Solvent-Mediated Phase Transformation Kinetics of an Anhydrate

Solvent-Mediated Phase Transformation Kinetics of an Anhydrate/Hydrate System Haiyan

Qu,*,†

Marjatta

Louhi-Kultanen,†

Jukka

Rantanen,‡

and Juha

Kallas†

Department of Chemical Technology, Lappeenranta UniVersity of Technology, P.O. Box 20, FI-53851 Lappeenranta, Finland, and Department of Pharmaceutics and Analytical Chemistry, The Danish UniVersity of Pharmaceutical Sciences, UniVersitetsparken 2, 2100 Copenhagen, Denmark

CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 9 2053-2060

ReceiVed February 2, 2006; ReVised Manuscript ReceiVed April 11, 2006

ABSTRACT: In-line monitoring of solid-state properties in crystallization processes is of great significance in controlling the quality of crystalline active pharmaceutical ingredients. In this work, the solvent-mediated phase transformation of anhydrous to dihydrated carbamazepine in ethanol-water mixtures was studied using an in-line Raman immersion probe. The solute concentration profile was measured by off-line sampling. The transformation experiments were conducted with different operation parameters in terms of solvent composition and temperature. The transformation rate depends on both solvent composition and temperature. The mechanism of the transition was interpreted with the two-step polymorphic form transformation mechanism. It was observed that the crystallization of the stable form was the rate-controlling step. The influence of the operation parameters on the transformation rate can be interpreted as the effects of solvent and supersaturation on the crystallization kinetics. Another interpretation is proposed by correlating the deviation of the water activity from the equilibrium value to the rate of phase transformation. It was observed that the correlation of the water activity deviation and the phase transformation rate was independent of solvent composition and temperature. 1. Introduction Controlling the solvent-mediated transformation of the anhydrate/hydrate phase of a drug compound is of crucial importance in the pharmaceutical industry. The transformation may happen during both primary manufacturing of the product (for example, crystallization) and secondary manufacturing (for example, wet granulation), since aqueous media are often preferred for safety reasons. The anhydrous and hydrate forms of a compound have distinct physical and chemical properties, such as solubility, dissolution rate, density, and chemical stability, and the form therefore strongly impacts on the bioavailability of the compound.1 An understanding of the thermodynamics of the anhydrate/hydrate system and the mechanism of the phase transformation is a prerequisite for controlling the solid phase during the manufacturing of drug products. Raman spectroscopy, which measures the vibrational modes of the molecules, has been extensively used for quantitative characterization of polymorphic and pseudopolymorphic systems. The application of Raman spectroscopy has been reported in the literature for quantification of polymorphic and pseudopolymorphic solid mixtures2,3 and quantification of the amorphous/ crystalline content of pharmaceutical compounds.4-6 Recently, the in-line monitoring of the polymorphic form transition during crystallization using a Raman immersion probe has been reported.7-11 The unique advantage of Raman spectroscopy coupled with an immersion probe over other analytical techniques such as X-ray powder diffraction, solid-state NMR, and differential scanning calorimetry is that the Raman probe can be inserted into a crystallizer. The real-time monitoring of the crystal form present and the solid-phase transformation from one form to another in the slurry can be implemented. This is of great significance in understanding the transformation mech* To whom correspondence should be addressed. E-mail: [email protected]. Tel: +358 5 6212195. Fax: +358 5 6212199. † Lappeenranta University of Technology. ‡ The Danish University of Pharmaceutical Sciences.

anism and offers potential for efficiently determining the crystallization parameters required to obtain a desired solid phase. Cardew and Davey12 and Davey and Cardew13 have interpreted the solvent-mediated polymorphic transformation as a two-step process. First, the metastable form is dissolved and, subsequently, the stable form crystallizes out. The transformation is classified into two groups, dissolution controlled and crystallization controlled, according to the relative kinetics of the dissolution of the metastable form and the crystallization of the stable form. In this concept, the difference between the solubilities of the metastable and stable forms drives the dissolution process and consequently determines the supersaturation level during the crystallization of the stable form. In an anhydrate/hydrate system in mixtures of water and an organic solvent, the water activity plays a crucial role. For a given temperature, there exists an equilibrium water activity value, at which the solubilities, and thus the stabilities, of the anhydrous and hydrate forms are identical.14-17 Any deviation from the equilibrium water activity will result in phase transformation, either from anhydrate to hydrate or in the opposite direction. Carbamazepine (CBZ), an antiepileptic drug, was selected as the model compound in this work. In a previous work,14 the effects of solvent composition and temperature on the solubility and relative stability of anhydrous (CBZA) and dihydrate (CBZH) forms of carbamazepine in ethanol-water mixtures were studied. The objective of this study is to investigate the mechanism of the solvent-mediated transformation of CBZ anhydrate to dihydrate in ethanol-water mixtures. A Raman in-line probe was used to get the real-time transformation rate during the transformation under various experimental conditions in terms of solvent composition and temperatures. The solute concentration profile in the liquid phase measured by off-line sampling allows the determination of the dissolution rate of the metastable form (CBZA). The dependence of the transformation rate on solvent composition and temperature was studied by interpreting the transformation with the two-step concept and by correlating the transformation rate to the deviation of water activity from the equilibrium value.

10.1021/cg0600593 CCC: $33.50 © 2006 American Chemical Society Published on Web 08/04/2006

2054 Crystal Growth & Design, Vol. 6, No. 9, 2006

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2. Experimental Section Materials. Analytical grade ethanol from Altia Corp. and deionized water were used as solvents. Carbamazepine (CBZ) was used as received from Orion Corp. (Batch No. 1074997). The XRPD pattern of the CBZ material was identical with that of the anhydrous form III of carbamazepine (CBZA) reported in the literature.18 As described in the previous work,14 the crystals of the dihydrate form (CBZH) were prepared by cooling crystallization from 61 mol % ethanol aqueous solution, and the obtained CBZH solid was identified with an X-ray diffractometer and by Raman spectroscopy. The XRPD pattern of CBZH was found to be identical with that reported in the literature.19 Raman Spectroscopy. Raman spectra were collected with a LabRam Raman spectrometer from Horiba Jobin Yvon. The system employed an external cavity-stabilized single-mode diode laser at 785 nm operating at 100 mW. The Raman spectrometer was interfaced with an optical microscope in the case of analyzing solid mixtures and an immersion probe sealed with a sapphire window in the case of in-line suspension monitoring. The laser light is focused into the solid or the slurry, using an optical microscope or the immersion optics, respectively. Backscattered Raman light is collected by the interfacial device and transmitted back to the spectrometer for analysis. The acquisition conditions were optimized so that a spectrum was captured with exposure times of 5 and 20 s for measurement of the solid and suspension, respectively, with 3 accumulations. XRPD. A Bruker AXS GmbH D8 Advance diffractometer with a Cu KR radiation source (40 kV, 40 mA) was used to collect powder diffraction patterns at ambient temperature and pressure. The patterns were recorded between 5 and 40° in 2θ with steps of 0.05° and a dwelling time of 1 s/step. Solubility of CBZA and CBZH. The solubilities of CBZA and CBZH in five different ethanol-water mixtures containing 68.9, 61.0, 54.0, 47.7, and 35.1 mol % of ethanol were measured gravimetrically with the isothermal method.14 Only CBZA was used as the starting solid material. After the suspension was kept at a certain temperature for 48 h with sufficient mixing to attain a solid-liquid equilibrium, around 20 mL of clear solution was taken through a syringe filter of 0.2 µm pore size. The solid isolated from the suspension was analyzed with a Raman spectrometer to identify the form of the solid. The solution samples were evaporated in an oven at 100 °C, which is much higher than the dehydration temperature of CBZH. No weight loss of the solid was observed after it was kept in an oven for 24 h. The dry solid from the oven was analyzed with a Raman spectrometer, and the characteristic peak for CBZH at 382.6 cm-1 was not seen. Therefore, the dry solid was confirmed to be the anhydrous form of carbamazepine. Calibration of Raman Spectra for Quantitative Analysis. The generation of representative calibration spectral data is essential for obtaining a reliable calibration model. Slurrying has been proposed to improve the mixing and homogeneity of the polymorphic mixtures.9 However, it is not applicable to anhydrate/hydrate systems, because it is difficult to find a solvent that will not alter the solid state of the anhydrate/hydrate mixtures. In the present work, the calibration model was constructed using the spectra taken from the binary powder mixtures of CBZA and CBZH. This calibration method has been used in the literature7,8 to obtain an in-line quantitative measurement of polymorphic mixture compositions during crystallization. Twelve dry powder mixtures of CBZA and CBZH were used for setting up the calibration model. The mixtures were created by manually mixing pure CBZA and CBZH powders, and the fraction of CBZH was calculated on the basis of the amounts of CBZA and CBZH used in the mixing. The mixtures were analyzed immediately after preparation using the following procedure: a certain amount of a mixture was placed on a 76 × 26 mm glass microscope slide, and after this slide was gently pressed with another slide, the mixture was analyzed with a Raman microscope. The Raman spectra were collected at 288 points, which were evenly distributed throughout the mixture, and the average of all spectra was considered as the Raman spectrum of the corresponding mixture. All solid mixtures were double-sampled, and the relative deviation of the duplicated samples was lower than 5%. In-Line Monitoring of Phase Transformation. The experiment was conducted in a 1 L jacketed glass crystallizer equipped with an impeller and thermostat (Figure 1). The mixing intensity was kept constant for all operations by keeping the agitation speed as 250 rpm. The temperature profile is shown in Figure 2. The CBZ solution was prepared by dissolving a certain amount of CBZA solid in solvent on

Figure 1. Setup of the in-line phase transformation monitoring system.

Figure 2. Temperature profile used in the transformation experiments (cooling rate 10 °C/h; CBZA solid was added 10 min after saturation temperature was reached). the basis of the solubility of CBZH at a given temperature. After 1 h of dissolution at a temperature 5 °C higher than the saturation temperature, the solution was cooled to the saturation temperature over 30 min, and the transformation was initiated 10 min after the saturation temperature was achieved by adding a certain amount of CBZA solid to the clear solution. The Raman probe was inserted into the crystallizer to get in-line monitoring of the solid form composition. To validate the calibration model, three suspension samples were taken at different stages of the transformation. After filtration, the solid was dried at room temperature for around 1 h and then analyzed with a Raman microscope to obtain off-line phase fraction data. The results of in-line and offline measurements were compared. Solution samples were taken through a syringe filter of 0.2 µm pore size during the transformation experiment. The concentration of CBZ in the solution was measured gravimetrically by a similar method of solubility measurement. Crystal Size and Morphology. At the end of the experiment, the suspension was filtered and the solid was dried at room temperature. The size distribution of the obtained CBZH crystals was measured with a Beckman Coulter LS 13320 laser diffraction particle size analyzer. The morphology of the crystals was studied with an optical microscope and a JEOL JSM-5800 scanning electron microscope.

3. Results and Discussion Solubility and Stability of CBZA and CBZH. The solubilities of CBZA and CBZH in five different mixed solvents are plotted in Figure 3 using the van’t Hoff equation:

lnx ) -

∆Hd ∆Sd + RT R

(1)

where x is the mole fraction of solute in the solution and ∆Hd and ∆Sd are the enthalpy and entropy of dissolution, respectively. The thermodynamic relationship between CBZA and CBZH can be determined from the solubility data.1,14,16,17 The intercept of the solubility curve of CBZA and CBZH represents the transition points of the two forms, in which the solubilities of the two forms are identical. It is well-known that the hydration state of a hydrate depends on the water activity in the mixed solvent at a given temperature.1,5 For a given temperature, there exists an equilibrium water activity value, at which the solubilities of

Kinetics of an Anhydrate/Hydrate System

Crystal Growth & Design, Vol. 6, No. 9, 2006 2055

Figure 3. Solubility and transition points of CBZA and CBZH in ethanol-water mixed solvents. Solid and open symbols represent the solubilities of CBZA and CBZH, respectively.

Figure 4. Water activity value a* at which CBZA and CBZH are in equilibrium in ethanol-water mixtures. The water activity was evaluated from data in the literature20,21 on the basis of a binary mixture of ethanol and water.

anhydrate and hydrate are identical. This equilibrium water activity depends on temperature. The water activity values at the transition points shown in Figure 3 were calculated from the water activity in ethanol-water binary mixtures reported in the literature.20,21 The dependence of the equilibrium water activity value on the temperature for CBZA/CBZH systems in ethanol-water mixtures is shown in Figure 4. The relative stabilities of CBZA and CBZH are determined by the temperature and water activity. If the temperature is specified, then the equilibrium water activity is defined; any deviation from this equilibrium water activity value will induce phase transformation, either from CBZA to CBZH at higher water activity values or from CBZH to CBZA in the case where the water activity is lower than the equilibrium value.

Calibration of Raman Spectra for In-Line Quantitative Monitoring. To perform quantitative analysis, a calibration model was developed to correlate the Raman spectra with the form composition in the slurry. A calibration model can be set up using a single-variable method by correlating the heights or positions of the characteristic peaks to the composition of the mixtures.7-9 Multivariable methods, such as partial least-squares regression (PLS), can also be used in the calibration.10 Rantanen et al.22 compared single-variable and multivariable methods in the quantification of anhydrate/hydrate powder mixtures of four pharmaceutical compounds. They showed that the prediction performances of the two methods were comparable for Raman spectra calibration, due to the fact that the variation in the analytical peak was large relative to the total variation over the extended spectra used for the multivariable analysis. The Raman spectra of pure CBZA and CBZH are shown in Figure 5. Several characteristic peaks for CBZA and CBZH can be observed from the figure. Hu et al.7 has reported the application of the Raman spectrometer to the simultaneous measurement of the desupersaturation profile and the polymorphic form composition in flufenamic acid systems. The authors set up two standard curves: one was based on a series of flufenamic acid solutions over a certain concentration range for the prediction of solute concentration, and the other was based on the polymorphic mixtures dispersed in aqueous solutions for the prediction of the polymorphic fraction in the solid phase. During the crystallization process, the solute concentration and the polymorphic fraction in the solid phase were both changing with time. A prerequisite for using the ex situ calibration curves


Figure 5. Raman spectra of (a) CBZA and CBZH powder and (b) CBZ solution in ethanol-water mixture (61 mol % ethanol, 20 °C).

to predict simultaneous solute concentration and solid-phase composition is that the selected variables (height of the characteristic peaks of the polymorphic forms and the solute) do not interfere with each other. On comparison of the spectra of CBZA and CBZH powders and that of the dissolved CBZ in the solvent, it can be observed that the characteristic peak of CBZA at 271.8 cm-1 and that for CBZH at 382.6 cm-1 did not overlap with the solute peaks. They were selected as the characteristic peak heights of CBZA and CBZH, referred to as HA and HH in this paper. However, all characteristic peaks for the dissolved CBZ are influenced by either CBZA peaks or CBZH peaks. Therefore, it was decided in this work that only the solid-phase composition would be in-line monitored with a Raman spectrometer, and the solute concentration in the liquid phase would be measured gravimetrically by off-line sampling. In addition to the solute effect, the temperature effect and solvent effect on the characteristic peak height of CBZA and CBZH had to be checked. It was observed that the relative peak height HH/(HA + HH) was independent of the temperature and solvent composition. The calibration model was set up by correlating the relative peak height HH/(HA + HH) with the fraction of CBZH in the slurry, where HH and HA are the heights of the selected characteristic peaks of CZBA and CBZH at 271.8 and 382.6 cm-1, respectively. The calibration model is shown in Figure 6. Authors from different research groups have confirmed that the calibration model built with polymorph powder mixtures can provide a reliable in-line prediction of the polymorphic composition in the slurry during crystallization.7,8 The generation of representative spectral data is crucial during the calibration. This can be a problem if the sampling volume of the Raman spectrometer is small relative to the particle size.23 It was reported recently that the crystal size distribution could have a significant effect on the calibration.24 In this work, particular attention was paid to obtain representative spectra from the prepared powder mixtures. As described in section 2, the Raman spectra were collected through a microscope. The powder

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Figure 6. Calibration model of Raman spectra (a) and size distribution of fine and coarse CBZH crystals (b). The equation shown in the figure was generated from fine CBZH particles.

mixture of CBZA and CBZH on the glass slide was moving along two dimensions, and the spectra were collected at 288 different points in the mixture, which covered an area of 2400 × 2000 µm. The final spectrum was the average of all 288 spectra obtained. The accuracy of the sampling was improved by this method. Bell et al.23 have reported that the sampling errors can be significantly decreased by collecting spectra at a series of grid points on a tablet surface. The calibration model shown in Figure 6a was generated from fine CBZH particles. To check the effect of the particle size on the calibration, four powder mixtures was prepared from coarse CBZH crystals and the same CBZA material. The particle size distributions of the fine and coarse CBZH crystals are shown in Figure 6b. The data generated from the coarse crystal mixtures are also shown in Figure 6a. It was observed that the deviation between the real and predicted values of the CBZH fraction was lower than 4.5 wt %, which means that the effect of particle size on the calibration was suppressed by applying an appropriate procedure for spectra collection. Effects of Temperature and Solvent Composition on the Transformation Kinetics. The solvent-mediated phase transformation is a complex process, due to the fact that several mechanisms, such as the dissolution of the metastable form, the primary heterogeneous nucleation and secondary nucleation of the stable form, and the growth of the stable form crystals, are involved in the transformation. The comparison of the solute concentration profile and the solid-phase composition measured with a Raman in-line probe allows for the identification of the fundamental mechanisms during the phase transformation. The in-line measured solid-phase composition and the concentration of CBZ in the solution for one operation are shown in Figure 7. The results of the off-line measurements of the CBZH fraction are also shown in the figure. The good agreement between the in-line and the off-line results indicated that the calibration model was reliable. It is worth noting that the measured CBZH fraction points exhibit scattering. The scattering is more


Figure 7. Fraction of CBZH and concentration of CBZ in the solution during the transformation of CBZA to CBZH in mixed solvent with 61 mol % ethanol at 16.9 °C.

significant in the very early stages, where the CBZH fraction was low, and in the very late stages of the transformation, where the solid phase consisted of mainly CBZH and only a minor amount of CBZH. A similar phenomenon has been observed by other authors.7,8,24 A possible explanation could be the low peak/noise ratio with the solid mixtures that contained mainly one form with only a small amount of another form. Three different stages are distinguishable in Figure 7. First, the solute concentration in the liquid phase increased from the solubility of CBZH to a plateau and remained at that level. This plateau concentration possibly corresponds to the apparent solubility of CBZA at this defined solvent composition and temperature. The solid-phase composition measured with the Raman spectrometer shows no presence of CBZH during this stage. The second stage started with an increase in the CBZH fraction in the solid phase, indicating the onset of nucleation and growth of CBZH. The solute concentration in the liquid phase remained constant during this stage. This indicates that the dissolution rate of CBZA was fast and that the nucleation and growth of CBZH was the rate-controlling step for the transformation.12,13 During the third stage, the solute concentration started to decrease and meanwhile the fraction of CBZH reached the final level around 100%. This indicates that, in this stage, the amount of CBZA crystals was already very small; thus, the generation rate of supersaturation via dissolution of these last CBZA crystals was lower than the desupersaturation rate through the crystallization of CBZH. At the end of the third stage, the solute concentration approached the solubility of CBZH, denoting the completion of the phase transformation. The effects of temperature and solvent composition on the transformation were studied by performing the transformation experiments at different solvent compositions and temperatures. The three stages discussed above are distinguishable for all experiments. The in-line measured weight fractions of CBZH in the solid phase during the transformation are shown in Figures 8 and 9. The dissolution of CBZA in the first stage was driven by the difference between the solubility of CBZA and CBZH. As shown in Figure 3, the transition temperature points of CBZA and CBZH are 24.7 and 41.0 °C, in mixed solvents containing 61 and 47.7 mol % ethanol, respectively. All experiments were carried out at temperatures lower than the equilibrium temperatures. The lower the temperature, the more the deviation from the equilibrium temperature, and the greater the difference between the solubilities of CBZA and CBZH. The large solubility difference consequently resulted in a fast dissolution and a high supersaturation level achieved during the phase transformation. The CBZH nucleation was delayed for a certain induction time after the supersaturation reached a plateau in all


Figure 8. Transition profile of CBZA to CBZH in mixed solvent with 61 mol % ethanol at various temperatures.

Figure 9. Transition profile of CBZA to CBZH in mixed solvent with 47.7 mol % ethanol at various temperatures.

experiments. The induction times were different at different solvent compositions and temperatures. The nucleation and growth of CBZH started in the second stage. The duration of the second stage, which denoted the rate of the transformation, strongly depended on the experimental conditions. To study the effects of solvent composition and temperature on the phase transformation in a more quantitative way, the induction time and transformation rate were quantified from the experimental data shown in Figures 8 and 9 with the following method: for every experiment CBZH fraction points in the range of 15-85 wt % were selected, and a trend line was drawn with Excel by fitting the line to all the selected points. The induction time and transformation rate were obtained from the slope and the intercept with the x axis of the fitted line (see Figures 8 and 9). The dissolution time of CBZA in the beginning of the first stage was not subtracted from the induction time, because the solute concentration was measured with off-line sampling and also it is difficult to obtain an accurate dissolution time with this method. This is acceptable, since the dissolution time was very short compared with the whole induction time, especially at low supersaturations. The tendency of the induction time to change with the supersaturation can be clearly seen from Table 1. Usually the induction time is considered to be inversely proportional to the rate of nucleation. As shown in Table 1, the induction time increased with decreasing supersaturation (increasing of temperature). The induction time increased more significantly with decreasing supersaturation in 61 mol % ethanol solvent. This probably implies that the nucleation rate of CBZH was lower in the solvent containing 61 mol % ethanol. The transformation rates are plotted against the supersaturation level in Figure 10. The points are clearly grouped as two series according to the solvent composition. The transformation rate increased more dramatically for the 47.7 mol % ethanol solvent with increasing supersaturation, suggesting a faster crystallization rate in 47.7 mol % ethanol solvent. This is consistent with


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Table 1. Supersaturation Level and Induction Time for Transformation at Different Solvent Compositions and Temperaturesa 61 mol % ethanol temp (°C)

C/C*

induction time tin (min)

9.8 11.8 14.3 16.9

1.44 1.34 1.26 1.19

7.4 46.9 71.0 77.1

47.7 mol % ethanol temp (°C)

C/C*

induction time tin (min)

26.9 30.8 32.8

1.24 1.19 1.05

8.8 32.0 48.2

a C represents the solute concentration in units of g of CBZ/100 g of solvent, and C* is the solubility of CBZH at the corresponding temperature.

Figure 10. Transformation rate versus supersaturation in different solvent compositions: (9) 61 mol % ethanol; (×) 47.7 mol % ethanol.

Figure 11. Crystal size distribution of the final CBZH produced at different solvent compositions and temperatures (measured on a Coulter LS 13320 laser diffraction analyzer; S is the supersaturation ratio C/C*).

the conclusion drawn above that the nucleation rate was faster in 47.7 mol % ethanol solution than in 61.0 mol % ethanol solution. Generally speaking, the final crystal size distribution of the product depends on the kinetics of all fundamental mechanisms that are involved in the phase transition process, such as heterogeneous primary nucleation and secondary nucleation, crystal growth, and some secondary process, for example agglomeration and attrition.25 The crystal size distribution (CSD) of the final CBZH produced at different solvent compositions and temperatures is shown in Figure 11. It can be observed that the operating conditions clearly influence the CSD of the CBZH crystals. The highest supersaturation in the experiment with 61 mol % ethanol at 9.8 °C produced the smallest crystal size with an extremely narrow size distribution. This probably implies that the heterogeneous primary nucleation and secondary nucleation were the dominant mechanisms in the transformation. The nucleation consumed the supersaturation so quickly that a very short crystallization time resulted (see Figure 8). The size distribution was very narrow in this situation because the desupersaturation was mainly taking place through nucleation. When the supersaturation ratio decreased from 1.44 to 1.34, the size distribution became wider; meanwhile, the mean crystal size and the size of the largest crystals both increased signifi-

Figure 12. Mean crystal size of final CBZH particles versus supersaturation level in different solvent compositions: (9) 61 mol % ethanol; (×) 47.7 mol % ethanol.

cantly. This changing trend of the CSD and crystal size was continued when the supersaturation ratio decreased from 1.34 to 1.26. This indicated that the effect of crystal growth on the final CSD was promoted at moderate supersaturation. However, when the supersaturation ratio was further decreased to 1.19, the CSD became narrower and bimodal. The size of the largest crystals decreased drastically, which probably implied that the attrition of large crystals became more pronounced. As discussed above, the crystallization of CBZH mainly occurred in the second and the third stages of the experiment. The duration of these stages increased with decreasing supersaturation. During the transformation, the largest crystals suffered most from the attrition, resulting in a distinct decrease in their size. This conclusion is also supported by the mean crystal size shown in Figure 12. The mean crystal size increased to a maximum value with decreasing supersaturation. The particle size distribution changed in a slightly different way when the solvent containing 47.7 mol % ethanol was used. All three CSD curves resulting from 47.7 mol % ethanol solution were bimodal. When the supersaturation decreased from 1.24 to 1.19, the CSD became distinctly wider and the size of the largest crystals was doubled. An increase in the size of the largest crystals was also observed when the supersaturation was further decreased to a very low level of 1.05. This suggested that the effect of crystal growth still surpassed that of attrition.25 Here it is confirmed again that the crystal growth rate was higher in the solvent containing 47.7 mol % ethanol. The optical microscope images (Figure 13a-c) show that the morphology of the obtained CBZH crystals is platelike. A closer study of the surface and morphology of the crystals was performed with a scanning electron microscope (Figure 13d). It shows that the large particles seem like an agglomeration of needlelike particles. This may suggest that agglomeration was also involved in the crystallization of CBZH crystals. The crystallization of a hydrate is different from that of an anhydrous compound. In anhydrous compound crystallization, the solute molecules solely experience the phase changing from solution to solid through nucleation and crystal growth. For hydrate crystallization, however, the water molecules have to be incorporated with the solute molecules to form the growth unit cell of the hydrate crystalline. The water activity in the solution plays an important role in the solvent-mediated anhydrate/hydrate transformation. As discussed above, the induction time (see Table 1), transformation rate (see Figure 10), and final crystal size distribution (see Figure 11), generated under different operating conditions, all suggested a faster rate of nucleation and growth for CBZH crystals in 47.7 mol % ethanol solvent with a higher water activity. It is conventional to correlate the supersaturation level with the growth rate in study of crystallization kinetics. However, the water activity is not taken into account in this correlation. This resulted in the



Figure 13. Images of the CBZH crystals taken with an optical microscope (a-c) and scanning electron microscope (d; the white bar represents 200 µm).

of the phase transformation was better described with the water activity based correlation. 4. Conclusions

Figure 14. Transformation rate of CBZA to CBZH versus the water activity based driving force: (9) 61 mol % ethanol; (×) 47.7 mol % ethanol. The water activity was evaluated from data in the literature20,21 on the basis of a binary mixture of ethanol and water.

grouping of the transformation rate into two distinguishable series corresponding to the solvent composition, as shown in Figure 10. Figure 4 shows that, at a given temperature, there exists a water activity value a*, at which CBZA and CBZH are in equilibrium. The transformation from CBZA to CBZH will occur if the water activity is higher than the equilibrium water activity value. The difference between the real water activity and the equilibrium water activity, a - a*, can be considered to be the driving force of the transformation, and it is reasonable to correlate the transformation rate with this water activity difference. The transformation rate was plotted against the difference between the real water activity and the equilibrium water activity, a - a*, in Figure 14. When Figures 10 and 14 are compared, it can be observed that the correlation of a - a* and transformation rate was much more independent of the solvent composition. This probably implies that the mechanism

The kinetics of the solvent-mediated phase transformation of anhydrous to dihydrated carbamazepine in ethanol-water mixtures was studied using a Raman immersion probe. In-line quantitative measurement of the fraction of dihydrate in the suspension was accomplished with a Raman spectrometer by setting up a calibration line using mixtures of CBZA and CBZH. The phase transformation was a two-step process, consisting of the dissolution of CBZA and the crystallization of CBZH. The transformation rate was affected by both solvent composition and temperature. The crystallization of CBZH was the ratecontrolling step during the transition, due to the relatively slow kinetics of the crystallization. The crystallization kinetics decreased with an increase in the ethanol concentration. The mechanism of the solvent-mediated phase transformation from the anhydrate to the hydrate can be well interpreted by correlating the transformation rate with the deviation of the water activity in the solution from the equilibrium water activity value. Acknowledgment. We thank The Academy of Finland for the financial support (Academy Research Fellow post No. 76440 and project No. 211014). Mr. Sabiruddin Mirza is thanked for assistance in sample analysis. Orion Corporation is thanked for providing the carbamazepine material. References (1) Brittain, H. G. Polymorphism in Pharmaceutical Solids; Marcel Dekker: New York, 1999.

2060 Crystal Growth & Design, Vol. 6, No. 9, 2006 (2) Deeley, C. M.; Spragg, R. A.; Threlfall, T. L. Spectrochim. Acta 1991, 47A, 1217-1223. (3) Tian, F.; Zeitler, J. A.; Strachan, C. J.; Saville, D. J.; Gordon, K. C.; Rades, T. J. Pharm. Biomed. Anal. 2006, 40, 271-280. (4) Taylor, L. S.; Zografi, G. Pharm. Res. 1998, 15, 755-761. (5) Niemela¨, P.; Pa¨a¨llysaho, M.; Harjunen, P.; Koivisto, M.; Lehto, V. P.; Suhonen, J.; Ja¨rvinen, K. J. Pharm. Biomed. Anal. 2005, 37, 907911. (6) Murphy, B. M.; Prescott, S. W.; Larson, I. J. Pharm. Biomed. Anal. 2005, 38, 186-190. (7) Hu, Y.; Liang, J. K.; Myerson, A. S.; Taylor, L. S. Ind. Eng. Chem. Res. 2005, 44, 1233-1240. (8) Ono, T.; ter Horst, J. H.; Jansens, P. J. Cryst. Growth Des. 2004, 4, 465-469. (9) Wang, F.; Wachter, J. A.; Antosz, F. J.; Berglund, K. A. Org. Process Res. DeV. 2000, 4, 391-395. (10) Starbuck, C.; Spartalis, A.; Wai, L.; Wang, J.; Fernandez, P.; Lindemann, C. M.; Zhou, G. X.; Ge, Z. Cryst. Growth Des. 2002, 2, 515-522. (11) Ono, T.; Kramer, H. J. M.; ter Horst, J. H.; Jansens, P. J. Cryst. Growth Des. 2004, 6, 1161-1167. (12) Cardew, P. T.; Davey, R. J. Proc. R. Soc. London 1985, A398, 415428. (13) Davey, R. J.; Cardew, P. T. J. Cryst. Growth 1986, 79, 648-653. (14) Qu, H.; Louhi-Kultanen, M.; Kallas, J. Int. J. Pharm. 2006, in press. (15) Zhu, H.; Yuen, C.; Grant, D. J. W. Int. J. Pharm. 1996, 135, 151160.

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CG0600593

Solvent-Mediated Phase Transformation Kinetics of an Anhydrate

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