The influence of moisture on the storage stability of co-amorphous systems
Co-amorphization has been utilized to improve the physical stability of the respective neat amorphous drugs. However, physical stability of co-amorphous systems is mostly investigated under dry conditions, leaving the potential influence of moisture on storage stability unclear. In this study, carvedilol-L-aspartic acid (CAR-ASP) co-amorphous systems at CAR to ASP molar ratios from 3:1 to 1:3 were investigated under non-dry conditions at two temperatures, i.e., 25 °C 55%RH and 40 °C 55%RH.
Under these conditions, the highest physical stability of CAR-ASP systems was observed at the 1:1 molar ratio. This finding differed from the optimal molar ratio previously obtained under dry conditions (CAR-ASP 1:1.5). Molecular interactions between CAR and ASP were affected by moisture, and salt disproportionation occurred during storage. Morphological differences of systems at different molar ratios could be observed already after one week of storage.
Furthermore, variable temperature X-ray powder diffraction measurements showed that excess CAR or excess ASP, existing in the binary systems, resulted in a faster recrystallization compared to equimolar system. Overall, this study emphasizes the influence of moisture on co-amorphous systems during storage, and provides options to determine the optimal ratio of co-amorphous systems in presence of moisture at comparatively short storage times.
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Introduction: Aqueous solubility of active pharmaceutical ingredients is a critical drug property that needs to be considered in the development of oral drug delivery formulations since poor aqueous solubility often results in a low and variable oral absorption, and thus a low and variable bioavailability with a potentially limited pharmacological effect (Babu and Nangia, 2011; Savjani et al., 2012). The use of amorphous forms of drug candidates is a promising approach to overcome this poor aqueous solubility challenge (Bikiaris, 2011; Grohganz et al., 2013; Kawabata et al., 2011). Amorphous forms exhibit higher internal energy and reactivity compared with their crystalline counterparts (Hancock and Zografi, 1997). Therefore, a drug in an amorphous form potentially provides an increased dissolution rate and an improved apparent solubility compared with the respective crystalline state(s) (Laitinen et al., 2017). However, the amorphous form is thermodynamically unstable, and as a result tends to undergo spontaneous recrystallization, leading to a risk in formulation development with regard to the drug’s physical instability (Korhonen et al., 2017).
Co-amorphization has been developed as a suitable method to stabilize the inherently unstable amorphous form of drugs (Dengale et al., 2016; Laitinen et al., 2013). In co-amorphous systems, two or more, initially crystalline, low-molecular weight components form a homogeneous singlephase amorphous mixture upon processing (Dengale et al., 2016; Liu et al., 2021). Different stabilization mechanisms of co-amorphous systems have been identified, including molecular interactions between the drug and the co-former, intimate molecular-level mixing and an elevated glass transition temperature (Tg) compared to the pure drug (Dengale et al., 2014; Han et al., 2020; Löbmann et al., 2013; Löbmann et al., 2012). Most physical stability tests of co-amorphous systems reported in the scientific literature were conducted at dry conditions, whilst only 18.7% of the totally studied co-amorphous systems also cover physical stability under humid conditions (Liu et al., 2021). Under humid storage conditions, moisture can be absorbed by the co-amorphous system and influence the various contributors to stabilization by disturbing molecular interactions, reducing the Tg, increasing molecular mobility and promoting amorphous-amorphous phase separation and recrystallization (Andronis et al., 1997; Jensen et al., 2016; Rumondor and Taylor, 2010).
In addition, the optimal molar ratio to achieve the highest physical stability in coamorphous systems closely links to these stabilization contributors, thus it is reasonable to assume that the optimal molar ratio to achieve the highest physical stability could also be affected by moisture. Therefore, it is of importance to expand the investigations of co-amorphous systems towards storage under elevated, i.e., more humid conditions. In this study, carvedilol (CAR) and L-aspartic acid (ASP) were chosen as the model drug and the co-former, respectively. The findings for co-amorphous CAR-ASP systems under dry storage conditions reported in our previous study can provide a comprehensive comparison with the results obtained under elevated storage conditions (Liu et al., 2020a). In CAR-ASP co-amorphous systems, salt formation was expected to occur between CAR and ASP at the 1:1 molar ratio based on their chemical structures. However, the optimal molar ratio to achieve the highest physical stability was found for the CAR-ASP 1:1.5 system under dry storage conditions (Liu et al., 2020a).
Therefore, samples with different CAR to ASP molar ratios (3:1, 2:1, 1:1, 1:1.5, 1:2 and 1:3) were prepared by spray drying in the current study. After preparation, the samples were stored at two conditions, i.e., 25 °C 55%RH and 40 °C 55%RH. X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA) and scanning electron microscopy (SEM) were performed to track physical stability, water content and morphology changes of the co-amorphous systems during storage. In order to obtain a deeper understanding of the systems’ behavior, modulated differential scanning calorimetry (mDSC), Fourier-transformed infrared spectroscopy (FTIR) and variable temperature XRPD (vtXRPD) measurements of samples before and after one week of storage under elevated conditions were also conducted.
Article information: Jingwen Liu, Thomas Rades, Holger Grohganz. The influence of moisture on the storage stability of co-amorphous systems, International Journal of Pharmaceutics, 2021. https://doi.org/10.1016/j.ijpharm.2021.120802.