(M1030-12-79) Improving Drug Solubility in Solid Oral Formulations Using Low Melting Point Systems

Purpose: Drug solubility is crucial for absorption and efficacy, so improving the solubility of active pharmaceutical ingredients (APIs) is a major concern of the pharmaceutical industry. Recently, the conversion of drug molecules into ionic liquids and deep eutectic mixtures (DEMs) has been proposed as another method of improving solubility. These low melting point multicomponent systems have showed promising results both in the improvement of the solubility of drugs and as a greener approach to synthesis and manufacturing. However, the full potential of these systems has not been fully realized yet, particularly when it comes to solid oral formulations. The aim of this work was to process a DEM by spray drying with lactose to produce powders suitable for tableting, and to study the impact of a low melting point system on spray drying and on a solid formulation. The DEM chosen for this work was a 1:1 molar mix of ketoprofen (KET) and lidocaine (LID), as ketoprofen is a common API with poor water solubility, and it forms a DEM as shown in the previous work (1).

Methods: The APIs were dissolved in ethanol, and lactose was either suspended in an ethanol/water mixture or dissolved in water and mixed with the ethanolic DEM solution, stirring continuously to maintain homogeneity. All materials were spray dried using a Büchi B-290 mini spray dryer (Switzerland) operated in the open mode. Different conditions of spray drying and concentrations of the DEM were tried to determine the optimal settings for the preparation of the powders (Table 1). Samples were named according to the method of spray drying and the concentration of DEM. Physicochemical properties of the dried samples were determined by powder X-ray diffraction, gas pycnometry, differential scanning calorimetry, dynamic vapor sorption and laser diffraction particle size analysis. Tablets were prepared by direct compression with a laboratory scale single punch NP-RD10 manually operated tablet press at 7 different compression pressures (25, 50, 100, 149, 199, 249 and 299 MPa). Tablets containing only non-spray dried lactose (L) and a non-spray dried physical mixture of the APIs and lactose (P2) were also prepared at 199 MPa. The compacts were then analyzed regarding their dimensions, weight, and hardness. Disintegration time and dissolution profiles (all as per Ph. Eur.) were then determined.

Results: The maximum concentration of DEM suitable for spray drying was determined for each method. For most methods, a concentration of 1% w/v in the solvent was determined to be optimal for spray drying, as higher concentrations led to clogging of the nozzle and low uniformity powders with a tendency to clump. Methods D and E proved to be very problematic even at low DEM concentrations. Method F showed the best tolerance for higher DEM concentrations, and it was possible to comfortably process a DEM concentration up to 1.5% w/v in the solvent. Powder analysis mostly displayed the profile for lactose with little changes between batches except for the samples prepared using method F. Powders made by this approach were amorphous due to full dissolution of lactose during their preparation. All samples formed cohesive tablets. The tabletability profiles of the samples are presented in Figure 2. It is evident that the tablets L, A2, B2 and C2 displayed a good linear correlation between the tensile strength of the tablets and the compression pressure. Samples F2 and F3 required pre-compression, had the highest tensile strength, and show a over-compaction profiles. They also displayed significant plastic behavior during the hardness test, with the tablets deforming before breaking. All samples disintegrated within the Ph. Eur. limits. The dissolution profiles of the samples show that ketoprofen dissolves in a much higher quantity and speed when formulated as a DEM compared to its starting crystalline form, with exception of samples F2 and F3.

Conclusion: It is possible to spray dry deep eutectic mixtures with lactose and obtain powders suitable for tableting, and the maximum concentration of DEM suitable for spray drying was determined. It was confirmed that the presence of the DEM affected the properties of the powder and had an influence on its processing and tableting. It is evident that ketoprofen in the DEM form had a faster dissolution rate compared to the original crystalline form and this benefit is still present in the tablets.

References: 1. Umerska, A., Zotova, J., & Tajber, L. (2021). Formation of low melting point binary systems comprising ketoprofen and an amide local anaesthetic. International Journal of Pharmaceutics, 607, 120969.

Acknowledgements: This research was funded by Science Foundation Ireland, grants 15/CDA/3602, SFI/12/RC/2275_P2 and CDT in Transformative Pharmaceutical Technologies (18/EPSRC-CDT/3587) as well as European Commission grant ORBIS (project no. 778051).

Table 1. Summary of the sample preparation and spray drying conditions

Figure 1. Tabletability profiles of the compacts.

Figure 2. Dissolution profiles showing ketoprofen releases (as 5). Tablets were prepared using 199 MPa compression pressure.