(M1330-12-83) Physical Stability of Amorphous Pharmaceutical Formulations Insights into Crystallization Behavior

Purpose: The pharmaceutical industry frequently encounters challenges due to the poor water solubility and bioavailability of new chemical entities. About 40% of marketed drugs and 90% of drugs in development fall into BCS class II or IV due to limited water solubility. To overcome this, the amorphous state of drugs, known for its enhanced dissolution and solubility compared to the crystalline state, holds promise as a solution for many drug candidates. Despite the advantages of amorphous formulations, their physical instability and tendency to recrystallize pose significant challenges.To stabilize the amorphous form, amorphous solid dispersions (ASDs) are created by adding polymers and other excipients. Yet, even with ASDs, slow recrystallization can occur during storage. However, our group observed an intriguing phenomenon: when the storage temperature is near or slightly below T_g (glass transition temperature), the crystallization rate, rather than decreasing, actually increased. This study aims to explore the crystallization behavior of drug-polymer ASDs under storage temperature (T) near the T_g. Indomethacin (IND) and polyvinylpyrrolidone (PVP) K12 ASD was used as the model ASD system for this study.

Methods: Melt-Quenching: ASDs of IND and PVP-K12 (50% - 99% drug loading) were prepared by a melt-quench and cryo-mill method. Physical mixtures were milled using a SPEX 6775 Cryogenic Grinder. IND sample was equilibrated to room temperature then melted in Teflon beakers at 190°C for 5 minutes. The molten sample was then placed directly into liquid nitrogen. The resulting glassy ASDs containing IND were lightly ground into a fine powder using a mortar and pestle. Differential scanning calorimetry (DSC): DSC experiments were performed to understand the T_g of ASDs using a Discovery TA 2500 DSC. The system was purged with 50 mL/min nitrogen gas and cooled with a RCS90 cooling accessory. Indium and sapphire were used to calibrate the DSC for temperature and heat capacity, respectively. 3 – 5mg of sample was placed in Tzero Hermetic Aluminum pans with a single pinhole. Powder X-ray Diffraction (PXRD): Samples were analyzed via PXRD for crystallization. The samples were scanned initially (before storage at elevated temperatures) and then periodically for upwards of three months using a Rigaku SmartLab diffractometer. Solid-state NMR (SSNMR): 2D SSNMR experiment will be done in the future to understand the intermolecular interaction in ASD. It might quantify the transitional/rotation movement of ASD.

Results: The DSC data showed a decrease in the T_g of IND-PVP ASD as the drug loading increased. The samples were stored in different T. The range of storage condition was between T/T_g = 0.88 to T/T_g = 1.1. The PXRD pattern confirmed that all initial samples were in the amorphous state. As the drug loading (DL) decreased below 90%, the crystallization rate increased with higher storage temperatures. However, when the DL equaled or exceeded 95%, the crystallization rate was observed to increase when storage temperature was closed to T_g. For example, 95%DL sample crystalized in 6 days when stored at T/T_g = 0.999 (store at T_g ) and crystalized in 62 days when it stored at T/T_g = 1.031. However, it crystalized in 12 days when it stored at T/T_g = 1.058. The sample didn’t crystalize in three months when it stored at T/T_g = 1.090. Similar trend was observed for 97%, 98%, 99% DL sample. The crystallization rate was increased when the storage temperature was closed to T_g.

Conclusion: In a crystal lattice, molecules, atoms, or ions are arranged in a repeating pattern, giving crystals their characteristic geometric shapes. To form a crystal, molecules must come together and lock into the proper orientation to build this regular arrangement. Nucleation is the initial formation of tiny crystal clusters (nuclei) from individual molecules or ions. The speed of nucleation determines the crystallization rate. Theoretically, the rate of crystallization was expected to decrease continuously through the glass transition as a reduction in molecular mobility creates conditions less favorable for nucleation and crystal growth. At storage temperatures higher than ASD's T_g, nucleation is diffusion-controlled, meaning the crystallization rate is influenced by translational motion. Molecules move rapidly, frequently interacting with each other in a dynamic manner. As the storage temperature approaches T_g, the overall process continues to be dominated by translational motion. However, with the decrease in translational motion, the molecules have a lower likelihood of meeting each other in the correct orientation, ultimately leading to a reduced crystallization rate. As the temperature approaches or slightly decreases below T_g, diffusionless crystallization becomes the predominant motion. In this process, molecules can change their orientation without undergoing diffusion away from one another. The rate of crystallization is now governed by rotational and vibrational motions. As the molecules cease to move away from each other and instead continue to rotate near each other, they have a higher probability of forming the correct orientation for crystallization. Consequently, this results in a faster crystallization rate compared to previous trends.

References: 1.Babu, N. J., & Nangia, A. (2011). Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Crystal Growth & Design, 11(7), 2662-2679.
2.Jarrells, T. W. (2022). "Investigating the Physical Stability of Amorphous Pharmaceutical Formulations."

50%-100% DL IND-PVP ASD Crystallization Onset

95%,97%,99% DL IND-PVP ASD Crystallization Onset

The mechanism of diffusion-controlled crystallization and diffusionless crystallization