Isolation of Pharmaceutical Intermediates through Solid Supported

Article pubs.acs.org/IECR

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

Department of Chemical Engineering and Technology, Royal Institute of Technology (KTH), 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 method to isolate dissolved compounds as a solid material. The solution is put in contact with granular porous polymer beads onto which the compounds deposit upon evaporation of the solvent. This brings some advantages over direct evaporation to dryness in terms of safety and handling of the solids. In this paper, SSE in batch mode is explored where the solution is added to the polymer beads at once, i.e. opposite to the semicontinuous mode where the solution is sprayed over a bed of beads. A number of compounds varying widely in their physical and chemical properties is studied. It is found that all compounds could be loaded onto the beads; however, the loading capacity depends on the properties of the compound and in general was lower than in the semicontinuous operating mode studied in an accompanying paper. For highly soluble compounds, higher loadings could be achieved when solvent evaporation was slow. In cases where tested, bead loading was found to be homogeneous within a batch. Recovery of compound from loaded beads was achieved by dispersing the beads in a solvent and washing of the filter cake after filtration. A relatively large amount of solvent is required to achieve full recovery.

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INTRODUCTION Chemical process development is an integral part in the development of pharmaceutical drug products. Typically, it is carried out by a Process R&D unit and starts once a drug candidate has been identified by Medicinal Chemistry.1,2 Thereby, the task given to Process R&D not only is to develop a safe, robust, and cost and resource efficient process but also to quickly produce the drug substance in kilo quantities to have it available for further testing and evaluations that run in parallel to process development. The production of this first kilo batch typically proceeds along the lab scale synthesis route proposed by medicinal chemistry, as the tight time line does not allow for a comprehensive optimization and adaption to the larger scale. This creates particular challenges to Process R&D, especially since lab scale synthesis routes usually conclude the stages by isolating the intermediate as a solid material, i.e. by employing precipitation, crystallization, or direct evaporation to dryness. As these processes are generally difficult to upscale, it thus not seldom occurs that transferring a work up procedure from the lab scale to the kilo scale results in poor performance in terms of yield, operability, and process safety. The latter two aspects are especially of concern regarding direct evaporation to dryness which often is applied early in the synthesis route where purity requirements are less stringent and, hence, resource intensive development of a crystallization process is not justified. Despite its simplicity on the lab scale, direct evaporation becomes problematic on larger scales, i.e. as the solid can form a sticking and dusting powder that is difficult to handle, and poor temperature control and increased © 2012 American Chemical Society

concentrations of reactive reagents and catalysts in the reduced liquor can cause unwanted side reactions or even thermal runaway to occur. A method that overcomes these difficulties but preserves the simplicity of direct evaporation has recently been proposed by Muller and Whitlock.3 In their solid supported evaporation (SSE), the solution containing the intermediate is put into contact with highly porous, inert polymer beads which act as carrier for the intermediate that deposits on them upon evaporation of the solvent (Figure 1). This brings several advantages over direct evaporation: (i) under proper operation, the loaded beads form a free-flowing granular material that is easily recovered and transferred between different processing vessels, (ii) crust formation and dusting is substantially reduced as the intermediate is contained within the porous beads, (iii)

Figure 1. Schematic of solid supported evaporation (SSE). The solution is put in contact with porous polymer beads that act as a support for taking up the solute upon evaporation of solvent. Received: Revised: Accepted: Published: 13445

May 24, 2012 September 7, 2012 September 21, 2012 September 22, 2012 dx.doi.org/10.1021/ie301358x | Ind. Eng. Chem. Res. 2012, 51, 13445−13453

Industrial & Engineering Chemistry Research

Article

Microporous polypropylene beads of the Accurel MP1000 type (Membrana, Obernburg, Germany) with particles size 99.5%), and p-aminobenzoic acid (≥99%) were purchased from Sigma-Aldrich (Stockholm, Sweden). Glycerol (99.5%), acetone (99.9%), and maleic acid (100%) were purchased from VWR (Stockholm, Sweden). Toluene (99.5%) was purchased from Merck (Darmstadt, Germany). Paracetamol (98%) was purchased from AstraZeneca (Södertälje, Sweden). Ethylene glycol distearate was purchased from Wako Chemicals (Neuss, Germany). Inakalant (CAS 335619-18-6, C23H34N4O5, purity 99.85%) was received from AstraZeneca (Loughborough, U.K.). Common digestive olive oil extra virgine was purchased from a supermarket. All compounds and solvents were used without further purification. 13446

dx.doi.org/10.1021/ie301358x | Ind. Eng. Chem. Res. 2012, 51, 13445−13453


Article

dried solid were negligible as the mass of recovered solid never exceeded the mass of solute and beads charged to the flask, and agglomeration was only observed at high flask charging for some compounds. In cases where the compound to be loaded was liquid at room temperature, i.e. olive oil and glycerol, the amount of compound dissolved in the initial solution was fixed to 3 mL in 20 mL of solvent, and the amount of beads charged to the flask was varied between 1 and 3 g. Evaporation of the compound under the given evaporation protocol was investigated for glycerol in separate experiments where the solvent was evaporated in absence of beads. From the two liquid compounds glycerol has a lower boiling point, i.e. 290 °C compared to ∼300 °C of olive oil, and it thus would be more prone to evaporation. The difference between the amount of compound recovered in the dry liquid and the amount of compound charged to the flask was found to be negligible, implying that evaporation of the compound can be ignored. Characterization of Loaded Beads. Free flowability was used as a criterion to characterize process performance. It is defined as the amount of solid material that could be poured out from the evaporation flask without scratching after the solvent was evaporated, divided by the total amount of beads and compound initially charged to the system. Despite being relatively rough and complex in its dependency on the physical properties of granular material, free flowability defined in this way provides an adequate measure to characterize the process, i.e. free flowability is the quantity relevant for the practitioner aiming at running SSE in the lab. Moreover, it is easy to measure and showed good reproducibility. In cases where all solid was recovered as a free-flowing granular material, i.e. no sticking of beads or deposition of neat compound occurred, the average bead loading is equal to the flask charging. This was confirmed for some compounds by differential scanning calorimetry (DSC) (TA Instruments, DSC 2920) where the amount of compound in a sample of loaded beads was estimated from the measured melting enthalpy. Applying this measurement to several samples from a single experiment allowed for assessing batch homogeneity. Dissolution from Loaded Beads. Loaded beads were prepared under conditions where all solute was loaded onto the beads, i.e., loaded beads formed a free-flowing granular material and neither sticking of beads nor deposition of neat compound on the glass wall occurred. About 1 g of loaded beads was dispersed in a given amount of solvent, and the mixture was stirred for 20 min at 25 °C. The beads were filtered off, and the filter cake was washed with a given amount of solvent. The amount of solute in the mother liquor from the first filtration and in the washing liquid was measured gravimetrically.

Figure 2. Porous polypropylene beads used in the present study: (a) microscope image, (b) particle size distribution form sieve analysis, and (c) and (d) SEM images.

pores of the size of the cells) is 1.96−1.99 cm3/g beads.8,9 Porosity is reported as 73 ± 2%,12 and tapped density was estimated as 0.120 ± 0.002 g/cm3. Solubility Measurements. A number of different compounds that vary widely in their physical and chemical properties was considered in the present study. An overview is given in Table 1. The compounds were chosen from different Table 1. Compounds Used in the Present Study compound paracetamol (PA) benzoic acid (BA) p-aminobenzoic acid (PABA) maleic acid (MA) inakalant (IN) sodium dodecyl sulfate (SDS) ethylene glycol distearate (EGD) olive oil (OL) glycerol (GL)

MW (g/mol)

solvent

solubility at 40 °C (g/g solvent)

151 122 137

methanol methanol methanol

0.464 ± 0.004 1.04 ± 0.003 0.338 ± 0.003

116 446 288

methanol methanol methanol

3.48 ± 0.24 2.76 ± 0.02 0.169 ± 0.001

595

toluene

0.791 ± 0.004

92

acetone methanol

fully miscible fully miscible

perspectives. Paracetamol (PA), benzoic acid (BA), and paminobenzoic acid (PABA) were chosen to represent typical pharmaceutical intermediates. PA is a well-known active pharmaceutical ingredient that is widely used in crystallization studies, whereas BA and PABA present primary materials for the synthesis of many drug compounds. Maleic acid (MA) is highly soluble in many solvents13 and was used as a model compound in a previous investigation of SSE.3 Inakalant (IN) was included as a high molecular weight pharmaceutical intermediate exhibiting complex phase behavior, i.e. the compound was found to exhibit stable oiling out in water/ ethanol mixtures.5 However, oiling out did not occur in the solvent used here, i.e. methanol, where IN exhibited a high solubility. Furthermore, sodium dodecyl sulfate (SDS) and ethylene glycol distearate (EGD) were used as model compounds for compounds having surfactant-like and waxlike character character, respectively. EGD also showed high solubility in toluene, a solvent that swells polypropylene. Lastly, normal digestive olive oil (OL) and glycerol (GL) were

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RESULTS Characterization of Polymer Beads. The polymer beads were analyzed by sieve analysis, microscopy, and SEM. The beads had an irregular shape and a relatively narrow size distribution with a peak diameter of 0.71 mm, as shown in Figure 2a and b. SEM images are shown in Figure 2c and d. The beads have a spongelike structure with cells of ca. 20 μm in diameter. Literature studies indicate that the cells are interconnected through pores in the meso- and macrorange having diameters of 3−15 nm.12 Reported values for the specific surface area vary in between 20−35 (Singh et al.,12 nitrogen adsorption and BET) and 56 m2/g (Sher et al.,8 mercury porosimetry), while the total pore volume (including 13447



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decreases as the flask charging increases due to sticking of loaded beads and deposition of free compound onto the wall of the glass flask. This is illustrated in Figure 5 showing the rotavap flask at the end of the experiments for different compounds and flask chargings. Figure 5a shows the rotavap flask for a relatively low flask charging where all compound is loaded onto the beads and practically no sticking or deposition occurred. In such a situation, free flowability reaches 100% and the average bead loading equals the flask charging, as all solute is loaded onto the beads. On the contrary, Figure 5b shows the rotavap flask under overloaded conditions where sticking of beads and deposition of compound occurred. In such a situation, the free flowability is smaller than 100% and the average bead loading might be higher or lower than the flask charging depending on the amount of beads and compound stuck onto the flask. Figure 6 illustrates this further by showing SEM images of loaded beads obtained at different flask chargings for the case of PA. It is seen that even for the smallest flask charging explored for this system, i.e. 0.5 g/g beads (Figure 6a), for which 100% free flowability was obtained, there is a significant amount of compound deposited on the surface of the beads. Interestingly, the visible deposition is concentrated on to a few spots on the surface of the beads, while the remaining surface still shows the typical cell-like structure of the neat beads. Similar observations were made by Muller and Whitlock3 for the case of MA in ethanol. With increasing flask charging the spots where the compound deposits grow and become denser (Figure 6b), which continues up to very high flask chargings where some of the beads appear to be fully covered by compound (Figure 6c). However, at such a high flask charging, where the free-flowing material comprised less than 10% of the solid mass, the bead loading is very nonhomogeneous and many beads showed only little loading while at the same time, the solid deposited on the glass wall of the flask comprised mainly neat compound with partly covered beads cemented in (Figure 6d). Under these conditions, it seems that deposition of neat compounds starts at the glass walls and the layer that forms glues the beads to the walls. From Figure 3 and 4 it is seen that 100% free flowability was achieved for nearly all compounds, however, at different flask chargings. Only for SDS (Figure 3d) and IN (Figure 4c) where deposition occurred at even very low flask charging, 100% free flowability was not reached. Maximum free flowability for these compounds were 98% and 93.5% (under evaporation protocol 2), respectively. The data for SDS also exhibited a minimum, as for this compound substantial agglomeration at higher flask charging took place. As the agglomerates had a low tendency to stick to the flask, the free flowability assumed a high value when the degree of agglomeration was high, leading to the minimum observed in Figure 4d. To quantify these findings, we determined the flask charging that lead to a free flowability of 95% (dashed lines in Figures 3 and 4) to which we refer to as the solute capacity under the given evaporation protocol. For PA, BA, and MA, relatively high solute capacities of 0.67, 0.52, and 1.0 g/g beads, respectively, were found under evaporation protocol 1. PABA, EGD, and SDS exhibited lower solute capacities of 0.31, 0.31, and 0.17 g/g beads, respectively. Very high solute capacities were found for the liquids OL and GL, i.e., 2.1 and 2.6 g/g beads, which when expressed in volume of solute reads as 2.3 and 2.0 mL/g beads, respectively. These values are close to the pore volume of the beads reported as 2.0

selected to account for compounds that are liquid at room temperature or compounds that form oil instead of crystallizing. The solubility of all compounds in their respective solvent at 40 °C is given in Table 1. The latter corresponds to the temperature of the water bath used in the evaporation experiments. The values shown refer to measurements conducted within this work as no literature data could be found for the given temperature or solvent. The measured solubility of PA is in good agreement with the extrapolated data of Granberg and Rasmuson14 who measured the solubility of PA in methanol at −5 to 30 °C. Likewise, the solubility of BA compares well with Thati et al.15 who report a solubility in ethanol at 40 °C of 0.810 ± 0.003 g/g solvent; the higher solubility in methanol is due to the higher polarity of the solvent. Lazzel and Johnston16 give the solubility of PABA in methanol at 40 °C obtained from interpolating their measurements as 0.38 g/g solvent, which is ca. 10% higher than our value. However, as mentioned by the authors their value is less certain as it is interpolated further from the experimental range. Regarding MA, the solubility in methanol was found to be very high. For this system Felthouse et al.13 report a solubility at 22.5 °C of 0.695 g/g of solvent, which differs by a factor 5 from our measurement at 40 °C. This can be explained by a very strong influence of temperature on the solubility of MA, or that MA formed an amorphous solid in our measurements. Notice that our indirect method used for estimating the solubility of such a highly soluble compound is more likely to underestimate the actual solubility instead of overestimating it (i.e., the time given for equilibration during the experiment might not be sufficient). No solubility data were found for the other compounds. Evaporation Experiments. Evaporation experiments were run for all nine compounds listed in Table 1. Different flask chargings were realized by varying the amount of compound dissolved in the original solution charged to the rotavap flask, while keeping constant the amount of solvent and beads. In the case of OL and GL, different flask chargings were achieved by varying the amounts of beads charged to the flask, while keeping the amount of solute and solvent constant. The evaporation protocol consisting of two stages of low (pressure P1) and high (pressure P2 < P1) vacuum strength, applied for a time t1 and t2, respectively, as given in Table 2. Table 2. Evaporation Protocols (Bath Temperature 40 °C) protocol

solvent

P1 (mbar)

t1 (min)

P2 (mbar)

t2 (min)

1a 1b 1c 2 3

methanol acetone toluene methanol methanol

300 300 100 300 200

20 5 20 40 20

100 100 50 100 100

20 10 40 20 20

Figures 3 and 4 show the free flowability, i.e. the relative amount of loaded beads that could be poured out from the flask without scratching, as a function of the flask charging. Measurements according to evaporation protocol 1 are shown by the square symbols, whereas circles and triangles refer to evaporation protocols 2 and 3, respectively. Error bars indicate the standard deviation in cases were experiments were repeated. In cases where free flowability was close to 100%, repeated experiments gave similar results leading to small error bars (i.e., smaller than the symbol size in Figures 3 and 4). As can be seen, for each compound the amount of free-flowing material 13448



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Figure 3. Free flowability as a function of flask charging under evaporation protocol 1 (cf. Table 2). Dashed lines indicate the flask charging leading to 95% free flowability. For panel (c) and (f), the x-axis shows volumetric flask charging.

Figure 4. Continuation of Figure 3. Square symbols refer to evaporation protocol 1, whereas circles and triangles refer to evaporation protocols 2 and 3, respectively (cf. Table 2). Dashed lines have the same meaning as in Figure 3.

Figure 5. Rotavap flask at the end of the evaporation for (a) adequate flask charging and (b) overloaded flask charging: (a) MA at a flask charging of 1 g/g beads and (b) SDS at 0.25 g/g beads.

mL/g beads8,9 suggesting that the loading capacity for liquid compounds is limited by the available pore volume. Batch Homogeneity. Uniformity of bead loading within a batch was explored by means of DSC for PABA and PA at a bead loading of 0.25 and 0.50 g/g beads, respectively, i.e. the highest feasible bead loadings that could be achieved for these compounds under evaporation protocol 1 (cf. Figure 3a and Figure 4a). Results are shown in Figure 7. In both panels curves refer to (from bottom to top) neat compound, neat beads, and loaded beads. Neat PABA (Figure 7a) gave a peak melting temperature of 191.2 °C and a melting enthalpy of hc,0 = 173.6 J/g, in good agreement with literature values.17 Neat PA (Figure 7b) gave a peak melting temperature of 171.3 °C and a melting enthalphy of hc,0 = 177.7 J/g, typical for polymorphic form I.18 The beads upon the first heating melted at around 160 °C giving a melting enthalpy of hb,0 ≈ 100 J/g which are typical values for polypropylene. For both compounds, the DSC of the loaded beads preserved the melting peaks of the compound and the polymer, implying that the two species exist as separate

Figure 6. SEM images of beads loaded with paracetamol obtained under evaporation protocol 1: (a) flask charging 0.5 g/g beads, (b) 1.0 g/g beads, (c) and (d) 2.0 g/g beads, (a−c) free-flowing beads, (d) solid manually scratched from the wall of the flask.

phases on the loaded beads, i.e. no eutectic was observed. The slightly higher melting temperature of the polymer seen in the DSC for the loaded beads is believed to be due to heat transfer effects within the sample. For PABA, the bead loading was estimated from the melting enthalpy of loaded PABA, hc, and loaded polymer, hb, according to

ϕ=

hc /hc ,0 hb /hb ,0

(1)

Results from eq 1 are given in the inset of Figure 7a that shows the bead loading for a number of samples taken while pouring 13449



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Figure 7. DSC analysis of loaded beads: (a) PABA at 0.25 g/g beads and (b) PA at 0.50 g/g beads. In both panels, curves 1 to 3 show DSC signals for neat compound, neat beads, and loaded beads, respectively. The heating rate was 10 K/min. The insets show the variation of bead loading for several samples estimated from (a) eq 1 and (b) the enthalpy ratio hc/hb.

Figure 8. Dissolution of solute from loaded beads for (a) MA and (b) PA. The contour plots show the amount of dissolution liquid (x1) versus the amount of washing liquid (x2) normalized by the total mass of solute in the system. Solid symbols show experiments with the yields of recovery (in %) printed next to it. The solid lines represent contour lines from eq 4. Inserts show the residuals of the yield, yexp − ymodel for the different experiments.

out the loaded beads from the flask. The samples show little variation around ϕ = 0.27 ± 0.01 which is slightly higher than the average bead loading from the mass balance; the difference is believed to be due to the estimate of the cold melting enthalpy of the polymer which in our measurements varied by 5%. Applying the same procedure to PA was not possible due to the overlapping peaks of the loaded beads (Figure 7b) which makes accurate determination of the melting enthalpies difficult. In this case bead homogeneity was characterized through the enthalpy ratio hc/hb. The latter is shown in the inset of Figure 7b for a number of samples taken while pouring out the loaded beads from the flask. The enthalpy ratio varies by 7% around the average value of 2.1, indicating good homogeneity. Dissolution Experiments. The recovery of solute from loaded beads was studied for MA and PA for which beads with a loading of 1.0 and 0.50 g/g beads, respectively, were prepared according to evaporation protocol 1 from Table 2. Dissolution in methanol was studied applying the procedure described above, consisting of a dissolution step followed by filtration and washing of the filter cake. Figure 8 shows the percentage of recovered solute in form of a contour plot with axes showing the amount of solvent used in the dissolution step (x1) and in the washing step (x2). Experimentally determined yields are printed next to the symbols representing the operation points. Lines and inserts refer to the model discussed shortly. The experiments presented here aimed at achieving complete recovery of the loaded solute. Hence, relatively large amounts

of solvents were used, and accordingly yields >99.5% could be achieved for both MA (Figure 8a) and PA (Figure 8b) by combining dissolution and washing steps.

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DISCUSSION Solute Capacity. Evaporation starts with a situation where the beads are suspended in a solution containing the compound. Initially, the concentration of the solution is uniform throughout the system, i.e. the concentration in the bulk equals the concentration within the pores of the beads. Upon evaporation, the solvent outside the beads will evaporate causing the concentration in the bulk to increase, and, hence, solute mass transfer into the pores of the beads will take place due to the concentration difference. Under ideal conditions, i.e., when the bulk concentration is far below the solubility and mass transfer is fast with respect to the rate of evaporation, evaporation of bulk solvent will proceed until all of it is gone while the solute is diffused into the pores, where it eventually solidifies upon drying of the beads. However, there are certain limitations to achieve these ideal conditions. On one hand, the solution has to be undersaturated until all of it is contained in the pores of the beads. This means the amount of compound to be loaded has to be soluble in the amount of solvent which is carried within the pores of the beads. If the solution becomes supersaturated when there is still bulk liquid nucleation might occur outside the beads. This will eventually cause deposition of free compound or, in the case the solidifying compound acts as a bridging agent, sticking of 13450



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the beads to the glass walls of the flask. On the other hand, mass transfer has to be fast with respect to evaporation such that local accumulation of solute outside the beads, and hence local supersaturation outside the beads, does not occur. Clearly, the former aspect is affected by the solubility of the compound with respect to the amount of solvent that is carried within the beads, whereas the latter aspect is affected by the rate of evaporation and better results in terms of free flowability are expected for a lower evaporation rate. The solvent carrying capacity of the beads can be approximated through the pore volume which is given in the literature as 2.0 cm3/g beads.8,9 Multiplied by the solubility at 40 °C (in units of g of solute per cm3 of solution, here approximated by multiplying the solubilities given in Table 1 by the solvent density) thus gives the maximal bead loading that can be achieved without solubility limitations. For PA, PABA, and SDS, that have moderate solubilities (cf. Table 1) these calculations give a solute capacity of 0.7, 0.5, and 0.3 g/g beads, respectively. Comparing these numbers to the experimentally determined solute capacity good agreement is found, i.e. the estimates are in the right order of magnitude. On the contrary, for the highly soluble compounds MA, BA, IN, and EGD, solubility would imply much larger solute capacities than found experimentally suggesting that mass transfer is the controlling mechanisms for these compounds. To explore this hypothesis, experiments with a lower evaporation rate were conducted for BA and IN. Circle symbols in Figure 4b and c show experiments run under evaporation protocol 2 where with respect to protocol 1, the duration of the low vacuum strength stage was doubled (cf. Table 2). As seen from Figure 4, the slightly lower evaporation rate of protocol 2 indeed gave better results and for a given flask charging the amount of free-flowing material increased with respect to experiments run under protocol 1. For further supporting our hypothesis, the influence of the evaporation rate was also explored for PABA whose loading under evaporation protocol 1 was found to be controlled by solubility. Experiments run under fast evaporation (evaporation protocol 3 in Table 2 with an increased vacuum strength in the first stage) gave smaller values for the free flowability as shown by the triangle symbols in Figure 4a, suggesting that under these conditions the system becomes mass transfer controlled. Interestingly, the free flowability at very high flask charging was found to be higher under fast evaporation, i.e. 41% compared to 15% under protocol 1. However, under conditions where deposition and sticking is strong as was the case here, reproducibility generally was poor such that observation made in Figure 4a was not explored further. Dissolution from Loaded Beads. For interpreting the recovery of solute from loaded beads presented in Figure 8, a simple model is developed, allowing us to determine optimal conditions for the recovery. It is assumed that during the dissolution step all solute is released from the beads and dissolves in the solvent. However, filtration of the beads does not remove all solvent, and a fraction of dissolved solute remains captured within the wet filter cake. According to this picture the yield of the dissolution step is y1 = (x1 − v0)/x1

liquid, the second step can be described as a washing out process. This leads to y2 = v0/x1(1 − e−fx2 / v0)

(3)

where x2 is the amount of solvent used for washing, and f is an efficiency factor that accounts for finite dispersion and mass transfer within the filter cake. Combining the above leads to the following expression for the yield of recovery: v y = y1 + y2 = 1 − 0 e−fx2 / v0 x1 > v0 x1 (4) Equation 4 applies when the amount of dissolution liquid can wet the bed of beads completely. In the case where this is not given, analogue considerations lead to y = 1 − e−f ′ [(x1+ x2)/ v0 − 1]

x1 < v0 ,

x1 + x 2 > v0 (5)

with an efficiency factor f ′ that may differ from f in eq 4. The lines in Figure 8 are contour lines according to eq 4; contour lines for small x1 according to eq 5 are omitted for the sake of clarity. As determination of the liquid holdup v0 was difficult in the experiments, both v0 and the efficiencies f and f ′ were estimated by fitting eqs 4 and 5 by hand to the experimental data. Thereby, we constrained v0 to be equal for the two sets of experimental data. From this, we obtained v0 = 5.2 mL/g beads, and f = 0.14 and f ′ = 0.25 for MA and f = 0.29 and f ′ = 0.27 for PA. The inserts show the residuals defined as the absolute difference between the experimental yields and the model predictions. The residuals scatter within ±0.04 and ±0.06 for MA and PA, respectively, which is reasonable with regards to the small amount of solute involved in the experiment and the simplicity of the model. Also, a liquid holdup of v0 = 5.2 mL/g is reasonable when contrasting it to the tapped density of the beads (ρt = 0.120 g/cm3) and the solid density of the polymer (ρp ≈ 0.9 g/cm3) from which we conclude that ca. half of the void volume is filled with hold up liquid. The difference in the washing efficiencies between MA and PA might be due to different mass transfer within the pores of the beads which was already recognized in the evaporation experiments to be a crucial factor. The higher washing efficiencies for small values of x1 for MA, i.e. f ′ being larger than f, might be due to a transient evolution of the holdup that was not considered in the model. From the model presented in eqs 4 and 5 optimal conditions for recovery can be determined. Optimal conditions refer to a minimum amount of solvent required to achieve a certain yield. Hence, the task is to minimize F(x1,x2) = x1 + x2 for a given yield y*. It is readily shown that the optimum is ⎧ x1 ⎪ ⎪ ⎪ ⎨ ⎪ x1 ⎪ ⎪ ⎩

= v0/f , x 2 = (v0/f ) ln[f /(1 − y*)] < v0 , x 2 = (v0/f ′)[f ′ − ln(1 − y*)] − x1

for y* < yc for y* > yc

(6)

where yc equates from ln(1 − yc) = f ′(1 − f + f)/( f ′ − f). The first of eq 6 implies that a combination of dissolution and washings is optimal, while the second implies that washing only is optimal. In the case of MA where f ′ is considerably larger than f we obtain yc = 0.92 which means that yields higher than 92% are optimally achieved by applying a single washing step. On the other hand, in the case of paracetamol where f ′ was

(2)

where x1 is the amount of solvent used in the dissolution step, and v0 is the liquid holdup that remains in the filter cake. The remaining solute is removed in the washing step. Considering a filter cake of small height and strong dispersion of the washing 13451



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found to be smaller than f we obtain yc > 1, and applying dissolution and washing is optimal to achieve a finite yield.

Also, we thank Michaela Salajkova (KTH) for SEM measurements and Zoran Bielobrk (KTH) for repeating some of the experiments.

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CONCLUSIONS All compounds studied in this work could be adequately loaded onto the beads. The maximum bead loading that leads to full recovery of the loaded beads (no sticking of beads or compound) depends on the compound and on the evaporation protocol. Two possibilities are considered to explain this, i.e. supersaturation is reached before all solution is comprised within the pores of the beads, and mass transfer of solute into the pores of the beads is slow with respect to the rate of evaporation causing creation of supersaturation outside the beads. In either case, nucleation would occur outside the beads giving rise to the formation of solid bridges that can glue the beads to the walls of the flask. Analyzing our experimental measurements, we found that the first mechanism applies to compounds with moderate solubility, whereas the second mechanism applies to compounds with high solubility. Homogeneity of the bead loading within a batch was investigated for two compounds by analyzing several samples by DSC. For PABA, the bead loading found by DSC was slightly higher than given by a mass balance but varied only by 2%, implying good homogeneity. For PA for which the melting peaks overlapped, the variation among the samples was higher due to the difficulty in estimating melting enthalpies. However, also in this case the variation was below 10% implying good homogeneity. Recovery of solute from loaded beads was studied for two compounds by dispersing the loaded beads in pure solvent and washing of the filter cake after filtering off the beads. Full recovery of solute required a relatively large amount of solvent. Analyzing the experimental data by a simple model we found that for PA optimal recovery is achieved by a combination of dispersing and washing, whereas for MA high recovery is optimally obtained by only washing of the beads. From our investigation we suggest the following design procedure for applying batch mode SSE. The bead loading, i.e. the amount of beads charged to the flask, is chosen such that all compound charged to the flask is well soluble in the amount of solvent captured inside the pores of the beads (whose volume is 2 mL/g beads). This gives a first estimate of the amounts of beads needed while a considerable increase may be required to achieve full recovery of the loaded beads (i.e., a factor 1.5 to 2 for moderately soluble compounds and even higher for higher soluble compounds). Slow evaporation is applied with vacuum pressures close to the vapor pressure of the solvent at the bath temperature until all bulk solvent is evaporated, followed by 2 to 3 times higher vacuum strength for drying of the beads. Slower evaporation can improve the process performance.

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LIST OF SYMBOLS AND ACRONYMS BA = benzoic acid EGD = ethylene glycol distearate GL = glycerol IN = inakalant (CAS 335619-18-6) MA = maleic acid OL = olive oil PA = paracetamol PABA = p-aminobenzoic acid SDS = sodium dodecyl sulfate SSE = solid supported evaporation f = washing efficiency hi,0 = melting enthalphy pure compound, J/g compound hi = melting enthalphy, J/g sample P = pressure, bar t = time, min v0 = bed holdup, mL xi = amount of solvent, mL y = yield of recovery, g/g ϕ = bead loading, g/g beads REFERENCES

(1) Federsel, H.-J. Chemical process research and development in the 21st century: Challenges, strategies, and solutions from a pharmaceutical industry perspective. Acc. Chem. Res. 2009, 42, 671−680. (2) O’Brien, M. K.; Kolb, M.; Connolly, T. J.; McWilliams, J. C.; Sutherland, K. Early chemical development at Legacy Wyeth Research. Drug Discovery Today 2011, 16, 81−88. (3) Muller, F. L.; Whitlock, B. An alternative method to isolate pharmaceutical intermediates. Org. Process Res. Dev. 2011, 15, 84−90. (4) Codan, L.; Babler, M. U.; Mazzotti, M. Phase diagram of a chiral substance exhibiting oiling out in cyclohexane. Cryst. Growth Des. 2010, 10, 4005−4013. (5) Deneau, E.; Steele, G. An in-line study of oiling out and crystallization. Org. Process Res. Dev. 2005, 9, 943−950. (6) Hoekstra, L.; Vonk, P.; Hulshof, L. A. Modeling the scale-up of contact drying processes. Org. Process Res. Dev. 2006, 10, 409−416. (7) Kontcho Kom, P.; Cook, W.; Kougoulos, E. Impact of laboratory vacuum contact drying on material drying rates and physical properties. Org. Process Res. Dev. 2011, 15, 360−366. (8) Sher, P.; Ingavle, G.; Ponrathnam, S.; Pawar, A. P. Low density porous carrier: Drug adsorption and release study by response surface methodology using different solvents. Int. J. Pharm. 2007, 331, 72−83. (9) Salis, A.; Sanjust, E.; Solinas, V.; Monduzzia, M. Characterisation of Accurel MP1004 polypropylene powder and its use as a support for lipase immobilisation. J. Mol. Catal. B: Enzym. 2003, 24−25, 75−82. (10) Sabbani, S.; Hedenström, E.; Nordin, O. The enantioselectivity of Candida rugosa lipase is influenced by the particle size of the immobilising support material Accurel. J. Mol. Catal. B: Enzym. 2006, 42, 1−9. (11) Kolling, D. J.; Suguino, W. A.; Brod, F. C. A.; Arisi, A. C. M. Immobilization of a recombinant esterase from Lactobacillus plantarum on polypropylene Accurel MP1000. Appl. Biochem. Biotechnol. 2011, 163, 304−312. (12) Singh, K.; Bharose, R.; Singh, V. K.; Verma, S. K. Sugar decolorization through selective adsorption onto functionalized Accurel hydrophobic polymeric support. Ind. Eng. Chem. Res. 2011, 50, 10074−10082. (13) Felthouse, T. R.; Burnett, J. C.; Horrell, B.; Mummey, M. J.; Kuo, Y. J. Maleic anhydride, maleic acid, and fumaric acid. Kirk-Othmer Encycl. Chem. Technol. 2001, 15, 1−49.

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. The authors thank Frans L. Muller (University of Leeds), Andy Godfrey (AstraZeneca), and Lorenzo Codan (ETH) for useful discussions and comments. 13452



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(14) Granberg, R. A.; Rasmuson, A. C. Solubility of paracetamol in pure solvents. J. Chem. Eng. Data 1999, 44, 1391−1395. (15) Thati, J.; Nordström, F. L.; Rasmuson, A. C. Solubility of benzoic acid in pure solvents and binary mixtures. J. Chem. Eng. Data 2010, 55, 5124−5127. (16) Lazzell, C.; Johnston, J. Solubility relations of isomeric organic compounds viii. solubility of the aminobenzoic acids in various liquids. J. Phys. Chem. 1928, 32, 1031−1041. (17) Gracin, S.; Rasmuson, A. C. Polymorphism and crystallization of p-aminobenzoic acid. Cryst. Growth Des. 2004, 4, 1013−1023. (18) Sacchetti, M. Thermodynamic analysis of DSC data for acetaminophen polymorphs. J. Therm. Anal. Calorim. 2001, 63, 345− 350.

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Isolation of Pharmaceutical Intermediates through Solid Supported

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