Category: Formulation and Quality
Purpose: Hot melt extrusion (HME) is an ever more widely applied technology for the creation of amorphous solid dispersions to enhance the bioavailability of low soluble active ingredients. To assure a successful formulation development an identification of suitable polymers needs to be addressed already at early stages. Different screening technologies are compared to allow a prediction of performance and stability of a hot melt extruded formulation.
Methods: Different polymers were assessed together with a low soluble model compound (ketoconazole) for HME processing: A dedicated PVA for HME, PCL-PVAc-PEG graft copolymer, PVP & PVP/VA copolymer. Drug loading was kept constant at 20%. Different technologies were evaluated for preparing amorphous solid dispersions:
An optimized differential scanning calorimetry (DSC) method was used to prepare small amounts of solid dispersions: Samples were prepared using a DSC 3+ from Mettler Toledo. Total sample amount per run was 25 mg using 100 µl aluminum pans. Cyclic scans were performed, heating and cooling rate were set to 30 K/min. Final temperatures were adapted to optimal range of the individual polymers. and remained constant in the targeted range for about 3 min followed by a cooling to room temperature. After the heating cycle DSC pans were opened, visually inspected and used for further analytical testing. A vacuum compression molding (VCM) technology was evaluated for preparing solid dispersions at small scale using the VCM essential tool from MeltPrep GmbH. The pre-mix of model compound and polymer was filled into the VCM tool. Vacuum was applied, the melting process was initiated. Temperatures were adapted to the individual polymers. Samples were visually inspected and used for further testing. To allow a comparison to the final processing technology hot melt extrusion was carried out using a Pharma 11 twin screw extruder from Thermo Fisher Scientific. All samples were analyzed concerning their solid state as well es their dissolution behavior. A dedicated dissolution method was applied to enable the screening of low sample amounts.
Results: Both evaluated screening technologies are well suitable to predict the formulation performance at small scale. Dissolution data of samples created via VCM screening are presented in Figure 1. Release kinetics of the milled samples are a good indicator for the performance of the HME formulation (Figure 3). For all polymers a significant increase of solubility is observed compared to the crystalline drug substance. Strongest supersaturation can be observed for PVA with peak concentrations of more than 700 µg/ml.
Dissolution results from DSC pans are presented in Figure 2. Drug release occurs from the film formed in the DSC pan. Therefore, an expected difference in release kinetics is observed compared to milled samples. With more than 800 µg/ml highest supersaturation is observed for PVA. For both screening technologies PVP and PVP/VA copolymer show similar release profiles. The highest performance concerning supersaturation is observed for PVA. The performance of PCL-PVAc-PEG graft copolymer is slightly underestimated using the DSC method.
Conclusion: Both evaluated technologies DSC as well as VCM show a high potential to estimate the performance of the final HME formulation. The DSC method can be easily established on existing devices and is highly interesting for preliminary tests. Limitations are the restricted sample amount as well as the direct relation of release characteristics to the performance of HME formulations. In contrast VCM technology provides the advantage of a more versatile and homogenous sample generation offering a high reliability in sample preparation. An increased sample amount allows further processing steps resulting in realistic estimation of formulation performance.
Nicole Di Gallo– MilliporeSigma, Darmstadt, Hessen, Germany
Alessandro-Giuseppe Elia– MilliporeSigma, Darmstadt, Hessen, Germany
Anja-Nadine Knüttel– Darmstadt, Hessen, Germany
Finn Bauer– Head of Solid Formulations R&D, MilliporeSigma, Darmstadt, Hessen, Germany