Eutectic Formation of Naproxen with Some Dicarboxylic Acids

Eutectic formation with additives is one of the established methods to improve the dissolution behaviors of active pharmaceutic ingredients (APIs). The improvement is mainly due to the increase in the surface area for dissolution, which originates from the finely divided micro-domains generated through the phase separation of the miscible liquid components upon solidification. The present study is to identify eutectic-forming additives for naproxen (NPX), a class II API of the biopharmaceutical classification system. A particular aim was to develop a eutectic mixture with NPX at least over 20 wt%, a minimum to be practical for oral delivery. Screening based on the proximity of the solubility parameter values identified dicarboxylic acids (succinic acid, glutaric acid, and suberic acid) as desirable additives for NPX. Binary melting diagrams were constructed to confirm the eutectic compositions, and the eutectic mixture with suberic acid (NPX 55 wt%) was further investigated. The dissolution (at pH 5.0) of the melt crystallized eutectics was enhanced compared to the simple physical mixture of the same compositions and neat NPX, which was attributed to the microscopically observed lamellar structures. The current study should support the systematic investigations of API eutectic mixtures by selecting appropriate eutectic-forming additives.

Enhanced Dissolution of Naproxen by Combining Cocrystallization and Eutectic Formation

Improving dissolution properties of active pharmaceutical ingredients (APIs) is a critical step in drug development with the increasing occurrence of sparingly soluble APIs. Cocrystal formation is one of the methods to alter the physicochemical properties of APIs, but its dissolution behavior in biorelevant media has been scrutinized only in recent years. We investigated the combined strategy of cocrystallization and eutectic formation in this regard and utilized the cocrystal model system of naproxen and three pyridinecarboxamide isomers. Binary melting diagrams were constructed to discover the eutectic compositions of the three cocrystals with excess amounts of pyridinecarboxamides. The melt–crystallized eutectics and cocrystals were compared in their dissolution behaviors with respect to neat naproxen. The eutectics enhanced the early dissolution rates of the cocrystals in both the absence and presence of biologically relevant bile salt and phospholipid components, whereas the cocrystal dissolution was expedited and delayed, respectively. The combined strategy in the present study will be advantageous in maximizing the utility of the pharmaceutical cocrystals.

On the Formation of Eutectics in Variations of the Al10Co25Cr8Fe15Ni36Ti6 Compositionally Complex Alloy

Superalloy inspired Al10Co25Cr8Fe15Ni36Ti6 compositionally complex alloy is known for its γ-γ′ microstructure and the third Heusler phase. Variations of this alloy, gained by replacing 0.5 or 1 at. pct Al by the equivalent amount of Mo, W, Zr, Hf or B, can show more phases in addition to this three-phase morphology. When the homogenization temperature is chosen too high, a eutectic phase formation can take place at the grain boundaries, depending on the trace elements: Mo and W do not form eutectics while Hf, Zr and B do. In order to avoid the eutectic formation and the potential implied grain boundary weakening, the homogenization temperature must be chosen carefully by differential scanning calorimetry measurements. A too low homogenization temperature, however, could impede the misorientation alignment of the dendrites in the grain. The influence of grain boundary phases and incomplete dendrite re-orientation are compared and discussed.

Binary Mixtures of Some Active Pharmaceutical Ingredients with Fatty Alcohols—The Criteria of Successful Eutectic Formation and Dissolution Improvement

Pharmaceutical eutectics are solid mixtures, where the crystals of active pharmaceutical ingredients (APIs) are finely divided in the phase-separated microstructures. The size reduction makes the eutectic formation a viable option to improve the dissolution rate of the poorly soluble APIs. In the present study, ibuprofen, naproxen, and sorafenib were investigated in terms of their phase behaviors with fatty alcohols, such as tetradecanol, octadecanol, and docosanol. Among the studied APIs, only ibuprofen was able to form eutectics with the fatty alcohols, and this was in agreement with the feasibility prediction based on the van ’t Hoff equation and solubility parameters. In vitro release behavior was significantly improved for the ibuprofen/octadecanol eutectic mixture, although the practical insolubility of octadecanol in water was the opposite of the outstanding hydrophilicity of usual eutectic formers. The feasibility prediction and the choice of eutectic formers in the present study will be useful in advancing the utility of the pharmaceutical eutectics.