The physicochemical properties and solubility of pharmaceuticals – Methyl xanthines

https://doi.org/10.1016/j.jct.2014.05.005Get rights and content

Highlights

  • Solubility of methyl xanthines in water and alcohols was measured.

  • Solubility in water, or alcohols was of the order of 10−4 in mole fraction.

  • Experimental aqueous pKa’s values are reported for the selected drugs.

  • The basic thermodynamic functions were determined.

Abstract

The aim of this study was to evaluate the physio-chemical properties and solubility of three pharmaceuticals (Phs): theophylline, 7-(β-hydroxyethyl) theophylline, and theobromine in binary systems in different solvents. The solvents used were water, ethanol, and 1-octanol. Score of the solubility of these substances is being important for their dissolution effect inside the cell, the transportation by body fluids and the penetration possibility of lipid membranes.

The Phs were classified to the group of methyl xanthines, which contain purine in their structure. Although they are mainly obtained via chemical synthesis, they can be also found in natural ingredients such as cocoa beans and tea leaves. These drugs are mainly acting on the central nervous system but are also used in the treatment of asthma or blood vessels.

Solubility of 7 (β-hydroxyethyl) theophylline and theophylline were tested using synthetic method. In case of theobromine, which solubility is very small in the solvents noted, the spectrophotometric method has been used to measure its solubility. After designating phase diagrams of each of the solubility in the bipolar system, the experimental points have been correlated with the equations: Wilson, NRTL, UNIQUAC. Results show that theophylline and its derivatives show the best solubility from all tested Phs.

Another method also used during this study was the differential scanning calorimetry (DSC), which allowed designation of the thermal properties of Phs. The fusion temperature and the enthalpy of melting were measured. Unfortunately, it was not possible to determine the fusion temperature and enthalpy of melting of theobromine, because of the decomposition of Ph at high temperature.

The important property tested was the constant acidity, to this end, the spectrophotometric method of Bates–Schwarzenbach was used. Unfortunately, with this method it was not possible to determine the value of pKa 7-(β-hydroxyethyl) theophylline. For other Phs, these values do not differ significantly from those proposed in the literature.

Both awareness and knowledge of values of the drug pKa and solubility are important in Phs production. This allows the selection of a suitable solvent and allows estimation of the correct dose and its capacity to absorb in human body.

Introduction

All xanthines belong to purine alkaloids group, which is known to be bi-cyclical hetero-cyclic ampholyte – it has both acidic and alkaline activity [1]. This group is known to exist in several tautomeric forms [2]. Theophylline (1,3-dimethylxanthine) and theobromine (3,7-dimethylxanthine) are called methyl xanthines due to substituted methylene functional groups in either 1,3 or 7-N-atom.

The final substance of purine metabolism is caffeine and its formation goes through several steps. The first of these is conversion of purine nucleotide to xanthosine the first intermediate [3]. Next stage is a methylation with assistance of several methyltransferase-enzymes [4]. During biosynthesis of caffeine several intermediates appear in the order: 7-methylxanthinose, 7-methylxanthine, 3,7-methylxanthine and theobromine.

Xanthine derivatives belong to alkaloids which are described as natural bases having nitrogen atoms in molecular structure and have strong physiological effect on human and animal organism. Coffeine (the tea and coffee culture) is the most famous substance of this group, and has several centuries of long tradition. In pharmaceuticals, caffeine is known to be applied as a medicine affecting the nervous system. Theophylline and theobromine, two other derivatives of xanthine, have a long history of use in the treatment of asthma. Despite losing competition to more modern pharmaceutically active substances (API) as corticosteroids and stimulators of β-adrenergic receptors, theophylline is still commonly used in medicine.

Theophylline and theobromine are able to form salts both with acidic and basic substances [5]. These molecules have a stronger basic nature than an acidic one, salt formation with acid is shown to be more preferable. They possess an ampholytic nature like purine [2], therefore these drugs can act also as acids according to their ability as a proton donator from position 7. Acidic behaviour of these molecules is also provided by ketoenole tautomerisation, which allows a shift of hydrogen atom.

All derivatives of xanthine have poor water solubility in contrast to their parent molecule purine. The reason for this behaviour is the existence of relatively strong intramolecular bonds between Nsingle bondH-groups [2]. Another factor, which has a noticeable effect on the poor solubility nature of xanthine derivatives, is the formation of strong inter-base hydrogen bonds and base stacking [6]. This is due to the increasing number of methylated groups as well as the possibility of proton elimination following hydrogen bonding at site formation. The high values of melting points of these pharmaceuticals are based on the same phenomenon, viz. larger aggregates require more energy and naturally more entropy to change condition from solid to liquid. Xanthine derivatives have different properties with respect to lipophility. They are hydrophilic and do not penetrate into the organic phase of binary solvent [7].

Xanthines are known to have several crystalline structures. Theophylline has great hydration ability and exists in two forms: monohydrate and anhydrate. Anhydrous theophylline appears as two stable crystalline lattices named as form I and II [8], [9]. These crystalline states are probably formed during the heat transition accompanying the dehydration of the monohydrous form. This process is going through drying of solid theophylline monohydrate and includes two stages: breaking of hydrogen bonds and further evaporation of the loosened water [10]. Dehydration is dependent on factors such as surface area and temperature, since an increase of temperature increases dehydration [11]. Form II of anhydrous theophylline [12] was shown to have better properties in terms of stability and solubility. It dissolves better and does not revert to the hydrate at room temperature. Due to this reason, it is the most commonly used form in formulation of solid dosage forms containing theophylline. Theophylline occurs as a metastable crystalline structure [13]. This form is noted during the formation of the monohydrate being an intermediate of the current process. The volume of the metastable phase has been shown to decrease with increasing temperature and drying time [14].

Pseudopolymorphism is the result of contact between the solid form and liquids. Products of this interaction are hydrates and solvates. The mechanism is explained as the penetration of water molecules into the bulk solid structure and with further change of the crystalline structure [15]. The role of this type of polymorphism in pharmaceutical science is significant because hydrates and solvates are known to possess huge differences in pharmacokinetic profiles compared to non-hydrous crystals. Theophylline actively absorbs water molecules during manufacture of pharmaceutical dosage forms [16]. Hydration of theophylline includes absorption of water molecules into the crystal surface followed by deep diffusion [17]. The hydrogen bonds are formed between water and the solid state. The next step is a formation of water tunnels, which assist penetration of greater aqua volumes. The strength of the hydrate is dependent on the strength of hydrogen bonds [14]. The final structure is known to have two water molecules with hydrogen bonded by two theophylline molecules [10]. Typical for pseudopolymorphic forms, theophylline anhydrate and monohydrate show differences in physicochemical habits [13], [18], [19].

Xanthines are absorbed in the GI-tract and show strong “in vivo” intake profiles [20]. Peak plasma concentration for theophylline and theobromine is achieved quickly. They belong to short-acting substances and their half-life is not long. Xanthine derivatives are delivered in per-oral forms as tablets, capsules and mixtures both for rapid release and for prolonged action.

Derivatives of xanthine belong to the pharmacological group of adenosine A-receptor antagonists [21]. Pharmacological action of these substances goes through inhibition of cyclic GMP and GABA A-receptors. Theophylline and theobromine show anti-inflammatory effects and thus are used in the treatment of asthma. Other important therapeutic areas of xanthines are cancer and Alzheimer’s disease and they are applied as heart and vascular agents due to diuretic effect. Having excellent CNS-penetration ability, caffeine is also available as a stimulant and antidepressant.

In this work the solubility of theophylline, 7-(β-hydroxyethyl) theophylline, and theobromine in water, ethanol, and 1-octanol was measured. The pKa with Bates–Schwarzenbach method are provided to compare to literature data.

Section snippets

Materials

Herein are reported origins of the pharmaceuticals from Sigma Aldrich, i.e. theophylline (CAS Registry No. 58-55-9), 7-(β-hydroxyethyl) theophylline (CAS Registry No. 519-37-9), and theobromine (CAS Registry No. 83-67-0). The Phs were used without further purification and were used as powder or small crystals. The names, sources, purity, molecular formula and molar masses of the compounds are listed in table 1. The structures of Phs are shown in figure 1.

Water used as a solvent was twice

Results and discussion

The chemical structure of these three compounds is very similar as all substances possess a pyridine ring. The substituent at nitrogen atom is the same with the only difference of methyl group for theophylline and 7-(β-hydroxyethyl) theophylline, or shortage groups for theobromine. The substituent at the other atom is of the single bondCH2CH2OH group for 7-(β-hydroxyethyl) theophylline, and the methyl group for theobromine (see TABLE 1, FIGURE 1).

The DSC of the Phs indicates that these xanthines exhibit a

Modelling

Since no (solid + solid) phase transitions were observed for the compounds, the simplified general thermodynamic equation has been fitted to the sets of experimental solubility data [33]:-lnx1=ΔfusH1R1T-1Tfus,1+lnγ1,where: x1 – mole fraction; ΔfusH1 – enthalpy of fusion of the pure solute; T – (solid + liquid) equilibrium temperature; Tfus,1 – melting temperature for the pure solute; γ1 – activity coefficient of the solute in the saturated solution.

The experimental data together with the calculated

Conclusions

To the best of our knowledge, most of the solubility data and thermophysical data for Phs chosen by us were not published. We employed differential scanning calorimetry (DSC) to measure the enthalpy of melting and the melting temperature of three measured pharmaceuticals. The equilibrium mole fraction solubility of three Phs in three different solvents (water, ethanol and 1-octanol) has been measured experimentally. We combined the calorimetric and solubility data to determine the activity

Acknowledgement

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

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    This paper was presented at the 3rd World Conference on Physico Chemical Methods in Drug Discovery, Development, Dubrovnik, Croatia, 22–26 September 2013.

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