(T1330-12-83) Role of Polymers in the Physical and Chemical Stability of Amorphous Solid Dispersion: A Case Study of Carbamazepine

Purpose: Amorphous solid dispersion (ASD) has emerged as a popular approach for enhancing the solubility of poorly water-soluble active pharmaceutical ingredients (APIs). The choice of polymer plays a crucial role in maintaining the physical stability of ASDs by preventing the recrystallization of the amorphous API. Strong intermolecular interactions between the drug and polymer, such as ionic interactions or hydrogen bonding, can effectively stabilize the amorphous drug. However, it should be noted that amorphous compounds are more susceptible to chemical degradation compared to their crystalline counterparts due to their higher mobility. Therefore, the objective of this study is to investigate the impact of different polymers on the chemical and physical stability of carbamazepine (CBZ), a model compound.

Methods: CBZ ASDs were prepared using rotary evaporation with four different polymers: polyvinylpyrrolidone (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA), polyacrylic acid (PAA), and hydroxypropyl methylcellulose (HPMCAS), at a drug-to-polymer ratio of 1:1 (w/w). The ASDs were characterized using X-ray diffractometry (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The strength of drug-polymer interactions was analyzed using Fourier transform infrared (FTIR) spectroscopy. The dissolution performance of the ASDs was evaluated under sink conditions, and the chemical degradation of CBZ was monitored during storage under dry conditions at 40°C and 75% RH.

Results: XRD and DSC analysis confirmed the amorphous nature of all the prepared ASDs, except for the HPMCAS system. The dissolution studies revealed a rapid release of the drug from all ASDs, except for HPMCAS. FTIR spectroscopy demonstrated that the interaction between CBZ and PAA was the strongest among all the ASDs, attributed to the acidic nature of PAA, which formed strong hydrogen bonds with CBZ. Additionally, hydrophobic interactions were observed between CBZ and HPMCAS. Under stability testing conditions (40°C/75% RH for 8 weeks), CBZ-PAA and CBZ-HPMCAS ASDs exhibited better physical stability compared to CBZ-PVP and CBZ-PVPVA ASDs. However, CBZ-PAA ASD showed chemical degradation due to the acidic microenvironmental pH created by PAA, which was further supported by TGA results.

Conclusion: This study highlights the importance of strong intermolecular interactions between CBZ and polymers in maintaining the physical stability of ASDs. It also emphasizes the need to consider the potential for chemical degradation when selecting an acidic polymer, as it can create an acidic microenvironment that leads to degradation. Achieving a balance between promoting physical stability and ensuring chemical stability is crucial when choosing a polymer for ASD formulation.