(T1230-12-82) Evaluation of Polymeric Excipients for Stabilization of High Drug Loaded Solid Dispersions of Itraconazole

Purpose: Incorporation of poorly soluble active pharmaceutical ingredients (API) into a polymer matrix to form an amorphous solid dispersion (ASD) is becoming an increasingly attractive approach for improving solubility and bioavailability. Since the amorphous form of the API is thermodynamically unstable, it tends to convert back into a lower energy crystalline form. Therefore, the use of efficient polymers that allow stabilization of the amorphous form upon storage is essential when formulating ASD. Several marketed products containing up to 30% drug loading have been formulated using amorphous solid dispersion approach¹. Attempting to load more drug in the ASD is associated with non-homogeneity of API in the polymer matrix and instability of the ASD upon storage. This result can be attributed to lower concentration of polymer in the matrix, unable to provide sufficient molecular interactions required for stabilization of the amorphous drug. To address this limitation of ASDs, a comparative evaluation was conducted at 40% and 80% drug loadings of a model BCS class II drug, Itraconazole (ITZ) using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), hydroxypropyl methyl cellulose (Affinisol^TM HPMC HME 15LV) and a novel linear polyacrylic polymer (Apinovex^TM ). The resulting solid dispersions were evaluated for their efficiency in formation and stabilization of the high drug loading ASDs.

Methods: ITZ was provided by LGM Pharma and polymers were provided as follows: Soluplus^® by BASF, Affinisol^TM HPMC HME 15LV by Dow Chemicals and Apinovex^TM by Lubrizol Life Science, Health. Lab scale batches were prepared by spray-drying API-polymer solution in ethanol or ethanol/dichloromethane using a Buchi B-290 spray drier. X-Ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC) were performed for physical characterization of the formulations. Dissolution testing was carried out on powders under non-sink condition using USP Apparatus II (paddle; 900 mL 0.1N HCl at 37 °C and 75 rpm). 100 mg Itraconazole equivalent spray-dried dispersions were transferred to each vessel. Collected samples were quantified using HPLC. The stability study was carried out at 40 °C/75%RH accelerated conditions over 6 months of storage.

Results: All spray-dried dispersions (SDDs) showed amorphous nature by XRPD evaluation. The DSC analysis confirms the XRPD observations regarding the amorphous character of the ITZ/Apinovex polymer ASD even at 80% drug loading (Figure 1). A single Tg of 95 °C was observed in ITZ-Apinovex SDDs indicating presence of homogenous amorphous phase. In contrast, 80% ITZ loaded SDDs of Soluplus and Affinisol showed a non-uniform amorphous system with amorphous-amorphous phase separation indicated by re-crystallization exotherm followed by melting endotherm at around 165 °C, corresponding to the melting point of ITZ. At 40% drug loading, all solid dispersions showed a homogenous phase; however, the Tg of ITZ-Soluplus and ITZ-Affinisol SDDs was significantly lower than that of ITZ-Apinovex SDD. The low Tg and amorphous-amorphous phase separation observed in the case of ITZ/Soluplus and ITZ/Affinisol SDDs are undesirable as they impact drug dissolution and long-term stability, with increase potential for drug crystallization over time. All SDDs showed at least 10-fold increase in the dissolution rate compared to the crystalline Itraconazole (Figure 2). Upon storage at the accelerated conditions, the dissolution rate of ITZ loaded Soluplus and Affinisol dispersions showed noticeable drop in the dissolution rate while ITZ-Apinovex SDD did not show significant change (Figure 3). The reduced dissolution in Soluplus and Affinisol SDDs can be attributed to either the amorphous drug converting back to crystalline state upon storage due to low Tg or the presence of unstabilized amorphous API regions rapidly converting to crystalline form upon introduction to the dissolution medium.

Conclusion: The Apinovex^TM polymer was able to form a homogenous amorphous system as well as stabilize ITZ at 80% high drug loading without any significant change in the dissolution rate upon storage under accelerated conditions. The Apinovex^TM polymer also performed favorably in drug loading capacity and stability when compared to Soluplus^® and Affinisol^TM HPMC HME 15LV polymers.

References: 1. NewMan A., & Zografi, G. (2023) Considerations in the Development of Physically Stable High Drug Load API- Polymer Amorphous Solid Dispersions in the Glassy State. Journal of Pharmaceutical Sciences, 112(1), 8-18.

Figure 1: DSC Overlay of 40% and 80% Solid Dispersions

Figure 2: In-Vitro Dissolution of Crystalline ITZ and Spray-Dried ITZ Solid Dispersions

Figure 3: Effect of Storage at Accelerated 40 °C/75%RH Condition on Release of ITZ from SDDs