Continuous filter cake washing performance

Journal of Pharmaceutical Sciences

Price

Steven

et al. 2019

The lack of a commercial laboratory, pilot and small manufacturing scale dead end continuous filtration and drying unit it is a significant gap in the development of continuous pharmaceutical manufacturing processes for new active pharmaceutical ingredients (APIs). To move small-scale pharmaceutical isolation forward from traditional batch Nutsche filtration to continuous processing a continuous filter dryer prototype unit (CFD20) was developed in collaboration with Alconbury Weston Ltd. The performance of the prototype was evaluated by comparison with manual best practice exemplified using a modified Biotage VacMaster unit to gather data and process understanding for API filtration and washing. The ultimate objective was to link the chemical and physical attributes of an API slurry with equipment and processing parameters to improve API isolation processes. Filtration performance was characterized by assessing filtrate flow rate by application of Darcy's law, the impact on product crystal size distribution and product purity were investigated using classical analytical methods. The overall performance of the 2 units was similar, showing that the prototype CFD20 can match best manual lab practice for filtration and washing while allowing continuous processing and real-time data logging. This result is encouraging and the data gathered provides further insight to inform the development of CFD20.

Section: Introductionmentioning

confidence: 99%

Development of a Novel Continuous Filtration Unit for Pharmaceutical Process Development and Manufacturing

Journal of Pharmaceutical Sciences

Price

Steven

et al. 2019

“…To be effective, the wash solvent should ideally have the following properties: 18 Sufficient solubility of unwanted impurities to ensure they remain in the solution or dissolve; Low solubility of the API product to minimize product loss during the washing process; Miscibility with the mother liquor to allow diffusion and dilution mechanisms; The viscosity of the wash solvent should be similar to that of the crystallization solvent to allow for appropriately long contact with the crystals to allow the removal of impurity from the cake without excessive filtration cycle time; 14 The API product should have thermal stability in the wash solvent under drying process conditions needed to remove the wash solvents; The volatility of the wash solvent should be kept appropriately low to assist with the drying process. …”

Section: Introductionmentioning

confidence: 99%

“…The viscosity of the wash solvent should be similar to that of the crystallization solvent to allow for appropriately long contact with the crystals to allow the removal of impurity from the cake without excessive filtration cycle time; 14 …”

Section: Introductionmentioning

confidence: 99%

Exploring the Role of Anti-solvent Effects during Washing on Active Pharmaceutical Ingredient Purity

Shahid

Sanxaridou

et al. 2021

Org. Process Res. Dev.

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.

“…If this mother liquor is not removed before the downstream drying process, the dissolved material will be deposited on the product crystal surfaces, resulting in the presence of impurities in the final product. 5 Therefore, washing is a vital purification step, which is required to remove impurities from the filtered cake.…”

Section: Introductionmentioning

confidence: 99%

Employing Constant Rate Filtration To Assess Active Pharmaceutical Ingredient Washing Efficiency

Shahid

Faure

et al. 2021

Org. Process Res. Dev.

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.