A molecular understanding of magnesium aluminium silicate - drug, drug - polymer, magnesium aluminium silicate - polymer nanocomposite complex interactions in modulating drug release: Towards zero order release.

This study reports the use of ITC in understanding the thermodynamics occurring for a controlled release system in which complexation has been exploited. In this study, a model drug, propranolol hydrochloride (PPN) was complexed with magnesium aluminium silicate (MAS) and these complexes were used in combination with polyethylene oxide (PEO) as a hydrophilic carrier at various concentrations to sustain the release of PPN. DSC, XRPD, ATR-FTIR and SEM/EDX were successfully used in characterising the produced complexes. 2D- SAXS data patterns for MAS and the produced complexes were shown to be symmetric and circular with the particles showing no preferred orientation at the nanometre scale. ITC studies showed differences between PPN adsorption onto MAS compared with PPN adsorption onto a MAS-PEO mixture. At both temperatures studied the binding affinity Ka was greater for the titration of PPN into the MAS-PEO mixture (5.37E + 04 ± 7.54E + 03 M at 25 °C and 8.63E + 04 ± 6.11E + 03 M at 37 °C), compared to the affinity obtained upon binding between PPN and MAS as previously reported suggesting a stronger binding with implications for the dissolution process. MAS-PPN complexes with the PEO polymer compacts displayed desired manufacturing and formulation properties for a formulator including, reduced plastic recovery therefore potentially reducing the risk of cracking/splitting and on tooling wear, controlled release of PPN at a significantly low (5%) polymer level as well as a zero-order release profile (case II transport) using up to 50% polymer level.

Real time calorimetric characterisation of clay - drug complex dispersions and particles.

Isothermal titration calorimetry (ITC) along with attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM/EDX) and high-performance liquid chromatography (HPLC) were employed to investigate the process of adsorption of propranolol hydrochloride (PPN) onto magnesium aluminium silicate (MAS) and to characterise the MAS-PPN particles formed upon complexation. The composition of MAS was confirmed by infrared (IR) spectroscopy and a calcimeter. The calorimetric results confirmed the binding between PPN and MAS at various pHs and temperatures. The overall change in enthalpy was found to be exothermic with a comparatively small entropic contribution to the total change in Gibbs free energy. These findings suggest that the binding process was enthalpically driven and entropically unfavourable (lower affinity) suggesting hydrogen bonding and electrostatic interactions dominating the interaction. The variation of pH and temperature did not have a great impact on the thermodynamics of the binding process, as observed from the similarity in enthalpy (ΔH), entropy (ΔS) or Gibbs free energy (ΔG). A slight reduction in the binding affinity (Ka) with varing pH and temperature was however observed. SEM/EDX studies showed the occurrence of changes in the microstructural properties of MAS following complexation which may explain the potential of MAS-PPN complexes for controlled drug release promoting pharmaceutical innovation.

Synchrotron X-ray microtomographic study of tablet swelling.

Tablet swelling behaviour was investigated by following the movements of embedded glass microsphere tracers, using X-ray microtomography (XmicroT) with intense illumination from a synchrotron. Specimens were prepared using combinations of hydroxypropyl-methyl-cellulose (HPMC) and microcrystalline cellulose (MCC) or pre-gelatinised starch (PGS), three materials commonly used as excipients for compacted tablets. The results revealed significant differences in swelling behaviour due to excipient type and compaction conditions. In particular, a sudden change was observed from gel-forming behaviour of formulations containing PGS or high HPMC content, to more rapid expansion and disintegration for formulations above 70% MCC. Although some radial expansion was observable with the higher PGS formulations and during later stages of swelling, axial expansion (i.e. the reverse of the compaction process) appeared to dominate in most cases. This was most pronounced for the 10/90 HPMC/MCC specimens, which rapidly increased in thickness, while the diameter remained almost unchanged. The expansion appeared to be initiated by hydration and may be due to the relaxation of residual compaction stress. This occurred within 'expansion zones', which initially appeared as thin bands close to the compacted (upper and lower) faces, but gradually advanced towards the centre and spread around the sides of the tablets. These zones exhibited lower X-ray absorbance, probably because they contained significant amounts of bubbles, which were formed by air released from the swelling excipients. Although, in most cases, these bubbles were too small to be resolved (<60 microm), larger bubbles (diameter up to 1mm) were clearly evident in the rapidly swelling 10/90 HPMC/MCC specimens. It is suggested that the presence of these bubbles may affect subsequent water ingress, by increasing the tortuosity and occluding part of the gel, which may affect the apparent diffusion kinetics (i.e. Fickian or Case II). These observations also suggested that axial expansion, initiated by water ingress, may be an important mechanism during tablet swelling.

Magnetic resonance imaging and X-ray microtomography studies of a gel-forming tablet formulation.

The capabilities of two methods for investigating tablet swelling are investigated, based on a study of a model gel-forming system. Results from magnetic resonance imaging (MRI) were compared with results from a novel application of X-ray microtomography (XmicroT) to track the movements of embedded glass microsphere tracers as the model tablets swelled. MRI provided information concerning the movement of hydration fronts into the tablets and the composition of the swollen gel layer, which formed at the tablet surface and progressively thickened with time. Conversely, XmicroT revealed significant axial expansion within the tablet core, at short times and ahead of the hydration fronts, where there was insufficient water to be observed by MRI (estimated to be around 15% by weight for the system used here). Thus, MRI and XmicroT may be regarded as complementary methods for studying the hydration and swelling behaviour of tablets.

Composition-controlled nanocomposites of apatite and collagen incorporating silicon as an osseopromotive agent.

The development of a novel biocomposite of apatite (Ap) and collagen incorporating low-level additions of silicon (Si) as an osseopromotive agent is detailed. Designed to mimic the structural and compositional characteristics of developing bone, this composite is produced via a coprecipitation method, through which the weight percentage of Ap (i.e., the Ap/collagen ratio) can be varied. Coprecipitates produced at Ap contents of 80 wt % (Ap/collagen=4:1), 60 wt % (Ap/collagen=3:2), and 40 wt % (Ap/collagen=2:3) Ap showed markedly different morphologies, ranging from ceramic-like particulates to rope-like macro-fibrils; at all three Ap contents, however, the nanostructural features of the composites remained qualitatively indistinguishable, with equiaxed Ap nanocrystals distributed randomly throughout a matrix of amorphous collagen. Si incorporation was observed to occur preferentially in the collagenous phase-a result with potential impact on local controlled release of Si.