Abstract
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.
Highlights
In the pharmaceutical industry, crystallization is a widely used purification technique employed to obtain active pharmaceutical ingredient particles of required size, purity, and crystal habit.[1,2] crystallization has been extensively researched to establish an understanding and control of the key mechanisms that take place during this process to create the desired product with the requisite chemical and physical properties.[3]Following crystallization, filtration, washing, and drying are the isolation steps required to separate the API crystals from the unwanted, impure mother liquor.[4]
Washing involves using a clean wash solvent to remove the unwanted impurities present within the mother liquors trapped between the API crystals in the filter cake
This study investigates the effect of wash solvent selection by considering the mechanisms taking place during the interaction between crystallization and wash solvent in the washing process
Summary
Crystallization is a widely used purification technique employed to obtain active pharmaceutical ingredient particles of required size, purity, and crystal habit.[1,2] crystallization has been extensively researched to establish an understanding and control of the key mechanisms that take place during this process to create the desired product with the requisite chemical and physical properties.[3]Following crystallization, filtration, washing, and drying are the isolation steps required to separate the API crystals from the unwanted, impure mother liquor.[4]. Drying is the final step required to remove the residual solvent (predominantly the wash solvent as most of the mother liquor will have been displaced during washing) from the API crystals forming the filter cake. The major objective is to investigate the mechanisms affecting the product crystal attributes during these processes This includes understanding the key mechanisms controlling the filtration and washing and involves designing continuous and semi-continuous filtration, washing, and drying rigs and investigating new analytical methods for effectively measuring the crystal product attributes obtained during and at the end of the isolation processes.[8−13]
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