Impact of Mother Liquor Recycle on the Impurity Build-Up in

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Impact of Mother Liquor Recycle on the Impurity Build-Up in Crystallization Processes Leila Keshavarz, René R. E. Steendam, and Patrick J. Frawley Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00308 • Publication Date (Web): 22 Oct 2018 Downloaded from http://pubs.acs.org on October 22, 2018

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Organic Process Research & Development

Impact of Mother Liquor Recycle on the Impurity Build-Up in Crystallization Processes Leila Keshavarz†*, René R. E. Steendam† and Patrick J. Frawley Synthesis and Solid State Pharmaceutical Centre (SSPC), Bernal Institute, University of Limerick, Castletroy, Limerick, Ireland. † Equal contribution * Corresponding author

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ABSTRACT Reusing the mother liquor fraction in crystallization processes significantly increases the product yield but will also lead to an accumulation of impurities. In this work, we investigate how a mother liquor recycle operation affects the crystallization of paracetamol as a result of the gradual build-up of impurity 4-nitrophenol. The results show that the rate of impurity build-up decreases with increasing number of cycles until the amount of impurity remains the same. The number of cycles required to reach a steady state increases when larger fractions of mother liquor are reused. A simple model was used to describe the impurity build-up and to estimate the largest possible mother liquor recycle fraction required to obtain the maximum achievable product yield while still maintaining the desired product specifications. The presented work shows how to optimize mother liquor recycle conditions which will lead to enhanced process efficiency by reducing product and solvent waste. Keywords: cooling crystallization, mother liquor recycle, impurity control, modelling, process optimization 1. INTRODUCTION The manufacture of active pharmaceutical ingredients (API) often involves a synthetic route that requires multiple reactions to obtain the desired product. Reaction products typically consist of the desired compound together with impurities resulting from unreacted starting material or side reactions.1 Impurities can exhibit undesirable biological effects and may also influence the properties of the desired product, even when impurities are present in minute quantities.2-5 Therefore, the FDA and ICH impose strict rules to confine the presence of impurities in pharmaceutical products.6,

7

Separation processes to reduce the level of impurities are

consequently widely used in the chemical- and pharmaceutical industry. Solution crystallization is a highly selective and scalable unit operation that is widely used to purify the desired product from its impurities.8 After crystallization, the suspension is filtered resulting in pure product crystals as well as a mother liquor fraction. However, in addition to impurities, the mother liquor still contains the desired product.9 Moreover, the solvents that are part of the mother liquor could represent a source of environmental waste and may require disposal steps in some processes.


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A reduction in mother liquor waste can be realized through a recycle operation, in which the mother liquor is used as part of the starting material for a new process. Through a recycle operation, high yields can be achieved while waste can be reduced at the same time. Improved yields and waste reduction have been realized for example in cooling single-stage continuous Mixed-Suspension, Mixed-Product Removal (MSMPR)9,

10,

anti-solvent cooling single stage

continuous MSMPR11, multistage continuous MSMPR12 and plug-flow processes13. The key challenge behind implementing a mother liquor recycle operation is to account for the gradual build-up of impurities in the solution. According to a simple mathematical model, the amount of impurities should stop to increase after a sufficiently large number of cycles have been conducted.14 The number of cycles that are required to reach a steady state impurity concentration is expected to depend on the amount of mother liquor that is recycled. However, it remains unclear how the fraction of mother liquor recycle affects the build-up of impurities in experimental work as no such mother liquor recycle studies have been conducted to the best of our knowledge. In the present work we used an experimental and modelling approach to investigate the maximum fraction of mother liquor that could be recycled while still maintaining the desired crystal product specifications. The target API investigated was paracetamol which was contaminated with impurity 4-nitrophenol. The results show that the amount of impurity stops building up after a sufficiently large number of cycles have been carried out and that reaching this steady state depends on the fraction of mother liquor that is recycled. The increasing amount of impurity did not affect the product quality, as indicated by the unchanging product purity, CSD and particle shape. Overall the presented results demonstrate that a link between experiments and a model enables the approximation of optimized mother liquor recycle conditions that lead to a significant increase in product yield while still maintaining the desired product specifications. 2. EXPERIMENTAL SECTION 2. 1. Materials and equipment Paracetamol (98.0-102.0%) and methanol (HPLC grade, 99%) were purchased from SigmaAldrich whereas 4-nitrophenol (99%) and 2-propanol (analytical grade, 99.97%) were acquired



from Alfa Aesar and Fisher Scientific respectively. All chemicals were used as received. The crystallization experiments were carried out in a Mettler-Toledo Easymax 402 workstation in combination with a stainless steel temperature probe and an overhead stirrer with a downward pitched-blade stirrer (ø 25 mm). 2. 2. Experimental Procedure A sequence of batch-cooling crystallization experiments was carried out to investigate the mother liquor recycle effect on the build-up of impurities. The start-up experiment (n=0) involved the crystallization of initial material SM0, resulting in paracetamol crystals P and mother liquor ML (Figure 1). The starting material in subsequent cycles (n ≥ 1) consisted of fraction x of the mother liquor from the previous experiment n-1 and a fraction 1-x of fresh starting material SM. The concentration of starting material SM was higher than the concentration of initial material SM0 used in the start-up phase as it was necessary to compensate for the loss of product as a result of the removal of product P from the start-up experiment. The design of the experiment mimics a continuous crystallization experiment as a continuous approach is often initiated through a batch process followed by a fixed continuous feed of starting material and recycle stream.11,

15

The yield Y represents the amount of crystalline

paracetamol P obtained from the process relative to the amount of paracetamol used as starting material. The total yield Yt is defined as the percentage of combined amount of paracetamol crystallized from each experiment relative to the combined amount of paracetamol and 4nitrophenol used in each experiment.


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Figure 1. Schematic overview of the experimental process. In cycles n≥1, shown within brackets, a fixed concentration of starting material SM was used in combination with a fraction x of the mother liquor ML from the previous experiment. 2.2.1. Start-up experiment (n=0) The first experiment n=0 of the recycle sequence involved the cooling crystallization of starting material SM0, which consisted of 62.25 g of paracetamol, 2.97 g of 4-nitrophenol (4.55 wt%) and 235.8 g of 2-propanol. As a result, a concentration C of paracetamol was 264 g/kg solvent. The suspension was stirred at 400 rpm and the temperature of the suspension was increased to 70 °C which is 10 °C higher than the theoretical solubility, as calculated using the reported solubility data.16 Stirring was continued at 70 °C for 1 hour to ensure complete dissolution after which the temperature was reduced to 15 °C at a rate of 0.9 °C/min during which crystallization occurred. The suspension was subsequently stirred for approximately 30 hours at a temperature of 15 °C to enable complete desupersaturation after which the solids were separated from the solution through vacuum filtration. During the desupersaturation period, the solution concentration was monitored by regularly taking samples for gravimetric analysis to ensure that a solid-liquid equilibrium had been reached. 2.2.2. Mother Liquor Recycle Experiments (n≥1) After the start-up experiment, subsequent mother liquor recycle experiments n≥1 involved the use of starting material SM which consisted of a fraction x of the mother liquor ML from the



previous experiment (n-1). In order to induce crystallization at 15 °C, it was essential that the initial paracetamol concentration C in starting material SM0 was 264 g/kg solvent. For our calculations, the total solution concentration C of paracetamol in the mother liquor was set to a fixed value of 120 g/kg solvent for all experiments. Furthermore, it was assumed that all of the impurity remained in the solution and that no solvent evaporation occurred. Using these simplifications, it was possible to complete the mass balance and to calculate the second fraction of starting material SM required to start the new experiment with a paracetamol concentration C of 264 g/kg. 2.3. Gravimetric Analysis The total solution concentration of paracetamol and 4-nitrophenol was determined through gravimetric analysis. A sample from the suspension was filtered using a 0.2 μm PTFE membrane (ø=15 mm) syringe filter and the mother liquor was collected in a pre-weighted glass vial. The vial was closed immediately and the combined weight of the solvent, solute, vial and cap was recorded. Subsequently, the vial was placed in an oven set at a temperature of 50 °C for longer than 24 hours to evaporate the solvent. The remaining weight of the solids was recorded and used to calculate the solution concentration. The masses were weighed using an analytical balance (Mettler Toledo AX054, sensitivity ±0.1 mg). 2.4. XPRD Analysis XPRD measurements were carried out to determine the polymorphism of the paracetamol and 4nitrophenol crystals. Samples of the crystals taken after each experiment were gently ground and the resulting powder was measured using a PANalytical EMPYREAN diffractometer with a Bragg−Brentano geometry in combination with an incident beam of Cu K-Alpha radiation (λ = 1.5406 Å). The sample was placed on a spinning silicon sample holder and the scans were conducted at room temperature. A step time of 68 s and a step size of 0.013° 2θ were applied. The obtained experimental XRPD patterns were compared with reference XRPD patterns which were taken from the Cambridge Structural Database as single crystal data and calculated into XRPD patterns using Mercury software. 2.5. HPLC Analysis


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An Agilent 1260 Infinity Quaternary LC system was used in combination with a ZORBAX eclipse XDB-C18 column (4.6x150 mm, 3.5µm) to calculate the ratio of paracetamol to 4nitrophenol in the solid and liquid samples. The mobile phase consisted of a 0.01 M sodium phosphate buffer of pH=3 and methanol in a 0.15/0.85 (v/v) ratio respectively. The flowrate was set to 1.000 mL/min, the column temperature to 20 °C and the injection volume ranged between 1-5 µL, depending on the concentration of the sample. Each solid sample was dissolved in methanol and measured in triplicate and the resulting low relative standard deviation of 0.999) for each compound (Figure 2).

Figure 2. HPLC Calibration lines in which the concentration C is plotted versus the peak area A for paracetamol (a) and impurity 4-nitrophenol (b). The measurements for paracetamol and 4nitrophenol were carried out at a wavelength of 254 and 310 nm, respectively. 2.6. Crystal Size and Shape Analysis Scanning electron microscope (SEM) images were taken using a JEOL Carryscope. The crystalline samples on the sample holders were coated with a thin layer of gold before analysis.



The crystal size distribution (CSD) of the samples were analysed using a Malvern Mastersizer 3000 in combination with a wet dispersion unit. A 1 gram sample of dried crystalline product was dispersed in cyclohexane and introduced into the flow cell of the Mastersizer unit. In order to ensure a sufficiently mixed suspension, a stirring speed of 2,500 rpm was applied. Sonication was not applied as no significant agglomeration was observed by SEM. A refractive index of n=1.619 and n=1.426 were used for paracetamol and cyclohexane respectively. An absorption of 0.1 and density ρ = 1.33 g/cm3 for paracetamol were used, as per the CAS datasheet. The laser alignment was adjusted and a stable background signal was recorded before addition of the sample. Three measurements of each sample were performed and the average values were used in this work. 3. RESULTS AND DISCUSSION 3.1. Paracetamol / 4-Nitrophenol Process Parameters The model system used in the present work involves the purification of paracetamol from its main impurity 4-nitrophenol through solution crystallization from 2-propanol. Paracetamol can crystallize in three different polymorphic forms whereas 4-nitrophenol can crystallize as two different forms.17, 18 In this work, paracetamol form I was used in combination with the alpha form of 4-nitrophenol, based on the CSD reference codes HXACAN01 and NITPOL01 respectively. No polymorphic transformations were encountered throughout the experimental procedure. To induce crystallization, the temperature of the solution was brought down from 70 °C to a steady temperature of 15 °C. Figure 3 shows that across the temperature range of 5–55 °C, the solubility of 4-nitrophenol is about 10 times higher than paracetamol, indicating that 4nitrophenol remains in solution. In addition, previous gravimetric solubility measurements show that the solubility of paracetamol did not significantly increase by the presence of up to 9.3 wt% of 4-nitrophenol at a temperature of 15 °C.19


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Figure 3. The solubility C of paracetamol (■) and 4-nitrophenol (●) as a function of temperature T in 2-propanol. Solubility data was taken from literature.16, 19 The purity of the crystalline paracetamol product P was >99.8% after crystallization, which could be maintained in combination with impurity levels up to 5 g (7.4 wt%) of 4-nitrophenol in solution. Therefore it appears that 4-nitrophenol did not incorporate into the crystal structure of paracetamol, which is in line with data reported in literature.4 The CSD and particle shape of the paracetamol product crystals did not significantly depend on the amount of 4-nitrophenol in solution (Figure 4). An increase in the amount of 4-nitrophenol in solution leads to smaller crystals but this shift stops when the amount of 4-nitrophenol becomes larger than 3.72 g or 5.64 wt% (Figure 4a).



Figure 4. a) CSD’s of product crystals P obtained from experiments in the presence of 2.97 g (solid line), 3.46 g (dashed line) and 3.72 g (dotted lines) of 4-nitrophenol. b) SEM image of product crystals P obtained from an experiment in the presence of 2.97 g of 4-nitrophenol. The scale bar represents 200 μm. The only process parameter that appears to be significantly affected by the amount of 4nitrophenol was the time required to reach solid-liquid equilibrium. The total solution concentrations as a function of time for cooling crystallization experiments involving different amounts of 4-nitrophenol are shown in Figure 5 and illustrate that the time required to reach solid-liquid equilibrium is longer when the amount of 4-nitrophenol in solution becomes larger. The 4-nitrophenol impurity is slowing down the desupersaturation process by possibly inhibiting the crystal growth of paracetamol. For our operation window it was necessary to limit the crystallization time to 10 hours, as the crystallization experiments were conducted only overnight. From Figure 5 it can be derived that a solid-liquid equilibrium can be achieved within 10 hours for experiments involving 5 g of 4-nitrophenol or lower. Therefore, the maximum allowable amount of impurity in our crystallization process is set to be 5 g (7.4 wt%) of 4nitrophenol. Therefore we used this as a criterion to define the threshold for the amount of impurity in our experiments. In the following paragraph we describe an approach to determine the recycle conditions which result in the maximum achievable yield in combination with the maximum impurity presence of 5 g.


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Figure 5. The solution concentration C of paracetamol and 4-nitrophenol plotted as a function of time t for crystallization experiments involving 1.48 g (■), 2.08 g (●), 2.97 g (▲), 4.17 g (▼) and 5.96 g (♦) of 4-nitrophenol. Time 0 is the time that the temperature of the suspension remained steady at 15 °C. The time required to reach solid-liquid equilibrium is estimated by an arrow. 3.2. Impurity Build-Up A sequence of batch cooling crystallization experiments was carried out to determine the buildup of impurities in the mother liquor. Initial material SM0 consisted of paracetamol and 2.97 g (4.55 wt%) 4-nitrophenol. Recrystallization of initial material SM0 proceeds through cooling crystallization according to (1)

𝑆𝑀0 →𝑃 + 𝑀𝐿𝐼,0

where P is the crystalline product of paracetamol and MLI,0 is the amount of impurities in the mother liquor from the first experiment n=0. The mother liquor also contains the solvent and paracetamol but these terms are omitted for simplicity. The yield of product P in the first step was 60% and the crystals were of 99.98% purity. After a wash step involving cold water, the crystal purity increased to 100% indicating that the impurity did not incorporate in the crystals but were present as a result of solvent evaporation. The high crystal purity shows that virtually all of the 2.97 g of the 4-nitrophenol in the starting material retained in solution. A fraction x of the impurities in the mother liquor from the first experiment was used in the second experiment n=1 according to (2)

𝑆𝑀 + 𝑥𝑀𝐿𝐼,0→𝑃 + 𝑥𝑀𝐿𝐼,0 + 𝑀𝐿𝐼,1

which after crystallization and filtration resulted in a mother liquor fraction that consisted of impurities from experiment n=0 (i.e. xMLI,0) and the impurities from experiment n=1 (i.e. MLI,1). Because product P was removed from the experiment through crystallization, the resulting solution concentration of the mother liquor was too low for subsequent cycles. To compensate for the concentration difference, a fixed high concentration of starting material SM was used in



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subsequent n≥1 cycles. The initial concentration of starting material SM in our experiments was increased by reducing the amount of fresh solvent. An alternative approach to increase the initial concentration is to concentrate the mother liquor recycle stream.10, 12 Reducing the amount of fresh solvent is more desirable than concentrating the mother liquor recycle stream as it allows one to recycle the solvent and to avoid additional concentrating steps. After the second experiment, fraction x of the mother liquor from the preceding experiment n=1 was used in the third experiment n=2 according to 𝑆𝑀 + 𝑥2𝑀𝐿𝐼,0 + 𝑥𝑀𝐿𝐼,1→𝑃 + 𝑥2𝑀𝐿𝐼,0 + 𝑥𝑀𝐿𝐼,1 + 𝑀𝐿𝐼,2

(3)

The 4-nitrophenol impurities in each experiment are the same (i.e. MLI,0 = MLI,1 = MLI,2 etc.). Therefore, after n cycles, the total amount of impurities MLI in the mother liquor can be expressed as 𝑛

𝑀𝐿𝐼 = 𝑀𝐿𝐼,0 +𝑥𝑀𝐿𝐼,1 +… + 𝑥𝑛𝑀𝐿𝐼,𝑛 = 𝑀𝐿𝐼,0∑0𝑥𝑛

(4)

In eq. 4, MLI represents the total amount of impurity in the mother liquor expressed in grams, where MLI,0 is the amount of impurity in the mother liquor in experiment n=0, which is 2.97 g of 4-nitrophenol in our experiments. Figure 6 shows the amount of impurity 4-nitrophenol in the mother liquor as a function of the number n of cycles in which a fraction x=0.3, 0.5 or 0.7 of mother liquor from the previous experiment was used as part of the starting material for the following experiment. Both the experimental data as well as a plot of eq. 4 are shown. The results in Figure 6 show that the amount of impurity in the mother liquor significantly increases in the first few cycles after which the impurity build-up slows down and eventually stops, reaching a steady state.


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Figure 6. The amount of impurity MLI in the mother liquor versus the number n of cycles in which a x=0.3 (●), x=0.5 (■) and x=0.7 (▲) fraction of mother liquor was used from the previous experiment n-1. Each data point represents a single crystallization experiment and the lines are plots of eq. 4. Figure 6 furthermore shows that the experimental build-up of impurities in solution can be estimated using eq. 4. The experimental amount of impurity was calculated assuming that no solvent evaporation occurred during filtration. If solvent evaporation occurred, this would result in smaller estimated experimental values for the amount of impurity. In experiment n=2 for recycle fraction x=0.3 it was found, based on gravimetric analysis, that solvent evaporation had taken place. Therefore, the experimental amount of impurity after experiment n=2 was higher than the predicted values. Figure 7 shows the theoretical impurity build-up as a function of the number n of cycles in combination with different recycle fractions x of mother liquor. Experiments involving a recycle fraction of up to x=0.7 would lead to a steady state within approximately 10 cycles. On the other hand, more than 15 cycles would be required to reach a steady state for experiments involving a recycle fraction of x=0.9.



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Figure 7. The estimated amount of impurity in the mother liquor MLI versus the number n of cycles in which a x=0.3 (●), x=0.5 (■), x=0.7 (▲) or x=0.9 (♦) fraction of mother liquor was used from the previous experiment n-1. The impurity build-up changes when different fractions x of mother liquor are reused. This can be mathematically expressed considering the normalized impurity profile MLI,norm = MLI / MLI,n , in which eq. 4 can be rewritten as

𝑛

𝑀𝐿𝐼, 𝑛𝑜𝑟𝑚 = ∑0𝑥𝑛 =

1 ― 𝑥𝑛 + 1

(5)

1―𝑥

When an infinite number of mother liquor recycle experiments were to be carried out (i.e. when n  ∞), the process enters a steady state and eq.5 simplifies into 1

(6)

𝑀𝐿𝐼, ∞ = 1 ― 𝑥 × 𝑀𝐿𝐼,0

where MLI,∞ is the amount of impurity in the mother liquor in steady state and MLI,0 is the amount of impurity in initial material SM0. Thus, by knowing the amount of impurity in the initial material it becomes possible to estimate the impurity build-up as a function of recycle fraction x and the number n of cycles. A plot of eq. 6 for the paracetamol / 4-nitrophenol system is shown in Figure 8 together with the experimental mass of impurity in the mother liquor after n cycles in which different fractions x of mother liquor were recycled. Figure 8 shows that more


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cycles are required to reach a steady state when a larger mother liquor recycle fraction x is used. The y-intercept of the line in Figure 8 denotes the amount of impurity in the starting material.

Figure 8. The amount of impurity in the mother liquor MLI versus the recycle fraction x after n=0 (O), 1 (∆), 2 (∇), 3 (◊) and 4 (□) cycles. The line is a plot of eq. 6 and represents the amount of impurity in steady state n  ∞. As described in the previous section 3.1, we sought a maximum recycle fraction through which a maximum yield could be achieved, while still limiting the amount of 4-nitrophenol to 5 g. The impurity limit of 5 g was set to be the criterion in our work as impurity quantities above this value would lead to crystallization processes becoming longer than 10 hours, as the 4nitrophenol was found to inhibit the time to reach solid-liquid equilibrium (Figure 5). Figure 9 shows that such threshold conditions involve a recycle fraction of x=0.55, which results in a steady state with 5 g of impurity in the solution and a yield of 75%. Without a mother liquor recycle operation, the product yield was around 60%.



Figure 9. The amount of impurity in the mother liquor MLI (open symbols) and total product yield Yt (filled symbols) plotted as a function of recycle fraction x after n=0 (○), 1 (Δ), 2 (∇), 3 (◊) and 4 (□) cycles. The dashed line depicts the maximum permitted amount of impurity in the mother liquor and the solid line represents the amount of impurity in steady state estimated through eq. 6 for n∞. Overall the presented work provides a strategy to seek optimum mother liquor recycle conditions that facilitate a maximum achievable yield while maintaining a controlled level of impurities. The presented model is expected to apply to other mother liquor recycle processes, provided that the impurities remain in solution. The aspects that could differ between crystallization systems are the process parameters described in section 3.1 and the y-intercepts of the figures in section 3.2, as these values are system specific. By increasing the recycle fraction of mother liquor, a significant reduction in solvent and solute waste can be realized. The presented experiments and model demonstrate that an easy approach can be applied to optimize crystallization processes involving mother liquor recycle steps, which enables increased efficiency in crystallization processes. 4. CONCLUSIONS A simple model was used to estimate the impurity build-up as a result of a mother liquor recycle operation. The experimental proof of principle for this model was demonstrated for the paracetamol / 4-nitrophenol system. The results show that a larger fraction of mother liquor recycle requires more cycles to reach a steady state. The experimental results were modelled


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from which the steady state impurity level for different mother liquor recycle fractions were estimated. The approach described herein also enabled the estimation of the optimum recycle fraction needed to achieve the highest possible product yield from a crystallization process. The results are expected to be applicable to other crystallization systems and as such can be used as a guide to estimate the optimum mother liquor recycle conditions that would lead to reduced product and solvent waste and improved process efficiency. Author Information Corresponding Author *E-mail: Leila.keshavarz.ul.ie ORCID René R. E. Steendam: 0000-0002-3363-4160 Funding This research has been conducted as part of the Synthesis and Solid State Pharmaceutical Centre (SSPC) and funded by Science Foundation Ireland (SFI) under Grant 12/RC/2275. REFERENCES (1)

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