DOI: 10.1021/cg900567z
Measuring Enthalpy of Sublimation for Active Pharmaceutical Ingredients: Validate Crystal Energy and Predict Crystal Habit
2009, Vol. 9 4706–4709
Pascal Taulelle,† Georges Sitja,† Gerard Pepe,† Eric Garcia,‡ Christian Hoff,‡ and Stephane Veesler*,† †
Centre Interdisciplinaire de Nanoscience de Marseille CNRS, Aix-Marseille Universit e, CINAM-UPR3118, Campus de Luminy, Case 913, 13288 Marseille cedex 09, France, and ‡ Sanofi-Aventis chimie, F-30390 Aramon, France Received May 27, 2009; Revised Manuscript Received September 29, 2009
ABSTRACT: Determining a reliable lattice energy is vital in the attachment energy approach for crystal habit prediction. In this paper, we present an experimental validation of the energies calculated with the software GENMOL by an indirect determination of the enthalpy of sublimation using the Knudsen effusion method. 1. Introduction Crystal habit determines most physical properties of crystallized materials: their behavior under downstream processes (filtering, washing, drying...) and during storage and handling. In pharmaceutical crystallization, the complexity of molecules to be crystallized and the need for good productivity often lead to the use of solvent mixtures in the crystallization process. The solute is dissolved in a good solvent and precipitated-out by adding antisolvent. This process leading to high supersaturation and low solubility often yields undesirable needle-like crystals. Improving crystal-habit means changing it to a more isotropic shape, which is performed by modifying the crystallization conditions, thus by experimental study of the respective influence of temperature, supersaturation, medium (chemical conditions), and hydrodynamics. The most commonly used means of crystal habit modification are additives.1 An alternative approach is molecular modeling, the idea being, first, to predict the crystal habit in a pure solvent and, second, to test, numerically, the effect of additives as habit modifiers; this approach has been described by many research teams.2-4 For this first step, study and prediction of crystal-habit, knowledge of the nature and the value of the interaction energies between a molecule and its neighbors in the crystal is required. These interaction energies are calculated from the crystal structure and interaction potentials. Here, we used crystalline phases of an active pharmaceutical ingredient (API), irbesartan, to experimentally determine the enthalpy of sublimation using the Knudsen effusion method. When compared with the crystal energy determined from molecular modeling, our results validate the energetic model used to predict crystal habit. 2. Experimental Section
b = 12.18 A˚, c = 9.37 A˚, R = 90.75°, β = 105.24° and γ = 112.92°6) (Figure 1c,d), resulting in a rare phenomenon, desmotropy.6 The crystals were observed under a scanning electron microscope (SEM) JEOL 6320F. The SEM photographs clearly show the needle-like crystals of irbesartan phase A (Figure 1b) and the tabular habit of irbesartan phase B (Figure 1d). 2.2. Molecular Modeling. For molecular modeling, the molecules were treated as rigid bodies in all calculations. The software used, GenMol, based on molecular mechanics, has its own empirical force field and uses the Dell Re method for atomic charge calculation. Crystal morphology is determined for crystal grown from vaccuo using the Bravais Friedel Donnay and Harker (BFDH) theory7 and attachment energy,8 as described previously.9 The BFDH approach is based on geometrical considerations, assuming that the linear growth rate of the face is inversely proportional to the interplanar distance. The attachment energy approach takes into account the intermolecular interactions energy, which is defined as the energy released per molecule when a slice of thickness dhkl is deposited onto the face (hkl).10 2.3. Enthalpy of Sublimation. In order to measure enthalpy of sublimation, two methods are commonly used. The direct method consists of measuring the enthalpy released during sublimation using a calorimeter with a Knudsen effusion cell.11 The indirect method, used in this work, is described below. We chose the indirect method due to degradation of irbesartan at T > 463 K observed by differential scanning calorimetry and the observation of a vapormediated phase transformation of irbesartan phase A in irbesartan phase B. Sublimation experiments were carried out using the Knudsen effusion method. In a typical experiment, the crystalline sample is placed at the bottom of a cylindrical cell kept at a constant temperature and the vapor is allowed to effuse through a small circular orifice located at the top of the cell into an ultrahigh vacuum chamber (Figure 2). The vapor is assumed to be at equilibrium with the solid. At temperature T, measuring the mass of the sample sublimed from the effusion cell in function of time, that is to say the flow at equilibrium φeq, gives the equilibrium vapor pressure according to the Knudsen equation: 1 2πRT 1=2 Peq ¼ o φeq ð1Þ A M
2.1. Materials. Irbesartan is an API used in the treatment of hypertension. This compound is an organic molecule (C25H28N6O) with a proton monosubstituted on the tetrazole ring leading to a proton transfer process called prototropic tautomerism. The two tautomers present in the liquid state can be isolated in the solid state as crystals of phase A (trigonal R3, a=b=37.09 A˚, c=9.65 A˚, R= β=90° and γ=120°5) (Figure 1a,b) and B (triclinic P1, a=11.17 A˚,
where A° is the area of the effusion orifice, R is the gas constant, and M is the molar mass. The equilibrium pressure between a vapor and its infinite crystal phase is related to the enthalpy of evaporation ΔHevap by the following equation:12
*To whom correspondence should be addressed. Phone: 336 6292 2866. Fax: 334 9141 8916. E-mail:
[email protected].
ΔHevap Peq ¼ ð2πMÞ3=2 ðkTÞ -1=2 ν3 exp kT
pubs.acs.org/crystal
Published on Web 10/15/2009
ð2Þ
r 2009 American Chemical Society
Article
Crystal Growth & Design, Vol. 9, No. 11, 2009
4707
Figure 1. (a) Tridimensional representation of irbesartan tautomer A from the crystallographic structure of phase A, (b) irbesartan phase A grown from 2-propanol solution observed by SEM, (c) tridimensional representation of irbesartan tautomer B from the crystallographic structure of phase B, and (d) irbesartan phase B grown from ethanol/water solution (80/20% weight) observed by SEM.
Figure 2. (a) Schematic side view, (b) top view of the effusion cell, and (c) UHV chamber. (1) 20 mm-diameter brass-lid with a central hole of 1 mm, (2) closed cell of diameter 20 mm and height 50 mm, (3) cylindrical effusion cell in brass, (4) heater covered with aluminum, and (5) thermocouple. At T < Tm, evaporation is replaced by sublimation, with Tm the melting temperature: ΔHsub Peq ¼ ð2πMÞ3=2 ðkTÞ -1=2 ν3 exp ð3Þ kT And by merging eqs 1 and 3, we obtain: ΔHsub φeq ¼ A exp kT
ð4Þ
A is a factor containing the pre-exponential term in eq 3 and the geometry of the effusion orifice in eq 1. The experimental sublimation enthalpy is related to the calculated lattice energy (Ecr) by the following equation:13 Ecr ¼ -ΔHsub - 2RT ð5Þ The homemade experimental setup developed to measure the sublimation enthalpy is presented in Figure 2. In practice, the sample (a few grams) is added to the cell and the cell is closed and inserted into the UHV chamber at a pressure of about 10-7 torr. The cell is heated to the desired temperature ((0.1 °C) allowing sample sublimation. The flow of the sample sublimed from the effusion cell is measured by a quartz microbalance (INFICON XTM/2) thermostatted at 10 °C. The quartz balance is the cold point where molecules are condensed.
3. Results and Discussion 3.1. Molecular Modeling. In our previous studies,14,15 experimental investigations of growth mechanisms of needlelike crystals were conducted, attachment energies were computed, and crystal habits were deduced (Figure 3). Here, we present (Tables 1 and 2) the attachment energy obtained with GENMOL and the interplanar distance required for the BFDH approach in the case of a crystal of irbesartan phase A and B, respectively. The calculated lattice energies are presented (Table 3) using a cutoff radius of 29 A˚. The
Figure 3. Predicted irbesartan phase A crystal habit by (a) BFDH and (b) attachment energy method, (c) is a zoom of (b). Table 1. dhkl and Eatt of Irbesartan Phase A hkl family {110} {010} {100} {110} {011} {001} {111} {101}
dhkl (A˚)
Eatt (kJ/mol)
32.12 32.12 32.12 18.54 9.24 9.65 8.56 9.24
-0.84 -1.17 -1.55 -35.79 -48.89 -63.12 -63.12 -71.96
experimental habit of irbesartan phase A (Figure 4) is perfectly predicted by the attachment energy approach, whereas the BFDH approach fails. On the other hand, for irbesartan phase B the agreement is poor between theoretical
4708
Crystal Growth & Design, Vol. 9, No. 11, 2009
Taulelle et al.
Table 2. dhkl, Eatt and Experimental Habit of Irbesartan Phase B hkl family {010} {110} {100} {011} {111} {001} {101} a
dhkl (A˚)
Eatt (kJ/mol)
11.12 9.55 9.84 6.98 7.71 8.96 7.86
-41.19 -59.78 -63.38 -68.32 -75.05 -75.47 -106.20
experimental (Figure 5) X X Xa X
The biggest face.
Table 3. Enthalpies of Sublimation and Calculated Lattice Energies (kJ/mol) crystal
ΔHsub
adipic acid 124.7 ( 20 irbesartan 197.2 ( 20 phase A irbesartan 254.5 ( 20 phase B
Ecr (calculated) Ecr = -ΔHsub - 2RT Ecr (calculated) - Ecr -222.3
-238.6
7%
-279.6
-302.6
8%
Figure 4. Crystal of irbesartan phase A grown from 2-propanol solution observed by (a) optical microscopy and (b) by SEM.
and experimental habits. Theoretical habits, calculated in a vacuum, are isometric; this is not the case in solution where the {001} form is the dominant (Figures 1d and 5 and Table 2). One reason16 for discrepancies between predicted and experimental habits is preferential adsorption of solvent (ethanol-water mixture) on the (001) face. The attachment energy model is able to take into account the solvent effect when predicting crystal habit.10 The attachment energy value is corrected from solvent adsorption energy on the considered face. The higher the adsorption energy value, the lower the growing rate. For ibesartan phase A, the solvent (2-propanol) adsorption energy values are equivalent on the limiting faces of the needle, (011) and (010). Therefore, solvent has no influence on the crystal habit of irbesartan phase A,17 while preferential adsorption of solvent (ethanol-water mixture) on the (001) face of irbesartan phase B explains the difference between the crystal habit predicted in a vacuum and the observed crystal habit. 3.2. Enthalpy of Sublimation. To validate the homemade experimental setup we developed, a Knudsen effusion cell, a first set of experiments was conducted on adipic acid for which data are available in the literature. Results are presented in Figure 6a according to eq 4; experiments were conducted for pressures between 3 10-5 and 5 10-5 torr and at temperatures between 353 and 373 K. We obtain ΔHsub = 124.7 kJ/mol, a value in very good agreement with the 129.3 kJ/mol tabulated by Pedley et al.18 For irbesartan phase A, since a first experiment at P=1 10-7 torr and 423 K produced a brown amorphous solid, the flow of irbesartan phase A and B sublimated were measured at temperatures between 403 and 421 K. Experimental
Figure 5. (a) Crystal of irbesartan phase B grown from ethanol/water solution (80/20% weight) and (b) its indexation.
Figure 6. Measured flow of sample sublimated: (a) adipic acid and (b) irbesartan phase A and B; lines are exponential curve fit.
Article
Crystal Growth & Design, Vol. 9, No. 11, 2009
results are plotted in Figure 6b, and in Table 3 enthalpies of sublimation and calculated lattice energies are compared. The error between measured and calculated lattice energies is 7% and 8% for irbesartan phase A and B, respectively. These results clearly confirm the validity of the lattice energy calculated using GENMOL and its empirical force field. Moreover, from the lattice energy we can confirm that phase B is the stable phase. 4. Conclusion Here the attachment energy approach succeeded in predicting the crystal habit of irbesartan phase A. Clearly, while the high anisotropy of a crystal structure explains its needle-like habit, this cannot be predicted by a pure crystallographic method such as the BFDH approach. A reliable lattice energy, therefore, needs to be determined in order to use the attachment energy approach. The results presented in this paper constitute an experimental validation of the energies calculated with the software GENMOL by an indirect determination of the enthalpy of sublimation. Acknowledgment. The authors are indebted to SANOFIAVENTIS for financial support and to M. Sweetko for English revision.
References (1) Weissbuch, I.; Leiserowitz, L.; Lahav, M. Tailor-Made Additives and impurities. In Crystallization Technology Handbook; Mersmann, A., Ed.; Marcel Dekker: New York, 1995; pp 401.
4709
(2) Winn, D.; Doherty, M. F. AIChE J. 1998, 44, 2501. (3) Cuppen, H. M.; Van Eerd, A. R. T.; Meekes, H. Cryst. Growth Des. 2004, 4, 989. (4) Lin, C. H.; Gabas, N.; Canselier, J. P.; Pepe, G. J. Cryst. Growth 1998, 191, 791. (5) Garcia, E. Etude de la dissolution et de la croissance de principe actifs. PhD, Universite Paul Cezanne Aix-Marseille III: Aix en Provence, France, 2000. (6) Bocskei, Z.; Simon, K.; Rao, R.; Caron, A.; Rodger, C. A.; Bauer, M. Acta Crystallogr. Sect. C 1998, 54, 808. (7) Donnay, J. D. H.; Harker, D. Am. Mineral. 1937, 22, 446. (8) Hartman, P.; Perdock, W. G. Acta Crystallogr. 1955, 8, 49. (9) Benazet, S.; Jacob, G.; Pepe, G. Propellants, Explosives, Pyrotechnics 2003, 28, 287. (10) Hartman, P.; Bennema, P. J. Cryst. Growth 1980, 49, 145. (11) Pfefer, G.; Sabbah, R.; Boistelle, R. J. Appl. Crystallogr. 1997, 30, 527. (12) Aquilano D.; Sgualdino G. Fundamental aspects of equilibrium and crystallization kinetics. In Crystallization Processes in Fats and Lipid Systems; Garti N., Sato K., Eds.; Marcel Dekker, Inc.: New York, 2001; pp 1. (13) Lifson, S.; Hagler, A. T.; Dauber, P. J. Am. Chem. Soc. 1979, 101, 5111. (14) Taulelle, P.; Astier, J. P.; Hoff, C.; Pepe, G.; Veesler, S. Chem. Eng. Technol. 2006, 29, 239. (15) Puel, F.; Verdurand, E.; Taulelle, P.; Bebon, C.; Colson, D.; Klein, J.-P.; Veesler, S. J. Cryst. Growth 2008, 310, 110. (16) Pfefer, G.; Boistelle, R. Trans IChemE 1996, 74, 744. (17) Taulelle P. Etude de l’influence d’ajout d’additifs lors de la cristallisation de molecules pharmaceutiques. PhD, Universite Paul Cezanne Aix-Marseille III: Aix en Provence, France, 2007. (18) Pedley J. B.; Naylor R. D.; Kirby S. P. Thermochemical Data of Organic Compounds; Hall, C. A., Ed.; Methuen Inc.: New York, 1986.
