Energy/Temperature Diagram and Compression Behavior of
`the Polymorphs of D-Mannitol
`
`ARTUR BURGER, JAN-OLAV HENCK, SILVIA HETZ, JUDITH M. ROLLINGER, ANDREA A. WEISSNICHT,
`HEMMA STO¨ TTNER
`
`Institut fu¨r Pharmakognosie der Universita¨t Innsbruck, Josef-Moeller-Haus, Innrain 52, A-6020 Innsbruck, Austria
`
`Received 18 March, 1999; accepted 23 December 1999
`
`ABSTRACT: Three modifications of D-mannitol were produced and investigated: mod. I
`(mp 166.5°C, heat of fusion 53.5 kJ mol−1), mod. II (mp 166°C, heat of fusion 52.1 kJ
`mol−1), and mod. III (mp incongruent 150–158°C, heat of transition, III to I 0.2 kJ
`mol−1). The measured densities are 1.490 ± 0.000 g cm−3 [95% confidence interval (CI)]
`for mod. I, 1.468 ± 0.002 g cm−3 (95% CI) for mod. II, and 1.499 ± 0.004 g cm−3 (95% CI)
`for mod. III. It was possible to relate the different modifications given in the literature
`to one of the three pure crystal forms or to mixtures of two or all three modifications.
`The thermodynamic relationship among the crystal forms is represented in a semi-
`schematic energy/temperature diagram. From these data we can conclude that mod. III
`is thermodynamically stable at absolute zero. It is enantiotropically related to mod. I
`and mod. II. FTIR and Raman spectra, differential scanning calorimetry curves, and
`X-ray powder patterns of these crystal forms are depicted for doubtless assignment in
`the future. The water uptake of the three modifications at 92% relative humidity and
`25°C is less than 1%. The differences of the heat capacities and the heats of solution
`between mod. II and III are not significant, whereas mod. I shows small significant
`differences compared with the other modifications. In addition, compaction studies of
`these crystal forms were performed by means of an instrumented hydraulic press. The
`results show that mod. III should have the best tableting behavior under these condi-
`tions. © 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:
`457–468, 2000
`
`INTRODUCTION
`The acyclic sugar alcohol D-mannitol is an excipi-
`ent commonly used in the pharmaceutical formu-
`lation of tablets or granulated powders for oral
`use. Several polymorphic forms have been de-
`scribed, but there are still some important ques-
`tions (e.g., the order of thermodynamic stability of
`the modifications at ambient conditions). Differ-
`ent names of the crystal forms by several authors
`have left behind a chaotic picture in the literature
`
`Correspondence to: A. Burger. (E-mail: Artur.Burger@uibk.
`ac.at)
`Parts of this work were presented at 40th Annual Confer-
`ence of the APV, Mainz (Germany) 9–12 March 1994. Ab-
`stract: Eur J Pharm Biopharm 1994;40:21.
`Dedicated to Prof. Dr. Maria Kuhnert-Brandsta¨tter on the
`occasion of her birthday.
`Journal of Pharmaceutical Sciences, Vol. 89, 457–468 (2000)
`© 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association
`
`about which physicochemical properties belong to
`which crystal form. Table 1 gives an overview of
`the polymorphic modifications of D-mannitol pre-
`sented in the literature and the assignment to the
`already known modifications given by the respec-
`tive authors.
`Groth1 already quoted in 1910 that Schabus,2
`Zepharovich,3 as well as Grailich and Lang,4 have
`described two polymorphic modifications of
`D-mannitol. He mentioned the lattice parameters
`of the a- and b-form. The latter is commonly
`known to be the commercial product. These de-
`scriptions were verified by Becker and Rose5 in
`1923, and they were specified by Marwick6 in
`1931. Rye and Sorum7 presented in 1952 besides
`form a and b a new form g. This modification was
`obtained by rapid cooling of a solution of D-
`mannitol in ethanol/water 1:1. The a8-form char-
`acterized by Mak8 in 1963 for the first time is
`
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`
`457
`Merck 2016
`Argentum v. Merck
`IPR2018-00423
`
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`

`458
`
`BURGER ET AL.
`
`Table 1. D-mannitol—Review of the Literature
`
`Designations and Allocation of the Modifications Worked On
`
`Chronological
`
`Groth1
`Becker and Rose5
`Marwick6
`Rye and Sorum7
`Mak8
`Berman et al.9
`Walter-Levy10
`Kim et al.11
`Jones and Lee12
`Debord et al.13
`Giron14
`Grindley et al.15
`Pitka¨nen et al.16
`Our results
`
`a
`
`a
`
`a
`
`a
`a
`
`II
`
`B
`k
`k
`II
`
`b
`
`b
`b
`b
`b
`
`b
`b
`
`I
`
`A
`b
`a + b
`I
`
`g
`
`g
`
`k
`
`k
`
`I + II/III
`
`mentioned in a review by Berman et al.9 Walter-
`Levy10 also described three modifications of
`D-mannitol in 1968. Besides the orthorhombic
`forms a and b, a monoclinic form was investigated
`for the first time. This modification was called
`d-form. Berman et al.9 published the X-ray crystal
`structure of the b-form and Kim et al.11 presented
`the form k in the same year. Kim et al. already
`assumed that their form K is identical with
`g-form of Rye and Sorum.7 In 1970 Jones and
`Lee12 investigated D-mannitol by means of
`thermomicroscopy.12 They confirmed the exis-
`tence of three modifications and designated them
`according to their stability above room tempera-
`ture as phase I (stable), phase II, and phase III.
`Debord et al.13 investigated several commercial
`products of D-mannitol in 1987. Besides the forms
`a, b, and d, they crystallized a new modification
`that they could not assign to one of the known
`modifications and therefore designated this one
`as form U (unidentified). Debord et al. supposed
`that this modification might be the g-form of Rye
`and Sorum.7 In 1990 Giron14 obtained four forms
`of D-mannitol, which were named A, B, C, and D.
`She equated form A to the b-form of Debord et
`al.,13 B to the a-form, C to the U-form and intro-
`duced form D as a new modification. In the same
`year Grindley et al.15 worked on three modifica-
`tions of D-mannitol. Their a-form corresponds to
`the a8-form of Mak8 and Berman,9 which they
`equated to the d-form of Walter-Levy.10 The
`b-form corresponds to the b-forms of other au-
`thors and as the third modification they inserted
`k, which they assumed is equal to the k form of
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 4, APRIL 2000
`
`d
`
`a8
`
`k
`
`U
`
`D
`
`a8
`
`d
`
`III
`
`d
`
`III
`a
`C
`a
`d
`III
`
`k
`
`U
`C
`
`D
`
`I + II/III
`
`I + II + III
`
`I + II
`
`Kim et al.,11 to form g of Rye and Sorum7 and the
`a-form of Walter-Levy.10 Pitka¨nen et al.16 pub-
`lished a thermoanalytical study on several crystal
`forms of D-mannitol. However, the results pre-
`sented in this article were not critically discussed
`and only increase the confusion on the polymor-
`phism of D-mannitol.
`The aim of this work is to scrutinize the mani-
`fold and often contradictory descriptions of the
`various polymorphic modifications of D-mannitol
`given in the literature and to present their
`thermodynamic relationship by an energy/
`temperature diagram. Furthermore, compaction
`studies on the different crystal forms were per-
`formed to investigate which modification shows
`the best properties for direct tableting. It is not
`the intention of this work to expand these inves-
`tigations to pseudo-polymorphic forms (e.g., a
`monohydrate), which was recently described in
`the literature.17–19 This hydrate can be formed in
`the process of freeze drying. It converts to anhy-
`drous crystal forms (mod. I and III) on gentle
`heating.19
`
`EXPERIMENTAL SECTION
`Materials and Solvents
`The studies of D-mannitol [C6H14O6, Mr 182.2]
`were carried out using the commercial product
`(mod. I) provided from Apoka ACM Handelsge-
`sellschaft m.b.H. (Vienna, Austria). The chemical
`identity of the commercial product was checked
`by measuring the optical rotation. The substance
`meets the requirements according to the Euro-
`
`

`

`pean Pharmacopoeia. Modification I is also ob-
`tained by crystallization from water and ethanol.
`Modification II is obtained by crystallization from
`70% ethanol. D-mannitol, 100 g, is dissolved in
`900 g of 70% ethanol and slowly cooled down to
`20°C. Afterwards, the solution is kept at 4°C for
`12 h. The received crystals are filtered and dried
`at 40°C.
`The reproducible production of mod. III is dif-
`ficult. The most successful procedure is to cool a
`hot saturated solution of D-mannitol in water rap-
`idly to 0°C using an ice bath. As soon as crystals
`appear, this solution must be filtered rapidly. The
`filtered crystal form is to wash with acetone to
`displace the water and dry at reduced pressure
`(~ 10 mbar). The received crystals are stored in a
`desiccator. A second route to obtain mod. III is the
`precipitation of a solution of D-mannitol in water
`by acetone. As described previously, the received
`crystals must be dried immediately to prevent the
`transformation into mod. I. Furthermore, crystals
`of mod. III can be obtained by freeze-drying.20,21
`For freeze-drying experiments we used a labora-
`tory freeze dryer Lyolab B (Inula, Vienna, Aus-
`tria) equipped with a mechanical vacuum pump
`type Alcatel 2004 A (Annecy, France). Aqueous
`solutions of D-mannitol (about 500 mL, 10% w/v,
`dissolved in deionized water) were frozen by drop-
`ping it into a 1000-mL glass beaker filled with
`liquid nitrogen, providing a large surface of the
`frozen solution. Then, the glass beaker was placed
`directly in the vacuum chamber of the freeze-
`dryer, which was not precooled because the tem-
`perature of the freeze-dryer cannot be controlled
`by the instrument used. The excess liquid nitro-
`gen ensured the solid state of the mannitol solu-
`tion until full vacuum was achieved. Thereafter, a
`vacuum was maintained for 10 days in which a
`pressure of 0.02 mbar could be reached. The
`freeze-dried samples produced in this way were
`stored at 105°C for 2 h to remove residual mois-
`ture and to advance crystallinity. This method al-
`lows the production of about 50-g scales of mod.
`III, although small admixtures of mod. I and II
`(<5%) can sometimes be detected by means of
`powder X-ray diffraction.
`
`Optical Rotation
`The optical rotation of this solution was measured
`using a Zeiss circular polariscope 0.01 (Carl Zeiss,
`Oberkochen, Germany) with a 10-cm polarimeter
`tube. D-mannitol, 200 g, and sodium tetraborate,
`2.6 g, were dissolved together in 25 mL of water at
`
`POLYMORPHS OF D-MANNITOL
`
`459
`
`30°C. According to the European Pharmacopoeia,
`the amount of rotation has to be between +23 and
`+25° at a wavelength of 589.3 nm and 20°C.
`
`Thermoanalytical Methods
`Polarized thermomicroscopy22,23 was performed
`using a Kofler hot stage microscope (Thermovar,
`Reichert, Vienna, Austria). To prepare a crystal
`film approximately 2 mg of D-mannitol was
`heated between a microscope slide and a cover
`glass using a Kofler hot bench (Reichert, Vienna,
`Austria). The molten film was quenched to 20°C
`by use of a metal block.
`Differential scanning calorimetry (DSC) was
`carried out with a DSC-7 and Pyris software for
`Windows NT (Perkin-Elmer, Norwalk, CT) using
`perforated aluminum sample pans (25 mL).
`Sample masses for quantitative analysis were
`1 to 3 (±0.0005) mg (Ultramicroscales UM3,
`Mettler, CH-Greifensee, Switzerland). Nitrogen
`99.990% (20 mL min−1) was used as purge gas.
`Calibration of the temperature axis was carried
`out with benzophenone (mp 48.0°C) and caffeine
`(mp 236.2°C). Enthalpy calibration of the DSC
`signal was performed with indium 99.999% (Per-
`kin-Elmer, Norwalk, CT). The normal heating
`rate was 2 or 5 K min−1. Specific heat was deter-
`mined with Perkin Elmer DSC 7 Series/UNIX
`Thermal Analysis Software using the two curve
`cp method with sapphire as the reference mate-
`rial. For measurements mannitol modifications
`were prepared as compacts (diameter, 5 mm;
`pressure, 4 kN) to achieve greater accuracy than
`using powders only.24
`
`Spectroscopic and Diffractometric Methods
`FTIR spectra were recorded with a Bruker IFS
`25 FTIR-spectrometer (Bruker Analytische
`Mebtechnik GmbH, Karlsruhe, Germany).
`Samples were scanned as potassium bromide pel-
`lets (diameter, 13 mm; 1 mg D-mannitol to 270 mg
`KBr; pressure, 740 MPa) at an instrument reso-
`lution of 2 cm−1; 50 interferograms were coadded
`for each spectrum.
`FT-Raman spectra were recorded with a
`Bruker RFS 100 FT-Raman spectrometer (Bruker
`Analytische Mebtechnik GmbH, Karlsruhe, Ger-
`many) equipped with a diode-pumped 100
`Nd:YAG Laser (1064 nm) as excitation source and
`a liquid nitrogen–cooled high-sensitivity detector
`(64 scans at 4 cm−1 instrument resolution).
`X-ray powder diffraction patterns were ob-
`
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`
`

`

`460
`
`BURGER ET AL.
`
`tained on a Siemens D-5000 X-ray diffractometer
`equipped with u/u-goniometer (Siemens AG,
`Karlsruhe, Germany) using monochromatic CuKa
`radiation (tube voltage, 40 kV; tube current, 40
`mA) from 2 to 40°; 2u at a rate of 0.005° 2u s−1.
`The diffractometer was fitted with a Go¨bel mirror
`(entrance slit, 1 mm; exit slit, 0.6 mm) and a scin-
`tillation counter (Soller slit; detector slit, 0.1
`mm). The single crystal data for mod. I11 and II9
`were used to calculate the idealized X-ray powder
`pattern for a CuKa radiation with the program
`PowderCell for Windows.25
`
`Density Measurements
`The determination of the powder volumes was
`carried out by means of an air comparison pyk-
`nometer (model 930, Beckman Instruments, Ful-
`lerton, CA) at 25°C with sample amounts of ~ 10
`mL and helium as purge gas.
`
`Solution Calorimetry
`The solution calorimetric experiments were per-
`formed with a LKB 8700-1 Precision Calorimetry
`System (LKB-Produkter AB, Bromma, Sweden)
`equipped with a precision thermostatic water
`bath, LKB 7600, and a 100-mL glass reaction ves-
`sel. The electrical calibration system was checked
`by chemical calibration with the enthalpy of reac-
`tion of TRIS (tris(hydroxymethyl)aminomethane
`p.a., Merck, Darmstadt, Germany) in 0.1 mol L−1
`HCl at 25°C (N.B.S.-724a: -29765 ± 10 J mol−1).
`The glass ampules (1 mL), plastic-plug stoppers,
`and the sealing wax for the ampules were pur-
`chased from Thermometric AB (Ja¨rfa¨lla, Sweden)
`and used as recommended. Sample mass: ~ 100
`mg ± 0.1 mg. Temperature change was calculated
`by graphical extrapolation based on Dickinson’s
`method.26
`
`Powder Compaction Studies
`Dry granulation: with a hydraulic labor press PW
`10; diameter of matrix, 13 mm; sample weight,
`500 to 900 mg. Production of sieve fractions:
`crushing with mortar and pestle and sieving with
`ALPINE-Luftstrahlsieb A200 Labortyp (Ho-
`sokawa-Alpine, Augsburg, Germany). The sieve
`fraction of granules between 50 and 100 mm were
`used for the consolidation. Compacts were pre-
`pared using a hydraulic labor press PW 10
`equipped with 8-mm matrix diameter flat-faced
`punches. The sample weight was 150 mg, the
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 4, APRIL 2000
`
`relative humidity was 43%, and the temperature
`was 24°C. The hydraulic labor press was instru-
`mented as follows: pressure measurements with
`load cell HBM Typ C9A (Hottinger-Baldwin
`Meßtechnik, Darmstadt, Germany), displacement
`with an inductive position transducer HBM
`W5TK. Pressures applied were 96, 143, 215, and
`322 MPa. The thickness of the compacts was mea-
`sured with a Helios digit-micrometer (Helios,
`Niedernhall, Germany). The crushing force was
`measured immediately after compaction and af-
`ter 7 days with a Schleuniger 2E/205 Tablet
`Tester (Schleuniger & Co, Switzerland). Tensile
`strength Q was calculated using the following
`equation:
`
`Q = 2 ? H
`p ? d ? h
`
`where H is the crushing force; d is the diameter;
`and H is the thickness of the compact.
`Crystal form identity before and after compac-
`tion was confirmed by FTIR spectroscopy. Enthal-
`py of fusion, density, solution calorimetry, and
`heat capacity measurements were performed in
`triplicate.
`
`RESULTS AND DISCUSSION
`
`Important physicochemical properties of the
`three modifications of D-mannitol are given in
`Table 2.
`
`Thermomicroscopy
`
`A melt film of D-mannitol quenched on a metal
`cooling block (20°C) and followed by heating
`(heating rate, 5 K min−1) on the polarizing hot
`stage microscope leads to gray spherulites of mod.
`II at 109 to 130°C. The center of these spherulites
`sometimes contain short varicolored brushs of
`mod. I. On the other hand, it is possible to find
`mod. III in the center of the spherulites of mod. II.
`Modification III crystallizes in fine rays or
`needles. In the crystal film mod. III transforms
`into mod. II during heating between 102 and
`118°C. To determine the melting difference be-
`tween mod. I and II, one small crystal of each
`form was placed next to each other on a micro-
`scope slide. After covering the crystals with a
`cover glass, this preparation was brought to the
`hot stage microscope and heated to 160°C with a
`
`

`

`POLYMORPHS OF D-MANNITOL
`
`461
`
`Table 2. D-mannitol—Important Physicochemical Parameters of the Modifications
`
`Modification
`
`I
`
`II
`
`III
`
`Crystal habit
`Melting point (°C) TMa
`Melting point (°C) DSC-onset
`temperature, 5 K min−1
`Enthalpy of fusion (kJ mol−1)
`Entropy of fusion (J mol−1 K−1)
`Transition into mod I (°C)
`DSC, 1.5 K min−1
`Enthalpy of transition (kJ mol−1)
`Selected FTIR bands (cm−1)
`
`Selected FT Raman band (cm−1)
`Density, measured (g cm−3)
`Density, calculated (g cm−3)10
`Heat of solution (kJ mol−1) at 25°C
`Specific heat (J g−1 K−1) at 25°C
`
`Prismatic rods
`166.5
`
`Prismatic rods
`166
`
`Needles
`~ 155 (incongruent)
`
`166
`53.5 ± 0.4b
`122 ± 0.9b
`
`166
`52.1 ± 0.9b
`119 ± 2.1b
`
`155 (incongruent)
`53.7c
`125d
`
`1210
`1081
`1019
`959
`930
`514
`1232
`1.490 ± 0.000b
`1.489
`22.3 ± 0.2b
`1.383 ± 0.009b
`
`1196
`1085
`1020
`953
`927
`519
`1258
`1.468 ± 0.002b
`1.470
`21.5 ± 0.2b
`1.273 ± 0.008b
`
`130
`+0.17 ± 0.01b
`1193
`1088
`1025
`968
`932
`522
`1251
`1.499 ± 0.004b
`1.501
`21.7 ± 0.4b
`1.263 ± 0.002b
`
`a Thermomicroscopy.
`b 95% CI.
`c calculated by adding the enthalpy of transition to the enthalpy of fusion of mod. I.
`d calculated by adding the entropy of transition to the entropy of fusion of mod. I.
`
`heating rate of 20 K min−1. Then the heating rate
`was reduced to about 0.5 K min−1 and the melting
`point of mod. II was observed at 166.0 and of mod.
`I at 166.°C.
`
`mod. I. The sorbitol amount usually contained in
`commercial mannitol mod. III showed admixtures
`of about 0.5%, which could be quantified by DSC
`evaluation of the eutectic heat of fusion.
`
`Differential Scanning Calorimetry
`
`FTIR and Raman Spectroscopy
`
`The DSC curves of mod. I and II show one endo-
`thermic peak representing the melting of the re-
`spective crystal forms (Fig. 1). Modification III
`(Fig. 1) shows incongruent melting between 150
`and 158°C, followed by the solidification of the
`melt to form mod. I and/or II and the melting of
`the respective crystal form or mixture. The endo-
`thermic transition of mod. III into mod. I was de-
`termined by applying a heating rate of 1.5 K
`min−1 to a mixture of mod. III and I (ratio 3:1).
`Thus, the transition of mod. III into mod. I was
`induced at about 130°C (Fig. 2).
`Another endothermic peak often observed dur-
`ing heating of mod. III at about 90°C does not
`belong to any process of D-mannitol. This effect is
`caused by almost small admixtures of D-sorbitol
`and corresponds to the eutectic melting in the bi-
`nary mixture of mannitol mod. III and sorbitol
`
`Both the FTIR (Fig. 3) and Raman spectra (Fig. 4)
`of the three modifications differ considerably, re-
`flecting the different interaction forces between
`and the different conformational arrangements of
`the molecules. The FTIR spectra of the modifica-
`tions show significant differences relating O-H
`and C-H stretching vibrations in the range be-
`tween 3700 and 2500 cm−1 as well as differences
`in the C-H deformation vibrations between 1400
`and 1200 cm−1. The vibrations involving the
`stretching of the C-O bond (1400 to 1200 cm−1)
`also show significant shifts for the three crystal
`forms. Furthermore, differences can be found in
`the region between 800 and 600 cm−1. IR spectra
`of the three modifications were also reported by
`Walter-Levy.10 The patterns of these spectra are
`in good agreement with the ones depicted in this
`article.
`
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`

`462
`
`BURGER ET AL.
`
`Figure 1. DSC curves of mod. I, II and III of D-
`mannitol (heating rate 5 K min−1).
`
`The spectral regions between 3000 and 2800
`cm−1 and 1150 and 1100 cm−1 are suitable to dis-
`tinguish the three modifications by FT Raman
`spectroscopy. In addition, mod. I shows a single
`peak at 876 cm−1, which is split and slightly
`shifted in the spectra of mod. II and III (Fig. 4).
`
`X-ray Diffractometry
`The three crystal forms can easily be distin-
`guished by their X-ray powder patterns as shown
`in Figure 5. X-ray single crystal data are avail-
`able for mod. I and II. The powder patterns of
`both modifications were calculated from the
`single crystal structure data as recommended by
`Bar and Bernstein.27 The computed diffracto-
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 4, APRIL 2000
`
`grams for mod. I and II are in agreement with the
`respective experimentally obtained patterns. Be-
`cause no atomic coordinates for mod. III have
`been published yet, we were not able to calculate
`the respective pattern.
`
`Energy/Temperature Diagram
`The physicochemical data of the D-mannitol modi-
`fications, summarized in Table II, allow an esti-
`mation of their thermodynamic relationship and
`the construction of the semi-schematic energy/
`temperature diagram (Fig. 6). For a detailed dis-
`cussion on the construction and interpretation of
`energy/temperature diagrams in general, refer-
`ence is made to the literature.28–32
`The lowest melting crystal form mod. III
`turned out to be enantiotropically related to mod.
`I on account of the endothermic transition from
`mod. III into I according to the heat-of-transition
`rule. Its enthalpy of transition comes to 0.17 ±
`0.01 kJ mol−1 registered by DSC. The enantio-
`tropic relation between mod. III and II follows by
`applying the density rule because the density of
`mod. III is about 2.1% greater than mod. II. Thus,
`mod. III is the thermodynamically stable crystal
`form at absolute zero. The only slightly higher
`density of mod. III in view of mod. I (0.6%) is not
`suitable to the application of the density rule.31
`Much more difficult to interpret are the experi-
`mental results concerning the energetic relations
`between mod. I and II. A monotropic relationship
`is suggested pursuant to the slightly, but signifi-
`cantly, higher enthalpy of fusion of mod. I than
`mod. II (heat-of-fusion rule). Especially in cases of
`small differences in the heat of fusion of two modi-
`fications, care must be taken in the application of
`the heat-of-fusion rule according to the diver-
`gence of H-isobars toward higher temperatures.
`This circumstance takes more effect the larger
`the melting point difference of the involved modi-
`fications is. In these cases the difference in the
`entropies of fusion are more meaningful to distin-
`guish between monotropism and enantiotropism
`than the difference in the heats of fusion.31–34 Be-
`cause the melting points of D-mannitol mod. I and
`mod. II only differ in 0.5 K, these considerations
`should not be taken into account comparing the
`very close values for entropies of fusion (95% CI)
`of mod. I and II (Table 2). However, the density of
`mod. I is about 1.5% higher than of mod. II. This
`is stated as a significant difference31 for the ap-
`plication of the density rule and suggests a mono-
`tropic relationship between mod. I and II.
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`POLYMORPHS OF D-MANNITOL
`
`463
`
`Figure 2. DSC curve of a mixture of mod. III and I (ratio 3:1) of D-mannitol (heating
`rate 1.5 K min−1).
`
`Other physicochemical properties of the modi-
`fications like hygroscopicity, heat capacity, heat
`of solution, and light stability are useful to distin-
`guish whether two modifications are monotr
`opically or enantiotropically related.30,31 Heat-of-
`solution experiments and heat capacity measure-
`ments were performed with the three modifica-
`tions. The order of the heats of solution of differ-
`ent modifications gives the enthalpy order. For
`D-mannitol these heats were determined at 25 °C
`
`(Table 2). From the statistical point of view the
`data only show a significantly higher heat of so-
`lution for mod. I (3.7%) in view of mod. II indicat-
`ing a monotropic relationship between these two
`crystal forms.
`According to the heat-capacity rule,30,33 a sys-
`tem is enantiotropic if the higher melting poly-
`morph has a higher heat capacity than the lower
`melting modification at a given temperature. Our
`results for the determination of the specific heat
`
`Figure 3. FTIR spectra of mod. I, II, and III of D-mannitol.
`
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`464
`
`BURGER ET AL.
`
`Figure 4. FT Raman spectra of mod. I, II and III of D-mannitol.
`
`of the different crystal forms obtained at 25°C are
`given in Table 2. Although the data for mod. II
`and III are not quite significantly different, the
`enantiotropic relation between III and I, as well
`as between III and II, is confirmed but not the
`monotropism between II and I.
`
`By means of the measured physicochemical
`properties of the three modifications of
`D-mannitol, the relative curve course of H- and G-
`isobars of mod. I and III could be explained in the
`energy/temperature diagram, whereas the ener-
`getic relationship between mod. I and II is doubt-
`
`Figure 5. X-ray powder patterns of mod. I, II (also calculated from single-crystal
`data) and III of D-mannitol.
`
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`
`In addition, water sorption experiments were
`performed on the three modifications. After stor-
`age for 3 months in a desiccator at 24°C and 43%
`relative humidity using potassium carbonate, the
`crystal forms were sieved (50 to 100 mm) and af-
`terward exposed to 0%, 75%, and 92% relative
`humidity at 25°C. The water sorption behavior of
`the three modifications is similar. The sample
`mass of the crystal forms increased 0.4 to 0.8% at
`75%, as well as 92%, relative humidity within 48
`h. The small differences in water uptake cannot
`be explained by the differences in the crystal lat-
`tices of the modifications. However, this behavior
`can be related to surface effects or differences in
`the degree of activation of the crystalline prod-
`ucts. Care must be taken that only chemically
`pure mannitol is used for the measurement of wa-
`ter sorption. An admixture of 0.5% sorbitol in-
`creases the water uptake by about 1% at 92%
`relative humidity and 25°C.
`The kinetic stability of the modifications is con-
`siderable because no transformation of mod. III
`and II into mod. I occurs during mechanical stress
`[milling, pressure (0.74 GPa)] or storing for more
`than 5 years at 25°C if kept dry. Therefore, it was
`possible to investigate the compaction behavior of
`the crystal forms.
`
`Powder Compaction Studies
`Because the crystallographic and thermodynamic
`properties of a polymorphic substance vary within
`the modifications, their compression behavior and
`therefore their tabletability can show significant
`differences.36–38 Thus, investigations on the com-
`pression behavior of different crystal forms of
`drug substances and excipients are of particular
`interest. The compression behavior of the three
`modifications of D-mannitol was studied by
`evaluation of (i) compressibility: compression
`pressure versus porosity; (ii) compactibility: com-
`pression pressure versus tensile strength; and
`(iii) friction of the compacts: compression pressure
`versus ejection force.
`Compressibility of a material is its ability to be
`reduced in volume as a result of an applied pres-
`sure. The simplest method to compare the com-
`pressibility of a set of substances consists in rep-
`resenting the gradual change in compact porosity
`as a function of any increase in compression pres-
`sure. The results obtained for the three modifica-
`tions of D-mannitol are represented in Figure 7.
`It can be observed that the compressibility of
`the three crystal forms is significantly different.
`
`JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 89, NO. 4, APRIL 2000
`
`Figure 6. Semi-schematic energy/temperature dia-
`gram of the crystalline modifications of D-mannitol and
`its melt: G, free energy; H, enthalpy; DHf, enthalpy of
`fusion; DHt, enthalpy of transition; liq, melt; mp, melt-
`ing point; RT, room temperature; measured enthalpy
`effects are drawn bold. The y-axis is without scale and
`the x-axis is enlarged against higher temperatures on a
`logarithmical basis.
`
`ful if a strict standard is applied. Therefore, in
`Figure 6 the curves of isobars of mod. II are de-
`picted as dotted lines assuming to be monotropi-
`cally related to mod. I.
`But how is the order of thermodynamic stabil-
`ity of the modifications at ambient conditions?
`Modifications III and II show a reproducible
`transformation into mod. I at 20°C within 1 day,
`when a suspension of the modification is stirred
`(magnetic stirrer) in a solvent (water, ethanol) at
`fluctuating temperatures between 15 and 25°C.
`Modification I remains unchanged. Thus, mod. I
`is the thermodynamically stable modification at
`ambient conditions and therefore the thermody-
`namic transition points of the enantiotropic sys-
`tems must be less than 20°C.
`
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`

`466
`
`BURGER ET AL.
`
`Figure 7. Compactibility of D-mannitol modifications.
`
`Modification III shows the best compressibility
`followed by mod. II and I. The increase in the
`compressibility of mod. III and II could be derived
`from an increase in densification during compres-
`sion or from a decrease in elastic recovery during
`decompression.
`Compactibility is the ability of a material to
`produce compacts with sufficient strength under
`the effect of densification. Figure 8 presents the
`relationship between compression pressure and
`tensile strength for different D-mannitol modifi-
`cations. These results strongly suggested that the
`interparticle bond structure of the three modifi-
`cations is significantly different. It can also be
`observed in Figure 8 that, for a similar porosity,
`the tensile strength of compacts of D-mannitol
`mod. III is substantially greater than that of the
`two other crystal forms.
`The friction of the compacts of the different
`D-mannitol modifications within the matrix is
`represented in Figure 9. Modification III shows
`
`the lowest diewall friction followed by mod. II and
`I. It can be concluded that mod. III contains the
`best self-lubricating activity within the three
`crystal forms.
`The results of the compaction studies on the
`crystal forms of D-mannitol show that mod. III
`exhibits the best consolidation behavior of the
`three crystal forms. From the compact technologic
`point of view mod. III is the crystal form of choice
`because at a given pressure the compacts made of
`this crystal form show the greatest hardness. Be-
`cause mod. III needs the lowest compression pres-
`sure to form suitable compacts, the attrition of an
`industrial compactor will be the lowest. There-
`fore, the use of mod. III is of interest from an
`economic point of view.
`
`CONCLUSION
`As given in Table 2, only Walter-Levy10 and
`Jones and Lee12 obtained the three pure modifi-
`
`Figure 8. Tabletability of D-mannitol modifications.
`
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`POLYMORPHS OF D-MANNITOL
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`467
`
`Figure 9. Friction of compacts of D-mannitol modifications within the matrix.
`
`cations of D-mannitol. There they studied crystal-
`lographic and optical properties. Grindley et al.15
`measured the solid-state 13C NMR spectra of the
`three pure crystal forms and of mixtures of modi-
`fications of D-mannitol. In this work a semi-
`schematic energy/temperature diagram (Fig. 6)
`was constructed by means of physicochemical
`data obtained. Therein the thermodynamic rela-
`tionship between the three modifications of man-
`nitol is explained. Modification III is enantio-
`tropically related to mod. I and II. Only small
`energetic differences between mod. I and II could
`be found, which is also manifested in small differ-
`ences of melting points and heats of fusion as well
`as in a similar crystal lattice belonging to the
`same space group (orthorhombic, P212121).9–11
`Obtained data show more evidence for monotrop-
`ism than enantiotropism, although there was no
`reliable assignation possible. However, mod. I is
`the thermodynamic stable crystal form at 20°C
`and greater.
`Besides the thermodynamic properties of the
`three modifications, we focused on their implica-
`tions to pharmaceutical technology. Although
`mod. III of D-mannitol is a thermodynamically
`unstable crystal form at ambient conditions, it
`shows significant kinetic stability. This crystal
`form is durable over a period of at least 5 years at
`25°C if kept dry, and even mechanical stress such
`as grinding or compacting does not cause a tran-
`sition into the room temperature thermodynami-
`cally stable mod. I. Several ways are described in
`the literature of how to crystallize mod. III exclu-
`sively. It seems to be possible to find a routine
`way to produce this crystal form in macroscopic
`amounts routinely and to take advantage of its
`
`excellent tabletability properties in the produc-
`tion of solid dosage forms containing D-mannitol.
`
`ACKNOWLEDGMENTS
`
`The authors are grateful