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An anti-solvent screening methodology is developed to quantitatively analyse the propensity for precipitation of paracetamol and its impurities during the washing process. Aim of this work was to validate the notion that the precipitation of API and its impurities occurs during the washing process. This analysis was conducted on paracetamol crystalized from three different solvents; ethanol, isopropanol and isoamyl alcohol. Three different wash solvents were evaluated; heptane, acetonitrile and isopropyl acetate. The solubility of paracetamol in different binary wash solutions was measured to support the wash solvent selection. A map of wash solution composition boundaries for the systems investigated was developed to depict where anti-solvent phenomena will take place.
For some crystallization and wash solvent systems investigated, as much as 90% of paracetamol and over 10% of impurities present in the paracetamol saturated mother liquor was found to precipitate out. Similar level of uncontrolled crystallization during washing in a pharmaceutical process can have drastic effect on final product purity.
The use of n-heptane as wash solvent always resulted in precipitation of both paracetamol and related impurities, for any given crystallization solvent. n-Heptane used to wash paracetamol crystallized from ethanol was found to produce the highest amount of precipitation. This is consistent with the largest difference in solubility of paracetamol between the crystallization and wash solvents. By using a mixture of heptane and ethanol as the initial wash solvent this effect could be minimized preventing precipitation of the API and its impurities.
Use of acetonitrile as a wash solvent does not result in any precipitation of the API or impurity. However, the high solubility paracetamol in acetonitrile, would result in dissolution of API during the washing process. Wash solvents with high solubility should therefore be used cautiously to prevent any reduction in yield. Also the presence of a wash solvent in which the API has appreciable solubility in a deliquored / damp cake can lead to the formation of crystal bridges, in between particles, during drying and will result in agglomeration.
X-Ray Powder Diffraction (XRPD) analysis was carried out on the paracetamol deposited API crystallizing out, this showed the presence of metastable form 1 (monoclinic) form. Therefore, no change in polymorphism was encountered due to this unwanted precipitation of API in the system investigated.
Future research involves deliberately wetting the API cake with selected wash solvent and controlling the rate of washing to aid both displacement and dilution washing mechanism.
 Ottoboni, S., Price, C., Steven, C., Meehan, E., Barton, A., Firth, P., Mitchell, P., Tahir, F., 2018. Development of a novel continuous filtration unit for pharmaceutical process development and manufacturing. J Pharm Sci, 1.
|Number of pages||1|
|Publication status||Published - 9 Jul 2019|
|Event||British Association of Crystal Growth 50th Annual Conference - Sussex Place, London, United Kingdom|
Duration: 9 Jul 2019 → 11 Jul 2019
Conference number: 50
|Conference||British Association of Crystal Growth 50th Annual Conference|
|Abbreviated title||BACG Annual Conferece|
|Period||9/07/19 → 11/07/19|
- active pharmaceutical ingredient
- washing solvents
FingerprintDive into the research topics of 'Understanding and mitigating the consequences of undesired crystallisation taking place during washing of active pharmaceuticals'. Together they form a unique fingerprint.
- 1 Finished
1/10/17 → 25/08/23
Project: Research Studentship - Internally Allocated
Shahid, M., Sanxaridou, G., Ottoboni, S., Lue, L. & Price, C., 9 Oct 2022.
Research output: Contribution to conference › Paper › peer-reviewOpen AccessFile
Development of a novel continuous filtration unit for pharmaceutical process development and manufacturingOttoboni, S., Price, C. J., Steven, C., Meehan, E., Barton, A., Firth, P., Mitchell, A. & Tahir, F., 31 Jan 2019, In: Journal of Pharmaceutical Sciences. 108, 1, p. 372-381 10 p.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile
Forbes, C., Nguyen, T. T. H., O'Leary, R. L. & Price, C. J., 9 May 2018, (E-pub ahead of print) In: Proceedings of Meetings on Acoustics. 32, 5 p., ICU2017 - 287.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile23 Downloads (Pure)