Abstract
Washing is a key step in pharmaceutical isolation to remove unwanted crystallization solvents and dissolved impurities (mother liquor) from the active pharmaceutical ingredient (API) filter cake to ensure the purity of the product whilst maximizing yield. It is therefore essential to avoid both product dissolution and impurity precipitation during washing, especially precipitation of impurities caused by the wash solvent acting as an antisolvent, affecting purity and causing agglomerate formation. This work investigates the wash solvent flow through a saturated filter cake to optimize washing by displacement, taking account of diffusional mechanisms and manipulating the wash contact time. Constant rate filtration/washing is employed in this study using readily available laboratory equipment. One advantage of using constant rate filtration in this work is that it allows for the collection of separate aliquots during all stages of filtration, washing, and deliquoring of the API cake. This enables a wash profile to be obtained, as well as providing an overall picture on the mass of API lost during isolation and so can assist in optimizing the washing strategy. Particle size analysis of damp cake obtained straight after washing is also performed using laser diffraction. This allowed for agglomerate formation caused during washing to be distinguished from agglomeration that would be caused by subsequent drying of the wet filter cake. This work aims at improving pharmaceutical product quality, increasing sustainability, and reducing manufacturing cost.
Highlights
In the pharmaceutical industry, the final drug substance and the key synthetic intermediates are mostly isolated as crystalline solids.[1]
Using the constant rate filtration/washing experimental setup shown in Figure 3 allows for the sequential collection of aliquots of wash filtrate using a fraction collector; this high resolution would be challenging to achieve in a laboratory environment using constant pressure vacuum filtration.[8]
This shows that no further washing of the active pharmaceutical ingredient (API) cake is required as all of the blue dye is removed, and washing could be stopped at that point without any further usage of the wash solvent
Summary
The final drug substance (active pharmaceutical ingredient, API) and the key synthetic intermediates are mostly isolated as crystalline solids.[1] A considerable amount of effort is spent in the crystallization process to produce a crystalline solid with the requisite chemical quality together with the right physical properties (filterability, product size, uniformity, and so forth) for isolation and further downstream processing to manufacture the drug product.[2] Whilst carefully designed upstream processes may attain the desired crystal properties in suspension, these are often compromised during the isolation of the API by filtration, washing, and drying. Washing is a vital purification step, which is required to remove impurities from the filtered cake
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