Monomeric and polymeric derivatives of 5-aminoisophthalic acid as selective inhibitors of the β-polymorph of L-glutamic acid

Joanne M. Kelleher , Simon E. Lawrence , Marie T. McAuliffe and Humphrey A. Moynihan *
Dept. of Chemistry/Analytical and Biological Chemistry Research Facility, University College Cork, College Road, Cork, Republic of Ireland. E-mail: h.moynihan@ucc.ie; Fax: +353-21-4274097; Tel: +353-21-4902488

Received 29th August 2006 , Accepted 30th October 2006

First published on 3rd November 2006


Abstract

The effect of 5-aminoisophthalic acid, 3, 5-acetamidoisophthalic acid, 4, a polymer-bound 5-amidoisophthalic acid, 5, and a cross-linked analogue of the latter, 5*, on crystallisations of L-glutamic acid from water were examined. The metastable α-polymorph was crystallised in the presence of additive at minimum loadings of 10, 5 and 1% w/w for 3, 4 and 5, respectively. The cross-linked polymer 5* was less effective compared to the parent polymer 5.


Introduction

It is well-known that formation of molecular crystals can be affected by the presence of other molecular species in the crystallisation medium. These may include solvent molecules, impurities, or compounds which have been deliberately added. Crystallisation outcomes that can be affected include crystal habit, size, size distribution, and structure. Hence, in the case of polymorphic systems, the actual form obtained may depend on the presence of molecules other than those of the crystallising substance.1 Molecular species which are in some way structurally analogous to molecules of the crystallising substance are particularly likely to act in this manner, as analogues are likely to have sufficient structural similarity to the crystallising compound to allow incorporation into pre-critical crystal nuclei, after which any structural dissimilarity can impede addition of further molecules of crystallising substance.2 That portion of the analogue structure which permits selective interaction with pre-critical nuclei has been referred to as the “binder”, while that portion which impedes further addition has been referred to as the “perturber”.3 In cases of concomitant polymorphism,4 control over polymorphic form by extraneous molecular species requires selective interaction with pre-critical nuclei. This selectivity can be based on molecular or supramolecular features of the crystallising system, such as crystal symmetry5 or hydrogen bonding networks.6

One system which has been investigated is L-glutamic acid, 1, (Fig. 1).7–10


Molecular structure of l-glutamic acid with numbering scheme.
Fig. 1 Molecular structure of L-glutamic acid with numbering scheme.

Two polymorphs of this compound have been reported, the metastable α-form7 and the more stable β-form.8 A significant difference between the two forms lies in the conformations of the constituent molecules, shown in Fig. 2. These conformations can be described in terms of the torsional angles defined by carbons 1, 2, 3 and 4 (τ1) and by carbons 2, 3, 4 and 5 (τ2). For the metastable α-form, τ1 and τ2 are 59.3° and 68.3°, respectively;7,9,10 and for the more stable β-form they are –171.5° and –73.1°, respectively.9,10 With respect to the relative orientations of the carboxyl groups, the β-form possesses a more open or extended conformation, with the carboxyl groups further apart; while the α-form possesses a more closed or folded conformation with the carboxyl groups closer together. This feature was exploited by Davey et al to identify compounds which could mimic the extended conformation of the β-form, and hence could selectively inhibit the appearance of that form.10 For example, in modelling studies, trimesic acid (benzene-1,3,5-tricarboxylic acid), 2, was found to closely mimic the disposition of the carboxyl groups of the β-form of L-glutamic acid, while the conformational rigidity of trimesic acid precluded it from adopting the conformation of the α-form. Addition of trimesic acid to crystallisations of L-glutamic acid from water was subsequently found to result in appearance of the metastable α-form.10


Conformations of l-glutamic acid1 in the α and β forms.
Fig. 2 Conformations of L-glutamic acid1 in the α and β forms.

Mimicry of the conformation of the β-form of L-glutamic acid by trimesic acid involves two of three carboxylic acid groups of trimesic acid, i.e. these groups constitute the “binder”. The remaining carboxylic acid group is not participating and could be replaced by other groups, i.e. benzene-1,3-dicarboxylic acids could generally be mimics of the β-form conformation of L-glutamic acid (Fig. 3), and hence might act as β-form inhibitors. In addition, it has been shown that polymeric additives are superior to monomeric additives as nucleation inhibitors by orders of magnitude due to co-operative binding.5,11 There is also current interest in the use of polymers as crystal heteronuclei.12 The inhibition of the β-form of L-glutamic acid by trimesic acid involves trimesic acid molecules adding in place of L-glutamic acid molecules to pre-critical nuclei, or fast-growing faces, of the β-form. It would seem likely that additives which are capable of co-operatively binding to many L-glutamic acid sites, rather than just one, are likely to be more efficient, i.e. effective in lesser quantity. In this context, 5-aminoisophthalic acid, 3, and derivatives thereof are interesting potential additives, as they possess the benzene-1,3-dicarboxylic acid arrangement capable of acting as a selective “binder” for pre-critical nuclei of the β-form while the 5-amino group provides access to a variety of potential “perturber” groups. Use of 5-aminoisophthalic acid derivatives allows exploitation of both conformational mimicry and co-operative binding in design of additives for L-glutamic acid crystallisation.

ugraphic, filename = b612412g-u1.gif


Overlap of the conformation of l-glutamic acid in the β-form and a general 5-substituted benzene-1,3-dicarboxylic acid.
Fig. 3 Overlap of the conformation of L-glutamic acid in the β-form and a general 5-substituted benzene-1,3-dicarboxylic acid.

Compound 3 possesses the same combination of carboxylic and amino functionalities as L-glutamic acid, and hence may be capable of mimicking the disposition of the amino and the side-chain carboxyl groups of L-glutamic acid, as well as, or in addition to, mimicking the disposition of the two carboxyl groups. Conversion of 3 into 5-amidoisophthalic acid derivatives, such as 5-acetamidoisophthalic acid, 4, would block the amino-mimicking functionality to give simple substituted benzene-1,3-dicarboxylic acids. Compound 3 could also be incorporated into a polymeric form for the investigation of a possible co-operative binding effect. Preparation of these derivatives and their effects on L-glutamic acid crystallisation are described herein.

Experimental

General

All materials were purchased from Sigma-Aldrich. Infrared spectra (pressed KBr discs) were recorded on a Perkin-Elmer 1000 spectrometer in the range 4000–500 cm–1. 1H NMR spectra were recorded at 300 MHz on a Bruker Avance 300 spectrometer. Unless otherwise stated, 1H spectra were recorded in d6-DMSO with tetramethylsilane (TMS) added. Chemical shifts (δH) are reported in parts per million (ppm) downfield from TMS. Coupling constants (J) are given in hertz (Hz) and splitting patterns are indicated as s (singlet), br s (broad singlet), t (triplet), and m (multiplet).

5-Acetamidoisophthalic acid, 4

To a stirred solution of 5-aminoisophthalic acid3 (3.62 g, 20 mmol) in 30 ml DMF, acetic anhydride (2.83 ml, 30 mmol) and acetic acid (0.6 ml, 10 mmol) were added. The reaction mixture was stirred at room temperature for 4 h. 20 ml H2O was then added and the reaction mixture was allowed to stir for further 30 min. The precipitate which formed was collected by filtration and recrystallised from ethanol. Amide 4 was isolated as a white solid, (2.88 g, 12.9 mmol, 65%), mp 226–230 °C (decomp); νmax(KBr/cm–1), 2360 (NH), 1722 (C([double bond, length as m-dash]O)OH), 1669 (C([double bond, length as m-dash]O)NH); δH, 2.07 [3H, s, –C([double bond, length as m-dash]O)–CH3], 8.13 (1H, s, ArH), 8.4 (2H, s, ArH × 2).

Poly-N-(11-(N′-(3,5-dicarboxyphenyl)carbamoyl)undecyl)acrylamide, 5

A solution of 5-aminoisophthalic acid (0.5 g, 2.76 mmol) in 20 ml saturated sodium bicarbonate solution was made to pH 8 with the addition of 10% aqueous sodium hydroxide solution. This was added to poly-N-(10-(chloroformyl)undecyl)acrylamide5 (0.46 g) and stirred at room temperature for 69 h. Polymer 5 was isolated by filtration as a brown solid (2.18 g), degree of grafting (determined from the relative intergration of the arylH and –CH2CH2C([double bond, length as m-dash]O)– resonances) 54%. νmax(KBr/cm–1), 3435.5 (OH), 1632 (C[double bond, length as m-dash]O); δH, 1.23 [14H, m, –(CH2)7–], 1.35–1.47 [6H, m, –HN(C[double bond, length as m-dash]O)–CH2– CH2–, –CH2–CH2–NH–, –C([double bond, length as m-dash]O)–CH–CH2–], 2.17 [2H, t, J 7.35 Hz, –NH(C[double bond, length as m-dash]O)–CH2– CH2–], 3.01–3.04 [3H, m, –C([double bond, length as m-dash]O)–CH–CH2, –CH2–NH–], 7.97 [1H, s, ArH], 8.93 [2H, s, ArH × 2].

Cross-linked poly-N-(11-carboxyundecyl)acrylamide

To a solution of 12-acryloylaminododecanoic acid, 6, (2.56 g, 9.5 mmol) in 40 ml DMF, 5 mol% N,N′-ethylene bisacrylamide, 7, (0.08 g, 0.475 mmol) and AIBN (0.06 g, 0.365 mmol) were added. The reaction mixture was stirred at 80 °C for 43 h. The product was concentrated under reduced pressure. The product was isolated as a beige solid (0.48 g); mp 101–108 °C; νmax(KBr/cm–1), 3431 (OH), 2853 (NH–C[double bond, length as m-dash]O), 1640 (C[double bond, length as m-dash]O); δH (300 MHz; CDCl3: Me4Si), 1.2–1.29 [16H, m, –(CH2)7–, –C([double bond, length as m-dash]O)–CH–CH–CH2–], 1.5–1.66 [7H, m, HO2C–CH2– CH2–, –CH2–CH2–NH–, –CH2–CH2–C([double bond, length as m-dash]O)–NH–, –C([double bond, length as m-dash]O)–H–CH–CH2–], 2.34 [2H, t, J 7.5 Hz, –CH2–CH2–C([double bond, length as m-dash]O)–], 3.29–3.3 [5H, m, –CH2–CH2–NH–, –NH–CH2–CH2–NH–, –C([double bond, length as m-dash]O)–CH–CH–].

Cross-linked poly-N-(11-(N′-(3,5-dicarboxyphenyl)carbamoyl)undecyl)acrylamide, 5*

5% Cross-linked poly-N-(11-carboxyundecyl)acrylamide (2.13 g) was dissolved in thionyl chloride (20 ml) and stirred at room temperature for 16 h. The thionyl chloride was removed under reduced pressure to yield the cross-linked polyacylchloride as a brown oil (3.46 g); νmax(film/cm–1), 2926 (NH), 1799 (C[double bond, length as m-dash]O–Cl), 1688 (C[double bond, length as m-dash]O–NH). This was treated with a solution of 5-aminoisophthalic acid (1.79 g, 9.87 mmol) in saturated aqueous sodium bicarbonate solution (20 ml) adjusted to pH 8 by addition of 10% aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 70 h and the product isolated by filtration as a brown solid (1.24 g), degree of grafting (determined from the relative intergration of the arylH and –CH2CH2C([double bond, length as m-dash]O)– resonances) 20%. νmax(KBr/cm–1), 3418 (OH), 2849 (NH–C[double bond, length as m-dash]O), 1638 (C[double bond, length as m-dash]O); δH, 1.29 [16H, br s, –(CH2)7–, –C([double bond, length as m-dash]O)–CH–CH–CH2–], 1.5 [7H, br s, HO2C–CH2– CH2–, –CH2–CH2–NH–, –CH2–CH2–C([double bond, length as m-dash]O)–NH–, –C([double bond, length as m-dash]O)–H–CH–CH2–], 2.22 [2H, t, J 7.5 Hz, –CH2–CH2–C([double bond, length as m-dash]O)–], 3.1–3.14 [5H, m, –CH2–CH2–NH–, –NH–CH2–CH2–NH–, –C([double bond, length as m-dash]O)–CH–CH–], 8.04 [1H, s, ArH], 9.0 [2H, s, ArH × 2].

Crystallisations

All recrystallisations were carried out in 100 ml round bottom flasks. Solutions of L-glutamic acid were prepared in de-ionised water at the following concentrations: 20 g L–1, 35 g L–1, 45 g L–1, maintained at 18, 38, and 45 °C, respectively. The solutions were boiled gently to dissolve the acid and additives. In some cases filtration was necessary prior to recrystallisation. Samples of the α-form of L-glutamic acid were prepared by the method of Garti and Zour12 as follows: monosodium-L-glutamate, (5 g, 29.5 mmol), was dissolved in 50 ml H2O. Conc. HCl (2 mL) was added dropwise and the solution was stirred for 10 min at room temperature. A further 1 mL conc. HCl was then added dropwise and the resulting precipitate was collected by filtration to yield rhombic crystals (1.99 g, 13.5 mmol, 45.7%), mp 199–204 °C.
Crystal habit. Crystal habits were observed using a Nikon ECLIPSE 50i POL Polarizing Microscope.
Powder X-ray diffraction (PXRD). Powder X-ray diffraction was performed using a Philips PANalytical X'Pert PRO diffractometer with a PW 3830 generator, a PW 3710 MPD diffractometer and an X'Celerator detector operated with an anode current of 40 mA and an accelerating voltage of 45 kV. Samples were ground into powder and back-filled into aluminium holders and exposed to Cu Kα radiation at diffraction angles (2θ) from 5° to 75° in continuous scan mode using a step size of 0.0167° and a step time of 10.16 s.
Simulated PXRD patterns. Structural data for the α- and β-forms of L-glutamic acid were obtained from the Cambridge Structural Database using ConQuest version 1.715 and simulated PXRD patterns generated using PLATON.16

Results

5-Acetamidoisopthalic acid, 4, was prepared by acetylation of 5-aminoisophthalic acid, 3. Compound 3 was reacted with poly-N-(10-(chloroformyl)undecyl)acrylamide4 to give the polymer-bound analogue 5. In order to probe the effect of reduced conformational freedom on the efficacy of the polymeric additive, a cross-linked version of polymer 5 was prepared by polymerisation of 12-acryloylamidododecanoic acid,46, in the presence of quantities of N,N′-ethylene bisacrylamide, 7, as cross-linking agent, followed by functionalisation of the resulting polyacid, as the acylchloride, with 5-aminoisophthalic acid, 3. Samples of polyacid were prepared in this manner with both 5 and 10% of cross-linking agent 7. However, the extent of functionalisation of the 5% cross-linked polymer with 3 was low (20%, compared to 54% for the non-cross-linked polymer), while no appreciable functionalisation was achieved for the 10% cross-linked material. Hence, only the 5% cross-linked analogue of polymer 5 (5*) was used as an additive.
ugraphic, filename = b612412g-u2.gif

Crystallisations of L-glutamic acid from water were carried out in the presence of quantities of compounds 2, 3, 4, 5 and 5* as additives. Polymorphic form was characterised on the basis of both morphology and by PXRD patterns. Specific reflections corresponding to d = 4.87 Å and d = 4.17 Å are quoted in the literature as being characteristic of the α- and β-forms, respectively.8,13 To provide complete confidence in assignment of form based on PXRD, simulated PXRD patterns were generated from crystallographic data for both forms obtained from the Cambridge Structural Database using PLATON.16 Excellent correspondence was observed between the measured and simulated PXRD patterns. Differences in intensity between the calculated and observed patterns are primarily due to preferred orientation of crystallites in the powder, and are a well-known phenomenon in powder diffraction.17 Crystals of the α-form are described in the literature as having well-formed prismatic or rhombic habit,7,9,12 while crystals of the β-form are described as being needle-like or as forming clusters of needles.8,10,13,14 We also observed this correspondence between habit and polymorphic form. In all cases, assignment of form was ultimately confirmed by PXRD. Mixtures of the α- and β-forms were identifiable by the presence of both prismatic and needle-like crystals, and by the presence of reflections characteristic of both forms in the PXRD patterns. The outcomes of the crysallization experiments with additives 2, 3, 4, 5 and 5* are given in Table 1.

Table 1 Outcomes of crystallisations of L-glutamic acid from water in the presence of additives 25 and 5*
Entry No. Conc.a /g L–1 Additive % w/wb Form
a Crystallisations were carried out at 20 g L–1, 35 g L–1 and 45 g L–1 concentrations maintained at 18, 38, and 45 °C, respectively, as described in ref 10. b % w/w of additive. c With seeding using previously prepared samples of the α-form (entry 2 only)
1 20 none α and β
2 20 nonec αc
3 20 2 10 α
4 20 2 1 α
5 20 3 10 α
6 20 3 5 α
7 20 3 1 α
8 20 4 10 α
9 20 4 5 α
10 20 4 1 α
11 20 5 10 α
12 20 5 5 α
13 20 5 2 α
14 20 5 1 α
15 20 5 0.5 α
16 20 5* 10 α
17 20 5* 1 α
18 35 none β
19 35 2 10 α
20 35 2 1 β
21 35 3 10 α
22 35 3 5 α and β
23 35 3 1 α and β
24 35 4 10 α
25 35 4 5 α
26 35 4 1 α
27 35 5 5 α
28 35 5 2 α
29 35 5 1 α
30 35 5 0.5 β
31 35 5* 10 α
32 35 5* 1 α and β
33 45 none α and β
34 45 2 10 α
35 45 2 1 α and β
36 45 3 10 α
37 45 3 5 α and β
38 45 3 1 α and β
39 45 4 10 α
40 45 4 5 α
41 45 4 1 β
42 45 5 10 α
43 45 5 5 α
44 45 5 2 α
45 45 5 1 α
46 45 5 0.5 β
47 45 5* 10 α
48 45 5* 1 α


Discussion

Consistent with the literature,10 crystallisations of L-glutamic acid from water were found to give the β-form at concentrations of 35 g L–1 (Table 1, entry 18), while crystallisations at 20 g L–1 or at 45 g L–1 concentrations gave α and β mixtures (Table 1, entries 1 and 33). Seeding could be used to obtain the α-form exclusively from crystallisations at 20 g L–1 (Table 1, entry 2), although the α-form could more conveniently be obtained by acidification of aqueous solutions of monosodium glutamate.13 The β inhibitory effect of addition of 10% w/w trimesic acid,102, was confirmed (Table 1, Entries 3, 19 and 34). Use of a lesser (1% w/w) quantity of trimesic acid, 2, as additive resulted in crystallisation of the pure α-form at 20 g L–1 (Table 1, entry 4). Use of 1% w/w trimesic acid, 2, at 35 or 45 g L–1 concentrations gave the β-form and α/β mixtures, respectively (Table 1, entries 20 and 35). This suggests that 1% w/w is at or near the minimum quantity of trimesic acid, 2, necessary to achieve complete inhibition of the β-form.

Crystallisations in the presence of 10% w/w of 5-aminoisophthalic acid, 3, gave crystals of the α-form at all concentrations (Table 1, entries 5, 21 and 36). Addition of 5% or 1% w/w was found to give the α-form at 20 g L–1 concentrations (Table 1, entries 6 and 7) and α/β mixtures at greater concentrations (Table 1, entries 22, 23, 37 and 38). Compound 3 therefore appears to be slightly more efficacious than trimesic acid, 2, as an inhibitor of the β-form. The interaction of compound 3 with pre-critical nuclei of the β-form may involve the amino group as well as the carboxylic acid groups, but interaction via the benzene-1,3-dicarboxylic acid unit seems most likely.

Crystallisations in the presence of 10 or 5% w/w of 5-acetamidoisophthalic acid, 4, gave exclusively the α-form at all concentrations (Table 1, Entries 8, 9, 24, 25, 39 and 40). Use of 1% w/w of additive 4 gave the α-form at 20 g L–1 concentration (Table 1, entry 10), however the β-form was obtained at greater concentrations (Table 1, entries 26 and 41). Compound 4 therefore gives full inhibition of the β-form when used in 5% w/w quantity, i.e.4 is more effective than 2 or 3.

Polymeric additive 5 resulted in exclusive crystallisation of the α-form when used at 10, 5, 2 or 1% w/w at all concentrations (Table 1, entries 11, 12, 13, 14, 27, 28, 29, 42, 43, 44 and 45), i.e polymer 5 displays a clear co-operative binding effect. When added in 0.5% w/w, polymer 5 results in exclusive formation of the α-form at 20 g L–1 concentration (Table 1, entry 15) but not at greater concentrations (Table 1, entries 30 and 46), .i.e. 0.5% w/w is close to the minimum quantity of polymer 5 necessary to achieve complete inhibition of the β-form. Polymer 5 is one order of magnitude more effective than the monomeric analogues 2, 3 or 4, but not more than that. One feature of polymer 5 which may be adversely affecting its efficacy in water are the hydrophobic dodecyl chains linking the 5-amidoisophthalic acid groups to the polyacrylamide backbone. These offer conformational flexibility which allows the polymer to achieve a good ‘fit’ when binding to crystal nuclei.5 However these chains are unlikely to be well solvated in water and hence the polymer may tend to exist in folded conformations which reduce the effectiveness of its interaction with crystal nuclei. Increasing the hydrophilicity of these chains through appropriate modification might be one approach to achieving greater efficiency.

The effect of reducing the conformational freedom of the polyacrylamide backbone was investigated using the cross-linked polymer 5*. When added in 10% w/w quantity, 5* resulted in exclusive crystallisation of the α-form at all concentrations (Table 1, entries 16, 31 and 47). When used in 1% w/w quantity, 5* gave α/β mixtures at 35 g L–1 (Table 1, entry 32), and exclusive α-form crystallisation at other concentrations (Table 1, entries 17 and 48). Cross-linking has therefore reduced the efficiency of the polymeric additive to some extent. The reduced coverage of the cross-linked polymer with 5-aminoisophthalic acid groups (20% compared to 54%) may also have caused reduced efficacy.

The relationships between additive structure and efficiency in terms of minimum % w/w required to achieve a full inhibitory effect are illustrated in Fig. 4. The α-form is most easily obtained from aqueous crystallisations carried out at 20 g L–1 concentration and at 18 °C. For all additives investigated, 1% w/w is sufficient to fully inhibit the β-form under these conditions. The co-operative binding effect is observed at the other crystallisation conditions studied, i.e 10% w/w of additives 2 and 3 are necessary to fully inhibit the β-form; 5% w/w of additive 4 is required, and only 1% w/w of the polymeric additive 5. Crystallisations carried out at 35 g L–1 concentration and at 38 °C have the least tendency to produce the α-form, and hence are the most sensitive to variation in additive structure. Under these condition, the co-operative binding effect is observed for polymeric additive 5, but not for cross-linked polymer 5*.


Comparisons of the minimum % w/w of additives 2, 3, 4, 5 and 5* required to achieve a complete inhibitory effect under the three crystallisation conditions studied.
Fig. 4 Comparisons of the minimum % w/w of additives 2, 3, 4, 5 and 5* required to achieve a complete inhibitory effect under the three crystallisation conditions studied.

The morphologies of the α-form crystals obtained conformed to the reported morphologies in the absence and presence of inhibition by benzene-1,3-dicarboxylic acid groups,9i.e. α-crystal grown from pure solutions appeared as well-formed rhombs, whereas α-crystals obtained in the presence of compounds 25* had a more tabular habit in which the {110} faces were well developed. This habit modification has been explained in terms of binding of benzene-1,3-dicarboxylic acid group to adjacent surface glutamic acid molecules at the {110} surfaces.9 In cases in which we observed mixtures of the α- and β-forms, the α-crystals displayed a rounded appearance consistent with partial dissolution, as previously described.10

Conclusions

5-Aminoisophthalic acid, 3, and 5-acetamidoisophthalic acid, 4, were found to inhibit crystallisation of the β-polymorph of L-glutamic acid, 1, allowing crystallisation of the metastable α-form. This is likely to involve conformational mimicry of the carboxylic acid groups of L-glutamic acid by the benzene-1,3-dicarboxylic acid units of 3 and 4, as achieved previously using trimesic acid, 2.10 Use of 10% w/w was found to be necessary to achieve complete inhibition of the β-form using compounds 2 and 3 at all conditions examined. Compound 4 was fully effective when used in 5% w/w quantity. A polymeric 5-amidoisophthalic acid, 5, was found to achieve complete inhibition of the β-form when used in 1% w/w quantity, i.e. a co-operative binding effect of one order of magnitude was observed. In terms of mole equivalence, 1% of polymer 5 was found to achieve the same level of efficiency as 100 to 1000 times the best of the monomeric additives (compound 4). Use of lesser quantity of this polymer did not provide complete inhibition of the β-form. A cross-linked version of this polymer, 5*, was found to be less effective than polymer 5.

Research into the molecular level action of solvents, additives and impurities1,6 during crystallisations has placed understanding of these issues on a rational basis. Co-operative binding5,11 provides a strategy for achieving a minimisation of the quantities of such impurities necessary to achieve control. The findings reported above provide an example of the combination of co-operative binding with another strategy for achieving crystal nucleation control, i.e. use of conformational mimicry,10 to control L-glutamic acid polymorphism. The benzene-1,3-dicarboxylic acid groups of compounds 2, 3, 4, 5 and 5* act as the “binder” groups2 providing stereoselective interaction with pre-critical nuclei of the β-form. Structural modification of the remaining “perturber”3 portions of the compounds allows for increased efficiency through the application of co-operative binding. Our findings also show the limits of efficiency which can be achieved in this case using a straightforward polyacrylamide-based additive. Further improvements in efficiency in this and other systems will require better exploitation of factors such as solvation and compatibility of polymer or oligomer structure with crystal nuclei.

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Footnote

Electronic supplementary information (ESI) available: Measured and simulated PXRD patterns of α and β forms of L-glutamic acid. See DOI: 10.1039/b612412g

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