Mechanistic Study on Complexation-Induced Spring and Hover Dissolution Behavior of Ibuprofen-Nicotinamide Cocrystal

Abstract

Pharmaceutical cocrystal has gained increasing interest due to its ability to modify various physicochemical properties of hydrophobic drugs, especially solubility and dissolution. The temporarily generated supersaturation during the dissolution of cocrystals, usually called “spring and parachute” effect, would favor the oral absorption of poorly soluble drugs. In this study, biopharmaceutics classification system II drug ibuprofen (IBU) was cocrystallized with nicotinamide (NIC) by slow solvent evaporation. An AP-type complexation between IBU and NIC was observed by phase solubility study, and complexation phenomenon was verified by fluorescence quenching method. Reduction of solvation barrier by inserting extremely soluble NIC in the crystal lattice of IBU makes the cocrystal gain a 70-fold higher aqueous solubility than that of original crystalline IBU. A novel mathematic model, considering both the ionization of IBU and the complexation between IBU and NIC, was developed and well-fitted to experimental pH solubility of cocrystal. Surprisingly, instead of common spring and parachute, the prepared IBU-NIC cocrystal demonstrated an initially rapid dissolution followed by a constant high concentration, like a helicopter hovering in the sky, during its nonsink dissolution. Such a result is interpreted with a spring and hover model, which should be ascribed to the enhanced IBU solubility by complexation with the coformer NIC.

Amorphous Solid Dispersions and the Confounding Effect of Nanoparticles in in Vitro Dissolution and in Vivo Testing: Niclosamide as a Case Study

“…To our surprise, this suspension remained stable for long periods of time. This drug behavior is similar to what was previously described as the "spring and hover" effect, in which a noticeable increase in apparent solubility reaches a plateau and persists over a long period of time [39]. Interestingly, in their work with nicotinamide-ibuprofen co-crystals, they achieved a 70-fold increase in supersaturation, and they measured the drug supersaturation using 0.22 µm filters (similar to our work).…”

Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study

“…To our surprise, this suspension remained stable for long periods of time. This drug behavior is similar to what was previously described as the "spring and hover" effect, in which a noticeable increase in apparent solubility reaches a plateau and persists over a long period of time [39]. Interestingly, in their work with nicotinamide-ibuprofen co-crystals, they achieved a 70-fold increase in supersaturation, and they measured the drug supersaturation using 0.22 μm filters (similar to our work).…”

“…The selection of the formulation composition was made using the solvent-shift method and FaSSIF, as described by Palmelund et al (2017), but employing 0.2 µm filters for quantification in order to measure an apparent solubility that included the presence of nanoparticles [37]. It is common to find studies in the literature that report dissolution testing using HPLC-or UV-Vis-based methodologies after a filtration step, similar to our present study [38,39].…”

Challenges and Progress in Nonsteroidal Anti-Inflammatory Drugs Co-Crystal Development

“…IDR is described as the cumulative amount of dissolved per unit surface of the drug preparation plotted against time in units (unit: mg/cm 2 /min). For example, co-crystallization of IBU with NIC could increase the dissolution rate by up to 2.5 times that of the single IBU [ 59 ]. The tramadol–celecoxib co-crystal (CTC) also increased dissolution rate three times more than CEL, which can accelerate absorption and increase bioavailability.…”