(W1030-09-60) Effect of Polymer Architecture on Crystal Growth in Amorphous Nifedipine: Bottlebrush vs. Linear Polymers PEGs

Purpose: To study the influence of polymer architecture on bulk crystal growth in amorphous pharmaceuticals, which are being investigated for delivering poorly aqueous soluble drugs and must resist crystallization in this role. Recent studies have shown that bottlebrush polymers can enhance apparent solubility and dissolution rate of poorly soluble drugs through post-polymerization end group modification. To enable efficient design of robust amorphous pharmaceutical products incorporating bottlebrush excipients, it is essential to investigate their impact on the crystallization kinetics of amorphous drugs, as crystallization during storage can compromise the solubility advantage that amorphous forms have over their crystalline counterparts.

Methods: Three bottlebrush PEGs (BB PEGs) with varying backbone degrees of polymerization (6.0, 56.6, and 107.6), referred as BB5, BB50, and BB100, were synthesized via ring-opening metathesis polymerization (ROMP). Bulk crystal growth rates were measured in nifedipine liquid/glass doped with these three synthesized BB PEGs, as well as a linear PEG with molecular weight equivalent to that of BB PEG side chain, using thermal stage microscopy.

Results: The bottlebrush architecture has a smaller impact on crystal growth kinetics compared to linear polymers, likely due to restricted segmental dynamics. As the backbone degree of polymerization increases, the perturbation to growth kinetics decreases.

Conclusion: Linear PEG accelerates crystal growth in nifedipine liquid/glass more effectively than bottlebrush PEGs. The effectiveness of crystallization modification by bottlebrush polymers depends on the backbone degree of polymerization.

References: M. L. Ohnsorg, P. C. Prendergast, L. L. Robinson, M. R. Bockman, F. S. Bates, T. M. Reineke "Bottlebrush Polymer Excipients Enhance Drug Solubility: Influence of End-Group Hydrophilicity and Thermoresponsiveness," ACS Macro Lett., 2021, 10, 3, 375–381.

Synthesis Route to bottlebrush PEGs.

Illustration of typical growth rate measurements: (a) NIF crystals without or with BB5 after various growth times at 313 K; and (b) NIF without or with BB5 crystal growth distance versus time, where the slope represents the growth rate.

Crystal growth rates of NIF in the presence of L1000 (linear PEG), BB5, BB50, and BB100 at (a) 303 K; (b) 313 K; and (c) 323 K.