- Email: [email protected]
Solubility of atenolol, amiodarone HCl and lamotrigine in polyethylene glycol 200 + water mixtures in the presence of β-cyclodextrin
J. DRUG DEL. SCI. TECH., 24 (5) 543-547 2014
Solubility of atenolol, amiodarone HCl and lamotrigine in polyethylene glycol 200 + water mixtures in the presence of β-cyclodextrin A. Jouyban1, 2*, S. Sajed-Amin3, V. Panahi-Azar4 1 Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Pharmaceutical Engineering Laboratory, School of Chemical Engineering, College of Engineering, University of Tehran, PO Box 11155/4563, Tehran, Iran 3 Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 4 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran *Correspondence: [email protected]
2
Solubilities of three drugs, i.e. atenolol, amiodarone HCl and lamotrigine in binary mixtures of polyethylene glycol 200 + water in the presence of beta-cyclodextrin (β-CD) along with the solubilities of atenolol and amiodarone HCl in this solvent mixture in the absence of β-CD using saturating shake flask method were studied. The generated solubility data was fitted to the Jouyban-Acree model and the solubility profile of each drug in the presence of β-CD was compared with solubility data in the absence of β-CD that the solubility data of lamotrigine taken from a previous paper. Key words: Solubility – Cosolvency – Complexing agents – Jouyban-Acree model
Solubility is a crucial physicochemical property in drug discovery and development [1]. Solubilization of drugs is very important to improve bioavailability of drugs and preparation of liquid dosage forms [2]. Cosolvency or solvent mixing is a common solubilization method and is used to prepare topical, oral and parenteral dosage forms of poorly soluble drugs [3]. So solubility data of drugs in solvent mixtures can be used in designing of required formulations and also it can help to understand the mechanism of solubility of drugs in these mixtures. Polyethylene glycols (PEGs) are non-toxic, non-volatile, odorless and non-irritating compounds with very high aqueous solubility. They were used in the pharmaceutical industry as cosolvent, dispensing agent, as base for ointments and suppositories and also as excipients in tablet formulations [4]. PEGs up to 800 g/mole are in liquid form and those with the molecular weights of more than 1000 are in solid form. PEGs are also used as a reaction media for synthesis of drugs [5]. In addition to various applications of PEGs as a mono-solvent, they are widely used as aqueous mixtures in the industry for various purposes including solubilizing agent for low water soluble drugs [2, 6, 7], synthesis of various compounds [8, 9], preparation of nanoparticles [10], improving bioavailability of drugs [11] and so many other applications. Complex formation of drugs is another well-established method for solubilization of drugs which improve the solubility and the chemical stability. These agents are used alone or in combination with other solubilization agents such as surfactants or cosolvents. Cyclodextrins (CDs), mainly beta-cyclodextrin (β-CD) are the main complexing agents used in the pharmaceutical industries and applied for parenteral solutions, tablet, ointment, suppository, eye drop and nasal spray formulations. The pharmaceutical applications of CDs were reviewed by the experts [12, 13]. Addition of the cosolvents and CDs was used to improve the aqueous solubility of drugs and was concluded that cosolvent size and polarity, destabilization of drug-ligand complex and the formation of a ternary drug-ligand-cosolvent complex affect the solubility of drugs [14, 15]. Determination of solubility is a time consuming process and mathematical models could be used to estimate drugs solubility as an alternative method. The Jouyban-Acree model was used to predict the solubility of drugs in solvent mixtures at various temperatures [3]:
2
[
log X m ,T = m1 log X 1,T + m2 log X 2 ,T + Σ J i i =0
m1 m2 ( m1 - m2 )i T
]
Eq. 1
where Xm,T is the mole fraction solubility of the solute in solvent mixture, X1,T and X2,T denote the solubility in the mono-solvents at temperature T (K), m1 and m2 are mass fractions of solvents 1 and 2 in the absence of the solute, respectively, and Ji terms are the model constants. This model requires two solubility data in the mono-solvents and at least three data points in mixed solvents as input values. Solubilities of three drugs in propylene glycol + water mixtures in the absence [16] and presence of β-CD [17] were reported in earlier works. The solubility of lamotrigine in PEG 200 + water mixtures in the absence of β-CD was reported in a previous work [18]. In this study, solubilities of atenolol and amiodarone HCl in PEG 200 + water mixtures at 25 ºC and also solubilities of atenolol, amiodarone HCl and lamotrigine (for chemical structures of drugs see Figure 1) in the presence of 10 mM of β-CD were determined. In addition, densities of the saturated solutions were measured and used to convert the molar solubilities to mole fraction solubilities. The mole fraction solubilities are required in some pharmaceutical engineering calculations for process designs. The main novelties of this work are; reporting new experimental data and application of the Jouyban-Acree model for representing both effects of solvent composition and concentration of complexing agent on the solubility of drugs. The solubilization power (w) of a cosolvent could be calculated according to [19]: Eq. 2 w = [log(Xm,max/Xmin,T)]/m1,max in which Xm,max is the maximum observed solubility and m1,max is the fraction of the cosolvent providing Xm,max [19]. Xmin,T is the minimum solubility, i.e. aqueous solubility of drugs in the absence of β-CD in this study.
I. METHODS AND MATERIALS 1. Materials
Atenolol was purchased from Darou Pakhsh (Tehran, Iran), amiodarone HCl was purchased from Behdashtkar company (Rasht, Iran), lamotrigine was purchased from Arastoo company (Tehran, Iran). Drug powders were pharmaceutical grade according to United States Pharmacopoeia. PEG 200 (purity of 0.99) and β-CD (purity of 0.99) were obtained from Merck (Germany). Double distillated water 543
Solubility of atenolol, amiodarone HCl and lamotrigine in polyethylene glycol 400 + water mixtures in the presence of b-cyclodextrin A. Jouyban, S. Sajed-Amin, V. Panahi-Azar
J. DRUG DEL. SCI. TECH., 24 (5) 543-547 2014
least three repeated measurements with the measured mole per liter solubilities being reproducible to within relative standard deviations (RSD) ranged from 0.7 to 5.1 %. Figure 2 shows the solubility profile of atenolol in PEG 200 + water and PEG 200 + water + 10 mM β-CD mixtures. Aqueous solubility of atenolol obtained in this work is 0.07116 M (or 0.001279 in mole fraction) and no significant increase is observed after addition of 10 mM β-CD (0.07946 M). These findings are in agreement with reported data [22] where the solubilities in water and in water + 10 mM β-CD were reported as 0.071 M and 0.077 M, respectively. Mole fraction solubility of atenolol in an aqueous buffer (pH 7.4) at 25 ºC was reported as 0.00149 [23] which is slightly higher than our measured datum, 0.001279 and could be justified using basic characteristics of atenolol (pKa 9.6). The solubility of atenolol in PEG 200 + water mixtures was increased with the addition of PEG 200, and a similar pattern was observed for PEG 200 + water + 10 mM β-CD mixtures. An inclusion complex between atenolol and β-CD has been reported in the literature [22, 24] and an increased solubility of atenolol after addition of β-CD was expected. Despite of our expectation, no significant change was observed for solubility of atenolol in the presence and absence of β-CD. A possible reason could be the equal solubility of atenolol and its complexed form in the mixed solvents. Figure 3 illustrates the solubility of amiodarone HCl in PEG 200 + water in the absence and presence of 10 mM β-CD. The intrinsic aqueous solubilities of amiodarone were reported as 15 nM [25] and 7.94 nM [26]. It was also reported as 100.18 mg/L (0.000024 M) which is significantly increased by addition of hydroxypropyl β-CD and sulfabuthylether β-CD [27]. Salt formation with HCl resulted in an increase in its aqueous solubility from 0.000024 M to 0.00034 M. The aqueous solubility of amiodarone HCl is increased from 0.00034 M
Atenolol: NH2
CH3 H3C
NH
O
O OH
Amiodarone HCl: I +
O
HN
H3C H3C
O I O CH - 3 Cl
Lamotrigine: H3C
N N N
Cl
N
Figure 1 - Chemical structures of the investigated drugs.
was used for preparation of the solutions and ethanol (mass fraction purity of 0.935) from Jahan Alcohol Teb (Arak, Iran) was used for dilution of the saturated solutions for spectrophotometric analyses.
Mole fraction solubility of atenolol
2. Experimental methods
The binary solvent mixtures of PEG 200 + water were prepared by mass with the uncertainty of 0.01 g. To prepare the solvent mixtures + 10 mM β-CD, aqueous and ethanolic solutions of 10 mM β-CD were prepared, then appropriate masses of the solutions were mixed up. Different methods were presented for determining the solubility of drugs [21]. The solubility of studied drugs was determined using saturating shake-flask method. Briefly, the excess drug was added to the prepared solutions and then they were placed on a shaker (Behdad, Tehran, Iran) in an incubator equipped with a temperature-controlling system (uncertainty of 0.2 ºC, Nabziran, Tabriz, Iran). After equilibrium (> 3 days), the saturated solutions were centrifuged in 10000 rpm for 10 min (MSE Micro Center MSB010.CX2.5, Sanyo, Muriguchi City, Japan) and diluted by water and/or ethanol (96 % or 0.935 in mass fraction). The absorption of diluted solutions was determined by a UV-Vis spectrophotometer (Beckman DU-650, Fullerton, California, United States) according to their calibration curves. Solubility data of lamotrigine in PEG 200 + water mixtures was collected from a previous report [18].
0.08
PEG 200 + water
0.07
PEG 200 + water + 10 mM β- CD PEG 200 + water
0.06
PEG 200 + water + 10 mM β- CD
0.05 0.04 0.03 0.02 0.01 0.00 0.0
0.2
0.4
0.6
0.8
1.0
Mass fraction of PEG 200
Figure 2 - Mole fraction solubility profile of atenolol, experimental data shown with n or l and the back-calculated data with the lines. 0.005
PEG 200 + water
Mole fraction solubility of aminodarone HCl
0.005
3. Computational methods
The experimental solubility data of drugs in PEG 200 + water mixtures in the absence and presence of 10 mM β-CD was fitted to Equation 1. The fitted data of each drug in the studied systems and the back calculated solubilities were used to calculate the accuracy of fitness using mean relative deviation (MRD) calculated by: Eq. 3 MRD = (100/N) Σ |(Xm,cal - Xm,exp)/Xm,exp| in which N is the number of data points in each set.
PEG 200 + water + 10 mM β-CD PEG 200 + water
0.004
PEG 200 + water + 10 mM β-CD
0.004 0.003 0.003 0.002 0.002 0.001 0.001 0.000 0.0
II. RESULTS AND DISCUSSION
0.2
0.4
0.6
0.8
1.0
Mass fraction of PEG 200
The measured solubilities of the studied drugs in PEG 200 + water in the absence and presence of 10 mM β-CD solutions at 25 ºC are listed in Table I. Each experimental data point is the average of at
Figure 3 - Mole fraction solubility profile of aliodarone HCl, experimental data shown with n or l and the back-calculated data with the lines. 544
Solubility of atenolol, amiodarone HCl and lamotrigine in polyethylene glycol 400 + water mixtures in the presence of b-cyclodextrin A. Jouyban, S. Sajed-Amin, V. Panahi-Azar
J. DRUG DEL. SCI. TECH., 24 (5) 543-547 2014
Table I - Molar and mole fraction solubilities of atenolol, amiodarone HCl and lamotrigine in the investigated systems at 25 ºC. Mass fraction of PEG 200
Solvent system Atenolol PEG 200 + water
Atenolol PEG 200 + water + β-CD
0.00
0.07116
0.07946
0.10
0.10842
0.20
0.13282
0.30 0.40
Amiodarone HCl PEG 200 + water
Amiodarone HCl PEG 200 + water + β-CD
Lamotrigine PEG 200 + water + β-CD
0.00034
0.00127
0.00332
0.10954
0.00090
0.00209
0.00463
0.13761
0.00147
0.00271
0.00575
0.18266
0.16248
0.00244
0.00371
0.01242
0.24180
0.20331
0.00315
0.00531
0.01563
0.50
0.28808
0.25710
0.00577
0.00762
0.04533
0.60
0.31276
0.28385
0.00755
0.00982
0.07335
0.70
0.31652
0.28085
0.01265
0.01551
0.16990
0.80
0.37227
0.32403
0.01486
0.01887
0.48523
0.90
0.39565
0.37922
0.01544
0.02099
0.58189
1.00
0.43624
0.43319
0.01973
0.02672
0.84341
0.00
0.001279
0.001428
0.000006
0.000023
0.000059
0.10
0.003833
0.003873
0.000032
0.000074
0.000165
0.20
0.006887
0.007148
0.000077
0.000143
0.000299
0.30
0.011059
0.012475
0.000171
0.000258
0.000857
0.40
0.020297
0.017121
0.000277
0.000456
0.001330
0.50
0.028261
0.025413
0.000595
0.000778
0.004528
0.60
0.031789
0.034915
0.000883
0.001149
0.008438
0.70
0.039481
0.035187
0.001644
0.002016
0.021647
0.80
0.051418
0.045014
0.002146
0.002732
0.065840
0.90
0.059767
0.057523
0.002467
0.003331
0.085165
1.00
0.071122
0.070659
0.003450
0.004637
0.128286
Molar solubility
Mole fraction solubility
to 0.00127 M (solubility enhancement factor of 3.7) revealing the formation of a complex between amiodarone and β-CD. A similar aqueous solubility data for amiodarone in 10 mM of β-CD solution has been reported in the literature [28]. More solubilized amiodarone (0.0025 M) has been achieved using 10 mM of hydroxypropyl β-CD [29]. Comparisons of the solubility of amiodarone HCl in water + β-CD and PEG 200 + β-CD mixtures with their corresponding values in the absence of β-CD reveal that the solubility of amiodarone-β-CD complex is more than that of amiodarone. The increased pattern of the solubility of amiodarone HCl is observed in PEG 200 + 10 mM β-CD mixtures with the solubility enhancement factor of 1.2. Figure 4 shows the solubility of lamotrigine in PEG 200 + water taken from a previous work [18] and in PEG 200 + water + 10 mM CD determined in this work. The aqueous solubility of lamotrigine is increased from 0.00073 M [18] to 0.00332 M (solubility enhancement factor of 4.6). Formation of a complex between lamotrigine and β-CD was confirmed by earlier observations [30]. An increased solubility of lamotrigine in water at 25 ºC by 1:1 inclusion complex of β-CD was reported with an enhancement factor of 2.1 [31]. The increased pattern of the solubility of lamotrigine is observed in PEG 200 + water + 10 mM β-CD whereas the pattern was increasing up to the 0.80 volume fraction of propylene glycol and further addition of propylene glycol resulted in a decreased solubility as shown in an earlier work [17]. Table II lists the model constants of fitting data to the Eq. 1 and MRD values of each studied system. These findings show that the solubility data in PEG 200 + water and in PEG 200 + water + 10 mM β-CD could be fitted to the Equation 1 with good accuracy. The MRD
0.14
PEG 200 + water PEG 200 + water+ 10 mM β-CD PEG 200 + water PEG 200 + water+ 10 mM β-CD
0.10
0.02 Mole fraction solubility of lamotrigine
Mole fraction solubility of lamotrigin
0.12
0.08
0.06
0.01
0.00 0
0.04
0.2
0.4
0.6
Volume fraction of PEG 200
0.02
0.00 0.0
0.2
0.4
0.6
0.8
1.0
Mass fraction of PEG 200
Figure 4 - Mole fraction solubility profile of lamotrigine, experimental data shown with n or l and the back-calculated data with the lines.
values vary between 4.1 to 11.6 % with the overall value of 7.0 %. Concerning the computed model constants, it is possible to predict the solubility of the investigated drugs in all possible compositions of the mixtures. 545
Solubility of atenolol, amiodarone HCl and lamotrigine in polyethylene glycol 400 + water mixtures in the presence of b-cyclodextrin A. Jouyban, S. Sajed-Amin, V. Panahi-Azar
J. DRUG DEL. SCI. TECH., 24 (5) 543-547 2014
solutions of pharmaceuticals may affect their solubility and stability. We did not study the effect of added excipients on the stability of the drugs and further investigations are required to show this effect. The Jouyban-Acree model fits very well to the data and could be used to predict the solubility data at other solvent compositions.
Table II - Numerical values of the adjusted parameters of Equation 1 and the mean relative deviation (MRD) for the fitting mole fraction solubilities of atenolol, amiodarone HCl and lamotrigine in PEG 200 + water mixtures and in presence of 10 mM β-CD. Drug
Solvent system
J0
J1
J2
MRD
Atenolol
PEG 200 + water
532.85
-319.58
0**
5.1
PEG 200 + water + 10 mM β-CD
493.09
-366.07
0**
4.1
REFERENCES
Amiodarone HCl
PEG 200 + water
685.59
-337.43
426.53
7.3
1.
PEG 200 + water + 10 mM β-CD
437.58
-185.22
270.20
4.8
Lamotrigine
PEG 200 + water*
574.64
0**
0**
8.7
PEG 200 + water + 10 mM β-CD
161.37
303.78
529.00
11.6
Overall
7.0
2. 3. 4.
*Data taken from a previous study [18]. **The value is not statistically significant (p > 0.1).
5.
Table III - Numerical values of the solubilization powers of PEG 200, PEG 200 + 10 mM β-CD, PG and PG + 10 mM β-CD for the investigated drugs in this work and a previous one [17]. Drug Atenolol Amiodarone HCl Lamotrigine
Atenolol Diazepam Lamotrigine*
Solvent system
w
6. 7.
PEG 200 + water
0.79
PEG 200 + water + 10 mM β-CD
0.78
PEG 200 + water
1.76
PEG 200 + water + 10 mM β-CD
1.90
PEG 200 + water*
2.46
PEG 200 + water + 10 mM β-CD
3.08
PG + water**
0.69
PG + water + 10 mM β-CD**
0.67
PG + water***
2.46
PG + water + 10 mM β-CD**
4.19
PG + water***
2.45
PG + water + 10 mM β-CD**
2.91
8.
9.
10. 11. 12.
Data taken from a previous study: *[18], **[16], ***[17].
13.
Table III reports the calculated w values for aqueous mixtures of PEG 200 and PEG 200 + 10 mM β-CD. No significant change in the solubilization power of the solubilizers for atenolol was observed. A similar observation was also the case for solubility of atenolol in propylene glycol + β-CD data reported in a previous work [17]. Addition of β-CD was improved the solubilization power of PEG 200 from 1.76 to 1.90 for amiodarone HCl. It should be noted that ω values are in logarithmic scale and one unit increase in ω means solubility enhancement by a factor of 10. Further increase in ω values was observed for lamotrigine in PEG 200 + β-CD. A similar pattern was observed for solubilization power of propylene glycol and propylene glycol + β-CD.
14.
15. 16.
17.
* 18.
In conclusion, the generated data in this work extends the available solubility database of pharmaceuticals [32] and could be used in the pharmaceutical industries. There are good agreements between generated data in this work and the previously reported data in the literature. The addition of a cosolvent and a complexing agent to the aqueous
19.
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MANUSCRIPT Received 20 February 2014, accepted for publication 18 March 2014.
547
Solubility of atenolol, amiodarone HCl and lamotrigine in polyethylene glycol 200 + water mixtures in the presence of β-cyclodextrin A. Jouyban1, 2*, S. Sajed-Amin3, V. Panahi-Azar4 1 Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Pharmaceutical Engineering Laboratory, School of Chemical Engineering, College of Engineering, University of Tehran, PO Box 11155/4563, Tehran, Iran 3 Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran 4 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran *Correspondence: [email protected]
2
Solubilities of three drugs, i.e. atenolol, amiodarone HCl and lamotrigine in binary mixtures of polyethylene glycol 200 + water in the presence of beta-cyclodextrin (β-CD) along with the solubilities of atenolol and amiodarone HCl in this solvent mixture in the absence of β-CD using saturating shake flask method were studied. The generated solubility data was fitted to the Jouyban-Acree model and the solubility profile of each drug in the presence of β-CD was compared with solubility data in the absence of β-CD that the solubility data of lamotrigine taken from a previous paper. Key words: Solubility – Cosolvency – Complexing agents – Jouyban-Acree model
Solubility is a crucial physicochemical property in drug discovery and development [1]. Solubilization of drugs is very important to improve bioavailability of drugs and preparation of liquid dosage forms [2]. Cosolvency or solvent mixing is a common solubilization method and is used to prepare topical, oral and parenteral dosage forms of poorly soluble drugs [3]. So solubility data of drugs in solvent mixtures can be used in designing of required formulations and also it can help to understand the mechanism of solubility of drugs in these mixtures. Polyethylene glycols (PEGs) are non-toxic, non-volatile, odorless and non-irritating compounds with very high aqueous solubility. They were used in the pharmaceutical industry as cosolvent, dispensing agent, as base for ointments and suppositories and also as excipients in tablet formulations [4]. PEGs up to 800 g/mole are in liquid form and those with the molecular weights of more than 1000 are in solid form. PEGs are also used as a reaction media for synthesis of drugs [5]. In addition to various applications of PEGs as a mono-solvent, they are widely used as aqueous mixtures in the industry for various purposes including solubilizing agent for low water soluble drugs [2, 6, 7], synthesis of various compounds [8, 9], preparation of nanoparticles [10], improving bioavailability of drugs [11] and so many other applications. Complex formation of drugs is another well-established method for solubilization of drugs which improve the solubility and the chemical stability. These agents are used alone or in combination with other solubilization agents such as surfactants or cosolvents. Cyclodextrins (CDs), mainly beta-cyclodextrin (β-CD) are the main complexing agents used in the pharmaceutical industries and applied for parenteral solutions, tablet, ointment, suppository, eye drop and nasal spray formulations. The pharmaceutical applications of CDs were reviewed by the experts [12, 13]. Addition of the cosolvents and CDs was used to improve the aqueous solubility of drugs and was concluded that cosolvent size and polarity, destabilization of drug-ligand complex and the formation of a ternary drug-ligand-cosolvent complex affect the solubility of drugs [14, 15]. Determination of solubility is a time consuming process and mathematical models could be used to estimate drugs solubility as an alternative method. The Jouyban-Acree model was used to predict the solubility of drugs in solvent mixtures at various temperatures [3]:
2
[
log X m ,T = m1 log X 1,T + m2 log X 2 ,T + Σ J i i =0
m1 m2 ( m1 - m2 )i T
]
Eq. 1
where Xm,T is the mole fraction solubility of the solute in solvent mixture, X1,T and X2,T denote the solubility in the mono-solvents at temperature T (K), m1 and m2 are mass fractions of solvents 1 and 2 in the absence of the solute, respectively, and Ji terms are the model constants. This model requires two solubility data in the mono-solvents and at least three data points in mixed solvents as input values. Solubilities of three drugs in propylene glycol + water mixtures in the absence [16] and presence of β-CD [17] were reported in earlier works. The solubility of lamotrigine in PEG 200 + water mixtures in the absence of β-CD was reported in a previous work [18]. In this study, solubilities of atenolol and amiodarone HCl in PEG 200 + water mixtures at 25 ºC and also solubilities of atenolol, amiodarone HCl and lamotrigine (for chemical structures of drugs see Figure 1) in the presence of 10 mM of β-CD were determined. In addition, densities of the saturated solutions were measured and used to convert the molar solubilities to mole fraction solubilities. The mole fraction solubilities are required in some pharmaceutical engineering calculations for process designs. The main novelties of this work are; reporting new experimental data and application of the Jouyban-Acree model for representing both effects of solvent composition and concentration of complexing agent on the solubility of drugs. The solubilization power (w) of a cosolvent could be calculated according to [19]: Eq. 2 w = [log(Xm,max/Xmin,T)]/m1,max in which Xm,max is the maximum observed solubility and m1,max is the fraction of the cosolvent providing Xm,max [19]. Xmin,T is the minimum solubility, i.e. aqueous solubility of drugs in the absence of β-CD in this study.
I. METHODS AND MATERIALS 1. Materials
Atenolol was purchased from Darou Pakhsh (Tehran, Iran), amiodarone HCl was purchased from Behdashtkar company (Rasht, Iran), lamotrigine was purchased from Arastoo company (Tehran, Iran). Drug powders were pharmaceutical grade according to United States Pharmacopoeia. PEG 200 (purity of 0.99) and β-CD (purity of 0.99) were obtained from Merck (Germany). Double distillated water 543
Solubility of atenolol, amiodarone HCl and lamotrigine in polyethylene glycol 400 + water mixtures in the presence of b-cyclodextrin A. Jouyban, S. Sajed-Amin, V. Panahi-Azar
J. DRUG DEL. SCI. TECH., 24 (5) 543-547 2014
least three repeated measurements with the measured mole per liter solubilities being reproducible to within relative standard deviations (RSD) ranged from 0.7 to 5.1 %. Figure 2 shows the solubility profile of atenolol in PEG 200 + water and PEG 200 + water + 10 mM β-CD mixtures. Aqueous solubility of atenolol obtained in this work is 0.07116 M (or 0.001279 in mole fraction) and no significant increase is observed after addition of 10 mM β-CD (0.07946 M). These findings are in agreement with reported data [22] where the solubilities in water and in water + 10 mM β-CD were reported as 0.071 M and 0.077 M, respectively. Mole fraction solubility of atenolol in an aqueous buffer (pH 7.4) at 25 ºC was reported as 0.00149 [23] which is slightly higher than our measured datum, 0.001279 and could be justified using basic characteristics of atenolol (pKa 9.6). The solubility of atenolol in PEG 200 + water mixtures was increased with the addition of PEG 200, and a similar pattern was observed for PEG 200 + water + 10 mM β-CD mixtures. An inclusion complex between atenolol and β-CD has been reported in the literature [22, 24] and an increased solubility of atenolol after addition of β-CD was expected. Despite of our expectation, no significant change was observed for solubility of atenolol in the presence and absence of β-CD. A possible reason could be the equal solubility of atenolol and its complexed form in the mixed solvents. Figure 3 illustrates the solubility of amiodarone HCl in PEG 200 + water in the absence and presence of 10 mM β-CD. The intrinsic aqueous solubilities of amiodarone were reported as 15 nM [25] and 7.94 nM [26]. It was also reported as 100.18 mg/L (0.000024 M) which is significantly increased by addition of hydroxypropyl β-CD and sulfabuthylether β-CD [27]. Salt formation with HCl resulted in an increase in its aqueous solubility from 0.000024 M to 0.00034 M. The aqueous solubility of amiodarone HCl is increased from 0.00034 M
Atenolol: NH2
CH3 H3C
NH
O
O OH
Amiodarone HCl: I +
O
HN
H3C H3C
O I O CH - 3 Cl
Lamotrigine: H3C
N N N
Cl
N
Figure 1 - Chemical structures of the investigated drugs.
was used for preparation of the solutions and ethanol (mass fraction purity of 0.935) from Jahan Alcohol Teb (Arak, Iran) was used for dilution of the saturated solutions for spectrophotometric analyses.
Mole fraction solubility of atenolol
2. Experimental methods
The binary solvent mixtures of PEG 200 + water were prepared by mass with the uncertainty of 0.01 g. To prepare the solvent mixtures + 10 mM β-CD, aqueous and ethanolic solutions of 10 mM β-CD were prepared, then appropriate masses of the solutions were mixed up. Different methods were presented for determining the solubility of drugs [21]. The solubility of studied drugs was determined using saturating shake-flask method. Briefly, the excess drug was added to the prepared solutions and then they were placed on a shaker (Behdad, Tehran, Iran) in an incubator equipped with a temperature-controlling system (uncertainty of 0.2 ºC, Nabziran, Tabriz, Iran). After equilibrium (> 3 days), the saturated solutions were centrifuged in 10000 rpm for 10 min (MSE Micro Center MSB010.CX2.5, Sanyo, Muriguchi City, Japan) and diluted by water and/or ethanol (96 % or 0.935 in mass fraction). The absorption of diluted solutions was determined by a UV-Vis spectrophotometer (Beckman DU-650, Fullerton, California, United States) according to their calibration curves. Solubility data of lamotrigine in PEG 200 + water mixtures was collected from a previous report [18].
0.08
PEG 200 + water
0.07
PEG 200 + water + 10 mM β- CD PEG 200 + water
0.06
PEG 200 + water + 10 mM β- CD
0.05 0.04 0.03 0.02 0.01 0.00 0.0
0.2
0.4
0.6
0.8
1.0
Mass fraction of PEG 200
Figure 2 - Mole fraction solubility profile of atenolol, experimental data shown with n or l and the back-calculated data with the lines. 0.005
PEG 200 + water
Mole fraction solubility of aminodarone HCl
0.005
3. Computational methods
The experimental solubility data of drugs in PEG 200 + water mixtures in the absence and presence of 10 mM β-CD was fitted to Equation 1. The fitted data of each drug in the studied systems and the back calculated solubilities were used to calculate the accuracy of fitness using mean relative deviation (MRD) calculated by: Eq. 3 MRD = (100/N) Σ |(Xm,cal - Xm,exp)/Xm,exp| in which N is the number of data points in each set.
PEG 200 + water + 10 mM β-CD PEG 200 + water
0.004
PEG 200 + water + 10 mM β-CD
0.004 0.003 0.003 0.002 0.002 0.001 0.001 0.000 0.0
II. RESULTS AND DISCUSSION
0.2
0.4
0.6
0.8
1.0
Mass fraction of PEG 200
The measured solubilities of the studied drugs in PEG 200 + water in the absence and presence of 10 mM β-CD solutions at 25 ºC are listed in Table I. Each experimental data point is the average of at
Figure 3 - Mole fraction solubility profile of aliodarone HCl, experimental data shown with n or l and the back-calculated data with the lines. 544
Solubility of atenolol, amiodarone HCl and lamotrigine in polyethylene glycol 400 + water mixtures in the presence of b-cyclodextrin A. Jouyban, S. Sajed-Amin, V. Panahi-Azar
J. DRUG DEL. SCI. TECH., 24 (5) 543-547 2014
Table I - Molar and mole fraction solubilities of atenolol, amiodarone HCl and lamotrigine in the investigated systems at 25 ºC. Mass fraction of PEG 200
Solvent system Atenolol PEG 200 + water
Atenolol PEG 200 + water + β-CD
0.00
0.07116
0.07946
0.10
0.10842
0.20
0.13282
0.30 0.40
Amiodarone HCl PEG 200 + water
Amiodarone HCl PEG 200 + water + β-CD
Lamotrigine PEG 200 + water + β-CD
0.00034
0.00127
0.00332
0.10954
0.00090
0.00209
0.00463
0.13761
0.00147
0.00271
0.00575
0.18266
0.16248
0.00244
0.00371
0.01242
0.24180
0.20331
0.00315
0.00531
0.01563
0.50
0.28808
0.25710
0.00577
0.00762
0.04533
0.60
0.31276
0.28385
0.00755
0.00982
0.07335
0.70
0.31652
0.28085
0.01265
0.01551
0.16990
0.80
0.37227
0.32403
0.01486
0.01887
0.48523
0.90
0.39565
0.37922
0.01544
0.02099
0.58189
1.00
0.43624
0.43319
0.01973
0.02672
0.84341
0.00
0.001279
0.001428
0.000006
0.000023
0.000059
0.10
0.003833
0.003873
0.000032
0.000074
0.000165
0.20
0.006887
0.007148
0.000077
0.000143
0.000299
0.30
0.011059
0.012475
0.000171
0.000258
0.000857
0.40
0.020297
0.017121
0.000277
0.000456
0.001330
0.50
0.028261
0.025413
0.000595
0.000778
0.004528
0.60
0.031789
0.034915
0.000883
0.001149
0.008438
0.70
0.039481
0.035187
0.001644
0.002016
0.021647
0.80
0.051418
0.045014
0.002146
0.002732
0.065840
0.90
0.059767
0.057523
0.002467
0.003331
0.085165
1.00
0.071122
0.070659
0.003450
0.004637
0.128286
Molar solubility
Mole fraction solubility
to 0.00127 M (solubility enhancement factor of 3.7) revealing the formation of a complex between amiodarone and β-CD. A similar aqueous solubility data for amiodarone in 10 mM of β-CD solution has been reported in the literature [28]. More solubilized amiodarone (0.0025 M) has been achieved using 10 mM of hydroxypropyl β-CD [29]. Comparisons of the solubility of amiodarone HCl in water + β-CD and PEG 200 + β-CD mixtures with their corresponding values in the absence of β-CD reveal that the solubility of amiodarone-β-CD complex is more than that of amiodarone. The increased pattern of the solubility of amiodarone HCl is observed in PEG 200 + 10 mM β-CD mixtures with the solubility enhancement factor of 1.2. Figure 4 shows the solubility of lamotrigine in PEG 200 + water taken from a previous work [18] and in PEG 200 + water + 10 mM CD determined in this work. The aqueous solubility of lamotrigine is increased from 0.00073 M [18] to 0.00332 M (solubility enhancement factor of 4.6). Formation of a complex between lamotrigine and β-CD was confirmed by earlier observations [30]. An increased solubility of lamotrigine in water at 25 ºC by 1:1 inclusion complex of β-CD was reported with an enhancement factor of 2.1 [31]. The increased pattern of the solubility of lamotrigine is observed in PEG 200 + water + 10 mM β-CD whereas the pattern was increasing up to the 0.80 volume fraction of propylene glycol and further addition of propylene glycol resulted in a decreased solubility as shown in an earlier work [17]. Table II lists the model constants of fitting data to the Eq. 1 and MRD values of each studied system. These findings show that the solubility data in PEG 200 + water and in PEG 200 + water + 10 mM β-CD could be fitted to the Equation 1 with good accuracy. The MRD
0.14
PEG 200 + water PEG 200 + water+ 10 mM β-CD PEG 200 + water PEG 200 + water+ 10 mM β-CD
0.10
0.02 Mole fraction solubility of lamotrigine
Mole fraction solubility of lamotrigin
0.12
0.08
0.06
0.01
0.00 0
0.04
0.2
0.4
0.6
Volume fraction of PEG 200
0.02
0.00 0.0
0.2
0.4
0.6
0.8
1.0
Mass fraction of PEG 200
Figure 4 - Mole fraction solubility profile of lamotrigine, experimental data shown with n or l and the back-calculated data with the lines.
values vary between 4.1 to 11.6 % with the overall value of 7.0 %. Concerning the computed model constants, it is possible to predict the solubility of the investigated drugs in all possible compositions of the mixtures. 545
Solubility of atenolol, amiodarone HCl and lamotrigine in polyethylene glycol 400 + water mixtures in the presence of b-cyclodextrin A. Jouyban, S. Sajed-Amin, V. Panahi-Azar
J. DRUG DEL. SCI. TECH., 24 (5) 543-547 2014
solutions of pharmaceuticals may affect their solubility and stability. We did not study the effect of added excipients on the stability of the drugs and further investigations are required to show this effect. The Jouyban-Acree model fits very well to the data and could be used to predict the solubility data at other solvent compositions.
Table II - Numerical values of the adjusted parameters of Equation 1 and the mean relative deviation (MRD) for the fitting mole fraction solubilities of atenolol, amiodarone HCl and lamotrigine in PEG 200 + water mixtures and in presence of 10 mM β-CD. Drug
Solvent system
J0
J1
J2
MRD
Atenolol
PEG 200 + water
532.85
-319.58
0**
5.1
PEG 200 + water + 10 mM β-CD
493.09
-366.07
0**
4.1
REFERENCES
Amiodarone HCl
PEG 200 + water
685.59
-337.43
426.53
7.3
1.
PEG 200 + water + 10 mM β-CD
437.58
-185.22
270.20
4.8
Lamotrigine
PEG 200 + water*
574.64
0**
0**
8.7
PEG 200 + water + 10 mM β-CD
161.37
303.78
529.00
11.6
Overall
7.0
2. 3. 4.
*Data taken from a previous study [18]. **The value is not statistically significant (p > 0.1).
5.
Table III - Numerical values of the solubilization powers of PEG 200, PEG 200 + 10 mM β-CD, PG and PG + 10 mM β-CD for the investigated drugs in this work and a previous one [17]. Drug Atenolol Amiodarone HCl Lamotrigine
Atenolol Diazepam Lamotrigine*
Solvent system
w
6. 7.
PEG 200 + water
0.79
PEG 200 + water + 10 mM β-CD
0.78
PEG 200 + water
1.76
PEG 200 + water + 10 mM β-CD
1.90
PEG 200 + water*
2.46
PEG 200 + water + 10 mM β-CD
3.08
PG + water**
0.69
PG + water + 10 mM β-CD**
0.67
PG + water***
2.46
PG + water + 10 mM β-CD**
4.19
PG + water***
2.45
PG + water + 10 mM β-CD**
2.91
8.
9.
10. 11. 12.
Data taken from a previous study: *[18], **[16], ***[17].
13.
Table III reports the calculated w values for aqueous mixtures of PEG 200 and PEG 200 + 10 mM β-CD. No significant change in the solubilization power of the solubilizers for atenolol was observed. A similar observation was also the case for solubility of atenolol in propylene glycol + β-CD data reported in a previous work [17]. Addition of β-CD was improved the solubilization power of PEG 200 from 1.76 to 1.90 for amiodarone HCl. It should be noted that ω values are in logarithmic scale and one unit increase in ω means solubility enhancement by a factor of 10. Further increase in ω values was observed for lamotrigine in PEG 200 + β-CD. A similar pattern was observed for solubilization power of propylene glycol and propylene glycol + β-CD.
14.
15. 16.
17.
* 18.
In conclusion, the generated data in this work extends the available solubility database of pharmaceuticals [32] and could be used in the pharmaceutical industries. There are good agreements between generated data in this work and the previously reported data in the literature. The addition of a cosolvent and a complexing agent to the aqueous
19.
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MANUSCRIPT Received 20 February 2014, accepted for publication 18 March 2014.
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