Spring and parachute approach for piroxicam dissolution; its phenomenological model on the thermodynamics of irreversible processes.

Even though the spring and parachute approach for poorly water-soluble drug candidates effectively improves their dissolution curves with eutectic mixtures, deep eutectic solvents, solid dispersion polymers, and solid solutions, we cannot consider that its enabling factor in these pharmaceutical modifications was enough to be clarified. Based on our previous study that oxybuprocaine acts as a role of parachute generator for piroxicam, the present study explored a small-molecule parachute generator and found that propranolol, a ß-adrenergic-blocking drug, has a parachute effect on the supersaturated state of piroxicam. In addition, changing the concentration of tetracaine and dibucaine to 10 mM and 2.5 mM also showed a parachute effect. These parachute generators control piroxicam's dissolved state kinetically by making the supersaturated state of piroxicam a steady state. However, as the piroxicam anhydrous crystals diminished and the piroxicam monohydrate crystals grew due to Ostwald ripening, it led to attenuating the supersaturated state. This finding advances the elucidation of the mechanism of the parachute effect of polymers.

Enthalpy-Entropy Compensation in the Structure-Dependent Effect of Nonsteroidal Anti-inflammatory Drugs on the Aqueous Solubility of Diltiazem.

Certain combinations of acidic and basic drugs can cause significant changes in physicochemical properties through the formation of ionic liquids, eutectic mixtures, or deep eutectic solvents. In particular, combining indomethacin and lidocaine is known to result in apparent increases in both the partition coefficients (hydrophobicity) and aqueous solubilities (hydrophilicity). The physicochemical interactions between drugs change the water solubility of the drugs and affect the bio-availability of active pharmaceutical ingredients. Therefore, we need to clarify the mechanism of changes of water solubility of drugs through the physicochemical interactions. In the present study, we identified a thermodynamic factor that regulates the dissolution of a basic drug, in the presence of various acidic nonsteroidal anti-inflammatory drugs. The results demonstrated that enthalpy-entropy compensation plays a key role in the dissolution of drug mixtures and that relevant thermodynamic conditions should be considered.

Stabilization of the Metastable α-Form of Indomethacin Induced by the Addition of 2-Hydroxypropyl-ß-Cyclodextrin, Causing Supersaturation (Spring) and Its Sustaining Deployment (Parachute).

The purpose of this study is to find that a small amount of 2-Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) can produce a parachute effect on indomethacin (INM). From the examination of dissolution curves and concentration after several days, the supersaturation of INM was observed for the mixtures containing HP-ß-CD at a molar ratio ≤ 0.5, and the sustained deployment of supersaturation was found not only in equimolar mixtures but also in mixtures with a shortage of HP-ß-CD. In the solid state, it was compared the physical properties of INM/HP-ß-CD mixtures using two different mixing methods and determined the stoichiometry of INM and HP-ß-CD. Differential scanning calorimetry (DSC) revealed that the polymorphs of INM were converted by HP-ß-CD into an amorphous state. Furthermore, X-ray powder diffraction (XRPD) and DSC-XRPD demonstrated that INM crystals from the INM/HP-ß-CD mixture prepared from an EtOH solution were metastable. In conclusion, these phenomena may be considered the "spring" and "parachute" effects of mixtures with a shortage of HP-ß-CD, as they depended on the presence of the metastable α-form of INM. The addition of 1/3 to 1/20 equivalents of HP-ß-CD to INM enhanced INM solubility.

The function of oxybuprocaine: a parachute effect that sustains the supersaturated state of anhydrous piroxicam crystals.

Polymers have been recognized to have the function of sustaining the supersaturated state of drugs. This function has been widely studied because it will improve the absorption of poorly water-soluble drugs. However, clarifying the mechanism of this sustaining pharmaceutical effect (parachute effect) on the supersaturated state as a result of polymers is remains a task. We have found that oxybuprocaine, which is a small molecule, has a parachute effect on the supersaturated state (due to an anhydrate-to-hydrate transformation) of piroxicam-anhydrate in the aqueous phase. We consider that oxybuprocaine controls the environment of the solution and the network of polymers is unnecessary. Therefore, oxybuprocaine not only becomes a clue for elucidating the essential mechanism of the parachute effect of polymers but also enables us to rationally propose a new type of solubilizer.