The Influence of Temperature and Viscosity of Polyethylene Glycol on the Rate of Microwave-Induced In Situ Amorphization of Celecoxib

Abstract

Microwaved-induced in situ amorphization of a drug in a polymer has been suggested to follow a dissolution process, with the drug dissolving into the mobile polymer at temperatures above the glass transition temperature (Tg) of the polymer. Thus, based on the Noyes–Whitney and the Stoke–Einstein equations, the temperature and the viscosity are expected to directly impact the rate and degree of drug amorphization. By investigating two different viscosity grades of polyethylene glycol (PEG), i.e., PEG 3000 and PEG 4000, and controlling the temperature of the microwave oven, it was possible to study the influence of both, temperature and viscosity, on the in situ amorphization of the model drug celecoxib (CCX) during exposure to microwave radiation. In this study, compacts containing 30 wt% CCX, 69 wt% PEG 3000 or PEG 4000 and 1 wt% lubricant (magnesium stearate) were exposed to microwave radiation at (i) a target temperature, or (ii) a target viscosity. It was found that at the target temperature, compacts containing PEG 3000 displayed a faster rate of amorphization as compared to compacts containing PEG 4000, due to the lower viscosity of PEG 3000 compared to PEG 4000. Furthermore, at the target viscosity, which was achieved by setting different temperatures for compacts containing PEG 3000 and PEG 4000, respectively, the compacts containing PEG 3000 displayed a slower rate of amorphization, due to a lower target temperature, than compacts containing PEG 4000. In conclusion, with lower viscosity of the polymer, at temperatures above its Tg, and with higher temperatures, both increasing the diffusion coefficient of the drug into the polymer, the rate of amorphization was increased allowing a faster in situ amorphization during exposure to microwave radiation. Hereby, the theory that the microwave-induced in situ amorphization process can be described as a dissolution process of the drug into the polymer, at temperatures above the Tg, is further strengthened.

The Influence of Drug–Polymer Solubility on Laser-Induced In Situ Drug Amorphization Using Photothermal Plasmonic Nanoparticles

“…It has been suggested that microwave-induced in situ drug amorphization follows a dissolution process of the drug into the polymer at temperatures above the glass transition temperature ( T g ) of the polymer. Thus, in accordance with the Noyes–Whitney equation, describing the dissolution rate of a solute into a solvent [ 11 ], a smaller drug particle size [ 2 ], a higher temperature reached during exposure to microwave radiation, and a lower viscosity of the polymer [ 12 ] have been demonstrated to be advantageous for in situ drug amorphization. Microwave-induced in situ drug amorphization is dependent on the presence of an enabling (dielectric) excipient inside the compact that absorbs the microwave radiation and consequently causes a temperature increase inside the compact [ 13 ].…”

“…Microwave-induced in situ drug amorphization is dependent on the presence of an enabling (dielectric) excipient inside the compact that absorbs the microwave radiation and consequently causes a temperature increase inside the compact [ 13 ]. So far, sorbed water, inorganic crystal hydrates, glycerol, and polyethylene glycol have been used as enabling excipients [ 2 , 3 , 9 , 12 ]. However, previous studies have shown that large amounts of these dielectric excipients are necessary inside the compact to enable complete microwave-induced in situ drug amorphization [ 2 , 3 , 9 , 12 ].…”

“…In connection with the T g , a relatively low molecular weight ( M w ) of the polymer has also been shown to be necessary to achieve a high degree of in situ drug amorphization, e.g., the use of PVP12 ( M w = 2500 g/mol) yielded a higher degree of amorphization compared to PVP17 ( M w = 9000 g/mol) [ 5 ]. The limitations of the temperature reached upon exposure to microwave radiation in relation to the T g and M w of the polymer, combined with the need for a high amount of dielectric excipient, have so far led to only four reported cases of complete in situ drug amorphization upon exposure to microwave radiation, namely CCX in PVP12 using sorbed water or sodium dihydrogen phosphate mono- or dihydrate as an enabling excipient, CCX in polyethylene glycol 3000 and 4000 using polyethylene glycol as the enabling excipient, and indomethacin in Soluplus ® using glycerol as the enabling excipient [ 2 , 3 , 9 , 12 ].…”

The Effect of the Molecular Weight of Polyvinylpyrrolidone and the Model Drug on Laser-Induced In Situ Amorphization

“…Furthermore, as in situ amorphization follows a dissolution process, which is a time- and temperature-dependent process [ 20 , 21 ], a certain temperature needs to be surpassed in the relatively short time-frame of laser exposure in order to obtain complete amorphization. With increasing drug dissolution into the mobile polymer, the viscosity of the polymer increases [ 22 ], which increases the temperature necessary to continue the dissolution process at the same dissolution speed and/or within the given time-frame. The temperature to (theoretically) obtain complete amorphization is labelled as the minimum temperature, T Min , where T Min > T Onset .…”

“…As the complete amorphization of CCX in PVP12 has been shown previously [ 4 ], it remains to be investigated how the rate and degree of amorphization of laser-induced in situ amorphization are affected using a higher M w of PVP, i.e., the same polymer with a higher viscosity due to a higher M w . It is suggested based on studies investigating microwave-induced in situ amorphization that a higher viscosity due to a higher M w will result in a slower rate and, therefore, an overall lower degree of amorphization upon exposure to radiation [ 22 , 23 ]. As the rate of amorphization is also dependent on the ‘drug in polymer’ solubility, it is important to mention that the solubility of CCX in PVP is independent of the M w of PVP, i.e., CCX has the same solubility in the polymers PVP12, PVP17 and PVP25 [ 24 ].…”