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Morphological evaluation of the γ-polymorph of indomethacin
Journal of Crystal Growth 237–239 (2002) 300–305
Morphological evaluation of the g-polymorph of indomethacin Paul A. Slavina, David B. Sheena, Evelyn E. A Shepherda, John N. Sherwooda,*, Neil Feederb, Robert Dochertyb, Snezena Milojevicb a
Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XL, Scotland, UK b Pfizer Central Research, Sandwich CT, England, UK
Abstract A study has been made of the polymorphic nature of crystals of the pharmaceutical indomethacin grown from a wide range of solvents and from the melt. In most solvents, growth at high supersaturations yielded either a 1:0.5 solvated form (approximately) or the a-polymorph. At low supersaturations the g-polymorph was commonly produced. Solutions in MeOH and t BuOH yielded a 1:1 solvate. The morphology of the g-form showed no variation with solvent type but changed with supersaturation in a manner consistent with a differential variation in growth rates of the faces. This lack of solvent influence was confirmed by the fact that a similar morphology resulted on growth from the melt. Morphology predictions were carried out for the g-polymorph and these show good agreement with experimental observations. r 2002 Elsevier Science B.V. All rights reserved. PACS: 81.10.Aj; 81.10.Dn; 81.10.Fq; 81.30.Hd Keywords: A1. Crystal morphology; A1. Morphology modelling; A2. Growth from melt; A2. Growth from solutions; A2. Polymorphism; B2. Indomethacin
1. Introduction Indomethacin is an anti-pyretic and anti-inflammatory drug used in many pharmaceutical preparations [1,2]. Despite its utility and the need to understand the morphological properties of product crystals for the purposes of formulation, surprisingly little has been published on the morphologies of the predominant polymorphic forms. *Corresponding author. Tel.: +44-0141-548-2797; fax: +440141-4822. E-mail address: [email protected] (J.N. Sherwood).
Indomethacin is reported to show a complicated polymorphism consisting of five true polymorphs and a wide range of solvate forms collectively named Form V (b) [3–8]. Of the true polymorphs only two, usually referred to as Forms I (g) and II (a), are regularly obtainable. The remainder exist only in thin films grown from the melt and in the presence of co-solutes [4,6,8]. One of these, Form III, is almost certainly a decomposition product of the melt growth process [9]. The remainder (Forms IV, VI and VII) are metastable and readily transform to Forms I or II on standing or heating. The solvates form readily from a wide range of solvents under high supersaturation conditions. Desolvation inevitably leads to Forms I or II as
0022-0248/02/$ - see front matter r 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 0 2 4 8 ( 0 1 ) 0 1 9 2 4 - 8
P.A. Slavin et al. / Journal of Crystal Growth 237–239 (2002) 300–305
does variation of the imposed supersaturation during crystallisation from solution. From this brief summary it can be seen that Forms I and II are the most regularly formed and potentially the most useful of the polymorphs. The g-form (I) is the most thermodynamically stable as implied by the melting point. The a-Form (II) can be prepared by direct crystallisation, however, and although metastable, has been shown to persist at room temperatures for periods of longer than 18 months without transformation. Of the two only the g-form shows a well defined morphology. The a-form grows as a fibrous/spherulitic structure. In the present paper we describe the morpholgical variations of the g-form and compare the results with modelling calculations.
2. Experimental procedure 2.1. Materials g-Indomethacin (Sigma or Fluka 99%) was further purified by crystallisation. All solvents were of analytical grade and were distilled, dried and filtered.
301
910 thermal analyser and FTIR using a Mattson 5000 spectrometer. The morphologies of the resulting crystals were determined by a combination of optical, photographic and X-ray goniometric techniques. 2.2.2. Molecular modelling Molecular modelling was carried out using the Cerius 2 morphology program with the Dreiding 2.21 force field selected [10]. Three basic calculation approaches were used: (1) Bravais–Friedel–Donnay–Harker (BFDH). The BFDH model is a geometrical calculation that uses the crystal lattice and symmetry to generate a list of possible growth faces and their relative growth rates. (2) Attachment energy (AE). The AE is model is based on the energy released as a growth slice attaches to a growing crystal surface. (3) Hydrogen bond energy minimisation (HBEM). The HBEM model constrains hydrogen bonds such that they are energy minimised. The crystallographic data used in the calculations were as follows: ( g-Indomethacin: triclinic P1% a=9.295 A, ( ( b=10.969 A, c=9.742 A, a=69.381, b=110.791, g=92.78, z=2 [11].
2.2. Methods 2.2.1. Crystal growth and analysis Solutions saturated at room temperature (B201C) were placed in crystallisation dishes, covered with transparent film and allowed to evaporate slowly with stirring under ambient conditions. Alternatively, solutions saturated at higher temperatures were allowed to cool. Nucleation and growth were allowed to occur spontaneously. Samples were farmed from solution after bulk precipitation had occurred. For growth from the melt, the a-form was melted (150–1541C) and held at 1571C for a period of 2 h. The g-form (T melting 160–1621C) nucleated and grew in the melt. Photomicrographs of the crystals were taken at different time intervals during growth. The polymorphic nature of the product was determined by powder X-ray diffraction using a Siemens D500 instrument, DSC using a DuPont
3. Results and discussion 3.1. Crystallisation studies The results of the crystallisation studies are summarised in Table 1. In summary most solvents yielded solvates under high supersaturation conditions. These predominantly developed as an encrustation at or near the surface of the liquor which rapidly spread through the bulk on rapid evaporation or cooling. In some cases small quantities of the apolymorph were detected in the solvate mass as precipitation progressed. For the bulk of the alcohols low supersaturation conditions yielded the g-form alone. Acetonitrile alone amongst the solvents examined gave the pure a-form at high supersaturations and the pure g-form at low supersaturations. The relative
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Table 1 Solvents C6H6, CHCl3, CH2Cl2, CCl4, THF, cyclohexanone Ethanol, propan-1-ol, propan-2-ol, butan-1-ol, isobutyl alcolhol, pentan-1-ol, isoamyl alcohol, octan-2-ol, cyclohexanol
Supersaturationa All
Product
Morphology
b
Fine short needles
b
Solvate
High
Solvate and/or a
Fine short needles
Low
g
Rhombic plates
MeOH
High Low
a Solvateb
Fine needles Columnar
t
All
Solvateb
Columnar
BuOH
b
Toluene, diethylether, ethyl acetate, acetone, butan-2-one
High Low
Solvate and/or a g
Fine short needles Rhombic plates
Acetonitrile
High
a
Low
g
Fine long needles and spherulites Rhombic plates
g
Rhombic plates
Melt a b
High supersaturationFrapid evaporation or cooling; Low supersaturationFslow evaporation or cooling. Solvates varied in composition but were predominantly indomethacin: 0.5 solvent. MeOH and t BuOH yielded 1:1 solvates.
Fig. 1. Photomicrographs of the morphology of indomethacin and its solvates crystallised from various solvents: (a) Solvate from CH2Cl2; (b) solvate from benzene; (c) solvate from CHCl3; (d) a-form (EtOH/H2O); (e) a-form (MeCN); (f) t BuOH solvate; (g) MeOH solvate; (h) g-form (propan-2-ol); and (I) g-form (melt).
P.A. Slavin et al. / Journal of Crystal Growth 237–239 (2002) 300–305
303
Fig. 2. Habit of the pure g-form of indomethacin developed under different conditions of preparation: (a)and (d) low supersaturation; (a) and (e) high supersaturation (short period of growth); (a) and (f) high supersaturation (long period of growth, the (1% 1 1) face has now grown out).
Fig. 3. Growth features on the habit faces of indomethacin: (a) (0 0 1), (b) (0 1 0), (c) (1% 1 1).
appearance of the two principle polymorphs is consistent with Ostwald’s rule which would predict that the a phase should form under rapid precipitation conditions followed by its transformation to the stable g-form on long periods of standing or lengthy growth periods. The potential for a solvent mediated transformation of this kind was tested by studying mixtures of the a- and gphases in solution. It was observed that the former converted to the latter. This confirms previous observations carried out in the indomethacin/ ethanol system [12]. Of most particular note was the close similarity of the morphologies of the g-species precipitated under similar conditions from a very wide range of solvent types. This implies that there is little or no solvent direction of the morphology or polymorphic type. This assumption was confirmed by
the observation of similar morphologies following growth from the melt where no solvent direction or mediation can be envisaged. Fig. 1 shows a range of photomicrographs and SEM images of typical crystals resulting from the growth experiments. These define well the morphological descriptions in Table 1 and show the ease of distinction between the solvate, a- and g-forms. The significant distinction between the MeOH and t BuOH solvates and the remainder underscores the difference in composition. Samples of these materials readily grow to a size useful for X-ray structural determination [13]. It is obvious from this summary that assessment of the morphologies of indomethacin polymorphs and solvates is restricted to the examination of the g-form and the MeOH and tBuOH solvate forms.
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defined solvate forms was unsuccessful. The metastable zones for these materials in the two solvents (MeOH and t BuOH) proved to be very narrow and with careful slow cooling led to three dimensional nucleation in solution before significant growth occurred. Experiments with the preparation of the g-form from acetonitrile proved to be most successful for obtaining crystals on which a full morphological assessment could be carried out. Solutions saturated between 351C and 451C, seeded and cooled at 0.31C/dayFlow supersaturation or 11C/dayFhigh supersaturation gave crystals such as those shown in Fig. 2. This figure shows photomicrographs of the crystals obtained together with labelled schematics defining the experimental morphology. The crystals grown at low supersaturations were columnar in habit with a low aspect ratio (Fig. 2a). The major forms were {0 0 1}, {0 1 0} and {1 0 0} with smaller {1% 0 1} faces. The capping faces were (1% 1 1), (0 1 1), (0 1 2) and (0 1 0). At the higher-supersaturations (Figs. 2b and c) the morphology changed to a rectangular tablet shape with large {0 0 1} faces bounded by smaller {1 0 0} and {0 1 0} faces. Occasionally, small {1% 1 1} faces appeared but these readily grew out on continued growth. These differences in morphology define well the solution growth rates of the different forms. The (0 1 1) and (0 1 2) obviously grow most rapidly and ‘‘grow out’’. The {1% 0 1} forms have a slightly lower growth rate. The occasional appearance of the (1% 1 1) places this next in the order followed by (0 1 0), (1 0 0) and (0 0 1) the slowest. The differences in growth rate follow the relative perfection of the faces and potentially underlying the sub-structure. The slow growing faces show few growth centres of any size (Fig. 3a). In contrast the faster growing faces show considerable growth activity (Figs. 3b and c). Fig. 4. Theoretical morphologies of indomethacin as defined by: (a) Bravais–Friedel–Donnay–Harker model; (b) attachment energy model; and (c) hydrogen bond energy minimisation model.
To achieve this it is necessary to obtain well developed specimens under defined conditions. Attempts to prepare large crystals of the well
3.2. Modelling Fig. 4 shows the results of three basic standard approaches to the modelling of the morphology. All succeed in that they define the basic forms of the crystal as seen experimentally. The attachment energy calculations lead to the best fit with the
P.A. Slavin et al. / Journal of Crystal Growth 237–239 (2002) 300–305
experimental at low supersaturation defining the major forms {1 0 0}, {0 1 0} and {0 0 1} with the (1% 1 1), (1% 0 1), (0 1 1) also present. The (0 1 2) face is not present in the calculated morphology although this is the fastest growing face so perhaps this is not unexpected. The hydrogen bond energy minimisation calculation leads to a good fit with the crystals grown at high supersaturation in that a tabular/plate-like morphology is predicted. However, the forms are not those observed experimentally i.e. {1 0 0}, {0 1 0} and {0 0 1}. This may be due to the fact that the hydrogen bond energy minimisation calculation constrains the hydrogen bond lengths such that they are in an energy minimised state, and not that of the experimentally observed structure.
4. Conclusion In conclusion, the morphologies of the predominant forms of indomethacin have been defined. The solvate forms and the a-polymorph all have a needle/columnar-like morphology. In contrast the g-form has a plate-like morphology which is found to be similar for all solvents and the melt and is easily distinguishable from the other forms. A full analysis of the morphology of the g-form has been
305
carried out for crystals grown from acetonitrile at both high and low supersaturation. Morphological modelling calculations were also carried out on the g-form and the attachment energy calculation with the Dreiding 2.21 force field showed good agreement with the crystals grown at low supersaturation.
References [1] T.Y. Shen, J. Am. Chem. Soc. 85 (1963) 488. [2] C.A. Winter, E.A. Risley, G.W. Nuss, J. Pharmcol. Exp. Ther. 141 (1963) 369. [3] R. Pakula, L. Pichnej, S. Spychala, K. Butkiewicz, Pol. J. Pharmacol. Pharm. 29 (1977) 151. [4] L. Borka, Acta. Pharm. Suec. 11 (1974) 295. [5] H. Yamamoto, Chem. Pharm. Bull. 16 (1) (1968) 17. [6] S.Y. Lin, J. Pharm. Sci. 81 (6) (1992) 572. [7] Z. Galdecki, M.L. Glowka, Z. Gorkiewicz, Acta. Polon. Pharm. 34 (5) (1977) 521. [8] S.Y. Lin, J.Y. Cherng, J. Therm. Anal. 45 (1995) 1565. [9] P.A. Slavin, D.B. Sheen, J.N. Sherwood, N. Feeder, R. Doherty, S. Milojevic, in preparation. [10] S.L. Mayo, J. Phys. Chem. 94 (1990) 8897. [11] T.J. Kistenmacher, R.E. Marsh, J. Am. Chem. Soc. 94 (4) (1972) 1340. [12] N. Kaneniwa, M. Otsuka, T. Hayashi, Chem. Pharm. Bull. 33 (8) (1985) 3447. [13] V. Joshi, J.G. Stowell, S. Byrn, Mol. Crystal Liq. Crystal 313 (1998) 265.
Morphological evaluation of the g-polymorph of indomethacin Paul A. Slavina, David B. Sheena, Evelyn E. A Shepherda, John N. Sherwooda,*, Neil Feederb, Robert Dochertyb, Snezena Milojevicb a
Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XL, Scotland, UK b Pfizer Central Research, Sandwich CT, England, UK
Abstract A study has been made of the polymorphic nature of crystals of the pharmaceutical indomethacin grown from a wide range of solvents and from the melt. In most solvents, growth at high supersaturations yielded either a 1:0.5 solvated form (approximately) or the a-polymorph. At low supersaturations the g-polymorph was commonly produced. Solutions in MeOH and t BuOH yielded a 1:1 solvate. The morphology of the g-form showed no variation with solvent type but changed with supersaturation in a manner consistent with a differential variation in growth rates of the faces. This lack of solvent influence was confirmed by the fact that a similar morphology resulted on growth from the melt. Morphology predictions were carried out for the g-polymorph and these show good agreement with experimental observations. r 2002 Elsevier Science B.V. All rights reserved. PACS: 81.10.Aj; 81.10.Dn; 81.10.Fq; 81.30.Hd Keywords: A1. Crystal morphology; A1. Morphology modelling; A2. Growth from melt; A2. Growth from solutions; A2. Polymorphism; B2. Indomethacin
1. Introduction Indomethacin is an anti-pyretic and anti-inflammatory drug used in many pharmaceutical preparations [1,2]. Despite its utility and the need to understand the morphological properties of product crystals for the purposes of formulation, surprisingly little has been published on the morphologies of the predominant polymorphic forms. *Corresponding author. Tel.: +44-0141-548-2797; fax: +440141-4822. E-mail address: [email protected] (J.N. Sherwood).
Indomethacin is reported to show a complicated polymorphism consisting of five true polymorphs and a wide range of solvate forms collectively named Form V (b) [3–8]. Of the true polymorphs only two, usually referred to as Forms I (g) and II (a), are regularly obtainable. The remainder exist only in thin films grown from the melt and in the presence of co-solutes [4,6,8]. One of these, Form III, is almost certainly a decomposition product of the melt growth process [9]. The remainder (Forms IV, VI and VII) are metastable and readily transform to Forms I or II on standing or heating. The solvates form readily from a wide range of solvents under high supersaturation conditions. Desolvation inevitably leads to Forms I or II as
0022-0248/02/$ - see front matter r 2002 Elsevier Science B.V. All rights reserved. PII: S 0 0 2 2 - 0 2 4 8 ( 0 1 ) 0 1 9 2 4 - 8
P.A. Slavin et al. / Journal of Crystal Growth 237–239 (2002) 300–305
does variation of the imposed supersaturation during crystallisation from solution. From this brief summary it can be seen that Forms I and II are the most regularly formed and potentially the most useful of the polymorphs. The g-form (I) is the most thermodynamically stable as implied by the melting point. The a-Form (II) can be prepared by direct crystallisation, however, and although metastable, has been shown to persist at room temperatures for periods of longer than 18 months without transformation. Of the two only the g-form shows a well defined morphology. The a-form grows as a fibrous/spherulitic structure. In the present paper we describe the morpholgical variations of the g-form and compare the results with modelling calculations.
2. Experimental procedure 2.1. Materials g-Indomethacin (Sigma or Fluka 99%) was further purified by crystallisation. All solvents were of analytical grade and were distilled, dried and filtered.
301
910 thermal analyser and FTIR using a Mattson 5000 spectrometer. The morphologies of the resulting crystals were determined by a combination of optical, photographic and X-ray goniometric techniques. 2.2.2. Molecular modelling Molecular modelling was carried out using the Cerius 2 morphology program with the Dreiding 2.21 force field selected [10]. Three basic calculation approaches were used: (1) Bravais–Friedel–Donnay–Harker (BFDH). The BFDH model is a geometrical calculation that uses the crystal lattice and symmetry to generate a list of possible growth faces and their relative growth rates. (2) Attachment energy (AE). The AE is model is based on the energy released as a growth slice attaches to a growing crystal surface. (3) Hydrogen bond energy minimisation (HBEM). The HBEM model constrains hydrogen bonds such that they are energy minimised. The crystallographic data used in the calculations were as follows: ( g-Indomethacin: triclinic P1% a=9.295 A, ( ( b=10.969 A, c=9.742 A, a=69.381, b=110.791, g=92.78, z=2 [11].
2.2. Methods 2.2.1. Crystal growth and analysis Solutions saturated at room temperature (B201C) were placed in crystallisation dishes, covered with transparent film and allowed to evaporate slowly with stirring under ambient conditions. Alternatively, solutions saturated at higher temperatures were allowed to cool. Nucleation and growth were allowed to occur spontaneously. Samples were farmed from solution after bulk precipitation had occurred. For growth from the melt, the a-form was melted (150–1541C) and held at 1571C for a period of 2 h. The g-form (T melting 160–1621C) nucleated and grew in the melt. Photomicrographs of the crystals were taken at different time intervals during growth. The polymorphic nature of the product was determined by powder X-ray diffraction using a Siemens D500 instrument, DSC using a DuPont
3. Results and discussion 3.1. Crystallisation studies The results of the crystallisation studies are summarised in Table 1. In summary most solvents yielded solvates under high supersaturation conditions. These predominantly developed as an encrustation at or near the surface of the liquor which rapidly spread through the bulk on rapid evaporation or cooling. In some cases small quantities of the apolymorph were detected in the solvate mass as precipitation progressed. For the bulk of the alcohols low supersaturation conditions yielded the g-form alone. Acetonitrile alone amongst the solvents examined gave the pure a-form at high supersaturations and the pure g-form at low supersaturations. The relative
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P.A. Slavin et al. / Journal of Crystal Growth 237–239 (2002) 300–305
Table 1 Solvents C6H6, CHCl3, CH2Cl2, CCl4, THF, cyclohexanone Ethanol, propan-1-ol, propan-2-ol, butan-1-ol, isobutyl alcolhol, pentan-1-ol, isoamyl alcohol, octan-2-ol, cyclohexanol
Supersaturationa All
Product
Morphology
b
Fine short needles
b
Solvate
High
Solvate and/or a
Fine short needles
Low
g
Rhombic plates
MeOH
High Low
a Solvateb
Fine needles Columnar
t
All
Solvateb
Columnar
BuOH
b
Toluene, diethylether, ethyl acetate, acetone, butan-2-one
High Low
Solvate and/or a g
Fine short needles Rhombic plates
Acetonitrile
High
a
Low
g
Fine long needles and spherulites Rhombic plates
g
Rhombic plates
Melt a b
High supersaturationFrapid evaporation or cooling; Low supersaturationFslow evaporation or cooling. Solvates varied in composition but were predominantly indomethacin: 0.5 solvent. MeOH and t BuOH yielded 1:1 solvates.
Fig. 1. Photomicrographs of the morphology of indomethacin and its solvates crystallised from various solvents: (a) Solvate from CH2Cl2; (b) solvate from benzene; (c) solvate from CHCl3; (d) a-form (EtOH/H2O); (e) a-form (MeCN); (f) t BuOH solvate; (g) MeOH solvate; (h) g-form (propan-2-ol); and (I) g-form (melt).
P.A. Slavin et al. / Journal of Crystal Growth 237–239 (2002) 300–305
303
Fig. 2. Habit of the pure g-form of indomethacin developed under different conditions of preparation: (a)and (d) low supersaturation; (a) and (e) high supersaturation (short period of growth); (a) and (f) high supersaturation (long period of growth, the (1% 1 1) face has now grown out).
Fig. 3. Growth features on the habit faces of indomethacin: (a) (0 0 1), (b) (0 1 0), (c) (1% 1 1).
appearance of the two principle polymorphs is consistent with Ostwald’s rule which would predict that the a phase should form under rapid precipitation conditions followed by its transformation to the stable g-form on long periods of standing or lengthy growth periods. The potential for a solvent mediated transformation of this kind was tested by studying mixtures of the a- and gphases in solution. It was observed that the former converted to the latter. This confirms previous observations carried out in the indomethacin/ ethanol system [12]. Of most particular note was the close similarity of the morphologies of the g-species precipitated under similar conditions from a very wide range of solvent types. This implies that there is little or no solvent direction of the morphology or polymorphic type. This assumption was confirmed by
the observation of similar morphologies following growth from the melt where no solvent direction or mediation can be envisaged. Fig. 1 shows a range of photomicrographs and SEM images of typical crystals resulting from the growth experiments. These define well the morphological descriptions in Table 1 and show the ease of distinction between the solvate, a- and g-forms. The significant distinction between the MeOH and t BuOH solvates and the remainder underscores the difference in composition. Samples of these materials readily grow to a size useful for X-ray structural determination [13]. It is obvious from this summary that assessment of the morphologies of indomethacin polymorphs and solvates is restricted to the examination of the g-form and the MeOH and tBuOH solvate forms.
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P.A. Slavin et al. / Journal of Crystal Growth 237–239 (2002) 300–305
defined solvate forms was unsuccessful. The metastable zones for these materials in the two solvents (MeOH and t BuOH) proved to be very narrow and with careful slow cooling led to three dimensional nucleation in solution before significant growth occurred. Experiments with the preparation of the g-form from acetonitrile proved to be most successful for obtaining crystals on which a full morphological assessment could be carried out. Solutions saturated between 351C and 451C, seeded and cooled at 0.31C/dayFlow supersaturation or 11C/dayFhigh supersaturation gave crystals such as those shown in Fig. 2. This figure shows photomicrographs of the crystals obtained together with labelled schematics defining the experimental morphology. The crystals grown at low supersaturations were columnar in habit with a low aspect ratio (Fig. 2a). The major forms were {0 0 1}, {0 1 0} and {1 0 0} with smaller {1% 0 1} faces. The capping faces were (1% 1 1), (0 1 1), (0 1 2) and (0 1 0). At the higher-supersaturations (Figs. 2b and c) the morphology changed to a rectangular tablet shape with large {0 0 1} faces bounded by smaller {1 0 0} and {0 1 0} faces. Occasionally, small {1% 1 1} faces appeared but these readily grew out on continued growth. These differences in morphology define well the solution growth rates of the different forms. The (0 1 1) and (0 1 2) obviously grow most rapidly and ‘‘grow out’’. The {1% 0 1} forms have a slightly lower growth rate. The occasional appearance of the (1% 1 1) places this next in the order followed by (0 1 0), (1 0 0) and (0 0 1) the slowest. The differences in growth rate follow the relative perfection of the faces and potentially underlying the sub-structure. The slow growing faces show few growth centres of any size (Fig. 3a). In contrast the faster growing faces show considerable growth activity (Figs. 3b and c). Fig. 4. Theoretical morphologies of indomethacin as defined by: (a) Bravais–Friedel–Donnay–Harker model; (b) attachment energy model; and (c) hydrogen bond energy minimisation model.
To achieve this it is necessary to obtain well developed specimens under defined conditions. Attempts to prepare large crystals of the well
3.2. Modelling Fig. 4 shows the results of three basic standard approaches to the modelling of the morphology. All succeed in that they define the basic forms of the crystal as seen experimentally. The attachment energy calculations lead to the best fit with the
P.A. Slavin et al. / Journal of Crystal Growth 237–239 (2002) 300–305
experimental at low supersaturation defining the major forms {1 0 0}, {0 1 0} and {0 0 1} with the (1% 1 1), (1% 0 1), (0 1 1) also present. The (0 1 2) face is not present in the calculated morphology although this is the fastest growing face so perhaps this is not unexpected. The hydrogen bond energy minimisation calculation leads to a good fit with the crystals grown at high supersaturation in that a tabular/plate-like morphology is predicted. However, the forms are not those observed experimentally i.e. {1 0 0}, {0 1 0} and {0 0 1}. This may be due to the fact that the hydrogen bond energy minimisation calculation constrains the hydrogen bond lengths such that they are in an energy minimised state, and not that of the experimentally observed structure.
4. Conclusion In conclusion, the morphologies of the predominant forms of indomethacin have been defined. The solvate forms and the a-polymorph all have a needle/columnar-like morphology. In contrast the g-form has a plate-like morphology which is found to be similar for all solvents and the melt and is easily distinguishable from the other forms. A full analysis of the morphology of the g-form has been
305
carried out for crystals grown from acetonitrile at both high and low supersaturation. Morphological modelling calculations were also carried out on the g-form and the attachment energy calculation with the Dreiding 2.21 force field showed good agreement with the crystals grown at low supersaturation.
References [1] T.Y. Shen, J. Am. Chem. Soc. 85 (1963) 488. [2] C.A. Winter, E.A. Risley, G.W. Nuss, J. Pharmcol. Exp. Ther. 141 (1963) 369. [3] R. Pakula, L. Pichnej, S. Spychala, K. Butkiewicz, Pol. J. Pharmacol. Pharm. 29 (1977) 151. [4] L. Borka, Acta. Pharm. Suec. 11 (1974) 295. [5] H. Yamamoto, Chem. Pharm. Bull. 16 (1) (1968) 17. [6] S.Y. Lin, J. Pharm. Sci. 81 (6) (1992) 572. [7] Z. Galdecki, M.L. Glowka, Z. Gorkiewicz, Acta. Polon. Pharm. 34 (5) (1977) 521. [8] S.Y. Lin, J.Y. Cherng, J. Therm. Anal. 45 (1995) 1565. [9] P.A. Slavin, D.B. Sheen, J.N. Sherwood, N. Feeder, R. Doherty, S. Milojevic, in preparation. [10] S.L. Mayo, J. Phys. Chem. 94 (1990) 8897. [11] T.J. Kistenmacher, R.E. Marsh, J. Am. Chem. Soc. 94 (4) (1972) 1340. [12] N. Kaneniwa, M. Otsuka, T. Hayashi, Chem. Pharm. Bull. 33 (8) (1985) 3447. [13] V. Joshi, J.G. Stowell, S. Byrn, Mol. Crystal Liq. Crystal 313 (1998) 265.