Characterisation of smectite
The powder XRD patterns of randomly orientated samples of the commercial pharmaceutical grade smectite clay used in this study after drying at 100 °C (SM) and after swelling in water (SM-H2O) are shown in Fig. 2. These XRD patterns are consistent with those in the literature for other smectite mixtures comprising montmorillonite and saponite [14,15,16]. The basal spacing of anhydrous smectite is typically 10 Å which increases incrementally to 12.5, 15.5 and 18.5 Å with the incorporation of 1, 2 and 3 homogeneous water layers between each of the aluminosilicate sheets [15]. The basal spacings of SM and SM-H2O are ~ 11 and 12.2 Å, respectively, indicating that the dried, as received, clay is not entirely anhydrous and that the water-swollen clay used for the uptake of theophylline possesses less than one complete water layer. The very broad basal reflections observed for both SM and SM-H2O are indicative of poor organisation of the layers in the c-axis direction.
The FTIR spectra of SM and SM-H2O, shown in Fig. 3, typify those of smectite clays [16, 17]. Stretching modes of structural hydroxyl groups are assigned to the discrete signal at 3615 cm−1 and those of adsorbed and bound water appear as a very broad signal centred around 3440 cm−1 [16, 17]. Bending modes of water occur at 1625 cm−1, and the signal at 1445 cm−1 is attributed to trace quantities of calcium carbonate. Various Si-O-Si lattice vibrations give rise to the bands at 990, 800 and 690 cm−1, and the signal at 525 cm−1 is assigned to Si-O-Al modes.
As anticipated, the DSC thermograms of SM and SM-H2O, presented in Fig. 4, are essentially uneventful with the exception of the endothermic removal of adsorbed water between 40 and 130 °C. Understandably, the endotherm is greater in the case of the more hydrated clay, SM-H2O.
Secondary electron images of SM (Fig. 5) show that this material is highly polydispersed with granules of varying aspect ratio and maximum particle dimension of approximately 100 μm. Higher magnification also reveals the platy texture of the clay particles within the granules.
Characterisation of theophylline
The powder XRD pattern of theophylline (TP) shown in Fig. 2 and the sharp melting point at 271 °C in the corresponding DSC curve (Fig. 4) both confirm that the material used in this study is pure crystalline anhydrous theophylline [18, 19]. The FTIR spectrum of theophylline (Fig. 3) also closely resembles those in the scientific literature [19, 20]. Various bands in the region 3440–2460 cm−1 are assigned to the stretching modes of the N-H group and to the aliphatic and aromatic C-H bonds present in theophylline. Characteristic stretching of the carbonyl groups occurs at 1710 and 1665 cm−1 and the amine N-H stretching gives rise to the signal at 1565 cm−1.
Uptake of theophylline by smectite
The rates of uptake of theophylline by the smectite clay at pH 1.2 as functions of theophylline concentration are plotted in Fig. 6. The initial rate of uptake is seen to increase with theophylline concentration, and in all cases, equilibrium is achieved within 1 min. Below pH 4, the imine nitrogen atom of theophylline becomes protonated and the resulting cation is stabilised by the electron resonance of the five-membered aromatic ring and inductive effects [21]. The rapid uptake of theophylline by smectite at pH 1.2 is indicative of the favourable electrostatic interaction between the protonated cationic form of the drug and the negatively charged clay sheets. It should be noted that the mechanism of interaction between smectite clays and theophylline is reported to proceed via a two-step process which involves initial rapid cation exchange followed by chemisorption [22].
The equilibrium uptake of theophylline as a function of smectite concentration is shown in Fig. 7. The quantity of adsorbed drug per unit mass of smectite decreases non-linearly with increasing smectite concentration which indicates that the clay presents multiple adsorption sites of differing energy. The concentration of smectite that gives the lowest drug-clay loading per unit mass of clay (i.e. 50 mg cm−3) was selected for further isotherm analysis. The rationale for this choice is that this system possesses the most energetically uniform drug-clay interactions. Under the selected batch conditions, a Langmuir-type isotherm is obtained for the equilibrium uptake of theophylline as a function of drug concentration (Fig. 8) and demonstrates that the maximum loading capacity for this drug-clay system is 67 ± 2 mg g−1.
Characterisation of theophylline-smectite hybrid
Samples corresponding to alternate points on the isotherm plotted in Fig. 8 were characterised by XRD, FTIR and DSC to determine the nature of the drug-clay interaction. Drug-clay hybrids, TP20SM, TP60SM and TP140SM, were prepared by contacting 50 mg cm−3 smectite with 1, 3 or 7 mg cm−3 solutions of theophylline, respectively, for 60 min.
Powder XRD patterns of TP20SM, TP60SM and TP140SM are shown in Fig. 2. The basal spacing of the smectite is seen to increase to 14.3 Å for all hybrid samples, demonstrating that the drug is intercalated within the clay. The sharp principal reflections for crystalline theophylline (at 2θ = 7.21, 12.69 and 14.36°) are absent from these XRD traces, and a weak broad signal at 13.59° arises from the intercalation of the drug. The comparatively sharp basal reflections of the drug-intercalated smectite samples indicate a superior stacking order along the c-axis relative to that of the original clay. DSC analysis confirms the absence of a theophylline melting event within the hybrid systems demonstrating that the intercalated drug is present in an amorphous form (Fig. 4). Secondary electron images of sample TP140SM are shown in Fig. 5 and illustrate that the larger granules tend to disintegrate during the drug intercalation process. However, the platy morphology of the clay appears unaffected by intercalation and there is no evidence for the precipitation of theophylline on the surface of the clay platelets.
Characteristic stretching vibrations of the carbonyl groups of theophylline are present in the FTIR spectra of the drug-clay hybrids (Fig. 3) at 1710 and 1665 cm−1 which are partially obscured by the bending modes of water in the clay. A shift in the position of the amine stretching signal of the hybrids relative to that of crystalline theophylline is observed from 1565 to 1578 cm−1. This may be attributed to the electrostatic interaction between the drug and clay; although, this cannot be fully confirmed as shifts may also arise from the protonation of the drug and its phase change from the crystalline to the amorphous state.
In vitro release of theophylline from the drug-clay hybrid
The in vitro release behaviour of theophylline from drug-clay hybrid TP60SM was monitored in PBS, SGF and SIF at pH 6.8 and pH 7.4 (which represent the environments of the duodenum and ileum, respectively). This hybrid has a drug loading of 57 ± 2 mg g−1 and was selected for the release study as it represents the most energetically uniform adsorption system with a loading below the theoretical maximum value (to prevent any ‘initial burst’ of loosely adsorbed drug).
Under the selected experimental conditions, theophylline is steadily released in PBS at pH 7.4 to a maximum extent of 80% after 60 min (Fig. 9a). The release profile does not conform to a simple diffusion model which indicates that the complex nature of interactions between the drug and clay lattice dictate the release behaviour [3, 22].
No detectible release of theophylline was observed from the drug-clay hybrid in simulated gastric fluid at pH 1.2 during an extended 72-h observation period. This finding demonstrates that the intercalation of theophylline in smectite at pH 1.2 is not readily reversible at the same pH despite the presence of potentially exchangeable K+ cations in the supernatant liquor.
The release profiles of theophylline in simulated intestinal fluid at pH 6.8 and at pH 7.4 are plotted in Fig. 9b, c, respectively. These data show that theophylline is released more rapidly at the higher pH with a maximum release of 43% after 60 min. Incremental dissolution of the drug at pH 6.8 continued throughout the 3-h observation period to give a maximum release of 41%.
Since the maximum release of theophylline in SIF is observed to be approximately 50% lower than that in PBS, the composition of SIF was modified to match the Na+ ion concentration of PBS (by addition of 8.0 mg cm−3 of NaCl). SIF was also prepared with the addition of a relatively low level (0.4 mg cm−3) of Na+ ions to determine the influence of concentration of this potentially exchangeable cation on the release of the drug. Accordingly, the release of theophylline in SIF-8.0 and SIF-0.4 at pH 7.4 and pH 6.8 is plotted in Fig. 9b, c, respectively. In both cases, the rate of release was enhanced as the Na+ ion concentration increased, with this effect being more pronounced at pH 6.8. It is clear that the mass action of cations in the supernatant solution accelerates the release of the drug, but has little impact on the ultimate quantity of theophylline that is discharged from the clay. Again, none of the release profiles obtained in the various SIF media conformed to a simple diffusion model [3, 22].
At present, the reason for the superior release of theophylline in PBS compared with that in the original and modified SIF media is unknown, but presumably relates to the influence of different concentrations of anionic phosphate species present in these liquors (Table 1).