Crystallization and Solid-State Characterization of the Hemihydrate of Albuterol Hemisulfate

Comprehensive
solid-state characterization and development of a
controlled crystallization process of the recently discovered hemihydrate
of albuterol hemisulfate (ASH) are presented. The ASH is physically
stable when stored at ambient conditions for at least 3 months and
at 0% relative humidity for at least 2 months. The thermal dehydration
of the hydrate occurs at ∼100 °C and proceeds without
a loss of crystallinity. The dehydrated crystal structure persists
up to decomposition temperature (∼160–185 °C).
An inspection of the single-crystal X-ray structure revealed an isolated-site
(class A) hydrate with a complex three-dimensional supramolecular
network sustained via multiple strong hydrogen bonds. Thermodynamic
stability studies established that the hydrate is more-stable relative
to the nonsolvated form at aw > 0.63
at
5 °C, aw > 0.65 at 20 °C,
and aw > 0.80 at 40 °C. The constructed
phase
diagram for the anhydrate–hydrate system guided the development
of a controlled crystallization process at a 0.5 g scale with a yield
of ∼92 wt % using a combination of cooling and antisolvent
addition crystallizations.

本研究针对新近发现的沙丁胺醇半硫酸盐半水合物（albuterol hemisulfate hemihydrate，ASH）开展了全面的固态表征，并开发了其可控结晶工艺。该ASH在室温环境条件下储存至少3个月、相对湿度为0%的环境中储存至少2个月时，均保持良好的物理稳定性。该水合物的热脱水过程发生于约100 ℃，且进行过程中无结晶度损失；脱水后的晶体结构可稳定维持至分解温度（约160~185 ℃）。对其单晶X射线衍射结构的解析结果显示，该水合物属于孤立位点型（A型）水合物，其通过多重强氢键作用构筑形成复杂的三维超分子网络。热力学稳定性研究表明，相较于无溶剂化物形式，该水合物在水分活度（water activity, a_w）大于0.63（5 ℃）、大于0.65（20 ℃）及大于0.80（40 ℃）时具有更高的稳定性。通过构建的无水合物-水合物体系相图，指导开发了0.5 g级别的可控结晶工艺，采用冷却结晶与反溶剂添加结晶联用的方式，产物收率可达约92 wt%。