(M1430-03-21) Computational Support to Identify Ternary Solid Dispersions of Hydroxypropyl Cellulose and Small Molecular Additives to Stabilize Challenging Drugs

Purpose: Solid dispersions comprising more than a polymer and a drug have been used for many years to formulate poorly water-soluble drugs. Such an additional excipient has been added for different purposes, for example to improve drug release or physical stability. Regarding the latter objective, the hypothesis of the present work was whether the addition of a digitally selected co-former in ternary solid dispersion as produced by hot melt extrusion would be a way to formulate unstable glass-forming model drugs. A new computational approach is presented to identify formulation candidates comprising hydroxypropyl cellulose (HPC) and drug (i.e., bifonazole or cinnarizine) with different small-molecular co-formers. Subsequently, an experimental melt extrusion screening and stability tests are conducted.

Methods: The conductor-like screening model for real solvents (COMSO-RS) is an advanced version of a dielectric continuum solvation model. The model uses a distribution of molecular surface segments having a specific charge density, which is based on density functional theory calculations. The software COSMOquick (v.2020, Biovia, Dassault Systèmes) was used to calculate solubility parameters and to estimate an excess enthalpy/mixing enthalpy of drug and co-former, H_ex and details can be inferred from previous work [1]. The experimental extrusion was then conducted on a small-scale ZE9 ECO twin-screw extruder (co-rotating screws with a 9-mm diameter and 180 mm in length) by ThreeTec Ltd. (Birren, Switzerland) at an extrusion temperature around 150 °C, which was about 15 °C higher for the extrudates of the co-former tartaric acid. For subsequent analysis of the produced mixtures, X-ray powder diffraction (XRPD) analysis was conducted on a D2 Phaser diffractometer (Bruker AXS Ltd., Karlsruhe, Germany) with a 1-D Lynxeye detector, while differential scanning calorimetry (DSC) was based on a DSC3 (Mettler Toledo Ltd., Greifensee, Switzerland).

Results: Interestingly, the calculated solubility parameter was for both drugs similar with 19 MPa^0.5 for cinnarizine and 20 MPa^0.5 in the case of bifonazole. Good miscibility was expected for HPC with a solubility parameter of 24 MPa^0.5 but for the screening of co-formers, an overlap range of solubility parameter (ORSP) was introduced. Thus, it is assumed that beyond ± 10 MPa^0.5 relative to a target solubility parameter, there is high risk of de-mixing. As a co-former must mix with both, drug and HPC, there are two resulting intervals of likely miscibility that have a distinct range of values in common, i.e., the ORSP. This ORSP provided 14- 29 MPa^0.5 for cinnarizine and 14- 30 MPa^0.5 for bifonazole. Subsequently, 34 candidate additives were selected that were all within this ORSP. In a next step, binary mixing energies (H_ex) were mapped together with a temperature process range of HPC. Fig. 1 suggests that within these limits for a hot melt extrusion process, malic-, citric-, and tartaric acid were for both drugs of high interest owing to their highly negative H_ex values. These co-formers were then selected together with ornithine that provided a reference of less favorable drug-interactions. Subsequent experimental manufacturing of formulations was first done as screening trials followed by selected stability testing with 15% (w/w) drug load. In line with the ORSP concept, a good miscibility of the components was generally observed in the experiments. As expected, the compounds posed a considerable challenge to keep drug in amorphous form and this was partly due to a low molecular flexibility [2]. Most promising was a combination of HPC and malic acid with either cinnarizine or bifonazole for which no traces of crystallinity were evidenced even after 12 weeks, which was a remarkable finding.

Conclusion: There is more long-term stability needed for a final assessment on the challenge to formulate unstable glass-forming drugs. However, it can be already concluded that computational pharmaceutics can guide scientists to formulate such challenging drugs and ternary solid dispersions of polymer and co-former provide a very promising formulation approach.

References: [1] Niederquell, A., et al., Hydroxypropyl Cellulose for Drug Precipitation Inhibition: From the Potential of Molecular Interactions to Performance Considering Microrheology. Mol. Pharm., 2022, 19, 690-703.
[2] Wyttenbach, N., Kuentz, M., 2017. Glass-forming Ability of Compounds in Marketed Amorphous Drug Products. Eur. J. Pharm. Biopharm., 112, 204-208.

Figure 1 - Mixing enthalpies of various additives with cinnarizine (upper panel) and bifonazole (lower panel) are shown together with the sigma surface of the respective drugs and further details are given in the text.