The physicochemical properties and solubility of pharmaceuticals – Methyl xanthines

Accepted Manuscript The physicochemical properties and solubility of pharmaceuticals – methyl xanthines Aneta Pobudkowska, Urszula Domańska, Justyna A. Kryska PII: DOI: Reference:

S0021-9614(14)00152-9 http://dx.doi.org/10.1016/j.jct.2014.05.005 YJCHT 3932

To appear in:

J. Chem. Thermodynamics

Received Date: Revised Date: Accepted Date:

7 January 2014 8 May 2014 12 May 2014

Please cite this article as: A. Pobudkowska, U. Domańska, J.A. Kryska, The physicochemical properties and solubility of pharmaceuticals – methyl xanthines, J. Chem. Thermodynamics (2014), doi: http://dx.doi.org/10.1016/ j.jct.2014.05.005

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1

J. Chem. Thermodynamics

2 3

The physicochemical properties and

4

5

solubility of pharmaceuticals – methyl

6

xanthines#

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Aneta Pobudkowska a*, Urszula Domańska a, Justyna A. Kryska a

8 9 10 11 12 13 14 15 16 17 18

a

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3, 00-664 Warsaw, Poland.

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*

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

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#

This paper was presented at the 3rd World Conference on Physico Chemical Methods in Drug Discovery and

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Development, Dubrovnik, Croatia, 22-26 September 2013.

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

1

ABSTRACT

2

The aim of this study was to evaluate the physio-chemical properties and solubility of

3

three pharmaceuticals (Phs): theophylline, 7-(β-hydroxyethyl) theophylline, and theobromine

4

in binary systems in different solvents. The solvents used were water, ethanol, and

5

1 - octanol. Score of the solubility of these substances is being important for their dissolution

6

effect inside the cell, the transportation by body fluids and the penetration possibility of lipid

7

membranes.

8

The Phs were classified to the group of methyl xanthines, which contain purine in their

9

structure. Although they are mainly obtained via chemical synthesis, they can be also found in

10

natural ingredients such as cocoa beans and tea leaves. These drugs are mainly acting on the

11

central nervous system but are also used in the treatment of asthma or blood vessels.

12

Solubility of 7 (β-hydroxyethyl) theophylline and theophylline were tested using

13

synthetic method. In case of theobromine, which solubility is very small in the solvents noted,

14

the spectrophotometric method has been used to measure its solubility. After designating

15

phase diagrams of each of the solubility in the bipolar system, the experimental points have

16

been correlated with the equations: Wilson, NRTL, UNIQUAC. Results show that

17

theophylline and its derivatives show the best solubility from all tested Phs.

18

Another method also used during this study was the differential scanning calorimetry

19

(DSC), which allowed designation of the thermal properties of Phs. The fusion temperature

20

and the enthalpy of melting were measured. Unfortunately, it was not possible to determine

21

the fusion temperature and enthalpy of melting of theobromine, because of the decomposition

22

of Ph at high temperature.

23

The important property tested was the constant acidity, to this end, the

24

spectrophotometric method of Bates – Schwarzenbach was used. Unfortunately, with this

25

method it was not possible to determine the value of pKa 7-(β-hydroxyethyl) theophylline.

26

For other Phs, these values do not differ significantly from those proposed in the literature.

27

Both awareness and knowledge of values of the drug pKa and solubility are important

28

in Phs production. This allows the selection of a suitable solvent and allows estimation of the

29

correct dose and its capacity to absorb in human body.

30

2

1

Keywords:

2

Xanthines

3

pKa

4

Solubilities

5

Thermodynamic correlation

6 7

3

1

1.

Introduction

2

All xanthines belong to purine alkaloids group, which is known to be bi-cyclical hetero-

3

cyclic ampholyte - it has both acidic and alkaline activity [1]. This group is known to exist in

4

several tautomeric forms [2]. Theophylline (1,3-dimethylxanthine) and theobromine (3,7-

5

dimethylxanthine) are called methylxanthines due to substituted methylene functional groups

6

in either 1, 3 or 7-N-atom.

7

The final substance of purine metabolism is caffeine and its formation goes through

8

several steps. The first of these is conversion of purine nucleotide to xanthonesine - the first

9

intermediate [3]. Next stage is a methylation with assistance of several methyltransferase-

10

enzymes [4]. During biosynthesis of caffeine several intermediates appear in the order: 7-

11

methylxanthinose, 7-methylxanthine, 3,7-methylxanthine and theobromine.

12

Xanthine derivatives belong to alkaloids which are described as natural bases having

13

nitrogen atoms in molecular structure and have strong physiological effect on human and

14

animal organism. Coffeine (the tea and coffee culture) is the most famous substance of this

15

group, and has several centuries of long tradition. In pharmaceuticals, caffeine is known to be

16

applied as a medicine affecting the nervous system. Theophylline and theobromine, two other

17

derivatives of xanthine, have a long history of use in the treatment of asthma. Despite losing

18

competition to more modern pharmaceutically active substances (API) as corticosteroids and

19

stimulators of β-adrenergic receptors, theophylline is still commonly used in medicine.

20

Theophylline and theobromine are able to form salts both with acidic and basic

21

substances [5]. These molecules have a stronger basic nature than an acidic one, salt

22

formation with acid is shown to be more preferable. They possess an ampholytic nature like

23

purine [2], therefore these drugs can act also as acids according to their ability as a proton

24

donator from position 7. Acidic behaviour of these molecules is also provided by ketoenole

25

tautomerisation, which allows a shift of hydrogen atom.

4

1

All derivatives of xanthine have poor water solubility in contrast to their parent molecule

2

purine. The reason for this behaviour is the existence of relatively strong intramolecular

3

bonds between N-H-groups [2]. Another factor, which has a noticeable effect on the poor

4

solubility nature of xanthine derivatives, is the formation of strong inter-base hydrogen bonds

5

and base stacking [6]. This is due to the increasing number of methylated groups as well as

6

the possibility of proton elimination following hydrogen bonding at site formation. The high

7

values of melting points of these pharmaceuticals are based on the same phenomenon, viz.

8

larger aggregates require more energy and naturally more entropy to change condition from

9

solid to liquid. Xanthine derivatives have different properties with respect to lipophility.

10

They are hydrophilic and do not penetrate into the organic phase of binary solvent [7].

11

Xanthines are known to have several crystalline structures. Theophylline has great

12

hydration ability and exists in two forms: monohydrate and anhydrate. Anhydrous

13

theophylline appears as two stable crystalline lattices named as form I and II [8, 9]. These

14

crystalline states are probably formed during the heat transition accompanying the

15

dehydration of the monohydrous form. This process is going through drying of solid

16

theophylline monohydrate and includes two stages: breaking of hydrogen bonds and further

17

evaporation of the loosened water [10]. Dehydration is dependent on factors such as surface

18

area and temperature, since an increase of temperature increases dehydration [11]. Form II of

19

anhydrous theophylline [12] was shown to have better properties in terms of stability and

20

solubility. It dissolves better and does not revert to the hydrate at room temperature. Due to

21

this reason, it is the most commonly used form in formulation of solid dosage forms

22

containing theophylline. Theophylline occurs as a metastable crystalline structure [13]. This

23

form is noted during the formation of the monohydrate being an intermediate of the current

24

process. The volume of the metastable phase has been shown to decrease with increasing

25

temperature and drying time [14].

5

1

Pseudopolymorphism is the result of contact between the solid form and liquids.

2

Products of this interaction are hydrates and solvates. The mechanism is explained as the

3

penetration of water molecules into the bulk solid structure and with further change of the

4

crystalline structure [15]. The role of this type of polymorphism in pharmaceutical science is

5

significant because hydrates and solvates are known to possess huge differences in

6

pharmacokinetic profiles compared to non-hydrous crystals. Theophylline actively absorbs

7

water molecules during manufacture of pharmaceutical dosage forms [16]. Hydration of

8

theophylline includes absorption of water molecules into the crystal surface followed by deep

9

diffusion [17]. The hydrogen bonds are formed between water and the solid state. The next

10

step is a formation of water tunnels, which assist penetration of greater aqua volumes. The

11

strength of the hydrate is dependent on the strength of hydrogen bonds [14]. The final

12

structure is known to have two water molecules with hydrogen bonded by two theophylline

13

molecules [10]. Typical for pseudopolymorphic forms, theophylline anhydrate and

14

monohydrate show differences in physicochemical habits [13] [18] [19].

15

Xanthines are absorbed in the GI-tract and show strong “in vivo” intake profiles [20].

16

Peak plasma concentration for theophylline and theobromine is achieved quickly. They

17

belong to short-acting substances and their half-life is not long. Xanthine derivatives are

18

delivered in per-oral forms as tablets, capsules and mixtures both for rapid release and for

19

prolonged action.

20

Derivatives of xanthine belong to the pharmacological group of adenosine A-receptor

21

antagonists [21]. Pharmacological action of these substances goes through inhibition of cyclic

22

GMP and GABA A -receptors. Theophylline and theobromine show anti-inflammatory

23

effects and thus are used in the treatment of asthma. Other important therapeutic areas of

24

xanthines are cancer and Alzheimer's disease and they are applied as heart and vascular

6

1

agents due to diuretic effect. Having excellent CNS-penetration ability, caffeine is also

2

available as a stimulant and antidepressant.

3

In this work the solubility of theophylline, 7-(β-hydroxyethyl) theophylline, and theobromine

4

in water, ethanol, and 1-octanol was measured. The pKa with Bates-Schwarzenbach method

5

are provided to compare to literature data.

6 7

2.

8

2.1 Materials

Experimental

9

Herein are reported origins of the pharmaceuticals from Sigma Aldrich, i.e.

10

theophylline (CAS Registry No. 58-55-9), 7-(β-hydroxyethyl) theophylline (CAS Registry

11

No. 519-37-9), and theobromine (CAS Registry No. 83-67-0). The Phs were used without

12

further purification and were used as powder or small crystals. The names, sources, purity,

13

molecular formula and molar masses of the compounds are listed in table 1. The structures of

14

Phs are shown in figure 1.

15

Water used as a solvent was twice distilled, degassed, deionized and filtered with

16

Milipore Elix 3. The remaining solvents, i.e., ethanol and 1-octanol, were obtained from

17

Sigma Aldrich with a >0.998 mass fraction purity. They were stored under freshly activated

18

molecular sieves of type 4x10 -8 m (4 Å). The buffers, 0.1 M sodium hydroxide and 0.1 M

19

hydrochloric acid solution, were prepared from substances delivered by POCH, i.e. sodium

20

chloride (CAS Registry No. 7647-14-5; 0.999 mass fraction purity), potassium dihydrogen

21

phosphate (CAS Registry No. 7778-77-0; 0.995 mass fraction purity), disodium hydrogen

22

phosphate (CAS Registry No. 7558-79-4; 0.99 mass fraction purity), ethanolamine (CAS

23

Registry No. 141-43-5; 0.99 mass fraction purity), sodium hydroxide (CAS Registry No.

24

1310-73-2; 0.988 mass fraction purity), and hydrochloric acid (CAS Registry No. 7647-01-0;

7

1

0.35-0.38 mass fraction purity). All solutes were filtrated twice with Schott funnel with 4µm

2

pores.

3 4

2.2 Density measurements

5

The densities of the pure solvent (water, ethanol and 1-octanol) were measured using

6

an Anton Paar GmbH 4500 vibrating-tube densimeter (Graz, Austria). The temperature was

7

controlled with two integrated Pt 100 platinum thermometers provided good precision of ±

8

0.01 K. The densimeter includes an automatic correction for the viscosity of the sample. The

9

apparatus is precise to within 1x10 -5 g·cm-3, and the overall uncertainty of the measurements

10

was estimated to be better than 5x10 -5 g·cm-3. The calibration of the densimeter was

11

performed at atmospheric pressure (p=0.1 MPa) using doubly distilled and degassed water,

12

specially purified benzene (CHEMIPAN, Poland 0.999) and dried air.

13 14

2.3 Differential scanning microcalorimetry (DSC)

15

Temperatures of fusion (Tfus,1) and enthalpy of fusion (∆fusH1), the basic thermal

16

properties of the Phs studied, have been measured with the differential scanning

17

microcalorimetry technique (DSC). The experiments were performed with DSC 1 STARe

18

System (Mettler Toledo) calorimeter equipped with liquid nitrogen cooling system and

19

operating in a heat-flux mode. The instrument was calibrated with the 99.9999 mol% purity

20

indium sample and with high purity heptane, octane, decane and water. The sample was

21

sealed in ambient air in hermetic aluminium pans having mass of about 50 mg. An empty

22

hermetic aluminium pan was used as a reference. Sample size of about 5 mg was used

23

throughout this study and the heat flow was normalized by the actual weight of each sample.

24

The sample cell was constantly fluxed with high purity nitrogen at constant flow rate of 20

25

mL·min-1. The experiments were carried out using 10 K·min-1 heating rate. The calorimetric

8

1

accuracy from calibration was 1 %. The experimental data were analysed using STAR

2

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

3

thermophysical characteristic of Phs is given in table 2 [22-26].

4 5

2.4 Phase equilibria apparatus and measurements

6

In the present work, a well known dynamic (synthetic) method for the solubility

7

measurements was used. Details of the procedure have been described in our earlier work

8

[27].

9

Mixtures (Ph + solvent) were prepared by weighing the pure components with uncertainty of

10

1x10 −4 g; errors did not exceed 5x10 -4 in mole fraction. The solvent was added to each point

11

by weighing. The sample was heated very slowly (< 2 K · h−1) with continuous stirring inside

12

a Pyrex glass cell placed in thermostat. The thermostat was filled up with water. The crystal

13

disappearance temperatures detected visually, were measured with an electronic thermometer

14

P 550 (DOSTMANN electronic GmbH). The uncertainties of the temperature measurements

15

were judged to be 0.1 K and that of the mole fraction did not exceed ±0.0005. The

16

repeatability of the solubility measurements was ±0.1 K. The measurements were carried out

17

over a wide range of Phs mole fraction region. The solid–liquid (SLE) phase equilibria

18

measurements of Phs in solvents (water, ethanol and 1-octanol) were carried out at

19

temperatures from 290 K to 365 K and at pressure 0.1 MPa. The results are presented in tables

20

3 to 5.

21

For the very low solubility of theobromine, the visual method was not applicable, and

22

the saturation shake-flak method with UV-Vis spectrophometer (Perkin-Elmer Life and

23

Analytical Sciences Lambda 35, Shelton USA) was used, within the temperature range of

24

(293.15 to 318.15) K. The procedure was described in our previous work [28].

25

9

1

2.5 The pKa measurements

2

The pKa measurements were performed with Bates-Schwarzenbach method [29] using

3

the UV-Vis spectrophotometer (Perkin-Elmer Life and Analytical Sciences Lambda 35,

4

Shelton USA). Solutions of each Ph were prepared with mol concentration 1x10-5 mol·dm-3.

5

Two buffers were prepared (mol concentration) i.e. borax (0.007780), sodium chloride

6

(0.014430; buffer, pH = 9.2), monoethanolamine (0.1600), and hydrochloric acid (0.0800;

7

buffer, pH = 9.7). The buffer was chosen on the basis of the literature value of pKa of Phs.

8

Values of acidity functions (p(a γ )) and ionic strength (I) for the buffers used are listed in

9

table 7. For each Ph, three samples were prepared: in a buffer solution, in 0.1M acid solution

10

and in 0.1M base solution, and were scanned with water-buffer, 0.1M water-acid and 0.1M

11

water-base solutions as a reference, respectively, with scan step 1 nm from 320 nm to 190 nm.

12

Using equation:   

p = p(  ) − log 

13

 

,

(1)

14

where pKa is an acidity constant, p(a HγCl) is an acidity function, DHA, DA-, D are absorbance

15

values in acid, base and buffer, respectively. The pKa values were calculated, and the error of

16

this measurement, calculated with the Gauss method is u(pKa) = ±0.025. The exact

17

procedure of measurements was described earlier [28].

18 19

3.

Results and discussion

20

The chemical structure of these three compounds is very similar as all substances possess

21

a pyridine ring. The substituent at nitrogen atom is the same with the only difference of

22

methyl group for theophylline and 7-(β-hydroxyethyl) theophylline, or shortage groups for

23

theobromine. The substituent at the other atom is of the –CH2CH2OH group for 7-(β-

24

hydroxyethyl) theophylline, and the methyl group for theobromine.

10

1

The DSC of the Phs indicates that these xanthines exhibit a very high temperature of

2

melting, Tfus,1 = 544.5 K and Tfus,1 = 435.8 K for theophylline, and 7-(β-Hydroxyethyl)

3

theophylline, respectively. These Phs do not show the solid-solid phase transition. The

4

enthalpies of fusion of two substances are quite high and typical for organic compounds,

5

∆fusH1 = 30.23 kJ·mol-1 for theophylline, and ∆fusH1 = 32.62 kJ·mol-1 for 7-(β-hydroxyethyl)

6

theophylline. It is noteworthy that no one substance revealed the glass-transition

7

temperature, and polymorphism, which is quite characteristic for organic compounds and

8

pharmaceuticals. Unfortunately, it was impossible to measure the thermophysical data for

9

theobromine.

10

In this work, altogether 9 binary systems {Ph (1) + solvent (2)} were studied. Solubilities

11

have been determined in three solvents: water, ethanol, and 1-octanol. Solubility was

12

determined for all the systems for which the visual method or the spectrophotometric method

13

was possible to use. The obtained results are presented in tables 3 to 5 and in figures 2 to 4.

14

On the basis of the data investigated, the following trends are noted: (a) all Phs are

15

composed of two aromatic rings, for which the solubility in water, or alcohols is very low;

16

(b) only the solubility of theophyline is greater in ethanol than that in 1-octanol; (c) the

17

solubility of all Phs in water is greater than those in alcohols; (d) the solubility of

18

theobromine is very low in all solvents and is detectable only by the spectrophotometric UV-

19

Vis method; (e) the solubility of two substances, 7-(β-hydroxyethyl) theophylline and

20

theobromine, is greater in 1-octanol that in ethanol. High solubility of 7-(β-hydroxyethyl)

21

theophylline and theobromine in water is comfortable because drugs are well soluble in polar

22

environment of our body. The greater solubility of theophylline in ethanol than that in 1-

23

octanol is a typical behaviour of most organic substances with polar functional groups. On

24

the other hand, Phs revealing high solubility in 1-octanol are stored in non-polar parts of

25

body, as in nervous systems and lipids. In water and alcohols, the hydrogen bonding and the

11

1

interstitial accommodation with the solvent may play the important role. High solubility in

2

water and alcohols helps the drug cross the blood-brain barrier. From the thermodynamic

3

point of view, the solubility is strongly dependent on the fusion temperature. Theophylline

4

with the higher fusion temperature, Tfus,1 = 544.5 K, is less soluble in 1-octanol that for

5

example 7-(β-hydroxyethyl) theophylline with Tfus,1 = 435.8 K. The literature data of

6

solubility for investigated drugs are scarce. The information is the intrinsic solubility at T =

7

310.15 K equal to 0.7 mg·mL-1, 11.8 mg·mL-1 for theobromine and theophylline,

8

respectively [30]. Our values extrapolated, or interpolated to T = 310.15 K are listed in table

9

6. The observed solubility in water is different in comparison to the literature data. The

10

reason is probably due to a different pH of the solution and the use of a buffer solution in the

11

previous measurements [30]. The solubility data for theophylline in ethanol, obtained in this

12

work, are compared with those reported by Subra et al. [31] measured by the gravimetric

13

method. The comparison is shown in figure 2. Data measured by dynamic method are

14

burdened with greater experimental uncertainty than for gravimetric method. Data obtained

15

by Subra et al. [31] lie within the confidence interval of u(x1) for any given temperature, thus

16

both of these data sets are statistically significant. Our values of solubility may be treated as

17

new data for the series of new Phs. For every Ph, we present many experimental points

18

obtained individually, which is a confirmation of precision of the method used.

19

The solubility of drugs in water increases with an increasing pH but the permeability

20

coefficient decreases [32]. The pKa studies show which form of drug is active at certain pH.

21

The effect of pH on the value of pKa and the usefulness of drug cannot be neglected. The pH

22

partition theory is also well documented for the general absorption of ionisable drugs a cross

23

the gastrointestinal tract. Values of the pKa were measured for three drugs by the

24

spectrophotometric Bates-Schwarzenbach method. Unfortunately, we could not find the

25

proper method to measure the pka of 7-(β-hydroxyethyl) theophylline. The traditional pH-

12

1

metric titration method of determining pKa values is less employed for the poor aqueous

2

drug’s solubility. Our experimental values are greater than the literature data previously

3

published. The pH of our values of pKa studied are listed in table 7, and the UV-Vis spectra

4

for the systems under study are presented in figures 5 – 7, where the absorbance as a

5

function of wavelength is presented for three solutions with buffer, 0.1 M NaOH and 0.1 M

6

HCl. The wavelengths were chosen for the maximum distance of the border absorbance, or

7

for the flat function of A (λ). Determination of the concentration ratio in the

8

spectrophotometric measurements is possible by respecting the absorbance additivity law

9

and the Bouguer-Lambert-Beer law by the presence of different drug forms in the solute.

10

The Bates-Schwarzenbach method is not using the high dissolution of various organic

11

solvents and the extrapolation to the pure substance. The method is using the

12

spectrophotometric detection of the concentration of the drug in the high dilution at known

13

pH. Our experimental values of pKa are higher at T = 310.15 K than those at T = 298.15 K.

14 15

4.

Modelling

16

Since no solid-solid phase transitions were observed for the compounds, the simplified

17

general thermodynamic equation has been fitted to the sets of experimental solubility data

18

[33]:

19

− =

∆ ! "#  %& $

−&



' +   ,

(2)

 !,#

20

where: x1 – mole fraction; ∆fusH1 – enthalpy of fusion of the pure solute; T – solid-liquid

21

equilibrium temperature; Tfus,1 – melting temperature for the pure solute; γ1 – activity

22

coefficient of the solute in the saturated solution.

23

The experimental data together with the calculated activity coefficients for solubility

24

in the systems {Ph (1) + solvent (2)} are listed in tables 3 – 5. The enthalpy of melting is

25

assumed to be temperature independent, whereas the activity coefficient and solubility are

13

1

temperature dependent. The calculation was made from the excess Gibbs energy (G* ) by

2

using the Gibbs-Duhem equation. The Wilson equation [34], the NRTL equation [35], and

3

the UNIQUAC equation [36] were used to describe the experimental data. The molar

4

volumes, which were calculated by the group contribution method described by Barton [22]

5

are presented in table 2. Number of segments (ri) and external contacts of the molecule (qi) of

6

type i occurring in the UNIQUAC equation are related to the molar volumes by the following

7

expressions:

8

r, = 0.029281 ∙ V5, ,

9

6 ∙ q, = (6 − 2) ∙ r, + 2,

(3)

10

where Z denotes the coordination number (it was assumed that Z = 10), and the bulk factor

11

li = 1 (it was assumed for the globular molecule). Two adjustable parameters P1 and P2,

12

which are determined by minimization of the objective function F(P1, P2), are defined as

13

follows:

14

:

8(9 , 9: ) = ∑E,F<=>?@,, − =ABCA,, (, , 9 , 9: )D ,

(4)

15

where n denotes the number of experimental points. A constant of proportionality to the non-

16

randomness constant of the NRTL equation, it is the parameter G: (G: = G: = 0.5, or

17

0.9), was taken into account in the calculations. In this work, Marquardt algorithm for solving

18

of non-linear least squares problem was successfully used. As a measure of the reliability of

19

the correlations, the root-mean-square deviation of temperature, H& /K, has been calculated

20

according to the following definition:

21

H& = I∑E,F

J&KLMN,O &PQRP,O S E:

T

⁄:

U

.

(5)

22

The calculated values of the equation parameters and corresponding root-mean-square

23

deviations of the binary systems obtained by three models are shown in table 9. The mixtures

24

investigated in this work show positive deviations from ideality in all the solvents. The

14

1

correlation was not provided for the spectrophotometric method, it is for the very small

2

solubilities.

3 4

5.

Conclusions

5

To the best of our knowledge, most of the solubility data and thermophysical data for

6

Phs chosen by us were not published. We employed differential scanning calorimetry (DSC)

7

to measure the enthalpy of melting and the melting temperature of three measured

8

pharmaceuticals. The equilibrium mole fraction solubility of three Phs in three different

9

solvents (water, ethanol and 1-octanol) has been measured experimentally. We combined the

10

calorimetric and solubility data to determine the activity coefficients of important

11

pharmaceutical compounds in the saturated solutions. As was expected, the solubility is

12

lower than the ideal solubility, which indicates the association of the drug molecule with the

13

highly polar solvents. The solubility of two of measured substances, of 7-(β-hydroxyethyl)

14

theophylline and theobromine was higher in water than in alcohol, and thus, is can be

15

delivered to the human body with water. Theophyline has revealed high solubility in ethanol.

16

With the assumption that the systems studied here revealed simple eutectic mixtures, the

17

correlation of the solubility data was carried out by means of three commonly known GE

18

equations, the Wilson, NRTL and UNIQUAC. The values of the pKa of three drugs have

19

been measured in water experimentally and compared to the literature data. Our experimental

20

values of pKa differ from the published earlier, because of the different buffers used and

21

methods usually connected with diluted solutions. We believe that our new solubility and

22

thermophysical data as well as the pKa data of three important drugs will enrich the data

23

banks and will improve PK/PD prediction methods development and precision.

24 25

Acknowledgements

15

1

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

2

Poland.

3

16

1

References

2

[1] E.I. Isaacson, CFentral Nervous System Stimulants, Lippincot Williams&Wilkins,

3

Remers WA (1998).

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[2] H.J. Roth, K. Eger, R. Trochütz, Purines and purine isomers, Elis Horwood LTd (1991).

5

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11 12

19

TABLES TABLE 1 Basic properties of Phs used in the investigations. Name of compound

Source

Mass fraction purity

Theophylline

Sigma Aldrich

≥0.99

7 (β-hydroxyethyl) theophylline

Sigma Aldrich

≥0.99

Theobromine

Sigma Aldrich

≥0.99

Water

Milipore Elix 3

Ethanol

Sigma Aldrich

>0.998

1-Octanol

Sigma Aldrich

>0.998

a

[37]; b [38]; c [39].

Systematic (IUPAC) name/ CAS Number 1,3-dimethylxanthine 3,7-dihydro-1,3-dimethyl-1 H purine-2,6-dione 2,6-dihydroxy-1,3-dimethylpurine/ 58-55-9 1,3-dimethyl-7-(2-hydroxyethyl) xanthine/ 519-37-9 2,6-dihydroxy-3,7-dimethylpurine 3,7-dimethylxanthine/ 83-67-0 dihydrogen monoxide ethyl alcohol/ 64-17-5 alcohol C8 capryl alcohol, octyl alcohol/ 111-87-5

Molecular formula

Molar mass M/ (g· mol-1)

Density ρlit/ρexp (298.15K)/ (g·cm-3)

Refractive Index n25/D

C7H8N 4O2

180.16

-

-

C9H12N4O 3

224.22

-

-

C7H8N 4O2

180.16

-

-

H2O

18.01

0.99704a/0.99703

1.39276b

C2H5OH

46.07

0.78504c/0.78512

1.35941b

C8H17OH

130.23

0.82302b/0.82299

1.42760b

TABLE 2 Physicochemical characteristics of the Phs: temperature, Tfus,1 and enthalpy of fusion, ∆fusH1 and molar volume, WX:YZ,[\ . Phs Theophylline

Tfus,1 /K 544.5

`a =]^_, /K. 545.3b,c 544.0d -

∆fusH1/(kJ·mol-1) 30.23

WX:YZ,[\ /(cm3·mol-1)a 114.60

-1 ∆`a ]^_ b /(kJ·mol ) b,c 30.9 30.43d,e -

7 (β-hydroxyethyl) 435.8 32.62 theophylline Theobromine a Calculated according to the Barton’s group contribution method [22], b ref. [23], e ref. [26]. Standard uncertainties u are as follows: u(Tfus,1) = ±0.1 K, u(∆fusH1)= ±0.1 kJ·mol-1.

146.30 c

114.60 ref. [24], d ref. [25],

TABLE 3 Experimental solubility equilibrium temperatures (T) for {Theophylline (1) + solvent (2)} mixtures and activity coefficients  at pressure p = 0.1 MPa. x1 a T b/K  c d Water 0.0004 308.5 15.12 0.0005 310.6 13.07 0.0007 314.5 10.80 0.0009 316.7 9.12 0.0010 319.3 9.01 0.0012 323.4 8.66 0.0018 326.2 6.35 0.0026 333.3 5.60 0.0039 337.6 4.28 0.0064 342.6 3.05 0.0070 343.1 2.84 1.0000 544.5e 1.00 Ethanol f 0.0008 309.4 7.81 0.0013 313.0 5.51 0.0020 318.6 4.39 0.0027 321.3 3.58 0.0036 325.2 3.08 0.0050 332.8 2.86 0.0083 340.1 2.17 0.0123 345.3 1.72 1.0000 544.5e 1.00 1-Octanol f 0.0010 322.3 10.02 0.0013 327.2 9.12 0.0017 330.2 7.72 0.0025 336.7 6.49 0.0027 337.5 6.17 0.0045 343.8 4.50 0.0063 352.1 4.13 0.0069 355.3 4.13 0.0080 364.5 4.63 1.0000 544.5e 1.00 Standard uncertainties u are as follows: a u(x1) = ±0.0005, b u(T/K) = ±0.1, Uc(T/K) = 0.2 K with 0.95 level of confidence (k ≈ 2), u(p) = ± 10 kPa. c Calculated from the Wilson equation for water, ethanol and NRTL equation for 1-octanol., d The pH of the solution was 6, e Melting temperature obtained in the calorimetric measurements, fThe pH of the solution was 7.

22

TABLE 4 Experimental solubility equilibrium temperatures (T) for {7 (β-hydroxyethyl) theophylline (1) + solvent (2)} mixtures and activity coefficients  at pressure p = 0.1 MPa. x1 a T b /K  c d Water 0.0027 290.7 4.13 0.0039 300.9 4.52 0.0041 301.6 4.45 0.0042 303.4 4.68 0.0048 304.6 4.32 0.0052 306.0 4.23 0.0067 312.5 4.28 0.0067 312.8 4.33 0.0086 316.2 3.87 0.0099 317.9 3.58 0.0119 320.5 3.30 0.0133 322.5 3.18 0.0155 324.9 2.99 0.0204 330.8 2.81 0.0260 334.7 2.54 0.0447 342.0 1.89 0.0623 347.3 1.62 0.0808 348.4 1.29 1.0000 435.8e 1.00 Ethanol f 0.0010 313.9 30.37 0.0016 321.2 25.17 0.0023 325.7 20.76 0.0029 327.4 17.54 0.0040 332.5 15.24 0.0055 336.8 12.90 0.0065 339.1 11.83 0.0068 339.7 11.52 0.0077 342.4 11.17 0.0081 343.8 11.12 0.0086 344.9 10.83 1.0000 435.8e 1.00 1-Octanol f 0.0026 323.2 16.74 0.0046 333.2 13.61 0.0060 335.2 11.18 0.0074 338.4 10.15 0.0095 343.5 9.37 0.0149 351.8 7.82 0.0200 355.5 6.54 0.0259 365.2 6.78 1.0000 435.8e 1.00 Standard uncertainties u are as follows: a u(x1) = ±0.0005, b u(T/K) = ±0.1, Uc(T/K) = 0.2 K with 0.95 level of confidence (k ≈ 2), u(p) = ± 10 kPa. c Calculated from the Wilson equation for ethanol, 1-octanol and NRTL equation for water., d The pH of the solution was 6, e Melting temperature obtained in the calorimetric measurements, fThe pH of the solution was 7.

23

TABLE 5 Experimental solubility equilibrium temperatures (T) for {Theobromine (1) + solvent (2)} mixtures at pressure p = 0.1 MPa. x1a T b/ K Water c x1·103 1.0037 293.15 1.0087 298.15 1.0139 303.15 1.0284 308.15 1.0413 313.15 1.0444 318.15 Ethanol d x1·105 1.5295 293.15 2.3263 298.15 3.1470 303.15 3.8528 308.15 5.4889 313.15 6.3411 318.15 1-Octanol d x1·104 2.1386 293.15 4.3320 298.15 6.1000 308.15 8.2351 318.15 Standard uncertainties u are as follows: a u(x1spect) = ±1·10-6, b u(T/K) = ±0.02, Uc(T/K) = 0.2 K with 0.95 level of confidence (k ≈ 2), u(p) = ± 10 kPa. c The pH of the solution was 6, d The pH of the solution was 7.

24

TABLE 6 Values of experimental solubility in water at pH = 6, extrapolated or interpolated to T = 310.15K. Phs Theophylline 7 (β-hydroxyethyl) theophylline Theobromine

c /(mol·dm-3) 2.44x10-2 0.37 5.73x10-2

x1 4.40x10-4 6.57x10-3 1.03x10-3

TABLE 7 Values of an acidity functions (d(  )) and ionic strength (I) for buffers [29]. Buffer, pH 9.2 9.7

Composition (mol concentration) borax (0.0078) sodium chloride (0.0144) monoethanolamine (0.1600) hydrochloric acid (0.0080)

T/K

d(  ))

298.15 310.15 298.15 310,15

9.237 9.142 9.673 9,341

I 0.0015 0.0400

TABLE 8 Experimental and literature values of pKa. pKa lit pKaexp a 8.8 9.38 8.6b 9.74 7 (β-hydroxyethyl) theophylline Theobromine 8.8a 10.35 9.85 a [40], b [41], Standard uncertainties u are as follows: u(pKa) = ±0.025, u(pH) = ±0.1. Phs Theophylline

25

T/K 298.15

Buffer/pH 9.2

310.15 298.15 310.15 298.15 310.15

9.2 9.2 9.2 9.7 9.7

TABLE 9 Results of correlation of the experimental solubility results of the {Ph (1) + solvent (2)} binary systems by means of the Wilson, NRTL, and UNIQUAC equations.

Wilson Phs

Solvent

a

Wilson σT

σT

σT

(K)

(K)

(K)

1.23

2.91a

1.88

2.67

4.19a

10.77

6.86

3.60a

7.13

∆g12 ∆g21

∆u12 ∆u21

(J ⋅ mol-1) 9133.52 1418.82 12804.54 -2082.54 5978.56 -886.75

(J ⋅ mol-1) -2193.42 11670.34 -2319.42 10349.04 -1920.43 10048.44

(J ⋅ mol-1) -1811.07 7419.65 -308.96 1711.30 -137.23 2039.82

Water

1276.52 3526.46

-2943.80 9409.21

4097.15 1783.96

1.57

1.19b

1.76

Ehtanol

9778.51 417.78

-251.70 9397.52

-2702.11 7691.47

1.24

1.47a

2.29

1-Octanol

9698.29 -1598.15

995.16 6855.91

-834.40 2906.30

2.31

2.40a

4.91

Ehtanol 1-Octanol

7 (βHydroxyethylo) theophylline

Rmsd’s NRTL UNIQUAC

UNIQUAC

g12- g11 g12- g22

Water Theophylline

Parameters NRTL

α12 = 0,9; b α12 = 0,5.

26

Captions to the figures:

FIGURE 1. Chemical structure of the three used drugs: a) theophylline, b) 7-(β-hydroxyethyl) theophylline, c) theobromine. FIGURE 2. Plot of temperature against mole fraction to show the experimental and calculated solubility of {theophylline (1) + solvent (2)} binary systems: (∆) water, (⋆) ethanol and (●) 1-octanol. Solid lines (—) have been designated by the Wilson equation for the water and 1-octanol and NRTL equation for ethanol; the dotted line refers to ideal solubility. (■) – literature data (ref. [35]) for ethanol. FIGURE 3. Plot of temperature against mole fraction to show the experimental and calculated solubility of {7 (β-hydroxyethyl) theophylline (1) + solvent (2)} binary systems: (∆) water, (⋆) ethanol and (●) 1-octanol. Solid lines (—) have been designated by the Wilson equation for the water and ethanol and NRTL equation for 1octanol; the dotted line refers to ideal solubility. FIGURE 4. Plot of temperature against mole fraction to show the experimental and calculated solubility of {theobromine (1) + solvent (2)} binary systems: (∆) water, (⋆) ethanol and (●) 1-octanol. FIGURE 5. pKa measurements (absorbance vs. wavelength) a) at T = 298.15 K, b) at T = 310.15 K: experimental points for {theophylline + water} mixtures: (—) buffer; (····) 0.1 M HCl; (- · -) 0.1 M NaOH. FIGURE 6. pKa measurements (absorbance vs. wavelength) at T = 298.15 K; experimental points for {7-(βhydroxyethyl) theophylline + water} mixtures: (—) buffer; (···· ) 0.1 M HCl; (- · -) 0.1 M NaOH. FIGURE 7. pKa measurements (absorbance vs. wavelength) a) at T = 298.15 K; b) at T = 310.15 K: experimental points for {theobromine + water} mixtures: (—) buffer; (· ···) 0.1 M HCl; (- · -) 0.1 M NaOH.

27

FIGURE 1. a)

O H N

H3C N N CH3

O

N

b)

O H3C N O

OH

N

N CH3

N

c)

O HN O

CH3 N

N CH3

N

28

FIGURE 2.

540 510 350

480

T/K

450 330

420 390

310

360 330

290 0

300 0.0

0.2

0.01

0.4

0.6

x1

29

0.02

0.8

1.0

FIGURE 3.

450

420

T/K

390

360

330

300 0.0

0.2

0.4

0.6

x1

30

0.8

1.0

FIGURE 4.

31

FIGURE 5. a)

A

1

0.5

0 275

285

295

λ/nm b)

A

1

0.5

0 275

285

295

λ/nm

32

FIGURE 6. a)

A

2 1 0 210

260

310

λ/nm

33

FIGURE 7. a)

2 1.5

A

1 0.5 0 280

290

300

λ/nm b)

2

A

1.5 1 0.5 0 280

290

300

λ/nm

34

GRAPHICAL ABSTRACT:

35