Crystal Structures of Tetramorphic Forms of Donepezil and Energy

Article pubs.acs.org/crystal

Crystal Structures of Tetramorphic Forms of Donepezil and Energy/ Temperature Phase Diagram via Direct Heat Capacity Measurements Yeojin Park,† Jangmi Lee,† Sun Hye Lee,† Hoo Gyun Choi,‡ Chen Mao,§ Sung Kwon Kang,∥ Sang-Eun Choi,† and Eun Hee Lee*,† †

College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong 339-700, Korea College of Pharmacy, Chosun University, Gwangju, Korea § Genentech Inc., One DNA Way, Mail Stop 432A, South San Francisco, CA 94080, USA ∥ Department of Chemistry, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-746, Korea ‡

S Supporting Information *

ABSTRACT: Donepezil is used for the palliative treatment of mild to moderate dementia of the Alzheimer’s disease. Donepezil crystallized as four solvent-free polymorphs including forms I, II, C, and F which differ in molecular conformations and packing. Conformational difference comes from the torsion of the 2, 3-dihydroinden-1-one moiety and methyl-benzyl ring with respect to piperidyl ring. Similar melting temperatures and heats of fusion were observed for four solvent-free polymorphic forms and made polymorph selection by solvent crystallization method poor. The relative thermodynamic stability relationships of each polymorph with respect to the amorphous form were determined using direct heat capacity (Cp) measurement and then used to evaluate the relative thermodynamic stability between polymorphs. Form F was the stable form over the temperature ranges we studied. Other than form F, form C was the stable form among three polymorphic forms including I, II, and C, below 53 °C, and is enantiotropically related to both forms I and II. Form II is the stable form above 53 °C and monotropically related to form I. The thermodynamic relationships between polymorphs were further confirmed by measuring the solubility over temperatures ranging from 35 to 60 °C in ethanol. Slurry conversion in ethanol, isopropyl alcohol, and cyclohexane was conducted to provide a guideline to obtain pure and desired polymorphic forms. The establishment of the thermodynamic relationships among four polymorphic forms greatly facilitated polymorph selections of donepezil.

■. INTRODUCTION Polymorphism is a common occurrence among small molecule organic compounds in the solid state.1,2 The number of polymorphs one can discover depends on the conformational flexibility that exists in molecular structure or diversity in molecular packing and probably “the time and money spent on research in the compound”, as McCrone stated.3 The variation in physicochemical properties among polymorphs is well recognized; however, no one knows how different physicochemical properties would be a priori. Therefore, it is ideal to obtain as many polymorphs as possible. The rank orders of the thermodynamic stability among polymorphs are of interest for further development. The thermodynamic stability among polymorphs can be assessed in many different ways, which include: (1) direct measurements such as observing transformation of solids stored at various temperatures or of slurried solids in solvents at various temperatures,4−7 (2) indirect measurements such as assessing the thermodynamic relationships by measuring solubility at different temperatures or by using thermal properties obtained by differential scanning calorimetry (DSC) measurement,8−10 or (3) application of the established stability rules, such as the heat-of-transition rule, the heat-of-fusion rule, density rule, and/or infrared rule.11 © 2013 American Chemical Society

The transformation from the metastable form to the stable form could take place at a timescale that is not practical, especially in the solid state. The timescale can be shortened tremendously by using slurry conversion/solution-mediated transformation. Seeding would also facilitate the timescale of such transformation by reducing the activation energy for nucleation.12 However, slurry conversion/solution-mediated transformation is unlikely to be practical when the transition temperature lies significantly above the room temperature. The narrow operating temperature range would also be the limitation for estimating the thermodynamic relationships between polymorphs by measuring solubility at different temperatures. The transformation from a metastable form to the stable form would also complicate a true solubility measurement of each polymorphic form at different temperatures. The benefits for using melting data/transition data via DSC would include a relatively short timescale of measurement, requirement of small sample quantity, and operation at a wide Received: September 21, 2013 Revised: October 30, 2013 Published: November 21, 2013 5450

dx.doi.org/10.1021/cg401405g | Cryst. Growth Des. 2013, 13, 5450−5458

Crystal Growth & Design

Article

temperature range. With the knowledge of thermal properties obtained by DSC, the energy-temperature phase diagram can be constructed. Donepezil (see Figure 1) is used for the palliative treatment of mild to moderate dementia of the Alzheimer’s disease. It is a

If one is to measure the free energy difference between crystalline and amorphous forms at any temperature below Tm, the heat capacity changes need to be considered. After the heat capacity changes are accounted for, the free energy changes can be expressed as ΔGCIA (T ) = (ΔHmCI −

∫T

T mC I

⎛ − T ⎜⎜ΔSmCI − ⎝

ΔGCIIA (T ) = (ΔHmCII −

ΔGCCA (T ) = (ΔHmCC −

centrally acting reversible acetylcholine esterase inhibitor, which increases acetylcholine concentrations and enhances cholinergic function. In accordance to literature, donepezil can have at least twelve polymorphs.13−19 The tetrahydrated form shows a melting point at 86 °C.14 Most of polymorphic forms whether, they contain solvent or not, show melting points ranging from 70 to 100 °C for those of which the melting temperatures were known. The similarities of the melting temperatures and the heats of fusion among polymorphic forms render donepezil an interesting system to study the thermodynamic relationships among polymorphs. These similarities also imply that polymorphic selection by conventional crystallization can be difficult. In this work, we attempted to establish the thermodynamic relationships among polymorphs of donepezil and to provide a guideline as to generating the desired polymorphic form of interest. Crystal structures of four solvent-free polymorphic forms of donepezil were obtained, and the thermodynamic relationships among them were assessed using direct heat capacity measurement and solubility measurement, as well as slurry conversion method.

ΔGCFA (T ) = (ΔHmCF −

T

∫T

∫T

(4)

⎞ dT ⎟⎟ ⎠

(5)

⎞ dT ⎟⎟ ⎠

(6)

⎞ dT ⎟⎟ ⎠

(7)

ΔC pCIIA T

ΔC pCCA dT )

T mCC

T mCF

⎞ dT ⎟⎟ ⎠

ΔC pCIIA dT )

T mC II

T mCC

∫T

ΔC pCIA

ΔC pCCA T

ΔC pCFA dT )

T mCF

ΔC pCFA T

ΔHmCI, TmCI, and ΔSmCI are defined as the heat of fusion at the melting temperature of form I, the melting temperature of form I, CA and the entropy of fusion of form I, respectively. ΔCp I is defined as the heat capacity difference between form I and amorphous at temperature T. The same definition was applied to form II, form C, and form F. ΔHmCI, TmCI, and ΔSmCI can be obtained by the conventional DSC method, and ΔCCp IA can also be obtained by direct Cp measurement using the DSC experiment, which will be described in Experimental Section. The Gibbs free energy− temperature phase diagram can be established by the eqs 1−7. Since four polymorphic forms I, II, C, and F are compared against the same reference form (amorphous prepared in DSC), the relative stability among polymorphs with respect to the amorphous reference can be constructed and evaluated.

(1)

■. EXPERIMENTAL SECTION Materials. The hydrochloride salt of donepezil (donepezil HCl) was purchased from Cangzhou Senary Chemical S. & T. Company, Ltd. (Hebei, China). Donepezil HCl was dissolved in water, and stoichiometric amounts of sodium hydroxide were added in order to prepare the donepezil free base. Donepezil was purified in isopropyl alcohol and ethanol, subsequently. After recrystallization, resulting solids were analyzed by high-performance liquid chromatography (HPLC). Pure donepezil free base was used for further analysis. Isopropyl alcohol (IPA), acetonitrile (ACN), and cyclohexane were purchased from Sigma-Aldrich (St. Louis, MO). Sodium hydroxide was obtained from Jin Chemical Pharmaceutical Company, Ltd. (Gyunggi-do, Republic of Korea). Ethanol was obtained from Pharmco (Brookfield, CT). Water was double-distilled and filtered with a Milli-Q ultrapure water purification system (Billerica, MA).

(2)

where CI and A represent forms I and amorphous. ΔGCIA is defined as the free energy difference between the crystalline form (donepezil form I) and the amorphous (GA − GCI), Since ΔHTm is the enthalpy of melting of crystalline form, and ΔGCIA(Tm) is equal to zero at the melting temperature, ΔSTm can be defined as

ΔHTm Tm

∫T

⎛ − T ⎜⎜ΔSmCF − ⎝

When we consider two states as one for one of polymorphic forms and the other for the corresponding liquid (amorphous), the Gibbs free energy changes between the two forms at temperature T is defined as

ΔSTm =

∫T

T mC I

T mC II

⎛ − T ⎜⎜ΔSmCC − ⎝

■. THEORETICAL SECTION Relative Thermodynamic Stability Measurement Method. The Gibbs free energy changes between two states at any given temperature T are defined as

ΔGCIA (T) = ΔHT − T ΔST

∫T

⎛ − T ⎜⎜ΔSmCII − ⎝

Figure 1. Molecular structure of donepezil with atomic numbering and torsion angles.

ΔG(T ) = ΔH − T ΔS

∫T

ΔC pCIA dT )

(3) 5451



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equilibrating at −90 °C for 5 min, and the temperature was raised to 400 °C at a rate of 20 °C/min. An isothermal condition at 400 °C was maintained for 5 min, and the temperature was equilibrated at 50 °C. After calibrating with an empty pan, baseline calibration using the sapphire was conducted, following the same procedure that was used for the empty pan. After baseline calibration, indium calibration was conducted by premelting indium in the DSC and, subsequently, heating the indium at a rate of 20 °C/min in the temperature ranging from 100−180 °C. Indium melting temperature and cell constant were used for thermal analysis. For heat capacity (Cp) measurement, the following procedure was adopted: (1) zero heat flow at 60 °C was selected, and sapphire was equilibrated at 0 °C and maintained isothermally for 5 min. (2) The sapphire was heated to 120 °C at a heating rate of 20 °C/min. The Cp value at 60 °C was obtained and compared with that of the sapphire. Cp constant was calculated by dividing the standard Cp value of sapphire at 60 °C by the Cp value obtained experimentally. Donepezil crystals were then carefully weighed and placed in a low mass pan and underwent two sequential scans: the sample was equilibrated at −30 °C and then heated to 120 °C at a heating rate of 20 °C/min; it was then cooled to −20 °C at a rate of 20 °C/min. The same procedure was used for the second scan. Data used in the study were averaged from at least three runs. Data were acquired and analyzed using Universal Analysis 2000 software v. 4.1D (TA Instruments). Thermogravimetric Analysis (TGA). The weight changes of donepezil polymorphs were measured using a TA Instruments thermogravimetric analysis system (TGA Q50 Thermogravimetric Analyzer) (TA Instruments, New Castle, DE). A sample of approximately 10 mg in weight was placed on the sample pan. The heating rate was 10 °C/min from room temperature to 120 °C. Data were acquired and analyzed using Universal Analysis 2000 v. 4.1D (TA Instruments). X-ray Data Collection and Structure Determination. The X-ray intensity data were collected on a Bruker SMART APEX-II CCD diffractometer using graphite monochromated Mo Kα radiation (λ = 0.71073 Å) at the temperature of 296 K. The structures were solved by applying the direct method using a SHELXS-97 and refined by a full-matrix least-squares calculation on F2 using SHELXL-97.21 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were positioned geometrically and refined using a riding model, with C−H = 0.93−0.98 Å with Uiso = 1.2 Ueq(carrier C) for aromatic- and methylene-H and 1.5 Ueq(carrier C) for methyl-H atoms. Hydrogen-bonding patterns were investigated under Mercury 3.1 (Cambridge Structural Database). Solubility Measurements. Excessive amounts of pure donepezil I, II, C, and F were placed in vials containing ethanol. The solution was stirred at 35, 40, 45, 50, 55, and 60 °C. The supernatant was taken at a predetermined time interval and filtered using a nylon filter with a pore size of 0.2 μm. The filtered solutions were diluted appropriately for HPLC measurements. The residual solids were analyzed by PXRD to determine the polymorphic purity at the end of equilibration. Slurry Conversion Method. Excessive amounts of the mixtures containing donpezil I, II, and C were placed in vials containing ethanol, isopropyl alcohol, and cyclohexane, respectively. The mixture was slurried over wide temperature ranges. The powder patterns of the slurried mixtures were obtained at a predetermined time interval.

Preparation of Polymorphs of Donepezil. Four solventfree polymorphs were obtained. Donepezil form I was obtained after recrystallization from ethanol (see Figure 2). Donepezil

Figure 2. Picture of donepezil crystallized from ethanol showing concomitant polymorphism: Form I crystallizes as square-shaped crystals while form II crystallizes as rod-shaped/needle crystals in the same vial.

form II was obtained by the following method: 150 mg of donepezil form I was dissolved in 1 mL ethanol at 40 °C in a scintillation vial. The open vial was then placed in a hood at room temperature. After the solvent was evaporated, doenepzil form II was obtained. Donepezil form C was obtained by slurrying mixtures of donepezil forms I and II powder in cyclohexane for three days at room temperature. Donepezil form F was obtained by slurrying mixtures of donepezil forms I and II powder in ethanol for at least one week at room temperature. Powder X-ray Diffraction (PXRD). The PXRD analysis was performed on donepezil polymorphs using a D8 ADVANCE with Davinci (Bruker AXS Inc., GmbH, Germany) equipped with Cu Kα radiation and a high speed LynxEye detector. Samples were analyzed over a 2θ range of 4−40° with an increment of 0.02° at a rate of 6°/min. Data was analyzed using DIFFRACplus Eva (Bruker AXS Inc., GmbH, Germany). High-Performance Liquid Chromatography (HPLC). The purity of recrystallized doenpezil was determined by 1260 infinity HPLC system (Agilent Technologies, Inc., Santa Clara, CA) with a diode array detector. HP Chemstation (Agilent Technologies, Inc.) was used for data analysis. A Phenomenex luna 5 μm, 4.6 × 250 mm analytical column (Phenomenex Inc., Torrance, CA) was used at 30 °C. The mobile phase consisted of A (0.01 M KH2PO4 with pH 3.0) and B (acetonitrile) (A:B = 65:35 v/v).20 The flow rate was 1 mL/min. Injection volume was 20 μL. The samples were analyzed at UV λ = 240 nm. Differential Scanning Calorimetry (DSC). Thermal analysis was conducted using a Q2000 DSC (TA Instruments, New Castle, DE). Q2000 DSC was calibrated with an empty sample pan and sapphire for cell resistance and capacitance; indium was used for the calibration of cell constant and temperature. In detail, an empty pan was equilibrated at −90 °C for 5 min, and the temperature was raised to 400 °C at a rate of 20 °C/min. The second scan was conducted again by

■. RESULTS AND DISCUSSION Crystal Structure Analysis of Four Solvent-Free Polymorphs of Donepezil. The crystallographic data for four polymorphs of doenpezil are summarized in Table 1. No 5452



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Table 1. Crystallographic Data of Four Solvent-Free Polymorphs of Donepezil Obtained from Single Crystal X-ray Analysis parameter

I

II

C

F

chemical formula temperature space group crystal system a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) density (mg/m3) Z reflections collected/unique R1 factor (%) wR2 factor (%)

C24H29NO3 296 (2) K P21/c monoclinic 16.610 (14) 9.549 (8) 14.357 (12) 90.00 112.545 (12) 90.00 2103.13 1.198 4 30153/5118 [Rint (%) = 6.59] 6.55 17.54

C24H29NO3 296 (2) K Pbca orthorhombic 10.408 (2) 11.342 (2) 35.927 (7) 90.00 90.00 90.00 4241.09 1.189 8 29948/3951 [Rint (%) = 15.8] 4.00 6.44

C24H29NO3 296 (2) K P1̅ triclinic 10.365 (6) 14.306 (8) 16.199 (9) 67.375 (6) 79.079 (7) 71.988 (7) 2101.69 1.199 4 58083/7831 [Rint (%) = 11.52] 4.57 9.83

C24H29NO3 173(2) K P1̅ triclinic 5.9523 (8) 11.8173(18) 15.072 (2) 79.253 (3) 84.287 (2) 75.924 (2) 1008.66 1.249 2 31331/4958 [Rint (%) = 3.47] 4.39 11.48

Figure 3. Crystal packing diagrams of donepezil form I. (a) A view perpendicular to the ab plane, and (b) a view perpendicular to the ac plane.

Figure 4. Crystal packing diagrams of donepezil form II. (a) A view perpendicular to the bc plane, and (b) a view perpendicular to the ac plane.

hydrogen bonds were observed in the crystal structures of four polymorphs, although hydrogen bonds are regarded as one of the

major driving forces for forming organic crystals. The Donepezil molecule contains one hydrogen bond acceptor but does not 5453



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Figure 5. Crystal packing diagrams of donepezil form C. (a) A view perpendicular to the bc plane, and (b) a view perpendicular to the ab plane.

Figure 6. Crystal packing diagrams of donepezil form F. (a) A view perpendicular to the bc plane, and (b) a view perpendicular to the ab plane.

dimethyoxy-2,3-dihydroinden-1-one moiety. Form C molecules are denoted as CI and CII, since the asymmetric unit contains two independent molecules. τ1 and τ2 represent how the 2,3dihydroinden-1-one ring is bent with respect to the piperidyl ring: τ1 represents how the piperidyl ring is bent with respect to the bond C8−C11, and τ2 represents how the 2,3-dihydroinden-1-one ring is bent with respect to the bond of C11−C12. τ1 differs from −179.1 to 76.0°, making the piperidyl ring from being tilted to perpendicular to nearly coplanar to the bond C8−C11 (Table 2). τ2 differs from −178.6 to 89.5°, making 2,3-dihydroinden-1-one from negatively to positively perpendicular with respect to the bond C11−C12 (Table 2). On the opposite side of 2,3-dihydroinden-1-one ring with respect to the piperidyl ring, the benzyl rings of CII and F are intertwined (Figure 7, panels a and b). Torsion angles τ3’s of CII and F are similar as −72.2 and −67.4°, respectively. Whereas, the difference in τ3 for I, II, and CI are 64.3, 73.7, and 66.9°, respectively, which make the benzyl rings of overlaid molecules being seen bifurcated with respect to the benzyl rings of CII and F (Figure 7, panels a−e). Torsion angles τ4’s also indicates the positions of the benzyl rings with respect to the piperidyl ring (Figure 7, panels a−e). Similar phenomena were observed for torsion angles τ4’s: I, II, and CI show negatively signed torsion angles, while CII and F show positively signed torsion angles. It is noteworthy that the angles ∠C9−C8−C11 vary from 112.5° to 121.0°. Powder X-ray Diffraction (PXRD). Donepezil polymorphs, including I, II, C, and F, showed distinct powder patterns (Figure 8). Since various donepezil polymorphs crystallize concomitantly, it is appropriate to compare the experimentally obtained powder patterns with the calculated powder patterns, as well as conducting the DSC analysis in order to confirm the phase purity. The experimentally

contain a hydrogen bond donor. As a result no inter- and intramolecular hydrogen bonds were observed in the crystal structure of all four polymorphs. Donepezil form I crystallized in the monoclinic crystal system with the P21/c space group. Donepezil molecules are packed like overlapped scissors when they are viewed perpendicular to the ab plane (Figure 3, panels a and b). Donepezil form II crystallized in the orthorhombic crystal system with Pbca space group. Figure 4 (panels a and b) show the crystal packing of donepezil II viewed perpendicular to the bc and ac planes. Donepezil form C crystallized in the triclinic space group with the P1̅ space group (Figure 5, panels a and b). Asymmetric unit contains two crystallographically independent donepezil molecules. Interestingly, the empty planelike spaces are observed along the (1 1 0) face when the crystal packing diagram is viewed perpendicular to the ab plane (Figure 5b). Donepezil form F crystallized in the triclinic crystal system with the P1̅ space group. Donepezil molecules are stacked perfectly along the a axis; in other words, no overlaid molecules are observed on the bc plane, when the crystal packing diagram is viewed perpendicular to the bc plane (Figure 6a). Similar to form C, the empty planelike spaces are observed along the (0 1 0) face when the crystal packing diagram is viewed perpendicular to the ab plane (Figure 6b). Each polymorph differs in four torsion angles C9−C8−C11− C12 (τ1), C8−C11−C12−C13 (τ2), C14−N15−C18−C19 (τ3), and N15−C18−C19−C24 (τ4) (Figure 1). Figure 7 shows overlaid molecular conformations of polymorphs of donepezil using form F as reference. In Figure 7 (panels a, c, and e), one of three polymorphs with form F were overlaid with respect to the piperidyl moiety, while in Figure 7 (panels b, d, and f), one of three polymorphs with form F were overlaid with respect to 5454



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Figure 7. Overlaid molecular conformations of polymorphs of donepezil from different views using form F as reference: Overlaid molecules are (a and b) forms C (CI and CII) and F, (c and d) forms I and F, and (e and f) forms II and F: form I is colored in red, form II in blue, form CI in pink, form CII in purple, and form F in green.

Table 2. Selected Structural Parameters of Polymorphs of Donepezil form

I

II

CI

CII

F

τ1 τ2 τ3 τ4 II (96.40 °C) > I (93.21 °C) > C (92.16 °C) (Figure 9 and Table 3). Form F shows the highest melting point as well as the largest heat of fusion, suggesting that form F is the most stable form on the basis of the heat-of-fusion rule. Other than form F, a heat of fusion of C was greatest (84.20 J/g) followed by II (77.41 J/g) and I (71.53 J/g). On the basis of the heat-of-fusion rule, it can be assumed that I and II are monotropically related, while I and C and II and C are enantiotropically related. Assessments of the Thermodynamic Stability of Four Solvent-Free Polymorphs using Direct Cp Measurements. We evaluated the thermodynamic stability of four solvent-free polymorphs of donepezil by using direct Cp measurements. During heating in DSC, each polymorph of donepezil melted and the molten phase did not crystallize upon cooling at a rate of 20 °C/min. The amorphous donepezil formed during the cooling process remained during the second heating. 5455



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Figure 8. Calculated vs experimentally obtained PXRD patterns of polymorphs of donepezil: forms F, C, II and I (from top to bottom).

Figure 9. Overlaid DSC thermograms of four solvent-free polymorphs of donepezil, showing similar melting temperatures between polymorphs.

temperatures were measured and shown in Figure 11. Form F showed the lowest solubility among four polymorphs over temperature ranges studied. This result is consistent with the heat of fusion rule, indicating that the polymorph with the highest melting point and the largest heat of fusion is the stable form and is monotropically related to other polymorphs. Therefore, form F is the stable form and monotropically related to the other three polymorphs, including I, II, and C. On the basis of thermodynamic stability data obtained by direct heat capacity measurements, forms I and II are monotrolically related to each other, and form II is the metastable form. Both forms I and II are enantiotropically related to form C. Thermodynamic relationships of polymorphs obtained by solubility measurements are

Table 3. Thermal Behavior of Polymorphs of Donepezil Measured by DSC and TGA Donepezil polymorphs

melting point [onset temperatue (°C)]

heat of fusion (J/g)

melting point (°C)

weight loss

I II C F

90.72 93.94 89.27 94.24

71.53 77.41 84.20 87.60

93.21 96.40 92.16 98.20

no loss no loss no loss no loss

Assessments of the Themodynamic Stability of Four Solvent-Free Polymorphs Using Apparent Solubility Measurements. Apparent solubilities of four solvent-free polymorphs over temperature ranges below and above transition 5456



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polymorphic transformation varied. However, the resulting polymorphic forms by slurry conversion method are consistent with those obtained by solubility measurements and provide a guideline to obtain a pure and desirable polymorphic form. Slurry conversion method showed that form II can be obtained by slurrying the mixtures in cyclohexane at temperatures above 55 °C, and form C can be obtained in ethanol at temperatures below 50 °C. It was observed that the nucleation of form F was slow as compared to other polymorphs. As a result, form C remained for some time after the mixture containing forms I, II, and C completely transformed to form C. The slow nucleation/ transformation kinetic makes it possible to obtain pure form C without traces of form F. However, it is necessary to closely monitor the transformation since all polymorphs eventually transform to form F, the stable form. Form F can easily be obtained by slurrying the mixtures for an extend period of time. It needs to be mentioned that it was difficult to obtain form I since it is the metastable form over all temperature ranges. Theoretically, form I is more stable than form C above 87 °C and therefore, form I can be obtained via slurrying form C above 87 °C. However, 87 °C is close to the melting point of forms C and I. Therefore, it is not practically possible to obtain form I by the slurry conversion method. Nevertheless, the establishment of the thermodynamic relationships among four polymorphic forms greatly facilitated the successful polymorph selection of forms I, II, and C.

Figure 10. Schematic energy−temperature phase diagram of donepezil polymorphs I, II, C, and F obtained by calculating the free-energy difference between amorphous and polymorphs via direct heat capacity measurement.

■. CONCLUSION We obtained the crystal structures of four solvent-free polymorphic forms of donepezil. Neither inter- nor intramolecular hydrogen bonds were observed in the four solvent-free polymorphic forms. Solid-state characterization showed that the melting points of four solvent-free polymorphic forms were similar. On the basis of the heat-of-fusion rule, it was concluded that form C is enantiotropically related to forms I and II. The calculation of the free-energy difference using direct Cp measurements indicated that form F is the stable form over the temperature range studied, forms I and II are monotropically related to each other, and forms I and II are enantiotropically related to form C: the transition temperature of forms II and C is 53 °C, and the transition temperature of forms I and C is 87 °C.

consistent with those obtained by DSC. The transition temperature between form C and form II seems to be 53 °C. The transition temperature between C and I was not seen below 53 °C. The rank of the thermodynamic stability is form F(stable) > form C > form II > form I below 53 °C, form F(stable) > form II > form C > form I above 53 °C. Assessments of the Themodynamic Stability of Four Solvent-Free Polymorphs by Slurry Conversion. We slurried the mixtures containing three polymorphic forms, including forms I, II, and C in three different solvents, including ethanol, isopropyl alcohol, and cyclohexane. With dependence on the solubility of polymorphs in each solvent, the rate of

Figure 11. Solubility curves of four solvent-free polymorphs of donepezil in ethanol. Transition between forms C and II are clearly seen between 50 and 55 °C. 5457



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Pharmaceutical Forms, and Methods of Making and Using the Same. WO 2005089511 A2, 2005. (16) Dubey, S.; Rehman, Z. U.; Dubey, S. K. Novel Polymorphic Forms of 1-Benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methyl Piperidine [donepezil] and Process for Preparing the Same. WO 2008050351, 2008. (17) Tomiyama, T.; Aota, N.; Akamatsu, H.; Takahashi, Y.; Imai, A.; Kuroda, H. Polymorphic Crystal of Donepezil and Process for Producing the Same. WO 2010071216 A1, 2010. (18) Imai, A.; Ichinohe, T.; Endo, T.; Tsurugi, T. Donepezil Polycrystals and Process for Producing the Same. WO 9929668, 1999. (19) Adin, I.; Iustain, C.; Arad, O.; Kaspi, J. EP 1935884 A2, 2008. (20) Reddy, K. V. S. R. K.; Babu, J. M.; Kumar, P. A.; Chandrashekar, E. R. R.; Mathad, V. T.; Eswaraiah, S.; Reddy, S.; Nyas, K. J. Pharm. Biomed. Anal. 2004, 35, 1047. (21) Sheldrick, G. M. Acta Cryst. A 2008, 64, 112.

Solubility measurements of polymorphs over the temperature ranges below and above transition temperature confirmed the thermodynamic relationships between polymorphs. Slurry conversion in ethanol, isopropyl alcohol, and cyclohexane also showed the consistent results and provided a guideline to obtain the pure and desired polymorphic form. The calculation of the free-energy difference using direct Cp measurements provides useful information regarding the thermodynamic relationships between polymorphs of donepezil, especially when the transition temperature is beyond the temperature that we can practically measure. The establishment of the thermodynamic relationships among four polymorphic forms enabled successful polymorph selection.

■

ASSOCIATED CONTENT

S Supporting Information *

Crystallographic data files (cif format), FT-IR spectra of donepezil polymorphs, and the free-energy difference plot. This material is available free of charge via the Internet at http:// pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: (+82) 44-860-1620. Fax: (+82) 44-860-1606. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Financial support for this project was provided by Korea University Research Foundation (Korea Univ., Republic of Korea).

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REFERENCES

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Crystal Structures of Tetramorphic Forms of Donepezil and Energy

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