Understanding and mitigating the consequences of undesired crystallisation taking place during washing of active pharmaceuticals

Research output: Contribution to conferencePoster

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. The mother liquor is typically replaced with a miscible solvent in which the API has lower solubility, to prevent any product loss, and lower boiling point to allow for easy removal during drying. However, precipitation of API and the associated impurities of synthesis in the mother liquor may occur during washing and can affect the purity of the isolated product. In addition, formation of crystal bridges in the cake leads to agglomeration, which affects the particle size distribution and powder flow properties.1
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.
References
[1] 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.

Conference

ConferenceBritish Association of Crystal Growth 50th Annual Conference
Abbreviated titleBACG Annual Conferece
CountryUnited Kingdom
CityLondon
Period9/07/1911/07/19
Internet address

Fingerprint

Crystallization
Washing
Acetaminophen
Pharmaceutical Preparations
Impurities
Solubility
Heptanes
Ethanol
Drying
Agglomeration
Crystals
2-Propanol
Boiling point
Polymorphism
Particle size analysis
Powders
X ray powder diffraction
Dilution
Wetting
Precipitates

Keywords

  • active pharmaceutical ingredient
  • crystallisation
  • washing solvents

Cite this

Shahid, M., Sanxaridou, G., Ottoboni, S., Lue, L., & Price, C. (2019). Understanding and mitigating the consequences of undesired crystallisation taking place during washing of active pharmaceuticals. 103. Poster session presented at British Association of Crystal Growth 50th Annual Conference, London, United Kingdom.
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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. The mother liquor is typically replaced with a miscible solvent in which the API has lower solubility, to prevent any product loss, and lower boiling point to allow for easy removal during drying. However, precipitation of API and the associated impurities of synthesis in the mother liquor may occur during washing and can affect the purity of the isolated product. In addition, formation of crystal bridges in the cake leads to agglomeration, which affects the particle size distribution and powder flow properties.1An 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.References[1] 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.",
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note = "British Association of Crystal Growth 50th Annual Conference, BACG Annual Conferece ; Conference date: 09-07-2019 Through 11-07-2019",
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Shahid, M, Sanxaridou, G, Ottoboni, S, Lue, L & Price, C 2019, 'Understanding and mitigating the consequences of undesired crystallisation taking place during washing of active pharmaceuticals' British Association of Crystal Growth 50th Annual Conference, London, United Kingdom, 9/07/19 - 11/07/19, pp. 103.

Understanding and mitigating the consequences of undesired crystallisation taking place during washing of active pharmaceuticals. / Shahid, Muhid; Sanxaridou, Georgia; Ottoboni, Sara; Lue, Leo; Price, Chris.

2019. 103 Poster session presented at British Association of Crystal Growth 50th Annual Conference, London, United Kingdom.

Research output: Contribution to conferencePoster

TY - CONF

T1 - Understanding and mitigating the consequences of undesired crystallisation taking place during washing of active pharmaceuticals

AU - Shahid, Muhid

AU - Sanxaridou, Georgia

AU - Ottoboni, Sara

AU - Lue, Leo

AU - Price, Chris

PY - 2019/7/9

Y1 - 2019/7/9

N2 - Washing is a key step in pharmaceutical isolation to remove the unwanted crystallization solvent (mother liquor) from the Active Pharmaceutical Ingredient (API) filter cake. The mother liquor is typically replaced with a miscible solvent in which the API has lower solubility, to prevent any product loss, and lower boiling point to allow for easy removal during drying. However, precipitation of API and the associated impurities of synthesis in the mother liquor may occur during washing and can affect the purity of the isolated product. In addition, formation of crystal bridges in the cake leads to agglomeration, which affects the particle size distribution and powder flow properties.1An 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.References[1] 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.

AB - Washing is a key step in pharmaceutical isolation to remove the unwanted crystallization solvent (mother liquor) from the Active Pharmaceutical Ingredient (API) filter cake. The mother liquor is typically replaced with a miscible solvent in which the API has lower solubility, to prevent any product loss, and lower boiling point to allow for easy removal during drying. However, precipitation of API and the associated impurities of synthesis in the mother liquor may occur during washing and can affect the purity of the isolated product. In addition, formation of crystal bridges in the cake leads to agglomeration, which affects the particle size distribution and powder flow properties.1An 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.References[1] 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.

KW - active pharmaceutical ingredient

KW - crystallisation

KW - washing solvents

UR - https://www.bacg.co.uk/bacg-50th-annual-conference/

M3 - Poster

SP - 103

ER -

Shahid M, Sanxaridou G, Ottoboni S, Lue L, Price C. Understanding and mitigating the consequences of undesired crystallisation taking place during washing of active pharmaceuticals. 2019. Poster session presented at British Association of Crystal Growth 50th Annual Conference, London, United Kingdom.