Exploring the Role of Anti-solvent Effects during Washing on Active Pharmaceutical Ingredient Purity.
Exploring the Role of Anti-solvent Effects during Washing on Active Pharmaceutical Ingredient Purity.
复制标题
探索洗涤过程中的反溶剂效应对活性药物成分纯度的作用。
DOI：
10.1021/acs.oprd.1c00005
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发表时间：
2021-04-16
影响因子：
3.4
通讯作者：
Price C
中科院分区：
文献类型：
--
作者：
Shahid M;Sanxaridou G;Ottoboni S;Lue L;Price C
清洗是药物分离的关键步骤，用于从活性药物成分（API）滤饼中除去不需要的结晶溶剂（母液）。本研究着眼于最佳清洗溶剂选择策略，该策略可最大限度地减少API产品晶体的溶解，同时防止产品或杂质沉淀。选择清洗溶剂以避免这两种现象可能具有挑战性，但对于在整个分离过程中保持产率、纯度和颗粒特性至关重要。开发了一种反溶剂筛选方法，用于定量评价原料药及其合成杂质在洗涤过程中的沉淀倾向。使用对乙酰氨基酚（PCM）和洗涤过程中合成的两种典型杂质说明了这一点。测定了PCM在不同二元洗涤溶液中的溶解度，为洗涤溶剂的选择提供依据。一个地图的洗涤溶液组成的边界沉淀的系统研究开发描绘反溶剂现象将发生。对于所研究的一些结晶和洗涤溶剂组合，发现多达90%的溶解的PCM和超过10%的存在于PCM饱和母液中的杂质沉淀出来。在药物分离过程中的洗涤期间，这种不受控制的结晶水平可能对最终产品纯度产生剧烈影响。通过使用API在其中的溶解度与母液中的溶解度相似的溶剂，可以避免产物和杂质从母液中沉淀;例如，使用乙腈作为洗涤溶剂不会导致PCM API或其杂质沉淀。然而，PCM在乙腈中的高溶解度将导致API在洗涤期间显著溶解，并将导致在随后的干燥步骤期间附聚。首先，使用正庚烷作为PCM晶体浆料的洗涤溶剂导致所评估的溶剂对中最高量的沉淀。这可以通过设计多阶段洗涤策略来减轻，其中使用不同洗涤溶剂浓度的洗涤溶液以使母液和洗涤溶剂接触时溶解度的阶跃变化最小化。
Washing is a key step in pharmaceutical isolation to remove the unwanted crystallization solvent (mother liquor) from the active pharmaceutical ingredient (API) filter cake. This study looks at strategies for optimal wash solvent selection, which minimizes the dissolution of API product crystals while preventing the precipitation of product or impurities. Selection of wash solvents to avoid both these phenomena can be challenging but is essential to maintain the yield, purity, and particle characteristics throughout the isolation process. An anti-solvent screening methodology has been developed to quantitatively evaluate the propensity for precipitation of APIs and their impurities of synthesis during washing. This is illustrated using paracetamol (PCM) and two typical impurities of synthesis during the washing process. The solubility of PCM in different binary wash solutions was measured to provide a basis for wash solvent selection. A map of wash solution composition boundaries for precipitation for the systems investigated was developed to depict where anti-solvent phenomena will take place. For some crystallization and wash solvent combinations investigated, as much as 90% of the dissolved PCM and over 10% of impurities present in the PCM saturated mother liquor were found to precipitate out. Such levels of uncontrolled crystallization during washing in a pharmaceutical isolation process can have a drastic effect on the final product purity. Precipitation of both the product and impurities from the mother liquor can be avoided by using a solvent in which the API has a solubility similar to that in the mother liquor; for example, the use of acetonitrile as a wash solvent does not result in precipitation of either the PCM API or its impurities. However, the high solubility of PCM in acetonitrile would result in noticeable dissolution of API during washing and would lead to agglomeration during the subsequent drying step. Contrarily, the use of n-heptane as a wash solvent for a PCM crystal slurry resulted in the highest amount of precipitation among the solvent pairs evaluated. This can be mitigated by designing a multi-stage washing strategy where wash solutions of differing wash solvent concentrations are used to minimize step changes in solubility when the mother liquor and the wash solvent come into contact.
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影响因子：
5.2
作者：
Lim, Hong Lee;Hapgood, Karen P.;Haig, Brian
通讯作者：
Haig, Brian
影响因子：
3.4
作者：
McWilliams, J. Christopher;Allian, Ayman D.;Braden, Timothy M.
通讯作者：
Braden, Timothy M.
影响因子：
4.7
作者：
Ruslim, Franky;Nirschl, Hermann;Carvin, Philippe
通讯作者：
Carvin, Philippe
DOI：
10.1007/bf01979491
发表时间：
1997-03-01
期刊：
JOURNAL OF THERMAL ANALYSIS
影响因子：
--
作者：
DiMartino, P;Conflant, P;GuyotHermann, AM
通讯作者：
GuyotHermann, AM
影响因子：
3.4
作者：
Conder, Edward W.;Cosbie, Andrew S.;Papageorgiou, Charles D.
通讯作者：
Papageorgiou, Charles D.