J. Phys. Chem. B 1997, 101, 9107-9112
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In Situ Optical Interferometric Studies of the Growth and Dissolution Behavior of Paracetamol (Acetaminophen) Crystals. 3. Influence of Growth in the Presence of p-Acetoxyacetanilide† Boris Yu. Shekunov* School of Pharmacy, UniVersity of Bradford, Bradford, West Yorkshire BD7 1DP, U.K.
David J. W. Grant Department of Pharmaceutics, College of Pharmacy, UniVersity of Minnesota, WeaVer-Densford Hall, 308 HarVard Street S.E., Minneapolis, Minnesota 55455-0343
Roger J. Latham Department of Chemistry, School of Applied Sciences, De Montfort UniVersity, Leicester LE1 9BH, U.K.
John N. Sherwood Department of Pure and Applied Chemistry, UniVersity of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, Scotland, U.K. ReceiVed: June 24, 1997; In Final Form: August 21, 1997X
The influence of p-acetoxyacetanilide (PAA) as an additive in the surrounding paracetamol solution was investigated during growth and dissolution of paracetamol crystals. The different crystal faces of paracetamol, {110}, {201h}, and {001}, exhibited two different mechanisms of interaction with the additive. According to the first mechanism, PAA molecules are adsorbed onto the crystal surfaces, i.e. {110} faces, and decrease both the step free energy and the step velocity functions. The second mechanism, which is characteristic for the {001} crystal faces, consists of a selective adsorption of PAA onto the active dislocation sites and suppression of more powerful growth centers in favor of elemental dislocations. The character of adsorption is defined by the affinity between the molecular structure of the crystal surface and the additive molecules, which permits incorporation into the {110} growth sectors. Lattice strain produced by incorporation of PAA exhibits a maximum followed by a relaxation process. This relaxation is caused by formation of cleavage defects and corresponds to an increase of the enthalpy of fusion and decrease of the crystal density as functions of PAA concentration.
1. Introduction The presence of additives (or impurities) at concentrations as small as several parts per million may bring about substantial changes in the growth kinetics. In most cases additives selectively inhibit the growth of certain crystallographic faces causing different crystal habits. Their influence on the dissolution process is usually less pronounced, although both dissolved and incorporated additives may effect the dissolution rate. The mechanism of additive influence has been discussed in a number of papers (for example, reviews 1-3). The literature is replete with references to additive-induced habit modification. Of these studies, only a limited number are sufficiently quantitative to provide adequate insight into the specific mechanisms involved. For pharmaceutical technology, understanding these mechanisms may help to control the quality and purity of raw crystalline substances and, consequently, to improve the manufacture and performance of the final dosage forms.
The present study examines the influence of p-acetoxyacetanilide (PAA) on the surface growth and dissolution kinetics of paracetamol (P). PAA is a known synthetic precursor, structurally similar to P4 and also a suggested prodrug.5 The strong modifying effect of PAA on paracetamol crystals was found by Chow and Grant.6 In this and the following papers,7,8 the authors have studied the influence of concentration, initial supersaturation, and mixing on the crystallization of paracetamol in presence of PAA additive. This approach involved a batch crystallization technique and thermodynamic analytical methodology. The crystals were obtained at relatively high initial supersaturation of 30%. The method developed in the present study consists of investigating the surface growth kinetics of single paracetamol crystals using laser interferometry. Shekunov et al. have applied this technique to investigate the surface kinetics and diffusion-hydrodynamic factors of paracetamol crystals in pure solution.9-11 2. Experimental Method
†
Some experimental results presented in this paper were obtained when the authors were working in the Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, Scotland, U.K. (B.Y.S., D.J.W.G., and J.N.S.) and at the Department of Pharmaceutical Sciences, De Montfort University, The Gateway, Leicester, LE1 9BH (B.Y.S. and R.J.L.). * Corresponding author. Fax: +44 (01274) 305570. X Abstract published in AdVance ACS Abstracts, October 1, 1997.
S1089-5647(97)02050-6 CCC: $14.00
Laser interferometric measurements of crystal growth (or dissolution) kinetics were carried out as described.10-11 The results were obtained at high Reynolds numbers of solution flow (high solution flow velocities) at which the growth parameters were independent of the hydrodynamic conditions.11 Density measurements were carried out by means of a flotation method © 1997 American Chemical Society
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using 1,1,1-trichloroethane as a flotation liquid.12 The enthalpy of fusion was determined using a Du Pont differential scanning calorimeter equipped with a data station (Thermal Analyst 2000). Finally, the residual strain of the crystals was characterized using Laue X-ray diffraction in relationship with the crystal mosaic spread.13 The bulk mosaic spread of small crystals (0.1-0.5 mm) was obtained as a function of impurity concentration using a white X-ray radiation beam (collimated with a lead pinhole) at the synchrotron radiation facility at Daresbury Laboratory (U.K.). The mosaic spread, η, can be found from the relationship
r ) 2ηl/cos2(2Θ)
(1)
where r is the radial Laue spot extension, l is the distance between the specimen and the film, and Θ is the Bragg diffraction angle. The mosaic spread, η, characterizes the asterism (radial distribution of the Laue spots) and defines the extent of crystal defects generated by the impurity. The mosaic spread function was calculated on the basis of five different measurements at each concentration point. The P used in all experiments was commercially available (Sigma Chemical Co.). PAA was prepared from P by the method described.15 3. Results 3.1. Growth Kinetics. For the crystal faces, {110}, {201h}, and {001}, the normal growth rate, R, the tangential velocity, V, and the slope of growth hillocks, p, were measured as functions of PAA concentration, ci, at relatively high constant supersaturations, σ ) 0.1, at which the faces were steadily growing. These dependencies are shown in Figure 1, parts a, b, and c, respectively. Both V and p of the {110} faces were strongly influenced by ci. PAA reduced the velocity of the growth steps to zero at some critical content. In contrast, PAA increased the hillock steepness as shown in Figure 1c (curve a). The combined effect on growth rate led to deceleration, and as the additive content increased, growth came to a complete halt. The critical additive concentration depended on the supersaturation and equaled 0.55 mol % when σ ) 0.1. Therefore, PAA expanded the “dead zone” of supersaturation, which is about σ ) 0.08 in the pure solution of P.10 The influence of PAA for the {110} faces was much stronger than for the others. As a result the crystal habit in the presence of PAA had a needlelike form in which the {110} faces dominated. PAA did not practically influence the step velocity on the {001} crystal faces (Figure 1b, curve c). The decrease of normal growth rate on these faces was related to a sharp decrease of the hillock steepness (Figure 1c, curve c), which resulted from a variation of dislocation source activity, as illustrated in Figure 2. A steep dislocation hillock (indicated in Figure 2a by the arrow) disappeared, leaving several hillocks of smaller activity (such new hillocks can be seen in Figure 2b). Measurements of p(σ) dependencies for the old and new hillocks (Figure 3) showed their different character. Thus, most of the new hillocks had the same linear dependencies p(σ), which corresponded to the smallest dislocation activity observed.10 This result implies a simple structure of the new centers formed by single dislocations. The observed variation of dislocation activity had a regular character and affected most of the hillocks on the {001} faces. Because of this phenomenon, the inhibition of normal growth rate for the{001} faces was greater than that for the {201h} faces (Figure 1). Consequently, the relative importance of the {001} faces increased with increasing concentration of PAA.
Figure 1. Dependencies of (a) normal growth rate, R, (b) tangential velocity, V, and (c) hillock steepness, p, as functions of concentration ci of PAA in solution. Curves correspond to the crystal faces {110} (a, 0), {201h} (b, O), and {001} (c, b). σ ) 0.1. T ) 35.5 °C.
The {201h} faces showed kinetics that were intermediate between those for the {110} and {001} faces. The step velocity
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Figure 2. Variation of dislocation activity on the (001) crystal face at σ ) 9.65 under the influence of PAA: (a) ci ) 0 and (b) 0.224 mol %.
Figure 4. (a) Normal dissolution rate, R, versus supersaturation, σ, in the presence of 1.26 mol % of PAA (solid lines) as compared to the dependencies in pure solution (dotted lines) for the (a, 0) {110}, (b, O) {201h}, and (c, b) {001} crystal faces. (b) Dependence of etch pit steepness, p, on supersaturation, σ, on the {001} crystal faces at the same additive level.
Figure 3. Dependencies p(σ) for two typical dislocation hillocks on the {001} faces at PAA level (a) ci ) 0 and (b) 1.26 mol %.
(Figure 1b, curve b) was lowered by PAA, although this effect was not strong and no “dead zone“ was observed. The hillock steepness slowly decreased with increasing concentration of PAA. 3.2. Dissolution Kinetics. Figure 4a represents the dependencies of dissolution rate versus undersaturation in the presence of PAA in comparison with the pure solution data. Dislocation etch pits were only observed on the {001} faces.10 On the other faces a rapid dissolution from the crystal edges did not permit such measurements. Figure 4a shows that the dissolution rates of the {001} and {201h} faces were lowered by the presence of PAA. For the {001} faces this retardation was caused by changes of the activity of dislocations, the same as for the crystal growth processes.
This effect was very distinctive because of the low critical undersaturation σ2*, which was needed to produce etch pits.10 In the solution containing PAA, σ2* = -0.021 in contrast to the value σ2* = -0.007 without PAA.10 This result is illustrated in Figure 4b, which shows that the steepness of the etch pits decreased as the concentration of PAA increased. There were no measurable effects on the velocity of the dissolving steps. The {110} faces were dissolving faster with PAA than without it (Figure 4a). The velocity of the dissolving steps, as well as the “dead zone” of supersaturation (σ < 0.08 in Figure 4a), was not significantly changed by the additive. This result pointed to an increase of dislocation activity, which contributed to the dissolution process. 3.3. Solid-State Properties of Paracetamol Crystals. Figure 5 (curve η) shows the mosaic spread of P crystals as function of PAA concentration in solution, ci. Curve u represents the uptake of PAA, which corresponds to the same additive levels in solution.6 Both curves were obtained for crystals grown at the initial supersaturation σ ) 0.28. Although the PAA uptake is a progressive function that reaches a plateau at high concentrations, the mosaic spread function has a maximum at some intermediate concentration about ci ) 0.5 mol % and shows a decrease within the interval of concentration ci ) 0.5-1 mol %. The defects that contribute to the mosaic spread of X-ray reflections are commonly associated with the strain of crystal
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Figure 5. Crystal mosaic spread, η, and uptake of PAA by paracetamol crystals, u, grown at supersaturation, σ ) 0.28, at various PAA concentrations, ci.
lattice and point defects. The relaxation of stress into larger, planar defects can explain the behavior of curve η in Figure 5. These planar defects can be observed under an optical microscope and are shown in Figure 6. Fractures parallel to the {010} cleavage planes (shown by the arrows) can be recognized by the mirrorlike reflections on them. The {010} crystal faces never existed during growth, and therefore these cleavage defects were formed in stressed regions of the crystals after growth. The larger relative refractive index of these defective regions indicates that they do not contain included solution. Figure 7 shows that the enthalpy of fusion exhibits a minimum and the crystal density a corresponding maximum at concentration ci ) 0.4-0.5 mol %. A relaxation process and a decrease of the both functions were observed at higher concentrations of PAA.
Figure 6. Planar cleavage defects (parallel to the {010} planes as shown by the arrows) formed in a paracetamol crystal grown at ci ) 0.72 mol % of PAA.
4. Discussion 4.1. Effect of Additive on Step Velocity and Hillock Steepness. The kinetic data indicate a selective influence of PAA on the growth and dissolution of the different crystallographic surfaces, i.e., {110}, {201h}, and {001}. Two different mechanisms of the crystal surface-additive interactions were observed distinctly for the {110} and {001} crystal faces. For the {201h} faces, the kinetics had an intermediate character. A sharp decrease of step velocity on the {110} faces (Figure 1b) suggests a strong adsorption of PAA molecules on these faces. Figure 8 shows a “slice” of crystal structure of P parallel to the {110} faces. Minimization of the surface energy10 showed that the {110} faces are composed of molecules half of which are aligned parallel to the {110} planes, whereas the others are nearly perpendicular to these planes. Each topmost molecule on the {110} faces has two surface hydrogen bonds in contrast with the {001} and {201h} faces, which have only one surface hydrogen bond per molecule. This fact leads to the greatest value of the calculated surface energy for these faces.10 The strong adsorption of PAA and its incorporation into the {110} faces might be explained by normal orientation of some paracetamol molecules, which allows the additive molecules to be easily substituted into this position because of the similarity between P and PAA molecules. Evidently, these PAA molecules have the same kind of hydrogen bonding with the {110} surfaces as the P molecules. The -COCH3 “tail”
Figure 7. Density, d, and enthalpy of fusion, ∆H, of paracetamol crystals grown at various PAA concentrations, ci. Each data point is the mean of triplicate determinations.
that discriminates PAA from the P molecule would then protrude from the surface into the solution to disturb deposition of the next layer and cause the noted influence on step velocity. The increase of dislocation hillock steepness observed on the {110} faces (Figure 1c) can also be related to the strong adsorption of PAA into the growth steps. This adsorption would decrease the specific step free energy, R, according to the linear relationship10
p ) b/(2πω1 /(ΩR/kTσ) + 2L)
(2)
where Ω ) 1.94 × 10-22 cm3 is the mean molecular volume of
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Figure 8. Structure of the {110} faces of the paracetamol crystal. Dashed lines indicate hydrogen bonds. Arrow shows a molecular position that is most convenient for incorporation of PAA molecules.
paracetamol, b is Burgers vector of the dislocation center, ω1 is the rotation frequency of the growth spiral, and L is the characteristic dimension of the center. An estimation based on relationship 2 and Figure 1c gives the magnitude of step energy R ≈ 0.4 × 10-2 J/m2 at ci ) 0.72 mol % of PAA as compared to R ) 0.63 × 10-2 J/m2 in the pure solution.10 The decrease of the step free energy would also increase the dissolution rate, R, which is proportional to p. Figure 4a shows that such dependencies were observed for the {110} crystals faces. 4.2. Effect of Additive on Dislocation Activity. On the {001} faces the step velocity was not affected by PAA, although the dislocation activity was altered. More powerful hillocks ceased to exist, and the simplest, presumably elemental, dislocation centers took over. This indicates, first, that adsorption of PAA is much stronger near the dislocations than into or between the growth steps and, second, that PAA selectively inhibits the more powerful complex dislocation centers. The mechanism of additive adsorption in the vicinity of the dislocation centers is not fully understood. A lattice distortion around such defects might create more favorable adsorption positions than those in the growth steps. Adsorbed PAA molecules would prevent movement of the growth spiral within the area of the dislocation center (L ≈ 4 × 10-7 m, as described10) and, effectively, reduce the activity of this center. The selective adsorption of PAA into the dislocation center is also consistent with the dissolution phenomena on the {001} crystal faces. These crystallographic faces can be characterized by the critical undersaturation σ2*, which is needed to produce etch pits. The existence of σ2* in a pure solution of P10 is explained by the phenomenon of dislocation hollow core instability. The formation of etch pits commences when
σ < σ2* ≈ -20R2Ω/(µb2/kT)
with a corresponding decrease of the effective Burgers vector by the factor 1.7. Thus, for both growth and dissolution processes of the {001} crystal faces, PAA influenced the active dislocation centers in contrast to the {110} faces where the surface step energy and the step velocity were affected. The structural similarity between the PAA and P molecules suggests that the selective adsorption of PAA near dislocations sites could also indicate a preferential adsorption of the “host” P molecules at these sites. The result of such adsorption could be difficult to distinguish at low supersaturations. At high σ, however, this adsorption would lead to a lower barrier for nucleation on the dislocation centers. 4.3. Formation of Defects. The crystal strain, characterized by the mosaic spread function, the density, and enthalpy functions (Figures 5 and 7) shows correlating dependencies with a minima (enthalpy of fusion) and maxima (mosaic spread and density). Thermodynamic functions of the solid state that behave in a similar manner have been observed before in the P + PAA system.6-8 In the present work, accumulation of strain due to point defects (incorporated PAA molecules) at lower additive concentrations led to fracture of the crystalline material along the cleavage planes {010} (Figure 6). This behavior can result in a relaxation of the lattice strain that is reflected, for example, in the increase of the enthalpy of fusion. Because the {110} faces are the major surfaces that adsorb and incorporate PAA molecules, the planar fracture defects were formed predominately in these growth sectors. 5. Conclusions A selective influence of PAA, as the additive, on the growth and dissolution kinetics of P crystals was observed. For the {110} crystal faces, both the step velocity and the step free energy decreased rapidly as a function of PAA concentration. The combined effect of the step velocity and the hillock steepness functions on the normal growth-dissolution rate caused deceleration of growth and promoted dissolution. Strong adsorption of PAA onto the {110} faces is consistent with the molecular structures of these faces, which permit the structurally similar functional groups of P and PAA molecules to penetrate into the crystal lattice. For the {001} faces the mechanism was different because the additive did not influence the step velocity and step energy but reduced the activity of the dislocation centers. This result indicates a preferential adsorption of PAA onto the dislocation sites. The additive, PAA, selectively suppresses more powerful growth centers in favor of the elemental dislocations and effectively reduces the growth and dissolution rates. The incorporation of the additive, mostly through the {110} crystal faces, caused initial accumulation of strain with a decrease of the enthalpy of fusion and an increase of the density of paracetamol. At some additive concentration (which is about 0.5 mol % for the conditions of the experiments), the strain relaxes by forming planar cleavage defects in the {110} growth sectors. Acknowledgment. The mosaic spread measurements were carried out at the SRS Laboratory, Daresbury. Financial support by the EPSRC and CLRC is gratefully acknowledged. We thank Ms. X. Cai for measuring the enthalpy of fusion and flotation density of paracetamol crystals.
(3)
According to this equation, derived elesewere,14 σ2* becomes more negative for the dislocations with a smaller b. In our experiments, the additive (of concentration 1.26 mol %) decreased σ2* by a factor of 3 (Figure 4b). As with growth, PAA split the complex dislocation centers into smaller sources
List of Symbols P ) paracetamol (acetaminophen) PAA ) p-acetoxyacetanilide, the additive {hkl} ) Miller indices of crystal form b ) Burgers vector of dislocation source
9112 J. Phys. Chem. B, Vol. 101, No. 44, 1997 ci ) concentration of PAA in solution d ) density of paracetamol L ) mean dimension of dislocation source p ) surface steepness R ) normal growth or dissolution rate u ) uptake of PAA by P crystals T ) absolute temperature of solution V ) R/p, tangential velocity of growth or dissolution (velocity of steps) R ) specific free energy of growth step µ ) shear elastic modulus η ) crystal mosaic spread defined by formula 1 σ ) ln(c/c0 ), supersaturation of solution (undersaturation if negative); c and c0 are the real and equilibrium concentrations of P in solution, respectively σ2* ) critical supersaturation of etch pit formation Ω ) mean molecular volume of paracetamol ω1 ) generalized rotation frequency of growth spiral References and Notes (1) Chernov, A. A. In Modern Crystallography III, Crystal Growth; Springer Series in Solid State Physics: Springer: Berlin, 1984.
Shekunov et al. (2) Mullin, J. W. Crystallization, 3rd ed.; Butterworth-Heinemann, London, 1993. (3) Davey, R. J. J. Cryst. Growth 1976, 34, 109. (4) Fairbrother, J. E. In Analytical Profiles of Drug Substances; Florey, K., Ed.; Academic Press: New York, 1973; Vol. 3, p 1. (5) Bauguess, C. T; Sadik, F; Fincher, J. H.; Hartman, C. W. J. Pharm. Sci. 1975, 64, 117. (6) Chow, A. H.-L.; Chow, P. K.; Zhongshan, K. W.; Grant, D. J. W. Int. Pharm. 1985, 24, 239. (7) Chow, A. H.-L.; Grant, D. J. W. Int. Pharm. 1988, 41, 29. (8) Chow, A. H.-L.; Grant, D. J. W. Int. Pharm. 1988, 42, 123. (9) Shekunov, B. Yu; Aulton, M. E.; Adama-Acquah, R.; Grant, D. J. W. J. Chem. Soc., Faraday Trans. 1996, 92, 439. (10) Shekunov, B. Yu.; Grant, D. J. W. J. Phys. Chem. 1997, 101, 3973. (11) Shekunov, B. Yu.; Chow, A. H.-L; Grant, D. J. W.; Sherwood J. N. Submitted for publication in J. Phys. Chem. (12) Duncan-Hewitt, W. C.; Grant D. J. W. Int. J. Pharm. 1986, 28, 75. (13) Roberts, K. J.; Sherwood, J. N.; Bowen, D. K.; Davies, S. T. Mater. Lett. 1983, 2, 104. (14) Chattaway, F. R. L. Chem. Soc. 1931, 2495. (15) Van der Hoek, B., van der Eerden, J. P.; Bennema, P. J. Cryst. Growth 1982, 56, 621.
