Journal of Crystal Growth 237–239 (2002) 2233–2239

Dissolution and phase transition of pharmaceuticalcompounds

Eric Garciaa, Christian Hoffb, St!ephane Veeslerc,*a SANOFI-SYNTHELABO Recherche, F-78440 Porcheville, France

b SANOFI-SYNTHELABO Chimie, F-30390 Aramon, Francec Centre de Recherche sur les M!ecanismes de la Croissance Cristalline CRMC21-CNRS, Campus de Luminy, Case 913,

F-13288 Marseille cedex 09, France

Abstract

This paper presents a laboratory study of a solution-mediated phase transition of irbesartan form A into form B. The

following stages are observed and studied: dissolution of form A until the apparent saturation is reached, form A

dissolution which strictly compensates for the form B nucleation and growth, form A is completely dissolved and

crystallization of form B is only observed until the concentration reaches the solubility of form B. In the first stages of

the transformation, the dissolution of form A, we evidenced two distinct behaviors in function of undersaturation: (1) at

higher undersaturation, dissolution is controlled by mass transfer and (2) at lower undersaturation, dissolution is

controlled by surface process. The influence of the temperature is also shown. In the last part of this work we showed

that from the knowledge of the crystal structure and experimental morphology additives can be selected. A surfactant,

dodecyl amine chloride, has an accelerating effect on the dissolution of form A and hinder the growth of form B. Adipic

acid slows down the dissolution rate of form A, but has no effect on the growth rate of form B. r 2002 Elsevier Science

B.V. All rights reserved.

PACS: 64.70 kb; 64.60 qb; 81.10 dn

Keywords: A1. Additives; A1. Dissolution; A1. Nucleation; A1. Phase transition; A2. Growth from solutions; B1. Organic compounds

1. Introduction

In this paper we present the second part of astudy concerning a solution-mediated phase tran-sition of a pharmaceutical compound, irbesartan(C25H28N6O) [1], used in the treatment of the

hypertension. Phase A is trigonal ðR%3Þ [2], whereasB is triclinic ðP%1Þ; this compound is an organicmolecule with an unsaturated N cycle and thetransformation of A into B is a tautomerictransformation, named a desmotropy (Fig. 1).Phase transition is very important in pharmaceu-tical industry [3,4], because the appearance of anew structure, the thermodynamically stable, andthe disappearance of the existing one, the meta-stable form, can change the bioavailability, stabi-lity and processing of the consideredpharmaceutical compound. The mechanism of this

*Corresponding author. Tel.: +336-6292-2866; fax: +334-

9141-8916.

E-mail address: veesler@crmc2.univ-mrs.fr (S. Veesler).1 Laboratory associated to the Universities Aix-Marseille II

and III.

0022-0248/02/$ - see front matter r 2002 Elsevier Science B.V. All rights reserved.

PII: S 0 0 2 2 - 0 2 4 8 ( 0 1 ) 0 2 2 8 2 - 5

phase transition is dissolution of the metastableform A, nucleation and crystallization of thethermodynamically stable form B. This transitionwas followed by in situ conductimetry and UVspectrophotometry. The influence of the massconcentration of crystal in solution, the crystalhabit and crystal size distribution was previouslyshown [1]. In this paper we focused on the role ofundersaturation, temperature, and the additiveson the dissolution and the phase transition.

2. Experimental Procedure

The experiments were carried out in a batchcrystallizer of 0.8 l at constant temperature, thecrystallizer was a double-jacketed glass vesselequipped with three wall baffles to prevent thesolution from rotating in the crystallizer. Stirringof the solution was ensured by a stainless-steelstirrer equipped with a mixel propeller type at astirring rate of 300 rpm. Both are covered withhalars (ECTFE) coating in order to avoidchemical pollution of the solution. For followingthe dissolution of form A and the nucleation andgrowth of form B we measured the variation ofconductivity of the solution as a function of time[1,5]. Metrohm 660 conductimeter (Metrohm

Herisau, Switzerland) with an open geometrymeasurement cell (constant cell of 0.57 cm�1) wasused.

The crystallizer was equipped with a peristalticpump (Gilson M312) connected to the circulationcell of an UV spectrophotometer (SHIMAZU UV-2401 PC). The signal, which is proportional to theconcentration and the chemical nature of themolecules, will allow us to follow the concentra-tion and the chemical reaction, if any occurs, insolution during the phase transition. In this study,

Fig. 1. Tautomeric transformation of Irbesartan form A into form B, from the crystallographic data.

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 100 120 140

ConductivityUV

Time (min)

UV

abs

orba

nce

and

cond

ucti

vity

Fig. 2. Comparison of conductimetric and UV spectrophoto-

metric measurements on the dissolution of Irbesartan form A in

water (data are normalized in order to be compared).

E. Garcia et al. / Journal of Crystal Growth 237–239 (2002) 2233–22392234

no reaction was detected, and the signal obtainedfrom the UV spectrophotometer was totallycorrelated with the one of the conductimeter(Fig. 2).

Single crystals for crystallography studies wereprepared in small crystallization cells of 1 mlthermostatted by Peltier elements. The whole setupwas placed under an inverted optical microscope(Nikon, Diaphot) in order to keep controlling thatthe crystals of only one polymorph were present[6]. The crystals were observed with a ScanningElectronic Microscope (SEM) JEOL 6320F andthe polymorphs were characterized by X-raydiffraction (XRD) INEL CPS120.

3. Results and discussions

3.1. In situ observation of the phase transition

A typical conductivity curve obtained fordissolution of 50 mg ml�1 of form A in pure waterat 401C is shown in Fig. 3. The pH of the solutionwas 3.6. The four different stages, observed inFig. 3, correspond to the dissolution of form A,the form B nucleation and growth. In this study,the kinetic of the tautomer transformation isconsidered as instantaneous. Several commentscan be made about the results displayed in Fig. 3.First, the dissolution of form A is fast. Below10 min a major quantity of form A is dissolved,

and the apparent solubility, i.e. 10 mg ml�1, isachieved after 60 ms�1, the plateau at 6 ms cm�1

does not correspond to an important inductionperiod for the nucleation of the form B, but thatthe form A dissolution compensates for the form Bnucleation and crystallization. At t ¼ 30 min, thepresence of form B was confirmed by XRD.

Third, at the end of the plateau at 6 ms cm�1 theoverall crystallization kinetics of form B passthrough a maximum, time at which all form A hasdissolved. Finally, in the last stage, the crystals ofform B grow until the concentration reaches thesolubility of form B.

The inflection points on the curves shown inFig. 3 are representative of the time of completedissolution of form A [1].

3.2. Influence of the undersaturation and the

stirring rate on the dissolution rate

In this part we present the influence of under-saturation on the dissolution rate of Irbesartanform A. During the dissolution, the irbesartanconcentration in solution increases, the massconcentration of crystal in solution decreases andthe crystal size distribution evolves so that in orderto have comparable experimental conditions onlyinitial dissolution rates were plotted.

The experiments consisted in dissolving aconstant mass of crystals in solutions at differentundersaturation from 0.2 to 1. Due to spontaneousnucleation of form B near the solubility of form A,the smallest undersaturations for which the solu-tion is metastable is 0.2. Undersaturation isdefined as follows:

�s ¼ 1 � C=Cs; ð1Þ

where C and Cs are the actual concentration andthe solubility respectively. In Fig. 4 we plotted theinitial dissolution rate at 401C in function of theundersaturation. The initial dissolution is deducedfrom the slope of the variation of the concentra-tion as a function of time during the first stage ofthe dissolution (up to 5 min) for a mass concentra-tion of 5 mg ml�1 at N ¼ 300 rpm.

We evidenced two distinct behaviors in functionof undersaturation: at higher undersaturation(greater than 0.6), dissolution rate varies linearly

0

1

2

3

4

5

6

7

0 100 200 300 400 500

Con

duct

ivit

y (µ

s/cm

)

Time (min)

Fig. 3. Variation of conductivity 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 401C in pure water.

E. Garcia et al. / Journal of Crystal Growth 237–239 (2002) 2233–2239 2235

with –s and at lower undersaturation (below 0.6),dissolution rate varies quadratically with �s asforeseen by the theory [7]. In order to determinethe process which controls the dissolution rate inthese domains, surface process or mass transfer,we performed experiments at different stirringrates in the 2 domains at �s ¼ 0:85 and 0.35(Fig. 5) with temperature and mass concentrationbeing the same. If volume diffusion were the rate-limiting factor, the dissolution rate would beinversely proportional to d; the thickness of theunstirred layer. Hence influence of the stirring rateon the dissolution rate will reveal a processcontrolled by mass transfer.

In Fig. 5a we observed that the dissolution rateincreases significantly with the stirring rate, whichshows that in this domain, high undersaturation(�s > 0:6), dissolution is controlled by masstransfer. On the contrary at lower undersaturation(�so0:6), Fig. 5b, dissolution rate is independentof the stirring rate, dissolution is controlled bysurface process.

3.3. Influence of the temperature on the dissolution

rate

Fig. 6 shows the influence of the temperature ona dissolution rate of 5 mg ml�1 of form A. Byincreasing the temperature from 401C to 451C thedomain in which dissolution is controlled by masstransfer (linear dependence of the dissolution ratewith �s) is increased. This means that surface

kinetics increases more quickly than volumediffusion kinetics with temperature. This agreeswith the theory which predicts that surface processhas higher activation energy than mass transfer [8].

Dis

solu

tion

Rat

e (m

g.L

-1.m

in-1

)

σ-

0

0.02

0.04

0.06

0.08

0.1

0.12

0 0.2 0.4 0.6 0.8 1

Fig. 4. Dissolution rate of 5 mg l�1 of Irbesartan form A as a

function of undersaturation at 401C and at N ¼ 300 rpm.

0

0.05

0.1

0.15

0.2

0 0.5 1 1.5

N =350rpmN =300rpm

Con

cent

rati

on (

mg/

L)

Time (min)

-0.05

0

0.05

0.1

0 0.2 0.4 0.6 0.8 1

N =350rpmN =300rpm

Con

cent

rati

on (

mg/

L)

Time (min)

(a)

(b)

Fig. 5. Evolution of the concentration of Irbesartan during the

first stage of the dissolution at 401C and at 300 and 350 rpm for

(a) �s ¼ 0:85; and (b) �s ¼ 0:35:

Dis

solu

tion

rat

e (m

g.L

-1.m

in-1

)

σ-

0

0.02

0.04

0.06

0.08

0.1

0.12

0 0.2 0.4 0.6 0.8 1

T=45°CT=40°C

Fig. 6. Dissolution rate as a function of �s for a mass

concentration of 5 mg l�1 at 401C and 451C.

E. Garcia et al. / Journal of Crystal Growth 237–239 (2002) 2233–22392236

3.4. Influence of the additives on the dissolution and

phase transformation rates

Using the concept of ‘‘tailor-made’’ additives[9], we can select additives that interact preferen-tially with the crystal faces of the form A and theninhibit the dissolution of the crystals of this form.Fig. 7a represents the experimental morphology,needle-like, obtained for crystals of irbesartanform A grown in water, Fig. 7b is a scheme ofthis experimental morphology [10]. In Fig. 7c we

represent the packing arrangement of irbesartanmolecules viewed along the c-axis. Two formshave to be considered the {1 0 0} lateral facesof the needle and the {1 1 1} terminal face of theneedle.

After examination of the surface morphologiesof the faces, it appears that the {1 0 0} faces have arather aliphatic character. {1 0 0} faces are hydro-phobic, which is the reason for the weak solubilityof irbesartan form A in water and their strongaggregation in solution. Surfactants are known for

Fig. 7. (a) Experimental morphology obtained for crystals of irbesartan form A grown in water, (b) scheme of the experimental

morphology and (c) packing arrangement of irbesartan molecules viewed along the c-axis.

E. Garcia et al. / Journal of Crystal Growth 237–239 (2002) 2233–2239 2237

their efficiency in accelerating dissolution [11],so we selected the dodecyl amine chloride (DAC)at a concentration of 50 ppm/water. And for the{1 1 1} faces, which have an hydrophilic character(the presence of oxygen at their surfaces), we testedthe adipic acid at a concentration of 0.22 ppm/water.

Fig. 8 shows the variation of conductivityversus time due to the solution-mediatedphase transition of form A into form B for aconcentration of 50 mg l�1 at 401C in the presenceof 50 ppm of DAC. The dissolution of form A isaccelerated and the apparent solubility of form Ais increased of about 10%. It is also interesting tonote that the growth rate of form B is sloweddown, the whole process lasts for 1300 min in thepresence of DAC instead of 300 min in pure water.The surfactant has a double effect, it acceleratesthe dissolution of form A and hinder the growth ofform B.

In Fig. 9 we show the variation of conductivityversus time due to the solution-mediated phasetransition of form A into form B for a concentra-tion of 50 mg l�1 at 401C in the presence of0.22 ppm of adipic acid, the dissolution is sloweddown and the apparent solubility of form A isdecreased of about 10%. The nucleation of form Boccurred at a lower supersaturation, but thegrowth rate of form B is not affected by theadditive, the decreasing part of the two curves

been nearly parallel. The adipic acid has only oneeffect on the dissolution of form A.

4. Conclusion

In this paper we evidenced the different stages ofthe solution-mediated phase transition of irbesar-tan form A into form B: dissolution of form Auntil the apparent saturation is reached, form Adissolution strictly compensates for the form Bnucleation and growth, form A is completelydissolved and crystallization of form B is onlyobserved until the concentration reaches thesolubility of form B.

In the first stages of the transformation, thedissolution of form A, we evidenced two distinctbehaviors as function of undersaturation: (1) athigher undersaturation, dissolution is controlledby mass transfer and (2) at lower undersaturation,dissolution is controlled by surface process. Theinfluence of the temperature is also showed. In thelast part of this work we showed that from theknowledge of the crystal structure and experimen-tal morphology additives can be selected. Asurfactant, DAC, has an accelerating effect onthe dissolution of form A and hinder the growth ofform B. Adipic acid slows down the dissolutionrate of form A, but has no effect on the growthrate of form B.

0

2

4

6

8

10

12

0 200 400 600 800 1000 1200 1400

waterDACC

once

ntra

tion

(mg/

L)

Time (min)

Fig. 8. Variation of conductivity versus time due to the

solution-mediated phase transition of form A into form B for

a concentration of 50 mg l�1 at 401C in the presence of 50 ppm

of DAC.

0

2

4

6

8

10

12

0 100 200 300 400 500

wateradipic acid

Con

cent

rati

on (

mg/

L)

Time (min)

Fig. 9. Variation of conductivity versus time due to the

solution-mediated phase transition of form A into form B for

a concentration of 50 mg l�1 at 401C in the presence of 0.22 ppm

of adipic acid.

E. Garcia et al. / Journal of Crystal Growth 237–239 (2002) 2233–22392238

Acknowledgements

The authors are indebted to SANOFI-SYNTHELABO for financial support, to Dr G.P"epe for stimuling discussions and computermodelling and to M. Audiffren, T. Bactivelaneand M.C. Toselli for technical assistance.

References

[1] E. Garcia, S. Veesler, R. Boistelle, C. Hoff, J. Crystal

Growth 198/199 (1999) 1360.

[2] E. Garcia, S. Veesler, C. Hoff, A. Kvieck, to be published.

[3] D. Giron, Thermochim. Acta 248 (1995) 1.

[4] J. Bernstein, R. Davey, J.O. Henck, Angew. Chem. Int.

Ed. 38 (1999) 3440.

[5] L. Amathieu, R. Boistelle, J. Crystal Growth 88 (1988)

183.

[6] R. Boistelle, J.P. Astier, G. Marchis-Mouren, V. Desseaux,

R. Haser, J. Crystal Growth 123 (1992) 109.

[7] G.H. Gilmer, R. Ghez, N. Cabrera, J. Crystal Growth 8

(1971) 79.

[8] J. Garside, R.J. Davey, A.G. Jones (Eds.), The role of

transport processes in crystallization, in: Advances in

Industrial Crystallization, Butterworth-Heinemann, Lon-

don, 1991, pp. 92–104.

[9] I. Weissbuch, L. Leiserowitz, M. Lahav, Tailor-made

additives and impurities, in: A. Mersmann (Ed.), Crystal-

lization Technology Handbook, Marcel Dekker, New

York, 1995, pp. 401–455.

[10] G. P"epe, D. Siri, in: J.L. Rivail (Ed.), Modeling of

Molecular Structure and Properties, Elsevier, Amsterdam,

1990, pp. 557–589.

[11] R.C. Zumstein, R.W. Rousseau, Ind. Eng. Chem. Res. 28

(1989) 334.

E. Garcia et al. / Journal of Crystal Growth 237–239 (2002) 2233–2239 2239