The use of molecular descriptors in the development of co-amorphous formulations.

Co-amorphous systems consisting of a drug and an amino acid have been investigated extensively for the enhancement of drug solubility and amorphous stability. The purpose of this study is to investigate which molecular descriptors are important for predicting the likelihood of a successful co-amorphisation between amino acid and drug. The predictions are thought to be used in an early screening phase to identify potential drug-amino acid combinations for further studies. A large variety of molecular descriptors was calculated for six drugs (carvedilol, mebendazole, carbamazepine, furosemide, indomethacin and simvastatin) and the twenty naturally occurring amino acids. The descriptor differences for all drug-amino acid combinations were calculated and used as input in the X-matrix of a Partial Least Square Discriminant Analysis (PLS-DA). The Y-matrix of the PLS-DA consisted of the X-ray powder diffraction response ("co-amorphous" or "not co-amorphous") obtained by ball milling all combinations for 60 min. The PLS-DA model showed a clear separation of the not co-amorphous and the co-amorphous samples and was successfully predicting the class membership of 19 out of the 20 completely left out drug-amino acid combinations of mebendazole. The approach seems to be promising for predicting the ability of new drug-amino acids combinations to become co-amorphous.

Influence of variation in molar ratio on co-amorphous drug-amino acid systems.

Molecular interactions were investigated within four different co-amorphous drug-amino acid systems, namely indomethacin-tryptophan (Ind-Trp), furosemide-tryptophan (Fur-Trp), indomethacin-arginine (Ind-Arg) and furosemide-arginine (Fur-Arg). The co-amorphous systems were prepared by ball milling for 90min at different molar ratios and analyzed by XRPD and DSC. Interactions within the co-amorphous samples were evaluated based on the deviation between the actual glass transition temperature (Tg) and the theoretical Tg calculated by the Gordon-Taylor equation. The strongest interactions were observed in the 50mol% drug (1:1M ratio) mixtures, with the exception of co-amorphous Ind-Arg where the interactions within the 40mol% drug samples appear equally strong. A particularly large deviation between the theoretical and actual Tgs was observed within co-amorphous Ind-Arg and Fur-Arg systems. Further analysis of these co-amorphous systems by (13)C solid-state NMR (ssNMR) and FTIR confirmed that Ind and Fur formed a co-amorphous salt together with Arg. A modified approach of using the Gordon-Taylor equation was applied, using the equimolar co-amorphous mixture as one component, to describe the evolution of the Tgs with varying molar ratio between the drug and the amino acid. The actual Tgs for co-amorphous Ind-Trp, Fur-Trp and Fur-Arg were correctly described by this equation, confirming the assumption that the excess component was amorphous forming a homogeneous single component within the co-amorphous mixture without additional interactions. The modified equation described the Tgs of the co-amorphous Ind-Arg with excess Arg less well indicating possible further interactions; however, the FTIR and ssNMR data did not support the presence of additional intermolecular drug-amino acid interactions.

Preparation and characterization of spray-dried co-amorphous drug-amino acid salts.

OBJECTIVES: Recently, co-amorphous drug-amino acid mixtures were introduced as a promising alternative to other amorphous stabilization approaches such as the use of polymers to form glass solutions. So far, these co-amorphous mixtures have been mainly prepared via vibrational ball milling on a lab scale. In this study, spray-drying was investigated as a scale up preparation method for co-amorphous indomethacin (IND)-amino acid mixtures. In addition, the physico-chemical properties of the different co-amorphous systems were investigated with respect to the amino acids' ability towards co-amorphous salt formation. METHODS: The mixtures were characterized for their solid state properties using differential scanning calorimetry, thermogravimetric analysis and X-ray powder diffraction. Fourier-transform infrared spectroscopy was used to analyze molecular interactions. Furthermore, intrinsic dissolution behaviour, and physical stability at various storage conditions, were examined. KEY FINDINGS: Results showed that IND could be converted into an amorphous form in combination with the amino acids arginine (ARG), histidine (HIS) and lysine (LYS) by spray-drying. Solid state characterization revealed elevated glass transition temperatures for all mixtures compared with the pure amorphous drug due to co-amorphization with the amino acids. Furthermore, strong intermolecular interactions in the form of salt/partial salt formation between the drug and amino acids were seen for all blends. All mixtures were physically stable (>10 months) at room temperature and 40°C under dry conditions. Intrinsic dissolution of the co-amorphous mixtures showed an improved dissolution behaviour under intestinal pH conditions for IND-ARG compared with the crystalline and amorphous forms of the drug. On the other hand, IND-LYS and IND-HIS revealed no significant improvement in the intrinsic dissolution rate of IND due to recrystallization of IND during dissolution. CONCLUSIONS: It could be shown that strong intermolecular interactions between drug and co-amorphous coformer that persist during the dissolution are crucial to prevent recrystallization and to enhance dissolution of a co-amorphous formulation.

Solid-state properties and dissolution behaviour of tablets containing co-amorphous indomethacin-arginine.

Co-amorphous drug formulations provide the possibility to stabilize a drug in its amorphous form by interactions with low molecular weight compounds, e.g. amino acids. Recent studies have shown the feasibility of spray drying as a technique to manufacture co-amorphous indomethacin-arginine in a larger production scale. In this work, a tablet formulation was developed for a co-amorphous salt, namely spray dried indomethacin-arginine (SD IND-ARG). The effects of compaction pressure on tablet properties, physical stability and dissolution profiles under non-sink conditions were examined. Dissolution profiles of tablets with SD IND-ARG (TAB SD IND-ARG) were compared to those of tablets containing a physical mixture of crystalline IND and ARG (TAB PM IND-ARG) and to the dissolution of pure spray dried powder. Concerning tableting, the developed formulation allowed for the preparation of tablets with a broad range of compaction pressures resulting in different porosities and tensile strengths. XRPD results showed that, overall, no crystallization occurred neither during tableting nor during long-term storage. Dissolution profiles of TAB SD IND-ARG showed an immediate release of IND by erosion. The solubility of crystalline IND was exceeded by a factor of about 4, which was accompanied by a slow crystallization. For TAB PM IND-ARG, an in situ amorphization of IND in the presence of ARG was observed. As a result, a supersaturation was obtained, too, followed by a faster crystallization compared to TAB SD IND-ARG. In conclusion, the AUC24h of TAB SD IND-ARG was twofold higher than the AUC24h of TAB PM IND-ARG. Interestingly, different plateaus were obtained for TAB SD IND-ARG, TAB PM IND-ARG and pure SD IND-ARG after 24h dissolution, which could be explained by the formation of different polymorphic forms of indomethacin.

Formation Mechanism of Coamorphous Drug-Amino Acid Mixtures.

Two coamorphous drug-amino acid systems, indomethacin-tryptophan (Ind-Trp) and furosemide-tryptophan (Fur-Trp), were analyzed toward their ease of amorphization and mechanism of coamorphization during ball milling. The two mixtures were compared to the corresponding amorphization of the pure drug without amino acid. Powder blends at a 1:1 molar ratio were milled for varying times, and their physicochemical properties were investigated using XRPD, (13)C solid state NMR (ssNMR), and DSC. Comilling the drug with the amino acid reduced the milling time required to obtain an amorphous powder from more than 90 min in the case of the pure drugs to 30 min for the coamorphous powders. Amorphization was observed as reductions in XRPD reflections and was additionally quantified based on normalized principal component analysis (PCA) scores of the ssNMR spectra. Furthermore, the evolution in the glass temperature (Tg) of the coamorphous systems over time indicated complete coamorphization after 30 min of milling. Based on the DSC data it was possible to identify the formation mechanism of the two coamorphous systems. The Tg position of the samples suggested that coamorphous Ind-Trp was formed by the amino acid being dissolved in the amorphous drug, whereas coamorphous Fur-Trp was formed by the drug being dissolved in the amorphous amino acid.

Improving co-amorphous drug formulations by the addition of the highly water soluble amino Acid, proline.

Co-amorphous drug amino acid mixtures were previously shown to be a promising approach to create physically stable amorphous systems with the improved dissolution properties of poorly water-soluble drugs. The aim of this work was to expand the co-amorphous drug amino acid mixture approach by combining the model drug, naproxen (NAP), with an amino acid to physically stabilize the co-amorphous system (tryptophan, TRP, or arginine, ARG) and a second highly soluble amino acid (proline, PRO) for an additional improvement of the dissolution rate. Co-amorphous drug-amino acid blends were prepared by ball milling and investigated for solid state characteristics, stability and the dissolution rate enhancement of NAP. All co-amorphous mixtures were stable at room temperature and 40 °C for a minimum of 84 days. PRO acted as a stabilizer for the co-amorphous system, including NAP-TRP, through enhancing the molecular interactions in the form of hydrogen bonds between all three components in the mixture. A salt formation between the acidic drug, NAP, and the basic amino acid, ARG, was found in co-amorphous NAP-ARG. In comparison to crystalline NAP, binary NAP-TRP and NAP-ARG, it could be shown that the highly soluble amino acid, PRO, improved the dissolution rate of NAP from the ternary co-amorphous systems in combination with either TRP or ARG. In conclusion, both the solubility of the amino acid and potential interactions between the molecules are critical parameters to consider in the development of co-amorphous formulations.