J. Phys. Chem. B 2001, 105, 9057-9066
9057
Macro- and Micromorphology of Monoclinic Paracetamol Grown from Pure Aqueous Solution R. I. Ristic,† S. Finnie,‡ D. B. Sheen, and J. N. Sherwood* Department of Pure and Applied Chemistry, UniVersity of Strathclyde, Glasgow, G1 1XL, Scotland, UK ReceiVed: October 12, 2000; In Final Form: April 30, 2001
The morphology of monoclinic paracetamol crystals has been investigated both theoretically and experimentally. Calculations using the computer program HABIT 95 with both DREIDING II and MOMANY force fields predict prismatic forms in which {100}, {001}, {110}, and {201h} show approximately equivalent morphological importance. Whereas all of these faces are observed experimentally, the real crystals showed a {110} dominance at low supersaturations which gave way to an increasing {001} dominance as the supersaturation increased. This variation was accompanied by a change from a columnar to a platelike habit. Surface examinations using phase contrast microscopy showed the habit changes to be due principally to changes in the growth mechanism of the {110} faces. A slow growth process involving two-dimensional nucleation at a few growth sources occurred at low supersaturations. This gave way to dislocation growth and finally at high supersaturations, to a fast growing mixed mechanism combining two-dimensional growth from the edges and vertexes of the {110} faces with the operation of dislocation sources at the face center. The increasing dominance of the two-dimensional growth contribution at the highest supersaturations coupled with an increase in macrostep formation resulted in the development of inclusions in the {110} sectors. This phenomenon will result in significant increases in the solvent impurity content of crystals at the high supersaturations normally used in the production of this material. The results of this study show well the dominant part that the growth mechanism can play in the definition of the morphology of crystals and hence the care which must be taken in the interpretation of modeling calculations.
1. Introduction The need to control the purification and crystallization characteristics of speciality chemicals such as pigments and pharmaceuticals has led to an increasing interest in the definition of the morphology and morphological stability of molecular crystals. Processing factors such as separation, flow, compaction, dissolution, and packing all depend to a considerable extent on particle shape and size distribution.1 Uncontrolled and unpredictable variations in crystal habit can lead to a loss of control over the process often with costly results. For example, an uncontrollable variation in crystal habit can present serious problems in pharmaceutical manufacturing, influencing the uniformity of tablet weight2 or causing difficulty in tabletting.3 The color of pigments can be similarly affected.4 Although these problems may be circumvented by grinding or milling the materials to provide more acceptable and reproducible properties, such treatments are often time-consuming and expensive. They may also introduce complications by promoting changes in crystal structure5 and crystal perfection.6 It is obvious that a better understanding of the underlying processes taking place during crystallization could lead to the optimization and control of the morphology and hence of the overall process. Most industrial crystallization processes use some form of habit modification to control both the production and the postproduction properties of crystalline material. This can be * To whom correspondence should be addressed. E-mail: j.n.sherwood@ strath.ac.uk. Fax: +44 141 548 4822. Phone: +44 141 548 2797. † Current address: Department of Chemical & Process Eng., Firth Court, Western Bank, Sheffield University, Sheffield S1O 2TN, UK. ‡ Current address: Scherer D. D. R., Blagrove Industrial Estate, Frankland Road, Swindon, UK.
achieved by controlling the cooling rate or evaporation of the solution, temperature, degree of supersaturation, selection of the solvent, pH adjustment, or by deliberately adding an impurity that acts as a habit modifier. Fundamental to the understanding of the influence of these factors on the habit modification process is the definition of their role in both the structural and mechanistic aspects of the growth process and hence on the macro- and micromorphology of the product. The macromorphology of a crystal depends on the relative growth rates of the different crystallographic faces. Those that grow rapidly have little or no effect on the growth shape. The slowly growing faces have most influence. The growth of a particular face is defined by the crystal structure and the density of active growth sites on one hand and by environmental conditions on the other. The micromorphology of solid surfaces, that is their structure on a scale of nanometers to micrometers, is the governing factor in processes such as crystal growth and habit (macromorphological) modification. One of the ways of developing a quantitative understanding of these processes is to study the microtopography of the crystal surfaces. This provides direct evidence for the mechanism governing the growth of each crystal face which in turn can be related to the macromorphological behavior of the crystal as a whole. The present work describes the macro- and micromorphology of monoclinic paracetamol crystals grown from pure aqueous solution at different supersaturations. Two approaches were used; a computer modeling approach based on crystal structure and intermolecular force fields and a detailed ex-situ microtopographic investigation of all habit faces of paracetamol by reflection optical microscopy.
10.1021/jp003757l CCC: $20.00 © 2001 American Chemical Society Published on Web 09/01/2001
9058 J. Phys. Chem. B, Vol. 105, No. 38, 2001
Ristic et al.
Figure 1. Macromorphology of paracetamol crystals grown at (a) low, (b) medium and (c) high supersaturation. showing both the observed habits and the forms of the crystals.
2. Experimental 2.1 Specimen Preparation. Paracetamol crystals were grown from aqueous and ethanolic solutions by the temperature lowering method7 using pharmaceutical grade material (RhonePoulenc; Rhodapap). A well-developed seed crystal of about 0.125 cm3 mounted on a thin cotton thread was placed in a thermostated (( 0.01 °C) saturated paracetamol solution and cooled at different rates; 0.2 °C/day, 1 °C/day and 1.5 °C/day designated low, medium and high corresponding to low (15%) supersaturations. After a period of a few weeks, a well-formed crystal of about 2.5 cm3 was obtained. On completion the crystal was withdrawn from the solution through a 2 cm deep surface layer of n-hexane. This displaces any solution adhering to the surface of the crystal and hence preserves the growth features.8 The crystal was finally washed with fresh n-hexane and dried on a soft tissue. Crystals were also grown from the vapor by sublimation in vacuo in a temperature gradient.9 2.2 Observation Techniques. The crystals were indexed by optical goniometry and X-ray single-crystal diffractometry to give Miller indices for the faces with respect to the space group P21/a Observation of the micromorphology of the habit faces was carried out by means of reflection optical phase contrast microscopy. Measurements of height differences and inclinations of growth hillocks were carried out by two-beam inteferometry using a mercury light source combined with a monochromator filter (λ ) 5460 A). For these studies, a Reichert Polyvar 2 MET microscope was used. To record extremely low contrast features a high contrast (Technical-Pan) photographic emulsion was used. X-ray topographs of whole small crystals (∼0.5 cm diameter) were recorded on Agfa Structurix film using Cu KR radiation.10 2.3 Growth Kinetic Studies. Growth kinetic studies were carried out under carefully controlled conditions of supersaturation in the range 0-20%. It proved impossible to exceed the upper end of this range due to the occurrence of threedimensional nucleation in solution. The solution was well stirred
to ensure that the growth was not diffusion-controlled, a condition defined by the fact that variation in stirring rate had no influence on the growth rate. The rate of advance of the individual faces was measured by direct observation with a microscope. A more detailed paper on these and associated experiments will appear elsewhere.11 2.4 Morphological Modeling. The prediction of the morphology of the crystal was carried out using the computer program Habit 9512 with the DREIDING II13 and MOMANY14 force fields. These potentials are particularly suited to address the type of molecule under consideration. They include welldeveloped routines for addressing both van der Waals and hydrogen bond interactions in the solid. 3. Observations and Interpretation 3.1 Macromorphology. 3.1.1. Growth from Pure Aqueous Solution. Figure 1 presents the typical morphologies of paracetamol grown from aqueous solution at low, medium, and high supersaturation. Growth of the crystals at low supersaturation (15%) yielded crystals of a flat, tabular morphology, in which the {001} clearly had the greatest morphological importance and dominated the habit. The decline in morphological importance of the {110} faces continued and these were seen to be very much smaller than in crystals grown under conditions of lower supersaturation. The {110} growth sectors were characterized by a much larger
Morphology of Monoclinic Paracetamol
J. Phys. Chem. B, Vol. 105, No. 38, 2001 9059
TABLE 1: Relative Morphological Importance of the Habit Faces of Paracetamol Crystals as Defined by Modeling and Experimental Assessment experimentala
modelling
face
low
medium
high
{110} {001} {201h} {011} {100} {111} {021} {2h11}
1 (0.850) 2 (0.097) 3 (0.028) 3 (0.025) - (0) - (0) - (0) - (0)
1 (0.400) 2 (0.267) 5(0.067) 3 (0.133) 3 (0.133) - (0) - (0) - (0)
2 (0.175) 1 (0.505) 3 (0.085) 2 (0.170) 4 (0.065) - (0) - (0) - (0)
DREIDING II MOMANY 4 1 3 3 1 5 6
4 3 2 6 1 4 7
a Low, medium and high refer to supersaturation levels of 15% respectively. The numbers in brackets refer to an analysis carried out on the relative areas of the faces on a series of crystals formed from solutions nucleated and grown under the noted conditions.
Figure 3. Habit of paracetamol crystals: (a) grown from ethanol and (b) grown from the vapor phase under equivalent conditions of (i) low and (ii) high supersaturations to those used to prepare the crystals shown in Figure 1.
Figure 2. Rates of growth of the dominant habit faces of paracetamol crystals as a function of supersaturation in the range 0-20%.
density of inclusions than observed in any of the other sectors. The {201h}, {100}, and {011} faces changed little relative to each other and to the {001} under this increase in supersaturation. To quantify these changes, the relative morphological importance of each face was determined as a ratio of the area of that face to the total area of the crystal grown at a particular supersaturation (Table 1). It is apparent that the change in macromorphology is governed largely by the relative morphological importance of the {110} and {001} faces. With an increase of supersaturation the relative morphological importance of the {110} faces decreases whereas the relative morphological importance of the {001} faces increases, effectively leading to a “squashing” of the form along the [001] axis of the crystal. The variations in morphology are consistent with the kinetic measurements the results of which are shown in Figure 2. These confirm that the {201h} and {011} faces show a small but gradual increase in growth rate over the range of supersaturation studied and therefore should remain similar in morphological importance. The {001} face follows this pattern remaining decreasingly lower in growth rate than these faces at all supersaturations. The most dramatic change however is noted for the {110} face from a virtually zero growth rate at low supersaturations (
