Co-amorphous drug-amino acid formulations

Poorly water soluble drugs are considered a major challenge within development of drug formulations for oral delivery. Several formulations strategies exist to overcome this issue including salt formation and solid dispersions to name a few. Recently, a new formulation approach was introduced combining two drug molecules or a drug and an amino acid to form a so-called co-amorphous system. Several drug-drug and drug-amino acid combinations have been investigated using mainly ball milling as preparative technique, and generally the drugs exhibited improved dissolution rate from the co-amorphous systems compared to the respective crystalline or amorphous drug alone. The purpose of this thesis was to further explore both, the underlying properties and the potential of co-amorphous drug-amino acids systems as a formulation approach to improve the dissolution rate of low molecular weight poorly water soluble drugs. Co-amorphous indomethacin (Ind)-tryptophan (Trp) and furosemide (Fur)-Trp mixtures (at a 1:1 molar ratio) were prepared to investigate the formation mechanism of co-amorphous mixtures during vibrational ball milling. An observed evolution in the glass transition temperature throughout the milling process suggested that either the drug molecule (in the case of Fur-Trp) or the amino acid (in the case of Ind-Trp) becomes amorphous first, creating an amorphous phase for the other component to dissolve in, eventually resulting in a single homogenous amorphous phase. The outline of the formation mechanism of co-amorphous systems can provide a useful tool for the selection of optimal excipients for a given drug in the future. Furthermore, the influence of the drug-amino acid ratio on the solid state properties of the resulting co-amorphous systems was investigated by preparing and analyzing samples with varying drug-amino acid content. For this purpose, four drug-amino acid systems (IndTrp, Ind-arginine (Arg), FurTrp, FurArg) were investigated. The strengths of the interactions between drug and amino acid were detected as the difference between the experimentally determined glass transition temperatures (Tg) of the different coamorphous systems and the corresponding theoretical Tg calculated by the Gordon Taylor equation. In all systems, the samples with equimolar content of drug and amino acid contained the highest amount of molecular interactions. It was found that the experimental Tgs were better described using a modified Gordon Taylor equation, treating the equimolar fraction of the sample as a separate component. Using this approach, it was suggested that the amorphous mixtures consisted of a co-amorphous phase where the drug and amino acid interact in an equimolar fashion (hetero-dimers), with the excess component being molecularly dispersed in the co-amorphous mixture. In addition, it was found that the differences in Tg between the samples at different molar ratios were comparable to the differences between the scores in a principal components analysis scores plot of solid state C CP/MAS NMR spectra of the same samples, suggesting that both methods (DSC and ssNMR) are suitable to detect the strength of interactions within co-amorphous mixtures. Ternary co-amorphous systems were formulated by ball milling the drug naproxen (Nap) with two amino acids at a 1:1:1 molar ratio, to investigate the influence of a highly water soluble amino acid (proline (Pro)) on a co-amorphous system (Nap-Arg and Nap-Trp). Pro, was included in order to further improve the dissolution rate of the drug from these systems compared to the crystalline drug and the binary co-amorphous system comprising the drug and the stabilizing amino acid. It was shown, that Pro could indeed further improve the overall solubility of the co-amorphous system, most likely due to the three components being dissolved synchronously. So far, co-amorphous formulations have mainly been prepared by ball milling. In order to investigate a production method more suitable for large scale manufacturing, spray drying was investigated for the preparation of co-amorphous drugamino acid systems. In this context, several stable co-amorphous drug amino acid combinations (Ind-Arg, Ind-lysine (Lys), and Ind–histidine (His)) were prepared by spray drying. The spray dried co-amorphous Ind-Arg was comparable to the corresponding ball milled product with regards to solid state characteristics and dissolution rate of the drug. Overall, this co-amorphous system appeared robust towards changes in manufacturing technique and spray drying appeared as a promising manufacturing technique for these systems. Finally, the interactions within varying co-amorphous drug-amino acid systems were characterized by FTIR and solid state C CP/MAS NMR. No specific interactions could be detected within co-amorphous systems including the aromatic amino acid Trp although these systems generally are observed to be physically stable. Generally, salt formation was detected within systems consisting of an acidic drug and a basic amino acid. Including the highly soluble Pro resulted in further interactions within the ternary mixture, which might further explain the improved dissolution rate of the drug from these systems. In summary, this thesis has shown that co-amorphous drug-amino acid systems are a promising formulation approach for improving poor solubility of low molecular weight molecules in the future. Whilst light could be shed on the formation mechanism, the formulation and the fabrication of co-amorphous drug-amino acid mixtures, as well as the drug amino acid molecular interactions, naturally, new questions have arisen form the work presented in this thesis that still remain to be answered. Future studies should include investigations on the impact of humidity on physical stability of the co-amorphous systems, a systematic and ideally high throughput testing of all amino acids for a larger number of drugs, a better understanding of drug-amino acid interactions in solution, and of course in vivo studies.