Structure of polymeric nanoparticles encapsulating a drug - pamoic acid ion pair by scanning transmission electron microscopy.

Drug-delivery systems based on polymeric nanoparticles are useful for improving drug bioavailability and/or delivery of the active ingredient for example directly to the cancerous tumour. The physical and chemical characterization of a functionalized nanoparticle system is required to measure drug loading and dispersion but also to understand and model the rate and extent of drug release to help predict performance. Many techniques can be used, however, difficulties related to structure determination and identifying the precise location of the drug fraction make mathematical prediction complex and in many published examples the final conclusions are based on assumptions regarding an expected structure. Cryogenic scanning transmission electron microscopy imaging in combination with electron energy loss spectroscopy techniques are used here to address this issue and provide a multi-modal approach to the characterisation of a self-assembled polymeric nanoparticle system based upon a polylactic acid - polyethylene glycol (PLA-PEG) block copolymer containing a hydrophobic ion-pair between pamoic acid and an active pharmaceutical ingredient (API). Results indicate a regular dispersion of spherical nanoparticles of 88 ± 9 nm diameter. The particles are shown to have a multi-layer structure consisting of a 25 nm radius hydrophobic core of PLA and pamoic acid-API material with additional enrichment of the pamoic acid-API material within the inner core (that can be off-centre), surrounded by a 9 nm dense PLA-PEG layer all with a low-density PEG surface coating of around 10 nm thickness. This structure suggests that release of the API can only occur by diffusion through or degradation of the dense, 9 nm thick PLA-PEG layer either of which is a process consistent with the previously reported steady release kinetics of the API and counter ion from these nanoparticle formulations. Establishing accurate measures of product structure enables a link to performance by providing appropriate physical parameters for future mathematical modelling of barriers controlling API release in these nanoparticle formulations.

Real time Raman imaging to understand dissolution performance of amorphous solid dispersions.

We have employed for the first time Raman spectroscopic imaging along with multi-variate curve resolution (MCR) analysis to investigate in real time and in-situ the dissolution mechanisms that underpin amorphous solid dispersions, with data being collected directly from the dosage form itself. We have also employed a novel rotating disk dissolution rate (RDDR) methodology to track, through the use of high-performance liquid chromatography (HPLC), the dissolution trends of both drug and polymer simultaneously in multi-component systems. Two formulations of poorly water-soluble felodipine in a polymeric matrix of copovidone VA64 which have different drug loadings of 5% and 50% w/w were used as models with the aim of studying the effects of increasing the amount of active ingredient on the dissolution performance. It was found that felodipine and copovidone in the 5% dispersion dissolve with the same dissolution rate and that no Raman spectral changes accompanied the dissolution, indicating that the two components dissolve as single entity, whose behaviour is dominated by water-soluble copovidone. For the 50% drug-loaded dispersion, partial RDDR values of both felodipine and copovidone were found to be extremely low. MCR Raman maps along with classical Raman/X-ray powder diffraction (XRPD) characterisation revealed that after an initial loss of copovidone from the extrudate the drug re-crystallises, pointing to a release dynamics dependent on the low water solubility and high hydrophobicity of felodipine. Raman imaging revealed different rates of transition from amorphous to crystalline felodipine at different locations within the dosage form.

Mechanistic insights into the dissolution of spray-dried amorphous solid dispersions.

We have investigated the dissolution mechanisms of spray-dried amorphous solid dispersions of the poorly water-soluble drug felodipine and the water-soluble polymer copovidone using a new combined spectrophotometric and magnetic resonance imaging technique and a mathematical modelling approach. Studies of the dissolution rates of both uncompacted and compacted solid dispersions revealed that compaction leads to a significant decrease in the rate and extent of dissolution and a strong dependence on drug loading, especially for the uncompacted samples. Low drug-loaded compacts [5% and 15% (w/w) felodipine] eroded with linear kinetics at identical rates, pointing to matrix control, whereas for compacts containing a higher proportion of felodipine (≥ 30%, w/w), dissolution performance was dominated by the drug. In these cases, felodipine concentrations were extremely low and the compact swelled rather than eroded. We have developed a mathematical population balance framework to model the processes of particle release, dissolution and crystal growth. This was found to accurately describe the bell-shaped dissolution profiles observed for the compacts containing a low felodipine loading.

Effect of encapsulating a pseudo-decapeptide containing arginine on PLGA: a solid-state NMR study.

The effects of incorporating an amorphous decapeptide in PLGA on the cooperative and local motions of the polymer chains have been evaluated. Whereas assessment of the bulk properties is used traditionally for studies of host-guest interactions, there are only rare examples where molecular-level understanding of such amorphous host-guest systems has been sought. Moreover, addressing the mechanism of interactions and stabilisation of a drug in a polymeric network is a key factor for the achievement of reproducibility of the formulations and ultimately the preparation of composites able to deliver drugs with consistency. We present a methodology combining the study of the dynamics by solid-state NMR and the characterisation of the bulk properties to address and localise the presence of interactions in PLGA/guest composites. The results (estimation of relaxation times, 2D wideline separation and T(g) measurements) suggested (1) the existence of a drug-polymer solid solution and (2) significant changes in the local dynamics of both the drug and the polymer in their composites depending on the loading level. The changes in the local dynamics as well as in the cooperative motions of the polymer chains in the composites were attributed to the formation of guest-polymer interactions. Differentiation of the affinity of glycolide or lactide units for interactions was also apparent.