Evolution of Phases and Habit during the Crystallization of Freeze-Dried Lactose/Salt Mixtures in Humid Air A. Shawqi
Barham,†
A. M. Elmonsef
Omar,‡
Yrjo¨ H.
Roos,‡
and B. K.
Hodnett*,†
Materials and Surface Science Institute and the Department of Chemical and EnVironmental Sciences, UniVersity of Limerick, Limerick, Ireland, and Department of Food and Nutritional Sciences, UniVersity College Cork, Cork, Ireland
CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 8 1975-1982
ReceiVed April 11, 2006; ReVised Manuscript ReceiVed May 23, 2006
ABSTRACT: Phase compositions, transient phases, and morphology of the crystallization of freeze-dried lactose/salt mixtures in humid air were estimated by in situ X-ray diffraction analysis complemented by ex situ scanning electron microscopy, powder diffraction, and analysis of the solid state R/β anomeric ratios by gas-liquid chromatography. The salts studied are calcium chloride (CaCl2), magnesium chloride (MgCl2), potassium chloride (KCl), and sodium chloride (NaCl) with lactose/salt molar ratios of 2:1, 4:1, and 9:1 mol/mol. Following an induction period during which water is sorbed, crystallization is rapid and the predominant phases observed using the in situ method in freeze-dried lactose/magnesium chloride (MgCl2), sodium chloride (NaCl), and potassium chloride (KCl) are mixtures of R-lactose monohydrate and β-lactose. In general, the R/β ratio of the solid state as measured by gas-liquid chromatography was similar to the crystalline phase composition as measured by X-ray diffraction. A transient phase appears in lactose/KCl (4:1 and 9:1 mol/mol), lactose/MgCl2 (9:1 mol/mol), and lactose/NaCl (9:1 mol/mol), namely, R/β mixed phase. Another transient effect observed with nearly all the lactose-salt mixtures was the observation of a subtle shift in the lattice parameters of R-lactose from a ) 8.006 Å, b ) 21.562 Å and c ) 4.800 Å for short crystallization times to a ) 7.982 Å, b ) 21.562 Å, and c ) 4.824 Å for longer times. The transient effects, namely, the observation of the R/β mixed phase and the distortion in R-lactose monohydrate lattice parameters, are explained in terms of stresses induced during the rapid onset of crystallization. 1. Introduction Lactose and lactose-salt mixtures are used throughout the food industry, usually in the form of anhydrous materials, and have desirable handling properties, especially in terms of flowability.1-4 These mixtures are commonly used as fillers in tablets and capsules and as a carrier for dry powder inhalation.5-8 However, these materials are very hygroscopic and can absorb up to 10 wt % of water within a few hours of exposure to humid air, turning them into sticky masses, which have a propensity to crystallize into extremely hard and unworkable materials.9,10 In the solid state, lactose can be amorphous or crystalline. Amorphous lactose can be prepared by several drying techniques such as hot air (fixed or fluidized), freeze-drying, spray-drying, milling, and rapid cooling of melt.11-14 Several researchers have studied the crystallization of amorphous lactose under storage conditions in humid air, such as the storage stability of many milk products.9,11,15-19 An important point is the reduction of glass transition temperature from above 105 °C for anhydrous lactose to values at and below room temperature as the water content of the lactose reaches 10 wt %.11,12 When this occurs, the plasticized material changes from its glassy state to a rubbery state followed by crystallization.16,18-20 The rate of crystallization of these materials is dependent on the storage relative humidity (RH), the water content, and the difference between the storage temperature and the glass transition temperature (Tg).16,20,21 Below Tg, crystallization is unlikely due to high viscosity and slow diffusion.16,20 However, above this temperature, molecular mobility increases as evidenced by a decrease in viscosity and increasing flow. Following crystallization, the material becomes hydrophobic and expulsion of water occurs * To whom correspondence should be addressed.
[email protected]. Tel: 35361202246. Fax: 35361213529. † University of Limerick. ‡ University College Cork.
E-mail:
until an equilibrium level of 4-5 wt % becomes established, due to the partial formation of R-lactose monohydrate. Loss of sorbed water is often taken as an indicator that crystallization has occurred.16,20,22 Due to the importance of lactose in both the food and pharmaceutical industries, its crystallization behavior has been studied extensively using a variety of techniques including isothermal or nonisothermal differential scanning calorimetry (DSC),18,23 X-ray diffraction (XRD),16,22 in situ X-ray diffraction analysis complemented by ex situ scanning electron microscopy,24 polarized light microscopy,23 gravimetric vapor sorption,19 and atomic force microscopy.25 Numerous researchers have studied the influence of additives, proteins, sugars, or salts on the growth rates of crystalline lactose from solution.5-8,26 Some additives resulted in marked retardation, whereas others accelerated growth on specific crystal faces. Jelen and Coulter evaluated the lactose crystal growth rates in the presence of certain salts and other substances found in cheese whey. They concluded that calcium chloride had the greatest growth-promoting effect; at the 10% impurity level, crystal growth rate was accelerated 3-fold. Acceleration of the crystal growth rate results in altered crystal shape, and there was a considerable flattening of the crystal base, whereas in control solutions the crystals continued to grow in pyramid-like structures.26 This paper describes a study of the crystallization of freezedried lactose and lactose-salt mixtures in moist air followed by in situ X-ray powder diffraction analysis, with complementary water sorption data, ex situ powder diffraction, gas-liquid chromatography, and scanning electron microscopy. The lactosesalt mixtures studied here are lactose-calcium chloride (CaCl2), lactose-magnesium chloride (MgCl2), lactose-potassium chloride (KCl), and lactose-sodium chloride (NaCl) with lactose/ salt molar ratios of 2:1, 4:1, and 9:1.
10.1021/cg060214d CCC: $33.50 © 2006 American Chemical Society Published on Web 06/29/2006
1976 Crystal Growth & Design, Vol. 6, No. 8, 2006
Barham et al.
Table 1. Summary of All Phases Observed Following Exposure to Moist Air for 144 Hours, Glass Transition Temperatures, and the Solid State Anomeric Composition of Lactose-Salt Mixtures Determined by GC Analysisa anhydrous
L-FD L9-CaCl2 L4-CaCl2 L2-CaCl2 L9-KCl L4-KCl L2-KCl L9-NaCl L4-NaCl L2-NaCl L9-MgCl2 L4-MgCl2 L2-MgCl2
RH 55%
XRD phases observed
Tg1 (°C)36
R/(R + β)
amorphous amorphous amorphous amorphous amorphous amorphous amorphous amorphous amorphous amorphous amorphous amorphous amorphous
105 122
0.50 0.47
99
0.41
100
0.45
114
0.42
XRD phases observed R+β R+β R+β R+β R + β + (R/β) R+β R+β R + β + (R/β) R+β R+β R R R
RH 66% R/(R + β) 0.55 0.64 0.50 0.52 0.96
XRD phases observed R+β R+β R R+β R+β R+β R+β R+β R+β R+β R R R
RH 76%
R/(R + β) 0.51 0.73 0.95 0.54 0.55 0.97
XRD phases observed R+β R R+β R+β R+β R+β R+β R R R R R R
R/(R + β) 0.53 0.98 0.60 0.99 0.96
a Lx-salt ) lactose-salt at molar ratios of x:1. RH X% ) relative humidity at X%. T ) onset of glass transition (°C). R/(R + β) ) anomeric composition g1 of lactose determined by GLC. R ) R-lactose monohydrate. β ) β-lactose anhydrous. R/β ) R/β mixed phase.
2. Experimental Section 2.1. Materials. R-Lactose was supplied by Dairy Gold, Ireland. Molecular sieves (calcium, sodium alumino-silicate, 1/16 in. pellets, nominal pore diameter 5 Å), calcium chloride (CaCl2, 96%), magnesium chloride (MgCl2, 98%), phosphorus pentoxide anhydride (P2O5, 98%), potassium chloride (KCl, 99%), sodium chloride (NaCl, 99.5%) and sodium nitrite (NaNO2, 99.5%) were purchased from Sigma-Aldrich, Ireland. Dry pyridine (99.8%), dimethyl sulfoxide (DMSO, 99.7%), and N-trimethylsilylimidazole (TMSIM, 98.0%) were purchased from Sigma-Aldrich, Ireland, and were used to derivatize lactose for GLC analysis. Aqueous solutions (15% w/w) of R-lactose, R-lactose-CaCl2 (2:1, 4:1, and 9:1 mol/mol), R-lactose-MgCl2 (2:1, 4:1, and 9:1 mol/mol), R-lactose-KCl (2:1, 4:1, and 9:1 mol/mol), or R-lactose-NaCl (2:1, 4:1 and 9:1 mol/mol) were poured into Petri dishes (30 mL in each). All samples were frozen at -20 °C for 12 h and subsequently at -80 °C for 24 h. The materials were freeze-dried (Lyovac GT2 freezedryer; Amsco Finn-Aqua GmbH, Hu¨rth, Germany) for 60-70 h (temperature less than -40 °C; pressure
