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

In the pharmaceutical industry, the final drug substance (active pharmaceutical ingredients (API)), and the key synthetic intermediates are mostly isolated as crystalline solids. A considerable amount of effort is spent in the crystallisation process to produce a crystalline solid with the requisite chemical quality together with the right physical properties (filterability, product size, uniformity, etc.), for isolation and further downstream processing to manufacture the drug product. 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. These isolation processes pose significant challenges to the production of crystals with the desired physical properties; avoiding granulating, or breaking the crystals, or precipitating dissolved product and impurities. Washing is a key step in pharmaceutical isolation to remove the unwanted crystallisation solvent and dissolved impurities (mother liquor) from the API filter cake to ensure the purity of the product whilst maximising yield. The aim of this thesis is to understand how the physiochemical properties of crystallized material and the wash solvent can affect the characteristic of the API product at the end of the washing process. Strategies for optimal wash solvent selections are explored to help minimise dissolution of API product crystals while preventing precipitation of product or impurities. This is done by taking solubility measurement of commonly used binary solvent mixtures of; paracetamol API, crystallisation solvent and wash solvent. The results of these solubility measurements are presented together with a methodology to analyse anti-solvent effect of different solvent combinations. The data from these results are used for selection of wash solvent to avoid both these phenomena which can be challenging but is essential to maintain yield, purity, and particle characteristics throughout the isolation process. A major objective of this work aims to improve pharmaceutical product quality, increase sustainability, and reduce manufacturing cost. Constant rate filtration/washing is employed that allows for 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. This constant rate methodology was tested using paracetamol API together with blue dye used as an impurity to allow for visualization of washing process of a filtered API cake. Analysis of the filtrate collected during this study was found to be useful in determining the endpoint of washing, the amount of API lost during the washing process and the likely extent of agglomeration occurring during washing to be evaluated. Further work looks at employing particle size distribution measurement techniques to quantify agglomerate formation caused during the washing process. Several different lab-based particle size distribution techniques were employed to analyse washed API cake, however, none of them were found to be successful in providing conclusive results. This work highlighted some of the challenges of characterising API particles obtained from a multi-component system at the end of the washing process. This demonstrates that sizing wet clumped material is even more challenging than sizing dried but agglomerated product. The final component of this work was the development of a wash process workflow to assist with design and optimisation of an API washing process. This workflow collates all the learning developed throughout the different studies in this PhD project to produce a workflow which provides an optimum strategy for designing of washing processes in pharmaceutical isolation of APIs. This workflow was validated using an industrial compound from AstraZeneca with the constant rate methodology successfully used to investigate optimum washing process parameters for the investigated compound.In the pharmaceutical industry, the final drug substance (active pharmaceutical ingredients (API)), and the key synthetic intermediates are mostly isolated as crystalline solids. A considerable amount of effort is spent in the crystallisation process to produce a crystalline solid with the requisite chemical quality together with the right physical properties (filterability, product size, uniformity, etc.), for isolation and further downstream processing to manufacture the drug product. 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. These isolation processes pose significant challenges to the production of crystals with the desired physical properties; avoiding granulating, or breaking the crystals, or precipitating dissolved product and impurities. Washing is a key step in pharmaceutical isolation to remove the unwanted crystallisation solvent and dissolved impurities (mother liquor) from the API filter cake to ensure the purity of the product whilst maximising yield. The aim of this thesis is to understand how the physiochemical properties of crystallized material and the wash solvent can affect the characteristic of the API product at the end of the washing process. Strategies for optimal wash solvent selections are explored to help minimise dissolution of API product crystals while preventing precipitation of product or impurities. This is done by taking solubility measurement of commonly used binary solvent mixtures of; paracetamol API, crystallisation solvent and wash solvent. The results of these solubility measurements are presented together with a methodology to analyse anti-solvent effect of different solvent combinations. The data from these results are used for selection of wash solvent to avoid both these phenomena which can be challenging but is essential to maintain yield, purity, and particle characteristics throughout the isolation process. A major objective of this work aims to improve pharmaceutical product quality, increase sustainability, and reduce manufacturing cost. Constant rate filtration/washing is employed that allows for 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. This constant rate methodology was tested using paracetamol API together with blue dye used as an impurity to allow for visualization of washing process of a filtered API cake. Analysis of the filtrate collected during this study was found to be useful in determining the endpoint of washing, the amount of API lost during the washing process and the likely extent of agglomeration occurring during washing to be evaluated. Further work looks at employing particle size distribution measurement techniques to quantify agglomerate formation caused during the washing process. Several different lab-based particle size distribution techniques were employed to analyse washed API cake, however, none of them were found to be successful in providing conclusive results. This work highlighted some of the challenges of characterising API particles obtained from a multi-component system at the end of the washing process. This demonstrates that sizing wet clumped material is even more challenging than sizing dried but agglomerated product. The final component of this work was the development of a wash process workflow to assist with design and optimisation of an API washing process. This workflow collates all the learning developed throughout the different studies in this PhD project to produce a workflow which provides an optimum strategy for designing of washing processes in pharmaceutical isolation of APIs. This workflow was validated using an industrial compound from AstraZeneca with the constant rate methodology successfully used to investigate optimum washing process parameters for the investigated compound

Exploring the role of anti-solvent effects during washing on active pharmaceutical product purity

Washing is a key step in pharmaceutical isolation to remove unwanted crystallisation solvent, rich in impurities, (mother liquor) from the Active Pharmaceutical Ingredient (API) filter cake. This study looks at strategies for optimal wash solvent selection, minimising dissolution of API product crystals while preventing precipitation of product or impurities. Selection of wash solvent to avoid both these phenomena can be challenging but is essential to maintain 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 and two typical impurities of synthesis during the washing process. The solubility of paracetamol 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 crystallisation and wash solvent combinations investigated, as much as 90% of the dissolved paracetamol and over 10% of impurities present in the paracetamol saturated mother liquor was shown to precipitate out. Such levels of uncontrolled crystallisation during washing in a pharmaceutical isolation process can have drastic effect on the final product purity. Whilst precipitation of both 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 use of acetonitrile as a wash solvent does not result in any precipitation of the paracetamol API or its impurities. However, the high solubility of paracetamol in acetonitrile, would result in noticeable dissolution of API during washing and would lead to agglomeration during the subsequent drying step. Conversely, use of n-heptane as wash solvent for a paracetamol crystal slurry resulted in the highest amount of precipitation amongst the solvent pairings evaluated. This can be mitigated by designing a multi-stage washing strategy where wash solutions of differing wash solvent concentration are used to minimise step changes in solubility when mother liquor and wash solvent come into contact

Exploring the role of anti-solvent effects during washing on active pharmaceutical ingredient purity

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

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

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

Employing constant rate filtration to assess active pharmaceutical ingredient washing efficiency

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

Developing a batch isolation procedure and running it in an automated semi-continuous unit : AWL CFD25 case study

A key challenge during the transition from laboratory/small batch to continuous manufacturing is the development of a process strategy that can easily be adopted for a larger batch/continuous process. Industrial practice is to develop the isolation strategy for a new drug/process in batch using the design of experiment (DoE) approach to determine the best isolation conditions and then transfer the isolation parameters selected to a large batch equipment/continuous isolation process. This stage requires a series of extra investigations to evaluate the effect of different equipment geometry or even the adaptation of the parameters selected to a different isolation mechanism (e.g., from dead end to cross flow filtration) with a consequent increase of R&D cost and time along with an increase in material consumption. The CFD25 is an isolation device used in the first instance to develop an isolation strategy in batch (optimization mode) using a screening DoE approach and to then verify the transferability of the strategy to a semicontinuous process (production mode). A d-optimal screening DoE was used to determine the effect of varying the input slurry. Properties such as solid loading, particle size distribution, and crystallization solvent were investigated to determine their impact on the filtration and washing performance and the characteristics of the dry isolated product. A series of crystallization (ethanol, isopropanol, and 3-methylbutan-1-ol) and wash solvents (n-heptane, isopropyl acetate and n-dodcane) were used for the process. To mimic a real isolation process, paracetamol-related impurities, acetanilide and metacetamol, were dissolved in the mother liquor. The selected batch isolation strategy was used for the semicontinuous isolation run. Throughput and filtration parameters, such as cake resistance and flow rate, cake residual liquid content and composition, cake purity, particle-particle aggregation, and extent and strength of agglomerates, were measured to evaluate the consistency of the isolated product produced during a continuous experiment and compared with the isolated product properties obtained during the batch process development. Overall, the CFD25 is a versatile tool which allows both new chemical entity process development in batch and the production of the active pharmaceutical ingredient in semicontinuous mode using the same process parameters without changing equipment. The isolated product properties gained during the semicontinuous run are overall comparable between samples. The residual solvent content and composition differs between some samples due to filter plate blockage. In general, the mean properties obtained during semicontinuous running are comparable with the product properties simulated using the DoE

Fluid and impurity transport during online isolation experiments conducted with X-ray tomography

Pharmaceutical ingredients (API’s) need to be pure and have the required particle size distribution, filtration and washing play an important part in achieving this Fluid flow and impurity transport during filtration, washing a drying are observed using tomography to: Visualize the location of impurities during incomplete and complete washing; Visualize the consequences of non-ideal filtration and washing; Visualize residual mother liquor inclusions after washing and link these with agglomeration during drying. A slurry of API particles, and saturated crystallization solution was filtered to dryland or breakthrough. The effect of particle size distribution was evaluated. Iodine was used to mimic impurities dissolved in the mother liquor and the filter cake was washed with n-heptane. The cake was dried at ambient temperature with flowing gas. Tomography was used to identify areas where particle agglomeration during drying is favoured

Integrated continuous process design for crystallisation, spherical agglomeration, and filtration of lovastatin

Purpose This work seeks to improve the particle processability of needle-like lovastatin crystals and develop a small-footprint continuous MicroFactory for its production. Methods General conditions for optimal spherical agglomeration of lovastatin crystals and subsequent product isolation are developed, first as batch processes, and then transferred to continuous MicroFactory operation. Results Methyl isobutyl ketone is a suitable bridging liquid for the spherical agglomeration of lovastatin. Practical challenges including coupling unit operations and solvent systems; mismatched flow rates and inconsistent suspension solid loading were resolved. The successful continuous production of lovastatin spherical agglomerates (D50 = 336 µm) was achieved. Spherical agglomeration increased the density of the bulk lovastatin powder and improved product flowability from poor to good, whilst maintaining lovastatin tablet performance. Conclusion A continuous, integrated MicroFactory for the crystallisation, spherical agglomeration, and filtration of lovastatin is presented with improved product particle processability. Up to 16,800 doses of lovastatin (60 mg) can be produced per day using a footprint of 23 m2