(M1430-05-25) Hydrolysis of Cellulose Acetate Phthalate and Hydroxypropyl Methylcellulose Phthalate in Amorphous Solid Dispersions

Purpose: The preparation of amorphous solid dispersions (ASDs) represents a promising strategy for addressing the solubility limitations of poorly soluble drugs, facilitating enhanced absorption. Acidic polymers such as cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose phthalate (HPMCP) have emerged as effective carriers for ASDs. This research aimed to explore the potential hydrolysis of CAP and HPMCP and how it influences the stability of ASDs containing ketoconazole (KTZ), at drug loadings of 10% and 50%.

Methods: Sample Preparation: Amorphous KTZ was prepared by melting the crystalline drug at 157 °C (5 °C higher than the melting point), followed by rapid cooling in liquid nitrogen. ASDs for stability testing were prepared using the GeneVac EZ-2 Plus evaporator (SP Scientific, PA). ASD Characterization: Differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), p</span>owder X-ray diffractometry (PXRD), and Infrared spectroscopy were conducted for ASD analysis. Stability Tests: The prepared amorphous samples were stored under the following conditions: (i) 60 °C, dry condition. (ii) 60 °C, 30% RH. (iii and iv) 45 and 60 °C, 75% RH. For the dry conditions, the samples were stored in desiccators containing anhydrite calcium sulfate. Saturated magnesium chloride and sodium chloride solutions were used to produce RH at 30 and 75%, respectively. At each predetermined time point, the physical form and water content were characterized. Moreover, the content of KTZ and free PA were quantified using the UPLC.

Results: ASD Characterization: The amorphous state of the prepared samples was identified using PXRD, wherein diffraction peaks of the crystalline drug were not observed. IR results suggest weak interactions between KTZ and HPMCP. However, the results show that in the 50-50 CAP ASD, compared to the relevant physical mixture, the IR peak assigned to C=O stretching shifted to a higher wavenumber, indicating the impact of KTZ on the dimerization of the carboxylic acid groups of the polymer, meaning the drug is dispersed effectively in the polymer matrix. Physical Stability: Amorphous KTZ (without polymer) recrystallized after one day under all different conditions. Interestingly, while the ASD with 50% drug loading remained amorphous after 60 days, diffraction peaks were observed in the X-ray patterns of the samples with 10% KTZ. The diffraction peaks were attributed to phthalic acid (PA), resulting from the hydrolytic degradation of the polymers, rather than KTZ recrystallization. However, it is worth noticing that PA could also be present in an amorphous state. Chemical Stability: By conducting an HPLC study to quantify PA release and KTZ degradation, we found that the PA content in CAP displayed a more pronounced increase compared to HPMCP. Moreover, the hydrolysis of the polymers appears to be more pronounced at higher temperatures and humidity (Figure 1). The hydrolysis of CAP and HPMCP accelerated the degradation of amorphous KTZ, with the mechanism illustrated in Figure 2. Furthermore, the degradation of KTZ does not follow a linear relationship with the detected PA concentration when comparing ASDs at the same drug loading but different polymer types. This may suggest that PA alone is not the sole factor responsible for KTZ degradation. For example, the acidic microenvironment provided by the polymer, even in the absence of free PA, could induce KTZ degradation.

Conclusion: CAP and HPMCP, two cellulose polymers with phthalate substituents, exhibit a notable propensity for hydrolysis. The hydrolytic degradation of these polymers in their ASD matrices produces PA, which can lead to drug degradation. The current study underscores the crucial role of polymers in ASDs: while they contribute to the physical stability of amorphous pharmaceuticals, they also have the potential to induce chemical degradation of the drug.


Graphics abstract


Figure 1: Amount of phthalic acid in CAP (red) and HPMCP (blue) ASDs during storage at 40 °C/75% RH (a), 60 °C dry (b), 60 °C/30% RH (c) and 60 °C/75% RH (d). The results of polymer alone, ASDs with 10% and 50% drug loading are shown in solid squares, circles and triangles, in either red and blue, respectively.


Figure 2: Degradation mechanism of CAP, HPMCP and KTZ in their ASDs.