Prehydration and the Reversibility of Solid-State Hydrogen-Deuterium Exchange.,Molecular Pharmaceutics

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Prehydration and the Reversibility of Solid-State Hydrogen-Deuterium Exchange.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-07-28 , DOI: 10.1021/acs.molpharmaceut.0c00571
Rajashekar Kammari ₁ , Elizabeth M Topp _{1,

2}

Affiliation

The reversibility of solid-state hydrogen–deuterium exchange (ssHDX) and the effects of prehydration on the rate and extent of deuterium incorporation were evaluated using poly-d,l-alanine (PDLA) peptides colyophilized with various excipients. In prehydration studies, samples were equilibrated at a controlled relative humidity (6% or 11% RH) for 12 h and then transferred to corresponding D₂O humidity conditions (6% or 11% RD) for deuterium labeling. In amorphous samples, the rate and extent of deuterium incorporation were similar in prehydrated samples and controls not subjected to prehydration. In reversibility studies, PDLA samples were maximally deuterated in controlled D₂O humidity conditions (6% or 11% RD) and then transferred to corresponding H₂O relative humidity (0%, 6%, 11%, or 43% RH). Hysteresis in deuterium removal was observed when compared with the deuterium incorporation kinetics for all formulations and conditions, confirming that the reaction is reversible in the solid state and that the forward and reverse processes differ. The extent of deuterium loss reached a plateau that depended on the delabeling relative humidity. Reverse reaction rate constants were quantified using a first-order kinetic model, a limiting case of the reversible first-order model applicable under sink conditions. For other conditions, plateau (steady-state) deuteration levels were related to forward and reverse rate constants in a reversible first-order kinetic model. The results support a mechanistic interpretation of ssHDX kinetics as a reversible first-order process, in which the forward (deuteration) rate depends on the activity of the deuterium donor.

中文翻译：

固态氢-氘交换的预水合和可逆性。

使用聚固态氢-氘交换（ssHDX）和预水化对速率和氘掺入的程度的影响的可逆性进行评价d，升丙氨酸（PDLA）与各种赋形剂colyophilized肽。在预水合研究中，将样品在受控的相对湿度（6％或11％RH）下平衡12 h，然后转移到相应的D ₂ O湿度条件下（6％或11％RD）进行氘标记。在无定形样品中，氘的掺入速率和程度在预水合的样品和未进行预水合的对照中相似。在可逆性研究中，PDLA样品在受控D ₂中最大程度地氘化O湿度条件（RD或6％或11％），然后转移到相应的H ₂O相对湿度（0％，6％，11％或43％RH）。当与所有制剂和条件的氘掺入动力学相比时，观察到氘去除的滞后现象，证实了该反应在固态下是可逆的，并且正向和反向过程不同。氘流失的程度达到了一个平台，这取决于取消标记的相对湿度。使用一级动力学模型对逆反应速率常数进行定量，这是可逆的一级模型在水槽条件下适用的一种极限情况。对于其他条件，在可逆的一级动力学模型中，平稳（稳态）氘化水平与正向和反向速率常数相关。结果支持对ssHDX动力学进行可逆的一阶过程的机械解释，

更新日期：2020-09-09

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