COMMENTARY Reversibility of Enantiotropically Related Polymorphic Transformations from a Practical Viewpoint: Thermal Analysis of Kinetically Reversible/Irreversible Polymorphic Transformations

KOHSAKU KAWAKAMI Banyu Tsukuba Research Institute, PreClinical Development, 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan

Received 8 June 2006; revised 20 July 2006; accepted 20 July 2006 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20748

ABSTRACT: Although enantiotropically related polymorphic transitions are thermodynamically reversible with temperature and pressure, they may be observed as either reversible or irreversible in practical investigations. This behavior may be explained simply by a difference in the energy barrier for the transition. However, this difference may have a signicant effect on strategy in formulation development. This article summarizes the characteristics of enantiotropic transitions with reference to the literature. Also provided are careful investigations of polymorphic transitions by thermal analysis, which is the most promising method to investigate transition behavior.
2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:982989, 2007

Keywords: polymorphism; enantiotropy; reversible transition; irreversible transition; thermal analysis

INTRODUCTION
Many pharmaceutical solids can exist in two or more crystalline states with different molecular arrangements and/or conformations. Different crystalline forms of the same compound are called polymorphs or modications.1 Various forms may appear during the crystallization process, depending on factors such as solvent, temperature, additives, and preparation method,25 and they may exhibit signicantly different physicochemical properties.1 If the form obtained is not the most stable one, polymorphic transition may occur spontaneously. Methods for determining
Correspondence to: Kohsaku Kawakami (Telephone: 8129-877-2176; Fax: 81-29-877-2165; E-mail: kohsaku_kawakami@merck.com)
Journal of Pharmaceutical Sciences, Vol. 96, 982989 (2007) 2007 Wiley-Liss, Inc. and the American Pharmacists Association

the stability relationship were rst summarized by Burger et al.,6,7 in which thermal methods proved to be the most promising means of characterization. The applicability of the heat of transition rule, which basically associates the endothermic transition with the enantiotropic relationship and the exothermic transition with the monotropic relationship, was shown to be greater than 90%. The heat of fusion rule, which distinguishes the transition mechanisms using the heat of fusion, has also been recognized to be useful, when the difference in melting temperature is small. 308C has been suggested as a rough threshold for the temperature difference.8 In addition, accurate measurement of heat capacity has been shown to be helpful in constructing energy-temperature diagrams for polymorphs.9 Solubility measurement has also been a powerful method for determining the stability order of

982

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

KINETICALLY REVERSIBLE/IRREVERSIBLE POLYMORPHS

983

polymorphs,1012 unless solvation or polymorphic transition occurs in the medium, because the most stable form has the lowest free energy and therefore shows the lowest solubility. However, the precise determination of solubility is relatively difcult.13 For example, in the pharmaceutical industry, crystallinity may signicantly affect the solubility value in the early developmental stage. Moreover, a recent survey showed that the solubility ratio between different crystal forms is typically between 1 and 2 with an averaged value of 1.7,14 which means that determination of solubility may not be sufcient for ranking stability. Another useful method for examining the stability order is the solvatemediated transformation method,3,5 however, the selected conditions do not necessarily induce polymorphic transitions, although many attempts have been made to identify the dominating factor to cause the transformation.3,5 It can be seen that there is no absolute method for determining the thermodynamic relationship between different crystal forms. Figure 1 shows traditional energy-temperature diagrams of polymorphs. In both gures, the most stable form at ambient temperature is dened as form I. When the polymorphs are enantiotropically related (Fig. 1a), their free energies become equal at the transition temperature TIII. Because the t enthalpy of form I is lower than that of form II at that temperature, the transition is observed as an endothermic process. However, the observed transition temperature may be higher than the free energy crossing point. It is even possible that form I melts without transformation. In this case, the enthalpy of fusion of form I is usually larger than that of form II as expected from Figure 1a. When polymorphs are monotropically related, the stability relationship does not depend on the temperature below their melting points. Heating of metastable form II may or may not cause polymorphic transition to form I. If it occurs, this transition is an exothermic process as shown in Figure 1b. If form II does not undergo transformation, it usually melts with a smaller enthalpy of fusion than that of the stable form I. Thus, it is obvious that thermal analysis can offer important insights into relationships between polymorphs, because it readily provides information on the enthalpy and the apparent temperature of the transition. Despite its importance in developmental researches, focus on the kinetic reversibility of transition behavior has been rare. Both tolbutamide (TLB) and sulfamerazine are known to
DOI 10.1002/jps

Figure 1. Free energy (G), enthalpy (H)temperature (T) diagrams of (a) enantiotropically or (b) monotropically related transitions. Superscript or subscript I, II, III, and L mean form I, form II, forms III transition, and liquid state, respectively. Form I is the stable form in the case of the monotropic transition, and the stable form at lower temperature in the case of enantiotropic transition. DHt and DHm are the enthalpies of polymorphic transition and fusion. Tt and Tm are the transition and the melting temperatures.

exhibit enantiotropic polymorphic transition. However, the transition of TLB is kinetically reversible, while that of sulfamerazine is not.15 This article aims to provide deeper insights into the kinetic reversibility of enantiotropic polymorphic transitions. Differential Scanning Calorimetry (DSC) Study of Enantiotropic Transitions Enantiotropic transitions are thermodynamically reversible, and thus the two crystal forms should coexist at the thermodynamic transition
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

984

KAWAKAMI

temperature. However, this does not necessarily mean that the direction of transition is reversible with temperature as described in Introduction. Examples of both kinetically reversible and irreversible enantiotropic transitions can be found in the literature without particular emphasis on reversibility. When the transition is kinetically reversible, its DSC thermogram appears as shown in Figure 2. The transition is observed at the same temperature regardless of the rate or direction of temperature change (i.e., heating or cooling). Table 1 summarizes examples of pharmaceutical compounds that exhibit this type of the transition. Although this observation is very common in actual developmental studies, a limited number of examples have been found in the literature. This is probably because the two forms are not available at the same temperature in actual experiments, which restrict the variety of possible experiments. In fact, all of the compounds in the table possess other metastable crystal forms which have been of interest to researchers, and reversible transitions have usually been outside the scope of those studies. On the other hand, the apparent transition temperature increases with heating rate, when the transition is not kinetically reversible. As an example, the dependency on heating rate of the transition behavior of sulfamerazine is shown in

Table 1. Examples of Reversible Enantiotropic Polymorphs Transition Temperature (8C) 57 75 58 136 39

Compound CHF 1035

Forms

References
16 16 17 2,15 15

Ia/Ib Ib/Ic CS-891 A/B Furosemide I/IV Tolbutamide Not dened

, This paper

Figure 3. In cooling experiments, transition to the original form was not observed. In other words, the stable form at higher temperature can be obtained at lower temperature as a metastable form for this type of compounds. Table 2 shows examples of pharmaceutical compounds which exhibit irreversible type transitions. It is notable that the thermodynamic transition temperature is usually considerably lower than the DSC transition temperature. In other words, the transition temperature determined in DSC study is not the thermodynamic transition temperature for this type of compounds. Care must be taken with physical stability when such a compound is developed, even if the process or storage temperature is well below the DSC transition temperature. Modulated-temperature DSC (MTDSC) is a powerful tool for investigating the kinetic reversibility of thermal events, allowing the peak of the kinetically reversible transition to be reproduced in the reversing signal. On the other hand, the kinetically irreversible transition can be found in

Figure 2. DSC thermograms of the polymorphic transition of TLB obtained on TA Q1000 (TA Instruments, New Castle, DE) calibrated with indium and sapphire. The heating rates were 0.1, 0.2, 0.5, 1, and 28C/ min (top to bottom). The transition temperature was observed at ca. 39.18C (peak top) regardless of rate and direction of the temperature change. The sample size was about 5 mg.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

Figure 3. DSC thermograms of the polymorphic transition of sulfamerazine obtained on TA Q1000. The sample size was about 5 mg. The heating rates were 2.5, 5, 10, and 208C/min (top to bottom).
DOI 10.1002/jps

KINETICALLY REVERSIBLE/IRREVERSIBLE POLYMORPHS

985

Table 2. Examples of Irreversible Enantiotropic Polymorphs Transition Temperature (8C) Compound Acetazolamide Carbamazepine Dyclonine HCl F2692 Falicaine HCl Flupirtine maleate Gepirone HCl Librol Mefenamic acid Neotame Nimodipine ROY Sulfamerazine Sulfathiazole Urapidil
a

Forms I/II III/I II/I II/I II/I A/B I/II II/I I/II A/G II/I DR/R II/I III/I II/I

Thermodynamic 78148 7378 <125 80 <115 6095 74 7085 87 3570 88 52 5155 103 45158

Experimental >148 150170 167 >156 156 164 150165 >125 179220 >92a >116a 95115 166184 105170 >158a

References
18 19,20 21 22 21 23 24 25 20,26 27 8 28 15,29

, This paper
30 31

Higher than the melting point of the lower melting form.

the nonreversing signal. Such experiments are described in detail elsewhere.15 We will now focus on the transition for the reversible polymorph. Although the energy barrier for this type of transition should be very low, the thermograms show a very broad transition. One possible explanation for this is instrumental artifact, such as a delay in heat transfer. Further thermal analysis was performed using TLB as an example. Heat Capacity Measurement Figure 4 shows the reversing heat capacity, Cp, of TLB, obtained by MTDSC. Because TLB readily crystallizes during the cooling process, the amorphous heat capacity at ambient temperature was obtained by extrapolating the heat capacity of the supercooled liquid state to the lower temperature as shown by the dashed line in the gure. Using the relationship Cp(@H/@T)p, where H and T are the enthalpy and the temperature, respectively, and the subscript p refers to constant pressure, the relative enthalpies of the crystalline (DHc) and the amorphous state (DHa) can be calculated as shown in Figure 5. If the glass transition temperature exists in this temperature range, the amorphous enthalpy line should have a break point. However, this is not likely, because amorphous TLB is difcult to obtain at ambient temperature. The glass transition temperatures of pharmaceutical glasses available at ambient temperature are typically in the range 25
DOI 10.1002/jps

1008C,3234 which suggests that the glass transition temperature of TLB is much lower. Solution Calorimetry Figure 6a shows the heat of solution of TLB obtained in an ethanol/water mixture, in which a

Figure 4. Reversing heat capacity of TLB obtained by MTDSC on TA Q1000. Temperature was changed at 28C/ min with a 60 s period and 18C amplitude. The sample size was about 3 mg. The black and gray (red in on-line version) lines express the crystalline state and the amorphous (supercooled liquid) states, respectively. The crystalline data was obtained simply by heating the intact solid up to the melting point, followed by cooling process to acquire the amorphous data. Because the amorphous was crystallized during the cooling process, the heat capacity at ambient temperature was determined by the extrapolation to lower temperature (see text).
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

986

KAWAKAMI

Figure 5. Enthalpy-temperature plot of TLB calculated from the heat capacity data (Fig. 4). The black and gray (red in on-line version) lines express the crystalline state and the amorphous (supercooled liquid) states, respectively.

drastic change was observed between 37 and 408C. Figure 6b shows the enthalpy difference between the crystalline and the amorphous state, DHa DHc, calculated from the DSC data. The heat difference just below and above the transition was ca. 56 J/g in both cases. The similarity of these curves suggests that the broad transition observed in the DSC measurements does not result from any kinetic effect. In other words, the transition of TLB does not occur at one dened temperature but seems to have a continuous nature which may be attributed to second-order transition. Slow-Scan DSC Recent progress in the development of thermal equipments has enabled us to select a wide range of ramp rates. Fast-scan DSC is now recognized as a very powerful tool to enhance sensitivity35 or to prevent transitions during heating.36 On the other hand, slow-scan DSC should enhance resolution and may reduce instrumental artifact. An isothermal microcalorimeter may be used for this purpose. Figure 7 shows thermograms obtained at a heating rate of 18C/h. Because information on the optimum sample size is not available for this experiment yet, various sizes were used. The thermogram obtained using a 5-mg sample has a low signal-to-noise ratio and the calculated transition enthalpy exhibited a large deviation, indicating that the amount used was too small for the
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

Figure 6. (a) Heat of solution of TLB at the polymorphic transition region obtained on 2225 Precision Solution Calorimeter (Thermometric AB, Spjutvagen, Sweden) using a 100-mL glass vessel. About 100 mg of the TLB powder was loaded in the glass cell, followed by its breakage in 100-mL of 50-vol% ethanol aqueous solution at various temperature. The measurements were done in triplicate to provide averaged enthalpy values with standard deviations. (b) Enthalpy difference between the crystalline and the amorphous (supercooled liquid) states at the polymorphic transition region calculated from the heat capacity data.

purpose. The reproducibility of the peak area was signicantly improved when the sample size was larger than 40 mg, although the values obtained at each size were not in agreement. DSC experiments also show that the apparent transition enthalpy depends on the sample size and the ramp rate (data not shown). The observed transition enthalpy of TLB seemed to depend strongly on the experimental conditions and the instruments
DOI 10.1002/jps

KINETICALLY REVERSIBLE/IRREVERSIBLE POLYMORPHS

987

Figure 8a. An important difference from Figure 1b is that the transition is continuous, although there remains a possibility that some degree of discontinuity is also involved. Virtual states that cannot be obtained experimentally were expressed by dashed lines. It should also be noted that the challenging assumption made in Figure 5 in our previous article15 is no longer required. Figure 8b is the energy-temperature diagram for kinetically irreversible transition. In this case, the stable form at higher temperature is

Figure 7. Thermograms of TLB obtained by slowscan DSC studies using an isothermal microcalorimeter. The observation was done on Thermal Activity Monitor III (Thermometric AB) in a temperature-controlled room at 258C. The ramp rate was 18C/h. Glass vials were used as sample cells. The general description on the use of the microcalorimeter can be found elsewhere.38,39

used. If the transition occurs at a specic temperature, the signal should start to change rapidly at the beginning of the transition. Broadness of the peak in this experiment also suggests the continuous nature of this transition. Distinction of Two Types of Transitions The main point to be made is that there are two types of enantiotropic transitions, which should be distinguished. Although it has already been pointed out in literature,37 little attention has been paid to this in the pharmaceutical eld. For kinetically reversible transitions, the transition always occurs at the transition behavior at the same temperature due to its continuous nature. On the other hand, for irreversible transitions, the transition does not occur at the thermodynamic transition temperature, probably due to the large energy barrier to alter the crystal structure. The energy-temperature relationship of the reversible transition may be redrawn as
DOI 10.1002/jps

Figure 8. Free energy (G), enthalpy (H)temperature (T) diagrams of (a) reversible or (b) irreversible enantiotropic transitions. Superscript or subscript I, II, III, and L mean form I, form II, forms III transition, and liquid state, respectively. Forms I and II are the stable form at lower and higher temperature, respectively. It should be noticed that the opposite expression was used for sulfamerazine in the text, because it is generally accepted. DHt and DHm are the enthalpies of polymorphic transition and fusion. Tt and Tm are the transition and the melting temperature.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

988

KAWAKAMI

available even below the thermodynamic transition temperature and vice versa.

CONCLUSIONS
Enantiotropic transitions were divided into two types, kinetically reversible and irreversible ones. In DSC studies of reversible polymorphs, the transition temperature is always the same regardless of the rate or direction of the temperature change. This type of transition is continuous to some extent. In contrast, the transition temperature of kinetically irreversible polymorphs depends greatly on the rate and direction of the temperature change. Assessment of polymorphic transition has been primarily focused on distinguishing between monotropic and enantiotropic transitions. However, distinguishing between kinetically reversible and irreversible transitions may be more important, and thus it should be kept in mind that enantiotropic transitions are not always kinetically reversible.

ACKNOWLEDGMENTS
The author would like to thank Prof. Y. Saruyama (Kyoto Institute of Technology), Prof. R. Suryanarayanan (University of Minnesota), and Mr. L. Thomas (DSC Solutions LLC) for valuable advice and fruitful discussions.

REFERENCES
1. Brittain HG. 1999. Polymorphism in pharmaceutical solids. New York: Marcel Dekker. 2. Matsuda Y, Tatsumi E. 1990. Physicochemical characterization of furosemide modications. Int J Pharm 60:1126. 3. Gu CH, Young V, Jr., Grant DJW. 2001. Polymorph screening: Inuence of solvents on the rate of solvent-mediated polymorphic transformation. J Pharm Sci 90:18781890. 4. Morissette SL, Soukasene S, Levinson D, Cima MJ, Almarsson O. 2003. Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization. Proc Natl Acad Sci USA 100:21802184. 5. Miller JM, Collman BM, Greene LR, Grant DJW, Blackburn AC. 2005. Identifying the stable polymorph early in the drug discovery-development process. Pharm Dev Technol 10:291297.

6. Burger A, Ramberger R. 1979. On the polymorphism of pharmaceuticals and other molecular crystals. I. Theory of thermodynamic rules. Mikrochimica Acta [Wien] II:259271. 7. Burger A, Ramberger R. 1979. On the polymorphism of pharmaceuticals and other molecular crystals. II. Applicability of thermodynamic rules. Mikrochimica Acta [Wien] II:273316. 8. Grunenberg A, Henck JO, Siesler HW. 1996. Theoretical derivation and practical application of energy/temperature diagrams as an instrument in preformulation studies of polymorphic drug substances. Int J Pharm 129:147158. 9. Sacchetti M. 2001. Thermodynamic analysis of DSC data for acetaminophen polymorphs. J Therm Anal Cal 63:345350. 10. Yu L, Reutzel SM, Stephenson GA. 1998. Physical characterization of polymorphic drugs: An integrated characterization strategy. Pharm Sci Tech Today 1:118127. 11. Gu CH, Grant DJW. 2001. Estimating the relative stability of polymorphs and hydrates from heats of solution and solubility data. J Pharm Sci 90:1277 1287. 12. Rodrguez-Spong B, Price CP, Jayasankar A, Matzger AJ, Rodrguez-Hornedo N. 2004. General principles of pharmaceutical solid polymorphism: A supramolecular perspective. Adv Drug Deliv Rev 56:241274. 13. Kawakami K, Miyoshi K, Ida Y. 2005. Impact of the amount of excess solids on apparent solubility. Pharm Res 22:15371543. 14. Pudipeddi M, Serajuddin ATM. 2005. Trends in solubility of polymorphs. J Pharm Sci 94:929939. 15. Kawakami K, Ida Y. 2005. Application of modulated-temperature DSC to the analysis of enantiotropically-related polymorphic transitions. Thermochim Acta 427:9399. 16. Giordano F, Rossi A, Moyano JR, Gazzaniga A, Massarotti V, Bini M, Capsoni D, Peveri T, Redenti E, Carima L, Alberi MD, Zanol M. 2001. Polymorphism of rac-5,6-diisobutyryloxy-2-methyl amino-1,2,3,4-tetrahydro-naphthalene hydrochloride (CHF 1035). I. Thermal, spectroscopic, and x-ray diffraction properties. J Pharm Sci 90:1154 1163. 17. Yada S, Ohya M, Ohuchi Y, Hamaura T, Wakiyama N, Usui F, Kusai A, Yamamoto K. 2003. Solid phase transition of CS-891 enantiotropes during grinding. Int J Pharm 255:6979. 18. Griesser UJ, Burger A, Mereiter K. 1997. The polymorphic drug substances of the European Pharmacopedia. Part 9. Physicochemical properties and crystal structure of acetazolamide crystal forms. J Pharm Sci 86:352358. 19. Behme RJ, Brooke D. 1991. Heat of fusion measurement of a low melting polymorph of carbamazepine that undergoes multiple-phase changes

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

DOI 10.1002/jps

KINETICALLY REVERSIBLE/IRREVERSIBLE POLYMORPHS

989

20.

21.

22.

23.

24.

25.

26.

27.

28.

during differential scanning calorimetry analysis. J Pharm Sci 80:986990. Park K, Evans JMB, Myerson AS. 2003. Determination of solubility of polymorphs using differential scanning calorimetry. Cryst Growth Des 3:991 995. Schmidt AC. 2005. Solid-state characterization of falicaine hydrochloride and isomorphic dyclonine hydrochloride. Part IV. Crystal polymorphism of local anaesthetic drugs. Eur J Pharm Sci 25:407 416. Chauvet A, Masse J, Ribet JP, Bigg D, Autin JM, Maurel JL, Patoiseau JF, Jaud J. 1992. Characterization of polymorphs and solvates of 3-amino1-(m-triuoromethylphenyl)-6-methyl-1H-pyridazin-4-one. J Pharm Sci 81:836841. Landgraf KF, Olbrich A, Pauluhn S, Emig P, Kutscher B, Stange H. 1998. Polymorphism and desolvation of upirtine maleate. Eur J Pharm Biopharm 46:329337. Behme RJ, Brooke D, Farney RF, Kensler TT. 1985. Characterization of polymorphism of gepirone hydrochloride. J Pharm Sci 74:1041 1046. Burger A, Lettenbichler A. 2000. Polymorphism and preformulation studies of librol. Eur J Pharm Biopharm 49:6572. Romero S, Escalera B, Bustamante P. 1999. Solubility behavior of polymorphs I and II of mefenamic acid in solvent mixtures. Int J Pharm 178:193202. Dong Z, Munson EJ, Schroeder SA, Prakash I, Grant DJW. 2002. Neotame anhydrate polymorphs II: Quantitation and relative physical stability. Pharm Res 19:12591264. He X, Griesser UJ, Stowell JG, Borchardt TB, Byrn SR. 2001. Conformational color polymorphism and control of crystallization of 5-methyl-2-[(4methyl-2-nitrophenyl)amino]-3-thiophenecarbonitrile. J Pharm Sci 90:371388.

29. Zhang GGZ, Gu C, Zell MT, Burkhardt RT, Munson EJ, Grant DJW. 2002. Crystallization and transitions of sulfamerazine polymorphs. J Pharm Sci 91:10891100. 30. Legas M, Lerk CF. 1981. The polymorphism of sulfathiazole. Int J Pharm 8:1124. 31. Botha SA, Guillory JK, Lotter AP. 1986. Physical characterization of solid forms of urapidil. J Pharm Biomed Anal 4:573587. 32. Hancock BC, Zogra G. 1994. The relationship between the glass transition temperature and the water content of amorphous pharmaceutical solids. Pharm Res 11:471477. 33. Crowley KJ, Zogra G. 2001. The use of thermal methods for predicting glass-former fragility. Thermochim Acta 380:7993. 34. Zhou D, Zhang GGZ, Law D, Grant DJW, Schmitt EA. 2002. Physical stability of amorphous pharmaceuticals: Importance of congurational thermodynamic quantities and molecular mobility. J Pharm Sci 91:18631872. 35. Hurtta M, Pitkanen I. 2004. Quantication of low levels of amorphous content in mannitol. Thermochim Acta 419:1929. 36. McGregor C, Saunders MH, Buckton G, Saklatvala RD. 2004. The use of high-speed differential scanning calorimetry (Hyper-DSCTM) to study the thermal properties of carbamazepine polymorphs. Thermochim Acta 417:231237. 37. Sato K. 1993. Polymorphic transformations in crystal growth. J Phys D; Appl Phys 26:B77B84. 38. Kawakami K, Ida Y. 2003 . Direct observation of the enthalpy relaxation and the recovery processes of maltose-based amorphous formulation by isothermal microcalorimetry. Pharm Res 20:14301436. 39. Kawakami K, Miyoshi K, Tamura N, Yamaguchi T, Ida Y. 2006. Crystallization of sucrose glass under ambient conditions: Evaluation of crystallization rate and unusual melting behavior of resultant crystals. J Pharm Sci 95:13541363.

DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007