Isolation of Pharmaceutical Intermediates through Solid Supported

Article pubs.acs.org/IECR

Isolation of Pharmaceutical Intermediates through Solid Supported Evaporation. Semicontinuous Operation Mode Matthaü s U. Bab̈ ler,*,† Mebatsion L. Kebede,† Raquel Rozada-Sanchez,‡ Per Åslund,¶ Björn Gregertsen,¶ and Åke C. Rasmuson†,§ †

Department of Chemical Engineering and Technology, KTH Royal Institute of Technology, SE-10044 Stockholm, Sweden AstraZeneca Pharmaceutical Development, Macclesfield SK10 2NA, U.K. ¶ AstraZeneca Pharmaceutical Development, SE-15185 Södertälje, Sweden § Department of Chemical and Environmental Science, Solid State Pharmaceutical Cluster, Materials and Surface Science Institute, University of Limerick, Limerick, Ireland ‡

ABSTRACT: Solid supported evaporation (SSE) is a simple, nonselective method for isolating nonvolatile compounds from a solution. The solution is put in contact with porous polymer beads onto which the compound deposits upon evaporation of the solvent. This brings some advantages over direct evaporation to dryness in terms of safety, thermal decomposition, and solid handling, as the loaded beads form a free-flowing granular material that is easily recovered. In this paper, SSE in a semicontinuous operating mode is investigated where the solution is continuously fed to (respectively sprayed over) an agitated bed of dry beads put under vacuum. It is found that under conditions where the solvent evaporation rate is high with respect to the feed rate, high bead loadings can be achieved before extensive sticking of beads and compound to the vessel walls occurs. The type of compound and solvent had little influence on the process performance, and, in cases where this was explored, the bead loading was found to be homogeneous. Based on a balance equation for the solvent fed to the system, a model is developed that results in a simple scale up criterion. The latter was successfully applied for transferring SSE from lab to the kilo lab scale.

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reactions during evaporation.6,7 A method that overcomes these limitations but preserves the simplicity and ease of development of direct evaporation has recently been proposed by Muller and Whitlock.7 In their solid supported evaporation (SSE) the solution containing the nonvolatile intermediates is put in contact with an inert porous polymer matrix in the form of granular beads onto which the compound deposits upon evaporation of the solvent. The resulting solid is in the form of a free-flowing granular material that is easy to handle and to recover. Also, the risk for thermal decomposition is lowered due to the additional heat sink provided by the polymer beads (cf. Muller and Whitlock7 for an experimental illustration). In this series of two papers, a detailed investigation of SSE is undertaken in order to explore its feasibility and applicability for isolation of typical pharmaceutical intermediates. While in the first paper,6 we studied SSE in batch mode where the polymer beads are dispersed into the solution and the solvent is evaporated thereafter, here, we consider a semicontinuous operation mode where the solution is continuously fed to the vacuum system of an evaporator where it is sprayed over an agitated bed of dry beads under simultaneous evaporation of the solvent (Figure 1). Such an operating mode appears particularly attractive in combination with microreactor8,9 and continuous flow reactor technology10,11 and continuous separators, such as SMB chromatography or extraction

INTRODUCTION Early in the development of a new drug product, soon after the candidate molecule has been selected, the drug compound needs to be produced in kilo quantities to have it available for toxicological tests and phase I trails.1,2 This typically proceeds along a quick adaptation of the lab synthesis route to the kilo scale as the tight timeline usually does not allow for a comprehensive route optimization. While relatively safe on the side of reactions, difficulties arise in the workup of the reaction products,3 in particular when they are to be obtained as solid materials. Crystallization, which is the common operation to obtain a solid, is notoriously difficult to scale up, partly due to insufficient process knowledge and poor controllability4 but mainly due to the inherent difficulty in upscaling mixing in particulate systems.5 Adapting these processes to the larger scale thus often calls for labor and resource intense development. However, at early stages (so-called crude stages) synthesis routes might allow for much simpler workup operations, i.e. processes where the intermediate is simply isolated from solution rather than purif ied as in the case of crystallization. Such nonstringent purity requirements might occur for, e.g. solvent swap operations, synthesis steps upstream to stages that can handle impurities or that include high grade purification, or processing of purified liquid streams coming from extraction or chromatography units. The most simple isolation method, i.e. direct evaporation to dryness that leaves behind the solidified nonvolatile intermediate, however, has some drawbacks that limit its applicability. These include poor solid handling, dusting, and the risk for thermal decomposition and side © 2012 American Chemical Society

Received: Revised: Accepted: Published: 14814

May 24, October October October

2012 8, 2012 20, 2012 21, 2012

dx.doi.org/10.1021/ie301359c | Ind. Eng. Chem. Res. 2012, 51, 14814−14823

Industrial & Engineering Chemistry Research

Article

sieve analysis, SEM, and literature data is presented in our accompanying work.6 Tapped density was estimated as 0.120 ± 0.002 g/cm3. Lab scale experiments were run in a desktop rotavap device (Büchi R-114, Flawil, Switzerland) equipped with a controlled water bath (Büchi B-480). Round glass flasks of two different sizes were used, namely 0.1 and 1 L. The condenser temperature was set at −10 °C using a cooler (Jubalo FP-50, Seelbach, Germany). A peristaltic pump (Medorex TL, Medorex, Nörten-Hardenberg, Germany) was used to feed the solution into the vacuum system. A metal capillary of 0.8 mm inner diameter and 1.2 mm outer diameter was used to channel the feed through one of the ports of the rotavap device into the vacuum system to the bed of beads. The end of the metal capillary was placed ca. 4 cm above the agitated bed of beads and was equipped with a spoonlike cap such as to guide the sprinkles downward onto the beads. The rotation speed of the rotavapor was set at a moderate value such as to keep the beads in a rolling motion. Kilo scale experiments were run in a bench scale rotavap device (Büchi R-220) equipped with a controlled water bath and a pressure controller (Vacuubrand CVC 211, Wertheim, Germany) having accuracies of ±1 °C and ±1 mbar, respectively. A round glass flask of 10 L volume was used, and the condenser temperature was set at −18 °C using a cooler (Huber UC020Tw, Offenburg, Germany). A peristaltic pump (Watson-Marlow 520S, Falmouth, U.K.) connected to a metal tube (outer diameter 4.5 mm, inner diameter 1.5 mm) was used to feed the solution into the vacuum system. The end of the metal tube was bent downward and fixed a few centimeters above the agitated bed of beads. No cap was used this time. Experimental Protocol. A given amount of fresh beads was charged to a round glass flask mounted to the rotavap device. The vacuum pressure and the bath temperature were set at given values, and the rotation of the flask was slowly increased until good bed mixing was achieved, i.e. the beads assumed a gentle tumbling motion. The flask was left under rotation for 5 min for equilibrating the bed temperature. A solution containing the dissolved compound was prepared at room temperature, and a certain amount was fed to the vacuum system using the peristaltic pump. In standard experiments, after feeding was stopped the beads were kept under vacuum until all solvent was evaporated, whereas in refined experiments, after feeding was stopped the vacuum was broken in order to measure the weight of the flask and its content, i.e. beads, solute, and solvent. The flask was then reconnected to the rotavap device and vacuum was reapplied in order to further evaporate the solvent. The flask with the dry beads was put in a fume hood at room temperature and left overnight to achieve complete dryness which was checked by recording the decrease in weight. As the decrease in weight during this additional drying period was very small, it was not applied in later experiments. From the weight difference of the flask containing the fresh beads and the flask containing the dry loaded beads, the amount of compound loaded onto the beads, mL, was obtained. The latter was used to estimate the actual flow rate of solution fed to the flask. Let c0 denote the concentration of the feed solution (in g/g solution), the actual flow rate Q (in g of solution per unit time) equates as Q = mL/(c0tF) where tF is the feeding time. Furthermore, from the weight difference of the flask immediately after feeding (as determined in refined

Figure 1. Schematic of semicontinuous SSE.

columns. In such cases, continuous processing of product streams by SSE would reduce the amount of solution that accumulate during a kilo lab campaign, an issue that is reported to be problematic when using continuous flow reactor technology.11 Our work thus complements the earlier study of Muller and Whitlock7 who studied SSE by piecewise addition of the solution to an agitated bed of beads put under vacuum. Various compounds resembling typical pharmaceutical intermediates (i.e., low molecular weight organic molecules) in different solvents were considered. Moreover, scale up of the process is explored both experimentally and theoretically by running experiments at different equipment size (vessel volumes ranging form 0.1 to 10 L) and by simple modeling based on mass and energy balances for the solvent fed to the system. In analogy to Muller and Whitlock,7 experiments were run in a rotary evaporator, which for the present purpose was equipped with a feeding system that allows for continuous addition of solution, and polypropylene beads of the Accurel MP1000 type were used as porous carriers. The latter recently received considerable attention as drug carriers12 and for immobilizing enzymes,13−15 as well as in other roles.16 From Figure 1 it is recognized that the process studied shares similarities with some related processes, e.g., dry impregnation for producing catalysts,17,18 tablet coating processes,19 or some type of continuous evaporators.20 All these processes involve spraying of a solution to a bed of beads under simultaneous evaporation of the solvent. The main difference between these processes and semicontinuous SSE lies in the desired product properties and amounts of material involved: In SSE, the aim is to load a relatively large amount of compound onto the beads while preserving their granular character, i.e. their free flowability, and avoiding extensive deposition of compound and sticking of beads to the vessel walls. On the contrary, crystallinity of the solidified compound and homogeneity within the beads are of secondary importance.

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EXPERIMENTAL SECTION Materials and Methods. Methanol (99.9%) and paminobenzoic acid (>99%) were purchased from Sigma-Aldrich Sweden (Stockholm, Sweden). Acetone (99.9%) and maleic acid (100%) were purchased from VWR Sweden (Stockholm, Sweden). 2-Propanol (99.7%) was purchased from Merck (Darmstadt, Germany). Paracetamol (98%) was purchased from AstraZeneca (Södertälje, Sweden). All chemicals were used as delivered without further purification. Microporous polypropylene beads of the Accurel MP1000 type (Membrana, Obernburg, Germany) with particles size 0.04 g/(min cm2), we found Js,0 = 0.035 g/(min cm2) as shown by the dashed curve in Figure 7. The latter gives an adequate description of the solvent loading for small flow rates, and in the case of Series B3 (triangles up) it even provides a better description than the linear model shown by the solid line. As semicontinuous SSE is favorably run at small flow rate and small solvent accumulation, assuming constant evaporation rate is a valid and useful simplification for developing simple process design and scale up rules as addressed next. Process Design and Scale Up. Successful operation of semicontinuous SSE requires the solvent accumulation to remain below a critical value. From the experiments shown in Figure 7 this critical value is determined as xF* ≈ 1 g/g beads. Based on this concept and the evaporation model presented above, a simple strategy for process design is proposed, and a scale up criterion is formulated. For the process design we assume that the vacuum pressure and the bath temperature are fixed a-priori, i.e. we would choose the highest possibles values dictated by either chemical constraints (such as to avoid side reactions and thermal decomposition), equipment and safety limitations, or the occurrence of clogging at a very high vacuum strength. In the cases studied in this work the vacuum pressure was 10−20 times lower than the vapor pressure of the pure solvent evaluated at the bath temperature. Also, we assume that the evaporation flux was determined in a previous lab experiment according to Js̅ = Q̅ evap/Ac, with Q̅ evap and Ac given by eqs 1 and 11, respectively. Ideally, Js̅ is determined from semicontinuous experiments although, in principle, it could be estimated from batch mode experiments, i.e. by estimating Q̅ evap from the slope of the drying curve as x → 0. Furthermore, the equipment size Vf and the feed concentration c0 are taken as given which typically is the case considering a kilo lab situation. As operators, we then have to select the amount of beads loaded to the flask, m0, and the bead loading ϕF we want to achieve. From this work, we conclude that a feasible bead loading is ϕF ≈ 1 g/g beads, while higher bead loadings required several feeding-drying cycles. Furthermore, the amount of beads is given by fixing the relative fill height to H/D ≈ 1/4 which was found to give satisfactory results; the amount of beads is then equated as described in the context of eq 11. Having these parameter fixed, the flow rate and the feeding time are readily obtained by solving eq 9 or eq 10 for Q; in the case of a

Figure 7. Solvent accumulation (main axis) and average evaporation rate (inset) from Series B1 (squares), B2 (diamonds), B3 (triangles up), and B4 (triangles down) from Table 2. Closed symbols indicate experiments leading to proper loading as shown in Figure 3c. The solid curve is the evaporation model with a linearly dependent evaporation rate (eq 9), while the dashed curve is with a constant evaporation rate.

accumulated solvent per g of beads at the end of feeding versus the feed flow rate divided by the contact area Ac, as calculated from eq 11. Experiments run in the 0.1 L flask are shown by squares (18% relative fill height, Series B1) and diamonds (26% relative fill height, Series B2), whereas experiments run in the 1 L flask are shown by upward triangles (18% relative fill height, Series B3) and downward triangles (26% relative fill height, Series B4). Although there is some scatter in the data, there is a clear correlation, and all data follow the same trend. Moreover, considering successful runs, i.e. runs that lead to proper loading as indicated by full symbols, it is seen that proper loading behavior correlates with a small solvent accumulation. Interestingly, experiments with a relative fill height of 18% in both flasks were successful up to a solvent accumulation of xF ≈ 1.3 g/g beads, whereas a relative fill height of 26% was 14821



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constant evaporation rate (Js̅ = Js,0) this can be done explicitly (cf. eq 10): Q=

Ac Js ,0 (1 − c0) − c0xF*/ϕF

;

tF =

continuous SSE as studied here is especially attractive in combination with continuous flow reactor systems, and continuous separators as the process streams could directly be processed which avoids the accumulation of large amounts of solution during a run. We successfully tested semicontinuous SSE for various compounds and various solvents. We found that adequate process performance required the evaporation rate to be high with respect to the feed rate of the solution such that solvent accumulation within the bed of beads remained low. A critical value for the latter was found to be x* ≈ 1 g/g beads. The evaporation rate is controlled by the vacuum strength and the bath temperature of the rotavap device. In our experiments these were set at relatively high values and, ignoring chemistry for once, were only limited by the occurrence of clogging of the feed pipe at too high vacuum strength. Our recommendation therefore is to operate the process at the maximum allowable vacuum strength and bath temperature, as dictated by equipment limitations, chemical constraints, and safety regulations. Based on a simple set of balance equations for the solvent fed to the systems and its evaporation, a simple rule for process design and scale-up was derived. The latter was successfully applied to run SSE at the kilo lab scale. The development time required was very short, particularly when compared to other down stream processes such as crystallization. Our model is readily employed to design different operating modes, such as piecewise addition of solution which was illustrated to allow for achieving bead loadings larger than 1 g/g beads.

m0ϕF Qc0

(12)

With these two quantities determined, all parameters for the process design are fixed. For illustration, eq 12 is applied to predict the adequate flow rate for the experiments run in the 10 L flask, i.e. Series B5 and B6 in Table 2. Using the evaporation flux determined from the data in Figure 7, i.e. Js,0 = 0.035 g/(min cm2), and Ac = 409 and 597 cm2 as given in Table 2 for Series B5 and B6, respectively, we find from eq 12 Qtheo = 18.4 and 27.0 g/min. Both these values are below the maximum feasible flow rates found experimentally, indicating that the former estimate is on the safe side and the calculated flow rates are likely to result in successful runs. Indeed, using the evaporation flux given above, the solvent loading for the three experiments of Series B5 equates to (from eq 10) xF = 0.73, 2.0, and 2.5, and the one of B6 to xF = 1.8. From these, only the last in B5 lead to deposition indicating that it is possible to work at higher solvent accumulation in the larger flask or that our estimate of the evaporation rate underestimates the 10 L flask. Investigations in this direction, however, were not undertaken within this work. For the scale up we consider a scenario where the process (with parameters selected as described above) has been successfully implemented in a vessel of volume V1, and we want to transfer it to a vessel of volume V2. The vessel are assumed to be of identical geometry, i.e. round flasks, and the same relative fill height of beads is used. Also, bath temperature, vapor pressure, feed concentration, and bead loading are kept constant on the two scales. Under these constraints, the amount of beads used on the larger scale is a factor (V2/V1) larger than the amount used on the smaller scale. Furthermore, the feed flow rate and the feed time scale as (see the Appendix for derivation) Q 2 = (V2/V1)2/3 Q 1 ,

tF ,2 = (V2/V1)1/3 tF ,1

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APPENDIX The scale up relation, eq 13, is readily derived by recasting the model equation, i.e. eq 2 with Qevap given by eq 6, in dimensionless form. The resulting equation reads as dx = 1 − c0 − acJs (x) dτ

(14)

where ac = Ac/Q and τ = tQ/m0. Under the given constraints, i.e. Ta, pG, c0, ϕF, H/D constant, both ac and τF (=tFQ/m0) are constant. Exploiting this, constant ac implies Q ∼ Ac while constant τF implies tF ∼ m0/Q. Noticing that Ac ∼ V2/3 and m0 ∼ V, the relations in eq 13 are obtained.

(13)

More detailed calculations based on eq 9 and 10 are required if the above constraints do not apply. For illustrating the application of eq 13 we notice that the first can equivalently be written as Q2/Ac,2 = Q1/Ac,1 which apparently implies equal ordinates in Figure 7 for the two scales. From Figure 7 we see that the highest feasible flow rate for the 0.1 L flask at 18% fill height is Q/Ac = 0.050 g/(cm2 min). Multiplied by the contact area of the 10 L flask at the same fill height, i.e. Ac = 409 cm2, we obtain Q = 20.7 g/min which is smaller than the largest feasible flow rate found on this scale (cf. B5 in Table 2). Hence, also in this case the estimated flow rate is on the safe side.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Funding from the European Community’s seventh Framework Program under grant agreement no. 228867, F3Factory, is gratefully acknowledged. Fruitful discussions with Lorenzo Codan (ETH), Frans L. Muller (University of Leeds), and Andy Godfrey (AstraZeneca) are gratefully acknowledged. Also, we thank Robert Carpenter (AstraZeneca) for help with the kilo lab experiments and Michaela Salajkova (KTH) for SEM measurements.

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CONCLUSIONS SSE provides a simple method for the isolation of intermediates at the lab and kilo lab scale. Typically, SSE would be applied in cases where purity requirements are not stringent and where direct evaporation to dryness is problematic, e.g. solvent swaps and simple solidification operations of hazard or reactive compounds. Limitations are given by solvents that have a very high boiling point and thus are unfeasible for evaporation or solvents that are incompatible with the polymer beads, i.e. solvents that dissolve or do not wet the polymer. Semi-

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LIST OF SYMBOLS Ac = surface area for heat transfer (eq 4), cm2 Am = surface area for mass transfer (eq 3), cm2 dx.doi.org/10.1021/ie301359c | Ind. Eng. Chem. Res. 2012, 51, 14814−14823


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Cp = heat capacity, J/(g K) c0 = feed concentration, g/(g solution) D = flask diameter, cm h = heat transfer coefficient (eq 4), J/(min cm2 K) H = bed fill height, cm Js = evaporation flux (eq 6), g/(min cm2) k = mass transfer coefficient (eq 3), g/(min cm2 Pa) m0 = mass of beads, g mL = mass of compound loaded on beads, g pG = vacuum pressure, Pa ps* = vapor pressure, Pa Q = feed rate, (g solution)/min Qevap = evaporation rate, (g solvent)/min T = temperature, K Ta = bath temperature, K tF = feeding time, min V = flask volume, cm3 x = solvent accumulation, g/g α = evaporation flux coefficient, g/(min cm2) ΔHv = heat of vaporization, J/g ϕ = bead loading, g/g

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Isolation of Pharmaceutical Intermediates through Solid Supported

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