Co-amorphous drug formulations

Abstract

Poor aqueous solubility of an active pharmaceutical ingredient (API) is one of the most pressing problems in pharmaceutical research and development because up to 90% of new API candidates under development are poorly water soluble. These drugs usually have a low and variable oral bioavailability, and therefore an unsatisfactory therapeutic effect. One of the most promising approaches to increase dissolution rate and solubility of these drugs is the conversion of a crystalline form of the drug into its respective amorphous form, usually by incorporation into hydrophilic polymers, forming glass solutions. However, this strategy only led to a small number of marketed products usually because of inadequate physical stability of the drug due to crystallization. Recently, co-amorphous drug formulations consisting of two small drug molecules, anticipated for combination therapy, were introduced as alternative to overcome limited solubility and to stabilize the amorphous state. In this thesis, the concept of co-amorphous drug-drug formulations was further investigated with respect to the factors influencing dissolution and stability, and expanded to the use of drug and low molecular weight excipient mixtures. In the former, two pharmacologically relevant drug formulations, namely mixtures of indomethacin (IND)/naproxen (NAP) and glipizide (GPZ)/simvastatin (SVS), were analyzed and characterized towards their solid state properties, molecular interactions, physical stability and dissolution behaviour. In the latter, amino acids were chosen as low molecular weight excipients for co-amorphous drug-excipient formulations. It could be shown, that a heterodimer is formed in co-amorphous IND/NAP mixtures at a 1:1 molar ratio with specific intermolecular interactions. Thus, the physical stability of the amorphous drugs was increased regardless of the glass transition temperature (Tg) of the resulting amorphous form. Furthermore, dissolution of the drugs in the co- amorphous formulation was increased compared to the individual crystalline and amorphous drugs and synchronized, i.e. both drugs were released at the same rate. It was concluded that specific molecular interactions between the components in a co- amorphous blend are crucial for the properties of these systems. The factors influencing the performance of co-amorphous systems were further investigated in systems without intermolecular interactions, namely co-amorphous mixtures of GPZ and SVS. Even in the absence of specific interactions, these formulations showed increased physical stability compared to the individual amorphous drugs and this could be connected to the molecular level mixing present in co- amorphous mixtures. However, the dissolution of these blends was not improved compared to the individual amorphous drugs, showing the importance of molecular interactions (e.g. hydrogen bonding) in co-amorphous drug formulations. In order to extend the concept of co-amorphous drug formulations, amino acids were employed for the first time as low molecular weight excipients to stabilize the amorphous form of the poorly soluble drugs carbamazepine (CBZ) and IND. Using arginine (ARG), phenylalanine (PHE) and tryptophan (TRP), it was possible to prepare several highly stable co-amorphous drug formulations with a high Tg, molecular interactions and significantly increased dissolution rate compared to the respective crystalline and amorphous drugs. Amino acids were therefore considered as promising excipients to improve the amorphous stability of poorly soluble drugs and increase their dissolution profile. Due to the general mechanism of stabilization (high Tg, molecular interactions, molecular level mixing) of these co-amorphous formulations, amino acids have the potential to form the basis for a new platform technique to overcome challenges associated with the amorphous state of poorly soluble drugs. Overall, it can be concluded that co-amorphous drug formulations are a promising way to increase the dissolution rate of poorly water soluble drugs and to stabilize the amorphous state of the drug. This approach can be seen as a potential alternative to solid dispersions (glass solutions) and as a future tool for pharmaceutical technologists to develop pharmaceutical dosage forms for poorly water soluble drugs.