(T1530-07-45) HPC-CA - A Novel Cellulose Derivate for Amorphous Solid Dispersion

Purpose: Hydroxypropycellulose-1,2-cylcohexanedicarboxylicacidester (HPC-CA) is a novel cellulose-based pharmaceutical polymer with structural features suggesting potential suitability for enteric coating applications. More importantly, HPC-CA may serve as an excipient for enhancing the solubility of poorly water-soluble drugs via the formation of amorphous solid dispersions (ASDs). To assess this potential, the BCS-Class II drug ketoconazole (KC) was selected as model compound. The non-sink dissolution performance of HPC-CA-based ASDs was compared to that of hydroxypropyl methylcellulose acetate succinate (HPMCAS), a well-established functional cellulose derivative commonly used in ASD formulations.[1,2]

Methods: ASDs containing 10 % or 20 % KC were prepared by ball milling (3 × 5 min, Retsch GmbH, Haan, Germany) followed by vacuum compression molding (VCM, 155–163 °C, 10–15 min, MeltPREP, Graz, Austria). Crystallinity was assessed by X-ray powder diffraction (XRPD, X’Pert MRD Pro, Almelo, Netherlands, 4–45° 2θ, CuKα1) and thermal behavior by differential scanning calorimetry (DSC 2, Mettler, Gießen, Germany) using heat and TOPEM mode (0–170 °C, 2 or 10 °C/min). Solid-state interactions were characterized via Fourier-transform infrared spectroscopy (FT-IR, 450–4000 cm⁻¹). Non-sink dissolution was performed using a modified USP II apparatus (Mini-Dissolution apparatus) in 20 mL PBS (pH 6.9, 37 °C, 75 rpm, 180 min), with 4 mg API per run (c_max = 0.2 mg/mL). KC concentrations were determined using a UV/VIS spectrophotometer (Agilent, Waldbronn, Germany) at 243 nm.

Results: All ASDs showed complete amorphization as confirmed by XRPD and DSC. HPC-CA-based thermograms showed a decrease in glass transition temperature with increasing drug load (T_g10%DL: 59.3 °C, T_g20%DL: 57.9 °C), confirming successful ASD formation at both levels. In dissolution, HPC-CA systems achieved higher final drug release and more stable supersaturation (180 min, 10 % DL: 62.1 %, 20 % DL: 50.7 %) with a 10 % reduction at 20% DL, indicating stoichiometric dependence of HPC-CA and KC. HPMCAS systems showed a rapid API burst at 40 min, even more pronounced at 20 % DL, followed by a fast decline to similar final levels (180 min, 10 & 20 % DL: 17.5 %). FTIR revealed disappearance of the amide carbonyl stretch at 1645 cm⁻¹, indicating specific KC/HPC-CA interactions similar to KC/HPMCAS.[1]

Conclusion: Successful ASD formation was achieved in all cases. Non-sink dissolution studies revealed that HPC-CA-based ASDs provided superior and more sustained solubility enhancement/supersaturation for KC compared to HPMCAS. Unlike HPMCAS, HPC-CA based ASDs showed an HPC-CA concentration dependent effect on the extent of solubility enhancement/supersaturation still, superior over HPMCAS ASDs. Despite polymer/KC interaction in solid state were similar for HPC-CA and HPMCAS, interaction in liquid phase were different and are subject of further investigation.

References: 1. Monschke M, Kayser K, Wagner KG. Influence of Particle Size and Drug Load on Amor-phous Solid Dispersions Containing pH-Dependent Soluble Polymers and the Weak Base Ke-toconazole. AAPS PharmSciTech. 2021;22:44.
2. Pöstges F, Kayser K, Stoyanov E, Wagner KG. Boost of solubility and supersaturation of celecoxib via synergistic interactions of methacrylic acid-ethyl acrylate copolymer (1:1) and hydroxypropyl cellulose in ternary amorphous solid dispersions. International Journal of Pharmaceutics: X. 2022;4:100115.

Acknowledgements: This research was partially sponsored by Nisso Chemical Europe GmbH. The company had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the abstract, or in the decision to publish the results. The other authors declare no conflict of interest.


Figure 1: KC release from HPC-CA- and HPMCAS-based ASDs at different drug loads under non-sink dissolution conditions (A), with corresponding thermal and crystallinity profiles (B and C). Solid-state interaction of KC with HPC-CA analyzed by FTIR spectroscopy (D).