Solid Forms of Amlodipine Besylate: Physicochemical, Structural

DOI: 10.1021/cg101127z

Solid Forms of Amlodipine Besylate: Physicochemical, Structural, and Thermodynamic Characterization

2010, Vol. 10 5279–5290

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Vishal Koradia,‡ Heidi Lopez de Diego,§ Karla Frydenvang,^ Michiel Ringkjøbing-Elema,† Anette M€ ullertz,‡ Andrew D. Bond, and Jukka Rantanen*,‡ ‡

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Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark, §H. Lundbeck A/S, Preformulation, Copenhagen, Denmark, †H. Lundbeck A/S, Pharmaceutical Development, Copenhagen, Denmark, ^Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark, and Department of Physics and Chemistry, University of Southern Denmark, Odense, Denmark Received August 26, 2010; Revised Manuscript Received October 11, 2010

ABSTRACT: Amlodipine besylate, a calcium channel antagonist widely used in the treatment of hypertension and coronary artery disease, has been found to exist in four solid forms: anhydrate, monohydrate, dihydrate, and amorphous. A comprehensive characterization of these forms is provided, based on single-crystal and powder X-ray diffraction, thermal, spectroscopic, microscopic and solubility measurements. The crystal structure of the dihydrate is reported at both 25 and -150 C. The crystal lattices of both the dihydrate and the stable monohydrate collapse upon removal of water molecules to create melt, from which the anhydrate subsequently crystallizes. Rapid cooling of the dehydration induced melt from any of the hydrates produces the amorphous form. Spectroscopic analysis in conjunction with the crystal structure analysis shows differences in the hydrogen bond networks in the different solid forms. The kinetic solubility rank order at 37 C in water is found to be anhydrate > monohydrate > dihydrate. In these conditions, the dihydrate is found to be the most stable form, and other forms undergo solvent-mediated transformation (SMT) to yield the dihydrate. Consistent with the SMT results, van’t Hoff analysis indicates anhydrate and dihydrate to be the stable phase above and below 71 C, respectively.

*Corresponding author: Tel: (þ45) 35 33 65 85. Fax: (þ45) 35 33 60 30. E-mail: [email protected].

term anhydrate is often used for the polymorphs while dealing with hydrate form(s) of the same substance, particularly when only one crystal structure without water molecules is present. The anhydrate-hydrate pair of the API presents a challenging as well as interesting opportunity to understand their properties, to explore their relative stability and solubility, and finally to select an optimum form to be used in the dosage form.14,15 Since water is a common medium employed in primary and secondary manufacturing, anhydrate-hydrate interconversions are possible during processing. Moreover, similar transformation(s) can also occur during storage of the finished dosage forms. The consequences of these transformations are often dramatic, for example, removal of water from the hydrate can produce an isomorphic dehydrated structure, a poorly crystalline or amorphous state, or a completely different anhydrate structure.16,17 Thus, a thorough characterization of anhydrate-hydrate forms and an understanding of their phase transformations during preformulation can guide later formulation development. With the advent of quality by design (QbD) and process analytical technology (PAT) based approaches, monitoring solid form changes during development has also become increasingly important. Spectroscopic techniques such as Raman and NIR are commonly employed for this purpose, and thus detailed spectroscopic characterization of the solid forms is necessary. The present work deals with the solid forms of amlodipine besylate (AMB, Figure 1). AMB is a calcium channel antagonist of the dihydropyridine class and is used in the treatment of hypertension and coronary artery disease.18 It has molecular weight 567.1 g/mol, pKa 9.1, log P (n-octanol/water) 2.96, and it is slightly soluble in water.19,20 Rollinger and Burger have reported anhydrate and monohydrate forms of AMB.21

r 2010 American Chemical Society

Published on Web 10/28/2010

Introduction Generation of different solid forms of an active pharmaceutical ingredient (API), and subsequently, selection of a suitable form for the intended use has become an essential part of drug development.1 Solid forms of APIs that are relevant to pharmaceutical preparations include polymorphs, solvates, hydrates, and amorphous forms. These solid forms possess different physicochemical properties such as solubility, stability, and processability, and thus, for any given API an understanding of the solid form properties is a guiding path for proper selection.2,3 In cases in which solubility differences among the solid forms are sufficiently great, bioavailability of the drug molecule may be affected.4-6 Moreover, a starting solid form can undergo phase transformation during pharmaceutical processing, and this can have an influence on the final product performance.7,8 The potential of phase transformations further imposes the necessity to monitor the solid form during manufacturing. Owing to the impact of the solid form on drug product safety, quality, and efficacy, regulatory guidelines have emerged focusing on the selection and control of API solid forms.9,10 Among the different solid forms mentioned, polymorphs and hydrates are the most commonly encountered in the pharmaceutical field.11 Polymorphs are different crystal structures of the same chemical entity arising from different arrangements and/or conformations of the molecules in the crystal lattice.12,13 Hydrates are crystalline adducts containing water as a guest molecule along with the parent molecule. The

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Figure 1. Chemical structure of amlodipine besylate (AMB).

Furthermore, dihydrate and amorphous forms have been disclosed in a patent.22 Our investigation is aimed at providing consistent preparation methods of AMB solid forms and their comprehensive characterization using various analytical techniques (thermal, spectroscopic, microscopy, X-ray diffraction). Further, the work aims to understand the phase transformations and thermodynamic relationship of these forms. Detailed analysis of thermal behavior is performed to obtain in-depth understanding of the dehydration of the monohydrate and dihydrate. The pharmaceutical relevance of these forms is exemplified by differences in their solubility profiles. We also report the crystal structure of the dihydrate and provide a comparison with the anhydrate and monohydrate structures. Experimental Section Materials. AMB was a gift from Matrix Laboratories Limited, Secunderabad, India (batch no. ADP0140208, EP/USP grade, assay: 99.9%) and was used as received. The X-ray powder diffraction (XRPD) pattern of this material was identical to the known anhydrate (AH) form (CSD ref code: XOZRUZ).23 All solvents used in this work were of either analytical or HPLC grade. Ultra pure water was generated using a Milli-Q plus system (Millipore, Milford, USA). Solid Form Preparation. Monohydrate (MH) and dihydrate (DH) forms of AMB were prepared from the received AH material. Considering the photosensitivity of AMB, all experiments were performed with minimal light exposure. MH was prepared by cooling crystallization: 25 g of AH was dissolved in 500 mL of water at 85 C with stirring for 30 min and the resulting solution was rapidly cooled using an ice bath. Crystallization started once the temperature reached about 45 C. The reaction vessel was kept in an ice bath for 60 min (final temperature 5 C). Subsequently, the product was harvested by vacuum filtration and washed with water (50 mL). The obtained product was dried in an air-circulated oven at 40 C for 150 min to afford the MH form. The DH was prepared by solvent-mediated transformation of the AH: 25 g of AH was suspended in 500 mL of water and was stirred for 2 days at 25 C. Afterward, the product was separated by filtration under a vacuum, washed with water (50 mL), and dried at 40 C for 4 h in an oven. Large crystals of the DH suitable for the single crystal X-ray diffraction were obtained by the following method. The AH (5.08 g) was dissolved in 50 mL of ethanol and water mixture containing 24 mol % ethanol at 25 C with the aid of stirring. The solution was filtered through a 0.45 μm pore membrane filter and transferred to a beaker. The beaker was covered with aluminum foil having a few circular holes and was left undisturbed in a fume hood. Crystals were separated from the mother liquor after 6 days and were used for the crystal structure determination and hot stage microscopy. All attempts to obtain good quality crystals of MH were unsuccessful. Also, several evaporative crystallization experiments were performed with pure organic solvents (methanol, ethanol, 2-propanol, cyclohexane, acetone, and dichloromethane) and the resulting product was found always to be the AH form. To prepare the amorphous (AM) form, 500 mg of either MH or DH was heated in a preheated oven at 105 C to afford post-dehydration melt (see DSC discussion for details). The melt was rapidly cooled in a freezer, and the obtained product was the AM form.

Koradia et al. X-ray Powder Diffractometry. X-ray powder diffractograms were measured on a PANalytical X0 Pert Pro diffractometer equipped with a theta/theta goniometer and a solid-state PIXcel detector (PANalytical B.V., Almelo, The Netherlands). Samples were placed on zero-background silicon plates for measurements at ambient conditions, and a continuous 2θ scan was performed in the range of 2 to 40 using CuKR radiation (λ=1.5418 A˚), incident beam optics (0.02-rad soller slit, 10 mm beam mask, programmable divergence slit at 10 mm and 2 antiscatter slit) and diffracted beam optics (0.02-rad soller slit, programmable antiscatter slit at 10 mm, nickel filter). The voltage and current applied were 45 kV and 40 mA, respectively. Each measurement was performed with a step size of 0.039 2θ and at a speed of 0.05 2θ/s. Sample spinning was employed during measurements to minimize the preferred orientation effects. For variable temperature XRPD (VT-XRPD) measurements, samples were placed in a 0.2 mm deep holder which was put in an Anton Paar CHC chamber (Anton Paar GmbH, Graz, Austria) mounted on the goniometer. The temperature was raised from 25 to 210 C at a heating rate of 10 C/min using a TCU 110 temperature controller. The sample temperature was held constant at each measurement temperature, and diffractograms were obtained using the settings previously described. All data were collected using X0 Pert Data Collector version 2.2 and analyzed with X0 Pert Highscore Plus version 2.2.4 (both from PANalaytical B.V., Almelo, The Netherlands). Single Crystal X-ray Analysis. Crystals of the DH suitable for structure determination were obtained by the method described above. Single crystal X-ray analysis was performed at room temperature (25 C) and at low temperature (-150 C). A single crystal was mounted and immersed in a stream of nitrogen gas for low temperature measurement. Data were collected using graphitemonochromated MoKR radiation (λ = 0.7107 A˚) on a Nonius KappaCCD diffractometer. Data collection and cell refinement were performed using COLLECT24 and DIRAX.25 Data reduction was performed using EvalCCD.26 Correction for absorption was performed using Gaussian integration27 as included in maXus.28 The structures were solved by direct methods and refined against all F2 data.29 H atoms bonded to C atoms were placed in calculated positions and refined as riding with Uiso(H) = 1.2Ueq(C) for CH or CH2, and Uiso(H) = 1.5Ueq(C) for CH3. H atoms bonded to N, O(water), and the aliphatic methine CH were located in difference Fourier maps and their positions were refined with fixed isotropic displacement parameters Uiso(H) = 1.2Ueq(C/N) for CH, NH, NH2 and Uiso(H) = 1.5Ueq(O) for OH). For the room temperature data, disorder was observed for the aromatic ring of the besylate group as well as for the ethyl portion of one of the ester groups. Two alternative positions (conformations) have been introduced in the refinement (final occupancy 0.58/0.42), but high displacement parameters indicate more positions might be relevant. For the same reason, the benzene moiety of the besylate is introduced as a rigid moiety with fixed geometry. The geometry of the aromatic ring was constrained to be hexagonal. Complex scattering factors for neutral atoms were taken from International Tables for Crystallography as incorporated in SHELXL97.29,30 Crystallographic data are summarized in Table 1. Differential Scanning Calorimetry (DSC). DSC experiments were performed using a Perkin-Elmer Diamond DSC (Perkin-Elmer, Shelton, CT, USA) coupled with an Intracooler 2P (ULSP B.V., Ede, The Netherlands) cooling unit and controlled by Pyris software version 7.0. Samples of approximately 2-4 mg were weighed ((0.002 mg) into 50 μL aluminum pans using an XP 26 delta range balance (Mettler, Greifensee, Switzerland) and were measured in either open or sealed condition. Two-point calibration using indium (purity 99.999%) and tin (purity 99.950%) was carried out to check the temperature axis and heat flow of the equipment. Samples were analyzed at a heating rate of 10 C/min under a dry nitrogen purge of 60 mL/min. Thermogravimetric Analysis (TGA). The loss of mass as a function of temperature was determined using a thermogravimetric analyzer (Perkin-Elmer TGA 7, Norwich, CT, USA) controlled by Pyris software version 7.0. The temperature was calibrated using a ferromagnetic standard, and weight calibration was performed using a 100 mg standard. Samples (6-7 mg) were analyzed in a

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Table 1. Selected Crystallographic Data for Amlodipine Besylate Dihydrate temperature (C) empirical formula formula weight crystal system space group a (A˚) b (A˚) c (A˚) β () volume (A˚3) Z calculated density (mg/m3) absorption coeff. (mm-1) F(000) crystal size (mm) data/param. goodness-of-fit (on F2) R1 [I > 2σ(I)] wR2 refln observed largest diff density peak (e 3 A˚-3) hole (e 3 A˚-3)

-150 C26H35ClN2O10S 603.1 monoclinic P21/c (No. 14) 18.892(2) 9.5070(6) 16.357(3) 105.285(12) 2833.9(6) 4 1.413 0.267 1272 0.38 0.38 0.11 10428/383 1.031 0.033 0.082 7916

25 C26H35ClN2O10S 603.1 monoclinic P21/c (No. 14) 19.1100(17) 9.6240(9) 16.6930(18) 106.690(9) 2940.8(5) 4 1.362 0.258 1272 0.47 0.25 0.16 6740/441 1.054 0.043 0.111 5579

0.42 -0.37

0.45 -0.47

flame-cleansed platinum pan under open conditions at a heating rate of 10 C/min with a dry nitrogen purge of 40 mL/min. Hot Stage Microscopy (HSM). An Olympus BX50 microscope (Hamburg, Germany) coupled with a Linkam hot stage LTS350 (Linkam Scientific Instruments Ltd., Surrey, UK) and Pixelink PLA662 digital camera (PixeLINK, Ontario, Canada) was used for optical polarized light microscopy and hot stage microscopy. Linksys 32 software (Linkam Scientific Instruments Ltd., Surrey, UK) was used for data acquisition and temperature control. For HSM experiments, sample was dispersed on a glass slide, which was mounted on the hot stage. The temperature was programmed to rise from 25 to 220 C at a heating rate of 10 C/min, and pictures were taken at every 60 s during the run under cross-polarized light. Raman Spectroscopy. Raman spectra were collected using a Raman spectrometer (Control Development Inc., South Bend, IN, USA) equipped with an enhanced diode laser system at 785 nm (Starbright 785S, Torsana Laser Technologies, Skodsborg, Denmark) and a thermoelectrically cooled CCD detector. Measurements in backreflectance geometry were carried out in an aluminum cup using a fiber optic probe (InPhotonics, Norwood, MA, USA) with an integration time of 3 s and a scan average of 8. Spectra were recorded from 81 to 2200 cm-1 with an approximate resolution of 8 cm-1. All Raman spectra were collected using CDI Spec32 software (Control Development Inc., South Bend, IN, USA). Cyclohexane was used as a reference to monitor wavenumber accuracy. Fourier Transform Infrared Spectroscopy (FTIR). The infrared spectra were collected on a Bomen MB 104 IR spectrometer (Bomen, Quebec, Canada). Approximately 1 mg of the sample was mixed with 300 mg of IR grade KBr, and physical mixtures were gently ground and compressed into a pellet. All spectra were acquired in absorbance mode in the 500-4000 cm-1 spectral range with a resolution of 4 cm-1 and a 32 scan average using Grams AI software (Thermo Galactic, Woburn, MA, USA). Instrument and sample chamber were purged with dry air to remove water vapor. Fourier Transform Near-Infrared Spectroscopy (FTNIR). The FTNIR spectra were acquired using an ABB Bomem MB-160 FTNIR spectrometer (Bomen, Quebec, Canada) equipped with a GAIN InGaAS detector. The analysis was carried out in reflectance mode in the range of 4000 cm-1 to 10 000 cm-1 with resolution of 8 cm-1. The final spectrum was a mean of 64 scans. Samples were measured in a glass vial using a rotation device. Spectra were collected using Grams AI software (Thermo Galactic, Woburn, MA, USA). Solubility Measurements. Kinetic solubility of all AMB solid forms was determined in water at 37 C. Before measuring the solubility, all powders were sieved through a 300 μm sieve to minimize any particle size effects. About 100 ( 10 mg of pure form was weighed in a glass vial, and 5 mL of water preheated to 37 C

Figure 2. Preparation routes and transformation pathways of the AMB solid forms. Key: AH - anhydrate, MH - monohydrate, DH dihydrate, AM - amorphous. Organic solvents used: methanol, ethanol, 2-propanol, cyclohexane, acetone, and dichloromethane. was added. Afterward, the closed vials were placed in a shaking water bath (Julabo SW23, Julabo Labortechnik GmBH, Seelbach, Germany) and maintained at 37 C ((0.02 C) with continuous shaking at 100 rpm. At predetermined time points, vials were taken out, the content was filtered through a 0.20 μm syringe filter, and filtrates were collected in new preheated glass vials, which again were maintained at 37 C until further analysis. The residual solids from the original vials were collected and dried at ambient conditions before Raman, NIR and XRPD analysis. The filtrates, after suitable dilution with water, were analyzed with a UV-visible spectrophotometer (Evolution 300, Thermo Scientific, Madison, WI) in a 1 cm quartz cuvette at 238 nm wavelength with a validated analytical method. Additionally, kinetic solubility measurements of AH, MH, and DH were also performed at 10, 25, 42, 47, 51, and 55 C to understand the thermodynamic stability of these forms. At all temperatures, the residual solid phase was measured with Raman, NIR, and XRPD.

Results and Discussion Crystallization and Characterization of the Solid Forms. Four different solid forms of AMB (AH, MH, DH, and AM) were identified in this work, and preparation routes for these forms are shown in Figure 2. All crystallization experiments using pure organic solvents resulted in the starting AH form and no new polymorphic forms or solvates were found. The phase pure MH form was obtained by crystallization from a supersaturated solution of AH in water using the described method. The crystallization of MH was found to be affected by the cooling rate; fast cooling using an ice bath produced the MH, whereas slow cooling gave a mixture of AH and MH. The solventmediated transformation pathway of AH was utilized to prepare the DH form. An aqueous suspension of the AH kept under stirring at 25 C led to complete transformation of AH to DH. The crystal morphologies of AH and DH were plate-like and prismatic, respectively, whereas the MH material consisted of dense agglomerates. During DSC and HSM measurements of the hydrates, melting was observed together with the dehydration. Similar results for the monohydrate were reported by Rollinger and Burger.21 A rapid cooling of the dehydration-melt produced the AM form irrespective of the starting hydrate form. The possibility of producing the AM form by this route using hydrates is quite important in the case of AMB, as the melt from the AH showed immediate decomposition and thus could not be utilized to produce the AM material. The described methods for AM, MH, and DH preparation were repeated at least five times, and reproducible results were obtained. The XRPD patterns of four solid forms of AMB are shown in Figure 3. The crystalline forms, AH, MH, and

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Figure 3. X-ray powder diffractograms of AMB solid forms. Calculated powder patterns are shown for comparison and are in dark gray. The AM pattern shown is of the sample prepared by the quench cooling of the dehydration melt of the MH. The XRPD pattern of the AM prepared in a similar way from DH was identical (Figure S1, Supporting Information).

DH, exhibited characteristic diffractions indicating their distinct crystal structures. The patterns of the AM forms prepared by dehydration of any of the hydrate forms were identical and exhibited a characteristic “amorphous halo” devoid of any sharp diffraction peaks. The experimental patterns of AH and DH provided an excellent match with the theoretical powder patterns calculated from the crystal structures (CSD refcode XOZRUZ23 for AH, and the 25 C DH structure reported herein). In the case of the AH, characteristic peaks were observed at diffraction angles of 5.8, 11.6, and 13.02θ corresponding to the (002), (004), and (023) planes, respectively. The prominent diffraction peaks for the MH were observed at 4.8, 9.6, and 13.92θ. The DH form showed intense diffraction peaks at 4.9, 13.4, 19.4, and 24.92θ, and these peaks correspond to the (100), (210), (400), and (222) planes, respectively. The experimental pattern for MH is generally in good agreement with a structure reported previously in the patent of Ettema et al.,22 except that there are a few peaks present in the simulated XRPD pattern which we have not been able to observe in the experimental pattern under any conditions (Figure S4, Supporting Information). The structure reported for MH is quite unusual (as discussed further below), and it is possible that the missing peaks are genuinely indicative of some kind of structural variation compared to the reported MH structure. However, we have been unable to obtain single crystals of MH suitable for diffraction analysis and we have not been able to resolve this issue to date. Crystal Structures of the AH, MH, and DH forms. The crystal structure of the AH form has been deposited previously in the Cambridge Structural Database (CSD refcode: XOZRUZ),23 and we use that as our reference AH structure. Partial structures (excluding H atoms and anisotropic displacement parameters) of the MH and DH forms at 25 C have been described previously in a patent,22 but we have sought to redetermine these structures to establish as far as possible details of the hydrogen bonding interactions. For

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Figure 4. Projection of the AH structure23 along the a axis showing two bilayers parallel to the (001) planes (horizontal). H-bonds are shown as blue lines. H atoms are omitted.

this purpose, single crystal analysis of the DH was performed at -150 C and also at 25 C to permit direct comparison with room temperature XRPD patterns. Crystals of the MH suitable for single crystal X-ray analysis could not be obtained, and the partial structure available from ref 22 is therefore the best available. All of the structures are characterized by “bilayers” in which the charged portions of the molecules and any water molecules are segregated from the hydrophobic regions at the bilayer surfaces. The AH and DH forms show some similarity. Within one-half of each bilayer, the amlodipine molecules are arranged in a closely comparable manner in the two structures (Figure 4). In the AH structure, the charged ammonium group of amlodipine forms one H-bond to the carbonyl group of a methyl ester side-chain in an adjacent amlodipine molecule, while the other two H atoms point toward the O atoms of besylate anions. An additional short N 3 3 3 O contact is made to an O atom of an ether side chain in an adjacent amlodipine molecule, with the O atom approaching approximately along the N-CH2 bond vector (i.e., toward the centroid of the NH3 face). Each besylate anion accepts H-bonds from two ammonium groups, and also from the NH group of the dihydropyridine ring. Although the H-bond network links the molecules into two-dimensional (2-D) bilayers (parallel to the (001) planes), the H-bonding interactions themselves are confined to one-dimensional (1-D) regions running parallel to the crystallographic a axis. In the DH structure, the NH3þ group of amlodipine forms H-bonds to two water molecules, and a third H-bond to one besylate anion. One O atom of a further besylate anion approaches along the N-CH2 bond vector, forming a similar N 3 3 3 O contact to that seen for the ether O atom in the AH structure. The H-bond motif in this case resembles a cubane in which water molecules make up four corners of the cube, the NH3þ groups make up two corners, and the SO3- groups of besylate make up the remaining two corners (Figure 5). The cubanes are linked through interactions between NH3þ groups and the SO3- groups of neighboring besylate anions. The two water molecules form different numbers of hydrogen bonds: water molecule W1 donates two H-bonds, one to an O atom of a besylate anion and one to the CdO group of a methyl ester substituent, and it accepts two H-bonds, one

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Figure 5. Left-side: projection of the DH structure along the b axis showing one bilayer parallel to the (100) planes (horizontal). H-bonds are shown as blue lines. H atoms are omitted. Right-side: expansion of the “cubane” H-bond motif.

Figure 6. Left-side: projection of the MH structure22 along the b axis showing two bilayers parallel to the (001) planes (horizontal). H atoms are omitted. Right-side: 2-D H-bond motif at the center of each bilayer. Only atoms involved in H bonding are shown, plus the C atoms attached to the SO3- and NH3þ groups.

from the NH3þ group and one from a neighboring water molecule. Water molecule W2 donates two H-bonds, one to a neighboring water molecule and one to an O atom of a besylate anion, but it accepts only one from the NH3þ group. Compared to the AH structure, the besylate anions occupy similar positions relative to the amlodipine molecules, but they are pulled further toward the center of the bilayers to form the H-bonding interactions with water. In both the AH and DH structures, the interactions between bilayers are formed principally between the chlorophenyl substituents and ester groups of amlodipine. The previously reported MH structure22 is unusual in that it has four formula units (C20H26ClN2O5þ, C6H5SO3-, H2O) in the asymmetric unit in the noncentrosymmetric space group Cc. There are obvious (pseudo) inversion centers between the molecules in the asymmetric unit, so that the bilayers themselves are centrosymmetric, but the stacking arrangement is such that these inversion centers are not retained as part of the space group symmetry (for discussion of similar cases see ref 31). The bilayer geometry is quite

different from that in the AH and DH forms. The NH3þ group of each amlodipine molecule forms one H-bond to a water molecule, and two other H-bonds to besylate anions. Each besylate accepts H-bonds from the NH3þ groups and from two water molecules. The resulting motif resembles centrosymmetric six-membered rings, linked by fourmembered rings into an extended 2-D network (Figure 6). The interactions between bilayers are again formed principally between the chlorophenyl substituents and ester groups of amlodipine. Thermal Analysis (TGA, DSC, and HSM). TGA curves are shown in Figure 7, left side. As expected, the TGA curve of AH did not show any weight loss before the postmelting decomposition at 210 C. The AM form exhibited constant weight loss (0.8%) from 25 to 70 C attributed to absorbed water, which is expected due to the hygroscopic nature of the AM form. The TGA curves of MH and DH clearly show distinct dehydration step(s). Dehydration proceeds in a single step for the MH, whereas two separate dehydration steps are observed for the DH. This was also confirmed by

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Figure 7. TGA curves (left) and DSC thermograms (right) of AMB solid forms. The inset figure in the DSC (expanded view of 50-90 C range of the AM form) shows glass transition (Tg). Both TGA and DSC were performed in open pan at a heating rate of 10 C/min. Table 2. Water Content of Monohydrate and Dihydrate Form (n=3) % w/w

monohydrate (MH) dihydrate (DH)

theoretical

TGA data

KF analysis

3.08 5.97

2.80 ( 0.04 5.77 ( 0.13

2.96 ( 0.04 5.74 ( 0.08

the first derivate of the TGA curves. The second dehydration step of DH occurred in a similar temperature range as that of the MH dehydration. Water content data of MH and DH based on the TGA analysis as well as Karl Fischer measurements are given in Table 2. The experimental data are in good agreement with the theoretical water content. The weight loss for the first (40-75 C) and second (75-100 C) dehydration steps of DH is 3.21% and 2.63%, respectively. Thus, approximately one molecule of water is removed during both dehydration steps, and in between, the sample should have a monohydrate composition. On the basis of the TGA data alone, it is not possible to postulate if it is the same monohydrate denoted as MH, and further discussion based on VT-XRPD data is given below. The DSC thermograms (Figure 7, right side) provided a better understanding of thermal phase transformations occurring in the AMB solid forms. It should be noted that the DSC thermograms shown in Figure 7 were obtained in the open pan condition. The AH form shows a melting endotherm at approximately 201 C (ΔHf = 51.54 ( 0.30 kJ/mol) followed by decomposition. In the case of MH, two endotherms at 87 and 201 C, and an exotherm at 135 C are observed (all onset temperatures). The first endotherm at 87 C is due to simultaneous dehydration and melting, on further heating the sample recrystallizes at 135 C and subsequently melts at 201 C. These thermal events in the MH are in agreement with the reported values in the previous work.21 The DH has a similar thermal behavior, but with two distinct dehydration endotherms, at 48 and 87 C, corresponding to the removal of first and second water molecules, respectively. The recrystallization exotherm at 135 C and the final melting endotherm at 199 C of the DH match with the similar events observed in the MH. The enthalpy of dehydration for the first and second step water loss from the DH is 18.55 ( 2.31 and 34.96 ( 1.04 kJ/mol, respectively. The MH dehydration enthalpy is 49.93 ( 0.92 kJ/mol. However, it should be noted that the enthalpies of the MH dehydration and the second step dehydration of the DH also include the melting enthalpy. Overall, DSC measurements

indicate that the complete dehydration of MH and DH leads to collapse of the crystal structure, forming the melt, which subsequently undergoes recrystallization to yield the AH. Supercooling of the melt obtained by dehydration provided a possibility to generate the AM form. A similar approach for preparing an amorphous form via dehydration has been reported for carbamazepine and trehalose.32-35 The AM form obtained from the MH showed a glass transition (Tg) at 72 C, recrystallization at 133 C and final melting at 196 C. Similar results were obtained for the AM form prepared from the DH. The final melting temperature of the recrystallized product from the MH, DH, and AM suggests that it is the same AH form. DSC measurements were also performed in sealed pan conditions with pin holes (Figure S6, Supporting Information). The DSC curves of AH were identical in open and sealed conditions. However, although the final melting temperatures for MH and DH were comparable in both conditions, recrystallization followed immediately after the dehydration during sealed pan DSC. The water released due to the dehydration may remain trapped in the melt, and thus, could facilitate the fast recrystallization while performing a DSC measurement using the sealed pan. The Tg of the AM form was also lowered to 53 C in sealed pan DSC, and this is also attributable to the plasticizing effect of moisture. The sealed pan DSC measurements showed large variation in terms of the dehydration onset temperatures for both hydrates, and open pan measurements were therefore considered more reliable for this work. To investigate any influence of the starting hydrate form on the AM form prepared by dehydration, the AM form was prepared in situ in the DSC pan under open conditions. This approach is most suitable to understand amorphous form characteristics because variability due to the environmental conditions and sample handling can be avoided. First, the dehydration was carried out by heating the MH or DH form at 10 C/min to 110 C, and the sample was kept at this temperature for 1 min to ensure complete dehydration and removal of the liberated water from the sample. Subsequently, the temperature was lowered to 0 C with a cooling rate of 100 C/min, and the temperature was held constant for 10 min. Afterward, the sample was heated at 10 C/min to obtain the thermograms shown in Figure 8. The AM form prepared from either MH or DH showed three events in the DSC thermogram: glass transition, recrystallization, and melting. The peak parameters for these

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events are summarized in Table 3. The onset-midpoint-end temperatures and heat capacity change at Tg are comparable for the AM prepared from both hydrates. However, the recrystallization onset temperature is 152 C for the AM prepared from MH, but 140 C for the AM prepared from DH. To probe molecular level differences between these two AM forms, FTIR and Raman spectroscopy were employed. The spectroscopic data revealed no difference, and thus, the two AM forms were considered to be similar. However, further studies are probably required in order to verify fully the similarity of the AM form prepared from the two hydrates. The melting enthalpy of AH recrystallized from the AM form (Table 3) is lower compared to the melting of

Figure 8. DSC thermograms of the AM form prepared by in situ dehydration of (a) MH and (b) DH form. The arrow in both thermograms indicates glass transition (Tg) event.

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the normal crystalline AH form (51.54 ( 0.30 kJ/mol). This could be due to the incomplete recrystallization from the AM within the time scale of the DSC measurement or partial decomposition during the thermal treatment. To further investigate the dehydration of MH and DH, hot stage microscopy (HSM) was employed. The AH form showed only a melting event at 208 C (Figure S7, Supporting Information), which agrees with the DSC findings. On the other hand, several thermal events were observed during HSM of the DH (Figure 9). At 60 C, the original crystal of the DH showed a change in birefringence, implicating some modification in the crystal structure. On further heating, the crystal fractured at 70 C, with the fractures forming systematically parallel to the (001) planes, and with the extent of the fractures increasing until 90 C. The crystal structure collapsed at 107 C to create a melt, from which nucleation occurred at about 131 C and crystallization of a new phase continued until the final melting at 208 C. These observations are supported by the previously presented DSC data (Figure 4) and VT-XRPD (Figure 8, vide infra). Similar events were observed in HSM of the MH, except for the absence of the first dehydration event (Figure S8, Supporting Information). Sample melting together with dehydration has also been observed for siramesine hydrochloride monohydrate,36 trehalose dihydrate,33-35 erythromycin dihydrate,37 tranilast monohydrate,38 and eprosartan mesylate dihydrate.39 VT-XRPD. The temperature resolved XRPD patterns of the MH and DH (Figure 10) are consistent with the thermal analysis. At 100 C, XRPD patterns of both the MH and DH were devoid of any peaks due to the formation of the melt, as observed in HSM. Recrystallization from the melt was

Table 3. The Peak Parameters for the DSC Events Observed in AM Form Prepared by in Situ Dehydration (n = 3)a AM prepared from MH

glass transition recrystallization melting a

AM prepared from DH

onset (C)

peak/Tg (C)

end (C)

ΔH (kJ/mol)/ ΔCp (kJ/mol 3 C)

onset (C)

peak/Tg (C)

end (C)

ΔH (kJ/mol)/ ΔCp (kJ/mol 3 C)

71.6 ( 0.2 151.9 ( 0.3 194.2 ( 1.9

74.3 ( 0.2 166.2 ( 0.5 201.0 ( 1.3

76.0 ( 0.3 176.8 ( 1.5 204.5 ( 1.3

0.21 ( 0.01 25.12 ( 0.23 27.11 ( 1.47

67.8 ( 0.9 139.8 ( 0.3 198.7 ( 0.3

72.1 ( 0.6 149.8 ( 0.5 204.8 ( 0.8

74.4 ( 0.4 159.4 ( 0.6 206.5 ( 0.9

0.21 ( 0.01 25.35 ( 0.72 33.80 ( 1.27

Values of ΔH and ΔCp are corrected for the weight change upon water loss during the dehydration.

Figure 9. Photomicrographs showing phase transformations of DH form during hot stage microscopy. The initial crystal is viewed along the a axis. The line in the right-hand corner denotes 200 μm. Similar events monitored with the crystal viewed along the b axis and the c axis are given in Supporting Information (Figure S9).

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Figure 10. VT-XRPD patterns of the DH (left) and MH (right). The XRPD patterns of the AH and MH are given for reference.

Figure 11. Characteristic FTIR (left) and Raman (right) spectra of the AMB solid forms.

evident in the diffractograms of both hydrates, with the first appearance of peaks at 130 C and peak intensities increasing until final melting at 200 C. The diffractograms from 130 to 190 C agree well with the AH, and thus confirm that the recrystallized form is AH. In the temperature range of 25 to 80 C, very few changes were observed in the XRPD pattern of either MH or DH, apart from some peak shifts due to thermally induced lattice expansion. Given that the thermal analysis (DSC, TGA, and HSM) clearly showed changes occurring in the same temperature range for DH, the similar XRPD patterns show that the first step dehydration must create an essentially isostructural monohydrate phase (with respect to the DH), which is different from the form labeled MH herein. A reduction in the intensity of the (100) reflection at 2θ ≈ 4.8 is observed over the temperature range, which is consistent with the proposal for the isostructural monohydrate: an XRPD pattern simulated for the DH structure with the water molecules omitted displays a similar reduction in the (100) intensity (Figure S5, Supporting Information). Consequently, a mechanism of dehydration for the DH can be postulated as follows: the first step dehydration occurs with the release of one water molecule per formula unit, rendering minimal change in the crystal lattice, and the second step dehydration is destructive, generating amorphous (melt) phase.17 It is difficult to state conclusively about the removal of individual water molecules, but it could be that water molecule W2 is removed preferentially to W1 since it forms fewer hydrogen bonds. Because of the extreme instability of the isomorphous monohydrate, it was not possible to carry out any further investigations on it.

Spectroscopic Analysis. Spectroscopic methods provide molecular level information about the solid forms and are also better suited to monitor process-induced transformations.40 Spectroscopic analysis of the AMB solid forms was carried out using FTIR, Raman, and NIR spectroscopy. The characteristic FTIR and Raman spectra of all four AMB solid forms are presented in Figure 11, and band assignments are listed in Supporting Information (Table S1). In the FTIR spectrum of the MH, a single absorbance band due to O-H stretching vibrations is observed at 3535 cm-1, which can be attributed to the water of crystallization. Two O-H stretching bands at 3470 cm-1 and 3382 cm-1 are present in the DH, indicating the different hydrogen bond patterns for the two water molecules in the crystal structure. Moreover, both O-H bands in the DH are situated at lower wavenumbers compared to the O-H band of the MH form. Thus, water molecules in the DH are possibly associated with a stronger or a larger number of hydrogen bond(s) than the MH water molecule. The amorphous form shows a broad O-H stretching band centered at 3510 cm-1, which can be ascribed to absorbed water. The O-H stretching band was absent in the FTIR spectrum of the AH form. All four forms show a characteristic N-H stretching band (due to dihydropyridine NH group) in the FTIR spectra. The N-H stretching band positions were observed in order of anhydrate (3299 cm-1)< monohydrate (3305 cm-1) < dihydrate (3327 cm-1) < amorphous (3371 cm-1). The lower wavenumber of the N-H band indicates stronger hydrogen bond involved with this group.41 In the AH crystal structure, the NH group of the dihydropyridine ring forms a bifurcated hydrogen bond (N 3 3 3 O distances: 3.288 and 3.280 A˚) with two O atoms of a

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neighboring besylate anion. The N-H bond strength decreases due to these two hydrogen bonds, and thus the N-H stretching band is at the lowest wavenumber for the AH. In case of MH and DH, the N-H group forms a single hydrogen bond with one O atom of a besylate anion, and thus the N-H band appears at a higher wavenumber compared to the AH. In DH, the N 3 3 3 O distance is relatively long (3.169 A˚ ), while in MH, the distances for the crystallographically independent interactions are generally shorter (3.086, 3.102, 3.110, and 3.172 A˚), consistent with the higher wavenumber observed for DH. The AM form has the highest wavenumber for the N-H stretching (upward shift of 72 cm-1 compared to the AH), and the peak shape appears broad. These observations suggest that the hydrogen bond strength decreases in the amorphous state. Similar phenomena have been observed for amorphous forms of other drug molecules having a dihydropyridine ring.42 The O-H and N-H vibrations could not be measured by the Raman spectrometer used in this work as the spectral region was outside of the instrument range. Both FTIR and Raman analysis show significant differences between AMB forms in the CdO and CdC stretching regions. The bands due to the CdO group are much stronger and well resolved in the FTIR spectra compared to the Raman, whereas the opposite is observed for the CdC stretching vibrations (Figure 11). These observations match with the established selection rules, wherein FTIR and Raman spectroscopy are sensitive for CdO and CdC vibrations, respectively.43 The AMB molecule possesses two CdO groups from ethyl ester and methyl ester side chains (Figure 1). The FTIR spectrum of the AH form gives two absorbance bands at 1674 cm-1 and 1699 cm-1, which are associated with the CdO stretching mode. On the basis of the crystal structure, the lower wavenumber peak 1674 cm-1 can be assigned to the methyl ester carbonyl, which accepts an NH 3 3 3 O = C hydrogen bond (N 3 3 3 O distance: 2.838 A˚). The peak at 1699 cm-1 is attributed to a non-hydrogen bonded carbonyl group of the ethyl ester side chain. The DH showed two CdO bands, at 1681 cm-1 and 1695 cm-1, which are associated with hydrogen bonded methyl ester carbonyl and non-hydrogen bonded ethyl ester carbonyl, respectively. The methyl ester carbonyl in the DH accepts a hydrogen bond from a water molecule with O 3 3 3 O distance of 2.819 A˚. The MH and AM exhibit only one CdO band at 1689 and 1691 cm-1, respectively. This single band is thought to be composed of contributions from both carbonyl functions, and the relatively high wavenumber indicates that these groups do not accept hydrogen bonds. In case of the AM, the carbonyl band is broad, which is also consistent with the absence of hydrogen bond interactions. Generally, the carbonyl band position(s) for all forms is toward a lower wavenumber (all below 1700 cm-1) than might be expected, as a result of resonance of the CdO groups with CdC bonds of the dihydropyridine ring.44 This observation is supported by the crystal structures, which show that the dihydropyridine ring and ester side chains are nearly coplanar. The Raman spectra of all forms show a single peak at 1695 cm-1 due to CdO stretching. A peak due to conjugated CdC stretching is prominent in the Raman spectra, and is present at 1651 cm-1 in the AH, at 1647 cm-1 in the MH, at 1642 cm-1 for the DH, at 1649 cm-1 for the AM. This region is highly useful to distinguish the different forms based on the Raman spectroscopy. The FTIR spectra show CdC peaks at similar positions as that of Raman, but with rather weak intensity.


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Figure 12. FTNIR spectra of the AMB solid forms.

The strongest peak in the Raman spectra of all forms was observed around 1000 cm-1 originating from C-C ring vibrations. The most significant differences in the FTNIR spectra were observed in the O-H overtone and combination regions (Figure 12). A band due to the O-H combination was observed at 5147 cm-1 and 5141 cm-1 in the MH and the DH, respectively. The first overtone of O-H stretching vibrations was observed at 6940 cm-1 in the MH and at 6842 cm-1 in the DH. The O-H bands in the FTNIR spectra of the MH and DH further confirm the presence of water molecules in their structure. The broad O-H combination band centered at 5161 cm-1 in the AM form is due to the absorbed water as observed earlier by TGA and FTIR. As expected, the AH form did not show any band due to the O-H group. Apart from this, there are subtle but consistent differences in the C-H overtone region in the FTNIR spectra, and the four solid forms of AMB were readily distinguishable by FTNIR spectroscopy. Solubility Measurements and Thermodynamic Analysis. Solubility difference among the solid forms is a key parameter to be evaluated during pharmaceutical development because the change in solubility of a drug usually also changes its dissolution rate, which may subsequently modify bioavailability and product performance.4-6 The solubility profiles of the AMB solid forms in water at 37 C are shown in Figure 13. The difference between the solubility profiles of the AMB forms is quite evident. The observed kinetic solubility (measured as the highest solubility value in the profile) is in the order of AH > MH > DH (Table 4). This is expected because hydrate forms usually have a lower kinetic solubility and dissolution rate in water compared to the anhydrate form, and the solubility decreases with an increase in the hydration level45 (although exceptions to this generalization are also reported46-48). Along with the solubility measurements, the residual solid phase was also analyzed to verify the solid form using XRPD, Raman and FTNIR. It was found that the AH and MH transform to the DH during measurements, and final equilibrium solubility is thus similar for these forms. This indicates that the DH is thermodynamically the most stable form at the employed experimental conditions, and that AH and MH are metastable. It is often difficult to determine solubility of the metastable forms if they undergo immediate transformation to the stable form.15,49 In this study, AH and MH were stable for a sufficiently long period to permit their solubility determination. However, the AM immediately converts to MH upon contact with water and subsequently transforms to the DH. Thus, the obtained kinetic

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Figure 13. Solubility curves of the AMB solid forms in water at 37 C. Each point in the curve is an average of three individual measurements. Table 4. Kinetic Solubility Values of the AMB Forms in Water at 37 C solid form

kinetic solubility (mg/mL)

AH to form solubility ratio

AH MH DHa AMb

4.46 ( 0.14 3.78 ( 0.03 2.93 ( 0.03 3.80 ( 0.16

1.2 1.5 1.2

a This is also equilibrium solubility for DH. b Actual kinetic solubility could not be measured due to rapid transformation to MH.

solubility value for AM corresponds to the MH, and it was not possible to measure the actual kinetic solubility of the AM. The solvent-mediated transformation, as observed here, is governed by two steps: dissolution of the metastable phase and subsequent nucleation and growth of the stable phase.8,50 Solubility profiles show that AH and MH quickly attained the peak solubility, thus dissolution is not the rate limiting step for transformation. Afterward, these metastable forms existed for a long period of time before the transformation to the stable DH was started. The induction time for the initiation of AH to DH and MH to DH transformation was 44 and 19 h, respectively. On the basis of these longer induction times, transformation is considered to be limited by either nucleation or growth of the stable phase. In the case of the AM form, the first transformation to the MH (AM to MH) and the second transformation to DH (MH to DH) are relatively faster. This might be due to a higher supersaturation generated by the dissolution of the AM, which can provide a driving force for the faster transformation kinetics. On the other hand, it was observed that the AH directly converts to the DH without having an intermediate MH form. The transformation of AM, AH, and MH to DH in the aqueous environment possibly indicates that a similar phenomenon could also occur during wet processing steps, such as granulation and coating. It is worth mentioning that during the solubility experiments formation of free base was not observed. To gain further insight into the thermodynamics of the AH, MH, and DH forms, additional kinetic solubility measurements were conducted in water at 10, 25, 42, 47, 51, and 55 C. On the basis of the generated solubility data, plots were constructed using a van’t Hoff equation (eq 1). ln s ¼ -

ΔHsθ ΔSsθ þ RT R

ð1Þ

where s is the mole fraction solubility, ΔHsθ is the enthalpy of solution, ΔSsθ is the entropy of solution, R is the gas constant (8.314 J K-1 mol-1), and T is the absolute temperature. It is assumed that ΔHsθ and ΔSsθ do not change significantly over

Figure 14. The van’t Hoff plot for the AH, MH, and DH forms of the AMB. Solubility data were obtained in water at different temperatures. The inset graph shows the expanded view of the AH-MH and AH-DH transition temperatures (Tt), observed at 64 and 71 C, respectively. The MH-DH transition temperature is found at 85 C. At 10 and 25 C, AH and MH were transformed to the DH (based on the XRPD analysis of the solid phase). Therefore, these temperatures are not included in the van’t Hoff plot of the AH and MH.

the temperature range and that the measured kinetic solubility represents the equilibrium solubility for the metastable phases. Consequently, ΔHsθ and ΔSsθ can be calculated from the slope and constant of the regression line of the van’t Hoff plot, respectively. Furthermore, the intersection of the individual solid form solubility line indicates the transition temperature between the anhydrate-hydrate forms.51,52 This interpretation stems from the fact that the Gibb’s free energy difference (ΔG) between the two forms is zero at the transition temperature, so that the solubilities should also be the same. Van’t Hoff solubility plots for AH, MH, and DH are shown in Figure 14. Solid residuals from the solubility measurements were measured using XRPD to check any phase transformations. AH and MH were completely transformed to the DH at 10 and 25 C, and therefore these data points were excluded in van’t Hoff analysis. For the 37 C point, kinetic solubility values of AH and MH (where both forms were found to be phase pure) were used. No transformation was observed at higher temperatures for any of the forms. The van’t Hoff plots are linear for the three forms indicating that ΔHsθ is constant over the studied temperature range. The transition temperature (Tt) is calculated as 64 C for the AH-MH pair, 71 C for the AH-DH pair, and 85 C for the MH-DH pair. Thermodynamic parameters based on the van’t Hoff plots are given in Table 5. The ΔHsθ values are more endothermic for the MH and DH than for the AH, corresponding to negative enthalpies of hydrate formation (ΔHh). Thus, hydrate formation is more favorable with decreasing temperature. Three pairs (AH-MH, AH-DH, MH-DH) need to be interpreted separately to understand the thermodynamic stability in equilibrium with water. In the case of the AHMH pair, AH is the stable form above 64 C, and below that temperature MH is stable. Similarly, for the AH-DH pair, AH and DH are stable above and below 71 C, respectively. Thus, starting with either MH or DH and increasing the temperature, both should give the AH, at least above 71 C. This phenomenon has significant implications for the MHDH pair in that the transition between them at 85 C is

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Table 5. Values of the Thermodynamic Parameters Obtained from van’t Hoff Plots enthalpy of solution (ΔHsθ, kJmol-1)a entropy of solution (ΔS sθ, Jmol-1K-1)b

AH

MH

DH

30.70 24.33

35.07 37.30

37.38 46.24

a From the slope of van’t Hoff plot (slope = -ΔHsθ/R). b From the constant of the regression line (constant = ΔSsθ/R).

practically unattainable, because both would convert to the AH before this temperature. On the basis of the foregoing discussion, thermodynamic stability can be summarized as (1) AH is the stable form above 71 C; (2) DH is the stable form below 71 C; (3) MH is metastable with respect to the AH and DH depending on the temperature. The stability of MH is better in the narrow temperature range of 64-71 C. The thermodynamic data correspond to the phase transformations observed at 37 C, where the DH was found to be the stable form (Figure 13). Thus, the crystallization of the MH from the aqueous solution is mainly due to kinetic factors, which favor the nucleation and growth of the less-stable MH compared to the stable DH form.53,54

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Acknowledgment. The Drug Research Academy (Copenhagen, Denmark) and H. Lundbeck A/S (Copenhagen, Denmark) are thanked for financial support. Matrix Laboratories Limited is thanked for providing amlodipine besylate sample. The technical assistance of Flemming Hansen, Department of Chemistry, University of Copenhagen, with collecting X-ray data is gratefully acknowledged. The grant from Lundbeckfonden (Copenhagen, Denmark) for the purchase of X-ray powder diffractometer is also acknowledged (grant decision 479/06). Supporting Information Available: XRPD pattern of the AM prepared by dehydration of the DH form; comparison of the powder pattern calculated from the DH structures determined at -150 and 25 C; discussion of the MH structure; DSC thermograms measured using sealed pan; HSM photographs of the AH and MH; HSM photographs of the DH along the b and c axis; table listing H-bond geometries in the AH and DH structures at 25 C: table listing tentative band assignments for Raman and FTIR spectra; crystallographic data (CIF) for the MH and DH structures. This information is available free of charge via the Internet at http:// pubs.acs.org/. CCDC-785520 and CCDC-785521 contain the supplementary crystallographic data for the structure determination.

References Conclusions Four different solid forms of amlodipine besylate (AMB) were prepared: anhydrate (AH), two hydrates, monohydrate (MH) and dihydrate (DH), and amorphous (AM). The solidstate properties of these forms were understood using a variety of analytical methods. Thermal analysis using DSC and HSM indicated a series of phase transformations for the MH and DH. Upon complete dehydration, both hydrates created melt, which subsequently recrystallized to the AH. This phenomenon was further exemplified from the VT-XRPD data. Formation of the chemically stable melt due to dehydration was utilized to produce the AM form, and this phenomenon has shown potential use of the dehydration to modify the solid-state properties. For the DH, one water molecule per formula unit could be removed without affecting the crystal structure, thereby creating an isomorphous monohydrate phase different from the MH phase described herein. The extreme instability of this form prevented any further study of it. The kinetic solubility was in the order of AH > MH > DH. The AH and MH converted to the DH during the course of the solubility measurement. Solvent-mediated transformation of the AH and MH occurs with fast dissolution and very slow nucleation or growth of the DH phase. No solubility advantage was found with the AM due to the very fast conversion to the MH. This calls for amorphous stabilization approaches to realize a solubility increase from the AM form. Van’t Hoff analysis showed that DH is the stable phase below 71 C, and AH is stable above this temperature. The MH was found to be metastable with respect to the AH and DH depending on the temperature. The reason for crystallization of the MH is mainly dominance of kinetic factors over thermodynamics. Spectroscopic investigations using FTIR, Raman, and FTNIR provided an insight into the molecular level interactions, and the results were in accordance with the crystal structure observations. Temperature-induced and aqueous environment mediated phase transformations observed here are important for the pharmaceutical processing, and necessitate proper monitoring and control strategy. The processing steps selected for dosage form manufacturing should be based on the solid form chosen.55

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