On the role of salt formation and structural similarity of co-formers in co-amorphous drug delivery systems.

Co-amorphous drug delivery systems based on amino acids as co-formers have shown promising potential to improve the solubility and bioavailability of poorly water-soluble drugs. Potential salt formation is assumed to be a key molecular interaction responsible for amorphous stability and increased solubility. However, little is known about the importance of the overall structure of the co-former. In this study, the structurally related amino acids arginine (basic) and citrulline (neutral) were chosen together with four model drugs (acidic furosemide and nitrofurantoin; basic cimetidine and mebendazole) to investigate the importance of salt formation versus structural similarity of co-formers. Drug-amino acid mixtures were ball milled at a molar ratio of 1:1. Generally, arginine showed a higher tendency to successfully form co-amorphous systems with the model drugs compared with citrulline, irrespective of assumed salt formation. Salt forming mixtures showed much higher Tgs, faster dissolution rates, higher solubility and physical stability compared to the corresponding non-salt forming mixtures. In conclusion, structural similarity of the co-formers does not lead to similar co-former performance for a given drug. Salt formation is not a prerequisite for the formation of a co-amorphous system, but if a co-amorphous salt system is formed, improved dissolution rate and physical stability are observed.

Development of a screening method for co-amorphous formulations of drugs and amino acids.

Using amino acids (AA) as low molecular weight excipients in the preparation of co-amorphous blends with the aim to stabilize the drug in the amorphous form have been discussed in a range of studies. However, there is currently no theoretical consensus behind which AA would be a suitable co-former for a given drug. In this work, a fast screening process to assess the co-former feasibility in co-amorphous drug-AA blends has been developed on the basis of the amorphization kinetics upon oscillatory ball milling. For this purpose, six model drugs were combined with 20 different AAs and co-milled at an equimolar ratio for different times (1, 5, 15, 30 and 60min). The degree of amorphization was then studied for the different time points by determination of the area under the curve of the diffraction peaks in X-ray powder diffraction measurements. The results of this study suggest that the choice of AA as co-formers for the formation of the co-amorphous blend could be significantly inferred after 15min of milling, since a crystallinity decrease higher than 90% after 15min resulted in successful co-amorphization in approximately 90% of the mixtures after 60min of milling. The results furthermore suggested that non-polar AAs, such as tryptophan, phenylalanine, leucine, isoleucine, methionine, valine and proline, are a good first choice in the selection of a co-former for a given drug in a co-amorphous formulation. Basic AAs appear suitable for amorphous salt formation in the case of acidic drugs. Acidic AAs however, were shown to be generally poor co-formers for co-amorphous systems.

Development and in vitro evaluation of a liposome based implant formulation for the decapeptide cetrorelix.

Semisolid phospholipid dispersions of vesicular morphology, so-called vesicular phospholipid gels (VPGs), were prepared by high-pressure homogenisation and tested in vitro for their suitability as implantable sustained release system for the decapeptide cetrorelix, a potent LH-RH antagonist. The VPGs contained 300-500 mg/g egg phosphatidylcholine (E80) and 0.5-10 mg/g cetrorelix acetate (CXA). The in vitro release experiments showed a wide variability of the system in release, ranging from complete release within less than 24 h (0.5mg/g CXA; 400 mg/g E80) to a predicted 80% sustained release over 3 months (8.6 mg/g CXA; 280 mg/g E80). Erosion of the phospholipid matrix, i.e. release of phospholipid vesicles was found to be the main release mechanism, following zero order or first order kinetics depending on the composition of the VPG. CXA-concentration dependent drug-drug or drug-lipid interactions are assumed to be responsible for the change in release kinetics and the decrease of CXA release at high concentrations of the peptide. Multivariate analysis revealed that both lipid concentration and peptide concentration and also the interactions between the two factors are significant factors for the release rate of the peptide. In summary: based on the presented in vitro release data sustained release of therapeutically relevant CXA doses over up to 6 weeks appears feasible. VPGs are thus considered as a promising new approach for the sustained release of peptide hormones.