(T1130-03-21) From Disorder to Order: Structural Evolution of Solid-State Phases in Pravastatin Sodium via a Liquid Crystalline State

Purpose: Liquid crystals (LCs) exhibit a fascinating duality, flowing like a liquid while maintaining the ordered alignment of crystals. Triggered by temperature or electric fields, their self-organizing behavior makes them compelling in pharmaceutics. Moreover, liquid crystal-like behavior is often observed in pharmaceuticals but is frequently overlooked and misclassified as amorphous. To fully leverage LCs, it is critical to investigate transitional states that bridge amorphous and crystalline phases. This study explores how temperature and humidity guide the structural evolution of liquid crystalline phases in pravastatin sodium (PS). Through controlled conditions and polymorph surface analysis, we aim to uncover molecular-level insights that may redefine how APIs are stabilized and formulated.

Methods: Amorphous PS was obtained by heating at ~180°C, while Form D was generated from other forms by heating any PS forms at 100°C. Forms E, F, C, and the hydrated crystal β (Hc β) were obtained by storing samples under various stability conditions (25°C/97% RH, 40°C/0% RH, and 40°C/75% RH). In addition, the hydrated crystal α (Hc α) was produced through a slurry process, and subsequent storage at room temperature led to the formation of Form E crystal. Solid-state characteristics, including crystal structure and molecular arrangement of the amorphous, liquid crystalline, and crystalline forms, were analyzed using PXRD, TGA, SAXS, polarized microscopy, and SEM. In particular, structural analyses were conducted using PXRD, Variable Temperature (VT)-XRD, and SAXS.

Results: PS exhibited diverse physical forms under storage conditions (RT, 25 °C/60% RH, 25 °C/97% RH, 40 °C/0% RH, 40 °C/75% RH), heating, and slurry methods. The amorphous form was obtained by heating all forms at ~180 °C. Form D, a thermotropic liquid crystal, formed at 100 °C from all other forms (except amorphous) and showed four broad peaks. Form F, stored at 40 °C/0% RH from Form E or Hc α, displayed a sharp peak with an amorphous halo. Form D stayed stable at 40 °C/0% RH, while Form F reverted to Form D upon heating. Interestingly, VT-XRD analysis demonstrated that Form D remains stable at temperatures exceeding 180°C, particularly for the high-humidity forms, Hc α and Hc β. LCs-related forms exhibited birefringence, and SEM showed distinct surface morphologies.

Conclusion: Pravastatin sodium undergoes a dynamic transformation across solid-state phases—transitioning from amorphous to liquid crystalline, and ultimately to crystalline structures. These changes, driven by temperature and humidity, reveal a transitional mesophase that plays a pivotal role in molecular organization. By characterizing these transitions, this study provides new insight into the structural evolution of pharmaceutical solids, emphasizing the importance of liquid crystalline states as bridges between disorder and order. These findings contribute to a deeper understanding of API behavior, supporting more precise control in formulation development.

Acknowledgements: This research was supported by a grant of the Korea Machine Learning Ledger Orchestration for Drug Discovery Project(K-MELLODDY), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea (grant number: RS-2024-00461138)


Figure. Polymorphic Transition Diagram; relationships between Pravastatin sodium polymorphs under various relative humidity and temperature conditions