Study of phase equilibria and the physicochemical properties of selected pharmaceuticals

Accepted Manuscript Title: Study of phase equilibria and the physicochemical properties of selected pharmaceuticals Author: Aneta Pobudkowska Barbara A. Jurkowska Maciej A. Wiatrowski PII: DOI: Reference:

S0378-3812(15)30052-2 http://dx.doi.org/doi:10.1016/j.fluid.2015.07.037 FLUID 10689

To appear in:

Fluid Phase Equilibria

Received date: Revised date: Accepted date:

2-3-2015 13-7-2015 17-7-2015

Please cite this article as: Aneta Pobudkowska, Barbara A.Jurkowska, Maciej A.Wiatrowski, Study of phase equilibria and the physicochemical properties of selected pharmaceuticals, Fluid Phase Equilibria http://dx.doi.org/10.1016/j.fluid.2015.07.037 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Fluid Phase Equilibria, Study of phase equilibria and the physicochemical properties of selected pharmaceuticals

Aneta Pobudkowskaa*, Barbara A. Jurkowskaa, Maciej A. Wiatrowskia

a

Department of Physical Chemistry, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3,

00-664 Warsaw, Poland. *

Corresponding author: Telephone: +48 22 234 74 75. Fax: +48 22 628 27 41. e-mail: [email protected].

Keywords:

Drug

Differential

+

solvent,

Scanning

Bates-Schwarzenbach

Microcalorimetry,

method,

Thermodynamic

correlation

Abstract In this work the phase equlibria in binary system: (Drug + solvent) was examined and their physicochemical properties were analyzed. The investigated substances were: Synephrine (SYN), Isoprenaline hydrochloride (IPR) and Metaraminol bitartrate (MET). Solubility of this drugs was determined in three solvents: water, ethanol and 1-octanol. The molecular structure of these drugs is based on a phenthylamine skeleton, therefore all studied pharmaceuticals have an aromatic structure with different amounts of hydroxyl groups located at an aromatic ring. They also have different substituents on the amino group inside the chemical chain. The amino-group confers basic properties of the molecule, whereas the phenolic -OH group is weakly acidic. The tested substances belong to the group of adrenergic drugs (adrenomimetics) and stimulate the sympathetic nervous system. Solubilies of three drugs were measured in the temperature range from 270 K to 450 K at constant pH. All of studied systems were described as simple eutectic phase diagrams, with

complete miscibility at liquid phase and non-miscibility in solid phase. The results are presenting as two phases in equilibrium as a function of temperature. These studies are necessity when the drugs are introducing into the pharmaceutical field. The obtained experimental data were correlated with three equations: Wilson, NRTL and UNIQUAC. Moreover dissociation constants and corresponding pKa values of drugs were obtained with Bates-Schwarzenbach method at temperature 298.15 K in the buffer solutions. The DSC (Differential Scanning Microcalorimetry) was used to measure thermal basic properties of pure drugs, that is: the glass-transition temperature, temperature of melting, enthalpy of fusion and the heat capacity at the glass-transition temperature. Nomenclature a activity D absorbance value f fugacity of component g12 molar energy of interaction between 1 and 2 (J mol-1) GE excess Gibbs free energy (J mol1 ) ∆fusH molar enthalpy of fusion (kJ mol-1) k number of parameters n number of experimental points p pressure pKa constant acidity r volume parameter R universal gas constant (J K-1mol1 ) T equilibrium temperature (K) ∆T estimated error of temperature (K) x mole fraction V mole values w weight of experimental point Z the coordination number Greek letters

α nonrandomness parametrer in the NRTL eq. τ binary interaction parameter in the NRTL model qi the surface parameter λ cross interaction energy parameter for Wilson equation (J/mol) λJi cross interaction energy parameter for Wilson equation (λjI −λii) (J/mol) Λ Wilson parameter γ activity coefficient σT root-mean-square deviation in temperature Superscript A- base value cal calculated value exp experimental value HA acid value l liquid s solid Subscripts 1 solute 2 solvent fus fusion i ith experimental point lit literature data

1.

Introduction Any substance introduced into the body for therapeutic or prophylactic uses,

irrespective of its origin is called drug. Medicinal properties of these substances consist in the inhibition of causes and symptoms of the disease or preventing their development. It is known that the difference effect of the drug is determined by a variety of chemical and physical conditions, which arise from the construction of the drug. Potency is not only dependent on the drug-receptor affinity and the strength of their mutual matching up arising from their structure. The main factor is the solubility of the drug in the target tissue. Today the solubility of drugs is measured with different methods: for very low solubility the classical staticsaturation shake-flask method at one temperature is commonly used and for lower solubility

the visual, dynamic method, where the solubility as a function of temperature is obtained [1]. Therefore, the drug development is a very laborious and expensive process. One of the major causes for failure during the clinical phases of drug development is inadequate pharmacokinetic information of the drug candidate. It would be advantageous if the pharmacokinetic properties of drug candidates may be expected earlier [2]. To illustrate the importance of the active substance and the active formulation on absorption, and distribution of the drug to the site of action, it is necessary to consider the sequence of events that precede elicitation of a drug's therapeutic effect [3]. Moreover, the fact that so much drug candidates are advanced in the development and clinical assesment is to proof of more and more sophisticated understanding of approaches that can be taken to promote the apparent solubility in the gastrointestinal tract and the promotion of exposure to the drug after oral administration [4]. Each drug, which will is to be absorbed must be present in aqueous solution at the absorption site. Most drugs are either weakly acidic or weakly basic having a poor solubility in water. Poor solubility and low dissolution rate of poorly water soluble drugs in the aqueous gastrointestinal fluids often cause insufficient bioavailability. Low water solubility therefore continues to be a challenge to successful drug development [5]. Low aqueous solubility and reduced dissolution rates are a common property of many new drug candidates, and these properties create a number of challenges during drug discovery and development pH adjustment. Poor water soluble drug may potentially dissolve in water by applying a pH change. To access the solubility of this approach, the buffer capacity and tolerability of the selected pH are important to consider [6]. An understanding of the determinants of solubility and dissolution provides a framework from which approaches to enhance solubilization may be developed [4]. The thermodynamic ideal solubility of solute depends only on the thermophysical data of solute (drug) and can be used as a first approximation of the solubility,

which is the same in all solvents [7]. The basic thermodynamic properties of drugs: melting point and enthalpy of fusion and of solid−solid phase transition determined by the differential scanning calorimetry technique are important informations for solubility. They can be used for the correct estimation of the ideal solubility of drugs in water, ethanol and 1-octanol [8]. The SYN, or more specifically, p–synephrine is an alkaloid, which stimulates mostly α-adrenergic receptors. It is one of the adrenergic amines that stimulates the beta-3 receptors with minimal impact on the other receptor sites. Stimulation of these receptors elicits the breakdown of lipolysis [9]. The action of this drug is similar to ephedrine, therefore it is considered to be a natural substitute. This drugs a natural phenylethylamine derivatives present in some food supplements containing Citrus aurantium, permitted in sport regulations [10]. Therefore, bitter orange extract and its principal protoalkaloidal constituent p-synephrine are widely used in weight loss and weight management. The SYN is present at concentrations ranging from 0.02 to 0.06 % in plant parts [11,12]. It is widely recognized as a slimming centre. It restores the desire to work and physical activity, so it is beneficial to athletes and obese people. This substance causes the blood pressure, bronchodilation facilitates breathing. In contrast, the IPR belongs to a group of medicines β-adrenergic receptors. It stimulates both receptors β1-adrenergic and β2-adrenergic. This drug is used for the treatment of bradycardia, heart block, and rarely for asthma. By activating β1-receptors on the heart, it induces positive chronotropic, dromotropic, and inotropic effects. The β2 receptors are located in the bronchi and the blood vessels [13]. This drug is obtained synthetically. The MET belongs to a group of medicines, stimulating both receptors β-adrenergic and α-adrenergic. This drug is a sympathomimetic amine that directly and indirectly affects adrenergic receptors, with alpha effects being predominant and has pharmacological action similar to, but less potent and more prolonged than that of norepinephrine. In humans, it increases cardiac output, peripheral resistance, and blood pressure. The MET is devoid of

central nervous system stimulatory [14,15]. The MET is also used in the treatment of priapism [16]. All tested drugs affect the sympathetic nervous system. Considering the chemical structure of the test drugs are derivatives of 2-phenylethylamine. The differences in the pharmacological effects associated with different substituents. The diversity of these substituents determines the affinity of the substance to a specific receptor. Therefore, this has a significant impact on the character and effects of the drug. When the compound has in its construction of a methyl group: increases the lipophilic character of the whole molecule, grows the solubility in lipid and decreases aqueous solubility. Probably a similar effect on the properties of drugs will also introduce their structure more aliphatic substituents. The presence of the amino group in the construction of the drug may increase the hydrophilic character of the whole molecule. It is increusing the solubility in water due to the formation of the salt and simultaneously decreases the solubility in lipids. The introduction of this group makes it possible to improve the strength of binding of the drug to the receptor in the target tissue and determine the affinity of pharmaceuticals for the respective receptors. The main objective of the present study was to examine the temperature dependent solubility of three drugs: Synephrine (SYN), Isoprenaline hydrochloride (IPR) and Metaraminol bitartrate (MET) at constant value of pH in water, ethanol and 1-octanol. The choice of these solvents was not accidental. Water is the most important component of any living organism. Ethanol is an organic compound responsible for the transport of the drug in the body. 1-Octanol is a model compound of human cell and skin membrane. The solubility in water is one of the most important parameters to achieve the desired concentration of drug in the circulation to accomplish required pharmacological response. Poorly water-soluble drug, frequently requires high doses to achieve a therapeutic serum concentrations after oral administration.

2.

Experimental

2.1. Materials The drugs were obtained from Sigma Aldrich, i.e. Synephrine (CAS Registry No. 9407-5), Isoprenaline hydrochloride (CAS Registry No. 51-30-9), and Metaraminol bitartrate (CAS Registry No. 33402-03-8). The drugs were used without further purification and were used as powder or small crystals. The name, source, molecular formula, structural formula and molar masses of the compounds are listed in Table 1. The solubility of drugs have been examined in three different solvents. There were water, ethanol and 1-octanol. Water used as a solvent was twice distilled, degassed, deionized and filtered with Milipore Elix 3. The alcohols, which we used as solvents: ethanol and 1octanol, were obtained from Sigma Aldrich with a >0.998 mass fraction purity. They were stored under freshly activated molecular sieves of type 4 Å. The buffers solution, 0.2 M sodium hydroxide and 0.2 M hydrochloric acid, were prepared from substances delivered by POCH, i.e. sodium chloride (CAS Registry No. 7647-14-5; 0.999 mass fraction purity), hydrochloric acid (CAS Registry No. 7647-01-0; 0.35-0.38 mass fraction purity), borax (CAS Registry No. 1303-96-4;0.988 mass fraction purity), monoethanolamine (CAS Registry No. 141-43-5;0.99 mass fraction purity). All solutes were filtrated twice with Schott funnel with 4µm pores.

2.2. Phase equlibria in binary systems The nine binary systems: drug (1) + solvent (2) have been studied in this work. Measurements were carried out mainly with a dynamic method. It is most appropriate, because in the studied systems, equilibrium was achieved relatively quickly. The samples of mixtures were prepared by weighning pure components within an accuracy of 1 · 10-4 g. The heating was slowly about 5 K·h-1 with continuous stirring inside a Pyrex glass cell located in

termostatted water bath. We detected temperatures of crystal disappearance visually and we were measured with an electronic thermomether P 550 (Dostmann Electronic GmbH, Germany). The errors of this study did not exceed 5 · 10-4 in mole fraction. The uncertainties of the temperature measurements were judged to be 0.1 K and The repeatability of the solubility measurements was ±0.1 K. For all nearly insoluble drugs system in 1-octhanol were used US-Vis spectrophotometry method, because the solubility values were really small. We used the UV-Vis spectrophotometer (Perkin-Elmer Life Analitycal Sciences, Shelton, USA). The samples were tested at temperature range from 270K to 450 K. The experimental data are presented in Tables 2 – 4.

2.3. Differential scanning microcalorimetry (DSC) Thermophysical characterization of three drugs have been done using a differential scanning microcalorimetry technique. We measured: temperatures and enthalpy of fusion, glass-transition temperature and the heat capacity at the glass-transition temperature. The apparatus (Mettler-Toledo DSC1 STAR System) was calibrated with a 0.999999 mol fraction purity indium sample. The applied scan rate was 10 K·min-1. Each sample was hold in ambient air in hermetic aluminium pans having of about 50 mg and the sample cell was constantly fluxed with pure nitrogen. As a reference sample the empty hermetic aluminium pan was used. Size of each sample was about 10 mg. The uncertainty of the melting and phase transition temperatures was ±0.1K. The uncertainty of the enthalpy of fusion was ±0.1 kJ·mol-1. The thermophysical characteristic were analyzed using STAR software. We calculated the molar volume of drugs using the method of Barton [17]. The results of this study are listed in Table 5.

2.4. The pKa measurements

The pKa were estimated by spectrophotometric Bates-Schwarzenbach method for all drugs using a UV-Vis spectrophotometer (Perkin-Elmer Life Analitycal Sciences, Shelton, USA) [18]. The main condition which allows to obtain an accurate and reliable results is that all solutions must perform the Beer-Lambert law. This is achieved by using a solution an ionic strength of not more than 0.1. In the such solutions deviations from Beer's law will be practically absent. This method of measurement has many advantages for example: the sensitivity and the accuracy of measurements are high, and the time of measurement is relatively short. This method makes it possible to measure values of pKa for sparingly soluble substances, therefore we can use Bates-Schwarzenbach method when we want to examine very low concentrations of the test substance. The method is universal, because the scope of the absorbance is in the range from 0.1 to 1.0. We used two buffers and two other solutions (0.2 M NaOH and 0.2 HCl) in this study. Buffers were chosen on a basis of the literature pKa, drug values. We measured values of pKa at two temperatures: ambient temperature and at human body temperature. The procedure used for the diluted solutions was described in our previous paper [8]. We have been calculated the values of pKa by the following equation:

 D − D spK a = p(aHγ Cl ) − log  HA   D − DA − 

(1)

where pKa is an acidity constant, p(aHγCl) is an acidity function, DHA, DA-, D are absorbance values in acid, base and buffer, respectively. The error of this measurement, calculated with the Gauss method is u(pKa) = ±0.025.

3.

Results and discussion

The Differential Scanning Microcalorimetry technique shows the basic thermophysical values for the drugs. The calorimetric results were used to determine the activity coefficients of the study drugs relative to the solvents used. This study exhibited the very high temperature of melting from 443.37 K for IPR to 463.53 K to SYN. The enthalpy of fusion of all substances are quite high and typical for organic compounds, ∆fusH1 = 99.7 kJ·mol-1 for SYN, ∆fusH1 = 79.9 kJ·mol-1 for IPR and ∆fusH1 = 77.6 kJ·mol-1 for MET. The highest the value of the enthalpy of melting for SYN can be caused by the fact that the signal (which determines the melting temperature) was observed together with the complete destruction of the substance. The values of the experimental data are very close to each other. This depend on the fact that the tested compounds have very similar structure. All drugs are derivatives of 2-phenylethylamine. It is noteworthy that, no one substance revealed the solid-solid phase transition, which is characteristic for many drugs. The solubility has been determined in three solvents: water, ethanol and 1-octanol. We examined in this work nine binary systems. The visual-dynamic method was used for the systems: the {drug (1) + water, or ethanol (2)}. The use of this method confused decay for last crystal with the dynamic method for the solubility in 1-octanol (2). Therefore, for these systems the spectrophotometric method has been used. On the basis of the investigated data the following trends can be noticed: all drugs reveal very low solubility in 1-octanol. The solubility of SYN in water is lower than in alcohols, but the solubility of SYN is greater in ethanol than in 1-ctanol, so these drugs can be administered to the body as alcoholic solution. . We also noted, that the solubility of IPR and of MET is higher in water than in other solvents, so these drugsmay be administered in the form of distribution of the drug in aqueous solutions. High solubility in water is comfortable because drugs are well soluble in polar environment of our body. In these two systems, the experimental solubility is close to the

ideal solubility. In contrast, the other systems reveal the experimental solubility larger than the ideal solubility. The results are presented in Tables 2 to 5 and in Figures 1 to 3. The solubility of drug in water increases with the growth pH values, but decreases permeability coefficient. The study of pKa shows that the active form of the drug exists at a specific pH [19]. The pKa values are slightly lower or higher for MET than the literature data. Values of an acidity function and the ionic strength for the buffers used in this work are shown in Table 6. Our experimental results and the literature data are listed in Tables 7 [2024] and Figures 4 to 5.

4.

Modeling For practical purposes, solubilities of solids in pure or mixed solvents are of interest

in chemical process design. The thermodynamic description of the (solid + liquid) (SLE) follows from the thermodynamic principle of equilibrium which require that the fugacities of each component in each of the coexisting phases are equal [25]. The state of equilibrium is a condition in which we have calculation criteria. They require that the fugacity of compound in the liquid ( f1l ) and solid ( f1s ) phases must be the same under constant temperature T and pressure p [26]. f1l (T , p, x l ) = f1s (T , p )

(2)In

the liquid phase f1l can be expressed as fugacity of solute with the help of the activity coefficient [25]. x1γ 1 f1 (T , p, x1 ) f1l (T , p ) = f1s (T , p ) (3)Therefore, the solubility equation for a solid without solid-solid phase transition in liquid has been fitted to the sets of experimental solubility data. The result is: [25] −lnx1 =

∆ fus H1  1 1  − + lnγ 1  R  T Tfus,1 

(4)

where: x1, ∆fusH1, T, Tfus,1, γ1 are mole fraction, enthalpy of fusion of the pure drug, solidliquid equilibrium temperature, melting temperature of the pure drug and activity coefficient in the saturated solution. The correlation of the experimental curves was made using the models, which are based on the thermodynamics of fluid - phase equlibia, and which describes the excess Gibbs energy as a function of composition or temperature. The may be used for interpolation, extrapolation and prediction in multi-component systems. There are many thermodynamic models that can be used for the calculation of γ1. In this work the Wilson equation [27], NRTL [28] equation and UNIQUAC [29] equation have been used. These equations are based on the theory of the local concentration. The experimental data together with the calculated values of activity coefficients are presented in Tables 2 – 4. The molar volumes, which were calculated using the group contribution method described by Barton [17] are presented in Table 5. The obtained binary parameters and the root-mean-square deviations (see eqn. (5)) are listed in Table 8. 1/ 2

 n (Texpt ,i − Tcalc ,i ) 2  σ T = ∑ i =1  n−2  

(5)

The number of components is n, i denotes the ith experimental point.

4.1. The Wilson model In the binary system the Wilson model is as follows [25, 27,30,31]:

 Λ12 Λ 21  lnγ 1 = − ln( x1 + Λ12 x2 ) + x2  −  x1 + Λ12 x2 Λ 21 x1 + x2  x is mole fraction and Λ is the parameter model of interaction between componts 1 and 2, which was defined as a function of temperature.

(6)

 − (λ12 − λ11 )   RT

V  Where: Λ12 = 2 e V1

(7)

in which (λ12 − λ11) are the cross interaction energy parameters, which meet the following equation.: λ12 − λ11=λ12 − λ11. The mole values of solute and solvent are V1 and.V2.

4.2. The NRTL model The NRT model has been reported by Renon and Prausnitz [22]. This model uses the concept of the local concentration of the theory of two Scott’s liquids [20,22]. The core of this theory is the relationship talking about the properties of the solution as the average properties of the hypothetical fluid composed of cells whose center is one of the components of the molecule. 2   G  τ12G12  21 + The NRTL model is described in equation [30]: lnγ 1 = x τ 21    ( x2 + x1G12 ) 2    x1 + x2G21   2 2

where: G12and τ12 are model parameters defined as: G12 = −α12τ 12

τ 12 =

g12 − g11 ; RT

(8)

(9)

(10)

(10)The NRLT equation has two binary parameters g12 = g21 and α12 is in most cases determined in an arbitrary manner and is treated as non-randomness parameters of the mixture, which generally varies between 0.20 and 0.9 [25, 27].

4.3. The UNIQUAC model

The number of segments ri (volume parameter) and the surface parameter qi in this model were obtained by the following expressions:

r1 = 0.029281⋅ V1 ,

(11) Z ⋅ q1 = ( Z − 2) ⋅ r1 + 2

(12)

where Z = 10 denotes the coordination number and the bulk factor was described as li. It was assumed for the globular molecule to 1 [ 28].

Conclusions To the best of our knowledge the solubility data and thermophysical data for drugs chosen by us were not published. We used differential scanning calorimetry (DSC) to measure the enthalpy of melting and the melting temperature of three measured coumponds. Summary of experimental data of the solubility and DSC allowed for the determination of activity coefficients of drugs in the three solvents. As was expected, the solubility is higher in water than in alcohols for Isoprenaline hydrochloride and Metaraminol bitartrate. The ideal solubility was lower than the experimental solubility. The correlation of the solubility data was carried out by means of three commonly known GE equations: with the Wilson, NRTL and UNIQUAC. The results of the correlation of solubility were acceptable for all binary systems. The pKa’s of all drugs have been measured in water experimentally and compared to the literature data. They are important because we can designate the pharmaceutical dosage and the activity of drugs at certain pH. Our experimental values of pKa differ from the published earlier, because of the different buffers used and methods usually connected with diluted solutions. We suppose that our new experimental data of solubility and thermophysical data as well as the pKa data of three important drugs will enrich the data banks.

Acknowledgements Funding for this research was provided by the Warsaw University of Technology, Warsaw, Poland.

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TABLE 1

Investigated drugs: name, source, molecular formula, structure and molar mass.

Name of drug

Synep hrine

Sourc e

Sigma Aldric h

Isopre naline hydroc hloride

Sigma Aldric h

Metara minol bitartr ate

Sigma Aldric h

Molecul ar Formula

C9H13N O2

C11H17N O3

C9H13N O3

Structural Fomula







Molar mass/ (g·mo l-1)

167.2 1

247.7 2

317.3 0

Purity (%)

Serial number

98 (Titr. By HClO4 anhyd)

061M1312V

98.5 (Thin Layer Chromatogr aphy)

BCBF4079 V

98 (Thin Layer Chromatogr aphy)

076K1721

TABLE 2

Experimental solubility equilibrium temperatures (T) for {Synephrine (1) + solvent (2)} binary systems and activity coefficients a, p = 101 kPa.b

x1b c Water d e 2.79·10-4 3.54·10-4 4.38·10-4 6.40·10-4 7.44·10-4 10.15·10-4 1.0000 Ethanol e f 0.0012 0.0015 0.0020 0.0031 0.0046 0.0070 1.0000 1-Octanol e f 3.22·10-4 4.46·10-4 5.46·10-4 6.77·10-4 9.51·10-4 10.05·10-4

a

T c d (K)

a

311.60 314.19 318.08 327.00 327.96 338.74 463.53

0.100 0.108 0.116 0.130 0.135 0.145 1.000

302.98 308.72 317.42 329.93 338.20 349.19 463.53

0.039 0.043 0.047 0.054 0.061 0.069 1.000

302.98 308.72 317.42 329.93 338.20 349.19

-

Calculated from the NRTL equation for water and UNIQUAC equation for ethanol.

Standard uncertainties u are as follows: b u(p/kPa) = ±1, b cu(x1) = ±0.0005, c d u(T/K) = ±0.1,

de ef

The pH of the solution was 6. The pH of the solution was 7.

TABLE 3

Experimental solubility equilibrium temperatures (T) for {Isoprenaline hydrochloride (1) + solvent (2)} binary systems and activity coefficients a, p = 101 kPa.b.

x1b c Water d e 0.0346 0.0394 0.0428 0.0462 0.0567 0.0576 0.0699 0.0720 0.0845 0.0916 0.1094 0.1311 0.1455 0.1578 1.0000 Ethanol e f 0.0038 0.0056 0.0062 0.0067 0.0073 0.0145 1.0000 1-Octanol e f 0.73·10-4 1.98·10-4 2.93·10-4 3.68·10-4 3.90·10-4

a

T c d (K)

a

302.63 304.33 309.11 310.71 317.85 319.33 325.98 326.86 333.88 337.79 347.22 356.87 360.44 366.33 443.37

0.001 0.001 0.002 0.002 0.003 0.004 0.006 0.006 0.010 0.012 0.023 0.040 0.047 0.066 1.000

310.74 318.40 327.61 331.03 335.18 348.29 443.37

0.025 0.036 0.076 0.095 0.126 0.186 1.000

293.15 298.05 303.15 308.15 313.15

-

Calculated from the Wilson equation for water and NRTL equation for ethanol. Standard uncertainties u are as follows: b u(p/kPa) = ±1, b cu(x1) = ±0.0005, c d u(T/K) = ±0.1,

de ef

The pH of the solution was 6. The pH of the solution was 7.

TABLE 4

Experimental solubility equilibrium temperatures (T) for {Metaraminol bitartrate (1) + solvent (2)} binary systems and activity coefficients a , p = 101 kPa.b.

x1b c Water d e 0.0486 0.0665 0.0759 0.0933 0.1076 0.1161 0.1258 0.1304 1.0000 Ethanol e f 0.0003 0.0006 0.0008 0.0008 0.0009 0.0009 0.0014 0.0015 0.0019 1.0000 1-Octanol e f 4.13·10-5 4.38·10-5 4.92·10-5 5.38·10-5 6.00·10-5 6.57·10-5

a

T c d (K)

a

298,53 312,76 318,74 333,10 337,29 346,24 348,54 354,97 452,69

0,002 0,004 0,006 0,011 0,018 0,022 0,028 0,032 1,000

299.32 321,71 313,82 325,71 318,09 329,67 304,62 336,80 346,08 452,69

0.319 0.407 0.430 0.431 0.447 0.446 0.482 0.487 0.500 1.00

293.15 298.05 303.15 308.15 318.15 323.15

-

Calculated from the Wilson equation for water and UNIQUAC equation for ethanol.

Standard uncertainties u are as follows: b u(p/kPa) = ±1, a c u(x1spect) = ±1·10-6, b du(T/K) = ±0.02,

ce df

The pH of the solution was 6, The pH of the solution was 7.

TABLE 5

Physicochemical characteristics of the drugs (p = 101 kPa): temperature of fusion, enthalpy of fusion and molar volumes, .

Drug

Tfus,1 /K

∆fusH1/(kJ·mol-1)

SYN

463.53

99.7

IPR

443.37

79.9

MET

452.69

77.6

a

/(cm3·mol-1)a 147.5 215.4 145.1

Calculated according to the Barton’s group contribution method [17],

Standard uncertainties u are as follows: u(Tfus,1) = ±0.1 K, u(∆fusH1)= ±0.1 kJ·mol-1.

TABLE 6

Values of an acidity functions ( and ionic strength (I) for buffers [18].

Buffer, pH 9.2 9.7

Composition (mol concentration) Borax (0.0078) Sodium chloride (0.0144) Monoethanolamine (0.0600) Hydrochloric acid (0.0300)

T (K) 298.15 310.15 298.15 310.15

9.237 9.142 9.654 9.319

I 0.015 0.015

TABLE 7

The experimental and literature values of pKa (p = 101 kPa).

Drug SYN

pKalit 9.60 a

pKaexp 9.80

T (K) 298.15

Buffer/pH 9.7

a

9.37 b

9.59

310.15

9.7

IPR

8.65a 8.6e

-

298.15 310.15

9.2 9.2

MET

8.60a, d 8.79 c

9.00 8.65

298.15 310.15

9.2 9.2

[20],

b

[21], c [22], d [23], e [24] Standard uncertainties u are as follows: u(pKa) = ±0.0025,

u(pH) = ±0.1.

TABLE 8

Results of correlation of the experimental solubility results of the {Drug (1) + solvent (2)} binary systems by means of the Wilson, NRTL, and UNIQUAC equations.

Parametres Wilson

Root-mean-square deviations

NRTL

UNIQUAC

∆g12

∆u12

∆g21

∆u21

[J⋅mol-1]

[J⋅mol-1]

[J⋅mol-1]

-18285.67

-8509.04

-3200.12

142222.24

20620.58

6103.84

5732.38

-4560.68

-4378.07

-3560.83

6626.20

7274.19

-8160.84

-10526.46

2208.01

595.09

3839.63

-3186.30

1804.66

-19498.28

-2703.02

-1198.93

33145.02

3773.07

-7808.57

-11487.62

-2897085.04

-1120.10

4132.07

2996.90

-8756.70

-3506.26

-3998.68

116252.01

7869.17

8649.36

Wilson

NRTL

UNIQUAC

σT

σT

σT

[K]

[K]

[K]

5.15

3.31a

5.59

8.63

6.24b

5.88

0.76

1.26c

2.23

7.53

6.08d

6.82

1.96

2.19c

11.39

11.44

11.28b

11.09

g12- g11 Drug

Solvent

g12- g22 λ12- λ11 λ12- λ22

Water Synephrine Ethanol

Isoprenaline

Wather

hydrochlorid e

Ethanol

Water Metaraminol bitartrate

a

Ethanol

= 0.4; b

= 0.9; c

= 0.2; d

= 0.1

Captions to the figures:

FIGURE 1. Experimental and calculated SLE of {Synephrine (1) + solvent (2)} binary systems: (x), water; (∆), ethanol; (○), 1-octanol. Solid lines have been designated by the NRTL equation for water and by UNIQUAC equation for ethanol. The dotted line represents ideal solubility. FIGURE 2 Experimental and calculated SLE of {Isoprenaline hydrochloride (1) + solvent (2)} binary systems: (x), water; (∆), ethanol; (○), 1-octanol. Solid lines have been designated by the Wilson equation for water and by NRTL equation for ethanol. The dotted line represents ideal solubility. FIGURE 3. Experimental and calculated SLE of {Metaraminol bitartrate (1) + solvent(2)} binary systems: (x), water; (∆), ethanol; (○), 1-octanol. Solid lines have been designated by the Wilson equation for water and by UNIQUAC equation for ethanol. The dotted line represents ideal solubility. FIGURE 4. UV-Vis spectra (absorbance as a function of wavelength) for acidity constant measurement, experimental points of {Synephrine + solvent}: (□), NaOH; (●), Bufor; (+), HCl. (a) at T = 298.15 K; (b) at T = 310.15 K. FIGURE 5.

UV-Vis spectra (absorbance as a function of wavelength) for acidity constant measurement, experimental points of {Metaraminol bitartrate + solvent}: (□), NaOH; (●), Bufor; (+), HCl. (a) at T = 298.15 K; (b) at T = 310.15 K.

fx1 .

390 370

T/K

350 330 310 290 270 0

gr1 .

0.004 x1

0.008

450 420 390 360

310

T/ K

T/K

320

300

330

290

300 280 0

1

2 3 x 1·104

4

5

270 0

0.2

0.4

0.6 x1

gr2 .

0.8

1

410 390

T/K

370 350 330 310 290 270 0

0.05

0.1 x1

gr3 .

0.15

a) 2

A

1.5 1 0.5 0 230

240

250

260

250

260

λ/nm

b) 2

A

1.5 1 0.5 0 230

240

λ/nm

gr4 .

a) 1.5

A

1 0.5 0 230

240

250

λ/nm

b) 1.5

A

1 0.5 0 230

240

λ/nm

gr5 .

250