Abstract
Microwave-induced in situ amorphization of a drug into a polymeric amorphous solid dispersion (ASD) has been suggested to follow a dissolution process of the drug into the polymeric network, at temperatures above the glass transition temperature (Tg) of the polymer. Thus, increasing the compact temperature, above the Tg of the polymer, is expected to increase the rate of drug dissolution in the mobile polymer, i.e., the rate of amorphization, in a direct proportional fashion. To test this hypothesis, the present study aimed at establishing a linear correlation between the compact temperature and the rate of drug amorphization using celecoxib (CCX) and the polymers polyvinylpyrrolidone (PVP) 12 and PVP17 as the model systems. Water sorbed into the drug–polymer compacts during 2 weeks of storage at 75% relative humidity was used as the dielectric heating source for the present drug amorphization process, and therefore directly affected the compact temperature during exposure to microwave radiation; the loss of water during heating was also studied. For this, compacts prepared with 30 wt% CCX, 69.5 wt% PVP12 or PVP17 and 0.5 wt% magnesium stearate (lubricant) were conditioned to have a final water content of approx. 20 wt%. The conditioned compacts were exposed to microwave radiation for 10 min at variable power outputs to achieve different compact temperatures. For compacts containing CCX in both PVP12 and PVP17, a linear correlation was established between the measured compact end temperature and the rate of drug amorphization during 10 min of exposure to microwave radiation. For compacts containing CCX in PVP12, a fully amorphous ASD was obtained after 10 min of exposure to microwave radiation with a measured compact end temperature of 71 °C. For compacts containing CCX in PVP17, it was not possible to obtain a fully amorphous ASD. The reason for this is most likely that a fast evaporation of the sorbed water increased the Tg of the conditioned drug–polymer compacts to temperatures above the highest reachable compact temperature during exposure to microwave radiation in the utilized experimental setup. Supporting this conclusion, evaporation of the sorbed water was observed to be faster for compacts containing PVP17 compared to compacts containing PVP12.
Highlights
The crystalline drug can be transformed into the amorphous form, allowing the final dosage form to have the characteristic advantages of the amorphous drug such as, e.g., higher solubility and faster dissolution rate compared to the crystalline form [8,9]
It has been suggested that microwave-induced in situ amorphization can be described as a dissolution process, which means that the rate of amorphization can be described by the Noyes–Whitney equation (Equation (1))
It is important to remember that this study only presents a case study based on one model drug and two different grades of PVP, PVP12 and PVP17, i.e., further studies are needed to investigate if the observed behavior applies for other polymers, including higher molecular weight polymers
Summary
In situ amorphization describes the process of transforming a crystalline state of a drug into an amorphous form by forming an amorphous solid dispersion (ASD) within the final dosage form (e.g., a tablet/compact) either in the final manufacturing step or immediately prior to administration [2,4,5,6]. Utilizing the concept of in situ amorphization, a physical mixture of a crystalline drug and a polymer can be manufactured into a final dosage form by using cheap, fast and standard direct tableting. The crystalline drug can be transformed into the amorphous form, allowing the final dosage form to have the characteristic advantages of the amorphous drug such as, e.g., higher solubility and faster dissolution rate compared to the crystalline form [8,9]
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