The formation and stability of fluoxetine HCl cocrystals investigated by multicomponent milling
The formation and stability of fluoxetine HCl cocrystals investigated by multicomponent milling
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多组分研磨研究盐酸氟西汀共晶的形成和稳定性
DOI：
10.1039/d2ce01341j
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发表时间：
2023
期刊：
影响因子：
3.1
通讯作者：
Schurko, Robert W.
中科院分区：
文献类型：
--
作者：
Peach, Austin A.;Holmes, Sean T.;MacGillivray, Leonard R.;Schurko, Robert W.
竞争性研磨（CM）和稳定性研磨（SM）机械化学反应用于全面评估氟西汀盐酸盐（X）的三种药物共晶（PCC）与三种不同的药学上可接受的共形成物（PAC，即，苯甲酸（B）、富马酸（F）和琥珀酸（S））。CM反应，其中涉及在两种或更多种不同的PAC的存在下研磨X，用于确定共结晶亲和力，而SM反应，其中涉及研磨X的PCC与不同的共形成物，用于确定相对热力学稳定性。在某些情况下，SM反应表现出显着的固态交换的共形成物，产生新的共晶形式。35 Cl（自旋I = 3/2）SSNMR用作CM和SM反应产物的主要探针，提供了鉴定和定量每种反应混合物中独特氢键环境中氯离子的可靠方法（13 C SSNMR光谱和pXRD图谱用于支持这些数据）。基于这些反应和数据，PAC与X的共结晶亲和力为B > F → S（最优选到最不优选），PCC稳定性为XB > X2 F → X2 S（最优选到最不优选），对应于共结晶的能力等级为Δ HCCX B <λ。发现PAC亲和力和PCC稳定性对于类似的缓慢蒸发实验和具有延长的研磨时间的机械化学反应的产物是相同的（即，90分钟）。初步的平面波DFT-D2* 计算支持共晶形成，然而，共晶的相对结晶度的定量仍然存在挑战。这项工作证明了CM和SM反应的巨大潜力，为合理设计、发现和生产新的共晶形式的API提供了途径。
Competitive milling (CM) and stability milling (SM) mechanochemical reactions are used to comprehensively assess the relative thermodynamic stabilities and cocrystallization affinities of three pharmaceutical cocrystals (PCCs) of fluoxetine HCl (X) with three different pharmaceutically acceptable coformers (PACs, i.e., benzoic acid (B), fumaric acid (F), and succinic acid (S)). CM reactions, which involve milling X in the presence of two or more different PACs, were used to determine cocrystallization affinities, whereas SM reactions, which involve milling a PCC of X with a different coformer, were used to determine relative thermodynamic stabilities. In certain cases, SM reactions exhibited a remarkable solid-state exchange of coformers, yielding new cocrystalline forms. 35Cl (spin I = 3/2) SSNMR is used as the primary probe of the products of CM and SM reactions, providing a reliable means of identifying and quantifying chloride ions in unique hydrogen bonding environments in each reaction mixture (13C SSNMR spectra and pXRD patterns are used in support of these data). On the basis of these reactions and data, the PAC cocrystallization affinities with X are B > F ≈ S (most to least preferred), and the PCC stabilities are XB > X2F ≈ X2S (most to least preferred), corresponding to enthalpies of cocrystallization ranked as ΔHCCXB < ≈ . PAC affinities and PCC stabilities were found to be the same for products of analogous slow evaporation experiments and mechanochemical reactions with extended milling times (i.e., 90 minutes). Preliminary plane-wave DFT-D2* calculations are supportive of cocrystal formation; however, challenges remain for the quantification of relative enthalpies of cocrystallization. This work demonstrates the great potential of CM and SM reactions for providing pathways to the rational design, discovery, and manufacture of new cocrystalline forms of APIs.
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DOI：
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Pharmaceutical development and technology (Print)
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