(T1230-04-19) Insights into the Impact of Interplay of Drug Loading and Buffer Capacity on the Release of Hydroxypropyl Methyl Cellulose Acetate Succinate (HPMCAS)-Based Dispersions

Purpose: Enteric polymers such as hydroxypropyl methyl cellulose acetate succinate (HPMCAS) have been shown to have a decreased pH near the polymer-water interface (unstirred water layer) compared to the bulk solution pH as a result of protons liberated during ionization of carboxylicacid groups. The impact of buffer capacity on minimizing the unstirred water layer pH gradient is well established in context of enteric-coated tablet dissolution. However, a comprehensive understanding of the combined impact of pH and buffer capacity variations on amorphous solid dispersion (ASD) dissolution is lacking. In an ASD, drug is molecularly dispersed within the polymer matrix, in contrast to an enteric coating. It is expected that the drug loading in an enteric polymer-based ASD will impact release of both drug and polymer as a function of medium pH and buffer capacity. The objective of this study was to gain insight into the rate limiting processes with respect to solution medium composition and drug loading. The ultimate goal is to optimize the maximum drug loading without sacrificing release performance, as well as to inform in vitro tests that better translate into the in vivo environment.

Methods: ASDs of indomethacin (IND) and its analog, indomethacin methyl ester (INDester), with HPMCAS were prepared by rotary evaporation at various drug loadings. The resultant ASDs were dried overnight in vacuum, cryomilled and sieved (desired particle size of 106- 250µm). The amorphous nature of the ASD was confirmed using powder x-ray diffraction (PXRD) and polarized light microscopy (PLM). Surface normalized dissolution experiments were performed at 37°C in a Wood’s intrinsic dissolution rate apparatus where only one face of the tablet is exposed to the dissolution medium, maintaining a constant surface area throughout the dissolution experiment. Medium buffer capacities in the range of 3mM/∆pH to 51mM/∆pH were studied to include in vivo-relevant buffer capacities (4-10mM/∆pH) as well as that of a commonly used dissolution medium, 50 mM phosphate buffer (corresponding to buffer capacity of 26mM/∆pH at pH 6.8). A UV-visible spectroscopy method was developed using chlorophenol red for quantifying the pH in the gel layer of the polymer at different buffer capacities. The dissolution experiments were performed in fasted state simulated intestinal fluid (FaSSIF) (pH 6.5) and fed state simulated intestinal fluid (FeSSIF) (pH 5.8) with buffer capacities of 12mM/∆pH and 25mM/∆pH respectively to understand the relative effects of buffer capacity, pH as well as the bile salts and digestive components.

Results: In dissolution experiments across all buffer capacities, drug and polymer released at similar normalized release rates indicating the release process was controlled by the polymer. Neat HPMCAS and ASDs showed a similar pattern of a linear increase in the normalized release rates up to a buffer capacity of 26mM/∆pH at pH 6.8, beyond which a near-plateau was observed. At the plateau buffer capacity (51mM/∆pH), an increase in pH from 6.8 to 9 did not increase the release of the polymer suggesting the unstirred water layer pH gradients are not controlling the release. The release pattern at different buffer capacities appeared to be controlled by the gel layer pH which increased up to 26mM/∆pH and then reaching a plateau. The ASDs showed comparable dissolution rates in FaSSIF (pH 6.5, buffer capacity of 12mM/∆pH) and in pH 6.8 phosphate buffer with buffer capacity of 11mM/∆pH indicating a negligible impact of bile salts and digestive components on the release. Neat HPMCAS showed comparable normalized release rates in FaSSIF (pH 6.5 and buffer capacity 12mM/∆pH) and in FeSSIF (pH 5.8, buffer capacity 25mM/∆pH) indicating that although the buffer capacity was high in case of FeSSIF, the pH was too low for complete polymer ionization. At some point between pH of 5.8 to 6.5 and beyond buffer capacity of 26mM/∆pH, neither gel layer pH nor buffer capacity altered the release suggesting a switch in the rate limiting mechanism. At low buffer capacities, buffer capacity controlled release. At higher buffer capacities, sufficient buffer capacity was achieved, and the presence of the drug had a greater impact on polymer release. Importantly, FaSSIF or in vivo buffer capacities showed less impact of drug loading, whereas drug loading effects were more apparent at higher buffer capacity.

Conclusion: Based on pH and buffer capacity of the medium, different mechanisms controlled the release at various drug loadings and these variations should be reflected while designing in vitro tests for enteric-polymer based ASDs.

References: 1. Harianawala et al., Int. J. Pharm., 2002, 247(1), 139-147.
2. Spitael et al., Pharm Ind. 1977;39(5):502-505.
3. Ozturk at al., Pharm Res. 1988;5(9):550-565.


Figure 1 Pattern of neat HPMCAS release in medium of various pH and buffer capacities.


Figure 2 HPMCAS release from neat polymer and ASDs at two drug loadings indicating two regions, one
where gel layer pH controlled the release and another around the plateau where the physicochemical
properties of drugs mainly controlled the polymer release.


Figure 3 Neat HPMCAS and ASDs release in FaSSIF.