Purpose: Physical stability is a major concern in the development of amorphous solid dispersion (ASD). Moisture and temperature are the major factors which affect the stability of ASDs. The polymers used in ASD tend to absorb moisture from the atmosphere which acts as a potent plasticizer and decreases the glass transition temperature (Tg) of ASD. This can compromise the physical stability of ASD by causing amorphous-amorphous phase separation and/or crystallization of a drug from the polymer matrix. Here, we have conducted a systematic study of hygroscopicity of neat polymers and their ASDs and the plasticizing effect of absorbed moisture on their Tg.
Methods: ASDs of itraconazole (ITZ) and polymer (Kollidon®VA64, HPMCAS-MG, and HPMCP-HP50) were prepared by film casting technique. These ASDs were used for isotherm generation at 25°C and 40°C using dynamic vapor sorption (DVS) instrument (VTI-SA, TA Instruments, DE). To study the effect of moisture on the Tg of neat polymers and their ASDs, they were equilibrated at 40°C/75%RH using DVS and sealed hermetically immediately once removed from the DVS and subjected to modulated differential scanning calorimetry (MDSC). Long-term stability study of the ASDs was conducted at 40°C/75%RH for 1 month or until the phase separation of drug and polymer was observed.
Results: The order of hygroscopicity of ASD films (at both 25°C and 40°C) from higher to lower can be arranged as following: Kollidon®VA64: ITZ>HPMCP-HP50:ITZ>HPMCAS:ITZ (Figure 1). In all mentioned polymers and their ASDs, at constant RH, the amount of absorbed moisture decreased with increased isotherm temperature (Figure 1). Since ITZ is a hydrophobic drug and has low Tg (59°C), the hygroscopicity and Tg of all mentioned ASDs decreased as its fraction increased. The miscible ratios with maximum drug load were HPMCP-HP50:ITZ (4:6), HPMCAS-MG:ITZ (5:5) and Kollidon®VA64:ITZ (8:2) with respective Tg of 80°C, 82°C and 100°C (Figure 2). At 40°C/75%RH, HPMCP-HP50:ITZ (4:6), HPMCAS-MG:ITZ (5:5) and Kollidon®VA64:ITZ(8:2) absorbed around 1.69, 2.25 and 14.35%w/w moisture (Figure 1) which decreased their Tg to 53°C, 58°C and 22°C, respectively (Figure 2). The cellulose-based (HPMCAS-MG and HPMCP-HP50) ASDs were stable at 40°C/75%RH for 1 month since their lowest Tg (even after plasticization) were significantly above their storage temperature of 40°C while Kollidon®VA64:ITZ ASDs underwent amorphous-amorphous phase separation within one week since their Tg decreased to 22°C (due to absorbed moisture at 40°C/75%RH), which is below its storage temperature of 40°C (Figure 3).
Conclusion: The Tg of an ASD should be significantly above its storage temperature (even after its plasticization due to absorbed moisture from surrounding atmosphere) to ensure its long-term physical stability. The decrease in Tg of ASD can be quickly found out by equilibrating the sample at storage conditions using DVS and by subjecting to MDSC. Thereafter only those ASD samples whose Tg stays significantly above its intended storage temperature can be carried forward for formulation development. Thus, this approach can help to narrow down the promising polymeric carriers for ASDs in relatively quick manner, which can then be subjected to long-term stability study.