Permeability of glibenclamide through a PAMPA membrane: The effect of co-amorphization.

Co-amorphous systems are an attractive alternative for amorphous solid polymer dispersions in the formulation of poorly soluble drugs. Several studies have revealed that co-amorphous formulations can enhance the dissolution properties of poorly-soluble drugs and stabilize them in the amorphous form. However, the interplay between the drug dissolution rate, drug supersaturation and different co-formers on membrane permeability of the drug for co-amorphous formulations remains unexplored. By using side-by-side chambers, separated by a PAMPA (parallel artificial membrane permeability assay) membrane, we were able to simultaneously test dissolution and passive membrane permeability of the co-amorphous combinations (1:1 molar ratio) of a poorly soluble drug glibenclamide (GBC) in combination with two amino acids, either serine (SER) or arginine (ARG). In addition, a known passive permeability enhancer sodium lauryl sulfate (SLS) was included in the co-amorphous mixtures at two concentration levels. The mixtures were also characterized with respect to their solid-state properties and physical stability. It was found that GBC mixtures with ARG and SLS had superior dissolution and physical stability properties which was attributable to the strong intermolecular interactions formed between GBC and ARG. These formulations also had optimal permeability properties due to their high concentration gradient promoting permeation and possible permeation enhancing effect of the co-formers ARG and SLS. Thus, simultaneous testing of dissolution and permeation through a PAMPA membrane may represent a simple and inexpensive tool for screening the most promising amorphous formulations in further studies.

Preparation and characterization of multi-component tablets containing co-amorphous salts: Combining multimodal non-linear optical imaging with established analytical methods.

Co-amorphous mixtures have rarely been formulated as oral dosage forms, even though they have been shown to stabilize amorphous drugs in the solid state and enhance the dissolution properties of poorly soluble drugs. In the present study we formulated tablets consisting of either spray dried co-amorphous ibuprofen-arginine or indomethacin-arginine, mannitol or xylitol and polyvinylpyrrolidone K30 (PVP). Experimental design was used for the selection of tablet compositions, and the effect of tablet composition on tablet characteristics was modelled. Multimodal non-linear imaging, including coherent anti-Stokes Raman scattering (CARS) and sum frequency/second harmonic generation (SFG/SHG) microscopies, as well as scanning electron microscopy, X-ray diffractometry and Fourier-transform infrared spectroscopy were utilized to characterize the tablets. The tablets possessed sufficient strength, but modelling produced no clear evidence about the compaction characteristics of co-amorphous salts. However, co-amorphous drug-arginine mixtures resulted in enhanced dissolution behaviour, and the PVP in the tableting mixture stabilized the supersaturation. The co-amorphous mixtures were physically stable during compaction, but the excipient selection affected the long term stability of the ibuprofen-arginine mixture. CARS and SFG/SHG proved feasible techniques in imaging the component distribution on the tablet surfaces, but possibly due to the limited imaging area, recrystallization detected with x-ray diffraction was not detected.

Spray drying of poorly soluble drugs from aqueous arginine solution.

Co-amorphous drug-amino acid mixtures have shown potential for improving the solid-state stability and dissolution behavior of amorphous drugs. In previous studies, however these mixtures have been produced mainly with small-scale preparation methods, or with methods that have required the use of organic solvents or other dissolution enhancers. In the present study, co-amorphous ibuprofen-arginine and indomethacin-arginine mixtures were spray dried from water. The mixtures were prepared at two drug-arginine molar ratios (1:1 and 1:2). The properties of the prepared mixtures were investigated with differential scanning calorimetry, X-ray powder diffractometry, Fourier-transform infrared spectroscopy and a 24h, non-sink, dissolution study. All mixtures exhibited a single glass transition temperature (Tg), evidence of the formation of homogenous single-phase systems. Fourier transform infrared spectroscopy revealed strong interactions (mainly salt formation) that account for the positive deviation between measured and estimated Tg values. No crystallization was observed during a 1-year stability study in either 1:1 or 1:2 mixtures, but in the presence of moisture, handling difficulties were encountered. The formation of co-amorphous salts led to improved dissolution characteristics when compared to the corresponding physical mixtures or to pure crystalline drugs.

Dissolution behavior of co-amorphous amino acid-indomethacin mixtures: The ability of amino acids to stabilize the supersaturated state of indomethacin.

Arginine, phenylalanine, and tryptophan have been previously shown to improve the solid-state stability of amorphous indomethacin. The present study investigates the ability of these amino acids to prolong the supersaturation of indomethacin in both aqueous and biorelevant conditions either when freely in solution or when formulated as co-amorphous mixtures. The co-amorphous amino acid-indomethacin mixtures (molar ratio 1:1) and amorphous indomethacin were prepared by cryomilling. Dissolution and precipitation tests were performed in buffer solutions (pH 5 and 6.5) and in Fed and Fasted State Simulated Intestinal Fluids (FeSSIF and FaSSIF, respectively). Precipitation tests were conducted with the solvent shift method. The supersaturation stability of indomethacin and the precipitation inhibitory effect of amino acids were evaluated by calculating the supersaturation factor and the excipient gain factor, respectively. Biorelevant media exerted a significant effect on indomethacin solubility but had little effect on the supersaturation stability. Arginine had the most significant impact on the dissolution properties of indomethacin, but also phenylalanine and tryptophan stabilized supersaturation in some media when formulated as co-amorphous mixtures with indomethacin. Only arginine stabilized supersaturation without co-amorphization, an effect only observed in media of pH 6.5. The unique behavior of the arginine-indomethacin mixture was further demonstrated by the abrupt formation of a precipitate, when an excess physical mixture of arginine and indomethacin was added to FeSSIF (pH 6.5). The solid-state investigation of this precipitate indicated that it probably consisted of crystalline arginine-indomethacin salt with possibly some residual crystalline starting materials.