(W1030-12-81) Structure-Functionality Relationship (SFR) of HPC for Solubility Enhancement: Importance of DS and MS for the HPC Hydration in Aqueous Solutions

Purpose: Understanding the relation between the excipient chemical structure and its functionality is one of the important steps in the drug development. The structure-functionality relationship (SFR) for excipients is important for the Quality by Design (QbD) and risk assessment of the drug development. Hydroxypropyl cellulose (HPC) is a cellulosic ether newly used as solubility enhancer for poorly soluble drugs^1-4 but only the low molecular weight (MW) HPCs were reported to possess supersaturation stabilization properties^3,4. Recently, some of us reported that HPC solubilizing activity in aqueous solutions might be caused by the favorable interplay between HPC chain length and hydration⁵. In this study, we aimed to obtain further insights into the sub-molecular interactions between HPC and water, looking for a correlation between degree of substitution (DS) and moles substitution (MS) and HPC hydration in solution.

Methods: Two HPC grades with average molecular weights of 100,000 g/mol (HPC-L, Nippon soda Co., Ltd.) and 40,000 g/mol (HPC-SSL, Nippon soda Co., Ltd.) were used. The liquid NMR experiments were conducted on a JEOL ECJ-500 (proton resonance at 500 MHz). Degree of substitution (DS) and moles of substitution (MS) were measured with ¹³C-NMR technique by using 10 % (w/w) HPC solutions in D₂O (D 99.8%, FUJIFILM Wako Pure Chemical) placed in 10 mm NMR tubes. The ¹³C-NMR of the solution was recorded with non-NOE quantitative mode. The exact MS and DS of the tested HPC grades were calculated with the peak of outer-methyl unit in 20ppm and the peak of inner-methyl unit in 16 ppm based on the peak of pyranose ring in 103 ppm.
WaterLOGSY liquid NMR (Ligand Observed via Gradient Spectroscopy) was conducted by using a published method⁵ with the following modifications: 2 % (w/w) HPC solution in D₂O / H₂O (10/90) in a 5 mm NMR tube; 180° inversion pulse was applied over the H₂O signal (~4.7 ppm) by using a sinc-shaped selective pulse of 7.5 ms and bandwidth of 75 Hz. The strong water peak was suppressed with W5-type watergate. All spectra were recorded over 256 scans with interscan relaxation delay and acquisition times of 4 sec and 1.6 sec, respectively; mixing time was 50 ms. The broad peak at 5-6 ppm is attributed to the hydration of the pyranose part in the HPC molecule, while the peak in at 1 ppm is attributed to the hydration of the pendant chain methyl groups (Figure 1). The relative area of each peak with respect to the total signal area in the same spectrum was calculated as a %-hydrated pyranoses and %-hydrated pendant chains (Table 1).

Results: The WaterLOGSY measurements revealed that the hydration of both pyranoses and pendant chains in the HPC molecule depends on the DS and MS but not in the same magnitude. While at the short polymer chain length HPC-SSL the dependency was relatively less expressed, the long polymer chain length HPC-L demonstrated a strong correlation between the hydrated regions in the polymer molecule and its DS/MS. Thus, for HPC-SSL, the decrease of the DS from 2.12 to 1.72 led to a slight increase of the pyranoses hydration by keeping the pendant chain hydration almost unchanged (Table 1, Figure 2). In the same way, a variation in the MS of the HPC-SSL molecule from 3.52 to 4.20 showed only minor changes in the pyranoses and pendant chains hydration (Table 1, Figure 2). For the short polymer chain length HPC-SSL, the hydration and the water residence time were found to not be dependent on the polymer DS and MS. In contrast to this, HPC-L pyranoses hydration percentage went down from 30% to 13 % when the DS and MS decreased, while the pendant chains hydration increased slightly from 23 to 31 % (Table 1, Figures 2). For the long polymer chain length HPC-L, the hydration layer surrounding the entire molecule was found to be strongly dependent on the polymer DS and MS. Since HPC-L structure in aqueous solutions is more bended and tangled compared to HPC-SSL⁶, the hydration percentage of the pyranoses increases but that of the pendant chains increases when increasing the MS and DS (Table 1). This is due to the “entrapped water” inside the larger and tangled polymer chain. On the other hand, the more open and linear chain of HPC-SSL shows slightly higher hydration percentages around the pyranoses and a very low but consistent hydration percentage of the pendant chains at different MS/DS values.

Conclusion: The short chain length HPC-SSL retains similar amounts of water around its hydrated molecule independently from DS and MS. This guarantees a more consistent functionality as crystallinity inhibitor for poorly soluble drugs in aqueous solutions The long chain length HPC-L shows hydration percentage that is in a relationship to the polymer MS/DS showing differences in the molecule parts. While the pyranoses hydration percentage decreases with decreasing MS/DS, the pendant chains hydration percentage increased.

References: [1] Osawa, M. et al, Characterization of Sulindac Solid Dispersion with Hydroxypropyl Cellulose Prepared by Hot Melt Extrusion, J. Pharm.Sci. Technol., Jpn., 74/2, 2014, 160-169.
[2] Zecevic, D.E., et al., Site specific solubility improvement using solid dispersions of HPMC-AS/HPC SSL – Mixtures, Eur. J. Pharm. Biopharm. 87, 2014, 264–270.
[3] Bachmaier, R. D. et al, In vitro and in vivo assessment of hydroxypropyl cellulose as functional additive for enabling formulations containing itraconazole, Int. J. Pharm., X3, 2021, 100076.
[4] Luebbert, C. et al., Phase behavior of ASDs based on hydroxypropyl cellulose, Int. J. Pharm. X3, 2021, 100070.
[5] Martin-Pastor, M., Stoyanov, E., Mechanism of interaction between hydroxypropyl cellulose and water in aqueous solutions: Importance of polymer chain length, J. Polym. Sci., 58, 2020, 1632-1641.
[6] Sakamoto, N., Stoyanov, E., Differential analysis of O-(2-hydroxypropyl)cellulose by using two-dimentional 1H-NMR spectroscopy, Biomed. Sci. Eng., 6/1, 2020, 010-015.

Figure 1. WaterLOGSY spectra with the characteristic peaks at 5-6 ppm (pyranoses) and 1 ppm (pendant chains)

Table 1. Summary of all NMR measurements

Figure 2. Pyranoses and pendant chains hydration dependency on MS/DS: HPC-L (blue), HPC-SSL (red)