Abstract
The distinction between surface and bulk crystallization of amorphous pharmaceuticals, as well as the importance of surface crystallization for pharmaceutical performance, is becoming increasingly evident. An emerging strategy in stabilizing the amorphous drug form is to utilize thin coatings at the surface. While the physical stability of systems coated with pharmaceutical polymers has recently been studied, the effect on dissolution performance as a function of storage time, as a further necessary step toward the success of these formulations, has not been previously studied. Furthermore, the effect of coating thickness has not been elucidated. This study investigated the effect of these polymer-coating parameters on the interplay between amorphous surface crystallization and drug dissolution for the first time. The study utilized simple tablet-like coated dosage forms, comprising a continuous amorphous drug core and thin polymer coating (hundreds of nanometers to a micrometer thick). Monitoring included analysis of both the solid-state of the model drug (with SEM, XRD, and ATR FTIR spectroscopy) and dissolution performance (and associated morphology and solid-state changes) after different storage times. Stabilization of the amorphous form (dependent on the coating thickness) and maintenance of early-stage intrinsic dissolution rates characteristic for the unaged amorphous drug were achieved. However, dissolution in the latter stages was likely inhibited by the presence of a polymer at the surface. Overall, this study introduced a versatile coated system for studying the dissolution of thin-coated amorphous dosage forms suitable for different drugs and coating agents. It demonstrated the importance of multiple factors that need to be taken into consideration when aiming to achieve both physical stability and improved release during the shelf life of amorphous formulations.
Highlights
Surface crystallization of amorphous drugs is distinct and orders of magnitude faster than bulk crystallization.[1−6] This is believed to be due to the higher molecular mobility of surface molecules, with multiple observations in the pharmaceutical setting consistent with this theory
This study investigates the surface stabilization of a simple dosage form consisting of an amorphous drug compact that was subsequently spray-coated with a thin polymer layer
This study shows that while crystallization inhibition during storage is important, the other factors associated with the polymers and the coatings themselves can have an important effect on dissolution
Summary
Surface crystallization of amorphous drugs is distinct and orders of magnitude faster than bulk (interior) crystallization.[1−6] This is believed to be due to the higher molecular mobility of surface molecules, with multiple observations in the pharmaceutical setting consistent with this theory. While the formation of solid dispersion can stabilize the bulk, surface crystallization may still occur.[11] An approach orthogonal to amorphous solid dispersions is to stabilize the more sensitive surfaces of amorphous materials, with or without stabilizing the bulk of the material. This strategy benefits from a lowered polymer (or other excipient used for stabilization) burden and ideally should be simple and scalable. Whether or not this approach requires specific types of interactions between the drug and the stabilizing agent or Received: December 12, 2019 Revised: February 5, 2020 Accepted: February 6, 2020 Published: February 6, 2020
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