(T1530-08-52) Continuous Manufacturing of Solvent-Free Cyclodextrin Inclusion Complexes for Enhanced Drug Solubility via Hot-Melt Extrusion: A Quality by Design Approach

Purpose: The objective of the current study was to statistically evaluate the effect of various process and material variables on the solubility enhancement and in-vitro dissolution performance of inclusion complexes produced by the HME process. Cyclodextrin (CD) complexes have been widely investigated and adopted over decades to improve the solubility of poorly water-soluble APIs in the pharmaceutical field. There are various methods for preparing CD-complexes, most of which are solvent intensive processes, for instance, kneading, solvent evaporation, spray drying, electrospinning, microwave irradiation, freeze drying, ball milling, etc. During the last decade, hot melt extrusion (HME) was used to prepare many inclusion complexes to enhance the solubility of API. Yet none of the studies details the critical material and process parameters involved in preparing CD complexes using HME. In this work, the Quality by design (QbD) approach was used to evaluate these parameters and their effect on the solubility and dissolution of a poorly soluble model drug called Ibuprofen (IBU). Further, various evaluation studies were conducted to confirm the complex formation between IBU and CD when processed through HME.

Methods: The suitable CD and stoichiometry of the complex formation with IBU were selected using molecular docking and phase solubility studies. Since, cyclodextrin is not thermoplastic material, an additive like polymer is required to aid in the HME process. Based on the existing literature, co-povidone was selected as an additive. Box-Behnken design (BBD) was used to evaluate the influence of various independent variables (polymer concentration, temperature, and screw speed) on the dependent variables (solubility and dissolution). A freeze-dried IBU-CD complex was prepared to compare and ensure the formation of a complex in the HME extruded granules (complexes). The HME extruded granules were subjected to Differential Scanning Calorimetry (DSC) and X-Ray Diffraction (XRD) to study the crystalline nature of IBU. At the same time, Attenuated Total Reflection (ATR) and Nuclear Magnetic Resonance (NMR) were used to evaluate the complex formation between IBU and CD. Finally, the prepared formulations (equivalent to 20mg IBU) were subjected to dissolution testing in 500mL 0.1N HCl and pH 7.2 phosphate buffer.

Results: The molecular docking and phase solubility studies revealed stable IBU complexes with HPβ-CD in a stoichiometry ratio of 1:1. The BBD experiments were successfully extruded, except for a few failed runs due to high torque obtained during extrusion. These failed runs have a common process temperature equivalent to that of Tg of polymer and a high polymer concentration, forming a solid bulk mass around the mixing zones in HME. Despite the experimental failures, the design was found to be statistically significant due to the high number of midpoint experiments (n=5). The DSC and XRD studies showed the amorphous conversion of IBU. The ATR studies revealed the disappearance of C=O stretching of IBU at 1720 cm^-1, confirming IBU's inclusion into the hydrophobic cavity of HPβ-CD, forming a binary complex. The same was further confirmed by NMR studies, wherein the chemical shifts of carboxylic acid proton peak at 12.24 ppm were not detected in both the complexes formed through HME and freeze-drying. The saturation solubility of all the extruded granules was found to be very soluble. The dissolution of extruded granules, physical mixture, and free drug have similar profiles in pH 7.2 phosphate buffer because of the pH-dependent solubility of IBU. While in the case of 0.1N HCl, the dissolution of extruded granules resulted in more than 85% release in 30min.

Conclusion: In this study, the cyclodextrin complexes were successfully prepared using HME. QbD was successfully applied to study various independent paraments like barrel temperature, screw speed, and polymer concentration on dependent variables like solubility and dissolution of IBU. Overall, the findings indicate that the polymer matrix and rheology of the polymer, which depends on the polymer concentration and barrel temperature, are crucial in forming CD complexes through the extrusion process. Increasing the temperature reduces the viscosity of the polymer, which in turn enables the melted drug to be miscible or suspended freely in the polymer matrix. Since the drug is hydrophobic, it tends to escape from the polymer matrix and hosts into the cyclodextrins hydrophobic cavity. The polymer concentration should be selected to provide the required viscosity for the extrusion, and it should also balance the bulkiness of the formulation. The temperature should be enough to give sufficient viscosity for HME processibility by liquefying the polymer, and the temperature above the Tm of the drug is preferred. The screw speed should be adjusted to generate the least amount of torque ensuring smooth processibility.

XRD diffractograms of Pure IBU and formulations

In vitro dissolution profiles of Pure IBU and various formulations in pH 7.2 phosphate buffer (A) and pH 1.2 0.1N HCl (B)

1H Nuclear Magnetic Resonance (1H NMR) Chemical Shift Data