Novel Supercritical Carbon Dioxide Impregnation Technique for the Production of Amorphous Solid Drug Dispersions: A Comparison to Hot Melt Extrusion

Abstract

The formulation of BCS Class II drugs as amorphous solid dispersions has been shown to provide advantages with respect to improving the aqueous solubility of these compounds. While hot melt extrusion (HME) and spray drying (SD) are among the most common methods for the production of amorphous solid dispersions (ASDs), the high temperatures often required for HME can restrict the processing of thermally labile drugs, while the use of toxic organic solvents during SD can impact on end-product toxicity. In this study, we investigated the potential of supercritical fluid impregnation (SFI) using carbon dioxide as an alternative process for ASD production of a model poorly water-soluble drug, indomethacin (INM). In doing so, we produced ASDs without the use of organic solvents and at temperatures considerably lower than those required for HME. Previous studies have concentrated on the characterization of ASDs produced using HME or SFI but have not considered both processes together. Dispersions were manufactured using two different polymers, Soluplus and polyvinylpyrrolidone K15 using both SFI and HME and characterized for drug morphology, homogeneity, presence of drug-polymer interactions, glass transition temperature, amorphous stability of the drug within the formulation, and nonsink drug release to measure the ability of each formulation to create a supersaturated drug solution. Fully amorphous dispersions were successfully produced at 50% w/w drug loading using HME and 30% w/w drug loading using SFI. For both polymers, formulations containing 50% w/w INM, manufactured via SFI, contained the drug in the γ-crystalline form. Interestingly, there were lower levels of crystallinity in PVP dispersions relative to SOL. FTIR was used to probe for the presence of drug-polymer interactions within both polymer systems. For PVP systems, the nature of these interactions depended upon processing method; however, for Soluplus formulations this was not the case. The area under the dissolution curve (AUC) was used as a measure of the time during which a supersaturated concentration could be maintained, and for all systems, SFI formulations performed better than similar HME formulations.

Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems

“…Thus current challenges in pharmaceutical industries are to develop advanced formulation strategies to enhance the rate of water solubility of active pharmaceutical ingredients (APIs) and to develop potential drug delivery systems and biomaterials. 35,36 SDs for the formulation of amorphous drugs alleviates the problems associated with storage and processing by the inclusion of excipients to enhance the properties of formulation. The drug in SDs experiences a maximum increase in surface area and the possible interface between the drug and the carrier is also utmost.…”

The Need for Restructuring the Disordered Science of Amorphous Drug Formulations

“…Some of the reasons given for excipient selection included reliance on previous reports of the use of similar excipients and their historical applicability in ASDs and oral dosage forms (100–125); the physicochemical properties and functions of the excipient, possible interactions between the compound and the excipient, and the miscibility/immiscibility of the compound and excipient (105–108,111,112,114,126–148); the processability or suitability of the excipient for the preparation method (73,105,119,127,149–152); and the possibility of designing a controlled-release profile and/or pH-dependent release of the compound from the amorphous formulation (99,100,107,123,153–156). An attempt to tailor and customize excipients by modifying the functional groups which could be potentially used in ASD formulations has also been reported (157).…”

“…More uncommon preparation methods which are not widely used and established industrially for the preparation of amorphous formulations such as supercritical fluid impregnation /solvent-antisolvent (84,92,102,149), electrospinning /electrospraying (72,91,141,153,174), confined impinging jet (107) and pressurized gyration (161) have also been explored even though the applicability in large scale is still a question.…”

“…The temperatures ranged from 2°C to 60°C and the relative humidity varied between 0% and 100%. The duration also varied significantly, with stability studies lasting from 24 h to two years (73,74,81,82,84,86,88,92,93,104,105,109,110,113,115,116,118,120,123,124,126,127,129,130,132,134,135,139,143,146,149,153,158,166,169,172,175,176). While most of the studies did not mention the container used for the physical stability test, a few specified, for example, whether a closed or open container was used (88,92,113,123,132,146).…”

Soluplus micelles for improving the oral bioavailability of scopoletin and their hypouricemic effect in vivo

“…Soluplus, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (57/30/13) graft copolymer, is an amphipathic copolymer. Due to its high fluidity and excellent extrudability, Soluplus shows superior performance in forming solid solutions, especially in hot melt extrusion processes [17,18] . As an amphiphile, Soluplus has been extensively used to improve the aqueous solubility and oral bioavailability of poorly soluble drugs [19] , and it can self-assemble into micelles above the critical micelle concentration (CMC) [20] .…”