Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs,Reaction Chemistry & Engineering

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Continuous reactive crystallization of an API in PFR-CSTR cascade with in-line PATs
Reaction Chemistry & Engineering ( IF 3.4 ) Pub Date : 2020-08-21 , DOI: 10.1039/d0re00216j
Chuntian Hu _{1,

2,

3} , Brianna T. Shores _{1,

2,

3} , Rachel A. Derech _{1,

2,

3} , Christopher J. Testa _{1,

2,

3} , Paul Hermant _{1,

2,

3} , Wei Wu _{1,

2,

3} , Khrystyna Shvedova _{1,

2,

3} , Anjana Ramnath _{1,

2,

3} , Liyutha Q. Al Ismaili _{1,

2,

3} , Qinglin Su _{1,

2,

3} , Ridade Sayin _{1,

2,

3} , Stephen C. Born _{1,

2,

3} , Bayan Takizawa _{1,

2,

3} , Thomas F. O'Connor _{3,

4,

5} , Xiaochuan Yang _{3,

4,

5} , Sukumar Ramanujam _{6,

7,

8} , Salvatore Mascia _{1,

2,

3}

Affiliation

The continuous reactive crystallization of an active pharmaceutical ingredient (API) in a plug flow reactor (PFR)-continuous stirred tank reactor (CSTR) cascade system with in-line PATs was developed and investigated. Residence time distribution (RTD) measurements of the PFR (stage 1), the CSTR cascade (stages 2–6), and the combined PFR-CSTR cascade (stages 1–6) were performed to estimate the performance of the reactors. Several continuous reactive crystallization experiments were performed, and consistent reaction yields of 91.3 ± 0.5 and 89.6 ± 0.4% were obtained with and without the PFR, respectively. The integration of PFR (stage 1) created a very high level of supersaturation by itself, and ∼25% lower supersaturation and a 2.7% higher crystallization yield in the following vessel (stage 2). In stages 3–6, the supersaturation levels and crystallization yields were similar (with and without the PFR). With the PFR, the lower supersaturation in stage 2 resulted in lower nucleation rates and higher crystal growth rates, resulting in a larger crystal size distribution. Also, in-line ReactIR and focused beam reflectance measurement (FBRM) were used to monitor the reactant concentration and crystal chord length, respectively, during the reactive crystallization process. The ReactIR predicted reactant concentrations in the mother liquor that matched well with corresponding HPLC results (prediction error < 0.17%). The FBRM results showed a relatively stable mean square-weighted chord length of ∼150 μm. In addition, the process mass intensities (PMIs) for the batch process, the integrated continuous manufacturing (ICM) process without the PFR, and the ICM process with the PFR were 3.49, 1.99, and 1.97, respectively.

中文翻译：

具有串联PAT的PFR-CSTR级联反应中API的连续反应结晶

开发并研究了具有在线PAT的活塞流反应器（PFR）-连续搅拌釜反应器（CSTR）级联系统中活性药物成分（API）的连续反应结晶。对PFR（阶段1），CSTR级联（阶段2-6）和组合的PFR-CSTR级联（阶段1-6）进行停留时间分布（RTD）测量，以估算反应堆的性能。进行了几个连续的反应性结晶实验，使用和不使用PFR的反应产率分别为91.3±0.5％和89.6±0.4％。PFR的整合（阶段1）本身产生了很高的过饱和度，在随后的容器（阶段2）中，过饱和度降低了约25％，结晶产率提高了2.7％。在第3-6阶段，过饱和水平和结晶产率相似（有和没有PFR）。使用PFR，阶段2中较低的过饱和度导致较低的成核速率和较高的晶体生长速率，从而导致较大的晶体尺寸分布。同样，在反应结晶过程中，使用在线ReactIR和聚焦光束反射率测量（FBRM）分别监测反应物浓度和晶体弦长。ReactIR预测母液中的反应物浓度与相应的HPLC结果非常吻合（预测误差<0.17％）。FBRM结果显示相对稳定的均方根弦长为〜150μm。此外，分批处理的过程质量强度（PMI），无PFR的集成连续制造（ICM）过程，

更新日期：2020-09-29

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