Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40506, USA.
J Pharm Sci. 2013 May;102(5):1544-53. doi: 10.1002/jps.23498. Epub 2013 Mar 11.
This study compares the kinetics of crystal growth of indomethacin from supersaturated suspensions at varying degrees of supersaturation (2 ≤ S ≥ 9) in the presence of seed crystals of the γ-form of indomethacin, the lowest energy polymorph. At high S (6 ≤ S ≥ 9), the crystal growth was first order with rate coefficients (kG ) that were nearly constant and consistent with the value predicted for bulk-diffusion control. At lower S (<6), kG values were significantly smaller, decreasing approximately linearly with a decrease in S. The decline in kG at low S was attributed to a prolonged period during the initial stages of crystal growth in which surface integration was rate limiting. The apparent solubility of indomethacin after crystal growth for 3 days increased by ∼1.6-fold at both low (S = 2) and high (S = 6) degrees of supersaturation suggesting that a higher energy surface layer was deposited on the γ-form seed crystals during crystal growth. When growth experiments were repeated at low S in the presence of indomethacin seed crystals isolated from a previous crystal growth experiment (i.e., seed crystals having higher energy surface), kG matched the higher values observed for bulk diffusion-controlled crystal growth. Crystal growth experiments were also conducted at S < 1.6 using a constant infusion of an indomethacin solution in the presence of γ-form seed crystals to obtain kG under conditions where deposition of a higher energy surface could not occur. At these conditions, the smaller value of kG indicative of surface integration control was again observed and the apparent solubility of indomethacin after crystal growth matched that of the γ-form. A quantitative mechanistic understanding of the crystal growth kinetics of indomethacin derived from experiments at high and low S may be useful in future studies aimed at understanding the inhibitory effects of pharmaceutical excipients on the crystal growth of poorly soluble compounds and their utility in maintaining drug supersaturation during oral absorption.
本研究比较了在γ-吲哚美辛晶种存在下，不同过饱和度（2≤S≥9）下的吲哚美辛过饱和悬浮液中晶体生长的动力学。γ-吲哚美辛是能量最低的多晶型物。在高过饱和度（6≤S≥9）下，晶体生长呈一级反应，速率系数（kG）几乎恒定，与体扩散控制预测值一致。在较低过饱和度（<6）下，kG 值显著较小，随过饱和度的降低呈近似线性下降。低过饱和度下 kG 的下降归因于晶体生长初始阶段表面整合速率限制的延长。晶体生长 3 天后，在低（S=2）和高（S=6）过饱和度下，吲哚美辛的表观溶解度分别增加了约 1.6 倍，这表明在晶体生长过程中，γ-晶种表面沉积了更高能量的表面层。当在低过饱和度下重复进行生长实验时，在先前的晶体生长实验中分离得到的吲哚美辛晶种（即具有更高能量表面的晶种）的存在下，kG 与体扩散控制的晶体生长观察到的更高值相匹配。在低过饱和度下（S<1.6），通过在γ-晶种存在下恒速输注吲哚美辛溶液进行晶体生长实验，以获得在不能发生更高能量表面沉积的条件下的 kG。在这些条件下，再次观察到较小的 kG 值表明表面整合控制，并且晶体生长后的吲哚美辛表观溶解度与γ-晶型相匹配。对高过饱和度和低过饱和度下的实验进行定量的晶体生长动力学研究，可能有助于未来研究理解药用辅料对低溶解度化合物晶体生长的抑制作用及其在口服吸收过程中维持药物过饱和度的应用。
