Influence of Ultrasound on the Nucleation of Polymorphs of p-Aminobenzoic Acid Sandra Gracin, Marketta Uusi-Penttila¨, and Åke C. Rasmuson* Department of Chemical Engineering and Technology, Royal Institute of Technology, S-100 44 Stockholm, Sweden Received February 12, 2005;
CRYSTAL GROWTH & DESIGN 2005 VOL. 5, NO. 5 1787-1794
Revised Manuscript Received May 24, 2005
ABSTRACT: p-Aminobenzoic acid crystallizes in two different polymorphic forms: the R-form and the β-form. The R-form crystals are needle-shaped, while the β-form crystals have a more favorable prismatic shape. The system is enantiotropic with the transition temperature at approximately 25 °C. Below the transition temperature, the β-form is the thermodynamically stable polymorph but can only be produced at very slow supersaturation generation either in water or in ethyl acetate. In the present work, the influence of ultrasound on the nucleation of p-aminobenzoic acid polymorphs has been investigated by use of several different sonication intensities and schemes. It is shown that sonication significantly reduces the induction time for nucleation. By using controlled sonication, we were able to more reproducibly crystallize the β-form at more reasonable cooling rates. In addition, sonication is found to quite selectively favor the appearance of the β-polymorph. It is even possible to produce the pure β-form above the transition temperature where it is the metastable form and impossible to produce without sonication. The R-form structure is based on centro symmetric dimers formed by the association of carboxylic acid groups, while the β-form contains four-membered hydrogen-bonded rings of alternating amino and carboxylic acid groups. It is suggested that ultrasound disturbs the building up of the dimers in the solution and thus favors the crystallization of the β-polymorph. Introduction Polymorphs are solid phases in which the chemical composition is equal but the crystal structure differs. Many organic compounds may appear in more than one crystalline structure, either because of a different arrangement of molecules in the latticespacking polymorphismsor because of a different conformation of the molecules in the latticesconformational polymorphism. Polymorphs of a substance usually differ in their chemical and physical properties such as stability, crystal shape, compressibility, density, and dissolution rate, which leads to differences in handling and processing properties of the compound and in the shelf life and bioavailability of a drug. Sometimes the most stable polymorph is difficult to produce or a metastable form has favorable properties. Regardless of which form is the target, it is of greatest importance for the pharmaceutical industry to ensure reliable and robust processes and conformity with Good Manufacturing Practice. Hence, it is important, and today even a regulatory requirement, to identify the possible polymorphic forms of the product. An increasing industrial interest into polymorphism is also due to patent protection. During the past decade, significant research efforts have been devoted to polymorphism, e.g., Bernstein,1 Bernstein et al.,2 Brittain,3 Kitamura,4 and Blagden and Davey.5 However, the appearance and disappearance of polymorphs are still experienced as somewhat mysterious, and the fundamental understanding of polymorphism and its control is insufficient. According to our previous studies,6 p-aminobenzoic acid (PABA) crystallizes in two different polymorphic forms: the R-polymorph, which is the commercially * To whom correspondence
[email protected].
should
be
addressed.
E-mail:
available form and appears as long, fibrous needles, and the β-polymorph, which appears in the form of prisms. By solubility determinations, the system is found to be enantiotropic with a transition temperature of 25 °C, below which the β-form is the stable polymorph. The β-form can be crystallized only in water and ethyl acetate and only well below the transition temperature, and the supersaturation has to be carefully controlled. Often the R-form appears concomitantly. The solubility difference between the polymorphs is small, and hence the transformation from the R-form to the β-form is very slow. The crystal structure of the R-polymorph is based on dimers formed by the association of the carboxylic acid groups. The crystal structure of the β-polymorph is based on four-membered rings of alternating amino groups and carboxylic acid groups, where the amino nitrogen act as a hydrogen bond acceptor. There are no carboxylic acid dimers in the β-structure. It is proposed that the preference for nucleation of the R-polymorph is related to the formation of dimers in the supersaturated solution. Only in solvents where the solvent molecules may associate strongly with the carboxylic acid groups of the solute is the formation of dimers reduced sufficiently to allow for the nucleation of the β-form. In the present study, the influence of ultrasound on the appearance of the β-form is examined. In crystallization processes, ultrasound is claimed to change the crystal habit, change the crystal size distribution, promote or prevent agglomeration, and improve product handling.7-9 Already in the 1950s, ultrasound was used to precipitate fine and uniform penicillin crystals.7 Sonication initiates primary nucleation, narrows the metastable zone width, shortens the induction time, and enhances the nucleation rate.8,10 Sonication can therefore be used to nucleate systems that are difficult to nucleate and to produce a more uniform
10.1021/cg050056a CCC: $30.25 © 2005 American Chemical Society Published on Web 07/15/2005
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particle size distribution and a smaller mean particle size. It is reported that sonication leaves a trace in the treated solution, and it takes a considerable amount of time for the system to return to the normal unsonicated state.11,12 Continuous sonication produces crystals with more imperfections.13 When an optimal ultrasonic scheme was used, Ueno et al.8 were able to crystallize directly the polymorphic form V of cocoa butter. However, to our knowledge there are no reports in the literature in which sonication selectively favors one of the polymorphs in solution crystallization. Acoustic energy of ultrasonic waves is mostly spent in heating the liquid and moving it around. Ultrasound can induce macroscopic flow, i.e., acoustic streaming, which can be seen as the conversion of sound energy into kinetic energy.14 Ultrasound also can cause microstreaming, i.e., generation of small eddies close to a solid/ liquid boundary,15 and when crystalline materials are treated with ultrasound, acoustic energy is absorbed in the solid lattice.16 However, often the most important effect in liquids is that part of the energy is used to form cavitation bubbles.17 The ultrasonic pressure wave causes rarefaction in the liquid where the average distance between the liquid molecules increases and exceeds the critical molecular distance necessary to hold the liquid intact. Thus, the liquid will rupture, and cavities are created.14 The generation of acoustic cavitation is a measure of the “dynamic tensile strength” of the liquid. The measured value for a liquid is orders of magnitude lower than the theoretical value, which is believed to be due to inhomogeneities at which the bonding is weaker. Pockets of gas serve as weak points in a liquid, and these gas pockets can be stabilized by foreign particles and by organic skins of surface active molecules.18 There are two theories for modeling the cavitation bubbles: the hot-spot theory models the cavitation bubble collapsing adiabatically, and the electrical theory is based on an electrical collapse of the bubble.19,17 The hot-spot theory is based on the production of high pressures and temperatures during sonication. It is estimated that pressures generated in adiabatically collapsing bubbles may amount to 1000-2000 bar, and the local temperature may reach 4000-6000 K.19 The electrical theory is based on phenomena similar to those in plasmas.19 This theory17 considers the charge distribution due to dipoles in a solvent and their distribution around a cavitation bubble. There are significant electrical field gradients during the collapse of a bubble, and these are strong enough to cause bond breakage and chemical activity.19 The main controversies between the two theories come from sonoluminescence phenomenon, mechanics of cavitational collapse, and the viability of creating the extreme local temperatures and pressures.20 There is considerable experimental evidence to support the hot-spot theory, and this is the generally accepted approach to explain cavitation. The extreme pressure, shear, and temperature gradients that are generated in the material by high-power, low-frequency (between 20 and 100 kHz) ultrasound14,21 can alter the physical and chemical properties of the material. Because of the increase in mass transfer, mixing, and temperature,19 chemical reaction rates may be enhanced, which may lead to improved yield, better
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product quality, and higher selectivity.20 However, there is no clear molecular level understanding of the influence of ultrasound on crystal nucleation. One theory states that during the expansion cycle of an acoustic wave the bubble content is adiabatically expanded, which gives rise to a localized cooling in the vicinity of the bubble and an increase in the supersaturation.22 According to Hem23 and Lyczko et al.,24 sonication seems to change the activation energy for nucleation by an influence on the solid-solution interfacial energy. Lyczko et al.25 suggest that the ultrasonic treatment can change the heterogeneous nucleation mechanism. For calcium carbonate crystallization, it has been proposed26 that ultrasound mainly influences nucleation due to the physical effect of mixing and not due to cavitation and microstreaming. A change in the ultrasonic frequency alters the resonant size of the cavitation event; however, there is no direct coupling between the frequency of ultrasound and the molecular species. The ultrasonic intensity can have a strong influence. Below a certain intensity level, the amplitude of the sound field is too small to induce bubble growth. Above a certain level, increasing the intensity increases the volume in which cavitation can occur.18 Experimental Section p-Aminobenzoic acid was crystallized in water in an agitated batch crystallizer, and the influence of sonication on the induction time for nucleation and the crystal structure of the product crystals was evaluated. Materials. Pure, distilled, and deionized water was used as solvent in all experiments, and PABA was purchased from Sigma-Aldrich with a purity of 99%. Identification of the Polymorphs. The crystal morphology, structure, and transitions have been examined by a transmitted light microscope Olympus SZX12, by differential scanning calorimetry using a TA Instruments MDSC-2920, and by single-crystal X-ray diffraction using a Bruker-Nonius KappaCCD diffractometer. Equipment. The experimental equipment consists of a 500 mL jacketed glass batch crystallizer. The temperature is controlled by a heating and refrigeration circulator to within (0.02 °C. The impeller is a 45°-pitched blade turbine of 35 mm diameter and the stirrer speed is 300 rpm. Ultrasound is applied at the top of the reactor with the titanium probe dipped 2 cm into the solution. The ultrasound generator is a Sonics & Materials Vibracell VCX 600 with a 2.5-cm-diameter titanium alloy probe with the frequency 20 kHz ( 50 Hz. The acoustic intensity of the probe is adjustable and was calibrated by the calorimetric method.27,28 The temperature increase during sonication of pure water was recorded as a function of time and the power; P[W] is calculated from eq 1
P ) ({dT}/{dt})mcp
(1)
where dT/dt is the temperature change per unit time [°C/s], m is the mass of solution [g] and cp is the heat capacity of water [J/g °C]. The acoustic intensity [W/cm2] is calculated from eq 2
I ) P/A
(2) cm2
where A is the probe tip area (5.08 ). The sonication can be changed by changing the duration of each pulse, ∆tson, the time from the beginning of one pulse to the beginning of the next (the pulse repetition period, PRP) and the percentage of maximum intensity (% MI) of the generator. The measured average intensities from two series of 10-min experiments for seven different sonication schemes are presented in Table 1
Influence of Ultrasound on PABA Polymorphs
Crystal Growth & Design, Vol. 5, No. 5, 2005 1789 Table 2. Experimental Conditions of Induction Time Experiments series
Teq
Tson
SR
Sβ
filtrationa
1 2 3 4 5 6 7 8
20 20 20 23 30 30 32 38
13 13 13 13 24 25 27.5 33
1.30 1.30 1.30 1.46 1.25 1.20 1.18 1.19
1.50 1.50 1.50 1.63 1.29 1.22 1.17 1.13
+ + + + + + +
a
+ means applied; - means not applied. Table 3. Sonication Schemes for Series 1 and 4-8
average intensity scheme of ultrasound [W/cm2] pulse on [s] pulse off [s] % MI
Figure 1. The sonication calibration curve. Table 1. Intensity of Ultrasound Measured by the Calorimetric Method scheme
pulse on [s]
pulse off
% MI
OSE
average intensity [W/cm2]
1/9-100 1/9-80 1/9-50 1/5-80 1/1-100 1/1-80 1/1-60 1/9-100 1/9-80 1/9-50 1/5-80 1/1-100 1/1-80 1/1-60
1 1 1 1 1 1 1 1 1 1 1 1 1 1
9 9 9 5 1 1 1 9 9 9 5 1 1 1
100 80 50 80 100 80 60 100 80 50 80 100 80 60
0.20 0.16 0.10 0.27 1.00 0.80 0.60 0.20 0.16 0.10 0.27 1.00 0.80 0.60
2.9 2.2 1.4 3.6 14.3 10.2 7.5 2.7 2.1 1.2 3.3 12.4 9.2 6.7
∆tson (% MI)/MSE PRP
1.3 2.1 2.6 3.4 4.2 10.1
1 1 1 1 1 1
9 9 9 5 5 1
50 80 100 80 100 80
Table 4. Sonication Schemes in Series 2: Influence of PRP
and in Figure 1. The average intensities are plotted as a function of the overall sonication exposure (OSE), a parameter that aims to include both the influence of the actual power used and the influence of the duration time and frequency of the sonication pulses. This concept is given the following definition
OSE )
1/9-50 1/9-80 1/9-100 1/5-80 1/5-100 1/1-80
(3)
where MSE is the maximum possible sonication exposure obtained by using the most powerful sonication scheme, i.e., a 1 s pulse using 100% generator intensity followed by 1 s rest. In example, this scheme is denoted as the 1/1-100 scheme. Procedures. Two types of crystallization experiments were performed: metastable zone width experiments and induction time experiments. Two series of metastable zone width experiments were performed at the constant cooling rate of 1 °C/min, one without sonication and the other applying sonication. Both series are repeated three times to establish the level of reproducibility. The nucleation temperature was determined by detecting the appearance of the first crystals becoming visible to the naked eye. A solution of a given concentration was heated to a few degrees above its saturation temperature (Teq ) 40, 38, 36, 32, 30, and 20 °C) and left until all crystals had dissolved. It was then filtered through a 0.20 µm membrane filter and added to the 500 mL jacketed glass batch crystallizer. The solution was again kept a few degrees above the equilibrium temperature for at least 1 h. After that, the solution was cooled with a linear temperature profile (1 °C/min). The sonication scheme (1/9-80) was started as the cooling began and was stopped after nucleation had occurred. Eight series of induction time experiments were performed to examine how the intensity of sonication, the temperature, and the supersaturation level influence induction time and the
scheme
average intensity of ultrasound [W/cm2]
PRP [s]
1/9-80 1/7-80 1/5-80 1/3-80 1/1-80
2.1 2.6 3.4 5.1 10.1
10 8 6 4 2
polymorphic form that crystallizes. A solution of a given concentration was prepared and heated to about 20 °C degrees above the saturation temperature (Teq ) 38, 32, 30, and 20 °C) until all crystals had dissolved. It was then filtered through a 0.20 µm membrane filter and added to the preheated 500 mL jacketed glass batch crystallizer. The solution was then again kept at about 20 °C degrees above the saturation temperature for at least 20 min. The solution was then rapidly cooled to the temperature Tson (Tson ) 33, 27.5, 25, 24, and 13 °C), chosen with respect to the desired supersaturation and always at least a few degrees above the expected metastable zone limit. Nucleation was never observed until well after the temperature Tson was reached. When the crystallizer temperature reached the desired temperature, the temperature was kept constant and the ultrasonic treatment was applied until the nucleation started. The experimental conditions of the eight induction time series are summarized in Table 2. The supersaturation ratio was calculated as S ) c/ceq, where c is the initial concentration of PABA and ceq is the equilibrium solubility of the solid phase appearing in the experiment at the temperature of the experiment. The solubility of PABA in aqueous solutions is calculated from the following equations that give a good fit to the experimental solubility data.6
CR ) 0.0035T2 + 0.0299T + 2.3545
(4)
Cβ ) 0.0054T2 - 0.0204T + 2.334
(5)
Several different sonication schemes were applied to examine the effect of the different parameters that determine the average intensity of sonication. The duration of each pulse, ∆tson, is always 1 s, though, because a long ∆tson leads to difficulties in the temperature control. In series 1 and 4-8, the intensity of sonication was changed by varying the PRP and the % MI according to Table 3. In series 2, the influence of the PRP of the sonication was varied as shown in Table 4. The % MI was held constant at 80%. Equilibrium and sonication temperatures were identical to those of series 1. In series 3, the % MI was varied from 10 to 100% according to the schemes shown in Table 5. ∆tson and PRP were held
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Figure 3. Influence of sonication on the induction time: experimental series 1-3. Figure 2. Influence of sonication on the metastable limit. Table 5. Sonication Schemes of Series 3: Influence of % MI scheme
average intensity of ultrasound [W/cm2]
% MI
1/9-10 1/9-15 1/9-50 1/9-80 1/9-90 1/9-100
0.3 0.4 1.3 2.1 2.3 2.6
10 15 50 80 90 100
constant at 1/9. Equilibrium and sonication temperatures were identical to those of series 1.
Results Nucleation Temperature. The nucleation temperature of solutions of various PABA concentrations at a constant cooling rate of 1 °C/min with and without application of ultrasound are presented in Figure 2. When applied the average sonication intensity in the experiments was 2.1 W/cm2. Figure 2 shows that the nucleation temperature was systematically higher when sonication was applied; i.e., the metastable zone is more narrow. In addition, when ultrasound was applied the nucleation temperature became more reproducible. Three identically performed experiments gave almost identical nucleation temperatures. The maximum undercooling without sonication is 12-15 °C, and with sonication it is 7-9 °C. The polymorphic form that crystallizes is almost always the R-form, except in the sonicated experiments performed at Teq ) 20 °C in which a mixture of the polymorphic forms is obtained. Induction Time. The results of series 1-3 are shown in Figure 3. As opposed to series 2 and 3, in series 1 the saturated solutions were not filtered prior to cooling. In all experiments of series 1-3, only the β-form appears. The shortest induction time was six minutes and was observed for the scheme 1/1-80 of series 1, which corresponds to the highest average ultrasound intensity. In our previous study,6 the induction time without ultrasound is 25-360 min for the R-form and 240-1140 min for the β-form at the same temperature and supersaturation. With ultrasound, the induction times are more repeatable: 6-35 min. Figure 3 also suggests that initially the induction time quite clearly decreases with increasing average sonication intensity. However, at higher intensities the curve levels out. In series 2 and series 3, the influence of the various schemes is further examined. Also in filtered solutions
Figure 4. Influence of sonication average intensity on the induction time at higher supersaturation: experimental series 4.
the induction time tends to decrease as the average intensity increases. In series 2 in which the influence of pulse repetition period is studied, the induction time decreases monotonically from 19 to 10 min when the PRP decreases and hence the average sonication intensity increases. In series 3 in which the influence of % MI was tested, the induction time decreases monotonically from 35 to 19 min as % MI increases. For intensities between 15 and 90%, induction times varied between 19 and 25 min. The largest change in induction is found between 10 and 15% MI corresponding to 0.3 and 0.4 W/cm2 average ultrasound intensity, respectively. Even though the results of 10 and 15% MI indicate a kind of step change, we recognize that for the nonsonicated experiments the shortest induction time was 240 min at the same conditions of temperature and supersaturation. If the results of series 2 and series 3 are combined, we can conclude that all the results essentially can be correlated to the average sonication intensity. There is no evidence that there is an influence of the more detailed format of the supply of the sonication energy. In series 4, the supersaturation is higher than in series 1-3, and the measured induction times were much shorter (Figure 4). In addition, in series 4 the crystallized form is always R. Hence, the β-form is obtained at lower supersaturation and the R-form is
Influence of Ultrasound on PABA Polymorphs
Figure 5. Influence of sonication average intensity on the induction time and polymorphic form: experimental series 5 and 6.
obtained at higher supersaturation. These results indicate that there is a threshold in the effect of the supersaturation ratio, i.e., the maximum value of the supersaturation ratio that still can be used to crystallize pure β-form. Also in series 4 the induction time decreases as the average intensity increases. In series 5, the temperature is increased to about 1 °C below the transition temperature, and in series 6 it is almost equal to the transition temperature of 25 °C. In both cases, Sβ is still slightly higher than SR. In series 5, the supersaturation ratios are slightly higher than in series 6 (Table 2). The results are shown in Figure 5. In series 5, the induction time decreases quite strongly with increasing average sonication intensity from 25 to 2.5 min. Furthermore, the polymorphic form that crystallizes shifts from the β-form at lower intensity to the R-form at higher intensity. When the supersaturation is reduced as in series 6 the induction time is longer and less dependent on the sonication intensity, even though there is a tendency for a reduced induction time as the average intensity increases. Furthermore, in series 6 the crystallized form is always β. These results clearly reveal that the induction time for nucleation is shorter if the conditions are such that the R-form appears, even when the supersaturation actually is higher with respect to the β-form. In addition, the results show again that there is a threshold in the supersaturation ratio for production of the β-form; i.e., the supersaturation ratio has to be lower than approximately 1.22. Furthermore, the results shown in Figure 5 suggest that depending on the supersaturation there is perhaps also a threshold in the average sonication intensity above which the preference for nucleating the β-form disappears. In series 7 and 8, the temperature is above the transition temperature, and the results are shown in Figure 6. In series 7, the supersaturation ratio Sβ is now slightly lower than SR, and the R-form is the stable phase. The induction times are fairly long but clearly decrease with increasing average sonication intensity. Furthermore, in all experiments of series 7, we only obtain the β-form. Hence, at moderate supersaturation, the sonication leads to that the β-form can be produced even above the transition temperature. In series 8, the temperature is 8 °C above the transition temperature. The induction time decreases
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Figure 6. Influence of sonication average intensity on the induction time and the polymorphic form: experimental series 7 and 8.
with increasing average sonication intensity. At low intensity, the β-form is obtained, and at high intensity the R-form is produced. On the basis of the results shown in Figures 5 and 6, it seems as though the threshold supersaturation for production of the β-form, both in terms of SR and in Sβ, tends to decrease with increasing temperature. Discussion There are two very significant effects of applying ultrasound in the crystallization of PABA. First, ultrasonic treatment at all levels of intensity of the present work significantly shortens the induction time for nucleation of both polymorphic forms, and this is in agreement with results reported previously for other compounds.10,24 In the present study, we also find that the induction time in general decreases with increasing ultrasound intensity, that the influence of ultrasound is more pronounced at low supersaturation, and that the detailed format of the supply of the ultrasonic energy is less important. Second, sonication clearly favors the formation of the β-form. In our previous work,6 the β-form was found to be quite difficult to nucleate, even well below the transition temperature of 25 °C where it is the most stable phase. To crystallize pure β-form at 13 °C, the supersaturation ratio with respect β cannot exceed 1.5 (i.e., Sβ e 1.5). Above the transition temperature, it was impossible to crystallize the β-form. When sonication is applied in the present work, the corresponding threshold supersaturation seems to be roughly the same, but the β-form can be crystallized at much higher temperatures and even above the transition temperature. Our sonicated experiments show that it is possible to crystallize pure β at 8 °C above the transition temperature. Furthermore, when the supersaturation is close to the threshold, the intensity of the applied ultrasound may influence the polymorphic form that crystallizes, and in these cases a lower intensity promotes the appearance of the β-form. As far as we know, this is the first time sonication has been reported to quite selectively favor the appearance of one of the polymorphs in solution crystallization. Unfortunately, our understanding of primary nucleation itself is quite insufficient, which clouds our
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understanding of the role of sonication. It is well known that primary nucleation of crystals tends to be quite stochastic29 but can be influenced by agitation, mechanical shock, friction, extreme pressures, radiation, and various external electric and magnetic fields. However, the more detailed mechanisms are not known. For example, the metastable zone width is much higher in a quiescent solution than in a solution under gentle agitation, and vigorous agitation considerably enhances nucleation. The explanation for this influence is normally given as “mechanical disturbances can enhance nucleation”, and it is suggested that the mechanical disturbance provides energy that assists the clusters to pass the thermodynamic barrier of nucleation. However, this is merely a suggestion so far. In addition, the effect of ultrasound itself on a solution is quite complex, and the conditions at generation and collapse of cavities are extreme. Sonication promotes primary nucleation either by influencing the instantaneous, local thermodynamic conditions and hence the supersaturation or by influencing kinetics by which molecules cluster and condense into a nuclei. A local cooling effect upon bubble formation at cavitation leads to increased supersaturation. We may find solvent and solute molecules in a vapor inside the cavity and at collapse the vapor attains very high temperature and pressure, and a shock wave is generated and penetrates through the vapor-liquid interface and the interface concentration of solute molecules. In sonochemistry, it has been found that the chemical reaction may occur both in the vapor phase and in the thin liquid shell surrounding the collapsing cavity. Using data over reactions of volatile metal carbonyls, it was estimated that the gas-phase reaction occurred at about 5200 K and that the liquid reaction zone was about 200 nm thick and had a lifetime of 2 µs.18 The solubility of a compound is dependent on the pressure, even though the effect is negligible except at very high pressures. Kashiev30 shows that if the partial volume of a solute molecule in the solution is larger than the partial volume of the solute molecule in the nucleating onecomponent condensed phase the nucleation rate will increase with increasing pressure because of an increasing driving force. The nucleation of a compound can also be influenced by the electrical field gradients during the collapse of a bubble. If the dielectric constant of the cluster is higher than the dielectric constant of the medium, the electric field may reduce the work of clustering.30 Furthermore, caviation bubbles can act as heterogeneous surfaces for nucleation or activate other surfaces, e.g., dust particles already present in the system. Of course, the cavitation definitely introduces mechanical disturbances into the system. Even though all of these mechanisms, via the classical nucleation theory, can be more or less relevant in the explanation of the influence on the induction time, they do not give much guidance for the quite selective preference for the β-polymorph. It is believed31 that in a supersaturated solution of a polymorphic compound there is a distribution of clusters of various sizes and of various molecular structures. Among the different structures lies the origin for the appearance of the different polymorphs. Depending on the conditions, certain structures are more frequent, which means that
Gracin et al.
Figure 7. p-Aminobenzoic acid.
the corresponding polymorphs are more likely to nucleate. In our previous paper on PABA (Figure 7) the relationship between the crystal structure and the structure of solution precursors is discussed. The crystal structure of the R-polymorph is based on centro symmetric carboxylic acid dimers. The structure of the β-form is based on four-membered hydrogenbonded molecular rings where carboxylic acid groups alternate with amino groups. Depending on the solvent, it is well-known that carboxylic acids tend to form centro symmetric dimers in solution. We have not found that this has been established specifically for PABA in solution, but this has been shown to occur for PABA in the vapor phase.32 We believe that the kinetic preference for formation of the R-polymorph even below the transition temperature is due to the presence in the solution of such centro symmetric dimer precursors. In solution there is a dynamic state of monomers and dimers and possibly even trimers and tetramers. The dimers can be centro symmetric or just involve one hydrogen bonds chain complexes. In dilute benzoic acid solutions, higher pressures and higher temperatures weaken the hydrogen bonds of the dimers and hence favor the dissociation of the hydrogen-bonded carboxylic acid dimers.33 In addition, there are several studies on the influence of ultrasound on acetic acid dimerization,34-37 where it has been found that the absorbed ultrasonic energy generates a shift in the dimer-monomer distribution in favor of the chain complex dimers and free monomers according to the scheme presented in Figure 8.37 An influence of ultrasound on the species distribution has also been found for other aliphatic acids.38 We assume that the same may apply to PABA. Hence, an interesting possible explanation to that fact that sonication preferentially promotes the crystallization of the β-form is that sonication reduces the centro symmetric carboxylic acid dimerization in solution, possibly as a result of the high pressure and temperatures at the collapse of the cavities in accordance with the hot spot theory. Another interesting aspect is the report that polarized laser light promotes the crystallization of the thermodynamically more stable but kinetically less favorable γ-polymorph of glycine.39 The γ-polymorph structure consists of helical chains of roughly parallel head-totail glycine molecules. Without polarized laser light the R-polymorph of glycine whose structure consists of hydrogen-bonded double layers, whose basic unit is a hydrogen-bonded dimer (two antiparallel glycine molecules) will nucleate. It is suggested39 that the influence of the polarized laser light is due to partial alignment of solute molecules because of an interaction between the solute molecules and the laser-induced electric field. In addition, it has been found that gas-phase samples
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Figure 8. Dimer and monomer configurations of acetic acid.37
of PABA that are subjected to laser radiation show the disruption of centro symmetric hydrogen-bonded dimers.32 However, unlike photochemistry, there is no direct coupling between the frequency of ultrasound and molecular species. On the other hand, there are significant electrical field gradients during the collapse of a bubble,17 and these are strong enough to cause bond breakage and chemical activity.19 Hence, the preferential crystallization of the β-polymorph of PABA can perhaps also be explained as being the result of the disruption of PABA dimers by the ultrasound-induced electric field. Conclusions In the present study, it is shown that sonication significantly reduces the induction time for nucleation of PABA crystallized in aqueous solutions. In addition, it is shown that sonication changes the relationship between the nucleation kinetics of the R-form and the β-form in favor of the latter. Below the transition temperature at 25 °C, the crystallization of the β-polymorph becomes faster and more reproducible when ultrasound is applied. The induction time decreases with increasing sonication intensity, but also at the lowest level used in this study there is a dramatic reduction in induction time compared to when ultrasound is not applied at all. By application of ultrasound, the β-polymorph can also be crystallized above the transition temperature, as long as the supersaturation is not too high. Close to the critical supersaturation threshold, there is a threshold in sonication intensity, above which pure β-form is not obtained. Overall there is an influence of the sonication average intensity, but there is no evidence that the more detailed format by which the ultrasound energy is supplied has an influence. There are several reports in the literature showing that sonication may reduce the induction time for nucleation. However, to our knowledge this is the first time in solution crystallization that it has been shown that ultrasound may have an influence such that one polymorph in particular is promoted. Our hypothesis is that this effect is due to an influence on the solute structuring in the solutionsthe clustering that precedes the nucleation of the two polymorphs. The R-form structure is based on centro symmetric carboxylic acid dimers. It is believed that the tendency to form dimers in the solution explains why there is a strong preference for the formation of the R-polymorph in an ordinary crystallization. When ultrasound is applied, it is known
from the literature that this dimerization tends to decrease, and it is our hypothesis that this is the explanation for the increased opportunity for the β-form to appear when the crystallizing solution is exposed to ultrasound. Acknowledgment. The Swedish Foundation for Strategic Research (SELCHEM Programme) is acknowledged for financial support. Notations Cp T m P I A c ∆ton PRP % MI MSE OSE S
heat capacity of water [J/g °C] temperature [°C] mass of solution [g] power of sonication [W] acoustic (sonication) intensity [W/cm2] probe tip area [cm2] concentration [g/kg] duration of the pulse [s] pulse repetition period percent of maximum intensity of the ultrasound generator maximum possible sonication exposure overall sonication exposure supersaturation ratio
R β eq son
Subscripts the R-polymorph the β-polymorph equilibrium sonication
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