12256
J. Phys. Chem. B 2000, 104, 12256-12262
Morphology of Crystals of r-Lactose Hydrate Grown from Aqueous Solution S. L. Raghavan,†,§ R. I. Ristic,†,# D. B. Sheen,† and J. N. Sherwood*,† Department of Pure and Applied Chemistry, UniVersity of Strathclyde, Glasgow, G1 1XL, Scotland, UK
L. Trowbridge‡,| and P. York‡ Department of Pharmaceutical Sciences, UniVersity of Bradford, Bradford, BD7 1DP, UK ReceiVed: June 7, 2000; In Final Form: September 26, 2000
When dissolved in aqueous solution, R-lactose, whether originally in the anhydrous or the monohydrated form, readily undergoes mutarotation to yield the β isomer. At equilibrium, which is reached in 6.5 h at 292 K and more rapidly with increasing temperatures, the latter is present to the extent of ca. 60% w/w. At saturation, R-lactose hydrate precipitates from this solution being considerably less soluble than the β form. The resulting crystals have a highly asymmetric, tomahawk shaped morphology characterized by large {01h1} faces. It is confirmed that this shape arises from growth inhibition due to the incorporation of the β isomer in the {01h1} sectors of the crystals coupled with a characteristic lack of growth in the [01h0] direction. Growth under conditions that restrict the formation of the β isomer yields more symmetrically shaped, needlelike crystals. These show a gradual transition to the tomahawk shape as the concentration of the β isomer in solution and hence in the crystal is increased. An assessment is made of the degree of incorporation of the β isomer into the crystal, its distribution and its influence on the defect structure of the material.
1. Introduction A byproduct of the milk industry, by which it is produced in considerable quantities per annum, R-lactose monohydrate (RLM) finds use in a wide range of products in the food and fine chemical industries.1 One of its main uses however is as an excipient in the pharmaceutical industry, being used in the formulation of many pharmaceutical products. Of paramount importance in such use is the definition and control of particle shape and size. Surface interactions between particles of like and dissimilar materials are influential in determining the efficiency of processes such as powder flow, blending and mixing, compaction, caking, and dissolution.2 To maintain control over such processes, the particle technologist must be able to understand the fundamental principles behind the formation and development of the particles. From this knowledge can come the definition of methods by which the bulk and surface properties of materials can be engineered to improve their processing. As part of a cooperative venture to define and understand the role of experimental growth parameters in the definition of the basic mechanical characteristics of particles, we have examined the formation and behavior under process conditions of typical drug materials and excipients. As a characteristic example of the latter group, we have chosen R-lactose monohydrate(RLM). The present paper describes our basic studies of particle formation, shape and purity. Later * To whom correspondence should be addressed. E-mail: J.
[email protected]. † Department of Pure and Applied Chemistry, University of Strathclyde. ‡ Department of Pharmaceutical Sciences, University of Bradford. § Welsh School of Pharmacy, University of Cardiff, Cardiff CF1 3XF, Wales, UK. Dept of Chemical and Process Engineering, Sheffield University, Firth Court, Western Bank, Sheffield S10 2TN, UK. | Sirius Analytical Instruments Ltd., Riverside,Forest Row Business Park, East Sussex RH18 5DW.
publications will deal with the potential for the control of the mechanical behavior of these materials using growth parameter variations. RLM crystallizes in the monoclinic structure, space group P21 with a ) 0.7982 nm, b ) 2.1562 nm, c ) 0.4824 nm, and β ) 109.57°; There are two molecules (R-lactose and water) in the asymmetric unit and two asymmetric units per unit cell (i.e., Z ) 2).3 The space group defines the structure as noncentrosymmetric, which confers on the crystal a number of characteristics, of which two are particularly noticeable. The first is that the crystals always adopt an asymmetric shape. This is usually referred to as a polar morphology since the crystal is polarized as a consequence of the alignment, relative to a particular crystallographic direction, of the component molecular dipoles in the structure.4 The second is that such crystals exhibit highly anisotropic growth, particularly in the polar directions. In extreme cases, this can result in a zero growth rate in one polar direction and a highly restricted growth rate in the other.4,5 Attempts to develop more rapid growth in the direction that propagates slowly, such as by increasing the supersaturation, often results in the development of morphological instabilities on the growing face and to the inclusion of solvent in the developing sector.5 RLM shows both characteristics. The crystals develop the well-defined asymmetric tomahawk shaped, polar morphology depicted in Figure 1. They grow only in one polar direction, the [010] direction, which corresponds to the broader end of the crystal. This means that the nucleation point of all crystals lies at the narrower tip.6 The crystal facets in this direction are usually rounded and rough. Solvent inclusions are often formed in the [010] sector. In indexing the morphology of the crystal, we have used the notation defined in previous publications. This takes account
10.1021/jp002051o CCC: $19.00 © 2000 American Chemical Society Published on Web 11/30/2000
Morphology of Crystals of R-Lactose Hydrate
Figure 1. Characteristic tomahawk-shaped morphology of R-lactose monohydrate crystallized from aqueous solution.
of the absolute configuration of the molecules in the crystallographic structure.7 A more unique aspect of the growth of the material is that when RLM is dissolved in aqueous solution it undergoes mutarotation to form β lactose.8 At equilibrium, the latter isomer is present to the extent of ∼60% w/w in solution. Thus, RLM, which is the less soluble component, always nucleates and grows from a highly impure solution in which the β-lactose impurity could well act as both a nucleation inhibitor and a habit modifier. A consequence of such inhibition is that the eventual nucleation and growth will take place under conditions of high supersaturation, a kinetic condition that can cause variations in growth rates and hence morphological variations in the product. As a result of this wide range of potential influences on the morphology of the crystal, it is a matter of debate as to whether the observed tomahawk morphology is natural, is a modification due to impurity effects or the result of growth under extreme conditions. The influence of supersaturation on the morphology of RLM has been studied by Herrington9 who showed that changes do occur over the range of supersaturations which he used. The potential role of β lactose as a habit modifier was considered by Michaels and van Kreveld.10 They demonstrated that a different and more symmetrical form of RLM crystallized from solutions that contained concentrations of β-lactose much lower than the mutarotation equilibrium concentration. The influence of β-lactose as a habit modifier was proposed to result from the similarity in molecular structure of the R and β-lactose molecules. Both contain the same galactosydal moiety linked to a different conformation of the monosaccharide glucose. This similarity allows the β-lactose molecule to insert into the RLM structure along particular crystallographic directions in the manner of the constituent molecules. The dissimilarity of the projecting portion then inhibits further crystallization. van Kreveld11 later confirmed this proposal by demonstrating that other di-saccharides of related structures were also effective inhibitors. The concept was later elaborated and confirmed by Visser and Bennema.12 The consequence is that such molecules could insert readily into the (01h0) and {01h1} faces, thus completely inhibiting the growth of the former and depressing the growth of the latter. In contrast, the β-molecules would be unacceptable at the (010) faces, growth of which requires the insertion of the counter orientation. This explanation accounts well for the tomahawk morphology and the zero growth rates along [01h0]. It must be
J. Phys. Chem. B, Vol. 104, No. 51, 2000 12257 recalled, however, that zero growth along one polar direction is a common feature of the growth of polar materials even from pure solutions, and this might arise from other causes.4,5 More recently, the work of Clydesdale et al. has raised questions on the above interpretations. Using a modeling approach13 they have demonstrated that the characteristic tomahawk shape can be predicted for growth from pure solution. They also note that experiments carried out at a range of supersaturations yielded crystals which, to a large extent, were tomahawk shaped. They did not observe the distinct variations in morphology noted by Herrington.9 These differences of interpretation have led us to reexamine the processes of nucleation and growth of RLM from aqueous solution. In the present paper, we address the question of the influence of β-lactose on the growth process and define the degree of its incorporation into the growing crystal. Later papers will consider the influence of supersaturation on the nucleation and growth process and its potential role in morphological change.14 2. Experimental Section 2.1 Materials. Commercially available R-lactose monohydrate (RLM) (DMV Pharmatose 50m) was used in all experiments in the as receiVed form. The material comprises crystals (size range 300-500 µm) of the tomahawk-shaped form (Figure 1) that were shown to contain 3-4% of the β isomer. No evidence was found for the presence of separate β isomer crystals in the mass. Their absence is usually ascribed to the fact that this material is considerably more soluble in aqueous solution (∼50% w/w @ 295K) than RLM (9% w/w, 295K). This suggests that the impurity is incorporated in the solid product either in solid solution or as included mother liquor. Anhydrous R-lactose was prepared by thermal dehydration at 423 K. Progress to the anhydrous form was monitored gravimetrically. DSC examination of the final product showed no trace of the hydrate (
