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Trends in Solubility of Polymorphs
COMMENTARY Trends in Solubility of Polymorphs MADHU PUDIPEDDI, ABU T.M. SERAJUDDIN Pharmaceutical & Analytical Development, Novartis Pharmaceutical Corporation, 1 Health Plaza, East Hanover, New Jersey 07936
Received 18 April 2004; revised 21 October 2004; accepted 18 November 2004 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20302
ABSTRACT: Polymorphism of drug substances has been the subject of intense investigation in the pharmaceutical field for over 40 years. Considering the multitude of reports on solubility or dissolution of polymorphs in the literature, an attempt is made in this study to answer the question: How big is the impact of polymorphism on solubility? A large number of literature reports on solubility or dissolution of polymorphs were reviewed and the data were analyzed for trends in solubility ratio of polymorphs. The general trend reveals that the ratio of polymorph solubility is typically less than 2, although occasionally higher ratios can be observed. A similar trend is also observed for anhydrate/hydrate solubility ratios, although anhydrate/hydrate solubility ratios appear to be more spread out and higher than the typical ratio for nonsolvated polymorphs. An attempt is also made in this commentary to estimate the ratio of solubilities of polymorphs from thermal data. The trend in estimated solubility ratio shows good agreement with the one observed with experimentally determined solubility values. ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:929–939, 2005
Keywords:
solubility; polymorphs
INTRODUCTION Polymorphism of drug substances has been the subject of intense investigation in the pharmaceutical field for over 40 years. A large number of studies on generation, identification, characterization, and pharmaceutical significance of polymorphism have been reported in the literature.1 Polymorphism has also been the subject of various regulatory considerations.2,3 The thermodynamics of pharmaceutical polymorphism has also been thoroughly investigated.4,5 It is important that crystalline forms of drug substances used in solid dosage forms be characterized, and the
Correspondence to: Madhu Pudipeddi (Telephone: 862-7787385; Fax: 973-781-4556; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 94, 929–939 (2005) ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association
appropriate forms selected to ensure that the product performance with respect to manufacturability, stability, and bioavailability remains unchanged. An early study by Aguiar et al6 reported the impact of drug polymorphism on bioavailability. Subsequently, a limited number of studies on the effect of polymorphism on bioavailability have been reported in the literature.7–9 Since solubility or drug dissolution are related to drug absorption, a large number of studies have focused on the effect of polymorphism on solubility or dissolution. Therefore, based on the large volume of polymorph solubility data, one might be able to answer the question: How big is the impact of polymorphism on drug solubility? In other words, is there a trend in the difference in solubility of polymorphic forms of a drug substance? Trend analysis of physicochemical properties is of general interest to pharmaceutical scientists. For example, Burnette and Connors10 surveyed
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the statistical properties of thermodynamic quantities for cyclodextrin complexes and concluded that they are normally distributed. Despite the large volume of literature on solubility of polymorphs, no systematic examination of a possible trend in polymorph solubility has been reported. It is the objective of this commentary to examine the ratio of solubility of polymorphs reported in the literature for possible trends. The term polymorphism is used in the context of nonsolvated crystal form modifications. To a limited extent, it is also the objective of this work to examine the trend in anhydrate/hydrate solubility ratios.
METHODS A large volume of published literature on polymorphism was surveyed for solubility or dissolution rate data. The survey examined solubility or dissolution rate of nonsolvated polymorphs in one category and anhydrate/hydrate forms in a separate category. Nonaqueous solvates were excluded due to their infrequent pharmaceutical use. Literature reports were reviewed carefully for solubility or dissolution data, and the ratio of solubility or dissolution rate of each form was calculated relative to the less soluble form. The experimental procedures were carefully reviewed to ensure that the reported (apparent) solubility or dissolution rate of the metastable form(s) was suitable for the purpose. For example, attention was paid to details such as testing of the undissolved solid phase after equilibration with the solvent to determine whether a change in crystal form had occurred. In those cases where a change in crystal form was observed during solubility determination, the data on intrinsic dissolution rate were considered, if appropriate, to calculate the ratio of solubilities. Because polymorph solubility ratio is independent of the solvent used, both aqueous and nonaqueous solubility data were utilized for nonsolvated polymorphs. For anhydrate/hydrate solubility ratios, only aqueous solubility ratios were used. Overall, solubility ratios of polymorphs of 55 compounds (81 solubility ratios due to the existence of multiple forms for some compounds) were compiled and examined for trends. Anhydrate/hydrate solubility ratios were compiled for 17 compounds (24 ratios due to existence of multiple forms). For the majority of compounds discussed in this work solubility or dissolution rates were reported in the temperature range of 20–408C. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 5, MAY 2005
In addition to the compilation of experimental values, solubility ratios of polymorphs was calculated using published thermal data. The general trend observed from the experimental values was compared with that seen with calculated values.
RESULTS AND DISCUSSION Literature Survey The solubility ratios of polymorphs of 55 compounds (81 solubility ratios due to the existence of multiple forms for some compounds) are listed in Table 1. When more than two forms were reported in a study, the solubility ratio of each form was calculated relative to the least soluble form. For example, four polymorphic forms (I, II ,III, and IV) of diflunisal were reported in ref. 25. Since form IV had the lowest solubility, the ratios were calculated as I/IV, II/IV, and III/IV. The trend in solubility ratio is shown in Figure 1a, where the X-axis shows the identification number of the compound in Table 1 and the Y-axis the corresponding solubility ratio. It can be seen that in the majority of cases the ratio was less than 2. In the case of premafloxacin,11 the solubility ratio in ethyl acetate was unusually high (a factor of 23.1). The general trend is better reflected in Figure 1b, in which premafloxacin is excluded. The solubility ratio of a glibenclamide polymorph12 in simulated gastric fluid (SGF) listed in Table 1 is not included in Figure 1b because a quantitative solubility (ratio >10) was not reported in this medium. The same polymorphs in simulated intestinal fluid (SIF) had a ratio of 2.6. Overall, the average solubility ratio for the polymorphs surveyed here is 1.7 (excluding premafolxacin or 2.0 with its inclusion). The anhydrate/hydrate solubility ratios surveyed in this work are listed in Table 2. The trend is plotted in Figure 2. Only aqueous solubilities were used for hydrate/anhydrate systems with the exception of glutethemide,13 where 13% ethyl alcohol was used by Shefter et al. to improve solubility for accuracy of analytical determination. Since the level of the nonaqueous component was low, glutethemide value was also included in the list. The ratios were calculated as anhydrate/ hydrate solubility (except LY334370, see below). In cases where multiple modifications of the anhydrous or hydrate form existed, the ratio was calculated in a way to represent the upper range of solubility ratios. To a large extent, the ratios listed in Table 2 are about 2 or less, but a few cases with
TRENDS IN SOLUBILITY OF POLYMORPHS
Table 1.
Solubility Ratio of Polymorphs
Compound No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55
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Compound
Solubility Ratio
19
1.0 1.7 4.7 2.1 2.8 1.1 1.1 1.3 1.2 1.3 2.2 1.2 2.0 4.2 3.6 2.0 1.4 1.3 1.3 1.2 1.2 1.9 1.8 1.1 1.3 1.6 1.4 1.0 1.8 2.0 1.2 2.6 (SIF) >10 (SGF) 1.6 1.6 1.0 1.1 1.5 1.2 1.3 2.3 3.5 2.0 1.2 1.7 1.6 1.3 1.3 1.6 1.3 1.1 1.2 1.1 1.1 1.5 1.3
A quinolone derivative Acemetacin (II/I)20 Acemetacin (III/I)20 Acemetacin (IV/I)20 Acemetacin (V/I)20 Acetazolamide21 Amiloridine (A/B)22 AWD-122-14 (a/e)23 AWD-122-14 (b/e)23 AWD-122-14 (g/e)23 Auranofin5 Carbovir (Hydrate III/Hydrate I) 24 Carbovir (Hydrate II/Hydrate I)24 Chloramphenicol palmitate9 Cyclopenthiazide (II/III)4 Cyclopenthiazide(I/III)4 Diflunisal (I/IV)25 Diflunisal (II/IV)25 Diflunisal (III/IV)25 DuP 74726 E210127 Etoposide28 F-269229 Fluconazole (AII/AI)30 Flunisolide31 Fluprednisolone (I/II)32 Fluprednisolone (III/II)32 Furosemide (II/I)33 Furosemide (III/I)33 Gepirone (II/I)34 GK-12835 Glibenclamide (a new insoluble form)12 Glibenclamide (II/I)36 Glibenclamide (IV/II)36 Glybuzole37 Indomethacin (a/g)17 (at 458C) Iopanoic acid19 Lamuvidine5 Lifibrol38 Losartan39 Mebendazole (B/A)40 Mebendazole (C/A)40 Mefenamic acid6,9 Methylprednisolone41 MK-57142 MK99643 Moricizine HCl44 Niclosamide45 An NK1 receptor atagonist46 Phenylbutazone (B/A)19 Phenylbutazone (C/A)19 Phenylbutazone (D/A)19 Phneylbutazone (E/A)19 Piretanide47 Piroxicam (I/III)48
(Continued ) JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 5, MAY 2005
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Table 1. (Continued ) Compound No. 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81
Compound 48
Piroxicam (II/III) Premafloxacin (I/III)11 Propranolol49 Ranitidine (I/IV)50 Ranitidine (II/IV)50 Ranitidine (III/IV)50 RG1252551 Ritonavir52 (at 58C) Roxifiban53 Salmeterol54 Succinyl sulfathiazole (Hydrate II/Hydrate I)55 Succinyl sulfathiazole (II/I)55 Succinyl sulfathiazole (III/I)55 Succinyl sulfathiazole (IV/I)55 Succinyl sulfathiazole (V/I)55 Sulfameter7 Sulfamethoxazole5 Sulfathiazole (III/I)56,57 Tenoxicam (I/III)58 Tenoxicam (II/III)58 Tolbutamide (IV/II)59 Tolubutamide (I/II)60 Toresamide61 Tranilast62 Urapidil5 WIN6384363
Solubility Ratio 1.3 23.1 1.4 1.4 1.4 1.3 1.3 4.0 1.2 1.2 1.8 1.8 1.9 2.9 3.9 1.8 1.2 1.7 1.9 1.9 1.5 1.1 2.4 1.5 4.4 1.0
Note: The nomenclature of the original authors (i.e., Roman numerals, English, or Greek alphabet) is retained.
significantly higher ratios (e.g., niclosamide) are also present. The anhydrate/hydrate solubility ratios appear to be more spread out and higher than the typical ratio for nonsolvated polymorphs. In the majority of cases, anhydrous forms are more soluble in aqueous media than the corresponding hydrate forms. Uncommon cases where the hydrate form exhibited higher solubility (or dissolution rate) than the anhydrous form have also
been reported. For example, LY334370 HCl hydrate form had approximately 6 times higher intrinsic dissolution rate (at 378C) in water than the anhydrous form.14 Due to this irregularity, the ratio was expressed as hydrate/anhydrate solubility ratio in Table 2, whereas all other values are anhydrate/hydrate. The ratio of intrinsic dissolution rate was used to estimate solubility ratio for LY334370 in Table 2.
Figure 1. (a) Solubility ratios for polymorphs (n ¼ 81). (b) Solubility ratios for polymorphs on an expanded scale (not including premafloxacin). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 5, MAY 2005
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Table 2.
Anhyrate/Hydrate Solubility Ratio
Compound No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
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Compound
Solubility Ratio
64
1.6 1.7 1.6 2.2 1.2 1.2 1.7 2.2 2.1 2.5 1.6 6.0 1.2 22.9 1.8 2.2 3.2 5.7 6.2 9.3 12.7 1.9 1.2
Ampicilline (A/Trihydrate) Caffeine13 Carbamazepine (A/Dihydrate)65 Erythromycin (A/Dihydrate)66 Fluconazole (A/H I)30 Flunisolide (A1/Hemi-hydrate)31 Flurpredisolone (A II/a-H)32 Flurpredisolone (A II/b-H)32 GK-128(A/hemi-hydrate)35 GK-128 (A/monohydrate)35 Glutethemide13 LY334370 HCl (Dihydrate/A)14 Naproxen sodium67 Niclosamide45 Nifedipine (Anhydrate/Dihydrate)68 Piroxicam (A III/H)48 Succinyl sulfathiazole (A I/HI)55 Succinyl sulfathiazole (A II/HI)55 Succinyl sulfathiazole (A III/H1)55 Succinyl sulfathiazole (A IV/H1)55 Succinyl sulfathiazole (A V/H 1)55 Theophylline69 Tranilast62
Note: A, anhydrate; H, hydrate. Roman numerals, English, or Greek alphabet designate multiple forms. No additional designation used when a single anhydrate and a single hydrate forms are described.
Theoretical Calculation The ideal solubility of a solid in a solvent can be expressed as a function of its solid-state properties by eq. 1.15 Symbols X, DHf and Tm denote mol fraction solubility, heat of fusion, and melting temperature of the solid, respectively, and DCpm is the heat capacity difference between the solid
and the liquid forms of the solute. DG1 is the free energy difference between the solid and liquid solute. When DCpm is assumed to be zero, eq. 1 reduces to eq. 2. When a solid exists in two crystalline modifications 1 and 2, a similar equation can be written for the second modification (designated by subscript 1 or 2). The solubility ratio of the two forms can be estimated from thermal data by eq. 3. T m1 T T m1 T þ DCpm1 TTm1 T Tm ð1Þ DCpm1 ln 1 T
Rln X1 ¼ DHf1
T m1 T ln X1 ¼ DHf1 or TTm1 T m1 T DG1 ¼ DHf1 T m1 Figure 2. Anhydrate/hydrate solubility ratio (n ¼ 23). LY334370 HCl is an anomaly where the dissolution rate of the hydrate was six times that of the anhydrate. The ratio for this compound is presented as hydrate/ anhydrate in the figure.
DHf 1 R
Tm T 1 TTm 1
ð2Þ
X1 e ¼ DH f2 Tm2 T X2 R TTm 2 e
ð3Þ
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Hoffman16 derived an extended form of eq. 2 by assuming that the heat capacity difference between the solid and liquid is independent of temperature but not zero. By Taylor series and other approximations, Hoffman proposed eq. 4 to estimate the free energy difference between the solid and liquid forms of the solute. When a solid exists in two crystalline forms 1 and 2, the solubility ratio of the two forms can be estimated by Hoffman approach by using eqs. 5, 6 and 7. DG1 ¼
DHf1 ðTm1 TÞT 2 Tm 1
ð4Þ
DG2 ¼
DHf2 ðTm2 TÞT 2 Tm 2
ð5Þ
X1 X2
ð6Þ
DG2 DG1 ¼ RT ln DG2 DG1 X1 ¼ e RT X2
ð7Þ
The difference between eq. 2 and eq. 5 is the additional factor T/Tm in eq. 5. In this report, the solubility ratio of polymorphs was calculated from thermal data using the ideal solubility equation and the Hoffman approach and the two ratios were compared. Thermal data of a number of polymorphs was obtained from the excellent report by Yu.4 In addition to the compounds compiled by Yu, a few additional compounds for which published thermal data are available in the literature were also included. Solubility ratios of polymorphs were calculated for compounds with a melting point >258C. All values were calculated for 308C, as this temperature represented the midrange of temperatures for the experimental values in Table 1. Solubility ratios calculated by the ideal solubility equation and Hoffman approach are given in Table 3. When the heats of fusion and melting points of the polymorphs are sufficiently close, the two equations yield comparable solubility ratios. Otherwise, the solubility ratio estimated by the two equations may be significantly different. In about 50% of the cases in Table 3 the two estimates agreed within 10%. In other cases the differences were about 20–30% or wider (the ideal equation generally yielding higher values). For a limited number of compounds, both experimental solubility value and thermal data were available in the literature, allowing comparison of estimated ratios with experimental ratios. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 5, MAY 2005
The calculated solubility ratios for these compounds were compared in Table 4 with the experimental ratios. The solubility ratios of these compounds were calculated at 308C (for indomethacin, at 458C) and compared with the experimental solubility ratios at the same temperature. Ratios obtained by both ideal solubility equation and Hoffman equation are shown in Table 4. Although the agreement is not perfect, the comparison of experimental and calculated values shows that thermal data can be used to estimate solubility ratios of polymorphs for the purpose of examining general trends. It appears that either the ideal solubility equation or the Hoffman equation can be used for the purpose of examining general trends in solubility ratio of crystalline forms. The ratios calculated by Hoffman approach appear to be slightly closer to the experimental ratios in Table 4, although no generalization is intended due to the limited number of compounds. Values generated by Hoffman equation in Table 3 are plotted in Figure 3 to illustrate the general trend in solubility ratios. The general trend in calculated solubility ratios of polymorphs is in agreement with the trend observed in Figure 1b. The solubility ratio typically decreases as the temperature increases (unless there is an enantiotropic transition between the temperature of solubility determination and the higher temperature of interest). The majority of solubility studies examined in this survey were conducted at 20– 258C with a few at 30–408C. The solubility ratio of polymorphs at physiological conditions is expected to be similar (i.e., less than 2), if not smaller. An extensive analysis of solubility ratios between amorphous and crystalline forms is beyond the scope of the present study. However, a cursory look into the literature17 indicates that the ratio of solubility of amorphous to crystalline forms is often higher (sometimes a factor of 10 or even higher). It is possible that the experimental solubility value of a solid form (stable or metastable) may be higher than that in its pure crystalline form due to undetected amounts of amorphous component. However, the analysis of polymorph solubility ratios presented here should represent the general trend. A possible reason for the limited spread in solubility ratios may be the rather small difference in the energy of modifications of molecular crystals, which often result from packing or conformational differences. Alternatively, unstable solid forms with extraordinarily high free energies might have eluded detection due to rapid conversion to
TRENDS IN SOLUBILITY OF POLYMORPHS
Table 3.
Calculated Solubility Ratios of Polymorphs at 303 K
No.
Compound Name
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
1-Methoxy-1,2-benzidoxolin-3-one 1-Methyl-2-nitro-5-vinylimidazole 2,3-Dibromopropionic acid 2,7-Dihydroxynapthalene 3-Nitro-p-acetotoluidide 4-Bromo-1,2-dinitrobenzene 5-aAndrostane-3-17-dione Acetamide Acetaminophen Bisacodyl Butyrophenone, R ¼ H Cetyl alcohol Chloracetic acid Chloramphenicol palmitate Chlorpropamide cis-Cinnamic acid Cyclopentanethiol Dehydroepiandrosterone70 Erythrital Ethyl arachidate Ethyl biscumacetate F2693 Flufenamic acid Flufenamic acid Fosinopril71 Gepirone HCl Gepirone HCl Glycolic acid Indomethacin17 M79175 Menadione Meprobamate MK571 Myristyl alcohol Myriystyl alcohol o-Aminobenzoic acid Oxyclozanide Oxyclozanide Oxyclozanide p-1-R3S-3thioanisole 1,2,2 trimethylcyclopentane carboxylic acid Paraiodophenol Paraisopropylphenol p-bromophenol p-chlorophenol p-cresol Phenylbutazone Piroxicam pivalate72 Progesterone Pyrithyldione Pyrithyldione Pyrithyldione
41 42 43 44 45 46 47 48 49 50 51
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Solubility Ratio Using Hoffman Equation
Solubility Ratio Using the Ideal Solubility Equation
1.2 1.1 1.8 1.2 1.2 2.4 1.5 1.2 1.2 1.2 2.7 1.7 1.2 4.2 1.2 1.3 1.6 1.2 1.6 1.4 1.4 1.2 1.5 1.0 1.4 1.3 1.9 1.1 1.8 1.6 1.5 1.5 1.8 1.3 1.0 1.2
1.3 1.2 1.9 1.3 1.3 2.6 1.7 1.3 1.5 1.3 4.9 1.8 1.2 6.0 1.3 1.4 1.3 1.3 2.0 1.4 1.8 1.2 1.9 1.1 1.7 1.0 2.0 1.2 2.6 1.8 1.7 1.7 2.7 1.3 1.0 1.3
2.6 2.1 1.0
5.1 3.4 1.0
1.5 1.2 1.5 1.2 1.1 1.1–1.3 1.1 1.3 2.9 1.2 1.1
1.7 1.2 1.6 1.2 1.1 1.1–1.2 1.3 1.5 3.7 1.3 1.1 (Continued )
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Table 3. (Continued )
No. 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Compound Name Resorcinol Spipirone St1396 HCl Sulfaethidole Sulfathiazole Sulfathiazole Sulfazamet Sulfur Tamoxifen citrate Theophylline Tolbutamide Toresemide61 Tropine benzylate HCl WIN6384363
Solubility Ratio Using Hoffman Equation
Solubility Ratio Using the Ideal Solubility Equation
1.1 1.1 6.6 1.5 1.8 1.0 1.5 1.2 1.3 1.1 1.8 2.1 1.6 1.0
1.1 1.2 29.6 1.6 3.5 1.2 2.0 1.1 1.3 1.2 2.4 2.8 2.2 1.0
Table 4. Comparison of Experimental and Calculated Solubility Ratios at 303 K
Compound Chloramphenicol palmitate4,6 F-26934 Gepirone (III/I)34 Indomethacin (at 458C)17 MK5714,42 Phenylbutazone4,19 Sulfathiazole (III/I)4 Tolbutamide (II/I)60 Toresamide61 WIN6384363
Experimental Ratio
Ratio Calculated by Ideal Equation
Ratio Calculated by Hoffman Equation
4.2 1.8 2.0 1.1 1.6 1.1–1.2 1.7 1.1 2.4 1.0
6.0 1.2 1.0 2.3 2.7 1.1–1.3 1.2 2.4 2.8 1.0
4.2 1.2 1.3 1.8 1.8 1.0–1.3 1.0 1.8 2.1 1.0
Figure 3. Solubility ratios of polymorphs calculated from melting data using Hoffman equation (n ¼ 65). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 5, MAY 2005
lower energy forms, thus limiting the observable range in measurable solubility difference. From the present analysis of solubility data, it is not possible to draw any conclusion regarding the impact of solubility on bioavailability of polymorphs. The impact on bioavailability would depend on additional factors such as solubility difference, dose, permeability, and formulation factors. Theoretical analysis based on the Biopharmaceutical Classification System18 and/or computational simulations (e.g., GastroPlus, Simulationsplus, Inc., Lancaster, CA) may be helpful in understanding relative sensitivity of polymorph bioavailability to solubility or other factors such as dose and permeability. Computational simulations of biopharmaceutical parameters also may
TRENDS IN SOLUBILITY OF POLYMORPHS
help conduct well-designed experiments for rational evaluation of impact of polymorphism on bioavailability.
13.
ACKNOWLEDGMENTS
14.
The authors gratefully acknowledge Dr. Venkatramana Mantri Rao (Bristol-Myers Squibb Pharmaceuticals) for the valuable technical discussions.
15.
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27. Kushida I, Ashizawa K. 2002. Solid state characterization of E2101, a novel antispastic drug. J Pharm Sci 91:2193–2202. 28. Shah JC, Chen JR, Chow D. 1999. Metastable polymorphs of Etoposide with higher dissolution rate. Drug Dev Ind Pharm 25:63–67. 29. Chauvet A, Masse J, Ribet JP, Bigg D, Austin JM, Patoiseau JF, Jaud J. 1992. Characterization of polymorphs and solvates of 3-amino-1-(m-trifluoromethylphenyl)-6-methyl-1H-pyridazin-4-one. J Pharm Sci. 81:836–841. 30. Alkhamis KA, Obaidat AA, Nuseirat AF. 2002. Solid-state characterization of fluconazole. Pharm Tech 7:491–503. 31. Bartolomei M. 2000. Solid-state studies on hemihydrate and the anhydrous forms of flunisolide. J Pharm Biomed Anal 24:81–93. 32. Haleblian JK, Koda RT, Biles JA. 1971. Isolation and characterization of solid phases of flurprednisilone. J Pharm Sci 60:1485–1488. 33. Matsuda Y, Tatsumi E. 1990. Physicochemical characterization of furosemide modifications. Int J Pharm 60:11–26. 34. Behme RJ, Brooke D, Farney RF, Kensler TT. 1985. Characterization of polymorphism of gepirone hydrochloride. J Pharm Sci 74:1041–1046. 35. Ito S, Nishimura M, Kobayashi Y, Itai S, Yamamoto K. 1997. Characterization of polymorphs and hydrates of GK-128, a serotonin3 receptor antagonist. Int J Pharm 151:133–143. 36. Suleiman MS, Najib NM. 1989. Isolation and physicochemical characterization of solid forms of glibenclamide. Int J Pharm 50:103–109. 37. Otsuka M, Ofusa T, Matsuda Y. 1999. Physicochemical characterization of glybuzole polymorphs and their pharmaceutical properties. Drug Dev Ind Pharm 25:197–203. 38. Burger A, Lettenbichler A. 2000. Polymorphism and preformulation studies in lifibrol. Eur J Pharm Biopharm 49:65–72. 39. Raghavan K, Dwivedi A, Campbell GC, Johnston E, Levorse D, McCauley JA, Hussain M. 1993. Spectroscopic Investigation of losartan polymorphs. Pharm Res 10:900–904. 40. Swanepoel E, Liebenberg W, Dewarakonda B, De Villiers MM. 2003. Developing a discriminating dissolution test for three mebendazole polymorphs based on solubility differences. Pharmazie 58: 117–121. 41. Higuchi WI, Lau PK, Higuchi T, Shell JW. 1963. Polymorphism and drug availability: Solubility relations in the methylprednisolone system. J Pharm Sci 52:150–153. 42. Ghodbane S, McCauley JA. 1990. Study of the polymorphism of 3-((3-(2-(7-chloro-2-quinolinyl)(E)-ethenyl)phenyl)((3-dimethylamino-3 oxopropyl) thio)methyl)-thio)propanoic yl)thio)methyl)-thio)propanoic acid (MK571) by DSC, TG, XRPD
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and solubility measurements. Int J Pharm 59:281– 286. Jahansouz H, Thompson KC, Brenner GS, Kauffman MJ. 1999. Investigation of the polymorphism of the angiotensin II antagonist agent MK-996. Pharm Dev Tech 4:181–187. Wu LS, Torosian G, Sigvardson K, Gerard C, Hussain MA. 1994. Investigation of moricizine hydrochloride polymorphs. J Pharm Sci 83:1404– 1406. van Tonder EC, Maleka TSP, Liebenberg W, Song M, Wurster DE, De Villiers MM. 2004. Preparation and physicochemical properties of niclosamide anhydrate and two monohydrates. Int J Pharm 269:417–432. Wang Y, Wenslow RM, McCauley JA, Crocker LS. 2002. Polymorphic behavior of an NK1 receptor antagonist. Int J Pharm 243:147–159. Chikaraishi Y, Otsuka M, Matsuda Y. 1995. Dissolution behavior of piretanide polymorphs at various temperatures and pHs. Chem Pharm Bull 43:1966–1969. Vrecer F, Vrbinc M, Meden A. 2003. Characterization of piroxicam crystal modifications. Int J Pharm 256:3–15. Bartolomei M, Bertocchi P, Ramusino MC, Santucci N, Valvo L. 1999. Physicochemical characterization of the modification I and II of (R,S) propranolol hydrochloride: solubility and dissolution studies. J Pharm Biomed Anal 21:299–309. Madan T, Kakkar AP. 1994. Preparation and characterization of ranitidine hydrochloride crystals. Drug Dev Ind Pharm 20:1571–1588. Carlton RA, Difeo TJ, Powner TH, Santos I, Thompson MD. 1996. Preparation and characterization of polymorphs for an LTD4 antagonist, RG 12525. J Pharm Sci 85:461–467. Bauer J, Spanton S, Henry R, Quick J, Morris J. 2001. Ritonavir: An extrordinary example of conformational polymoprhism. Pharm Res 18:859–866. Maurin MB, Vickery RD, Rabel SR, Rowe SM, Foris CM. 2002. Polymorphism of roxifiban. J Pharm Sci 91:2599–2604. Tong HH, Shekunov BY, York P, Chow AH. 2001. Characterization of two polymorphs of salmeterol xinofoate crystallized from supercritical fulids. Pharm Res 18:852–858. Byrn S, Pfeifer RR, Stowell JG. 1999. Polymorphs. In: Byrn S, Pfeiffer RR, Stowell RR, editors. Solidstate chemistry of drugs. West Lafayette, IN: SSCI, Inc., pp 143–232. Lagas M, Lerk CF. 1981. The polymorphism of sulfathiazole. Int J Pharm 8:11–24. Milosovich G. 1964. Determination of solubility of a metastable polymorph. J Pharm Sci 53:11–24. Cantera RG, Leza MG, Bachiller CM. 2002. Solid phases of tenoxicam. J Pharm Sci 91:2240– 2251.
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59. Kimura K, Hirayama F, Uekama K. 1999. Characterization of tolbutamide polymorphs (Burger’s Forms II and IV) and polymorphic transition behavior. J Pharm Sci 88:385–391. 60. Rowe EL, Anderson BD. 1984. Thermodynamic studies of tolbutamide polymorphs. J Pharm Sci 73: 1673–1675. 61. Rollinger JM, Gstrein EM, Burger A. 2002. Crystal forms of toresamide: New insights. Eur J Pharm Biopharm 53:75–86. 62. Kawashima Y, Niwa T, Takeuchi H, Hino T, Itoh Y, Furuyama S. 1991. Characterization of polymorphs of tranilast anhydrate and tranilast monhydrate when crystallized by two solvent change spherical crystallization techniques. J Pharm Sci 80:472–478. 63. Rocco WL, Swanson JR. 1995. WIN63843 polymorphs: prediction of enantiotropy. Int J Pharm 117:231–236. 64. Zhu H, Grant DJW. 1996. Influence of water activity in organic solvent þ water mixture on the nature of the crystalline drug phase 2. Ampicillin Int J Pharm 139:33–43. 65. Dugue J, Ceolin R, Rouland JC, Lepage F. 1991. Polymorphism of carbamazepine: Solid-state studies on carbamazepine dihydrate. Pharm Acta Helv 66:307–310. 66. Fukumori Y, Fukuda T, Yamamoto Y, Shigitani Y, Hanyu Y, Takeuchi Y, Sato N. 1983. Physical
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characterization of erythromycin dihydrate, anhydrate and amorphous solid and their dissolution properties. Chem Pharm Bull 31:4029–4039. Di Martino P, Barthelemy C, Palmieri GF, Martelli S. 2001. Physical characterization of naproxen sodium hydrate and anhydrate forms. Eur J Pharm Sci 14:293–300. Caira KC, Robbertse Y, Bergh JJ, Song M, De Villiers MM. 2003. Structural characterization, physicochemical properties, and thermal stability of three crystal forms of nifedipine. J Pharm Sci 92:2519–2533. Fokkens JG, van Amelsfoort JGM, de Blaey CJ, de Kruif CG, Wilting J. 1983. A thermodynamic study of the solubility of theophylline and its hydrate. Int J Pharm 14:79–92. Chang LC, Caira MR, Guillory JK. 1995. Solidstate characterization of dehydroepiandrosterone. J Pharm Sci 84:1169–1179. Brittain HG, Morris KR, Bugay DE, Thakur AB, Serajuddin ATM. 1993. Solid-state NMR and IR for the analysis of pharmaceutical solids: polymorphs of fosinopril sodium. J Pharm Biomed Anal 11: 1063–1069. Giordano F, Gazzaniga A, Moyano JR, Ventura P, Zanol M, Peveri T, Carima L. 1998. Crystal forms of piroxicam pivalate: Preparation and characterization of two polymorphs. J Pharm Sci 87:333–337.
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Received 18 April 2004; revised 21 October 2004; accepted 18 November 2004 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20302
ABSTRACT: Polymorphism of drug substances has been the subject of intense investigation in the pharmaceutical field for over 40 years. Considering the multitude of reports on solubility or dissolution of polymorphs in the literature, an attempt is made in this study to answer the question: How big is the impact of polymorphism on solubility? A large number of literature reports on solubility or dissolution of polymorphs were reviewed and the data were analyzed for trends in solubility ratio of polymorphs. The general trend reveals that the ratio of polymorph solubility is typically less than 2, although occasionally higher ratios can be observed. A similar trend is also observed for anhydrate/hydrate solubility ratios, although anhydrate/hydrate solubility ratios appear to be more spread out and higher than the typical ratio for nonsolvated polymorphs. An attempt is also made in this commentary to estimate the ratio of solubilities of polymorphs from thermal data. The trend in estimated solubility ratio shows good agreement with the one observed with experimentally determined solubility values. ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:929–939, 2005
Keywords:
solubility; polymorphs
INTRODUCTION Polymorphism of drug substances has been the subject of intense investigation in the pharmaceutical field for over 40 years. A large number of studies on generation, identification, characterization, and pharmaceutical significance of polymorphism have been reported in the literature.1 Polymorphism has also been the subject of various regulatory considerations.2,3 The thermodynamics of pharmaceutical polymorphism has also been thoroughly investigated.4,5 It is important that crystalline forms of drug substances used in solid dosage forms be characterized, and the
Correspondence to: Madhu Pudipeddi (Telephone: 862-7787385; Fax: 973-781-4556; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 94, 929–939 (2005) ß 2005 Wiley-Liss, Inc. and the American Pharmacists Association
appropriate forms selected to ensure that the product performance with respect to manufacturability, stability, and bioavailability remains unchanged. An early study by Aguiar et al6 reported the impact of drug polymorphism on bioavailability. Subsequently, a limited number of studies on the effect of polymorphism on bioavailability have been reported in the literature.7–9 Since solubility or drug dissolution are related to drug absorption, a large number of studies have focused on the effect of polymorphism on solubility or dissolution. Therefore, based on the large volume of polymorph solubility data, one might be able to answer the question: How big is the impact of polymorphism on drug solubility? In other words, is there a trend in the difference in solubility of polymorphic forms of a drug substance? Trend analysis of physicochemical properties is of general interest to pharmaceutical scientists. For example, Burnette and Connors10 surveyed
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the statistical properties of thermodynamic quantities for cyclodextrin complexes and concluded that they are normally distributed. Despite the large volume of literature on solubility of polymorphs, no systematic examination of a possible trend in polymorph solubility has been reported. It is the objective of this commentary to examine the ratio of solubility of polymorphs reported in the literature for possible trends. The term polymorphism is used in the context of nonsolvated crystal form modifications. To a limited extent, it is also the objective of this work to examine the trend in anhydrate/hydrate solubility ratios.
METHODS A large volume of published literature on polymorphism was surveyed for solubility or dissolution rate data. The survey examined solubility or dissolution rate of nonsolvated polymorphs in one category and anhydrate/hydrate forms in a separate category. Nonaqueous solvates were excluded due to their infrequent pharmaceutical use. Literature reports were reviewed carefully for solubility or dissolution data, and the ratio of solubility or dissolution rate of each form was calculated relative to the less soluble form. The experimental procedures were carefully reviewed to ensure that the reported (apparent) solubility or dissolution rate of the metastable form(s) was suitable for the purpose. For example, attention was paid to details such as testing of the undissolved solid phase after equilibration with the solvent to determine whether a change in crystal form had occurred. In those cases where a change in crystal form was observed during solubility determination, the data on intrinsic dissolution rate were considered, if appropriate, to calculate the ratio of solubilities. Because polymorph solubility ratio is independent of the solvent used, both aqueous and nonaqueous solubility data were utilized for nonsolvated polymorphs. For anhydrate/hydrate solubility ratios, only aqueous solubility ratios were used. Overall, solubility ratios of polymorphs of 55 compounds (81 solubility ratios due to the existence of multiple forms for some compounds) were compiled and examined for trends. Anhydrate/hydrate solubility ratios were compiled for 17 compounds (24 ratios due to existence of multiple forms). For the majority of compounds discussed in this work solubility or dissolution rates were reported in the temperature range of 20–408C. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 5, MAY 2005
In addition to the compilation of experimental values, solubility ratios of polymorphs was calculated using published thermal data. The general trend observed from the experimental values was compared with that seen with calculated values.
RESULTS AND DISCUSSION Literature Survey The solubility ratios of polymorphs of 55 compounds (81 solubility ratios due to the existence of multiple forms for some compounds) are listed in Table 1. When more than two forms were reported in a study, the solubility ratio of each form was calculated relative to the least soluble form. For example, four polymorphic forms (I, II ,III, and IV) of diflunisal were reported in ref. 25. Since form IV had the lowest solubility, the ratios were calculated as I/IV, II/IV, and III/IV. The trend in solubility ratio is shown in Figure 1a, where the X-axis shows the identification number of the compound in Table 1 and the Y-axis the corresponding solubility ratio. It can be seen that in the majority of cases the ratio was less than 2. In the case of premafloxacin,11 the solubility ratio in ethyl acetate was unusually high (a factor of 23.1). The general trend is better reflected in Figure 1b, in which premafloxacin is excluded. The solubility ratio of a glibenclamide polymorph12 in simulated gastric fluid (SGF) listed in Table 1 is not included in Figure 1b because a quantitative solubility (ratio >10) was not reported in this medium. The same polymorphs in simulated intestinal fluid (SIF) had a ratio of 2.6. Overall, the average solubility ratio for the polymorphs surveyed here is 1.7 (excluding premafolxacin or 2.0 with its inclusion). The anhydrate/hydrate solubility ratios surveyed in this work are listed in Table 2. The trend is plotted in Figure 2. Only aqueous solubilities were used for hydrate/anhydrate systems with the exception of glutethemide,13 where 13% ethyl alcohol was used by Shefter et al. to improve solubility for accuracy of analytical determination. Since the level of the nonaqueous component was low, glutethemide value was also included in the list. The ratios were calculated as anhydrate/ hydrate solubility (except LY334370, see below). In cases where multiple modifications of the anhydrous or hydrate form existed, the ratio was calculated in a way to represent the upper range of solubility ratios. To a large extent, the ratios listed in Table 2 are about 2 or less, but a few cases with
TRENDS IN SOLUBILITY OF POLYMORPHS
Table 1.
Solubility Ratio of Polymorphs
Compound No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55
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Compound
Solubility Ratio
19
1.0 1.7 4.7 2.1 2.8 1.1 1.1 1.3 1.2 1.3 2.2 1.2 2.0 4.2 3.6 2.0 1.4 1.3 1.3 1.2 1.2 1.9 1.8 1.1 1.3 1.6 1.4 1.0 1.8 2.0 1.2 2.6 (SIF) >10 (SGF) 1.6 1.6 1.0 1.1 1.5 1.2 1.3 2.3 3.5 2.0 1.2 1.7 1.6 1.3 1.3 1.6 1.3 1.1 1.2 1.1 1.1 1.5 1.3
A quinolone derivative Acemetacin (II/I)20 Acemetacin (III/I)20 Acemetacin (IV/I)20 Acemetacin (V/I)20 Acetazolamide21 Amiloridine (A/B)22 AWD-122-14 (a/e)23 AWD-122-14 (b/e)23 AWD-122-14 (g/e)23 Auranofin5 Carbovir (Hydrate III/Hydrate I) 24 Carbovir (Hydrate II/Hydrate I)24 Chloramphenicol palmitate9 Cyclopenthiazide (II/III)4 Cyclopenthiazide(I/III)4 Diflunisal (I/IV)25 Diflunisal (II/IV)25 Diflunisal (III/IV)25 DuP 74726 E210127 Etoposide28 F-269229 Fluconazole (AII/AI)30 Flunisolide31 Fluprednisolone (I/II)32 Fluprednisolone (III/II)32 Furosemide (II/I)33 Furosemide (III/I)33 Gepirone (II/I)34 GK-12835 Glibenclamide (a new insoluble form)12 Glibenclamide (II/I)36 Glibenclamide (IV/II)36 Glybuzole37 Indomethacin (a/g)17 (at 458C) Iopanoic acid19 Lamuvidine5 Lifibrol38 Losartan39 Mebendazole (B/A)40 Mebendazole (C/A)40 Mefenamic acid6,9 Methylprednisolone41 MK-57142 MK99643 Moricizine HCl44 Niclosamide45 An NK1 receptor atagonist46 Phenylbutazone (B/A)19 Phenylbutazone (C/A)19 Phenylbutazone (D/A)19 Phneylbutazone (E/A)19 Piretanide47 Piroxicam (I/III)48
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Table 1. (Continued ) Compound No. 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81
Compound 48
Piroxicam (II/III) Premafloxacin (I/III)11 Propranolol49 Ranitidine (I/IV)50 Ranitidine (II/IV)50 Ranitidine (III/IV)50 RG1252551 Ritonavir52 (at 58C) Roxifiban53 Salmeterol54 Succinyl sulfathiazole (Hydrate II/Hydrate I)55 Succinyl sulfathiazole (II/I)55 Succinyl sulfathiazole (III/I)55 Succinyl sulfathiazole (IV/I)55 Succinyl sulfathiazole (V/I)55 Sulfameter7 Sulfamethoxazole5 Sulfathiazole (III/I)56,57 Tenoxicam (I/III)58 Tenoxicam (II/III)58 Tolbutamide (IV/II)59 Tolubutamide (I/II)60 Toresamide61 Tranilast62 Urapidil5 WIN6384363
Solubility Ratio 1.3 23.1 1.4 1.4 1.4 1.3 1.3 4.0 1.2 1.2 1.8 1.8 1.9 2.9 3.9 1.8 1.2 1.7 1.9 1.9 1.5 1.1 2.4 1.5 4.4 1.0
Note: The nomenclature of the original authors (i.e., Roman numerals, English, or Greek alphabet) is retained.
significantly higher ratios (e.g., niclosamide) are also present. The anhydrate/hydrate solubility ratios appear to be more spread out and higher than the typical ratio for nonsolvated polymorphs. In the majority of cases, anhydrous forms are more soluble in aqueous media than the corresponding hydrate forms. Uncommon cases where the hydrate form exhibited higher solubility (or dissolution rate) than the anhydrous form have also
been reported. For example, LY334370 HCl hydrate form had approximately 6 times higher intrinsic dissolution rate (at 378C) in water than the anhydrous form.14 Due to this irregularity, the ratio was expressed as hydrate/anhydrate solubility ratio in Table 2, whereas all other values are anhydrate/hydrate. The ratio of intrinsic dissolution rate was used to estimate solubility ratio for LY334370 in Table 2.
Figure 1. (a) Solubility ratios for polymorphs (n ¼ 81). (b) Solubility ratios for polymorphs on an expanded scale (not including premafloxacin). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 5, MAY 2005
TRENDS IN SOLUBILITY OF POLYMORPHS
Table 2.
Anhyrate/Hydrate Solubility Ratio
Compound No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
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Compound
Solubility Ratio
64
1.6 1.7 1.6 2.2 1.2 1.2 1.7 2.2 2.1 2.5 1.6 6.0 1.2 22.9 1.8 2.2 3.2 5.7 6.2 9.3 12.7 1.9 1.2
Ampicilline (A/Trihydrate) Caffeine13 Carbamazepine (A/Dihydrate)65 Erythromycin (A/Dihydrate)66 Fluconazole (A/H I)30 Flunisolide (A1/Hemi-hydrate)31 Flurpredisolone (A II/a-H)32 Flurpredisolone (A II/b-H)32 GK-128(A/hemi-hydrate)35 GK-128 (A/monohydrate)35 Glutethemide13 LY334370 HCl (Dihydrate/A)14 Naproxen sodium67 Niclosamide45 Nifedipine (Anhydrate/Dihydrate)68 Piroxicam (A III/H)48 Succinyl sulfathiazole (A I/HI)55 Succinyl sulfathiazole (A II/HI)55 Succinyl sulfathiazole (A III/H1)55 Succinyl sulfathiazole (A IV/H1)55 Succinyl sulfathiazole (A V/H 1)55 Theophylline69 Tranilast62
Note: A, anhydrate; H, hydrate. Roman numerals, English, or Greek alphabet designate multiple forms. No additional designation used when a single anhydrate and a single hydrate forms are described.
Theoretical Calculation The ideal solubility of a solid in a solvent can be expressed as a function of its solid-state properties by eq. 1.15 Symbols X, DHf and Tm denote mol fraction solubility, heat of fusion, and melting temperature of the solid, respectively, and DCpm is the heat capacity difference between the solid
and the liquid forms of the solute. DG1 is the free energy difference between the solid and liquid solute. When DCpm is assumed to be zero, eq. 1 reduces to eq. 2. When a solid exists in two crystalline modifications 1 and 2, a similar equation can be written for the second modification (designated by subscript 1 or 2). The solubility ratio of the two forms can be estimated from thermal data by eq. 3. T m1 T T m1 T þ DCpm1 TTm1 T Tm ð1Þ DCpm1 ln 1 T
Rln X1 ¼ DHf1
T m1 T ln X1 ¼ DHf1 or TTm1 T m1 T DG1 ¼ DHf1 T m1 Figure 2. Anhydrate/hydrate solubility ratio (n ¼ 23). LY334370 HCl is an anomaly where the dissolution rate of the hydrate was six times that of the anhydrate. The ratio for this compound is presented as hydrate/ anhydrate in the figure.
DHf 1 R
Tm T 1 TTm 1
ð2Þ
X1 e ¼ DH f2 Tm2 T X2 R TTm 2 e
ð3Þ
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Hoffman16 derived an extended form of eq. 2 by assuming that the heat capacity difference between the solid and liquid is independent of temperature but not zero. By Taylor series and other approximations, Hoffman proposed eq. 4 to estimate the free energy difference between the solid and liquid forms of the solute. When a solid exists in two crystalline forms 1 and 2, the solubility ratio of the two forms can be estimated by Hoffman approach by using eqs. 5, 6 and 7. DG1 ¼
DHf1 ðTm1 TÞT 2 Tm 1
ð4Þ
DG2 ¼
DHf2 ðTm2 TÞT 2 Tm 2
ð5Þ
X1 X2
ð6Þ
DG2 DG1 ¼ RT ln DG2 DG1 X1 ¼ e RT X2
ð7Þ
The difference between eq. 2 and eq. 5 is the additional factor T/Tm in eq. 5. In this report, the solubility ratio of polymorphs was calculated from thermal data using the ideal solubility equation and the Hoffman approach and the two ratios were compared. Thermal data of a number of polymorphs was obtained from the excellent report by Yu.4 In addition to the compounds compiled by Yu, a few additional compounds for which published thermal data are available in the literature were also included. Solubility ratios of polymorphs were calculated for compounds with a melting point >258C. All values were calculated for 308C, as this temperature represented the midrange of temperatures for the experimental values in Table 1. Solubility ratios calculated by the ideal solubility equation and Hoffman approach are given in Table 3. When the heats of fusion and melting points of the polymorphs are sufficiently close, the two equations yield comparable solubility ratios. Otherwise, the solubility ratio estimated by the two equations may be significantly different. In about 50% of the cases in Table 3 the two estimates agreed within 10%. In other cases the differences were about 20–30% or wider (the ideal equation generally yielding higher values). For a limited number of compounds, both experimental solubility value and thermal data were available in the literature, allowing comparison of estimated ratios with experimental ratios. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 5, MAY 2005
The calculated solubility ratios for these compounds were compared in Table 4 with the experimental ratios. The solubility ratios of these compounds were calculated at 308C (for indomethacin, at 458C) and compared with the experimental solubility ratios at the same temperature. Ratios obtained by both ideal solubility equation and Hoffman equation are shown in Table 4. Although the agreement is not perfect, the comparison of experimental and calculated values shows that thermal data can be used to estimate solubility ratios of polymorphs for the purpose of examining general trends. It appears that either the ideal solubility equation or the Hoffman equation can be used for the purpose of examining general trends in solubility ratio of crystalline forms. The ratios calculated by Hoffman approach appear to be slightly closer to the experimental ratios in Table 4, although no generalization is intended due to the limited number of compounds. Values generated by Hoffman equation in Table 3 are plotted in Figure 3 to illustrate the general trend in solubility ratios. The general trend in calculated solubility ratios of polymorphs is in agreement with the trend observed in Figure 1b. The solubility ratio typically decreases as the temperature increases (unless there is an enantiotropic transition between the temperature of solubility determination and the higher temperature of interest). The majority of solubility studies examined in this survey were conducted at 20– 258C with a few at 30–408C. The solubility ratio of polymorphs at physiological conditions is expected to be similar (i.e., less than 2), if not smaller. An extensive analysis of solubility ratios between amorphous and crystalline forms is beyond the scope of the present study. However, a cursory look into the literature17 indicates that the ratio of solubility of amorphous to crystalline forms is often higher (sometimes a factor of 10 or even higher). It is possible that the experimental solubility value of a solid form (stable or metastable) may be higher than that in its pure crystalline form due to undetected amounts of amorphous component. However, the analysis of polymorph solubility ratios presented here should represent the general trend. A possible reason for the limited spread in solubility ratios may be the rather small difference in the energy of modifications of molecular crystals, which often result from packing or conformational differences. Alternatively, unstable solid forms with extraordinarily high free energies might have eluded detection due to rapid conversion to
TRENDS IN SOLUBILITY OF POLYMORPHS
Table 3.
Calculated Solubility Ratios of Polymorphs at 303 K
No.
Compound Name
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
1-Methoxy-1,2-benzidoxolin-3-one 1-Methyl-2-nitro-5-vinylimidazole 2,3-Dibromopropionic acid 2,7-Dihydroxynapthalene 3-Nitro-p-acetotoluidide 4-Bromo-1,2-dinitrobenzene 5-aAndrostane-3-17-dione Acetamide Acetaminophen Bisacodyl Butyrophenone, R ¼ H Cetyl alcohol Chloracetic acid Chloramphenicol palmitate Chlorpropamide cis-Cinnamic acid Cyclopentanethiol Dehydroepiandrosterone70 Erythrital Ethyl arachidate Ethyl biscumacetate F2693 Flufenamic acid Flufenamic acid Fosinopril71 Gepirone HCl Gepirone HCl Glycolic acid Indomethacin17 M79175 Menadione Meprobamate MK571 Myristyl alcohol Myriystyl alcohol o-Aminobenzoic acid Oxyclozanide Oxyclozanide Oxyclozanide p-1-R3S-3thioanisole 1,2,2 trimethylcyclopentane carboxylic acid Paraiodophenol Paraisopropylphenol p-bromophenol p-chlorophenol p-cresol Phenylbutazone Piroxicam pivalate72 Progesterone Pyrithyldione Pyrithyldione Pyrithyldione
41 42 43 44 45 46 47 48 49 50 51
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Solubility Ratio Using Hoffman Equation
Solubility Ratio Using the Ideal Solubility Equation
1.2 1.1 1.8 1.2 1.2 2.4 1.5 1.2 1.2 1.2 2.7 1.7 1.2 4.2 1.2 1.3 1.6 1.2 1.6 1.4 1.4 1.2 1.5 1.0 1.4 1.3 1.9 1.1 1.8 1.6 1.5 1.5 1.8 1.3 1.0 1.2
1.3 1.2 1.9 1.3 1.3 2.6 1.7 1.3 1.5 1.3 4.9 1.8 1.2 6.0 1.3 1.4 1.3 1.3 2.0 1.4 1.8 1.2 1.9 1.1 1.7 1.0 2.0 1.2 2.6 1.8 1.7 1.7 2.7 1.3 1.0 1.3
2.6 2.1 1.0
5.1 3.4 1.0
1.5 1.2 1.5 1.2 1.1 1.1–1.3 1.1 1.3 2.9 1.2 1.1
1.7 1.2 1.6 1.2 1.1 1.1–1.2 1.3 1.5 3.7 1.3 1.1 (Continued )
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Table 3. (Continued )
No. 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Compound Name Resorcinol Spipirone St1396 HCl Sulfaethidole Sulfathiazole Sulfathiazole Sulfazamet Sulfur Tamoxifen citrate Theophylline Tolbutamide Toresemide61 Tropine benzylate HCl WIN6384363
Solubility Ratio Using Hoffman Equation
Solubility Ratio Using the Ideal Solubility Equation
1.1 1.1 6.6 1.5 1.8 1.0 1.5 1.2 1.3 1.1 1.8 2.1 1.6 1.0
1.1 1.2 29.6 1.6 3.5 1.2 2.0 1.1 1.3 1.2 2.4 2.8 2.2 1.0
Table 4. Comparison of Experimental and Calculated Solubility Ratios at 303 K
Compound Chloramphenicol palmitate4,6 F-26934 Gepirone (III/I)34 Indomethacin (at 458C)17 MK5714,42 Phenylbutazone4,19 Sulfathiazole (III/I)4 Tolbutamide (II/I)60 Toresamide61 WIN6384363
Experimental Ratio
Ratio Calculated by Ideal Equation
Ratio Calculated by Hoffman Equation
4.2 1.8 2.0 1.1 1.6 1.1–1.2 1.7 1.1 2.4 1.0
6.0 1.2 1.0 2.3 2.7 1.1–1.3 1.2 2.4 2.8 1.0
4.2 1.2 1.3 1.8 1.8 1.0–1.3 1.0 1.8 2.1 1.0
Figure 3. Solubility ratios of polymorphs calculated from melting data using Hoffman equation (n ¼ 65). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 94, NO. 5, MAY 2005
lower energy forms, thus limiting the observable range in measurable solubility difference. From the present analysis of solubility data, it is not possible to draw any conclusion regarding the impact of solubility on bioavailability of polymorphs. The impact on bioavailability would depend on additional factors such as solubility difference, dose, permeability, and formulation factors. Theoretical analysis based on the Biopharmaceutical Classification System18 and/or computational simulations (e.g., GastroPlus, Simulationsplus, Inc., Lancaster, CA) may be helpful in understanding relative sensitivity of polymorph bioavailability to solubility or other factors such as dose and permeability. Computational simulations of biopharmaceutical parameters also may
TRENDS IN SOLUBILITY OF POLYMORPHS
help conduct well-designed experiments for rational evaluation of impact of polymorphism on bioavailability.
13.
ACKNOWLEDGMENTS
14.
The authors gratefully acknowledge Dr. Venkatramana Mantri Rao (Bristol-Myers Squibb Pharmaceuticals) for the valuable technical discussions.
15.
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