European Journal of Pharmaceutics and Biopharmaceutics
Research paperThe solubilization of the poorly water soluble drug nifedipine by water soluble 4-sulphonic calix[n]arenes
Introduction
The 1,4-dihydropyridine L-type calcium-channel blocker nifedipine, Fig. 1, is an important calcium channel blocker that is used extensively for the clinical management of a number of cardiovascular diseases such as essential hypertension, congestive heart failure, and cerebral ischemia [1]. A major pharmaceutical problem associated with nifedipine is its poor aqueous solubility, 5–6 μg/ml over a pH range of 2–10, which may account for its highly variable bioavailability in humans [1], [2]. Among the various techniques employed to enhance the dissolution and/or aqueous solubility of nifedipine, drug-excipient complexes with increased solubility have been reported for the following complexing agents: salicylates [3], phenolic ligands [1], nicotinamide [4], β-cyclodextrin and hydroxypropyl β-cyclodextrin [5], [6], [7].
Since cyclodextrins are able to encapsulate nifedipine into their hydrophobic cavity [5], [6], [7], other supramolecular host compounds might also form host–guest complexes with nifedipine. Along with the cyclodextrins and crown ethers, calixarenes are the third major class of supramolecular host systems [8], [9]. The calixarenes, Fig. 1, are a class of cyclooligomers formed via a phenol–formaldehyde condensation. They exist in a ‘cup’ like shape with a defined upper and lower rim and a central annulus. Their rigid conformation enables calixarenes to act as host molecules because of their preformed hydrophobic cavities. Due to this ability to form host–guest type complexes with a variety of organic or inorganic compounds the calixarenes have received increasing attention during the last two decades [8], [9], [10]. In addition, the ease with which various functional groups can be introduced to either the upper or the lower rim of the ‘cup’, makes it easy to change the affinity of these cyclooligomers towards target molecules and/or increase the solubility of the calixarenes [11], [12], [13]. One such modified calixarene, the water-soluble 4-sulphonic calix[n]arenes may selectively include various guests according to their size and hydrophobicity in a manner similar to cyclodextrins [14], [15], [16]. Although the calixarenes are currently not approved by the FDA for use in medicines to date the calixarenes have demonstrated neither toxicity nor immune responses [9]. This further increases interest their use in the field of biopharmaceutical applications beyond their current use for the chiral separation of molecules [11], as carriers of marker molecules in novel analytical techniques [22] and as complex forming agents to remove molecules from the environment [26].
To date only one report about the effect of the water-soluble 4-sulphonic calix[n]arenes on the solubility of drugs has been reported [17]. This study showed that depending on the size of the calixarene and the pH of the solution, the sulphonated calixarenes significantly increased the aqueous solubility of the water insoluble drug testosterone. The aim of the present study was to determine the effect of 4-sulphonic calix[n]arenes on the solubility behavior of nifedipine. Three sulphonated calixarenes with increasing number of phenolic units in the ring, the pH of the aqueous solubility medium, and the concentration of calix[n]arene were changed to gain a better understanding of the solubilizing effect of 4-sulphonic calix[n]arene had on nifedipine.
Section snippets
Materials
Nifedipine (Fig. 1, C17H18N2O6, MW=346) was purchased from Sigma Chemical Company (St Louis, MO, USA). 4-Sulphonic calix[4]arene hydrate (C28H24O16S4·9H2O), 4-sulphonic calix[6]arene hydrate (C42H36O24S6·13H2O), 4-sulphonic calix[8]arene hydrate (C56H48O32S8·21H2O) were purchased from Acros Organics (Geel, Belgium). The molecular structures of the calix[n]arenes are given in Fig. 1. Methanol used for chromatographic assay of nifedipine was of HPLC grade (Spectrum Chemical Company, Gardena, CA).
Results
Some important physicochemical properties of the three water-soluble 4-sulphonic calix[n]arenes with n=4, 6 and 8 repeating phenolic units (Fig. 1) are given in Table 1. 4-Sulphonic calix[4]arene, 4-sulphonic calix[6]arene and 4-sulphonic calix[8]arene are hydrates that contain between 9 and 21 water molecules in their crystal structures. In this study, the percentage water of crystallization was measured by TG analysis (Fig. 2) and Karl Fisher titration, and the results (Table 1) were of the
Discussion
Since the solubility of nifedipine was not significantly changed with an increase in pH from 5 to 12 but did significantly increase when various concentrations of three 4-sulphonic calix[n]arenes were added to the solutions, it was clear that the calixarenes must in some way interact with nifedipine to form more soluble nifedipine–calixarene associations. This interaction was not micellar aggregation of the calixarenes around the nifedipine molecules because the sulphonated calix[n]arenes does
Conclusions
To conclude, the solubilizing effect of 4-sulphonic calix[n]arenes on the solubility of nifedipine showed that the size of the 4-sulphonic calix[n]arenes, the pH of solubility medium, and the concentration of the calix[n]arenes all significantly influenced the solubility of nifedipine. 4-sulphonic calix[8]arene improved the solubility of nifedipine the most, about 3 times the control at 0.008 M and pH 5, followed by 4-sulphonic calix[4]arene, about 1.5 times the control at 0.008 M and pH 5,
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