0.56 0.51
−3912 −3689 −3393 −3049
−1497 −1596 −2295 −3242
concentrations. For same concentration of polymers the value of ΔGt follows the trend:
PEG
where β is the counterion binding degree which is related to the degree of micelle ionization in the following way: ð2Þ
where α was calculated by taking the ratio between the slopes of the linear portions above and below the cmc. In the presence of the polymer, two values α1 and α2 are obtained corresponding to C1 and C2 respectively. Therefore, free energy associated with the interaction between polymer and amphiphilic drug (ΔGagg) and the free energy of micellization (ΔGmic) can be written as: ΔGagg ¼ RT ð1 þ β1 Þ lnC1 and ΔGmic ¼ RT ð1 þ β2 Þ lnC2 :
ð3Þ
The free energy of transfer can be given as [36]: ( ) ΔGt ðC1 Þð1þβ1 Þ : ¼ ln RT ðC2 Þð1þβ2 Þ
ð4Þ
From the respective values of (ΔGagg) for various polymers and their different concentrations, it can be concluded that it decreases on increasing the polymer concentration owing to the increased interaction which makes the process energetically more favorable. Free energy of aggregation is much higher as compared to the free energy of micellization in polymer free solution. This suggests that the complexation of drug and polymer is a more favorable process as compared to the micellization of drug in the absence of polymer. It is supposed that ΔGmic will become less favorable on increasing the polymer concentrations but there is no considerable change in the case of nonionic polymers on doing so. However, anionic polymers face a small change in the value of ΔGmic. In the presence of anionic polymers a strong electrostatic interaction may lead to a delayed micellization of drugs due to which the micellization becomes more energetically unfavorable. Both qualitative and quantitative aspects of binding interactions between drug and polymers can easily be understood with the help of ΔGt values obtained for different polymers and at various
Table 4 Degrees of micelle ionizations (α1 and α2), Free energies (ΔGagg, ΔGmic, and ΔGt) associated with the solution properties of DxS and CPZ at 25 °C evaluated on the basis of conductometric measurements. %Dextran 103C1 103C2 α1 (w/v) mol dm−3 mol dm−3
α2
ΔGagg ΔGmic ΔGt (J mol−1) (J mol−1) (J mol−1)
0.1 0.2 0.5 1.0
0.53 0.59 0.67 0.68
−4928 −5226 −5851 −5961
6.2 5.6 5.3 4.5
26.7 27.5 29.2 31.9
0.59 0.58 0.55 0.55
−4208 −3617 −2922 −2832
−720 −1608 −2929 −3128
It was easy to compare the relative interactions of nonionic polymers with each other on the basis of observed and calculated values. However, in the case of anionic polymers (NaCMC and DxS) all the reported values and fitted parameters were close enough and it was difficult to distinguish which one is a strongly interacting anionic polymer.
4. Conclusions Interaction of amphiphilic drug chlorpromazine hydrochloride (CPZ) with several biocompatible polymers has been studied using conductometry. Being a cationic drug, CPZ interacts more strongly with anionic polymers as compared to the nonionic ones. The onset of interaction decreases on increasing the concentration of the polymer which also indicates that interaction between the drug and polymer was cooperative. Hydrophobicity plays an important role in the interaction as revealed by the comparative interaction of nonionic polymers with CPZ. Acknowledgment The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RGP-VPP-148.
10 HPMC PEG PVP
9
DxS NaCMC
8
c1(mM)
β ¼ ð1−α Þ
7
6
5
4 0.0
0.2
0.4
0.6
0.8
1.0
[polymer] (wt/vol) Fig. 6. Critical aggregation concentration as a function of concentrations of various polymers.
M.S. Ali, H.A. Al-Lohedan / Journal of Molecular Liquids 177 (2013) 283–287
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