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Volume 61 
Part 8 
Pages o2499-o2501  
August 2005  

Received 29 June 2005
Accepted 5 July 2005
Online 13 July 2005

Key indicators
Single-crystal X-ray study
T = 150 K
Mean [sigma](C-C) = 0.003 Å
R = 0.033
wR = 0.079
Data-to-parameter ratio = 8.1
Details

[alpha]-Lactose monohydrate: a redetermination at 150 K

aChemistry Department, Loughborough University, Loughborough, Leicestershire LE11 3TU, England, and b3M Health Care Ltd, Drug Delivery Systems Division, Ashby Road, Loughborough, Leicestershire LE11 3GR, England
Correspondence e-mail: s.e.dann@lboro.ac.uk

The structure of the monohydrate of [alpha]-4-([beta]-D-galactopyranosido)-D-glucopyranose, more commonly known as [alpha]-lactose monohydrate, C12H22O11·H2O, has been previously studied by single-crystal diffraction at ca 296 K [Beevers & Hansen (1971[Beevers, C. A. & Hansen, H. N. (1971). Acta Cryst. B27, 1323-1325.]). Acta Cryst. B27, 1323-1325; Fries et al. (1971[Fries, D. C., Rao, S. T. & Sundaralingham, M. (1971). Acta Cryst. B27, 994-1005.]). Acta Cryst. B27, 994-1005; Noordik et al. (1984[Noordik, J. H., Beurskens, P. T., Bennema, P., Visser, R. A. & Gould, R. O. (1984). Z. Kristallogr. 168, 59-65.]). Z. Kristallogr. 168, 59-65]. This redetermination at low temperature [150 (2) K] shows improved precision of geometry. Graph-set analysis of the hydrogen-bonding motifs is presented for the first time.

Comment

[alpha]-Lactose monohydrate, (I)[link], is the most common form of lactose and may be used as the parent material for at least four different (pseudo)polymorphs of this disaccharide (Garnier et al., 2002[Garnier, S., Petit, S. & Coquerel, G. (2002). J. Therm. Anal. Calorim. 68, 489-502.]; Figura & Epple, 1995[Figura, L. O. & Epple, M. (1995). J. Therm. Anal. 44, 45-53.]). This reducing sugar is built from a moiety of [beta]-D-galactose and a moiety of [alpha]-D-glucose, joined by a 1,4 glycosidic bond between C1' of the galactose and C4 of the glucose unit (Fig. 1[link]).

[Scheme 1]

A search of the Cambridge Structural Database (Allen, 2002[Allen, F. H. (2002). Acta Cryst. B58, 380-388.]; Fletcher et al., 1996[Fletcher, D. A., McMeeking, R. F. & Parkin, D. (1996). J. Chem. Inf. Comput. Sci. 36, 746-749.]; Version 5.26, November 2004 update) highlighted previous research on this hydrate with data collections performed at ca 296 K (Beevers & Hansen, 1971[Beevers, C. A. & Hansen, H. N. (1971). Acta Cryst. B27, 1323-1325.]; Fries et al., 1971[Fries, D. C., Rao, S. T. & Sundaralingham, M. (1971). Acta Cryst. B27, 994-1005.]; Noordik et al., 1984[Noordik, J. H., Beurskens, P. T., Bennema, P., Visser, R. A. & Gould, R. O. (1984). Z. Kristallogr. 168, 59-65.]). The redetermination of (I)[link] presented here, obtained from low temperature [150 (2) K] single-crystal diffraction data, has resulted in improved precision compared to the previously determined room-temperature structures. Standard uncertainties on C-O and C-C bond lengths are improved to ca 0.003 compared to ca 0.004 at room temperature, with an improvement to ca 0.0017 compared to ca 0.002 for standard uncertainties on C-O-C angles. The unit cell volume measured at 150 K [768.85 (14) Å3] is ca 0.88% smaller than that determined at room temperature [775.7 (5) Å3; Noordik et al., 1984[Noordik, J. H., Beurskens, P. T., Bennema, P., Visser, R. A. & Gould, R. O. (1984). Z. Kristallogr. 168, 59-65.]], this latter unit-cell volume itself being smaller than that derived from previous measurements.

The unit cell has previously been reported as 7.937 (2) Å, 21.568 (7) Å, 4.815 (1) Å and [beta] = 109.77 (2)° (Noordik et al., 1984[Noordik, J. H., Beurskens, P. T., Bennema, P., Visser, R. A. & Gould, R. O. (1984). Z. Kristallogr. 168, 59-65.]); the unit cell reported here is related to the Noordik unit cell by a simple transformation and is currently regarded as the conventional unit cell, having the shortest possible vectors in the ac plane (International Tables for X-ray Crystallography, 1969, Vol. 1).

An examination of the final difference Fourier map reveals a peak of 0.27 e Å-3 at a distance of 1.48 Å from C1, close to the equatorial atom H1. Since the [alpha] and [beta] anomers establish a 40:60 equilibrium in solution over time, the question arises whether there is a small component of [beta]-lactose present, even though only the [alpha]-anomer spontaneously crystallizes below 366.5 K (Walstra & Jenness, 1984[Walstra, P. & Jenness, R. (1984). Dairy Chemistry and Physics, Carbohydrates, ch. 3, pp. 27-41. New York: Wiley.]). In this present determination, the largest ten difference map features lie in the range 0.22-0.32 e Å-3, so this dubious peak is, in fact, indistinguishable from the noise. This means that, if present at all, the percentage of the [beta]-anomer must be in the low single figures and any significant [beta] component can definitely be ruled out.

Graph-set analysis of the hydrogen-bonding patterns (Bernstein et al., 1995[Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.]; Etter et al., 1990[Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256-262.]) within the structure shows the complicated nature of the linking together of the lactose and water molecules. There are 15 different ring motifs involving one molecule of hydrated [alpha]-lactose (Figs. 2[link] and 3[link]). The motifs use either two or three molecules of (I)[link], hydrogen bonding with zero, one or two water molecules. Fig. 4[link] shows a stacking formation of the lactose molecules when viewed, as a packing plot, along the crystallographic c axis. The molecules are held rigidly by a chain, C22(4), of hydrogen bonds between O6-H6A...O2iii and O2-H2A...O6i [symmetry codes: (i) x - 1, y, z - 1; (iii) x, y, 1 + z] propagating along the crystallographic a axis and are also linked through hydrogen bonding to water molecules.

As well as those motifs present along the crystallographic a axis (Fig. 2[link]), higher order motifs R66(21), R44(20), R55(20), R66(23) and R44(18) can be found between layers of (I)[link] and interconnecting water molecules (Figs. 3[link] and 4[link]).

[Figure 1]
Figure 1
View of (I)[link], showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. Only hydroxyl H atoms involved in hydrogen bonding are labelled. Dashed lines indicate hydrogen bonds. One intramolecular hydrogen bond is present, viz. O9-H9A...O5.
[Figure 2]
Figure 2
Packing diagram of (I)[link] showing graph-set notation for hydrogen bonding within the crystal structure when viewed along the crystallographic a axis. It can be observed that each system of (I)[link], results in motifs: (A) S(7); (B) R33(16); (C) R33(14); (D) R33(9); (E) R44(18); (F) R43(16); (G) R33(19); (H) R43(18); (J) R43(15); (K) R54(21) approximately in the bc plane.
[Figure 3]
Figure 3
View of (I)[link] along the crystallographic b axis, showing the remaining hydrogen bonding motifs formed between layers of (I)[link] and water molecules; containing O2-H2A...O6i, O3-H3A...O12, O6-H6...O2iii, O8-H8A...O11iii, O9-H9A...O5, O11-H11A...O9i and O12-H12B...O3v hydrogen bonds [symmetry codes: (i) x - 1, y, z - 1; (iii) x, y, 1 + z; (v) 1 + x, y, z].
[Figure 4]
Figure 4
Packing diagram of (I)[link], viewed along the crystallographic c axis, showing the hydrogen bonding linking molecules of (I)[link] and water, above and below a central molecule.

Experimental

Colourless X-ray quality crystals of (I)[link] were produced using powdered D-(+)-[alpha]-lactose monohydrate (supplied by Fluka Biochemica, Stenheim). A 10% aqueous solution of (I)[link] was prepared as in methods previously studied by Larhrib et al. (2003[Larhrib, H., Martin, G. P., Prime, P. & Marriott, C. (2003). Eur. J. Pharm. Sci. 19, 211-221.]). This solution was then diluted through addition of acetone, resulting in a 35:65 mixture of 10% lactose solution-acetone. Crystallization occurred upon standing at room temperature over a period of 48 h. A second crystalline sample of (I)[link] was produced by a similar method except that acetone was substituted with a 10% potassium methoxide aqueous solution. Diffraction data from this sample were recorded by the EPSRC National Crystallographic Service, affording very similar unit-cell dimensions.

Crystal data
  • C12H22O11·H2O

  • Mr = 360.31

  • Monoclinic, P 21

  • a = 4.7830 (5) Å

  • b = 21.540 (2) Å

  • c = 7.7599 (8) Å

  • [beta] = 105.911 (2)°

  • V = 768.85 (14) Å3

  • Z = 2

  • Dx = 1.556 Mg m-3

  • Mo K[alpha] radiation

  • Cell parameters from 3523 reflections

  • [theta] = 2.7-28.2°

  • [mu] = 0.14 mm-1

  • T = 150 (2) K

  • Block, colourless

  • 0.53 × 0.27 × 0.21 mm

Data collection
  • Bruker SMART 1000 CCD diffractometer

  • Narrow-frame [omega] scans

  • Absorption correction: multi-scan(SADABS; Sheldrick, 2003[Sheldrick, G. M. (2003). SADABS. Version 2.08. University of Göttingen, Germany.])Tmin = 0.878, Tmax = 0.971

  • 6697 measured reflections

  • 1864 independent reflections

  • 1692 reflections with I > 2[sigma](I)

  • Rint = 0.022

  • [theta]max = 28.9°

  • h = -6 [rightwards arrow] 6

  • k = -27 [rightwards arrow] 27

  • l = -9 [rightwards arrow] 9

Refinement
  • Refinement on F2

  • R[F2 > 2[sigma](F2)] = 0.033

  • wR(F2) = 0.079

  • S = 1.10

  • 1864 reflections

  • 231 parameters

  • H atoms treated by a mixture of independent and constrained refinement

  • w = 1/[[sigma]2(Fo2) + (0.0394P)2 + 0.1957P] where P = (Fo2 + 2Fc2)/3

  • ([Delta]/[sigma])max < 0.001

  • [Delta][rho]max = 0.32 e Å-3

  • [Delta][rho]min = -0.17 e Å-3

Table 1
Selected geometric parameters (Å, °)[link]

O1-C1' 1.398 (3)
O1-C4 1.437 (3)
C1-O7 1.399 (3)
C1'-O1-C4 116.88 (17)

Table 2
Hydrogen-bond geometry (Å, °)[link]

D-H...A D-H H...A D...A D-H...A
O2-H2A...O6i 0.84 1.85 2.665 (2) 163
O3-H3A...O12 0.84 1.89 2.722 (3) 168
O4-H4A...O8ii 0.84 1.97 2.806 (3) 173
O6-H6...O2iii 0.84 1.90 2.707 (2) 161
O7-H7A...O12iv 0.84 1.97 2.772 (2) 161
O8-H8A...O11iii 0.84 1.91 2.700 (3) 157
O9-H9A...O5 0.84 2.02 2.819 (2) 159
O11-H11A...O9i 0.84 1.92 2.755 (2) 174
O12-H12B...O3v 0.85 (1) 1.89 (2) 2.740 (3) 174 (4)
O12-H12A...O8vi 0.84 (1) 2.23 (2) 2.920 (2) 140 (3)
Symmetry codes: (i) x-1, y, z-1; (ii) [-x, y+{\script{1\over 2}}, -z+2]; (iii) x, y, z+1; (iv) [-x, y-{\script{1\over 2}}, -z+1]; (v) x+1, y, z; (vi) [-x+1, y+{\script{1\over 2}}, -z+2].

Non-water H atoms were placed in geometric positions using a riding model [C-H = 0.99 (methylene H) and 1.00 Å (methine H); O-H = 0.84 Å], and Uiso(H) = 1.2Ueq(C) and 1.5Ueq(O). The data set was truncated at 2[theta] = 52°, as only statistically insignificant data were present above this limit. Water H atoms were located in a difference Fourier map and refined using restraints on the O-H bond length [target value 0.840 (15) Å] and the 1,3-distance [target value 1.43 (2) Å] and Uiso(H) = 1.5Ueq(O). In the absence of significant anomalous dispersion effects, 1526 Friedel pairs were merged during the refinement of (I)[link].

Data collection: SMART (Bruker, 2001[Bruker (2001). SMART (Version 5.611) and SAINT (Version 6.02a). Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT (Bruker, 2001[Bruker (2001). SMART (Version 5.611) and SAINT (Version 6.02a). Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2000[Sheldrick, G. M. (2000). SHELXTL. Version 6.10. Bruker AXS Inc., Madison, Wisconsin, USA.]); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL and local programs.

Acknowledgements

The authors acknowledge the use of the EPSRC's Chemical Database Service at Daresbury (Fletcher et al., 1996[Fletcher, D. A., McMeeking, R. F. & Parkin, D. (1996). J. Chem. Inf. Comput. Sci. 36, 746-749.]) and the EPSRC National Crystallographic Service in Southampton. We also thank 3M Health Care, Loughborough, England, for funding.

References

Allen, F. H. (2002). Acta Cryst. B58, 380-388. [details]
Beevers, C. A. & Hansen, H. N. (1971). Acta Cryst. B27, 1323-1325. [details]
Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573. [CrossRef] [ChemPort] [ISI]
Bruker (2001). SMART (Version 5.611) and SAINT (Version 6.02a). Bruker AXS Inc., Madison, Wisconsin, USA.
Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256-262. [details]
Figura, L. O. & Epple, M. (1995). J. Therm. Anal. 44, 45-53. [ChemPort]
Fletcher, D. A., McMeeking, R. F. & Parkin, D. (1996). J. Chem. Inf. Comput. Sci. 36, 746-749. [CrossRef] [ChemPort] [ISI]
Fries, D. C., Rao, S. T. & Sundaralingham, M. (1971). Acta Cryst. B27, 994-1005. [details]
Garnier, S., Petit, S. & Coquerel, G. (2002). J. Therm. Anal. Calorim. 68, 489-502. [CrossRef] [ChemPort]
Larhrib, H., Martin, G. P., Prime, P. & Marriott, C. (2003). Eur. J. Pharm. Sci. 19, 211-221. [CrossRef] [PubMed] [ChemPort]
Noordik, J. H., Beurskens, P. T., Bennema, P., Visser, R. A. & Gould, R. O. (1984). Z. Kristallogr. 168, 59-65. [CrossRef] [ChemPort]
Sheldrick, G. M. (2000). SHELXTL. Version 6.10. Bruker AXS Inc., Madison, Wisconsin, USA.
Sheldrick, G. M. (2003). SADABS. Version 2.08. University of Göttingen, Germany.
Walstra, P. & Jenness, R. (1984). Dairy Chemistry and Physics, Carbohydrates, ch. 3, pp. 27-41. New York: Wiley.


Acta Cryst (2005). E61, o2499-o2501   [ doi:10.1107/S1600536805021367 ]