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Investigation of Nucleation under High-Shear Conditions for a Pharmaceutical Compound in an Unseeded System
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2019-12-10 , DOI: 10.1021/acs.oprd.9b00155 Pablo M. Martin-Soladana 1 , Moiz Diwan 1 , Huayu Li 2 , Fredrik L. Nordstrom 2 , Ahmad Sheikh 1
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2019-12-10 , DOI: 10.1021/acs.oprd.9b00155 Pablo M. Martin-Soladana 1 , Moiz Diwan 1 , Huayu Li 2 , Fredrik L. Nordstrom 2 , Ahmad Sheikh 1
Affiliation
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The effect of in situ high energy mixing on primary nucleation of an active pharmaceutical compound (ABT-089) has been investigated by measuring the induction time for 1, 5, and 140 mL scales via different shear-inducing mechanisms, namely, magnetic stirrer, Couette device, and high-shear rotor–stator mixer known as wet-mill in pharmaceutical industry. Experiments performed on previously untested scale and equipment show that the onset time of nucleation decreases with an increase in average energy input per unit volume of the solution (i.e., specific energy input) as previously reported (Liu, J.; Svard, M.; Rasmuson, Å.C. Influence of Agitation on Primary Nucleation in Stirred Tank Crystallizers, Cryst. Growth Des. 2015, 15, 4177–4184). The variability in the induction time is found to decrease with an increase in volume and specific energy input. Studies at different scales are compared using the Rasmuson (Liu, J.; Svard, M.; Rasmuson, ÅC. Influence of Agitation on Primary Nucleation in Stirred Tank Crystallizers, Cryst. Growth Des. 2015, 15, 4177–4184) approach based on the classical nucleation theory. It is shown that the effect of specific energy input can be adequately described by the kinetic term “A” or pre-exponential factor within the classical nucleation theory framework because the critical free-energy term appears to be constant for the same scale. A semiempirical correlation specific to ABT-089 is proposed between the energy input to a system and the average onset of primary nucleation for each of the means of shear induction. The generic approach presented in this work can be used as part of the overall development strategy to scale-up and scale-down crystallization experiments by estimating the specific energy input or the corresponding tip speed requirement to induce primary nucleation within a specified time range. However, given the practical limitations on the amount of data that can be generated and used to develop such correlations, appropriate caution is necessary in defining the scope of their applicability.
中文翻译：
在非种子系统中高剪切条件下药物化合物成核的研究
通过使用不同的剪切诱导机制，即磁力搅拌器，1,5和140 mL标度的诱导时间，研究了原位高能混合对活性药物化合物（ABT-089）初级成核的影响。 Couette设备和高剪切转子-定子混合器在制药工业中被称为湿磨机。如先前所报道，在未经测试的规模和设备上进行的实验表明，成核的开始时间随着每单位体积溶液的平均能量输入（即比能量输入）的增加而减少（刘，J. ; Svard，M .；拉斯穆森（A.C.） 搅拌对搅拌槽结晶器Cryst中 初级成核的影响。增长目标。2015年，15，4177-4184）。发现感应时间的可变性随着体积和比能输入的增加而减小。使用Rasmuson（刘，J. ; Svard，M .；Rasmuson，ÅC。 搅拌对搅拌槽结晶器Cryst中 初级成核的影响。增长目标。2015年15（4177–4184）方法基于经典成核理论。结果表明，经典的成核理论框架内的动力学术语“ A”或预指数因子可以适当地描述比能输入的影响，因为临界自由能项在相同范围内似乎是恒定的。提出了一种特定于ABT-089的半经验相关性，其中输入到系统的能量与每种剪切诱导方式的一次成核的平均开始时间之间。通过估算特定能量输入或在指定时间范围内引起初级成核的相应尖端速度要求，这项工作中提出的通用方法可以用作按比例放大和按比例缩小结晶实验的整体开发策略的一部分。然而，
更新日期：2019-12-11
中文翻译：
在非种子系统中高剪切条件下药物化合物成核的研究
通过使用不同的剪切诱导机制，即磁力搅拌器，1,5和140 mL标度的诱导时间，研究了原位高能混合对活性药物化合物（ABT-089）初级成核的影响。 Couette设备和高剪切转子-定子混合器在制药工业中被称为湿磨机。如先前所报道，在未经测试的规模和设备上进行的实验表明，成核的开始时间随着每单位体积溶液的平均能量输入（即比能量输入）的增加而减少（
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