Molecular Implications of Drug–Polymer Solubility in Understanding the Destabilization of Solid Dispersions by Milling

Abstract

The solubility of drugs in polymer matrixes has been recognized as one of the key factors governing the physical stability of solid dispersions. This study has explored the implications of drug solubility on the destabilization that occurs on milling, which is often used as an additional process for hot melt extruded (HME) solid dispersions. The theoretical drug solubility in the polymer was first predicted using various theoretical and experimental approaches. The destabilization effects of high-energy mechanical milling on the solid dispersions with drug loadings below and above the predicted solubility were then investigated using a range of thermal, microscopic, and spectroscopic techniques. Four model drug-polymer combinations were studied. The HME formulations with drug loading below the predicted solid solubility (undersaturated and true molecular dispersion) showed good stability against milling. In contrast, milling destabilized supersaturated HME dispersions via increasing molecular mobility and creating phase-separated, amorphous, drug-rich domains. However, these additional amorphous drug-rich domains created by milling show good stability under ambient conditions, though crystallization can be accelerated by additional heating. These results highlighted that the processing method used to prepare the solid dispersions may play a role in facilitating the stabilization of amorphous drug in supersaturated solid dispersions. The degree of supersaturation of the drug in the polymer showed significant impact on the destabilization behavior of milling on solid dispersions. An improved understanding of the destabilization behavior of solid dispersions upon milling can provide new insights into the processing related apparent solubility of drugs in polymers.

Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin

“…The use of too low a concentration of polymer can also result in an unstable product. 35 Therefore, a higher concentration of 60% (w/w) PVA, 6 hour milling time and milling temperature of 2-5 o C were implemented. This resulted in a product which was almost fully amorphous, however very small peaks could still be detected at approximately 20 and 25 2θ degrees due to the presence of residual crystalline CIP (Figure SI.2).…”

Two Faces of Ciprofloxacin: Investigation of Proton Transfer in Solid State Transformations

“…41 The CIP starting material was composed of the zwitterionic form of the drug. As can be seen from Figure 4, ball milling at room temperature for 4 hours did not produce the fully amorphous form of CIP; however it did reduce the intensity of the peaks seen in PXRD over time.…”

Determination of drug-polymer solubility from supersaturated spray-dried amorphous solid dispersions: A case study with Efavirenz and Soluplus®

“…However, cryomilling is a longstanding process and have some limitations to control and to standardize particle characteristics such as size, morphology, shape and surface properties [23]. In contrast, the dissolution endpoint method enables the measurement of the endpoint of the dissolution step and thus might be more accurate [24]. The end point value represents the melting point of the final composition, assuming complete mixing has occurred.…”

“…The supersaturation of the API into the polymer can be obtained from a physical mixture of crystalline API and polymer carrier by different techniques such as film casting method [19] and comilling [13,24] that forces the miscibility of the two compounds to reach supersaturation. The supersaturated glass solution is then loaded in a DSC analyzer and annealed above its T g during a sufficient time to complete the demixing process: release the excess of API in the mixture and reach the equilibrium solution concentration at the annealing temperature.…”