An Investigation of the Applicability of Microcalorimetry for the

Article pubs.acs.org/crystal

An Investigation of the Applicability of Microcalorimetry for the Measurement of Supersaturation during Batch Crystallization from Solution L. Derdour*,† and F. Buono‡ †

Drug Product Science and Technology, and ‡Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08901, United States ABSTRACT: The aim of this Article is to present new applications of reaction microcalorimetry for crystallization development. Using a multichannel reaction microcalorimeter, key information needed for crystallization development such as detection of primary nucleation can be obtained with minute material quantity and easy sample preparation. In addition, microcalorimetric measurement during small-scale (5 g) since the pioneering studies of Fevotte and Klein23−26 and Monnier et al.27 This technique is based on the measurement of the heat evolved during physicochemical transformations in solution. In the case of the crystallization processes, the amount of heat released is a combination of the desolvation energy needed to extract the solute from the solvent and the heat of crystallization, which is released upon formation of intermolecular bonds in the crystal. Calorimetry continues to be actively used in crystallization development. Recent examples from the literature include Lai et al. 28 for crystallization of urea and Kim et al.29 for the crystallization of poly(hydroxybenzophenone).

1. INTRODUCTION Determination of the metastable zone width (MSZW) during crystallization is critical for developing effective seeding protocols for solution crystallization. Knowledge of the variation of supersaturation during crystallization helps in the development and optimization of a robust crystallization process. Several techniques are described in the literature to determine the supersaturation (and the MSZW) during batch crystallization: density measurement (Garside and Mullin1), conductivity measurement (Hlozny et al.2 and Nyvlt and Karel3), refractometry (Sidkar and Randolph4 and Helt and Larson5), and weight measurement of crystals formed by fouling (Kuhberger and Mersmann6). In addition, spectroscopic techniques are also routinely utilized to determine the supersaturation during batch crystallization from solution. Examples from the literature of using spectroscopic techniques for crystallization monitoring and/or control include fluorescence measurements (Yedur and Berglund7) and ultrasound waves measurements (Omar and Ulrich8 and recently Gherras et al.9). The most used spectroscopic technique for crystallization monitoring and control is undoubtedly FTIR/ATR, which was first applied for crystallization monitoring by Dunuwila et al. 10 Turbidity measurement was also utilized to determine the variation of supersaturation during crystallization (Rawlings et al., 11 Miller and Rawlings, 12 and Matthews and Rawlings13). Turbidity measurements and FBRM are also routinely used in determining the MSZW. Calorimetry is a well-established technique for extracting kinetic information for chemical reactions since the pioneering work of Sawada et al.14 Examples of this application © 2012 American Chemical Society

Received: December 7, 2011 Revised: February 27, 2012 Published: March 7, 2012 1899

dx.doi.org/10.1021/cg201622p | Cryst. Growth Des. 2012, 12, 1899−1912

Crystal Growth & Design

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Figure 1. Depiction of heat evolved during solution crystallization.

In contrast, only a few examples are reported in the literature about application of microcalorimetry in the crystallization arena. To the best of our knowledge, this technique was not applied in extracting information about the variation of supersaturation during agitated batch crystallization from solution. At a small scale, single cell microcalorimeters were used for crystallization and dissolution studies, and several examples are described in the literature using the microcalorimetry technique. The isothermal solid-state crystallization kinetics of amorphous lactose was determined by Buckton and Darcy30 and Angberg.31 Darcy et al.32 employed this technique to determine crystal growth kinetics and the enthalpy of crystallization of hen egg-white lysozyme for an isothermal nonagitated system. Ohta et al.33 used the technique to determine the amorphous content of Cefditoren Pivoxil by determining the isothermal heat of dissolution. Ahmed et al.34 determined crystallization kinetics of partially amorphous griseofulvin in water vapor. Yonemochi et al.35 evaluated isothermal crystallization behavior of amorphous ursodeoxycholic acid. Fang et al.36 used a single cell microcalorimeter to determine crystal growth kinetic parameters of Zn(Met)SO4·H2O. Chen et al.37 used the technique to determine crystal growth parameters of Zn(Val)Ac2. Finally, Song et al.38 utilized microcalorimetry to quantify the crystallization of an amorphous drug during powder mixing. The main advantage of microcalorimetry is the small sample quantity needed to study exothermic reaction at very high sensitivity. This makes the technique an attractive tool for early stage development in the pharmaceutical industry when the material available for process and material development is often available in minute amounts. In this Article, we evaluate the possibility of using microcalorimetric data to extract information related to the metastable zone width (MSZW) and variation of supersaturation during small-scale ( 15 °C).

Figure 3. Expected heat flow generated during cooling crystallization of 0.001 mol of hypothetical small organic molecules. Heat of fusion range: based on compilation of Acree.41,42 Crystallization duration: based on typical duration encountered in industrial settings.

of fusion data of 570 organic molecules with molecule weights ranging from 80 to 930 g/mol and having a melting point at atmospheric pressure above 15 °C extracted from the compilations of Acree.41,42 A statistical analysis of this data indicates an average enthalpy of fusion of 26.4 kJ/mol with a standard deviation of 12.95 kJ/mol. The data also show that 99% of substances reported have an enthalpy of fusion higher than 2 kJ/mol. In contrast, enthalpies of desolvation of organic substances are rarely reported in the literature possibly because of the lack of methods for direct measurement. However, several accounts of enthalpies of solution are documented in the literature, and the data reported are usually obtained by calorimetry via solid dissolution. Knowing the enthalpy of fusion of the solid and the enthalpy of solution, one can estimate the enthalpy of desolvation with the help of eq 2. Enthalpies of solution and corresponding enthalpies of desolvation extracted from the literature are reported in the Appendix.43−61 On the basis of those data, the average ratio ΔHdesolv/ΔH fus is found to be 0.35 with a standard deviation of 0.263. From eq 1, it is evident that the higher is the enthalpy of desolvation, the lower is the heat evolved during crystallization and hence the lower is the ratio signal/noise obtained during microcalorimetric measurement. Therefore, the quality of the microcalorimetric measurement can deteriorate for systems exhibiting a large enthalpy of desolvation. On the basis of the literature data reported in the Appendix, the

average heat flow generated during small-scale crystallizations is in most cases higher than the typical microcalorimeter sensitivity (ca. 50 μW for agitated systems). On the basis of these data, we envisaged utilizing microcalorimetry as a tool for determining primary nucleation and possibly estimating the variation of transient concentration during small-scale crystallization. This interest for microcalorimetry was driven by the many advantages this technique offers, which are: • ability to carry out parallel small-scale experiments • small amount of material required • simplicity of experimental setup • speed of data generation • insensitivity to the presence of multiple liquid phases • minimal/no requirement for calibration • insensitivity to opacity of solution In the following sections, we will derive equations needed to extract concentration information from microcalorimetric data and approaches to obtain a simple relationship for crystal growth rate for needle-shaped crystals. The interest for deriving expressions for the case of growing acicular crystals is driven by the experience of the authors that a large number of active pharmaceutical ingredients (APIs) moving from discovery to development stage in the past decade crystallize in the needle-shaped habit. This is exemplified by the model compound utilized in this study, which crystallized as needles, the elongation factor of which depends on the crystallization solvent system (see 1901



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the same amount of solution but no solute. In this case, eq 3 can be simplified into eq 5:

Experimental Section). The internal structure of the crystal can influence the final crystal shape with faces perpendicular to large d-spacing being the dominant faces in the final crystal (BFDH theory62−64). The BFDH theory was refined by Hartman and Perdok65−67 to include the energetic aspect of intramolecular bonds within the crystal. This modified theory is known as the attachment energy (AT) theory and is based on the energy involved in the attachment of solute on the crystal surface on each face. The AT theory predicts that the larger is the energy released upon the attachment of the solute, the faster is the growth the corresponding face. The AT theory was considered to provide a better simulation than the BFDH theory (Docherty and Roberts68) and is more likely to provide a better explanation to the formation of the acicular habit. A growing number of substances having both lipophilic (to allow permeation through membranes) and hydrophilic (to enhance aqueous solubility) functional groups are being transitioned from discovery to development (Surajudin and Pudipeddi69 and Lapinski et al.70). During the growth of the crystal, the attachment of lipophilic (less polar) fragments is expected to be less energetic than the attachment of hydrophilic (more polar) sites. According to the AT theory, this leads to a difference in growth rates between hydrophilic and lipophilic faces with the latter being the dominant faces in the final crystal, which can result in the acicular habit observed in many crystals of pharmaceutical interest. 2.1.1. Determination of the Variation of Concentration (and Supersaturation) from Microcalorimetry Data. Case of Cooling Crystallization. The heat evolved during a cooling crystallization can be expressed as the sum of the heat needed to desolvate the solute and the heat produced due to the formation of the crystals. An internal mathematical correction is applied to allow compensation for the time lag of heat through the reactor walls. If heat losses can be neglected, which is usually the case with the use of the microcalorimeter, the heat evolved during cooling can be expressed as:

Q̇ = ΦΔHfus

(5)

dt

where (6)

Φ=1−α

Integration of eq 5 yields the expression of the temporal mass of solute crystallized: mcryst =

1 ΦΔHfus

∫0

t

Q̇ dt

(7)

Assuming a perfect mixing, the transient concentration can easily be found as: mo − C(t ) =

t 1 ∫ Q̇ dt ΦΔHfus 0

V

(8)

2.1.2. Case of Antisolvent Crystallization. For the case of isothermal antisolvent crystallization, antisolvent is added at the same rate to vials containing solutions and to the reference containing only the solvent. This allows subtracting the heat evolved due to mixing the antisolvent with the solvent. In this case, the heat evolved during antisolvent addition crystallization can be derived from a heat balance as: dmAS dQ Q̇ = = ΔHmixing dt dt dmcryst dΔHloss ( −ΔHfus + ΔHdesolv ) + − dt dt

(9)

ΔHmixing is the specific heat of mixing of the antisolvent with the solvent (negative). For antisolvent addition crystallization, the ΔH desolv is expected to vary during crystallization. The impact of the variation of ΔH desolv on the calorimetric measurement depends on its level of dependence upon solvent composition and on the ratio ΔHdesolv/ΔHfus. Let us define the relative error induced by neglecting the variation of the enthalpy of desolvation with solvent composition as:

dmCpT dmcryst dQ (ΔHcryst + ΔHdesolv ) Q̇ = = − dt dt dt dΔHloss + (3) dt

⎡ |Δ(ΔHdesolv )solv1 → solv2 | ⎤ Err = 100⎢ ⎥ (ΔHdesolv )solv1 ⎣ ⎦ ⎡ |(ΔHdesolv )solv1| ⎤ ×⎢ ⎥ ΔHfusion ⎣ ⎦

where mcryst is the mass of solute crystallized during the time dt, ΔHcryst ≈ −ΔHfus is the molar heat of crystallization (negative), ΔH desolv is the molar heat of desolvation (positive), and ΔHloss is the heat lost (negative). For cooling crystallization, the solvent composition is constant, and hence the heat required for desolvation can be approximately as proportional to the heat of crystallization for a given system: ΔHdesolv = αΔHfus

dmcryst

(10)

From eq 10, it is evident that a combination of large dependence of ΔHdesolv on solvent composition and high ΔHdesolv leads to the largest errors. On the other hand, systems with low ΔHdesolv are less sensitive to its variation with solvent composition. Very few accounts of variation of enthalpy of desolvation with solvent composition are reported in the literature. However, a fair amount of data of enthalpy of solution in different solvents is published43−61 (cf., Appendix). On the basis of that data, the average error induced by neglecting the variation of the heat of desolvation with solvent composition is 5.2% with a maximum of 12%. It should be noted that the data used for the calculation correspond to a complete solvent swap. In practical antisolvent crystallizations, both solvent and antisolvent are present during crystallization.

(4)

The microcalorimeter is well-insulated and hence can be considered as adiabatic (ΔHloss ≈ 0). In addition, the term related to the variation of the internal energy is subtracted from the heat evolved in the reference, which contains approximately 1902



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Figure 4. Evolution of size for the case of needle-shaped crystals.

number of crystals is practically constant (no nucleation, breakage, and agglomeration), and the mass deposition rate can be expressed in terms of the variation of the volume of the crystals:

Hence, for practical crystallizations, the maximum error induced in heat of crystallization is expected to be lower than 12%. This error is acceptable for the purpose of the method presented in this Article. However, the method should be corrected for the variation of heat of desolvation during antisolvent crystallization if more accuracy of the measurement is required. For an antisolvent addition crystallization, solution concentration can be easily found to be: mo − C(t ) =

ṁ =

(11)

where AR = (1/(moρAS))((dmAS)/(dt)) is the normalized antisolvent volumetric addition rate (reported to unit mass of initially dissolved solute). In both cases of cooling crystallization and antisolvent crystallization, the total mass of the material crystallized can be easily calculated from the heat flux data using the following relationship: mcryst‐final =

1 ΦΔHfus

ṁ =

(12)

2aL da ≪ a2 dL

The heat of fusion data are obtained from DSC measurements, and the final mass crystallized is obtained from measurement of the final solute concentration HPLC or H NMR: (mcryst‐final )exp = mo − C finalVfinal

1 (mo − C finalVfinal)ΔHfus

ρcrystNcrysta2 dL ṁ = mo dt

(13)

(17)

(18)

Hence, linear growth rate (G) for needles is approximately proportional to the mass deposition rate: ⎛ ⎞ mo ⎜ ⎟ṁ G=⎜ 2⎟ ρ N a ⎝ cryst cryst ⎠

t

∫0 final Q̇ dt

(16)

In this case, eq 16 can be simplified as:

Combining eq 12 with eq 10 for the case of an antisolvent crystallization (eq 8 for the case of cooling crystallization) leads to the following expression for the parameter Φ: Φ=

Ncrystρcryst ⎛ 2aL da + a2 dL ⎞ ⎟⎟ ⎜⎜ mo dt ⎠ ⎝

where a is the characteristic length of the face at the extremity of the crystal, and L is the length of the lateral face of the crystal. Considering that for needles (growing mostly in one direction) the face at the extremity of the crystal grows at a much higher rate than the lateral face, one can assume that (cf., Figure 4):

t

∫0 final Q̇ dt

(15)

where Ncryst is the total number of crystals, ρcryst is the density of crystals, Vcryst is the volume of a crystal, and mo is the mass of the solute initially dissolved in solution. For needle-like crystals, eq 15 can be written as:

t 1 ∫ Q̇ dt ΦΔHfus 0

Vo + mo(AR)t

1 d(NcrystρcrystVcryst) mo dt

(14)

Once identified, Φ is substituted in eq 8 for cooling crystallization and in eq 11 for antisolvent crystallization to determine the evolution of concentration (and hence supersaturation) during crystallization from microcalorimetric data. In addition, with the knowledge of Φ and the heat of fusion (ΔHfus), the heat of desolvation can be estimated using eqs 4 and 6. 2.2. Determination of Crystal Growth Rates for Acicular Crystals. The substance used as model compound in this study crystallizes as needles. In addition and as mentioned above, a large number of APIs crystallize in the acicular habit. Therefore, it is very helpful to identify a technique/method that allows the estimation of crystal growth rate of needles at an early stage using only a small amount of material. If crystallization is crystal growth dominated, the total

(19)

Consequently, for the case of growth of acicular crystals and for a crystal-growth dominated crystallization, the variation of the mass deposition rate versus supersaturation reflects the variation of crystal growth versus supersaturation. Hence, if phenomena such as nucleation, breakage, and agglomeration can be neglected, information about crystal growth kinetics for the case of needle-like crystals can be obtained at an early stage of process development by determining the mass deposition rate from microcalorimetric measurements. This can help in tailoring crystallization procedures at an early stage of drug development and ultimately can result in a tremendous savings of time needed for crystallization process development. 1903



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Figure 5. Omnical Insight RT-10 calorimeter.

internal magnetic stirring (30−300 rpm) in a temperature range from −40 to 200 °C. Several processes were optimized and scaled-up using kinetic data and safety values obtained from this technique, which makes it a useful tool for kinetic investigation and process scale-up. The multichannel version of Super CRC was developed by Omnical as Insight-RT-10 (cf., Figure 5). The Insight RT-10 calorimeter is a 10channel calorimeter (8 for measurement and 2 for reference compartment in each temperature zone) with an internal magnetic vortex stirring and two temperature zones. The sample vessel is a 16 mL vial equipped with a stirring bar, and the volume of the reaction solution during the experiment is approximately 2−6 mL. The reaction is monitored by measuring the heat flow as compared to the reference heat flow every 2−6 s. As mentioned above, the instrument software package compensates for the time lag of heat through the reactor walls. The design of Insight RT-10 offers the possibility to execute simultaneously multiple small-scale experiments with different temperature ramps (from 0.5 to 2 °C/min) externally controlled for cooling crystallization. Because of its specification with an internal reference containing the reaction solvent, the heat detected due to a change of temperature of reaction solution is compensated by the reference; therefore, only the heat due to the crystallization phenomena is detected. 3.2.1. Materials and Methods. Experimental Method for Cooling Crystallization. Up to eight vials equipped with stirring bars can be loaded with solutions having different solute concentrations. The eight sample vials and the two reference vials with stirring bars containing the same volume of solvent were introduced to the Insight RT-10 calorimeter. When the vials are thermally equilibrated at the desired temperature, the temperature was decreased at the desired cooling rate (between 18 and 35 °C/h) to the final temperature (typically 20 °C). 3.2.2. Experimental Method for Antisolvent Addition Crystallization. Similarly, up to eight vials equipped with stirring bars with solutions having different solute concentration can be loaded in the Insight RT-10 calorimeter; two reference vials with stirring bars containing the same volume of solvent were introduced as well. When the vials are thermally equilibrated, the antisolvent is added to the reference reactor as well as in the remaining vials, and the rate of addition is controlled by the pump. 3.2.3. Baseline Correction. It is evident that the absence of solute in the reference and slight variation in volume between cells (and reference) due to the different amount of solute dissolve in each cell can induce differences in heat capacity, which can lead to errors in

In this study, the applicability of microcalorimetry in estimating the transient concentration and supersaturation during small-scale crystallizations was evaluated using Omnical Insight Rt-10 for cooling crystallizations and antisolvent addition crystallization. Bristol-Myers Squibb Co.’s investigational and proprietary compounds that crystallize as needles and noted hereafter A and B for the sake of confidentiality were crystallized at scales varying from 0.2 to 0.5 g. The heat evolved and measured by the instrument was utilized to determine the evolution of transient concentration during the crystallization process.

3. EXPERIMENTAL SECTION 3.1. Microcalorimeter Description. Reaction calorimetry (RC) has different applications and can deliver several specific data such as thermodynamic data (e.g., heat capacities, changes of enthalpy during phase transition, adsorption and chemical reactions), determination of kinetic constants, establishment of safety limits, and instantaneous measurement of heat flow and heat transfer coefficient for reactor design. There are a lot of different calorimeters available on the market, and the reaction calorimeters can be classified according to their measurement and control principles mainly into four categories: heat flow reaction calorimeters, power compensation reaction calorimeters, heat balance reaction calorimeters, and Peltier calorimeter. Reaction calorimetry is a rather straightforward technique for crystallization development as the measured information is used to determine the heat of crystallization, and thus the rate of crystal growth. The most used calorimeters are the differential scanning calorimeter (DSC) and the reaction calorimeter (RC). Reaction calorimeters operate under specific conditions close to the industrial process because of the similarity of the mixing devices, with a required amount of material (e.g., ∼10 g and typically more material is available for late stage project). The main advantage of DSC is the small quantity needed for the experiments. However, these microcalorimeters operate under conditions different from most of the industrial processes (e.g., no stirring, no use of solution). In the literature, several studies for reaction kinetic investigation and process safety are described using a Multi-Reactor Omnical Calorimeter Super CRC. This calorimeter operates as a differential scanning calorimeter by comparing the heat released or consumed in a sample vessel (16 mL) to a reference compartment with an 1904



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Figure 6. Typical baseline correction of original heat evolved curves (for an antisolvent addition crystallization). the calculation of the concentration from the heat evolved measurements. Prior to the onset of nucleation, no heat should be measured if the heat evolved in the reference is the same as the one evolved in the cells (i.e., if the reference subtraction is ideal). However, in reality, a nonzero heat evolved is measured even when no crystallization was occurring. This “residual” heat evolved was attributed to differences in heat capacity and/or in volume between the cell and the reference. Hence, to account for the effect of the difference in heat capacity and/or in volume between the reference and cells, the following baseline correction method was performed on the original curves of heat evolved obtained. The section of the curve prior to nucleation is fitted with a polynomial expression obtained by a partial least-squares method. This is the expression of the baseline, which essentially provides the heat evolved due only to the difference between heat capacity and/or volume between the reference and cells that is assumed to hold throughout crystallization. The expression of the baseline is then omitted from the original curves of heat evolved, which then provides the curves of the heat evolved due only to nucleation and crystallization (cf., Figure 6). In this approach, the difference between the heat capacity of the dissolved solute and the crystal is considered as negligible. 3.3. Detection of Primary Nucleation. At first, we were interested in the ability of the technique in detecting primary nucleation. For this purpose, we chose one Bristol-Myers Squibb Co.’s early stage investigational and proprietary compound (noted A) that is isolated by cooling crystallization. Compound A was dissolved in an organic solvent at different concentrations in two vials. The solid was dissolved at 70 °C, and a cooling ramp with a constant cooling rate was initiated and the heat flow was measured. Figure 7 shows the variation of heat flow during the simultaneous cooling of the two vials.

As expected, the heat flow is practically nil during the initial part of the cooling ramp due to the heat compensation from the reference. At different temperatures, for each vial, a spike of heat attributed to the onset of nucleation was observed. As expected, the temperature of nucleation obtained increases with the concentration. Microcalorimetry was then used to determine the onset of nucleation of compound B. The effect of agitation on the onset of nucleation was investigated. In addition, the onset of nucleation was also determined by FBRM on a larger scale (30 g). The data obtained are compared to data from microcalorimetry in Figure 8.

Figure 8. Comparison between the onset of nucleation obtained by microcalorimetry and FBRM for compound B (SR, stirring rate; CR, cooling rate). This figure shows the agitation does not have an impact on the metastable zone width obtained with the microcalorimeter in the range investigated. On the other hand, an acceptable agreement between FBRM data and calorimeter data is obtained. The slight difference observed for the onset of nucleation can be attributed to the different mixing profiles and instrument/reactor geometries and can be considered in the experimental errors range. However, the data generated by the microcalorimeter can be more reliable because the instrument measures the heat generated upon nucleation without any delay while the FBRM starts recording the

Figure 7. Evolution of heat flow for two 0.5 g-scale cooling crystallizations conducted in parallel. 1905



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increase in chord length once the latter reaches the minimal size detectable (i.e., 1 μm). 3.4. Determination of Transient Concentration, Supersaturation, and Mass Deposition Rate. In addition, to determine the onset of nucleation and hence the metastable zone width by microcalorimetry, we were interested in evaluating the applicability of the technique to determine the transient concentration and supersaturation for either cooling or antisolvent crystallization. The method used to determine the transient concentration from the heat flow data is described in section 1. The crystallization procedure initially developed for compound A is an antisolvent crystallization. The compound was first dissolved in ethanol to which water was added as an antisolvent. Several crystallizations were conducted in parallel in the microcalorimeter to evaluate the applicability of this technique to generate supersaturation profiles. 3.4.1. Antisolvent Addition Crystallization. Compound A was dissolved in ethanol at 20 °C in two vials at different concentration. Water was added to the mixture at a rate of 2.5 mL/(h·g), while the heat flow was measured continuously. The two simultaneous crystallizations were repeated with a higher antisolvent addition rate. Figure 9 shows the corrected heat flow recording during a

of solute crystallized and should increase in vials with higher concentrations (and same volume). This trend is reflected in Figure 9. The initial concentration and the antisolvent addition rate were varied, and the variation of concentration during crystallization was determined from the corrected heat flow according to eq 11. To check the validity of the transient concentration obtained from calorimetric measurement, similar small-scale (0.5 g) antisolvent crystallizations were performed under the same conditions using a multiwell rack equipped with magnetic stirrers and temperature control, and concentration was measured during crystallization by NMR. Figure 10a and b shows curves of transient concentration versus solvent composition obtained from calorimetric data and HNMR data, and Figure 11 shows a statistical comparison between concentrations

Figure 11. Comparison between transient concentration obtained from H NMR and microcalorimetry for antisolvent crystallization. obtained from microcalorimetric data and HNMR data for antisolvent crystallizations, which indicates a good agreement between calorimetric and NMR data. As shown in these figures, the use of microcalorimetry provides a good estimate of transient concentrations during small-scale antisolvent crystallizations conducted in parallel. Corresponding variation of supersaturation during four antisolvent crystallizations of A is reported in Figure 12. 3.4.2. Cooling Crystallization. Antisolvent crystallization of compound A affords long needles that are not suitable for

Figure 9. Corrected heat flow during antisolvent crystallization of compound A at two different initial concentrations (AR: antisolvent volumetric addition rate). typical antisolvent crystallization. The area under the curve (AUC) of heat evolved versus time corresponds to the total heat evolved during crystallization. This heat is proportional to the total amount

Figure 10. Transient concentration during antisolvent addition crystallization determined from microcalorimetric data and HNMR analysis at different antisolvent additions rates: (a) Co = 14 wt %, (b) Co = 16.7 wt %. 1906



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Figure 12. Variation of the relative supersaturation during antisolvent crystallization.

Figure 14. Comparison between transient concentration obtained from H NMR and microcalorimetry data for cooling crystallization.

formulation because of poor powder flowability. Hence, there was a need to engineer the crystals to adopt a habit that will lead to better flowability. One option we considered was to investigate the possibility of developing a cooling crystallization that permits temperature cycling. After solvent screening, it was found that crystallization of compound A can be achieved by crystallization from DMF/water 3/2 (w/w) from 75 to 20 °C. Self-nucleation of the material was problematic as it produces a large number of small particles that would require several temperature cycles to reach acceptable sizes and habit. We decided to use microcalorimeter in determining the metastable zone width (MSZW) to select a seeding point for this crystallization. Microcalorimetry data were also utilized to determine the transient concentration for unseeded cooling crystallization. In the case of cooling crystallization, initial concentration and cooling rate were varied, and the variation of concentration during crystallization was determined from the corrected heat flow according to eq 8. Similar to antisolvent crystallization, small-scale crystallizations were also performed using a multiwell rack equipped with magnetic stirrers and temperature control similar to the setup used by the microcalorimeter to determine the variation of concentration by HNMR. Figure 13a and b shows curves of transient concentration versus temperature obtained from calorimetric and HNMR data. For the case of cooling crystallization, the agreement between HNMR and calorimetric is very good as shown in Figure 14, which shows a statistical comparison between the two techniques.

Figure 15. Variation of relative supersaturation during cooling crystallization (extracted from microcalorimetry measurement). Figure 15 shows the variation supersaturation during cooling crystallization. A comparison of Figure 15 with Figure 12 indicates that the level of supersaturation reached for cooling crystallization is much lower than the level reached for antisolvent crystallization. This can

Figure 13. Transient concentration during cooling crystallization determined from microcalorimetric data and HNMR analysis: (a) Co = 6.1 wt %, (b) Co = 6.8 wt %. 1907



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Figure 16. Microscope images of crystals obtained of compound A: (a) antisolvent crystallization, (b) cooling crystallization.

Figure 17. Variation of the mass deposition rate with supersaturation. case of antisolvent crystallization since it is conducted at 20 °C. If crystallization is proven to be crystal growth-dominated, mass deposition rate is proportional to crystal growth for acicular crystals (cf., section 2.2), and mass deposition rate data can be useful in identifying crystal growth mechanisms. However, for the case study presented in this Article, no clear evidence for a growth-dominated crystallization could be identified, and hence no conclusion related to crystal growth mechanism can be drawn from the data in Figure 17.

lead to lower level of nucleation and larger crystal for the case of cooling crystallization as nucleation importance is expected to be lower for lower supersaturations. Microscope images indeed showed that crystals obtained using cooling crystallization were indeed much larger and less elongated than crystallization obtained by antisolvent addition crystallization (cf., Figure 16). A comparison of Figure 15 with Figure 12 indicates that the level of supersaturation reached for cooling crystallization is much lower than the level reached for antisolvent crystallization. This can lead to lower level of nucleation and larger crystal for the case of cooling crystallization as nucleation importance is expected to be lower for lower supersaturations. Microscope images indeed showed that crystals obtained using cooling crystallization were indeed much larger and less elongated than crystallization obtained by antisolvent addition crystallization (cf., Figure 16). 3.4.3. Mass Deposition Rates. For both cooling and antisolvent crystallization of compound A, the concentration obtained from microcalorimetry was utilized to determine the mass deposition rate as a function of supersaturation, and the data obtained are reported in Figure 17. This figure indicates that similar mass deposition rates are obtained for both cooling and antisolvent crystallization. However, the corresponding supersaturations are much lower in the case of cooling crystallization. As mentioned above, nucleation occurs at higher supersaturations for the case of antisolvent crystallization. At higher supersaturations, a larger number of nuclei and hence more surface available for growth are usually created. On the other hand, because growth rate phenomenon is an activated process, lower crystal growth rates are expected at lower temperatures. On the basis of the considerations above, the similarity in mass deposition rates obtained for different supersaturations for cooling and antisolvent crystallization can possibly be explained by a larger number of nuclei due to higher supersaturation at nucleation and by a lower crystal growth rate for the

4. CONCLUSION In this Article, applications of a parallel microcalorimetric technique (Omnical Insight RT-10 calorimeter) to the development of solution crystallization processes for early stage compounds are presented. Using a minimal amount of material, this technique proves to be a reliable, user-friendly, and a versatile tool to determine primary nucleation curves for both cooling and antisolvent crystallization. Further, it was demonstrated that microcalorimetry can be utilized to determine the transient concentration and supersaturation for small-scale crystallizations. This application represents a tremendous amount of savings in time and material, particularly significant for early stage compounds when material is scarce and time for process development is limited.

■

APPENDIX A list of literature accounts of enthalpy of fusion and enthalpy of solution for selected organic compounds is shown in Table A1. 1908



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Table A1. Accounts of Heat of Solution and Heat of Fusion from the Literature author(s) Kuramochi at al.43 Kuramochi at al.44

Kuramochi at al.45

Li et al.46 Grant and York47 Tong et al.48 Cammenga and Steppuhn49 MacNab and Joy50 Lloyd et al.51 Hojati and Rohani52 Puppepedi et al.53

substance

solvent

tetrabromobisphenol 4,4′-dibromo diphenyl ether 2,2′,2,2′-tetrabromodiphenylether 2,2′,4,4′,5-pentabromodiphenyl ether 2,2′,4,4′,5,5′-hexabromodiphenyl ether 1,4-dibromobenzene 1,2,4-tribromobenzene 1,2,4,5-tetrabromobenzene hexabromobenzene 1,2,4,5-tetrabromobenzene adipic acid salmeterol SX-1 salmeterol SX-2 gama sorbitol sorbitol hydrate 4-chlorobenzenesulfonic acid paracetamol DL-pseudoephedrine DL-pseudoephedrine

Canotilho et al.54

terfanadine form C

Canotilho et al.55

terfanadine form A2

water water

water

water water water water water water

(25 °C) (30 °C)

water EtOH/water 5/95 w:w EtOH/water 10.2/89.8 w:w EtOH/water 15.3/84.7 w:w EtOH MeOH EtOH MeOH heptane cyclohexane CCl4 1,1,1-tricholoroethane ClH2CCH2Cl triethylamine butyl ether ethyl acetate dimethyl formamide dimethyl sulfoxide benzene toluene mesitylene water MeOH water MeOH water

terfanadine form C Stephensen and Fushs56 Yang et al.57

1-octanol

Bauer-Brandl et al.58

cimetidine A cimetidine D

Burrows et al.59

Schwarz60

harmine harmane norhamine D-mannopyranose 1-methoxy-α-D-mannopyranose α-D-glucopyranose 1-methoxy-α-D-glucopyranose 1-phenoxy-α-D-glucopyranose 1-H-D-glucopyranose 2-H-D-glucopyranose 2-F-D-glucopyranose 3-H-D-glucopyranose 3-F-D-glucopyranose 3-methoxy-α-D-glucopyranose 6-H-D-glucopyranose 6-F-D-glucopyranose

water

1909

100 ΔHsolv/ ΔHfus

ΔHsol

ΔHfus ΔHdesolv

29.1 40.5 17.3 30.6 38.6 26.2 31.9 41.3 45.6 41.3 33.19 32.29 27.73 17.36 26.27 22.2 24.18

24.1 19.6 32.2 27.5 30.2 18.6 17.9 24.4 24.6 24.4 33.91 68.29 42.02 31.36 30.79 10.6 28.1

5 20.9 14.9 3.1 8.4 7.6 14 16.9 21 16.9 0.72 36 14.29 14 4.52 11.6 3.76

20.75 106.63 46.27 11.27 27.81 40.86 78.21 69.26 85.37 69.26 2.12 52.72 34.01 44.64 14.68 52.25 13.38

10.9 13 22.18 23.82 24.62 20.2 16.5 21.1 19.8 23.37 23.78 19.9 17.72 18.81 5.06 8.11 11.29 7.23 10.7 18.18 16.8 16.93 31.7 24 32.3 25.2 11.9 25.5 18.5 19.6 56.3 30.7 32.1 53.5 20 18.9 27.1 28.7 18.1 31 13.7 28.5

7.83 7.83 53.2 53.2 53.2 50.7 50.7 53.2 53.2 23.757

3.07 5.17 31.02 29.38 28.58 30.5 34.2 32.1 33.4 0.33 0.08 3.8 5.98 4.89 18.64 15.59 12.41 16.47 13 5.52 6.9 6.77 8 15.7 8.7 15.8 36.9 1.7 7 5.1 11.6 3.6 5.5 14.5 7.4 15.6 11.1 3.9 0.2 10.3 9 1.3

28.17 39.77 58.31 55.23 53.72 60.16 67.46 60.34 62.78 1.41 0.36 16.05 25.22 20.63 78.65 65.78 52.38 69.49 54.85 23.28 29.1 28.57 20.15 39.55 21.22 38.54 75.61 6.25 27.45 20.65 25.95 10.5 14.63 37.18 27.01 45.22 29.06 11.96 1.09 24.94 39.65 4.78

39.7 39.7 41 41 48.8 27.2 25.5 24.7 44.7 34.3 37.6 39 27.4 34.5 38.2 32.6 18.3 41.3 22.7 27.2



Article

Table A1. continued author(s) Zingg et al.61

■

substance

solvent

phenylethylamine mandelate salt S(−),R(−) phenylethylamine mandelate salt R(+),S(+) phenylethylamine mandelate salt S(−),S(+) phenylethylamine mandelate salt R(+),R(−) ephedrine mandelate salt (1S,2R)(+), S(+) ephedrine mandelate salt (1R,2S)(−), R(−) ephedrine mandelate salt (1S,2R)(+), R(−) ephedrine mandelate salt (1R,2S)(−), S(+) pseudoephedrine mandelate salt (1S,2S)(+), S(+) pseudoephedrine mandelate salt (1R,2R)(−), R(−) pseudoephedrine mandelate salt (1S,2S)(+), R(−) pseudoephedrine mandelate salt (1R,2R)(−), S(+)

dimethyl sulfoxide

AUTHOR INFORMATION

ΔHsol

ΔHfus ΔHdesolv

100 ΔHsolv/ ΔHfus

7.19 7.21 8.74 8.86 9.5 9.51 6.49 6.54 5.89

6.1 6.38 11.1 11.4 12.5 12.3 6.71 6.52 5.87

1.09 0.83 2.36 2.54 3 2.79 0.22 0.02 0.02

17.87 13.01 21.26 22.28 24 22.68 3.28 0.31 0.34

5.78

5.77

0.01

0.17

7.29

4.01

3.28

81.8

7.15

3.57

3.58

100.28

Vo = initial volume (in the case of antisolvent crystallization) (m3)

Corresponding Author

*E-mail: [email protected].

Greek Letters

α = proportionality constant (eq 2) (−) σ = standard deviation (%) ρ = specific density (kg/m3) Φ = constant (eq 4) (−)

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We are very grateful to Prof. G. Fevotte for valuable technical discussions and to Dr. C. Lai and Dr. Q. Gao for constructive comments. The Senior Leadership Team at Bristol-Myers Squibb Co. is also kindly acknowledged for providing means and incentives that made this study possible.

Subscripts

■

NOMENCLATURE a = characteristic length of face at extremity of needle-shaped crystal (m) AR = antisolvent volumetric addition rate per unit mass solute dissolved initially for the case of antisolvent addition crystallization (mL/(h·g)) C = concentration (kg/m3) Co = initial concentration (prior to crystallization) (kg/m3) Cp = specific heat capacity (J/(g·K)) CR = cooling rate for the case of cooling crystallization (°C/h) E = relative error (%) Err = error induced by neglecting ΔHdesolv (eq 10) (%) G = growth rate (m/s) ΔHcryst = specific enthalpy of crystallization (J/g) ΔHdesolv = specific enthalpy of desolvation (J/g) ΔHmixing = specific enthalpy of mixing of the antisolvent with the solvent (J/g) ΔHloss = heat lost (J) L = length of lateral face of needle-shaped crystal (m) m = mass (kg) mo = mass of solute dissolved prior to crystallization (kg) ṁ = mass deposition rate (g/(g·s)) N = total number of crystals (−) Q̇ = heat flux evolved (W) Q = heat evolved (J) SR = stirring rate (min−1) t = time (s) T = temperature (K, °C) V = volume (m3)

■

AS = related to the antisolvent cryst = related to crystals exp = related to experiment final = related to the end of crystallization dissolv = related to dissolved solute max = maximum value min = minimum value

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An Investigation of the Applicability of Microcalorimetry for the

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