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Organic Process Research & Development 2003, 7, 983−989
Phase Transitions in Supersaturated Drug Solution
Ste´phane Veesler,*,‡ Laurent Lafferre re,‡ Eric Garcia,§ and Christian Hoff Centre de Recherche sur les Me´canismes de la Croissance Cristalline, CRMC2† - CNRS, Campus de Luminy,Case 913, F-13288 Marseille Cedex 09, France, Sanofi-Synthe´labo Recherche, F-78440 PorcheVille, France, andSanofi-Synthe´labo Chimie, F-30390 Aramon, France which have possible consequences on the processing, the In this contribution we present two cases of phase transitions,
physicochemical stability of the active substance alone and in which the ability to control the reproducible formation of
in its formulations, and on the bioavailability of the the desired physical form requires a control of crystallization
considered pharmaceutical compound. An example, in 1998, parameters and a deep understanding of the phase diagram.
was Abbott's ritonavir, marketed for AIDS treatment asNorvir, which developed problems with appearance of the The different stages of the solution-mediated phase new less soluble, stable form which had different physico- transition, i.e., dissolution of the metastable phase and chemical properties with respect to the form registered with nucleation and growth of the stable phase, were studied for the U.S.Food and Drug Administration.5 irbesartan, a pharmaceutical compound. The influence of The complexity of the molecules to be crystallized and crystal sizes and habits and of additive on the kinetics of the necessity of good productivity often lead to the use of a dissolution and growth has been shown.
solvent mixture in the crystallization process, which causes The second case of phase transition describes a liquid- a rather complicated crystallization medium, at least a ternary liquid phase separation which is metastable with respect to system, mixture of two solvents and a solute. A better the crystallization of the two polymorphs FI and FII of understanding of the crystallization process is essential to C35H41Cl2N3O2 in an ethanol/water mixture. Thermodynamic control nucleation and growth, and thus the phase, quality, stability of the phases toward each other with temperature and size of crystals. With that aim, it becomes clear that the and the impact of the liquid-liquid phase separation on important stage is the determination of the phase diagram.
crystallization have been investigated. Our results show thata deep control of the crystallization parameters and the In the phase diagram there is a region where two coexisting understanding of the phase diagram lead to the achievement liquids can be observed, which corresponds to a miscibility of the desired polymorph, in a reproducible manner. More- gap in the phase diagram. This liquid-liquid phase separation over, the dilute solution studied was shown to be nonideal (LLPS), or demixing, may have an impact on the crystal- since it was correlated with the existence of the metastable lization process. If the LLPS appears in the metastable zone liquid-liquid demixing which was observed and character- for crystallization, a competition between the LLPS and the ized. In our experiments the liquid-liquid phase transition crystal formation might occur, crystallization might thus be prevented the drug from crystallizing, while it changed the hindered or accelerated. Recent works6-9 suggest that a medium and the conditions of crystallization, which conse- metastable LLPS can affect nucleation. Nucleation was thus quently affected the process.
expected to be different above and below the coexistence orbinodal curve. Experimental results and simulation calcula- tions seem to indicate that nucleation is enhanced in the Many industries, such as food, agrochemicals, and vicinity of this curve.7,10-12 LLPS is known in colloid physics pharmaceuticals, are frequently confronted with the presenceof multiple crystal polymorphs.1-4 Indeed, polymorphism (5) Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris means different physicochemical properties of the solid, J. RITONAVIR: An Extraordinary Example of Conformational Polymor-
phism. Pharm. Res. 2001, 18, 859-866.
(6) Muschol, M.; Rosenberger, F. Liquid-liquid phase separation in supersatu- * Corresponding author. E-mail: veesler@crmc2.univ-mrs.fr. Telephone: 336 rated lysozyme solutions: coupling to precipitate formation and crystalliza- 6292 2866. Fax: 334 9141 8916.
tion. J. Chem. Phys. 1997, 107, 1953-1961.
‡ Centre de Recherche sur les Me´canismes de la Croissance Cristalline, (7) Haas, C.; Drenth, J. Understanding protein crystallization on the basis of CRMC2 - CNRS, Campus de Luminy.
the phase diagram. J. Cryst. Growth 1999, 196, 388-394.
§ Sanofi-Synthe´labo Recherche.
(8) Bonnett, P. E.; Carpenter, K. J.; Dawson, S.; Davey, R. J. Solution Sanofi-Synthe´labo Chimie.
crystallisation via a submerged liquid-liquid phase boundary: oiling out.
† Laboratory associated with the Universities Aix-Marseille II and III.
Chem. Commun. 2003 698-699.
(1) Giron, D. Thermal analysis and calorimetric methods in the characterisation (9) Lafferrere, L.; Hoff, C.; Veesler, S. Polymorphism and liquid-liquid demixing of polymorphs and solvates. Thermochim. Acta 1995, 248, 1-59.
in supersaturated drug solution. Eng. Life Sci. 2003, 3, 127-131.
(2) Garcia, E.; Hoff, C.; Veesler, S. Dissolution and phase transition of (10) Wolde, P. R.; Frenkel, D. Enhancement of protein crystal nucleation by pharmaceutical compounds. J. Cryst. Growth 2002, 237-239, 2233-2239.
critical density fluctuations. Science 1997, 277, 1975-1978.
(3) Sato, K. Polymorphic transformations in crystal growth. J. Phys. D: Appl. (11) Galkin, O.; Vekilov, P. G. Control of protein crystal nucleation around the Phys. 1993, 26, B77-B84.
metastable liquid-liquid phase boundary. Proc. Natl. Acad. Sci. U.S.A. 2000,
(4) Matsuoka, M.; Yamanobe, M.; Tezuka, N.; Takiyama, H.; Ishii, H.
Polymorphism, morphologies and bulk densities of DL-methionine agglomer- (12) Anderson, V. J.; Lekkerkerker, H. N. W. Insights into phase transition ate crystals. J. Cryst. Growth 1999, 198/199, 1299-1306.
kinetics from colloid science. Nature 2002, 416, 811-815.
10.1021/op034089f CCC: $25.00 2003 American Chemical Society Vol. 7, No. 6, 2003 / Organic Process Research & Development Published on Web 11/21/2003 and in the protein area as a gas-fluid13,14 and a fluid-fluidtransitions6,15-17 respectively.
In this contribution we present two cases of phase transitions, in which the ability to control the reproducibleformation of the desired physical form requires a control ofcrystallization parameters and a deep understanding of thephase diagram.
The first case is the study of dissolution and pseudopoly- morphic transition of irbesartan, where the effects of crystalsizes and habits and of additive are discussed. The secondcase describes a LLPS which is metastable with respect tothe crystallization of the two polymorphs of a drug.
2. Materials and Methods
2.1. Materials. The pharmaceutical compounds studied
are organic molecules with the following basic formula:C25H28N6O (irbesartan) and C35H41Cl2N3O2. The first com-pound is used in the treatment of hypertension and presentsa solution-mediated phase transition (SMPT) of phase A intophase B in water. Phase A is trigonal (R3 h),18 whereas B is triclinic (P1 h),19 this compound is an organic molecule with an unsaturated N cycle and the transformation of A into Bis a tautomeric transformation in liquid state isolated in solid Figure 1. (a) Tautomeric transformation of irbesartan form
state, called a desmotropy (Figure 1). The second compound A into form B from crystallographic data. (b) Structure of
C

crystallizes two polymorphs, F I and FII, but the transformation of FI into FII had not been observed thus far. FI is monoclinic, prevent the solution from rotating in the crystallizer. Solution whereas FII is orthorhombic. The crystallization process stirring is ensured by a stainless steel stirrer equipped with imposes the solvent: an ethanol/water mixture (54.2/45.8% a mixel TT propeller type at a stirring rate of 300 rpm. Both weight). Note that solubility of the polymorphs is high in are covered with halar(ECTFE) coating to avoid chemical ethanol but very low in water.
interactions with the stirrer. At the beginning of the dissolu- 2.2. Solid Characterization. The crystals were observed
tion experiment, crystal seeds of irbesatan form A were under a scanning electron microscope (SEM) JEOL 6320F.
poured into the crystallizer previously filled with pure water.
The SEM photographs clearly show differences in the crystal To determine the concentration as a function of time we habits of irbesartan form A and B, Figure 2, a and b, measured the conductivity variation of the solution. Metrohm respectively. Figure 2c shows platelet crystals, and Figure 660 conductimeter (Metrohm Herisau, Switzerland) with an 2d shows needle habits of polymorphs FI and FII, respec- open geometry measurement cell (constant cell of 0.57 cm-1) tively, of C35H41Cl2N3O2. In this study all the solid phases was used. If not specified in the text, the dissolution were characterized by X-ray diffraction INEL CPS 120.
experiments were carried out with the crystal seeds presented 2.3. Phase Diagram and Transformation. Dissolution
in Figure 2a.
and water-mediated desmotropy of irbesartan were performed The technique used to determine the solubility of the stable in a batch crystallizer of 0.8 L at constant temperature widely as well as the metastable polymorphs of C35H41Cl2N3O2 ver- described in a previous work.20 This crystallizer is a double- sus temperature was the bracketing technique.21,22 This jacketed glass vessel equipped with three wall baffles to technique consists of observing the growth or the dissolutionof small single crystals seeded in solutions at known concen- (13) Noro, M. G.; Kern, N.; Frenkel, D. The role of long-range forces in the trations, under optical microscope (Nikon, Diaphot), at given phase behavior of colloids and proteins. Europhys. Lett. 1999, 48, 332-
338.
temperatures. Using the experimental setup previously de- (14) Cahn, J. W.; Hilliard, J. E. Free energy of a nonuniform system. III.
scribed23 (Figure 3), the temperature in the solution is moni- Nucleation in a two-component incompressible fluid. J. Phys. Chem. Phys.
1959, 31, 688-699.
tored by Peltier effect ((0.1 °C), and the crystal temperature (15) Ishimoto, C.; Tanaka, T. Critical behavior of a binary mixture of protein equilibrium is measured. When we measure the solubility of and salt water. Phys. ReV. Lett. 1977, 39, 474-477.
(16) Thomson, J. A.; Schurtenberger, P.; Thurston, G. M.; Benedek, G. B. Binary the metastable polymorph, the stable form does not sponta- liquid phase separation, critical phenomena in a protein/water solution. Proc. neously nucleate; thus, the concentration within the solution Natl. Acad. Sci. U.S.A. 1987, 84, 7079-7083.
(17) Grouazel, S.; Perez, J.; Astier, J.-P. Bonnete´ F.; Veesler, S. BPTI liquid- liquid phase separation monitored by light and small-angle X-ray scattering.
(21) Beckmann, W. Seeding the desired polymorph: background, possibilities, Acta Crystallogr. 2002, D58, 1560-1563.
limitations, and case studies. Org. Process Res. DeV. 2000, 4, 372-383.
(18) Garcia, E. 148 (Aix-Marseille III, Marseille, 2000).
(22) Beckmann, W.; Boistelle, R.; Sato, K. Solubility of the A, B and C (19) Bocskei, Z.; Simon, K.; Rao, R.; Caron, A.; Rodger, C. A.; Bauer, M.
polymorphs of stearic acid in decane, methanol, butanone. J. Chem. Eng. Irbesartan Crystal Form B. Acta Crystallogr., Sect. C 1998, 54, 808-810.
Data 1984, 29, 211-214.
(20) Garcia, E.; Veesler, S.; Boistelle, R.; Hoff, C. Crystallization and dissolution (23) Boistelle, R.; Astier, J. P.; Marchis-Mouren, G.; Desseaux, V.; Haser, R.
of pharmaceutical compounds an experimental approach. J. Cryst. Growth Solubility, phase transition, kinetic ripening and growth rates of porcine 1999, 198/199, 1360-1364.
pancreatic R-amylase isoenzymes. J. Cryst. Growth 1992, 123, 109-120.
Vol. 7, No. 6, 2003 / Organic Process Research & Development Figure 2. SEM photographs of irbesartan form A (a) and form B (b), and polymorphs of C35H41Cl2N3O2, FI platelet (c) and FII
needle (d) habits.

Figure 4. Variation of concentration versus time due to the
solution-mediated phase transition of form A into form B for a
mass concentration of 50 mg
L-1 at 40 °C in pure water.
scattered at 90° to the temperature for which I-1 reacheszero.16 In this work we present the isoplethe section of theternary phase diagram.
3. Results and Discussion
Figure 3. Quiescent thermostated cell by Peltier effect placed
3.1. Dissolution and Desmotropic Transition of Irbe-
under a microscope equipped with a camera.
sartan. Here is presented a laboratory study of the SMPT
of irbesartan. Mechanisms and effects of some crystallization
remains constant throughout the experiment. The temperature parameters are discussed.
range for the solubility measurements was 10-57 °C.
3.1.1. Dissolution and Desmotropic Transition of Irbe-
This setup was also used to observe and to characterize sartan in Pure Water. Figure 4 shows the variation of
the liquid-liquid demixing. The coexistence curve for the concentration versus time due to the SMPT of form A into liquid phases, also called the TL-L boundary (L-L for form B, for an initial solid concentration of 50 mg‚L-1 at liquid-liquid), was determined through light-scattering 40 °C in pure water. As shown in a previous report2 the intensity measurements. To determine the spinodal temper- different stages observed in Figure 4 correspond to the ature of each solution used, we extrapolated the temperature dissolution of form A (increase in the concentration). When dependence of the reciprocal intensity, I-1, of the light the apparent solubility of the metastable form A is reached, Vol. 7, No. 6, 2003 / Organic Process Research & Development Figure 5. Variation of concentration versus time for acicular
and tabular crystal habit of irbesartan form A for a mass
concentration of 100 mg
L-1 at 40 °C in pure water.
the dissolution of form A strictly compensates form Bnucleation and growth (presence of a plateau at 11 mg‚L-1corresponding to the apparent solubility of form A at 40 °C).
Then dissolution of form A cannot compensate anymore forthe growth of form B, the concentration decreases until itreaches form B solubility (5 mg‚L-1 at 40 °C). It isnoteworthy that this behaviour is characteristic of SMPT,for instance the setting of plaster, gypsum or CaSO ‚ which is obtained by a SMPT of CaSO ‚ 4 0.5H2O, presents the same transformation curve.24,25 Figure 6. (a) Experimental morphology obtained for crystals
When mass concentration of form A increases from 50 of irbesartan form A grown in water, (b) scheme of the
to 100 mg‚L-1, the length of the plateau increases, and the experimental morphology, and (c) packing arrangement of
total time of the transformation increases from 280 to 405 irbesartan molecules viewed along the c-axis.
min (Figures 4 and 5). These results correspond to the fact Because of this lower dissolution rate, the plateau has a lower that when mass concentration of form A increases, the value. In that case, the diminution of both dissolution rate amount of form A available to compensate the diminution and plateau concentration values reveals a dissolution- of the concentration in solution due to the growth of form B controlled process.26 is greater; therefore, the plateau is much longer.
The use of additives to control SMPT is very promising, Another interesting point is that the overall kinetics of and many reports deal with such an approach.27-30 By using the SMPT is controlled either by the dissolution kinetics of the concept of "tailor-made" additives, molecules can be the metastable form or by the growth kinetics of the stable selected from examination of crystal structure and indexation form or by both. The process which kinetically controls the of the experimental morphology of irbesartan form A (Figure SMPT can be determined26 from the shape of the transfor- 6).2 Two forms have to be considered, the {100} lateral faces mation curve, Figure 4 in our example. The SMPT of form and the {111} terminal faces of the needle. The weak A into form B is controlled by the growth of the form B at solubility of crystals of irbesartan form A in water (about 40 °C in water (Figure 4).
11 mg‚L-1 at 40 °C) and their aggregation in water are due 3.1.2. Influence of the Crystal Habits and of Additive
to the hydrophobic nature of the {100} form. These results, on the Dissolution and Desmotropic Transition of Irbe-
together with a previous work31 in which we evidenced that sartan. As the SMPT uses the concept of dissolution,
the first step in the dissolution process of irbesartan form A nucleation, and growth, all the factors usually met in is disaggregation of the powder lead us to use a surfactant, crystallization from solution play a role: solvent, tempera- 50 ppm of dodecylamine chloride (DAC), to accelerate the ture, hydrodynamics, crystal sizes and habits, additives, etc.
dissolution (Figure 7). The dissolution of form A is acceler- Here we show the influence of crystal sizes and habits ated, and the apparent solubility of form A is increased about and of additive on the SMPT of irbesartan. Figure 5 showsthe differences in the overall kinetics of the SMPT of form (27) Staab, E.; Addadi, L.; Leiserowitz, L.; Lahav, M. Control of polymorphism A into form B, when larger tabular crystals are used instead by tailor-made polymeric crystallization auxiliaries. Preferential precipitation
of a metastable polar form for second harmonic generation. AdV. Mat. 1990,
of smaller acicular crystals (Figure 2a). The transition lasts 2, 40-43.
700 min instead of 400 min. This is due to a dissolution (28) Weissbuch, I.; Leiserowitz, L.; Lahav, M. In "Tailor-Made" AdditiVes and Impurities; Mersmann, A., Ed.; Marcel Dekker: New York, 1995.
rate of tabular crystals lower than that of acicular crystals.
(29) Davey, R. J.; Bladgen, N.; Potts, G. D.; Docherty, R. Polymorphism in molecular crystals: stabilization of a metastable form by conformational (24) Amathieu, L.; Boistelle, R. Crystallization kinetics of gypsum from dense mimicry. J. Am. Chem. Soc. 1997, 119, 1767-1772.
suspension of hemihydrate in water. J. Cryst. Growth 1988, 88, 183-192.
(30) Gu, C.; Chatterjee, K.; Young, V., Jr.; Grant, D. J. W. Stabilization of a (25) Badens, E.; Veesler, S.; Boistelle, R. Crystallization of gypsum from metastable polymorph of sulfamerazine by structurally related additives. J. hemihydrate in the presence of additives. J. Cryst. Growth 1999, 196, 704-
Cryst. Growth 2002, 235, 471-481.
(31) Garcia, E.; Gerard, S.; Hoff, C.; Mangin, D.; Klein, J. P.; Veesler, S. In (26) Cardew, P. T.; Davey, R. J. The kinetics of solvent-mediated phase 15th International Symposium on Industrial Crystallization; Sorrento, Italy, transformation. Proc. R. Soc. London A 1985, 398, 415-428.
2002, pp 1413-1418.
Vol. 7, No. 6, 2003 / Organic Process Research & Development Figure 8. TL-L boundary, spinodal curve, and solubility of
polymorphs FI and FII in mixture ethanol/water (54.2/45.8%
weight).

Figure 7. (a) Variation of concentration versus time due to
the SMPT of form A into form B for a mass concentration of
50 mg
L-1 at 40 °C in pure water and in the presence of 50
ppm of DAC, (a) the whole process and (b) the first stage.

10%. It is also interesting to note that the growth rate ofform B is slowed, and the whole process lasts 1300 min inthe presence of DAC instead of 300 min in pure water. Thesurfactant has a double effect; it accelerates the dissolutionof form A and hinders the growth of form B.
3.2. Polymorphism and Liquid-Liquid Phase Separa-
tion of C35H41Cl2N3O2. The second case studied concerns a
more complicated system, in which two polymorphs have
Figure 9. Solubilities of polymorphs F
been identified. The use of a solvent mixture is at the origin I and FII in mixture
ethanol/water(54.2/45.8% weight) versus the inverse of the
of LLPS or demixing which affects the crystallization absolute temperature. The solid lines are empirical fits to the
process, with sometimes a poor nucleation ability which may be avoided by seeding.21 Thus, in this part we will describe be 52.5 ( 1 °C by graphic determination, this is the reason polymorph selection and influence of LLPS on seeding.
the transformation of F 3.2.1. Isoplethe Section of the Phase Diagram of
I into FII had never been observed previously, since all prior studies were conducted well below C35H41Cl2N3O2. Figure 8 shows the TL-L boundary, spinodal
curve, and solubility of polymorphs F I and FII in ethanol/ The solubility variation with temperature of any solute water mixture (54.2/45.8% weight). The temperature range in any solvent is commonly represented by the van't Hoff corresponds to that used in the industrial crystallization plot32 (Figure 9). In our study, the van't Hoff fit gave a process. This diagram exhibits four regions: one homoge- transition temperature of 62.6 °C. There is a difference of neous region (region I: one liquid) and three two-phase about 10 °C (Figure 9) with respect to the transition regions (region II: one liquid + one solid FI; region III: temperature estimated by graphic determination; this showed one liquid + one solid FII; region IV: two liquids), the two that the van't Hoff plot was clearly inappropriate here.
solid phases correspond to the two polymorphs FI and FII.
According to Grant et al.,33 this nonlinearity of the van't The region IV is divided into two sub-regions by the spinodal Hoff plot is particularly relevant to drugs and other hydro- curve in which the mechanisms to set off demixing are phobic substances in water and in other self-associated different (IV(a) and IV(b)).14 solvents over the temperature range of approximately 0-50 The graph shows that the polymorphs FI and FII make an enantiotropic system with a crossover temperature of transi- (32) Van't Hoff, J. H. L'e´quilibre chimique dans les syste mes gazeux ou dissous tion noted T a l'e´tat dilue´. Nature 1886, 20, 239-302.
p. Under this temperature the polymorph FI is thermodynamically stable, but above T (33) Grant, D. J. W.; Mehdizadeh, M.; Chow, A. H.-L.; Fairbrother, J. E. Non- p, the form FI becomes linear van't Hoff solubility-temperature plots and their pharmaceutical metastable with respect to the form FII. Tp was estimated to interpretation. Int. J. Pharm. 1984, 18, 25-38.
Vol. 7, No. 6, 2003 / Organic Process Research & Development Figure 10. In situ observations under optical microscopy, of
polymorphs FI and FII in different phase diagram areas. (a) FI
and FII in solution at point A in Figure 8, and (b) FII crystals
have completely dissolved and FI has grown at point B in Figure
8.

°C. That is why these authors suggested that it was preferableand normally adequate to assume that the apparent partialmolar enthalpy of solution, which is independent of tem-perature only for ideal solutions, is a linear function oftemperature. With this assumption, the solution has to beconsidered as nonideal.
Consequently, this result reminds pharmaceutical scientists of the danger to erroneously attribute the nonlinear solubilitybehaviour as a phase change in the solid state, such aspolymorphism or solvate formation. The slope discontinuityis not necessarily due to the existence of a new polymorph, Figure 11. Photographs of drug solution concentrated to 14.6
but it may also be the result of the "nonideality" of the wt % in mixture ethanol/water (54.2/45.8 wt %), point D in
Figure 8. (a) In situ observations under optical microscopy, of
3.2.2. Polymorph Selection. The understanding of the
appearance of droplets in the drug solution at 35 °C and (b)
phase diagram and the experimental setup, quiescent ther- photograph of drug solution at 35 °C after 15 min. (The arrow
indicates the limit between the two phases.)

mostated cell by Peltier effect placed under a microscope(Figure 3), lead to the achievement of the desired polymorph, presented in another report in preparation).34 In a quiescent in a reproducible manner. Our study was aimed at obtaining solution, we observed the decantation of the droplets (Figure only one polymorph, for instance FI, in solution. Thus, when 11b), whereas in a stirred medium we observed an emulsion.
the solution of this drug molecule was concentrated up to As shown in Figure 8 (point D), this phase separation 4% weight at 20 °C, (point A in Figure 8), both polymorphs occurred in the supersaturated area of the phase diagram with were in suspension (Figure 10a). When the solution was respect to the two solid phases FI and FII, and at 35 °C FI is heated to 35 °C (point B in Figure 8) form FII dissolved the stable form and FII is the metastable form. This metastable while FI remained stable as shown in Figure 10b. As the LLPS can significantly affect the crystallization by changing solubility curves of FI and FII cross at 52.5 °C, it is easy to its kinetics. For instance, in a case of seeding with crystals select either polymorph by slightly changing the temperature.
of FI at point D (Figure 8), crystals which are the stable phase 3.2.3. Liquid-Liquid Phase Separation and Crystal-
can coexist with the metastable phase, i.e., the droplets lization. A solution of this pharmaceutical compound at a
(Figure 12a). In Figure 12b, after 12 h, droplets have concentration of 14.6% weight at 60 °C (point C in Figure increased their size by both growth and coalescence. The 8) was cooled to 35 °C (point D in Figure 8). A cloud coalescence of droplets was confirmed by their decreasing appeared in the solution, despite a supersaturated solution, number (Figure 12b). Crystals were still growing, and we this cloud was not due to an amorphous precipitation, observed a nucleation of droplets by an heterogeneous gelation, or crystallization of one polymorph but to the mechanism (Figure 12, b and c). At the end of the appearance of droplets in solution (Figure 11a). The solution crystallization process, in the isothermal experiment, the separated into two coexisting liquid phases of different solute concentration reached the solubility of FI by crossing compositions, with different densities; one of the phases willbe solute- and ethanol rich, and the other will be water rich (34) Lafferre re, L.; Hoff, C.; Veesler, S. Liquid-liquid demixing from drug solution. Study on temperature dependence using static light scattering and (the complete characterization of the phase diagram will be titration. Manuscript in preparation.
Vol. 7, No. 6, 2003 / Organic Process Research & Development terization of the system. In the scale-up procedure the mostwidely used criterion for crystallization process is based onconstant power input per unit volume.35 In the case ofemulsion,36 scale-up at constant power per unit volumeproduces smaller drops.
We thus conclude that the existence of a LLPS is correlated with the "nonideality" of the solution. Therelevance of this LLPS for crystallization is evident becauseof the composition changes in both liquid phases. Thatmeans, at least, that supersaturation and viscosity are affectedduring the process. The probability of forming a miscibilitygap or liquid-liquid demixing increases with the numberof components in the system.37 Thus, the use of a solventmixture for the sake of the process could lead to a liquid-liquid demixing, and crystallization might thus be hindered.
The different stages of the solution-mediated phase transition, i.e., dissolution of the metastable phase andnucleation and growth of the stable phase, were studied forirbesartan, a pharmaceutical compound. The influence ofcrystal sizes and habits and of additive on the kinetics ofdissolution and growth has been shown.
For a system having a liquid-liquid phase separation which is metastable with respect to the crystallization of thetwo polymorphs, FI and FII of C35H41Cl2N3O2 in an ethanol/water mixture, thermodynamic stability of the forms witheach other with temperature was investigated. Thermody-namic stability of the phases towards each other withtemperature and the impact of the liquid-liquid phaseseparation on crystallization have been investigated. Ourresults show that a deep control of the crystallizationparameters (temperature, supersaturation, solution composi-tion, etc.) and the understanding of the phase diagram leadto the achievement of the desired polymorph, in a reproduc-ible manner. Moreover, the dilute solution studied was shownto be nonideal since it was correlated with the existence ofthe metastable liquid-liquid demixing which was observed Figure 12. In situ observations under optical microscopy of
and characterized. In our experiments the liquid-liquid phase seeding with polymorph FI of drug solution concentrated to 14.6
transition prevented the drug from crystallizing, while it wt % in mixture ethanol/water (54.2/45.8 wt %) at 35 °C; (a)
t
) 0, (b) t ) 12 h and (c) t ) 22 h. (The arrow indicates the
changed the medium and the conditions of crystallization, heterogeneous nucleation of droplets onto crystal surface).
which consequently affected the process.
the liquid-liquid coexistence curve so that droplets disap- peared, crystals grew at the expense of the droplets. Despite We are indebted to Sanofi-Synthe´labo for financial the large supersaturation, the crystallization was hindered, support, M. C. Toselli for technical assistance, and F.
and the suspension took a long time to reach equilibrium.
Farnarier for her help in the manuscript correction. We The scale-up of such a process will be uneasy because of acknowledge the suggestions the reviewers made to clarify the presence of an emulsion and of a ternary phase diagram.
It will be difficult to extrapolate the behavior of thesuspension of crystals and droplets without further charac- Received for review June 30, 2003.
(35) Mersmann, A. Design of crystallizers. Chem. Eng. Process. 1988, 23, 213-
(36) Baldyga, J.; Bourne, J. R.; Pacek, A. W.; Amanullah, A.; Nienow, A. W.
Effects of agitation and scale-up on drop size in turbulent dispersions: (37) Lupis, C. H. P. Chemical Thermodynamics of Materials; Elsevier Science: allowance for intermittency. Chem. Eng. Sci. 2001, 56, 3377-3385.
New York, 1983.
Vol. 7, No. 6, 2003 / Organic Process Research & Development

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Submitted to PSA Conference 2016 Yasmin M. Khodary - the British University in Egypt Is the "Good" Good Enough for Decision Makers? Well-being Indices Informing Public Policies and Decisions in UK Abstract: For too long, philosophers, thinkers and human beings have been preoccupied with searching for the ‘Good life'. However, as the world changes, different priorities appeared on the top of

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