Sucrose Conformational Polymorphism: A Jigsaw Puzzle with Multiple

Sucrose Conformational Polymorphism: A Jigsaw Puzzle with Multiple Routes to a Unique Solution Tu Lee* and Gen Da Chang Department of Chemical & Materials Engineering, National Central UniVersity, 300 Jhong-Da Road, Jhong-Li City 320, Taiwan, R.O.C.

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 8 3551–3561

ReceiVed March 13, 2009; ReVised Manuscript ReceiVed June 10, 2009

ABSTRACT: Scale-up sucrose crystals grown from a furfuryl alcohol-water sucrose solution at 60 °C exhibited a wide endothermic peak from 140° to 170 °C by differential scanning calorimetry (DSC) at 10 °C/min, whereas commercial sucrose crystals displayed only one sharp melting peak around 185° to 189 °C. Surprisingly, it was found that the inclusion of trace amounts of salts and water or degradation of sucrose did not offer a satisfying explanation for the occurrence of the wide low-melting peak from 140° to 170 °C. On the basis of powder X-ray diffraction (PXRD), single-crystal X-ray diffraction (SXD), solid-state nuclear magnetic resonance (SSNMR), Fourier transform infrared spectroscopy (FTIR), hot-stage optical microscopy (HSOM), variable temperature powder X-ray diffraction (VT-PXRD), electron spectroscopy for chemical analysis (ESCA), and solubility measurements, one possible explanation for the low-melting peak in differential scanning calorimetry (DSC) was because the sucrose crystals grown from the furfuryl alcohol-water sucrose solution at 60 °C consisted of sucrose molecules having different degrees of conformational disorders about the -CH2-OH functional groups of the fructofuranose ring such that the inter-residue intramolecular hydrogen bonds between the hydroxyl groups and the glucopyranose ring oxygen were misaligned. The activation energy, Ea, and the enthalpy, ∆H, for the polymorphic transformation of the low melting metastable polymorph around 150° to 160 °C to the high melting thermodynamically stable form around 185 °C were 185.2 kJ/mol (i.e., 44.2 kcal/mol) and 2.9 kJ/mol (i.e., 0.7 kcal/mol), respectively. This polymorphic transformation could be kinetically controlled by mass-transfer through viscosity, solvent evaporation rate, and mixing. However, under the orchestration of intermolecular and intramolecular hydrogen bonds, the polymorphic transformation could be achieved by different pathways in different microdomains to produce various degrees of conformational polymorphs if the micromixing was poor. As a result, a mixture of crystals or microdomains with a wide range of melting temperatures and relatively high solubility were produced. Introduction Self-assembly and self-recognition of molecules, atoms, or ions under the orchestration of intermolecular forces often give rise to several long-range packing orders.1 Each of this order at the sub-nanometer level in the solid state is called a crystal polymorph. Therefore, each polymorph is a unique material with its own thermodynamic, spectroscopic, kinetic, surface, and mechanical properties in the solid state.2 However, sucrose (Figure 1) is commonly believed to exist only in monoclinic hemihedral form3-6 which generally melts and decomposes around 185° to 190 °C.7 Although melting points between 160° and 192 °C were observed,7 the temperature variations were thought to be the sole consequences of the melting determination method,7 the sample sources,7 traces of impurities,8 and the thermal degradation.9 However, recently the occurrence of an earlier endothermic peak at 150 °C has been observed for the sucrose solids which were recrystallized from an undersaturated aqueous solution with a concentration of 100 g of sucrose in 25 mL of water by cooling from 128° to 25 °C.10 Interestingly, based on the differential scanning calorimetry (DSC) and the supplementary experiments of adding mineral salts, adding aprotic solvents, and increasing the stirring speed to significantly reduce the value of the enthalpy of the endothermic peak at 150 °C, it was inferred that (1) water inclusion in the crystal lattice was responsible for the appearance of the endothermic peak at 150 °C, and (2) the available water was reduced by the affinity of added impurities and by the increased rate of crystal nucleation and growth via good mixing.10 * Corresponding author. Telephone: +886-3-422-7151 ext. 34204. Fax: +8863-425-2296. E-mail: [email protected].

Figure 1. The molecular structure of sucrose, C1 of glucose and C2′ of fructose are joined by a glycoside link. The inter-residue hydrogen bond took place between C6′-O-H · · · O-C5 from the fructofuranose to the glucopyranose residue (labeled as red bonds) and the intramolecular hydrogen bond occurred between C5-O · · · H-O-C6 (labeled as blue bonds).

As yet, a sound explanation for the mysterious appearance of the endothermic peak around 150 °C for some crystalline sucrose has been of paramount importance, especially if the peak at a lower temperature such as the one at 150 °C did point to the existence of a new polymorph as discovered in many other cases.11-13 This is because the presence of a new polymorph would presumably affect the solubility, melting point, and mechanical and even piezoelectric properties not only in the quality of waffles and cotton candy14 but also in the many latest advanced applications of sucrose such as added functionality excipients (AFEs),15 microemulsion glasses,16 sugar holograms,17 sacrificial sugar structures for an artificial 3-dimensional vascular network,18 directly compressible excipients,19 and triboluminescent damage sensors.20 Only by truly comprehending the cause of the mysterious appearance of the endothermic peak around 150 °C can a tight quality control of sucrose be possibly made by a manufacturing protocol.

10.1021/cg900294d CCC: $40.75  2009 American Chemical Society Published on Web 06/23/2009

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Although we had repeatedly recrystallized sucrose with the endothermic peak at 150 °C from the methanol-water solution at 60 °C, which contained less water than the commercially available sucrose without the peak at 150 °C,21 the aim of this paper is 4-fold: (1) to find a better process to produce sucrose with a stronger endothermic peak at 150 °C, (2) to verify the existence of a new sucrose polymorph thoroughly by hot-stage optical microscopy (HSOM), scanning electron microscopy (SEM), single crystal X-ray diffraction (SXD), solid-state nuclear magnetic resonance spectroscopy (SSNMR), and variable temperature powder X-ray diffraction (VT-PXRD) in addition to other conventional characterization methods21 such as differential calorimetry (DSC), thermal gravimetric analysis (TGA), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR), and Karl Fisher titrimetry, (3) to determine the solubility, melting point, dissolution rate of sucrose with a significant endothermic peak at 150 °C, the activation energy, and the enthalpy for the polymorphic transformation, and (4) to understand how the operating conditions of the crystallization process affect the polymorphism of sucrose. Materials and Methods Chemicals. Sucrose (C12H22O11, reagent grade, 99.9%, invert sugar: to pass test, ignition residue (sulfate): max 0.01%, acid (as CH3COOH): max 0.006%, chloride (Cl): max 5 ppm, sulfate (SO4): max 0.003%, calcium (Ca): max. 0.003%, lead (Pb): max. Three ppm, iron (Fe): max 5 ppm, MW ) 342.30, Lot: ST-2541H) was purchased from Showa Chemical Co. Ltd. (Tokyo, Japan). A commercial granulated sucrose with a purity of 99.6% was obtained from Domino Foods, Inc. (New York, USA). L-(+)-Ascorbic acid (Vitamin C) (C6H8O6, 99.7%, MW ) 176.13, mp ) 190°-192 °C, Lot: 70390) was received from Sigma Aldrich Co. (Steinheim, Germany). Microcrystalline cellulose (MCC, PH-101) (C6H10O5)220, > 80%, MW ) 36000, Lot: 1512) was purchased from Asahi Kasei (Tokyo, Japan). Sodium phosphate monobasic monohydrate (NaH2PO4 · H2O, 99.6%, FW ) 137.99, Lot: E07165) was obtained from Mallinckrodt Baker, Inc. (New Jersey, USA). Solvents. Methanol (CH3OH, HPLC-Spectro grade, 99.9%, MW ) 32.04, bp ) 64.7 °C, Lot: 411070) was bought from Tedia Company (Fairfield, OH, USA). Furfuryl alcohol (C5H6O2, 98%, MW ) 98.1, bp ) 170 °C, Lot: 1012748) was purchased from Acros Organics Company (New Jersey, USA). Tetrahydrofuryl alcohol (C5H10O2, 99%, MW ) 102.1, bp ) 178 °C, Lot: A02037690) was received from Alfa Aesar (Massachusetts, USA). Ethanol (CH3CH2OH, HPLC-Spectro grade, 99.5%, bp ) 78 °C, MW ) 46.7) was obtained from Echo Chemical Co. Ltd. (Taipei, Taiwan). Standard solutions of sodium 1000 ( 3 µg/mL in 1% HNO3 (Lot: 0717321) and potassium 1000 ( 3 µg/ mL in 1% HNO3 (Lot: 0728814) for inductively ion plasma were purchased from High-Purity Standards (Charleston, SC, USA) and reversible osmosis (RO) water was clarified by a water purification system (model Milli-RO Plus) bought from Millipore (Billerica, MA). Preparation of Sucrose Crystals. Two kinds of crystal were under investigations: (1) commercial sucrose (CS) from Showa Chemical Co. Ltd. (reagent Showa CS) and Domino Foods, Inc. (Domino CS), and (2) the recrystallized sucrose (RS) from a 1:1 v/v methanol-water at 60 °C (MRS), a 1:1 v/v furfuryl alcohol22-water at 60 °C (FARS) and a 1:1 v/v tetrahydrofuryl alcohol22-water at 60 °C (TARS). RS was prepared as follows: 1 mL of furfuryl alcohol or 1 mL of tetrahydrofuryl alcohol preheated at 60 °C was added all at once into the saturated aqueous sucrose solution containing 2.87 g of CS and 1 mL of water in a 20 mL scintillation vial with intermittent shaking. After 5-7 days, the recrystallization of sucrose was complete. RS crystals were filtered and vacuum-dried at 40 °C for 24 h. FARS crystals were also scaled up as follows: 176.3 g of reagent Showa CS were dissolved in 60 mL of water in a 350 mL three-neck round-bottomed flask at 60 °C. 60 mL of furfuryl alcohol preheated at 60 °C were added slowly into the saturated aqueous sucrose solution. The solution was stirred at 500 rpm until it turned cloudy in 50-60 min. Recrystallization

Lee and Chang was complete in 5-7 days. FARS crystals were filtered, rinsed by acetone, and vacuum-dried at 40 °C for 24 h. The yield was about 70 wt %. Solubility Curves. About 10 mg of sucrose samples were weighted in a 20 mL scintillation vial. Drops of water were titrated carefully by a micropipet into the vial with intermittent shaking until all sucrose solids were just dissolved. The solubility of sucrose in water at a given temperature was calculated as the weight of sucrose in a vial divided by the total volume of water added to a vial. Solubility of sucrose in water at five different temperatures of 5°, 15°, 25°, 40°, and 60 °C was determined. All temperatures were maintained and controlled by a water bath. Although the gravimetric method appeared to have an inherent inaccuracy of about ( 10%, its advantages were its robustness, simplicity, without the need of performing any calibration, and without the concern of solvate formation. All measurements were repeated at least three times. Preparation of Ball Milled Sucrose Powders. Showa CS and FARS were milled by a ball miller (type: MUBM-236-RTD, series no.: 061025, Shin Kwang Machinery, Taiwan) to standardize the particle size distribution. 50 g of sucrose was added to the 1.5 L ceramic jar filled with 36 ceramic balls with 2 cm in diameter. The jar was rotated at 335-341 rpm for 120 min. Particle Size Control and Analysis. Ball milled sucrose powders were passed through a stack of metal sieve plates from the largest aperture to the finest in the order of 500 µm, 350 µm (Der Shuenn, Taiwan), 250 µm, 150 µm, 75 and 45 µm (Cole-Palmer, Illinois, USA). To eliminate the unwanted mesh plugging and to minimize particle breakage and aggregation on the mesh, a small sample loading of 0.8-1.0 g of powders was placed at the center of the 500 µm sieve plate first. Vibration was generated by holding the 500 µm sieve plate with one hand and tapping the sieve plate sideways with a spatula by another hand until no more powders (or granules) on the 500 µm sieve plate passed through by eye. Particles which passed through the 500 µm were collected on the surface of the 350 µm sieve plate. The same shaking method was then repeated successively for other sieve plates with smaller-sized openings. Only the powders retained on the 75-µm sized sieve were considered as primary crystals as double checked by optical microscopy. The true particle size distributions of the “75-µm sized cut” ball milled reagent Showa CS and scale-up Showa FARS were characterized by Beckman Coulter LS 230 particle size analyzer with a micro volume module (Fullerton, CA, USA) by dispersing about 0.1 g of sucrose powders in 20 mL of 99.5% ethanol. The “75-µm sized cut” ball milled reagent Showa CS and scale-up Showa FARS would be considered for use in formulations to ensure surface uniformity. Wet Granulation. 217.5 g of vitamin C, 7.5 g of microcrystalline cellulose, and 5 g of sucrose23 were dry blended in a planetary mixer with an 8-L bowl (Tian Shuai Food Machine CO., LTD, Taiwan) for 3 min with a rotation speed of 135 rpm. Water was then added to the mixer at a flow rate of 2-2.5 mL/min through a metering pump for 17-20 min. The wet granules were then oven-dried at 50 °C until there was no significant weight loss. Dried granules between the 1.19 mm sieve plate with a diameter of 25 cm (mesh no. 16, Der Shuenn, Taiwan) and the 500 µm sieve plate with a diameter of 11.5 cm (mesh no. 35, Der Shuenn, Taiwan) were collected for dissolution studies. 0.523 g of formulation (i.e., 500 mg of vitamin C) was weighed out for each dissolution trial. Dissolution Rate Determination. A dissolution test station (SR6, Hanson Research Corporation, Chatsworth, CA, USA) type II (paddle method) at rotation speed of 50 rpm was used for in vitro testing of vitamin C dissolution from the various formulated granules grown from different RS and CS. Dissolution was carried out on an equivalence of 500 mg of vitamin C. Consequently, 528 mg of the formulated granules were weighed out on a piece of weighing paper, transferred and added directly to the dissolution medium. Ultrapure water with the pH adjusted to 7 by the addition of sodium phosphate monobasic monohydrate was used as the dissolution medium. The volume and temperature of the dissolution medium were 900 mL and 37.0 ( 0.2 °C, respectively.24 Instrumentations. Electrical Conductance. An electrical conductivity meter (CONSOR K611, Conductivity Instruments, Turnhout, Belgium) was used to monitor the conductivity of the 900 mL of vitamin C aqueous solution as a function of time. Data were collected for every 5 s for the first 6 min and every 10 s for the next 14 min. The measured conductivity (µS), y, was converted into the corresponding concentration (mg/mL), x, by a linear correlation of y ) 1.5663 - 0.2704x based on

Sucrose Conformational Polymorphism five different sample concentrations. The instrument was calibrated with 0.01 M of KCl each time before use with an extrapolated conductivity of 1413 µS at 25 °C. Hot-Stage Optical Microscopy (HSOM). Microscopy was performed on Olympus BX51 microscope using a Linkam THMS 600 hot stage (Linkam Scientific Instruments, Surrey, UK) equipped with a digital camera (Moticam 2000 2.0 M Pixel USB2.0; Motic, Inc., Xiamen, China) to take images. Crystal habits and melting of sucrose were visualized using Motic Images Plus 2.0 ML (Motic, Inc., Xiamen, China) with a Linkam temperature controller (CI94; Linkam Scientific Instruments, Surrey, United Kingdom) for hot stage control. Contact thermal microscopy was conducted by heating from room temperature using a 10 °C/min heating rate and discontinued on melting of all materials. Scanning Electron Microscopy (SEM). Samples of sucrose were mounted on an aluminum stub by a double-sided carbon conductive adhesive tape (product number 16073, Ted Pella Inc., Redding, CA). The solid sample was sputter-coated with a 6-nm thick gold film in a Hitachi E-1010 Auto Sputter Coater (Hitachi Ltd., Tokyo, Japan). SEM was carried out using a Hitachi S-3500N (Hitachi Ltd., Tokyo, Japan) instrument equipped with a tungsten filament cathode source. Goldcoated samples were examined with beam energies of 15 kV with a chamber pressure of 10-5 Pa (resolution of ∼3 Å at these voltages). Single Crystal X-ray Diffraction (SXD). Single crystal X-ray diffraction (SXD) data of sucrose samples were recorded on the Siemens SMART CCD-based Bruker X8 APEX X-ray diffractometer (Karlsruhe, Germany) equipped with Mo KR source (λ ) 0.7137 Å) operated at 3 kW. Data collection was performed by Bruker Apex2 software package, and the structure was solved and refined using Bruker SHELXTL version 5.10 software package. Size of the crystal sample was 0.1-1.0 mm. Crystal packing plot of SXD was drawn by Diamond 3.1 computer software (Crystal Impact GbR, Brandenberg Germany). Solid-State NMR Spectroscopy (SSNMR). All solid-state NMR spectra were used to identify polymorphism of sucrose. All SSNMR spectra of sucrose were acquired on a Varian Infinity Plus-500 NMR spectrometer which was equipped with a Chemagnetics 5.0 mm magic angle spinning (MAS) probe and a double-tuned wide-line probe. The Larmor frequencies for 13C were required at 125.36 MHz. MAS of the samples in the range of 5 kHz was employed for obtaining 13C and 1H NMR spectra. The Hartmann-Hahn condition for 13C crosspolarization (CP) experiments was determined using adamantine (ADS). The 13C and 1H chemical shifts were externally referenced to ADS at 38.56 and 29.50 ppm. The 13C CP/MAS NMR spectra were also recorded as a function of contact time of 1 ms. Differential Scanning Calorimetry (DSC). DSC analysis was mainly used to identify the enthalpy of fusion and solid-liquid (melting) temperature. Thermal analytical data of 3-5 mg of samples in perforated aluminum sample pans (60 µL) were collected on a PerkinElmer DSC-7 calorimeter (Perkin-Elmer Instruments LLC, Shelton, CT, USA) with a temperature scanning rate of 10 °C/min from 50° to 200 °C under a constant nitrogen 99.990% purge. The instrument was calibrated with indium and zinc 99.999% with reference temperatures of 156.6° and 419.47 °C, respectively (Perkin-Elmer Instruments LLC, Shelton, CT, USA). Additionally, the activation energy required for the polymorphic transformation was obtained by DSC measurements at six different heating rates of 2°, 5°, 10°, 15°, 20°, and 25 °C/min. Thermal Gravimetric Analysis (TGA). TGA analysis was carried out by TGA 7 (Perkin-Elmer, Norwalk, CT, USA) to monitor sample weight loss as a function of temperature. The heating rate was 10 °C/ min ranging from 50° to 350 °C. Weight loss was usually associated with solvent evaporation close to the boiling point of a solvent as in the case of solvates or sample decomposition. The open platinum pan and stirrup were washed by ethanol and burned by spirit lamp to remove all impurities. All samples were heated under nitrogen atmosphere to avoid oxidization. About 3 mg of sample were placed on the open platinum pan suspending in a heating furnace. Powder X-ray Diffraction (PXRD). PXRD diffractograph at 25 °C provided another piece of information for the polymorphism and crystallinity of sucrose solids. PXRD diffractograms were detected by Bruker D8 Advance (Germany). The source of PXRD was Cu KR (1.542 Å) and the diffractometer was operated at 40 kV and 41 mA. The X-ray was passed through a 1 mm slit and the signal a 1 mm slit, a nickel filter, and another 0.1 mm slit. The detector type was a scintillation counter. The scanning rate was set at 0.05° 2θ/s ranging from 5° to 35°. The quantity of sample used was around 20-30 mg.

Crystal Growth & Design, Vol. 9, No. 8, 2009 3553 To minimize the preferred orientation for the disappearing PXRD diffraction peaks, sucrose powders were mounted on a glass substrate smeared with silicon grease to randomize the sample orientation effect. Variable Temperature Powder X-ray Diffraction (VT-PXRD). VT-PXRD diffractographs at 30°, 130°, 140°, 160°, 180°, and 190 °C provided other pieces of information for the temperature dependence of the polymorphism and crystallinity of sucrose solids. VT-PXRD diffractograms were collected by Philips (PANalytical, Almelo, The Netherlands) X’Pert Pro MRD System (PW3040/60 type). The source was a Cu KR (1.542 Å) X-celerator which was operated at 40 kV and 50 mA. The scanning rate was set at 0.03° 2θ/s ranging from 5° to 35°. The time step was 32 s and the heating rate was 10 °C/min. The quantity of sample used was around 20-30 mg. Transmission Fourier Transform Infrared (FTIR) Spectroscopy. Transmission FTIR spectroscopy was utilized to measure purity, detect bond formation, and verify chemical identity. Transmission FTIR spectra were recorded on a Perkin-Elmer Spectrum One spectrometer (Perkin-Elmer Instruments LLC, Shelton, CT, USA). The KBr sample disk was scanned with a scan number of 8 from 400 to 4000 cm-1 having a resolution of 2 cm-1. Polarimetry. Samples were diluted by weight and their optical rotation at λ ) 589 nm (the yellow sodium D line) in a 1 dm cell, measured using an ATAGO Polax-2 L polarimeter (Hipont Corporation, Kaohsiung, Taiwan R.O.C.) at 25 °C. The specific rotation,

[R]D )

100R lC

(1)

where R ) observed rotation in degree, l ) path length in dm, and C ) concentration of sample (12 g of sample/100 mL of water). Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES). The ICP-AES used for this work was the HORIBA Jobin Yvon JY24 (Edison, USA). Plasma conditions were as follows: conventional ICP-AES torch, rf power: 1.0 kW, reflected power e10 W, plasma argon gas flow: 14 L/min, auxiliary argon gas flow: 1.0 L/min, and nebulizer argon gas flow: 0.8 L/min. Calibration curves for Na+ ion and K+ ion concentrations were established based on the five different concentrations of 1, 5, 10, 25, and 50 ppm prepared from the standard solutions. Electron Spectroscopy for Chemical Analysis (ESCA). The ESCA VG-Scientific sigma probe manufactured by Thermo (East Grinstead, U.K.) with a probe size of 400 µm was used to determine traces of heavy metals and organic impurities in sucrose powders. All sucrose powders were mounted on a copper conductive tape (Prod. No. 16074, TED Pella Inc., California, USA). All sucrose powders in a preparation chamber were first vacuumed down to 10-8 torr before being transferred to an analytical chamber of 10-10 torr. A Super Dynamic II CCD camera (Panasonic, Tokyo, Japan) was used to locate the area of analysis. The spectra were collected on a monochromatic spectrometer (Thermo Electron Corporation, Minneapolis, MN, U.S.A.) using an Al KR source (600W, 1486.6 eV). The angles of incidence and reflection of the X-ray made with the crystal surface were 45°. The survey scan ranged from 0 to 1400.00 eV in 1.00 eV step. Karl Fisher Titrimetry. Bulk water contents of CS and RS were determined by a moisture meter (model DL-38, Mettler Toledo, Columbus, OH, USA). Samples in the 5-10 mg range were weighed by difference and quickly transferred to the titration vessel containing anhydrous methanol prior to volumetric titration. All water contents were reported as weight/weight ratios.

Results and Discussion DSC thermograms in Figure 2 demonstrated that Showa FARS (Figure 2C) and Showa TARS (Figure 2D) both exhibited a very pronounced endothermic peak at 150 °C as opposed to the subtle endotherm around 150 °C and a sharp melting endotherm around 185° to 188 °C for reagent Showa CS7,9,10 (Figure 2A with an enlarged scale in y-axis) and Showa MRS21 (Figure 2B). Interestingly, the TGA measurements in Figure 3 did not show any weight loss in the temperature range of 150°-200 °C until around 260 °C when the decomposition had clearly started.7,9 This indicated that the endotherms observed at 150 °C in DSC scans (Figure 2C,D) were not due to

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Figure 2. DSC scans of (A) reagent Showa CS, (B) Showa MRS, (C) Showa FARS, and (D) Showa TARS.

Figure 4. SEM micrographs of (A) reagent Showa CS, and (B) scaleup Showa FARS (scale bar ) 500 µm). Figure 3. TGA measurements of (A) reagent Showa CS, (B) Showa MRS, (C) Showa FARS, and (D) Showa TARS.

dehydration or desolvation. Since the DSC scan of Showa FARS looked more pronounced and well-defined than the ones of Showa MRS and Showa TARS, respectively, we had chosen the furfuryl alcohol-water system with a pH of 5.9 for making about 125 g of scale-up Showa FARS with a constant stirring of 500 rpm at 60 °C for 5-7 days for further investigations. The SEM micrographs of reagent Showa CS and scale-up Showa FARS exhibited a similar prismatic structure25 in Figure 4 and the DSC scans of reagent Showa CS and scale-up Showa FARS illustrated different endotherms at 150 °C in Figure 5. The subtle endotherm at 150 °C for reagent Showa CS (Figure 5A) had become apparent with an enlarged scale in the y-axis of heat flow and the endotherm at 150 °C for scale-up Showa FARS had merged from one peak and one shoulder (Figure 2C) to one wide peak (Figure 5B) spanning from 140° to 175 °C. Once again, the TGA measurements in Figure 6 showed that the endotherms observed around 150 °C in the DSC scans in Figure 5 were not due to dehydration or desolvation. Apparently, the endotherms at 150 °C did not have to be caused by trace amounts of salts and water or degradation of sucrose.9,26 This was because Domino CS having no endotherm at 150 °C but only a sharp melting peak at 185 °C (Figure 7) had the highest concentrations of Na+ ion and K+ ion of 1.62 ppm and 5.84 ppm, respectively, a relatively high KF water content of 0.53 w/w% and a similar specific rotation of + 64.58° as compared with the corresponding values of 1.13 ppm, 1.45 ppm, 0.32

Figure 5. DSC scans of (A) reagent Showa CS, and (B) scale-up Showa FARS.

w/w% and + 64.58° for reagent Showa CS and 0.98 ppm, 1.28 ppm, 0.58 w/w% and + 64.98° for scale-up Showa FARS. Obviously, the inclusion of trace amounts of salts and water or degradation of sucrose alone did not offer a satisfying explanation for the endotherm around 150 °C observed for scale-up FARS. In addition, ESCA survey spectra encompassing binding energies of 0-1400 eV also showed identical peaks of C1s and O1s for both reagent Showa CS and scale-up Showa FARS (Figure 8) related to (1) the aromatic carbon binding energy of 284.45 eV,27 (2) the aromatic carbon linking to an oxygen atom

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Figure 6. TGA measurements of (A) reagent Showa CS, and (B) scaleup Showa FARS.

Figure 7. DSC scan of Domino CS.

binding energies of 285.88 and 286.46 eV,27 (3) O-C binding energy of 532.6 eV,28 and (4) C-OH binding energy of 533.18 eV.29 Therefore, no trace amount of inorganic or organic impurities was detected. The sharp PXRD diffractograms in Figure 9 indicated that both reagent Showa CS (Figure 9A) and scale-up Showa FARS (Figure 9B) were in a crystalline form and not in an amorphous form, and both diffractograms closely resembled the calculated PXRD pattern from the SXD data of reagent Showa CS (Figure 9C and Table 1). However, there were some minor differences between the patterns of reagent Showa CS and scale-up Showa FARS. The diffraction peaks of the many crystals of scale-up Showa FARS in Figure 9B at 2θ ) 18.8°, 20.7°, 24.7° and 25.1° corresponding to the (111), (1j12), (112) and (003) reflections seemed to be slightly shifted to the lower angle due to lattice expansion with respect to the diffraction peaks of the many crystals of reagent Showa CS in Figure 9A. To further help explain the nature of the PXRD peak shift for the scale-up Showa FARS in Figure 9B, the single crystal X-ray crystallographic data of a randomly picked crystal of reagent Showa CS and scale-up Showa FARS were presented in Table 2 against the reference data.30 However, the slight shift of the PXRD peaks at 2θ ) 18.8°, 20.7°, 24.7°, and 25.1° did not cause any significant unit cell volume expansion. On the contrary, the unit cell volume of scale-up FARS of 714.8 Å3 was less than the one for reagent Showa CS of 726.2 Å3 (Table 2). It was interesting to see that the (111), (1j12), (112), and

Figure 8. ESCA survey spectra encompassing binding energies of 0 to 1400 eV of (A) reagent Showa CS, and (B) scale-up Showa FARS.

(003) planes cut through the scale-up FARS in its crystalline conformation illustrated in Figure 10 at one inter-residue hydrogen bond of C6′-O-H · · · O-C5 from the fructofuranose to the glucopyranose residue (Figure 1) and one intramolecular hydrogen bond of C5-O · · · H-O-C6 (Figure 1).31 In addition, the almost identical CP-MAS 13C NMR spectra of the many crystals of reagent Showa CS (Figure 11A) and scale-up Showa FARS (Figure 11B) giving relatively narrow resonance lines had once again verified that both kinds of sucrose were crystalline.32 The resonances at C-2′, C-1, C-5′, C-4′, C-1′, and C-6 in Figure 1 were found at relative chemical shift positions of δ ) 101.9, 92.7, 81.1, 73.2, 67.4, and 60.5 ppm, respectively.33 For reagent Showa CS (Figure 11A), there was one peak per carbon, indicating only one crystallographically inequivalent molecule in the unit cell. For scale-up Showa FARS (Figure 11B), the line width broadening and a slight 13C chemical shift of 0.5 to 1 ppm from δ ) 60 to 65 ppm for C6′ and C6 suggested conformational nonequivalence, bond distortion by crystal packing, and variation in local susceptibility.32 One possible reason that SSNMR spectroscopy detected the changes in forms and PXRD or SXD did not was that the conformation of the sucrose molecules did change between forms, but the unit cell parameters did not change significantly.34,35 Furthermore, the FTIR spectrum of reagent Showa CS (Figure 12A) was different from the one of scale-up Showa FARS (Figure 12B) that scale-up Showa FARS exhibited a narrow

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Lee and Chang Table 1. Calculated Structure Factors Based on Single-Crystal X-ray Diffraction

Figure 9. PXRD diffractograms of (A) reagent Showa CS, (B) scaleup Showa FARS where s ) shift, and (lower panel) calculated PXRD pattern based on SXD of reagent Showa CS.

band at 3600 cm-1 due to free OH groups,36 a relatively short band around 1700 cm-1 assigned to C-H stretching vibration, and many small vibration lines in the middle infrared of 1000-1200 cm-1 assigned to -CH2-OH deformation as indicated by the black arrows.17 On the basis of all these data, we proposed that scale-up Showa FARS actually could have consisted of sucrose molecules having different degrees of conformational disorders about the -CH2-OH functional groups at C-6′ and C-6 such that the hydrogen bond between the hydroxyl groups and the glucopyranose ring oxygen was misaligned (Figures 1 and 10B). Since the hydrogen bond energy ranged from -0.73 to -6.01 kcal mol-1,31 the misalignment of the hydrogen bond would help lower the melting temperature significantly from 189 °C (Figure 2A) to 150 °C (Figure 2C). Agreeing with the DSC scans, HSOM experiments further demonstrated that while reagent Showa CS melted around 190° to 192 °C (Figure 13A), scaleup FARS melted at a much lower temperature of 162° to 163 °C (Figure 13B). This was vividly indicated by the disfiguration of the well-defined crystal habits. VT-PXRD diffractograms in Figure 14 further supported the HSOM results in Figure 13 that reagent Showa CS crystals had a sharp melting point at 180 °C as revealed by a sudden drop of the intensity of all diffraction peaks between the two diffraction patterns at 160 and 180 °C (Figures 14A(d) and 14A(e)). However, scale-up FARS crystals behaved differently. The scale-up FARS crystals began to melt partially first around 160 °C and then continually until 180 °C was reached as indicated by the lowering of the intensity of all diffraction peaks between the two diffractograms at 140 and 160 °C (Figures 14B(c) and 14B(d)) in the beginning, and followed immediately by a complete disappearance of all diffraction peaks at 180 °C (Figure 14B(e)). The misalignment of the hydrogen bonds should also give sucrose crystals with higher solubility. As expected, the solubility curve of scale-up Showa FARS (Figure 15B) was located above the one of reagent Showa CS (Figure 15C). However,

2θ (°)

h

k

l

d-spacing (Å)

8.305 11.645 12.691 13.084 15.432 15.784 16.24 16.654 18.057 18.769 19.511 20.263 20.727 21.932 22.453 23.006 23.412 23.432 23.981 24.671 25.094 25.178 25.183 25.54 25.551 25.789 26.342 26.631 27.109 27.192 27.27 27.525 28.545 30.104 30.331 30.424 30.843 31.153 31.759 31.827 31.878 32.043 32.464 32.535 32.818 32.842 33.052 33.246 33.519 33.674 33.693 34.493 34.609 34.643 35.035

0 1 -1 0 1 1 -1 0 -1 1 0 0 -1 0 1 -2 2 1 -1 1 0 -2 -1 -2 2 1 0 2 0 -1 -1 -2 2 1 -2 1 -2 2 0 1 2 -2 0 -1 -2 1 -1 -1 2 0 2 -3 1 -1 0

0 0 0 1 1 0 -1 0 0 1 1 2 1 2 0 0 0 2 -2 1 0 -1 0 0 1 2 2 0 1 1 2 -1 1 0 0 2 -2 2 3 1 0 1 2 2 -2 3 0 -3 1 0 2 0 3 1 3

1 0 1 1 0 1 1 2 2 1 2 0 2 1 2 1 0 0 1 2 3 1 3 2 0 1 2 1 3 3 2 2 1 3 3 2 1 0 1 3 2 3 3 3 2 0 4 1 2 4 1 1 1 4 2

10.6376 7.5934 6.9697 6.7613 5.7372 5.61 5.4536 5.3188 4.9086 4.7239 4.5461 4.379 4.2819 4.0493 3.9566 3.8627 3.7967 3.7934 3.7079 3.6057 3.5459 3.5343 3.5334 3.4849 3.4835 3.4519 3.3807 3.3446 3.2867 3.2768 3.2677 3.2379 3.1245 2.9662 2.9445 2.9357 2.8968 2.8686 2.8152 2.8094 2.805 2.791 2.7557 2.7499 2.7268 2.7249 2.708 2.6927 2.6713 2.6594 2.658 2.5981 2.5897 2.5872 2.5592

Table 2. Crystal Data of Sucrose As Revealed by Single Crystal X-ray Diffraction

a (Å) b (Å) c (Å) β (°) cell volume (Å3) density (Mg/m3) (calculated) space group Z crystal system

reagent Showa CS

scale-up Showa FARS

7.795 8.758 10.920 103.058 726.2 1.565

7.7523 8.7063 10.865 102.902 714.8 1.590

7.7585 8.7050 10.8633 102.945 715 1.590

P21 2 monoclinic

P21 2 monoclinic

P21 2 monoclinic

ref 30

both solubility curves were below but close to the solubility curve obtained from the literature37 (Figure 15A). This could be due to the inherent inaccuracy of our solubility measurement method or because a different source of sucrose was used to establish the literature data.



Figure 10. Visualization of scale-up Showa FARS in its crystalline conformation as depicted by a computer software (Diamond 3.1, Crystal Impact Gbr, Brandenberg, Germany): (A) the (111) plane, (B) the (1j12) plane, (c) the (112) plane, and (D) the (003) plane were all in gray color.

The particle size distributions in Figure 16 revealed that ballmilled sucrose products contained a large number of fines. Totally around 60 vol % of the “70-µm sized cut” sucrose powders were less than 70 µm, and only 14 to 20 vol % of sucrose powders in total were actually around 70 µm. However, the ball milled Showa scale-up FARS had a little more fines than the ball-milled reagent Showa CS below 40 µm size and the ball-milled reagent Showa CS had only 2 vol % more largesized particles than the ball-milled Showa scale-up FARS above 60 µm size. Generally speaking, the particle size distributions of the two sucrose products were similar enough for us to assume that the effect of the surface area of the ball-milled sucrose products on the dissolution study on Figure 17 could be overlooked. As a consequence of largely the polymorphic effect, the dissolution profile of the formulated L-ascorbic acid (vitamin C) using scale-up Showa FARS as a functional excipient gave a more rapid 50% drug release time, t50, of 15 s than t50 of 50 s for reagent Showa CS (Figure 17). Although a DSC endotherm at 150 °C similar to the one in Figure 2C had been observed before for ground sucrose and for freeze-dried sucrose glass crystallized with a high moisture content around 6-9 wt %, it was proposed that the results were more likely due to defects in the lattice structure and not polymorphism38 because it was claimed that no distinct differences were observed in the PXRD, 13C NMR experiments, and FTIR measurements. However, those data were missing.38 According to our Figure 13B, the wide melting peak in the DSC scan of Figures 2C and 5B were all attributed to the melting of some amount of low-melting crystals or microdomains and then

followed immediately by some residual high-melting crystals or microdomains. The energy barrier of aligning the hydrogen bond between the hydroxyl groups and the glucopyranose ring oxygen caused by the different degrees of conformational disorders about the -CH2-OH functional groups at C-6′ and C-6 could be approximated by the activation energy of the polymorphic transformation of the low melting metastable polymorph around 150°-160 °C to the high melting thermodynamically stable form around 185 °C. Therefore, DSC measurements of reagent Showa CS containing both polymorphs at six heating rates of 2, 5, 10, 15, 20, and 25 °C/min were shown in Figure 18. The activation energy for the polymorphic transformation was determined by means of the Kissinger plot based on the first endotherms around 150°-160 °C of reagent Showa CS:39

( )

ln

Ea b ) +C RT T2

(2)

where b ) the heating rate (K min-1), T ) the specific temperature, R ) the gas constant, C ) constant, and Ea ) the activation energy (J mol-1 K-1). By using the values of peak temperatures (Tp) for different heating rates, a plot of ln(b/Tp2) vs 1/Tp yielded a straight line. Figure 19 displayed the Kissinger plot of the polymorphic transformation of the low melting metastable polymorph around 150°-160 °C to the high melting thermodynamically stable form around 185 °C of reagent Showa CS. From the slope of the plot, the activation energy, Ea, was calculated to be 185.2 kJ/mol, which was comparable with the

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Lee and Chang

Figure 13. HSOM of (A) reagent Showa CS, and (B) scale-up Showa FARS. The high-melting crystals or microdomains were indicated by a black arrow (scale bar ) 250 µm).

Figure 11. 13C CPMAS NMR spectra of (A) reagent Showa CS, and (B) scale-up Showa FARS.

Figure 12. FTIR spectra of (A) reagent Showa CS, and (B) scale-up Showa FARS. Their main differences are pointed out by the black arrows.

Figure 14. VT-PXRD diffractograms of (A) reagent Showa CS at (a) 30 °C, (b) 130 °C, (c) 140 °C, (d) 160 °C, (e) 180 °C, and (f) 190 °C, and (B) scale-up FARS at (a) 30 °C, (b) 130 °C, (c) 140 °C, (d) 160 °C, and (e) 180 °C.

activation energy of 100 kJ/mol of polymorphic transition of anhydrous caffeine from Form I to Form II.40 However, the polymorphic transition enthalpy, ∆H, of the low melting metastable polymorph around 150°-160 °C to the high melting thermodynamically stable form around 185 °C of reagent Showa

CS was 8.56 J/g (i.e., 0.7 kcal/mol), which was calculated from the peak area of the endotherm around 150 °C obtained at a heating rate of 10 °C/min. The polymorphic transformation enthalpy of 0.7 kcal/mol fell within a similar window of 0.5-8 kcal/mol for polymorphic transformation caused by bond torsion and intermolecular interactions.41


Figure 15. Solubility curves of (A) ref 37, (B) scale-up Showa FARS, and (C) reagent Showa CS.

Figure 16. Particle size distributions of the “75-µm sized cut” of the ball-milled reagent Showa CS (filled bars), and the “75-µm sized cut” of the ball-milled scale-up Showa FARS powders (shaded bars).

Figure 17. Dissolution profiles of the formulated L-ascorbic acid (vitamin C) using (A) reagent Showa CS, and (B) scale-up Showa FARS, as a functional excipient. The concentration limit was 500 mg of vitamin C per 900 mL of water ) 0.56 mg/mL.

Normally, when metastable sucrose polymorphs with different degrees of conformation were nucleated in water, they would be transformed rapidly into only one thermodynamically stable form by Ostwald’s Rule of Stages.42 However, since the viscosity of furfuryl alcohol > tetrahy-


Figure 18. DSC measurements of reagent Showa CS at six different heating rates: (A) 25 °C/min, (B) 20 °C/min, (C) 15 °C/min, (D) 10 °C/min, (E) 5 °C/min, and (F) 2 °C/min.

Figure 19. The Kissinger plot of the polymorphic transition from the low melting metastable polymorph around 150°-160 °C to the high melting thermodynamically stable form around 185 °C.

drofuryl alcohol > methanol, the presence of furfuryl alcohol in water could slow down the polymorphic transformation of sucrose significantly and would in turn preserve the different degrees of conformational polymorphs of sucrose better than the other two solvents. As a consequence, a wide endotherm ranging from 140° to 170 °C in a DSC scan was produced (Figure 2C). However, a good mixing in scale-up could ensure a narrower range of conformations existing among sucrose polymorphs, and the endotherm could then be more peak-like in a DSC scan (Figure 5B). Logically, one would expect that the other way to kinetically produced the conformational polymorphs was to remove water rapidly from a viscous 10 mL of saturated aqueous sucrose solution at 25 °C in a scintillation vial by vacuum at 80 °C for 12 h. The DSC scan of the evaporation-produced sucrose indeed gave an endotherm at 150 °C (Figure 20). But to our surprise, a rapid evaporation of a droplet of the same saturated aqueous sucrose solution at 25 °C under a constant vacuum at 80 °C for 1 h gave only a sharp endotherm at 189 °C in a DSC scan (Figure 21). It was believed that the polymorphic transformation was induced by the fast mixing in a droplet caused by convection as water was being evaporated. As the temperature had increased to 140 °C, the sucrose crystallized from the 10 mL of saturated aqueous sucrose solution at 25 °C in a scintillation vial under a constant vacuum for 12 h gave a sharp endotherm at 189 °C (Figure 22). This

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Figure 20. DSC scan of sucrose crystallized from 10 mL of a saturated aqueous sucrose solution at 25 °C in a scintillation vial in vacuum at 80 °C for 12 h.

Lee and Chang

Figure 22. DSC scan of sucrose crystallized from 10 mL of a saturated aqueous sucrose solution at 25 °C in a vacuum at 140 °C for 1 h.

microdomain in sucrose was important since it was the driving force for internal editing similar to protein folding kinetics: a jigsaw puzzle, with multiple routes to a unique solution.43

Figure 21. DSC scan of sucrose crystallized from a droplet of a saturated aqueous sucrose solution at 25 °C in a vacuum at 80 °C for 1 h.

interesting result was believed to be due to the decrease in viscosity of the sucrose solution as the temperature was increased. Conclusions Metastable sucrose polymorphs were formed when different degrees of conformational disorder about the -CH2-OH functional groups of the fructofuranose ring such that the inter-residue intramolecular hydrogen bonds between the hydroxyl groups and the glucopyranose ring oxygen took place. These metastable conformational polymorphs would be transformed into one thermodynamically stable form by Ostwald’s Rule of Stages. This polymorphic transformation could be kinetically controlled by mass-transfer through viscosity, solvent evaporation rate, and mixing. However, under the orchestration of intermolecular and inter-residue intramolecular hydrogen bonds, the polymorphic transformation could be achieved by different pathways in different microdomains to produce various degrees of conformational polymorphs if the micromixing was poor. As a result, a mixture of crystals or microdomains with a wide range of melting temperatures and relatively high solubility were produced. In this respect, the instability of any part of a

Acknowledgment. This work was supported by the grants from the National Science Council of Taiwan, R. O. C. (NSC 97-2113-M-008-006). We thank Ms. Jui-Mei Huang, Ms. Ching-Tien Lin, and Ms. Shew-Jen Weng for their assistance with DSC, TGA, PXRD, ESCA, SEM, and ICP-AES at the Precision Instrument Center in National Central University, Prof. Hsien-Ming Kao and Mr. Yu-Chi Pan for their assistance with SSNMR at the Department of Chemistry in National Central University, Ms. Pei-Lin Chen for her assistance with SXD at the Department of Chemistry in National Tsing Hua University, Prof. Chung-Wen Lan for his assistance with the particle size characterization at Yen Tjing Ling Industrial Research Institute and Particulate Technology Laboratory in National Taiwan University, and Mr. Chien-Hsiang Hsieh and Mr. Chao-Chen Hsu for their assistance with VT-PXRD at the Department of Chemistry and Center for Nanotechnology in Chung-Yuan Christian University. The assistance in the KF measurements by Prof. Kung-Tu Kuo at the Department of Chemical and Materials Engineering is gratefully acknowledged. We would also like to give special thanks for the many valuable comments from Stephen Clarke, Ph.D., Director of Industrial R & D at Florida Crystals.

References (1) Lee, T.; Hung, S. T.; Kuo, C. S. Polymorph Farming of Acetaminophen and Sulfathiazole on a Chip. Pharm. Res. 2006, 23, 2542–2555. (2) Brittain, H. G. Polymorphism in Pharmaceutical Solids; Marcel Dekker, Inc.: New York, 1999. (3) Honig, P. Principles of Sugar Technology, Vol. 1.; West Indies Sugar Corporation: New York, 1965; p 1. (4) Brown, G. M.; Levy, H. A. Further Refinement of the Structure of Sucrose Based on Neutron-Diffraction Data. Acta Crystallogr. B 1973, 29, 790–797. (5) Hanson, J. C.; Sieker, L. C.; Jensen, L. H. Sucrose: X-ray Refinement and Comparison with Neutron Refinement. Acta Crystallogr. B 1973, 29, 797–808. (6) Brown, G. M.; Levy, H. A. Sucrose: Precise Determination of Crystal and Molecular Structure by Neutron Diffraction. Science 1963, 141, 921–923. (7) Hurtta, M.; Pitka¨nen, I.; Knuutinen, J. Melting Behavior of D-Sucrose, D-Glucose and D-fructose. Carbohydr. Res. 2004, 339, 2267–2273. (8) Shah, S. V.; Chakradeo, Y. M. A Note of the Melting of Cane Sugar.

Sucrose Conformational Polymorphism Curr. Sci. 1936, 4, 652. (9) Eggleston, G.; Trask-Morrell, B. J.; Vercellotti, J. R. Use of Differential Scanning Calorimetry and Thermogravimetric Analysis to Characterize the Thermal Degradation of Crystalline Sucrose and Dried SucroseSalt Residues. J. Agric. Food Chem. 1996, 44, 3319–3325. (10) Beckett, S. T.; Grazia Francesconi, M.; Geary, P. M.; Mackenzie, G.; Maulny, A. P. E. DSC Study of Sucrose Melting. Carbohydr. Res. 2006, 341, 2591–2599. (11) Yu, L. Growth Rings in D-Sorbitol Spherulites: Connection to Concomitant Polymorphs and Growth Kinetics. Cryst. Growth Des. 2003, 3, 967–971. (12) Shinohara, Y.; Kawasaki, N.; Ueno, S.; Kobayashi, I.; Nakajima, M.; Amemiya, Y. Observation of the Transient Rotator Phase of nHexadecane in Emulsified Droplets with Time-Resolved TwoDimensional Small- and Wide-Angle X-Ray Scattering. Phys. ReV. Lett. 2005, 94, (097801-1)-(097801-4) . (13) Woo, E. M.; Sun, Y. S.; Yang, C.-P. Polymorphism, Thermal Behavior, and Crystal Stability in Syndiotactic Polystyrene vs. Its Miscible Blends. Prog. Polym. Sci. 2001, 26, 945–983. (14) Okuno, M.; Kishihara, S.; Otsuka, M.; Fujii, S.; Kawasaki, K. Variability of Melting Behavior of Commercial Granulated Sugar Measured by Differential Scanning Calorimetry. Int. Sugar J. 2003, 205, 29–35. (15) Joshi, A. A.; Duriez, X. Added Functionality Excipients: An Answer to Challenging Formulations. Pharm. Technol. 2004, 12–19, Excipients & Solid Dosage Forms. (16) Dave, H.; Gao, F.; Lee, J.-H.; Liberatore, M.; Ho, C.-C.; Co, C. C. Self-Assembly in Sugar-Oil Complex Glasses. Nat. Mater. 2007, 6, 287–290. (17) Ponce-Lee, E. L.; Olivares-Pe´rez, A.; Fuentes-Tapia, I. Sugar (Sucrose) Holograms. Opt. Mater. 2004, 26, 5–10. (18) Bellan, L. M.; Singh, S. P.; Henderson, P. W.; Porri, T. J.; Craighead, H. G.; Spector, J. A. Fabrication of an Artificial 3-Dimensional Vascular Network Using Sacrificial Sugar Structures. Soft Matter 2009, 5, 1354–1357. (19) Gohel, M. C. A Review of Co-processed Directly Compressible Excipients. J. Pharm. Pharmaceut. Sci. 2005, 8, 76–93. (20) Sage, I.; Badcock, R.; Humberstone, L.; Geddes, N.; Kemp, M.; Bourhill, G. Triboluminescent Damage Senors. Smart Mater. Struct. 1999, 8, 504–510. (21) Lee, T.; Lin, Y. S. Dimorphs of Sucrose. Int. Sugar J. 2007, 109, 440–445. (22) Moye, C. J. Non-Aqueous Solvents for Carbohydrates. AdV. Carbohydr. Chem. Biochem. 1972, 27, 85–125. (23) Ashida, H.; Izutsu, D.; Yamashita, A. Takeda Chemical Industries, Ltd. Water-Soluble Vitamin Composition Having Excellent Tablet Properties and Process for Production Thereof. U.S. Patent 5994324, 1999. (24) Sorasuchart, W.; Wardrop, J.; Ayres, J. W. Drug release from spray layered and coated drug-containing beads: effects of pH and comparison of different dissolution methods. Drug DeV. Ind. Pharm. 1999, 25, 1093–1098. (25) Quense, J. A.; Dehn, W. M. Microscopic Identification of Sugars. Ind. Eng. Chem. 1939, 11, 555–559. (26) Angel, S. J. The Lobry de Bruyn-Alberda van Ekenstein Transformation and Related Reactions. Topics in Current Chemistry, Vol. 215; Springer-Verlag: Berlin Heidelberg, 2001; pp 1-14.

Crystal Growth & Design, Vol. 9, No. 8, 2009 3561 (27) Perruchot, C.; Watts, J. F.; Lowe, C.; White, R. G.; Cumpson, P. J. Angle-Resolved XPS Characterization of Urea Formaldehyde-Epoxy System. Surf. Interface Anal. 2002, 33, 869–872. (28) Malitesta, I.; Lossto, I.; Sabbatini, L.; Zambonin, P. G. New Findings on Polypyrrole Chemical Structure by XPS Coupled to Chemical Derivatization Labeling. J. Electron Spectrosc. Relat. Phenom. 1995, 76, 629–634. (29) Jouan, P. Y.; Peignon, M. C.; Cardinaud, Ch.; Lempe´rie`re, G. Characterisation of TiN Coatings and of the TiN/Si Interface by X-ray Photoelectron Spectroscopy and Auger Electron Spectroscopy. Appl. Surf. Sci. 1993, 68, 595–603. (30) Pe´rez, S. The Structure of Sucrose in the Crystal and in Solution. In Sucrose Properties and Applications; Mathlouthi, M.; Reiser, P., Eds.; Blackie Academic & Professional: New York, 1995; Chapter 2, p 14. (31) Pe´rez, S. The Structure of Sucrose in the Crystal and in Solution. In Sucrose Properties and Applications; Mathlouthi, M.; Reiser, P., Eds.; Blackie Academic & Professional: New York, 1995; Chapter 2, pp 14-20. (32) Saitoˆ, H. Conformation-dependent 13C Chemical Shifts: A New Means of Conformational Characterization as Obtained by High-Resolution Solid-State 13C NMR. Magn. Reson. Chem. 1986, 24, 835–852. (33) Pe´rez, S. The Structure of Sucrose in the Crystal and in Solution. In Sucrose Properties and Applications; Mathlouthi, M.; Reiser, P., Eds.; Blackie Academic & Professional: New York, 1995; Chapter 2, pp 20-22. (34) Offerdahl, T. J.; Salsbury, J. S.; Dong, Z.; Grant, D. J. W.; Schroeder, S. A.; Prakash, I.; Gorman, E. M.; Barich, D. H.; Munson, E. J. Quantitation of Crystalline and Amorphous Forms of Anhydrous Neotame using 13C CPMAS NMR Spectroscopy. J. Pharm. Sci. 2005, 94, 2591–2605. (35) Zell, M. T.; Padden, B. E.; Grant, D. J. W.; Schroeder, S. A.; Wachholder, K. L.; Prakash, I.; Munson, E. J. Investigation of Polymorphism in Aspartame and Neotame Using Solid-State NMR Spectroscopy. Tetrahedron 2000, 56, 6603–6616. (36) Lescure, J. P. Analysis of Sucrose Solutions. In Sucrose Properties and Applications; Mathlouthi, M.; Reiser, P., Eds.; Blackie Academic & Professional: New York, 1995; Chapter 7, p. 157. (37) Bubnı´k, Z.; Kadlec, P. Sucrose Solubility. In Sucrose Properties and Applications; Mathlouthi, M.; Reiser, P., Eds.; Blackie Academic & Professional: New York, 1995; Chapter 5, p 107. (38) Kawakami, K.; Miyoshi, K.; Tamura, N.; Yamaguchi, T.; Ida, Y. Crystallization of Sucrose Glass under Ambient Conditions: Evaluation of Crystallization Rate and Unusual Melting Behavior of Resultant Crystals. J. Pharm. Sci. 2006, 95, 1354–1363. (39) Kissinger, H. E. Reaction Kinetics in Differential Thermal Analysis. Anal. Chem. 1957, 29, 1702–1706. (40) Lehto, V.-P.; Laine, E. A Kinetic Study of Polymorphic Transition of Anhydrous Caffeine with Microcalorimeter. Thermochim. Acta 1998, 317, 47–58. (41) Nangia, A. molecular Conformation and Crystal Lattice Energy Factors in Conformational Polymorphs. In Models, Mysteries and Magic of Molecules; Boeyens, J. C. A., Ogilvie, J. F. Eds.; Springer: New York, 2008; Chapter 3, pp 63-86. (42) Threlfall, T. Structural and Thermodynamic Explanation of Ostwald’s Rule. Org. Proc. Res. DeV. 2003, 7, 1017–1027. (43) Harrison, S. C.; Durbin, R. Is There a Single Pathway for the Folding of a Polypeptide Chain? Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 4028–4030.

CG900294D

Sucrose Conformational Polymorphism: A Jigsaw Puzzle with Multiple

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