Accepted Manuscript. Thermodynamics of Fenoxycarb in Solution. Manuel Kuhs, Michael Svärd, A ke C. Rasmuson

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1 Accepted Manuscript herodynaics o Fenoxycarb in Solution Manuel Kuhs, Michael Svärd, A ke C. Rasuson PII: S00-964(3)006-7 DOI: Reerence: YJCH 3577 o appear in: J. Che. herodynaics Received Date: 5 April 03 Revised Date: 3 June 03 Accepted Date: 0 June 03 Please cite this article as: M. Kuhs, M. Svärd, A. Rasuson, herodynaics o Fenoxycarb in Solution, J. Che. herodynaics (03), doi: his is a PDF ile o an unedited anuscript that has been accepted or publication. As a service to our custoers we are providing this early version o the anuscript. he anuscript will undergo copyediting, typesetting, and review o the resulting proo beore it is published in its inal or. Please note that during the production process errors ay be discovered which could aect the content, and all legal disclaiers that apply to the journal pertain.

2 herodynaics o Fenoxycarb in Solution Manuel Kuhs a*, Michael Svärd b and Åke C. Rasuson a,b a Departent o Cheical and Environental Science, Materials and Surace Science Institute, University o Lierick, Lierick, Ireland. b Departent o Cheical Engineering and echnology, KH Royal Institute o echnology, Stockhol, Sweden. * Corresponding author at: Departent o Cheical and Environental Science, Materials and Surace Science Institute, University o Lierick, Lierick, Ireland. el.: E-ail address: anuel.kuhs@ul.ie (Manuel Kuhs) Abstract he solubility o enoxycarb has been deterined between 78 and 38 K in several organic solvents. he solid phase at equilibriu and soe indication o polyorphis has been properly exained by powder XRD, DSC, Raan and AR-FIR spectroscopy, solution H NMR and SEM. Using literature data the activity o the solid phase within a Raoult s law deinition has been calculated, based on which solution activity coeicients have been estiated. In ethyl acetate, the van t Ho enthalpy o solution is constant over the teperature range and equals the elting enthalpy. However, it is shown that the solution is slightly non-ideal with the heat capacity dierence ter copensating or the activity coeicient ter. In toluene, the van t Ho enthalpy o solution is constant as well but clearly higher than the elting enthalpy. In ethanol, ethanol and isopropanol, van Ho curves are strongly non-linear, the slope however clearly approaching the elting enthalpy at higher teperatures. In all solvents, positive deviations ro Raoult s law are prevailing. he activity coeicients ollow a decreasing order o isopropanol > ethanol > ethanol > toluene > ethyl acetate, and in all solvents decrease onotonically with increasing teperature. he highest activity coeicient is about 8 corresponding to about.5 kj/ol o deviation ro ideality. Keywords solubility, activity, activity coeicient, van t Ho enthalpy, ideal solution, heat capacity

3 Introduction Prediction o elting point and solubility o a copound is o high interest in pharaceutical research since it has a signiicant inluence on the bioavailability o drugs and provides a basis or process design. Industrial crystallization processes, considered the single ost iportant unit operation in the pharaceutical industry [] because over 90% o all pharaceutical products contain crystalline ingredients [], oten require accurate knowledge o the solubility and elting point o the crystalline aterial or its precursors. Measuring solubility is not only tie-consuing but also notoriously diicult, with inconsistencies in reported data existing even within the paper in which the data is published [3]. Melting points are soeties ipossible to easure experientally when the solid phase o interest is etastable or becoes etastable (enantiotropy) at higher teperatures [4; 5]. hus, any techniques are being developed to predict solubility and elting point, though none are as yet suicient to replace experiental work or accurate data [6]. A coon ethod or estiating elting teperature is through linear extrapolation o solubility data in a van t Ho plot, which assues ideal solution behaviour and negligible heat capacity dierence between solid and elt [7]. More coplex ethods include classical Quantitative Structure-Property Relationship (QSPR) odelling[8], group contribution ethods [9] and correlating siilar copounds [0]. Prediction o the solubility at dierent teperatures is done by the Hildebrand-Scatchard odels [], as well as several ethods that involve experientally obtaining one or ore solubility data points [6; ]. As expected, the latter are ar ore accurate, with one ethod s odelled solubility atching the real solubility within 5 K on average [6], while the orer deviate on average by 50% []. Soe o these ethods also assue ideal solution behaviour and negligible heat capacity dierences between solid and elt, while a recent one includes activity coeicients estiation [6]. Fenoxycarb is an insect growth regulator with juvenile horone activity [3]. It has cheical orula C 7 H 9 NO 4 and systeatic nae -(p-phenoxyphenoxy)ethylcarbaate. he olecular structure, Figure, shows signiicant siilarity to soe pharaceutical olecules, e.g. enoibrate. Its elting

4 teperature and enthalpy are reported as 36.3 K and 6.98 kj ol -, respectively [4]. o our knowledge, the only previously reported solubility data is or water at 93.5 K (viz g / kg) [5]. Here, we report careul easureent o the solubility in several organic solvents. Using published calorietric data [4] o elting properties and solid and elt heat capacities, we have rigorously calculated the ideal solubility, which is then used to estiate activity coeicients o enoxycarb in the dierent solvents over the easured teperature range. he solubility relects the equilibriu situation between two dierent phases: the solute as a solid phase and the solute in solution. At least one third o all organic copounds are polyorphic, i.e. they can or dierent crystals structures. Since the physical properties dier or polyorphs o the sae copound, the solubility o a copound depends on the polyorph, and it is vital that solubility easureents are associated with a proper identiication and control o the solid phase [6; 7]. Accordingly, this paper also contains an investigation o the solid phase or which the solubility data is deterined, and soe concerns about possible polyorphis are careully analysed. o our knowledge only one crystal or o enoxycarb has been reported, and recently we reported its structure or the irst tie [8]. Figure. Fenoxycarb.

5 Experiental he purities and suppliers o all cheicals are reported in able. All aterials are used directly without urther puriication. Fenoxycarb is received as a large, congealed ass; no aorphous content was ound by powder x-ray diraction. able. Source and ass raction purity o cheicals. Cheical Nae Source Purity Fenoxycarb Syngenta, Switzerland Isopropanol VWR Methanol Siga-Aldrich Ethanol Siga-Aldrich Ethyl Acetate Siga-Aldrich oluene Siga-Aldrich Solubility Solubility was deterined using a odiied or o a gravietric technique previously described [6; 9] which is considered to be one o the ost accurate ethods or easuring solubility [3]. Solutions saturated at predeterined teperatures between 78 and 38 K were created by adding an excess o solid enoxycarb to a solvent in a sealed vial (30 l, PFE/EDPM screw cap), equipped with a agnetic stirring bar (0.5 x 0.8 in), placed on top o a subersible agnetic stirring plate (Mag) in a teperature-controlled water bath (Grant GR50, stability ± K and uniority ± 0.0 K at 30 K). he teperature o the water bath was easured with a calibrated digital theroeter (Dostann P650, accuracy ±0.03 K). he solutions were stirred or hours at 400 rp, ollowed by a 6 hour settling period during which the stirring was turned o. Syringes (5 l) and syringe ilters (0. µ PFE) were pre-heated/cooled to the sae teperature as the water bath. hese were then used to ilter ~0.5 l o the supernatant into pre-weighed glass vials, which were quickly sealed to

6 prevent evaporation. he vials were weighed, uncovered and placed in a ue hood or solvent evaporation, weighed regularly until ully dried (< 0.% ass loss over 48 hours) and the solubility calculated. he balance used had an accuracy o ±0.000 g. o test the repeatability o achieving an equilibrated solution, the solubility at 78, 83 and 88 K was deterined in duplicate. he repeatability o the iltration and drying processes was tested by iltering and drying the 93, 303 and 33 K supernatants in duplicate. he concentration o a known solution o enoxycarb in isopropanol was also deterined by the sae gravietric ethod and diered only 0.5% ro the known concentration. o veriy that hours dissolution is suicient to achieve equilibriu, saturation was also approached ro supersaturation as ollows. he solutions were heated 0 K above the desired teperature and stirred or hours, allowing ost o the excess solid to dissolve. he water bath was then set to the desired teperature, and the solutions let stirring at this teperature or hours. he solids were allowed to settle or 6 hours and the supernatant analysed as above. his was done only or the lowest teperature analysed (i.e. 5 K) since it was presued that reaching equilibriu would be slowest at this teperature.. Solid Phase Characterisation A ¼ inch diaeter iersion probe attached to a Kaiser RaanRxn Analyzer with an Invictus 785 n NIR laser set to 00 W was used to obtain the Raan IR spectra o the solutions and undissolved solids used in. by direct insertion o the probe into the vials. ic Raan sotware, version 4., was used to collect the spectra ro 50 3,400 c - with an exposure tie between 5 and 45 s (calibrated or each saple to give a pixel ill o around 50% at the detector), 3 accuulations, a resapling interval o c -, cosic ray reoval and intensity correction. Solvent subtraction yielded the spectra o the dissolved and undissolved enoxycarb. Beore drying and without any saple preparation, the excess solids (in the or o slurries) were reoved ro the solubility vials using a spatula and placed on a PerkinEler Universal AR Sapling Accessory attached to a PerkinEler Spectru 00 F-IR instruent. he IR spectru

7 between 600 and 4,000 c - was collected using 4 background-subtracted co-added scans. he saples were then dried and ground using a ortar and pestle and analysed again by AR-FIR. Filtration could not be used during the drying process because clogging o the pores would occur due to the thickness o the slurry, and so unaided air drying at roo teperature (because o the low elting point o enoxycarb and to prevent any potential phase transoration) was eployed. Dried saples both beore and ater grinding were spin-coated with gold and analysed using a JEOL CarryScope Scanning Electron Microscope JCM Dried, ground saples were also placed on a silicon crystal zero-background disc, soothed using a glass slide and then analysed using a Phillips PANalytical X Pert MPD Pro with PW3064 saple spinner using a Cu Kα source (λ =.548 Å), nickel ilter, ixed divergence slit o /, and accelerating voltage and anode current o 40 kv and 35 A, respectively. Data was collected ro 5 70 θ in steps o at a rate o s per step and a saple rotation o 5 rp using PANanalytical Data Collector, version.0. he sae saples were then checked or presence o solvent or ipurities using a JEOL JNM-GSX 70 F Nuclear Magnetic Resonance (NMR) instruent by dissolving the in deuterated chloroor (99.8% deuteration, 0.03% MS, VWR BDH Prolabo) and carrying out H solution NMR at 70 MHz. Using a PerkinEler Pyris Dierential Scanning Calorietry (DSC) instruent, the theral properties o the dried, ground saples were easured by placing around 5 g o a saple into a 40 μl aluiniu pan without holes, which was then sealed by a 30 μl aluiniu lid with holes and placed into the saple holder. he reerence pan consisted o the sae two aluiniu pans without saple. he saple was heated ro 88.5 to K at a rate o K/in (the irst cycle), cooled back to 88.5 K at 00 K/in, held at that teperature or 0 inutes and then reheated to K at K/in (the second cycle). Ater baseline subtraction, the elting point (extrapolated onset teperature) and enthalpy o usion were calculated.

8 he Kaiser RaanRxn Analyzer was then used to obtain the Raan spectra o the dried, ground saples. Operating conditions were the sae as above except using an MR Probe in an enclosed saple container or non-contact analysis instead o an iersion probe. 3 Results & Discussion 3. Solubility he solubility o enoxycarb in various organic solvents at dierent teperatures is presented in able (as ole raction) and shown graphically in Figure (as g/g solvent). Values obtained by approaching saturation ro supersaturation did not show any signiicant dierence, coniring that the values in able represent the true equilibriu solubility at the given teperatures. he low CVs or the 78 K, 83 K and 88 K data conir that achieving equilibriu is reproducible, while the low CVs at 93 K, 303 K and 33 K veriy the repeatability o the drying process (see.). Clearly the solubility is very high in all these solvents, partly relecting that the teperature range is close to the elting point o enoxycarb. able. Mole raction solubility (x eq ) o enoxycarb at teperature in various solvents, along with standard uncertainties u(x). Methanol Ethanol Isopropanol Ethyl Acetate * oluene * (K) x eq u(x) x eq u(x) x eq u(x) x eq u(x) x eq u(x) * Solubilities at 98.4, and 37.8 K were only deterined or the alcohols as the teperature dependence is ost arked in these solvents. Standard uncertainty u() = K. At 9.99 K.

9 Figure. Solubility o enoxycarb in ive organic solvents together with regression lines (Eqn. ). Nordströ and Rasuson [6] evaluated dierent regression odels or the solubility o various organic solutes in organic solvents, and ound that in ost cases a siple two- or three-paraeter equation suices to obtain a good it to the data. However, it is ound that or enoxycarb in the solvents evaluated in the present work the teperature dependence o the solubility in the investigated teperature interval is ore coplex. he solubility data over the teperature range K was ound to be satisactorily described by Eqn., which has been shown to provide good accuracy and robustness [6]. For ethyl acetate, a sipler unction was used (linear with respect to /) by setting two paraeters equal to zero. x eq denotes the ole raction solubility and the teperature in Kelvin. Coeicients o Eqn. are given in able 3. A B ln x eq = C D ln () able 3. Coeicients o Eqn. or enoxycarb in various solvents, with associated goodness o it. Methanol Ethanol Isopropanol Ethyl Acetate oluene 0 8 A B C D χ

10 he ole raction solubility decreases in the order: ethyl acetate > toluene > ethanol > ethanol > isopropanol. Also, although not quantitatively easured in this work, it was observed that enoxycarb has by ar the lowest solubility in water. In the lower teperature range the solubility is clearly lower in all the alcohols. Fenoxycarb has two aroatic rings, and both hydrogen bond donating and accepting unctionality. All tested solvents are capable o accepting a hydrogen bond (the π-electron syste o toluene s aroatic ring can act as a weak hydrogen bond acceptor [0]), while ethyl acetate and toluene are incapable o hydrogen bond donation. Hence, neither ethyl acetate nor toluene can hydrogen bond internally, and both are clearly capable o solvating the enoxycarb olecule. he alcohols have higher cohesive energy and lower capability o solvating the aroatic rings. 3. herodynaics o the Solid Phase Choosing the sae reerence state or the activity o the pure solid as or the solute in solution, viz. the pure copound as a supercooled elt at the sae teperature, we have: a = a eq = x eq γ () eq where a is the activity o solid enoxycarb, being equal to the activity o the solute in the saturated solution, a eq, soeties called the ideal solubility, and γ eq is the activity coeicient, deined within a Raoult s law raework. he solid-state activity is directly related to the Gibbs ree energy o usion, according to: ln a = ΔG R = ΔS R ΔH R (3) I calorietric data is available, values o the enthalpy and entropy o usion at a given teperature can be obtained by integration ro the elting point :

11 ( ) Δ Δ Δ = p p d C R d C R R H a ln (4) where ΔH ( ) is the enthalpy change upon elting, and ΔC p is the heat capacity dierence between the supercooled pure elt o the solute (used as reerence state in the deinition o the activity coeicient) and the solid. he elting teperature and the elting enthalpy o enoxycarb are 36.3 K and 6.98 kj/ol, respectively [4]. he heat capacity dierence has been deterined ro the heat capacity o the solid and the elt [4] by linear extrapolation o the latter to the supercooled region, Figure 3. In the teperature interval 70 K 330 K, the heat capacity dierence is accurately (R = 0.998) described by a linear equation: ( ) r q C p = Δ (5) resulting in q = 06.5 J/(ol K) and r = J/(ol K ). Insertion o Eqn. 5 into Eqn. 4 and integrating results in: ( ) Δ = ln ln ln R r R q R H a (6) Figure 3. Heat capacity o the solid (blue), elt (red) with sybols showing experiental data points [4], dashed lines showing linear extrapolations, and the dierence between elt and solid shown in green. and the Gibbs ree energy, enthalpy and entropy o usion can be calculated by:

12 Δ = Δ ln ln ) ( ) ( r q H G (7) ) ( ) ( ) ( ) ( r q H H = Δ Δ (8) Δ = Δ r q H S ln ln ) ( ) ( (9) Figure 4 shows the Gibbs ree energy, enthalpy and entropy o usion versus teperature. Notably, the Gibbs ree energy o usion is a reasonably sall dierence between airly large enthalpic and entropic contributions (~0% at 73 K, decreasing to zero at the elting point). In engineering literature the heat capacity ters are oten neglected in calculation o the activity o the solid phase. For coparison, Figure 4 also shows the corresponding curves using the approxiation ΔC P = 0, i.e. the enthalpy and entropy o usion are independent o teperature, leaving only the irst ter on the right-hand side in Eqn. 6. Notably, this approxiation, although generally poor at teperatures ar below the elting teperature [] in this instance leads to only a sall error in ΔG. However, it is clear ro Figure 4 that this is due to the inluence o teperature on the entropy o usion and on the enthalpy o usion copensating each other.

13 Figure 4. ΔG (solid lines), ΔH (dashed lines) and ΔS (dotted lines) calculated using ΔC P = q r( ) (thick dark blue lines) and ΔC P = 0 (thin red lines). 3.3 Solubility eperature Dependence he teperature dependence o the solubility yields the so-called van t Ho or apparent enthalpy o solution, Δ H : vh So ln vh ln x ΔH (0) So ln = R eq where R is the universal gas constant and ΔH vh So ln at a given teperature is equal to the slope in a van t Ho plot ultiplied by -R. I ΔH vh So ln is constant, integration o Eqn. 0 yields: vh ΔH So ln x = R ln const () Figure 5 shows the solubility data in a van t Ho plot. While the curves or ethyl acetate and toluene are very linear, the alcohol curves are strongly non-linear. Figure 5. van t Ho plot o enoxycarb solubilities in ive organic solvents together with regression lines. Black solid line represents the calculated ideal solubility (Eqn. 6). In ost reported solubility data, a van t Ho plot is presented as a straight or alost-straight line, and it is not uncoon to ind iplicit or explicit stateents that a van t Ho plot should yield a straight

14 line, i.e. that the van t Ho enthalpy o solution is independent o teperature []. However, it can be shown [6] that the ull therodynaic interpretation o the van t Ho enthalpy o solution is given by: ΔH vh Soln = ΔH ( ) lnγ ΔC pd R eq () he irst two ters on the right-hand side in Eqn. together represent the enthalpy o usion at, while the third ter contains the teperature derivative o the activity coeicient at equilibriu, γ eq, in a saturated solution deined within a Raoult s law raework. It is to be noted that this ter is not equal to the enthalpy o ixing, which explains why the van t Ho enthalpy o solution diers ro the therodynaic enthalpy o solution [3]. It ollows ro Eqn. that non-linearity o the van t Ho curve can occur because the heat capacity ter cannot be neglected, and/or because o the teperature dependence o the activity coeicient. he teperature derivative o the activity coeicient includes the eect o the strongly increasing concentration o the saturated solution with increasing teperature. he behaviour shown in Figure 5 agrees with that predicted by Nordströ and Rasuson [6]. For positive deviations ro Raoult s law signiicant non-linearity ay occur, leading to van t Ho plots quite siilar to those experientally observed in the present work. It has also been shown [6] that all solubility curves should converge to the elting teperature/enthalpy o usion at increasing teperature, which again is observed in our data. In Figure 6, the van t Ho enthalpy o solution is shown together with its coponent ters (Eqn. ), as a unction o teperature or the ive organic solvents. For the sake o this analysis, Eqn. 3, a three-paraeter equation obtained ro a 3 rd order polynoial with respect to /, has been itted to the experiental solubility data. With decreasing -, Eqn. 3 exhibits the appropriate liiting behaviour as given by Eqn. 4 a-b, and the it is only arginally worse overall than that obtained or Eqn..However, as approaches the lower liit o experiental data, the odel starts to deviate in its slope ro the experiental data, ost clearly seen or ethanol and isopropanol. For this reason, the lower liit o the teperature range in Figure 6 (and in Figure 7 and 8) is 80 K.

15 Δ = ln 3 ) ( ln 3 3 G F E R H x eq (3) ln = 0 eq x at = (4 a) eq vh So H x R H Δ = = Δ ln ln at = (4 b)

16 Figure 6. he van t Ho enthalpy o solution and its coponents (Eqn. ) plotted against teperature or ive organic solvents. It can be seen in Figure 6 that the heat capacity ter (i.e. the dierence between the red and the green curve) has a relatively weak inluence on the van t Ho enthalpy o solution, and that it is chiely the third ter in Eqn., the enthalpy change related to dissolving the solute into the solvent, that governs the shape o the van t Ho curves, in particular or the alcohols. he van t Ho plot in ethyl acetate ors a straight line (R value o the linear it is ) reaching ln x = at the elting point o 36.3 K. he resulting constant van t Ho enthalpy o solution in ethyl acetate is essentially identical to the reported enthalpy o usion at the elting point, 6.98

17 kj/ol [4]. Accordingly, the ethyl acetate solution could easily have been istaken or a perect ideal solution. However, Figure 6 shows that the heat capacity ter is ar ro negligible but is very well copensated or by the activity coeicient derivative ter in ethyl acetate. In toluene, the van t Ho enthalpy o solution becoes soewhat higher as the activity coeicient ter is larger (i.e. the teperature derivative is ore negative). In the alcohols, the activity coeicient ter doinates copletely, and depends signiicantly on teperature. 3.4 Solution Activity Coeicients Inserting the calculated solid-state activity according to Eqn. 6 together with solubility described using Eqn. 3 into Eqn. allows us to estiate the activity coeicient as a unction o teperature in the dierent solvents, Figure 7. In ethyl acetate the axiu value o the activity coeicient within the experiental teperature range is.7 and in toluene it is.7, in both cases at 78 K. In ethanol and ethanol the values are clearly larger and in isopropanol the activity coeicient ranges up to about 8 in the teperature range investigated. All solutions show positive deviation ro Raoult s law and the activity coeicients gradually approach unity with increasing teperature. Activity coeicients close to unity suggest that solute-solute, solute-solvent and solvent-solvent interactions are roughly equal (ideality), while coeicients greater than unity iply solute-solvent interactions signiicantly weaker than either solvent solvent interactions and/or solute-solute interactions. hus it is evident that the alcohol olecules interact ore strongly with each other than with enoxycarb olecules while all interolecular interactions in enoxycarb solutions o ethyl acetate and toluene are airly siilar in strength. his is probably owing to the act that alcohols are both hydrogen donating and accepting while ethyl acetate and toluene are hydrogen bond accepting only.

18 Figure 7. Activity coeicients in saturated solutions in ive organic solvents. By dierentiating Eqn. 3 according to Eqn. 0, and inserting the resulting van't Ho enthalpy into Eqn., the teperature derivative o the saturated solution activity coeicient in the ive solvents is estiated, Figure 8. In general the derivative is negative, i.e. the activity coeicient decreases with increasing teperature, as seen in Figure 7. At teperatures below the range o experiental solubility data soe derivatives turn positive; this is an artiact steing ro the use o Eqn. 3 to correlate experiental solubility data. he activity coeicient derivatives range ro zero to about - 0., eaning that in isopropanol at approx. 93 K the activity coeicient changes by about % or every degree Kelvin. On the other hand it ight appear surprising that such nuerically sall values have such a strong ipact on the van t Ho enthalpy o solution, Figure 6. However, it should be noted that the actor R in Eqn. ranges ro 64 to 840 kj K/ol over the experiental teperature range, i.e. even very low activity coeicient derivatives will have a sizeable ipact, as in the case o ethyl acetate. For the values observed or the alcohols the contribution ro the activity coeicient derivative copletely doinates the van t Ho enthalpy o solution, Figure 6, and the slope o the van t Ho curves, Figure 5.

19 Figure 8. eperature derivative o the activity coeicient in saturated solutions o ive organic solvents. 3.5 Solid Phase Identiication It is conceivable that the strongly non-linear van t Ho plots in the alcohols could be a ix o two curves representing two dierent solid phases (polyorphs or solvate), i.e. a solid phase transoration could occur between 90 and 33 K [4]. During the course o this work, crystals appearing to the naked eye to be quite dissiilar in size and shape have been obtained. hree distinct types o crystals have been ound, without any apparent preerence, in all solvents and at all teperatures, as shown in Figure 9. ype consists o large (up to in the largest diension), translucent crystals, visibly plate-like in habit, while types and 3 consists o saller crystals.

20 Figure 9. Side (a) and top (c) views o type and 3 crystals, with close-up o type crystals (b), and type crystals (d). Scale bar represents 0.6. SEM icroscopy revealed all three types to be o the sae basic habit (thin platelets) o dierent sizes and orientation (Figure 0). ype is indeed large platelets (a, b), while crystals o types (c, d) and 3 (e, ) also consist o thin platelets, but tightly packed and with less deined edges. Figure 0. SEM iages o crystals appearing as large translucent platelets (a, b), sall yellow granules (c, d) and a congealed yellow ass (e, ).

21 Ex-situ AR-FIR analysis o slurries and dried crystals was carried out in all solvents between and inclusive o the teperatures at which solubilities were deterined. he sae was done in-situ in isopropanol using Raan spectroscopy. However, in no cases were dierences in spectra observed ater solvent subtraction. his suggests that all crystals were o a single polyorph. Pressure induced polyorph conversion during IR easureent [4] is unlikely as the Raan results, which involve no pressure application, also show no evidence o polyorphis. Powder XRD analysis resulted in two slightly dierent diraction patterns, one or type and the other or both and 3 (Figure ). here are apparent dierences in peak position which occur only between about 8 and 5 θ, in which region peaks overlap and the signal does not return to the baseline. he sall dierences observed in the powder XRD data are typical o the eects o preerred orientation occurring due to slight dierences in habits o the sae polyorph, which can change peak intensity by up to 00%.[4] Although the habit o both types appears to be identical, it is plausible that the dierences in crystal size, aggregation and orientation could lead to preerred orientation eects. Powder XRD spectra o ground crystals o all types (not shown) show no clear dierence in preerred orientation. Figure. Powder XRD diraction patterns observed or enoxycarb, representative o type (blue) and type (red), with Y axis showing intensity in arbitrary units. Dierences in peak position only occur between 8 and 5 θ, shown agniied in insert. he saples analysed by powder XRD were also analysed on the sae day by solution H NMR in deuterated chloroor. In all cases only peaks corresponding to pure enoxycarb, trace water ro

22 solvents and undeuterated chloroor were detected, i.e. no evidence o solid-state solvation was ound. Although the H NMR water peaks could conceivably hide a water peak ro hydrated enoxycarb, DSC runs up to 353 K show no theral events characteristic o dehydration. Analysis o the dierent solid aterials by DSC again yielded two slightly dierent sets o results (Figure ). In all cases only a single elting endother was observed, with a slightly dierent onset teperature or the dierent types, given in able 4. his dierence partly reains ater a eltingrecrystallization cycle. he slight reduction in elting point or the second cycle in both cases is expected since coplete elting and recrystallization in the saple pan should iprove heat transer. Due partly to the sall nuber o scans (4 and, respectively), 95% conidence intervals or the extrapolated onset elting teperatures o types and overlap but all our type values are higher than both type values and closer to the literature value [4]. Values o the enthalpy o usion or the second cycle were also higher or type than /3, but with overlapping conidence intervals. Since the second DSC heat cycle is preceded by coplete elting, the inor but signiicant dierence in elting points and enthalpies o usion between types and /3 is ost likely caused by a dierence in ipurity content, rather than dierences in crystal size, shape or structure, as elting should reove all solid-state inoration. As higher ipurity content is expected to decrease the elting point [5], type /3 is hypothesized to be less pure than type. able 4. DSC elting data (ean extrapolated onset teperatures,, and associated heats o usion, ΔH, with standard uncertainties, u, and 95% conidence intervals) or crystals o types and beore and ater a elting-recrystallization cycle. ype ypes & 3 Lit. data * st cycle nd cycle st cycle nd cycle ean [K] u % CI ΔH [kj ol - ] ean u % CI * Xiao-Hong et al. (005) Calculated as ean ± u t, where t is Student s t-value.

23 Figure. wo DSC plots representative o the two dierent sets o results observed in the DSC analysis. Blue: type ; red: type /3; solid: irst cycle; dotted: second cycle. Our conclusion is that the observed crystal dierences are due only to dierences in ipurities and crystal size, orientation and aggloeration. Probably, type crystals are ored in the bulk o the solution under low nucleation rates, while the saller crystals nucleate later, at the air-solution interace at higher nucleation rates, incorporating a larger share o the ipurities. 4 Conclusions Fenoxycarb is highly soluble in ethyl acetate, toluene, and the three lower alcohols at roo teperature. All solutions show positive deviation ro Raoult s law. However, in ethyl acetate and toluene these deviations are airly weak while in the alcohols they are quite strong reaching a axiu activity coeicient in isopropanol o 8. he heat capacity correction to the enthalpy o usion o pure enoxycarb is not negligible at roo teperature, but there is signiicant enthalpyentropy copensation as the teperature changes. he activity coeicient ter in the equation or the van t Ho enthalpy o solution is sall in ethyl acetate and toluene but has a doinating inluence in ethanol, ethanol and propanol. Acknowledgeents Syngenta, Switzerland is grateully acknowledged or the donation o the enoxycarb aterial. M.K. and Å.C.R. grateully acknowledge the support o the Science Foundation Ireland (0/IN./B3038) and o the Solid State Pharaceutical Cluster. M.S. grateully acknowledges the inancial support o the Swedish Research Council ( ).

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25 Highlights Solubility o enoxycarb in alcohols presents strongly non-linear van't Ho plots. Rigorously calculated ideal solubility vs teperature is presented. he activity coeicients show positive deviation ro Raoult's law. he activity coeicient derivative doinates the van't Ho enthalpy o solution.

26 Graphical abstract