Solubility and Saturation Apparent Volume of Propranolol

Article pubs.acs.org/jced

Solubility and Saturation Apparent Volume of Propranolol Hydrochloride in Some Binary Aqueous Cosolvent Mixtures at 298.15 K Zaira J. Cárdenas, Daniel M. Jiménez, and Fleming Martínez* Grupo de Investigaciones Farmacéutico-Fisicoquímicas, Departamento de Farmacia, Facultad de Ciencias, Universidad Nacional de Colombia, Cra. 30 No. 45-03, Bogotá D.C., Colombia ABSTRACT: The equilibrium solubility of propranolol hydrochloride in aqueous binary mixtures of 1,4-dioxane (D), acetonitrile (ACN), polyethylene glycol 400 (PEG), propylene glycol (PG), or methanol (MeOH), at T = 298.15 K was determined. In all cases the maximum solubility values expressed in molarity (mol·dm−3) in a mixture instead of neat water were obtained, while the lowest drug solubility values in the neat cosolvents were obtained. Otherwise, if the maximum mole fraction solubility obtained in every cosolvent system is considered, the following order is obtained: ACN + W > D + W > MeOH + W > PEG + W > PG + W; whereas, if the molarity scale is considered the maximum solubility decreases in the order: ACN + W > MeOH + W > D + W > PG +W > PEG + W. In a quantitative way the drug solubility expressed in mole fraction varies from 1.77 × 10−4 in neat 1,4-dioxane to 2.95 × 10−2 in the mixture with 0.50 in mass fraction of acetonitrile. A correlation of the solubility data obtained was made by means of the modified NIBS/R-K model; thus, regressions in second and third order were obtained according the cosolvent system. Otherwise, apparent specific sp 3 −1 volumes at saturation (ϕsp was obtained. V ) in all the mixtures were also calculated; in particular, a ϕV mean value of 0.837 cm ·g

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INTRODUCTION Propranolol hydrochloride (PPN·HCl, Figure 1) is a nonselective β-adrenergic blocker used in the treatment of

volumes in water as a function of drug concentration and temperature7−9 have also been studied. As has been already described, the solubility behavior of drugs in cosolvent mixtures is very important because cosolvent blends are frequently used in purification methods, preformulation studies, and pharmaceutical dosage forms design, among other applications.10−12 For these reasons, it is still very important to determine systematically the solubility of pharmaceutical compounds. The systematic study of the solubility of a drug as a function of the dielectric constant allows the identification of a peak solubility or “dielectric requirement” occurring at a value independent of the nature of the solvent or solvent mixture medium,10,11 and it can be very useful to take into account this requirement when formulating suitable aqueous vehicles in the design of liquid dosage forms. Moreover, the use of pharmaceutical salts is the most common and effective method of increasing solubility and dissolution rates of acidic and basic drugs.13,14 With this in mind, the present work studied the solubility of PPN·HCl in several aqueous cosolvent binary mixtures obtained with 1,4-dioxane (D), acetonitrile (ACN), polyethylene glycol 400 (PEG 400), methanol (MeOH), or propylene glycol (PG), at 298.15 K. All these cosolvents are miscible with water in all compositions. It is well-known that propylene glycol and PEG 400 are cosolvents widely used in

Figure 1. Molecular structure of propranolol hydrochloride. The hydrochloride form is established by protonation of the secondary amine group.

hypertension, angina pectoris, and cardiac disrhythmias.1 Although PPN is widely used nowadays in therapeutics, the physicochemical information about its aqueous solutions is not complete at present.2,3 In this way, the solution thermodynamics in aqueous media for the molecular form and for the saline form (PPN·HCl) in ethanol + water mixtures have already been presented in the literature.4,5 If terms of approximate solubility are used this drug is considered as soluble in neat water and ethanol.2 Other contributions to the physicochemical information on this drug were reported in the literature, such as the thermodynamics of transfer of this drug between organic solvents of different hydrogen-bonding capability and aqueous media.6 Also the apparent molar © XXXX American Chemical Society

Received: February 21, 2015 Accepted: April 15, 2015

A

DOI: 10.1021/acs.jced.5b00167 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

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Table 1. Source and Purities of the Compounds Used in This Research

a

compound

CAS

formula

molar mass g·mol−1

source

purity in mass fractiona

propranolol hydrochloride 1,4-dioxane acetonitrile polyethylene glycol 400 propylene glycol methanol water

318-98-9 123-91-1 75-05-8 25322-68-3 57-55-6 67-56-1 7732-18-5

C16H21NO2·HCl C4H8O2 C2H3N H(OCH2CH2)nOH C3H8O2 CH4O H2O

295.81 88.10 41.05 380−420 76.09 32.04 18.02

Hefei TNJ Chemical Ind. Co., Ltd., China Scharlau, Spain Merck, Germany Dow Chemical Co., USA Dow Chemical Co., USA Merck, Germany obtained by distillation

0.990 0.995 0.997 0.995 0.995 0.997 1.000

All reagents were used as received without further purification.

connected to a recirculating thermostatic bath (Neslab RTE 10 Digital One Thermo Electron Company, U.S.A.) at T = (298.15 ± 0.05) K. Densities were also used to calculate the volumetric contribution of the drug in the saturated solutions.

the design and development of liquid medicines, especially those intended for parenteral administration.10,11 Several examples of pharmaceutical formulations using these cosolvents have been presented in the literature. Oppositely, 1,4-dioxane, acetonitrile, and methanol are toxic solvents, and therefore they are not used in formulation of medicines; nevertheless, they are used in other applications in chemical/pharmaceutical industries and they are very good model solvents for cosolvency studies.15

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RESULTS AND DISCUSSION Experimental Solubility of PPN·HCl. Tables 2 and 3 summarize the experimental solubility of PPN·HCl in all the

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Table 2. Experimental Solubility of Propranolol Hydrochloride (3) in Cosolvent (1) + Water (2) Mixtures Expressed in Mole Fraction at T = 298.15 K and Local Atmospheric Pressure, p = 73.9 kPa

EXPERIMENTAL SECTION Reagents and Materials. Propranolol hydrochloride USP 16 ((RS)-1-(1-methylethylamino)-3-(1-naphthyloxy)propan-2-ol.HCl, PPN·HCl, Hefei TNJ Chemical Ind. Co., Ltd., China), 1,4-dioxane A.R. (D, Scharlau, Spain), acetonitrile A.R. (ACN, Merck, Germany), PEG 400 NF16 (PEG, Dow Chemical Co., USA), propylene glycol USP16 (PG, Dow Chemical Co., USA), methanol A.R. (MeOH, Merck, Germany), distilled water (W) with conductivity < 2 μS·cm−1 were used in this research. The properties of the compounds studied are presented in Table 1. Molecular sieve (numbers 3 and 4, Merck, Germany) and Millipore Corp. Swinnex-13 (USA) filter units were also used. Solvent Mixtures Preparation. All cosolvent (1) + water (2) mixtures were prepared by mass, using an Ohaus Pioneer TM PA214 (U.S.A.) analytical balance with sensitivity ± 0.1 mg, in quantities of 10.00 g. The mass fractions of cosolvent of the nine binary mixtures prepared varied by 0.10 from 0.10 to 0.90 to cover all the rank of compositions. Solubility Determinations. The procedures followed in this research were similar to the ones used previously for studying other saline drugs in ethanol (1) + water (2) mixtures.5,17,18 Briefly, an excess of PPN·HCl was added to approximately 10 g of each cosolvent mixture or neat solvent, in stoppered dark glass flasks. The flasks with the solid−liquid mixture were placed in an ultrasonic bath (Elma E 60 H Elmasonic, Germany) during 15 min, and later they were stirred and placed in a thermostatic mechanical shaker (Julabo SW23, Germany) kept at T = (298.15 ± 0.05) K at least for 5 days to reach the saturation equilibrium. After this time the supernatant solutions were filtered to ensure that they were free of particulate matter before sampling. Drug concentrations were determined after appropriate aqueous dilution by measuring the UV light absorbance at 287 nm (UV/vis BioMate 3 Thermo Electron Company spectrophotometer, U.S.A.) and interpolation from a previously constructed UV spectrophotometric calibration curve. All the solubility experiments were run in triplicate at least. To make the equivalence between mole fraction and molarity (mol·dm−3) concentration scales, the density of the saturated solutions was determined with a digital density meter (DMA 45 Anton Paar, Austria)

1000 x3b,c a,b

D+W

ACN + W

PEG + W

PG + W

MeOH + W

0.000 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 1.000

5.98 9.91 13.77 16.98 21.35 24.31 27.26 28.88 27.70 19.29 0.177

5.98 13.70 20.60 24.84 27.52 29.54 28.20 26.77 20.76 10.59 0.335

5.98 6.16 6.87 8.30 9.60 11.77 13.40 15.97 17.37 18.29 21.28

5.98 5.53 5.79 6.53 8.18 10.29 12.58 14.59 16.22 18.20 18.06

5.98 6.76 8.74 12.31 16.40 20.27 22.43 24.60 24.60 25.06 23.57

w1

a

w1 is the mass fraction of cosolvent (1) in the cosolvent (1) + water (2) mixtures free of drug (3). bStandard uncertainties are u(T) = 0.05 K, u(p) = 2.2 kPa, and u(w1) = 0.0003. Relative standard uncertainty in solubility is ur(x3) = 0.015 (or 1.5%). cNotation: D, 1,4-dioxane; ACN, acetonitrile; PEG, polyethylene glycol 400; PG, propylene glycol; MeOH, methanol.

five cosolvent (1) + water (2) systems at 298.15 K, expressed in mole fraction and mol·dm−3, respectively. In almost all cases the relative mean deviations were smaller than 2.0 % and the significant figures were defined according to the literature.19 Figures 2 and 3 present the same data in a graphical way, where the respective solubility trends were adjusted to regular polynomial models in order four. If the mole fraction is considered, initially the drug solubility increases with the cosolvent proportion reaching a maximum in a mixture and later it decreases in the neat cosolvents, except with PG. It is interesting to note that the mole fraction solubility is highest in neat cosolvents instead of neat water for PEG, PG, and MeOH although the drug is a salt. Nevertheless, the behavior is different if the molarity scale is considered in the case of PEG and PG where the molar solubilities are greater in water rather than in the cosolvents. This behavior is a consequence of the definitions of the respective scales.20 Similar behaviors have B



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been reported in the literature for other saline drugs.21−24 In general, if mole fraction solubility in neat cosolvents is considered, this property decreases in the order: MeOH > PEG > PG ≫ ACN > D (Table 2); whereas, if molarity is considered the solubility decreases in the order: MeOH > PG > PEG > ACN > D (Table 3). If the empiric terms of approximate solubility are considered,20 this drug could be considered as freely soluble in MeOH, soluble in water and PG, sparingly soluble in PEG, slightly soluble in ACN, and very slightly soluble in D. Otherwise, if the maximum mole fraction solubility obtained in every cosolvent system is considered, the following order is obtained: ACN + W > D + W > MeOH + W > PEG + W > PG + W (Table 2); whereas, if molarity scale is considered the maximum solubility decreases in the order: ACN + W > MeOH + W > D + W > PG +W > PEG + W (Table 3). In a quantitative way the drug solubility expressed in mole fraction varies from 1.77 × 10−4 in neat 1,4-dioxane to 2.95 × 10−2 in the mixture with 0.50 in mass fraction of acetonitrile (Table 2). Up to the best of our knowledge no solubility values of this drug in these systems have been published and no comparisons are possible. On the other hand, Figures 4 and 5 show the experimental solubility of PPN·HCl as a function of two polarity indices of

Table 3. Experimental Solubility of Propranolol Hydrochloride (3) in Cosolvent (1) + Water (2) Mixtures Expressed in Molarity at T = 298.15 K and Local Atmospheric Pressure, p = 73.9 kPa 100 mol·dm−3b,c w1a,b

D+W

ACN + W

PEG + W

PG + W

MeOH + W

0.000 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 1.000

30.8 45.8 57.1 63.5 70.8 71.8 70.6 64.6 52.5 29.8 0.207

30.8 61.0 81.3 89.2 90.8 89.5 79.2 68.4 48.4 22.4 0.633

30.8 29.3 29.7 32.0 32.6 34.2 32.5 30.6 24.3 15.7 6.01

30.8 26.8 26.0 26.8 30.3 33.8 36.3 36.3 34.0 30.9 23.6

30.8 32.7 39.2 50.3 61.2 69.4 71.4 72.7 67.9 63.2 54.2

a

w1 is the mass fraction of cosolvent (1) in the cosolvent (1) + water (2) mixtures free of drug (3). bStandard uncertainties are u(T) = 0.05 K, u(p) = 2.2 kPa and u(w1) = 0.0003. Relative standard uncertainty in solubility is ur(mol·dm−3) = 0.014 (or 1.4%). cNotation: D, 1,4dioxane; ACN, acetonitrile; PEG, polyethylene glycol 400; PG, propylene glycol; MeOH, methanol.

Figure 4. Solubility of propranolol hydrochloride (3) expressed in mol·dm−3 as a function of the dielectric constant in binary cosolvent (1) + water (2) mixtures at T = 298.15 K: ○, 1,4-dioxane + water; +, acetonitrile + water; □, PEG 400 + water; ×, ethanol + water; ◇, methanol + water; △, propylene glycol + water.

Figure 2. Solubility of propranolol hydrochloride (3) expressed in mole fraction as a function of the binary cosolvent (1) + water (2) mixtures composition at T = 298.15 K: ○, 1,4-dioxane + water; +, acetonitrile + water; □, PEG 400 + water; ◇, methanol + water; △, propylene glycol + water.

Figure 5. Solubility of propranolol hydrochloride (3) expressed in mole fraction as a function of the Hildebrand solubility parameter in binary cosolvent (1) + water (2) mixtures at T = 298.15 K. ○, 1,4dioxane + water; +, acetonitrile + water; □, PEG 400 + water; ×, ethanol + water; ◇, methanol + water; △, propylene glycol + water.

Figure 3. Solubility of propranolol hydrochloride (3) expressed in mol·dm−3 as a function of the binary cosolvent (1) + water (2) mixtures composition at T = 298.15 K: ○, 1,4-dioxane + water; +, acetonitrile + water; □, PEG 400 + water; ◇, methanol + water; △, propylene glycol + water. C



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the cosolvent mixtures, that is, mol·dm−3 vs dielectric constant (ε) (Figure 4) and mole fraction vs Hildebrand solubility parameter (δ/MPa1/2) (Figure 5).25−27 It is important to note that the polarity indices of the cosolvent mixtures were calculated as additive properties based on volume fractions.28,29 In this point it is noteworthy that a method to calculate dielectric constant in mixtures, based on the Jouyban-Acree model (J-A), has been developed,30 but we decided to use the additive model proposed by Moore,28 because of its simplicity and because not all the J-A constants, for the binary systems studied in this research, have been reported in the literature.30 In this way, ε and δ values of the neat solvents were taken from the literature.26,27,31 The respective solubility trends were adjusted to regular polynomial models in order four.32 These figures also include the solubility values reported in the literature in ethanol (1) + water (2) mixtures adjusted to regular polynomials in degree five.5 It is interesting to note that the molar solubilities reach a maximum in dielectric constants varying from 40 to 50, except in ACN (1) + water (2) mixtures (with εmax = 60), which is in agreement with the concept of approximate dielectric requirement (ADR) of the solute.10 In a similar way, if the mole fraction solubility is analyzed in terms of the Hildebrand solubility parameters, the maximum values are obtained in mixtures of similar polarity, with the exception of PEG (1) + water mixtures, in which the maximum is obtained in the neat cosolvent. On the other hand, the maximum solubility in mixtures instead of neat water could be interpreted in terms of the behavior of a hydrophobic ion due to the big size of the protonated drug, in particular because of the naphthyl group.33 Solubility Correlation with the Modified Nearly Ideal Binary Solvent/Redlich−Kister (NIBS/R-K) Model. One of the most powerful models to calculate the solubility of drugs in cosolvent mixtures at constant temperature is the NIBS/R-K. This model has been used to correlate the solubility of many drugs and other kinds of organic compounds. It has been used for both nonelectrolyte and electrolyte compounds.3,34,35 The modified NIBS/R-K could be written as eq 1 when the cosolvent mixtures are expressed in mass fraction (w1). Here, the drug solubility in mixtures (S3,1+2) or in neat monosolvents (S3,1 and S3,2) could be expressed as mole fraction or mol·dm−3 as well.

Table 4. Parameters of eq 1 and Mean Percentage Deviations (MSD) of Calculated Solubility of Propranolol Hydrochloride (3) in Cosolvent (1) + Water (2) Mixtures at T = 298.15 K parameter A0 A1 A2 A3 R2 MPD/% A0 A1 A2 A3 R2 MPD/%

ACN + W

PEG + W

PG + W

Mole Fraction Solubilitya 11.29 11.28 0.1845 −0.138 6.09 4.33 0.6736 2.072 25.44 18.42 −1.2534 −0.519 27.67 15.16 0.986 0.989 0.929 0.991 22.3 12.1 1.8 1.5 Solubility Expressed in Molarity (mol·dm−3)a 12.02 11.17 3.577 0.812 6.54 4.69 4.348 2.406 25.78 18.30 2.192 −0.242 27.96 15.24 0.986 0.989 0.989 0.993 22.4 12.3 3.9 1.5

MeOH + W 2.070 1.244 −1.735 0.957 2.6 2.071 1.226 −1.459 0.960 2.4

a

Notation: D, 1,4-dioxane; ACN, acetonitrile; PEG, polyethylene glycol 400; PG, propylene glycol; MeOH, methanol.

obtained with both aprotic solvents (1,4-dioxane and acetonitrile) despite more complex polynomials being employed for correlations. Nevertheless, these deviations are allowed for practical purposes in the pharmaceutical industry. In particular it is noteworthy that the deviations observed with the hydroxyl-cosolvents were lower than 4.0 %, which makes the NIBS/R-K model a very adequate tool to correlate the solubility of this electrolyte drug.36,37 Apparent Specific Volume of PPN·HCl at Saturation. The volumetric contribution of drugs in solution is relevant from practical and theoretical points of view. A very well considered property of drugs at saturation is the specific 3 −1 38 apparent volume (ϕsp V / cm ·g ), calculated according to eq 3: ϕVsp =

w3 + w1 + 2(1 − ρ /ρ1 + 2 ) w3ρ

(3)

where, w3 and w1+2 are the mass fractions of solute and cosolvent mixture at drug saturation, respectively; whereas, ρ and ρ1+2 expressed in g·cm−3, are the densities of the saturated solution and cosolvent mixture. The density of the cosolvent mixtures free of drug at 298.15 K were taken from the literature.39−43 The density of all the saturated solutions at the same temperature is presented in Table 5. The apparent specific volumes of PPN·HCl are presented in Table 6. If the ϕsp V values in the neat cosolvents are not considered (because of the low solubilities observed in 1,4-dioxane, acetonitrile, and 3 −1 PEG 400), the ϕsp with V values vary from 0.770 to 0.857 cm ·g 3 −1 a mean value of 0.837 cm ·g , which is varying in 2.13 %. This variation is normally accepted in the design of liquid pharmaceutical dosage forms.20,36

n

ln S3,1 + 2 = w1 ln S3,1 + w2 ln S3,2 + w1w2 ∑ Ai (w1 − w2)i i=0

(1)

Mathematically the Ai parameters of eq 1 could be obtained from regular polynomial regression by using y = {ln S3,1+2 − (w1 ln S3,1 + w2 ln S3,2)}/(w1w2) and x = (w1 − w2). Table 4 shows the respective Ai coefficients for all the binary cosolvent systems and both concentration scales. Mean percentage deviations (MPD) were calculated by using eq 2, where N is the number of mixtures considered in each case, that is, nine. MPD values are also reported in Table 4. ⎛ |S exp − S calc | ⎞ 100 MPD = ∑ ⎜⎜ 3,1 + 2 exp 3,1 + 2 ⎟⎟ N S3,1 + 2 ⎝ ⎠

D+W

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CONCLUSIONS From that discussed previously it can be concluded that the solution processes of PPN·HCl (3) in all the cosolvent (1) + water (2) mixtures studied are highly dependent on the cosolvent nature and composition and that the NIBS/R-K model correlates adequately with the solubility of this salt drug, especially for the aqueous mixtures of hydroxylated cosolvents. The mean apparent specific volume in the cosolvent mixtures

(2)

Regressions in the third degree were used for 1,4-dioxane (1) + water (2), and acetonitrile (1) + water (2) mixtures, whereas for the other three systems polynomials in second order were used. It is interesting to note that the highest deviations were D



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Table 5. Density of the Saturated Solutions of Propranolol Hydrochloride (3) in Cosolvent (1) + Water (2) Mixtures at T = 298.15 K D+W

ACN + W

PEG + W

PG + W

MeOH + W

0.000 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 1.000

1.0142 1.0317 1.0450 1.0579 1.0673 1.0742 1.0767 1.0746 1.0674 1.0485 1.0284

1.0142 1.0184 1.0251 1.0225 1.0143 1.0015 0.9755 0.9406 0.8890 0.8291 0.7774

1.0142 1.0274 1.0428 1.0601 1.0763 1.0916 1.1049 1.1160 1.1224 1.1243 1.1234

1.0142 1.0192 1.0260 1.0335 1.0407 1.0474 1.0532 1.0554 1.0544 1.0514 1.0444

1.0142 1.0015 0.9925 0.9865 0.9834 0.9796 0.9721 0.9635 0.9495 0.9166 0.8798

a w1 is the mass fraction of cosolvent (1) in the cosolvent (1) + water (2) mixtures free of drug (3). bStandard uncertainties are u(T) = 0.05 K, u(p) = 2.2 kPa, u(w1) = 0.0003 and u(ρ) = 0.0005 g·cm−3. c Notation: D, 1,4-dioxane; ACN, acetonitrile; PEG, polyethylene glycol 400; PG, propylene glycol; MeOH, methanol.

Table 6. Apparent Specific Volumes at Saturation of Propranolol Hydrochloride (3) in Cosolvent (1) + Water (2) Mixtures at T = 298.15 K 3 −1b,c ϕsp V /cm ·g

w1a,b

D+W

ACN + W

PEG + W

PG + W

MeOH + W

0.000 0.100 0.200 0.300 0.400 0.500 0.600 0.700 0.800 0.900 1.000

0.831 0.828 0.839 0.834 0.843 0.841 0.846 0.849 0.844 0.838 0.602

0.831 0.847 0.837 0.833 0.830 0.831 0.823 0.838 0.846 0.857 0.403

0.831 0.839 0.842 0.840 0.845 0.853 0.853 0.849 0.841 0.840 0.860

0.831 0.824 0.833 0.843 0.861 0.863 0.858 0.856 0.858 0.858 0.852

0.831 0.818 0.819 0.835 0.835 0.832 0.817 0.803 0.770 0.778 0.773

a

w1 is the mass fraction of cosolvent (1) in the cosolvent (1) + water (2) mixtures free of drug (3). bStandard uncertainties are u(T) = 0.05 3 −1 K, u(p) = 2.2 kPa, u(w1) = 0.0003 and u(ϕsp V ) = 0.018 cm ·g . c Notation: D, 1,4-dioxane; ACN, acetonitrile; PEG, polyethylene glycol 400; PG, propylene glycol; MeOH, methanol.

without consideration of the neat cosolvents is 0.837 cm3·g−1. Ultimately, it can be established that the data presented in this report expand the physicochemical information about saline drugs in aqueous solutions.

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REFERENCES

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ρ/g·cm−3b,c w1a,b

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Department of Pharmacy of the Universidad Nacional de Colombia for facilitating the equipment and laboratories used. E



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Solubility and Saturation Apparent Volume of Propranolol

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