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SEPARATIONS Quantitative Study on Polymorphic Form in Solution Crystallization of Clopidogrel Hydrogen Sulfate Hye-Jin Kim and Kwang-Joo Kim* Crystallization Process & Engineering Laboratory, Department of Chemical Engineering, Hanbat National UniVersity, Yuseong, Daejeon 305-719, South Korea
The concentration of polymorphs was explored by the ultrasonic measuring technique during crystallization in solution. The polymorphic form of the crystallized solid, the concentration of the solution, and the transformation of polymorphs were found by the ultrasonic measuring technique. The ultrasonic velocity calibrated at known solid and liquid concentrations has been applied to determine quantitatively the polymorphic compositions for various process conditions. Additionally, it can be used to estimate the solute concentration and the supersaturation of solution during the transformation of polymorphs. Multivariate data analysis from the ultrasonic measuring technique was used to determine the kinetics of polymorph transformation and to simulate the transformation process. It was found that the transformation of polymorphs occurred simultaneously with crystallization of a polymorph in the solution. 1. Introduction Screening of polymorphism is important in the pharmaceutical industry.1 The polymorphic form of the active pharmaceutical ingredient is closely connected with its bioavailability, bioactivity, compressibility, dissolution, shelf life, and stability. Thus, polymorph screening is a challenging task for quality control of pharmaceutical drugs. Crystallization in solution is one of the most widely used methods for polymorph screening.2 Grinding, milling, spray drying, and kneading can induce the polymorph transformation.3,4 In the crystallization process, a metastable polymorph may often be obtained first during the process, and then a stable polymorph is crystallized through polymorphic transformation.5 To prepare a metastable polymorph by crystallization from solution, operating parameters such as solvent, temperature, supersaturation, etc., should be considered. Because the transformation rate depends on these parameters, the transformation of polymorphs should be monitored during crystallization. Screening the polymorph is a time-consuming task. It is also very difficult to find the time required for the transformation from metastable to stable forms. To screen for polymorphs during crystallization, in situ measurement for polymorph monitoring is necessary. There are many methods for monitoring the transformation of polymorphs. X-ray powder diffraction (XRPD), solid-state nuclear magnetic resonance spectroscopy (SS-NMR),6,7 differential scanning calorimetry (DSC),8 thermal gravimetric analysis (TGA), and optical spectroscopy9,10 such as mid-infrared (IR), near-infrared (NIR), Raman, and terahertz pulsed spectroscopy (TPS) were used. Even though these analytical techniques were convenient for identifying the polymorphs, they were used for routine offline tests of the polymorph form. In the previous work,11 the measurement of ultrasonic velocity was found to be useful for screening polymorphs during crystallization. In general, variations of the ultrasonic velocity are a result of densities determined of the solid and liquid. * To whom correspondence should be addressed. Tel.: +82 42 821 1527. Fax: +82 42 821 1593. E-mail:
[email protected].
The ultrasonic measuring techniques were used as one of the methods, which enable one to determine solubility, supersaturation, and metastable zone width in crystallization. Several works have presented the validity of ultrasonic measuring techniques to determine the solubility and metastable zone width of inorganic salts and online measurement of crystallization processes.12-14 With the technique of ultrasonic monitoring, measurement of the concentration of solution and in situ diagnostic of zeolite crystallization were developed.12 Hence, significant changes of the ultrasonic velocity in crystallization are expected as a result of a change of concentration of solution and solid during the crystal growth. This ultrasonic measuring technique was successfully applied for determining the crystal forms and monitoring their change. In a previous study,11 we reported that the formation and the transformation behaviors of clopidogrel hydrogen sulfate (CHS) in drowning out crystallization with methanol-isopropyl alcohol (IPA) solvent were monitored by the measurement of ultrasonic velocity. It was shown that the polymorph observed depended on both the temperature and the composition of the methanol-IPA solvent mixture. CHS was used here as a target material for screening the polymorph transformation. CHS is a common antithrombotic and has two crystal forms. Although there are patents on the preparation of CHS,15,16 screening of CHS polymorphs during crystallization in solution has never been reported. In this study, CHS was crystallized in a methanol-IPA mixture solvent for screening the polymorph. The influence of CHS concentration and methanol to IPA ratio on crystallization and transformation was investigated. Polymorphic composition and concentration of solution were estimated by the ultrasonic velocity measuring technique during crystallization. 2. Experimental Section 2.1. Materials. Form II of CHS (C16H16ClNO2S · H2SO4, MW 419.2, 99.0% pure; supplied by Daehee Chemical Co., Gyunggi, South Korea) was used without purification. Organic solvents
10.1021/ie900715w CCC: $40.75 2009 American Chemical Society Published on Web 10/13/2009
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such as iso-propyl alcohol (IPA) and methanol (purity >99.9%) were purchased from Aldrich. 2.2. Experiment. The experimental setup was previously presented. It consists of a crystallizer, the ultrasonic velocity measurement system, and a temperature control system. These experiments were conducted in batch crystallization mode. During operation, ultrasonic velocity and temperature were measured every 2 s. XRPD pattern was measured every 10 min. The crystallizer was a 200 mL-jacketed cylindrical glass vessel equipped with a 5 cm marine type propeller (stirring speed: 400 rpm) and an ultrasonic sensor. After the Form II crystals were dissolved in methanol at 10 °C higher than the saturation temperature, which was presented in the previous work,11 the CHS solution was maintained at the same temperature for 1 h. The operating temperature was set by adjusting the temperature of IPA contained in the crystallizer before adding the CHS solution. The solution was then fed to the agitated IPA. The feed rate of the solution was 15 mL/min, which was selected to control transformation time of polymorphs. The mass ratio of methanol to IPA ranged from 0.09 to 0.15. The mass ratio of CHS to methanol was in the range from 0.5 to 1.0. The operating temperature ranged from 10 to 35 °C. The crystals were sampled at regular intervals using a solid-liquid separator with a glass filter. The polymorphic form of crystals was identified by off-line XRPD analysis. Ultrasonic velocity and temperature of the solution and/or the suspension were measured using the model LiquiSonic 30 (SensoTech GmbH, Magdeburg, Germany) immersion sensor connected to a data acquisition system. This system can measure the velocity of ultrasonic waves through the liquid media with a precision of 0.01 m/s and can record the temperature with a precision of 0.01 °C. The sensor sends very low frequency longitudinal ultrasonic waves (1.5 MHz), which has no cavitation effect in the solution. Nucleation point was not affected by ultrasonic measuring system. The measuring principle was explained by the previous work.13 2.3. Composition of Polymorphic Form. X-ray powder diffraction was used to identify the polymorphs and to determine the polymorphic compositions. XRPD profiles were acquired using an X-ray diffractometer (D/MAX 2500H, RigakuQ6 Co.). The measurement conditions were as follows: target, Cu KR1, 60 kV; current, 300 mA; receiving slit, 0.3 mm; scan range, 18-40° (2θ); step size, 0.02°; scanning speed, 18/min. XRPD charts for Forms I and II were presented.11 The samples were scanned from 3° to 40° 2θ at a step size of 0.01° and at 2 s per step. The peaks at 9.4°, and 8.9° and 9.7° 2θ, corresponding to CHS Form I and Form II, respectively, were chosen to determine the polymorphic composition by comparing the integrated peak areas, as described previously.11 Figure 1a shows the peaks obtained in the condition that a mass fraction of Form I is 0.6. The fraction of the peak areas for these characteristic peaks was calibrated by the known mixtures of Forms I and II.17 The detection limit was determined to be less than 1%, which enabled Form II to be detected in the presence of Form I with ease and with good reproducibility. The polymorphic composition was calculated by fraction of Form I )
area of peak at 9.4◦ area of peaks at 8.9° and 9.70° + area of peak at 9.4°
(1)
Figure 1b shows results of calibration between the polymorphic composition and the peak areas in XPRD chart. It shows a good linear relationship with calibration parameter. As can be seen
Figure 1. Correlation between mass fraction of polymorphic form and peak area fraction of XRPD: (a) XRD peaks for Forms I and II and (b) correlation results with equation.
in Figure 1b, mass fraction of Form I was correlated by multiplying 1.17 by the area fraction of XPRD chart. 3. Results and Discussion 3.1. Calibration of Ultrasonic Velocity. Because the ultrasonic velocity is affected both by the solid as well as by the liquid phase, an appropriate calibration is required to monitor the concentration of solution and fraction of polymorphic form. Calibration was carried out by considering the solid fraction, solute concentration, and temperature, which affect the ultrasonic velocity. Calibration for the effect of the solution on ultrasonic velocity was done by adding methanol-CHS solution to IPA. Here, even though the solution concentration was above the saturation concentration, crystals were not nucleated during the measurement because the solution was within the metastable zone for crystallization. The metastable zone means the zone between saturation and supersaturation points, and inside this zone the nucleation does not occur. Calibration for the effect of the solid on ultrasonic velocity was done by adding a known amount of solid CHS into a saturated solution of CHS at a constant temperature. Therefore, CHS solids added in the saturated solution were not dissolved. Different solute concentrations, solid fraction, and temperatures were included to obtain a multivariate calibration of the ultrasonic velocity measured. Methanol/IPA ratios of 0.11-0.14 and temperatures of 10-35 °C were investigated.
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Figure 4. Effect of solution concentration on ultrasonic velocity at various methanol/IPA ratios. Figure 2. Effect of CHS concentration in solution and solid fraction on the ultrasonic velocity at a methanol/IPA ratio of 0.11 and 25 °C for Forms I and II.
Figure 3. Plot of variation of ultrasonic velocity against variation of solid fraction included in saturated solution.
Figure 2 shows the effect of CHS concentration in solution and solid fraction on the ultrasonic velocity at a methanol/IPA ratio of 0.11 and 25 °C for Forms I and II. The mean crystal size of CHS solids used was 53 µm. The CHS/solvent ratio was in the range of 0-0.132. Ultrasonic velocity increases with increase in the concentration of CHS in solution as well as in the content of CHS solid. The relationship between ultrasonic velocity and concentration shows a good linearity. The effect of solution is stronger than the effect of solid on ultrasonic velocity, because the slope of the curve for solution is higher than that for the solid. It was found that the difference between ultrasonic velocities of Form I and Form II in solution is very small and can be neglected. The slopes of the curves for Forms I and II are the same. This means that, independent of the polymorphic form, the effect of solid fraction on ultrasonic velocity is the same for Forms I and II. Figure 3 shows the plot of the ultrasonic velocity against the fraction of the Form II solid included in the saturated solution. The previous work by Ulrich et al.12 presented that the effect of crystal size on ultrasonic velocity is negligible at 20 wt % solid content and at size range 10-500 µm. In our work, solid content is maximum 10% of solution and size range of 10-300 µm. Therefore, the size and CSD effects were not considered. When the solid fraction is increased, the ultrasonic velocity is
increased. A linear relationship between the variations of solid fraction and ultrasonic velocity was found. As a result, ultrasonic velocity varied by 8.2 m/s per solid fraction of 0.1 (CHS g/methanol + IPA g). When crystallization occurs, point A at the feed concentration of 0.132 (CHS g/methanol + IPA g) is moved into point B in Figure 2, and the ultrasonic velocity decreases from points A to B. Even though the solid fraction increases and the solution concentration decreases during crystallization, ultrasonic velocity decreases because solution concentration depends on higher than solid concentration. Point B indicates the limitation of crystallization due to reaching a saturated concentration of Form II. The ultrasonic velocity of solution at point A is 1168 m/s. At point B, crystal of 0.128 CHS g per solvent g exists with the saturated solution. Therefore, ultrasonic velocity at point B is obtained by summing ultrasonic velocity of solution 1141 m/s and ultrasonic velocity of solid 10.5 m/s (for 0.128 g/solvent g as ultrasonic velocity increases 8.2 m/s per solid fraction of 0.1). Therefore, the ultrasonic velocity of point B is 1151.5 m/s. Thus, the concentration of the solution can be calculated by using the calibration line presented in Figure 2, which reflects the solution and the solid effects. From the calibration curve, the relationship between ultrasonic velocity and concentration can be expressed as: Vus ) 150.4w + 1151.5
(2)
where Vus is ultrasonic velocity and w is solution concentration as g of CHS/g of methanol + IPA. Figure 4 shows the effect of solution concentration on ultrasonic velocity at various methanol/IPA ratios. The ultrasonic velocity increases with increasing solute concentration and decreasing methanol/IPA ratio. The calibration curves for each methanol/IPA ratio can be determined by combining the solution concentration effect shown in Figure 4 and the solute concentration effect shown in Figure 3. Figure 2 is an example for a methanol/IPA ratio of 0.11 and temperature of 25 °C. 3.2. Monitoring of Polymorph Formation. Transformation of polymorphs was monitored by measuring the ultrasonic velocity with elapsed time during crystallization. Figure 5a shows the variation of the ultrasonic velocity measured during crystallization of CHS in methanol-IPA as solvent. It was carried out at a methanol/IPA ratio of 0.14, CHS/methanol ratio of 1.2, and 298 K. The recorded graphs are reproducible and typical for the experiments. They have four different zones that are associated with nucleation and growth of Forms I and II. Despite the difficulty in finding the nucleation point of Form II
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crystals of Form II are obtained. With the ultrasonic velocity for 100% Form I in the crystals formed in the solution, cI can be found at the end of Zone B, while with that for 100% Form II, cII is at the end of Zone C. Growth of Form II to which the ultrasonic velocity is sensitive occurs rapidly in this period, due to desupersaturation. This results from variation of the solution concentration and the solid fraction. As a result, the ultrasonic velocity data fit well to the transformation of polymorph from Form I to II. Zone C observed in the ultrasonic velocity signals correlates to the crystal growth step of the formation of Form II. Form I is consumed, and the remaining solution is the only source for building units. Crystallization was complete when the ultrasonic velocity reached its minimum. 3.3. Transformation of Polymorph. In this study, a simple theoretical equation to establish a relationship between the ultrasonic velocity of Form I and Form II was used. To a first approximation, the ultrasonic properties of a multiphase material can be described according to McClements.18 n
Figure 5. Variation of the ultrasonic velocity observed during crystallization at a methanol/IPA ratio of 0.14 and CHS/methanol ratio of 1.2 at 298 K: (a) variation of ultrasonic velocity of solution and solid CHS and (b) variation of ultrasonic velocity of dissolved CHS and solid CHS.
n
φj
∑φF ∑ c F
1 ) c2
j j
j)1
j)1
(3)
2 j j
where Fj, cj, and φj are density, ultrasonic velocity, and volume fraction of phase j, respectively. The phase consists of solvent, dissolved Form I, dissolved Form II, solid Form I, and solid Form II. As can be seen in Figure 5a, the points that indicate 100% Form I and 100% Form II were found as cI and cII, respectively, from measuring the ultrasonic measuring system. Here, cI means sum of ultrasonic velocities of solvent, dissolved CHS, and Form I solid, while cII means sum of ultrasonic velocities of solvent, dissolved CHS, and Form II solid. During the transformation of polymorphic form, the solvent fraction was constant, the dissolved CHS content decreases, and the solid content increases. Figure 5b shows variation of the ultrasonic velocity for the dissolved CHS and solid content. Thus, as can seen in Figure 5b, to simplify eq 3, the phases can be divided into the dissolved CHS and solid Form I as CI, and the dissolved CHS and solid Form II as CII.
(
φII φI 1 ) (φIFI + φIIFII) 2 + 2 2 C CI FI CIIFII
Figure 6. A typical result for the polymorph transformation at 25 °C and at a methanol/IPA ratio of 0.14.
by ultrasonic velocity only, XPRD identified the transformation as reported in previous work.11 Zone A and Zone B are the induction periods for nucleation of Form I and the zone for growth of Form I, respectively. Transformation from Form I to II occurs in Zone C. Transformation is carried out by nucleation and growth. In the nucleation step, Form II is nucleated at the surface of Form I. At the same time, Form I is also formed. In the growth step, Form II is grown by supersaturated solution. It will be explained by Figure 9. As presented with XPRD patterns,11 the starting point of nucleation of Form II was disclosed. During the growth of Form II, the ultrasonic velocity decreases. This indicates that the degree of change from Forms I to II can be measured. In Zone D, the
)
(4)
where subscripts I and II represent Form I and Form II, respectively. The solid densities of Form I and Form II are very similar at about 1.43 and 1.50 g/cm3, respectively. The density of Form I and Form II dissolved is the same. Thus, it can be assumed that volume fraction is converted into the mass fraction. This simple relationship gives a good description of the ultrasonic properties in the case that the densities of the two forms are similar and the scattering of ultrasound is negligible.19,20 Polymorph transformation can be expressed in the following manner:
(
(1 - xI) xI 1 ) 2 + 2 C CI CII2
)
(5)
where xI is the mass fraction of the Form I, and CI and CII are the ultrasonic velocities of 100% solid Form I and of 100% solid Form II at the measurement temperature, respectively. The xI can be determined by rearranging eq 5 to xI )
1/C2 - 1/CII2 1/CI2 - 1/CII2
(6)
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Figure 7. Polymorphic transformation as a plot of polymorphic composition against time at 25 °C for a methanol/IPA ratio of (a) 0.11, (b) 0.12, (c) 0.13, and (d) 0.14.
Thus, transformation from Form I into Form II can be determined by measuring ultrasonic velocity, providing that the ultrasonic velocities of 100% Form I and 100% Form II are known at the same temperature. In Zone C shown in Figure 5b, the fraction of Form I, xI, can be calculated from C, CI, and CII found in the curve of Zone C by eq 6. A typical result for the polymorph transformation at 25 °C and at methanol/IPA ratio of 0.14 is shown in Figure 6. As can be seen, transformation of polymorph shows the S curve, which is similar to the pattern presented in the previous works reported in different active pharmaceutical ingredients.21,22 The experimental solid compositions are given as a symbol and are calculated by eq 1 using XRPD charts. Calculation and experiment are in good agreement, and it is noticeable that the polymorph transformation process can be predicted on the basis of the ultrasonic measuring technique. 3.4. Monitoring the Transformation. To obtain more evidence that ultrasonic velocity measurements truly reflect the transformation, the experiments were repeated with different mixtures. The transformation period is affected by operating conditions such as methanol/IPA ratio and temperature. Thus, in the crystallization, supersaturation directly affects the transformation. The supersaturation is a function of temperature, solvent fraction, and solubility. For the understanding of the observed ultrasonic velocity measurements, the temperature effect, effect of solvent/nonsolvent, and variation of the properties of the solution during the crystallization are required.
Figure 7 shows the polymorphic transformation as a plot of polymorphic composition against time, which is calculated from the ultrasonic velocity. The polymorphic transformation from Form I to Form II was monitored in situ at different methanol/ IPA ratios ranging from 0.09 to 0.16. The transformation time was found to be 2200, 2300, 2400, and 4000 s for the methanol/ IPA ratios of 0.11, 0.12, 0.13, and 0.14, respectively. Figure 8 shows the polymorphic transformation as a plot of polymorphic composition against time, which is calculated from ultrasonic velocity. The polymorphic transformation from Form I to Form II was monitored in situ at a methanol/IPA ratio of 0.13 for the range of temperatures from 10 to 35 °C. The transformation time was found to be 37 000, 5500, 2400, and 2450 s for the temperatures of 10, 20, 25, and 35 °C, respectively. The transformation time decreases with increasing temperature. It means that mass transfer of solute in solution increases with increasing temperature. Higher diffusion rate of solute in solution as a mass transfer rate results in a higher crystallization rate. Above 25 °C, the transformation time changes little. In the previous work, the polymorphic system of CHS was found to be monotropic, and Form II is the thermodynamically stable form, while Form I is the metastable form.11 If Form I and Form II are monotrophs and Form II is the stable form, the solubility of Form II will be lower than that of Form I. This was confirmed by thermal analysis that showed that the melting enthalpy of Form I is greater than that of Form II. The ultrasonic
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Figure 8. Polymorphic transformation as a plot of polymorphic composition against time at a methanol/IPA ratio of 0.13 for temperatures of (a) 10 °C, (b) 20 °C, (c) 25 °C, and (d) 35 °C.
velocity technique is consistent with this in predicting that Form I and Form II are monotrophs. The phase transformation phenomenon observed by ultrasonic velocity is consistent with Ostwald’s law of stages, which states that the formation of a metastable phase will precede the appearance of a thermodynamically stable phase once the supersaturation has spontaneously decreased.5 3.5. Concentration of Solution by Ultrasonic Measuring Technique. Polymorph transformation at 25 °C at a methanol/IPA ratio of 0.11 was selected as a representative experiment in which in situ monitoring of ultrasonic velocity was applied. Ultrasonic velocity monitoring revealed nucleation of Form I and later transformation to Form II in the previous observations.11 The CHS concentration in solution was obtained from the measured ultrasonic velocity by means of the calibration line between ultrasonic velocity and concentration shown in Figure 2, which is expressed by eq 2. Figure 9 shows the variation of solute concentration in solution against time at a methanol/IPA ratio of 0.11 and 25 °C for Forms I and II. In batch crystallization, the supersaturation defined as the difference between saturation concentration and solution concentration is a function of the operating time because the concentration decreases during crystallization. After the transformation was finished, the solution concentration differed with saturation concentration. This means that the final supersaturation depends on the kinetic effect of crystallization such as mixing, adding rate, impurity levels, etc. To indicate the broad applicability of
Figure 9. Variation of solute concentration in solution against time at a methanol/IPA ratio of 0.11 and 25 °C for Forms I and II.
the quantitative presented approach, multiple polymorph transformations were monitored and analyzed by means of ultrasonic velocity. In Zone B, during the crystallization, supersaturation decreases as Form I is crystallized from the solution as the initial solid form. When IPA is added as nonsolvent, the concentration of the solution decreases until the solubility of Forms I and II is reached. As the solubility of Form I is higher than that of Form II, the solution is supersaturated with respect to Form I
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in Zone B. Therefore, Zone B is operated inside the metastable zone for formation of Form I, which is the zone for nucleation and crystallization of Form I. In zone C, the transformation from Form I to Form II occurs. As the solubility difference is not so large, Form I is transformed into Form II as a major solid phase in the mixture, and some nuclei of Form I may also be formed during the transformation. Evidence that Forms I and II are formed simultaneously in the transformation period can be seen in the yield presented in Figure 9. Yields of Form I and II can be calculated from the concentration difference in Zone B and in Zone B + C, respectively. From Figure 9, yields of Form I and Form II are 0.01 and 0.08 CHS g/(methanol + API) g, respectively. The yield of Form II is much higher than that of Form I. This means that Form I solid is lacking for transformation into Form II solid. Therefore, in Zone C, Forms I and II must be formed simultaneously and then transformation from Form I to Form II occurs as well. As the growth of the CHS consumes the supersaturation of Form II, the solution goes into the metastable zone for formation of Form II, which makes it possible for Form I to be dissolved and produces continuous supersaturation for Form II to be grown. The transformation will be complete when all of Form I is dissolved and the solution approaches a final supersaturation with Form II crystals within the metastable zone for the formation of Form II. 4. Conclusions Polymorphic composition and concentration of solution were obtained by measurement of ultrasonic velocity during the transformation of polymorphs. The ultrasonic velocity was calibrated with both the solid and the liquid concentrations to estimate the concentration. Additionally, this calibration can be used to estimate solute concentration and supersaturation during transformation of polymorphs. Data analysis of the ultrasonic velocity measurement can be used in modeling to determine the kinetics of polymorph transformation and to simulate the transformation process. It was found that the transformation of polymorphs occurs simultaneously with the formation of polymorphs in solution crystallization. Literature Cited (1) Haleblian, J.; McCrone, W. Pharmaceutical applications of polymorphism. J. Pharm. Sci. 1969, 58, 911–929. (2) Laird, T. Special feature section: Polymorphism and crystallization. Org. Process Res. DeV. 2000, 4, 370–371. (3) Otsuka, M.; Ofusa, T.; Matsuda, Y. Effect of environmental humidity on the transformation pathway of carbamazepine polymorphic modifications during grinding. Colloids Surf., B 1999, 13, 263–273.
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ReceiVed for reView May 4, 2009 ReVised manuscript receiVed July 6, 2009 Accepted September 28, 2009 IE900715W
