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Polymorphism of drugs has been the subject of intense interest in the pharmaceutical industry for over forty years. Although identical in chemical composition, polymorphs differ in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, colour, filterability, density, flow properties, and many other properties. The difference in solubility is particularly important for pharmaceuticals, as it can affect drug efficacy, bioavailability and safety. Despite significant investment in processes to find all the possible polymorphs of active pharmaceutical ingredients (APIs), new polymorphs can suddenly appear without warning. Polymorphs tend to convert spontaneously from less stable to more stable forms, and, therefore, it is best to discover and characterize the stable form as early as possible. Ideally the most stable polymorph will be found while the drug candidate is still in the discovery process, so that this is the form used for subsequent testing. The most stable polymorph will be the least soluble and solubility may be a limiting factor in the efficacy of the API. Despite the huge importance of polymorphism in the properties of materials, however, there is no method that can produce all the stable polymorphs of a compound, or even one that can provide confidence that the most stable polymorph has been obtained. Here we describe a new method, `potentiometric cycling for polymorph creation (PC)2', which is able to generate the most stable polymorph in aqueous solution. This new method has been applied to sulindac, a non-steroidal anti-inflammatory drug, which also shows promise in anticancer treatment, producing two polymorphs of this API, including a new more stable one. By adjusting the conditions, this method is able to produce either polymorph exclusively.
Supporting information
CCDC reference: 637252
Program(s) used to solve structure: DASH, GSAS (see text for citations); program(s) used to refine structure: GSAS.
2-[6-fluoro-2-methyl-3- [(4-methylsulfinylphenyl)methylidene]inden-1-yl]- acetic acid
top
Crystal data top
| C20H17FO3S | V = 1776.83 (6) Å3 |
| Mr = 356.41 | Z = 4 |
| Monoclinic, P21/c | F(000) = 744 |
| Hall symbol: -P 2ybc | Dx = 1.332 Mg m−3 |
| a = 12.6858 (3) Å | Co Kα radiation, λ = 1.78892 Å |
| b = 8.1894 (2) Å | T = 293 K |
| c = 17.7934 (5) Å | yellow |
| β = 106.011 (3)° | ?, ? × ? × ? mm |
Data collection top
Stoe Stadi-P
diffractometer | Scan method: step |
| Radiation source: Short-focus sealed ceramic tube | 2θmin = 2.126°, 2θmax = 70.116°, 2θstep = 0.01° |
| Ge (111) monochromator | |
Refinement top
| Least-squares matrix: full | Profile function: CW Profile function number 3 with 19 terms
Pseudovoigt profile coefficients as parameterized in
P. Thompson, D.E. Cox & J.B. Hastings (1987). J. Appl. Cryst.,20,79-83.
Asymmetry correction of L.W. Finger, D.E. Cox & A. P. Jephcoat (1994).
J. Appl. Cryst.,27,892-900.
#1(GU) = 763.466 #2(GV) = 0.000 #3(GW) = -5.792
#4(GP) = 0.000 #5(LX) = 8.510 #6(LY) = 0.000
#7(S/L) = 0.0130 #8(H/L) = 0.0350
#9(trns) = 0.00 #10(shft)= 0.0000
#11(stec)= 0.00 #12(ptec)= 0.00 #13(sfec)= 0.00
#14(L11) = 0.000 #15(L22) = 0.000 #16(L33) = 0.000
#17(L12) = 0.000 #18(L13) = 0.000 #19(L23) = 0.000
Peak tails are ignored where the intensity is below 0.0010 times the peak
Aniso. broadening axis 0.0 0.0 1.0 |
| Rp = 0.038 | 150 parameters |
| Rwp = 0.051 | 145 restraints |
| Rexp = 0.031 | H atoms treated by a mixture of independent and constrained refinement |
| R(F2) = 0.07490 | (Δ/σ)max = 0.03 |
| χ2 = 2.789 | Background function: GSAS Background function number 1 with 15 terms.
Shifted Chebyshev function of 1st kind
1: 725.334 2: -363.062 3: -69.4872 4: 119.798
5: -10.2295 6: -70.0540 7: 33.7373 8: 39.3149
9: -45.5570 10: 3.81882 11: 29.1700 12: -21.7529
13: -10.9817 14: 16.8347 15: -8.63052 |
| 6800 data points | |
Crystal data top
| C20H17FO3S | β = 106.011 (3)° |
| Mr = 356.41 | V = 1776.83 (6) Å3 |
| Monoclinic, P21/c | Z = 4 |
| a = 12.6858 (3) Å | Co Kα radiation, λ = 1.78892 Å |
| b = 8.1894 (2) Å | T = 293 K |
| c = 17.7934 (5) Å | ?, ? × ? × ? mm |
Data collection top
Stoe Stadi-P
diffractometer | 2θmin = 2.126°, 2θmax = 70.116°, 2θstep = 0.01° |
| Scan method: step | |
Refinement top
| Rp = 0.038 | 6800 data points |
| Rwp = 0.051 | 150 parameters |
| Rexp = 0.031 | 145 restraints |
| R(F2) = 0.07490 | H atoms treated by a mixture of independent and constrained refinement |
| χ2 = 2.789 | |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top| | x | y | z | Uiso*/Ueq | |
| S1 | −0.5029 (4) | 0.0558 (8) | −0.3781 (3) | 0.197 (2)* | |
| F1 | 0.0418 (6) | −0.3523 (10) | 0.0918 (4) | 0.197 (2)* | |
| O1 | 0.3937 (8) | 0.1517 (9) | −0.0136 (6) | 0.197 (2)* | |
| H17 | 0.396 (5) | 0.1028 (17) | 0.1134 (13) | 0.197 (2)* | |
| O2 | 0.3906 (9) | 0.0020 (11) | 0.0898 (4) | 0.197 (2)* | |
| O3 | −0.5407 (11) | 0.2059 (8) | −0.3439 (8) | 0.197 (2)* | |
| C1 | 0.0519 (4) | −0.0399 (16) | −0.1829 (5) | 0.197 (2)* | |
| C2 | 0.1712 (4) | −0.0334 (14) | −0.1646 (4) | 0.197 (2)* | |
| C3 | 0.2157 (4) | −0.0983 (13) | −0.0930 (4) | 0.197 (2)* | |
| C4 | 0.1340 (4) | −0.2304 (16) | 0.0104 (4) | 0.197 (2)* | |
| H1 | 0.2011 (5) | −0.257 (4) | 0.0453 (12) | 0.197 (2)* | |
| C5 | 0.0332 (5) | −0.2680 (16) | 0.0240 (4) | 0.197 (2)* | |
| C6 | −0.0668 (4) | −0.2488 (16) | −0.0271 (5) | 0.197 (2)* | |
| H2 | −0.1308 (5) | −0.271 (4) | −0.0133 (9) | 0.197 (2)* | |
| C7 | −0.0685 (4) | −0.1733 (16) | −0.0992 (5) | 0.197 (2)* | |
| H3 | −0.1357 (5) | −0.149 (4) | −0.1344 (12) | 0.197 (2)* | |
| C8 | 0.0268 (4) | −0.1160 (14) | −0.1144 (4) | 0.197 (2)* | |
| C9 | 0.1290 (4) | −0.1587 (16) | −0.0626 (5) | 0.197 (2)* | |
| C10 | −0.0117 (4) | 0.0311 (11) | −0.2464 (4) | 0.197 (2)* | |
| H4 | 0.0271 (6) | 0.067 (3) | −0.2806 (8) | 0.197 (2)* | |
| C11 | −0.1301 (4) | 0.0322 (14) | −0.2809 (4) | 0.197 (2)* | |
| C12 | −0.1840 (5) | −0.019 (2) | −0.3563 (5) | 0.197 (2)* | |
| H5 | −0.1427 (8) | −0.053 (5) | −0.3893 (8) | 0.197 (2)* | |
| C13 | −0.2962 (5) | −0.0197 (19) | −0.3837 (4) | 0.197 (2)* | |
| H6 | −0.3293 (8) | −0.054 (5) | −0.4346 (9) | 0.197 (2)* | |
| C14 | −0.3599 (4) | 0.0376 (16) | −0.3385 (3) | 0.197 (2)* | |
| C15 | −0.3099 (5) | 0.0768 (16) | −0.2582 (4) | 0.197 (2)* | |
| H7 | −0.3516 (9) | 0.121 (4) | −0.2278 (6) | 0.197 (2)* | |
| C16 | −0.1984 (5) | 0.0739 (19) | −0.2312 (4) | 0.197 (2)* | |
| H8 | −0.1652 (7) | 0.107 (5) | −0.1802 (8) | 0.197 (2)* | |
| C17 | 0.2317 (7) | 0.0649 (12) | −0.2097 (5) | 0.197 (2)* | |
| H9 | 0.187 (5) | 0.078 (14) | −0.263 (2) | 0.197 (2)* | |
| H10 | 0.249 (9) | 0.170 (8) | −0.186 (7) | 0.197 (2)* | |
| H11 | 0.298 (6) | 0.010 (7) | −0.210 (9) | 0.197 (2)* | |
| C18 | 0.3338 (4) | −0.1076 (10) | −0.0486 (4) | 0.197 (2)* | |
| H12 | 0.3480 (10) | −0.2121 (10) | −0.0221 (7) | 0.197 (2)* | |
| H13 | 0.3785 (7) | −0.0986 (19) | −0.0848 (6) | 0.197 (2)* | |
| C19 | 0.3655 (8) | 0.0286 (8) | 0.0122 (4) | 0.197 (2)* | |
| C20 | −0.5445 (9) | −0.1001 (10) | −0.3369 (7) | 0.197 (2)* | |
| H14 | −0.499 (6) | −0.193 (2) | −0.339 (9) | 0.197 (2)* | |
| H15 | −0.539 (11) | −0.075 (8) | −0.283 (3) | 0.197 (2)* | |
| H16 | −0.619 (4) | −0.125 (11) | −0.364 (5) | 0.197 (2)* | |
Geometric parameters (Å, º) top
| S1—O3 | 1.5071 (17) | C13—H6 | 0.9302 (17) |
| F1—C5 | 1.3688 (16) | C13—C14 | 1.3708 (16) |
| O1—C19 | 1.2020 (16) | H6—C13 | 0.9302 (17) |
| H17—O2 | 0.9202 (17) | C14—C13 | 1.3708 (16) |
| O2—H17 | 0.9202 (17) | C14—C15 | 1.4300 (16) |
| O2—C19 | 1.3473 (16) | C15—C14 | 1.4300 (16) |
| O3—S1 | 1.5071 (17) | C15—H7 | 0.9300 (17) |
| C1—C2 | 1.4593 (16) | C15—C16 | 1.3623 (16) |
| C1—C8 | 1.4797 (16) | H7—C15 | 0.9300 (17) |
| C1—C10 | 1.3278 (16) | C16—C11 | 1.4392 (16) |
| C2—C1 | 1.4593 (16) | C16—C15 | 1.3623 (16) |
| C2—C3 | 1.3513 (16) | C16—H8 | 0.9299 (17) |
| C2—C17 | 1.4896 (17) | H8—C16 | 0.9299 (17) |
| C3—C2 | 1.3513 (16) | C17—C2 | 1.4896 (17) |
| C3—C9 | 1.4418 (16) | C17—H9 | 0.9602 (17) |
| C3—C18 | 1.4904 (16) | C17—H10 | 0.9601 (17) |
| C4—H1 | 0.9301 (17) | C17—H11 | 0.9599 (17) |
| C4—C5 | 1.4001 (16) | H9—C17 | 0.9602 (17) |
| C4—C9 | 1.4099 (16) | H9—H10 | 1.568 (17) |
| H1—C4 | 0.9301 (17) | H9—H11 | 1.567 (15) |
| C5—F1 | 1.3688 (16) | H10—C17 | 0.9601 (17) |
| C5—C4 | 1.4001 (16) | H10—H9 | 1.568 (17) |
| C5—C6 | 1.3500 (16) | H10—H11 | 1.568 (13) |
| C6—C5 | 1.3500 (16) | H11—C17 | 0.9599 (17) |
| C6—H2 | 0.9298 (17) | H11—H9 | 1.567 (15) |
| C6—C7 | 1.4201 (16) | H11—H10 | 1.568 (13) |
| H2—C6 | 0.9298 (17) | C18—C3 | 1.4904 (16) |
| C7—C6 | 1.4201 (16) | C18—H12 | 0.9702 (17) |
| C7—H3 | 0.9301 (17) | C18—H13 | 0.9697 (17) |
| C7—C8 | 1.3908 (16) | C18—C19 | 1.5284 (16) |
| H3—C7 | 0.9301 (17) | H12—C18 | 0.9702 (17) |
| C8—C1 | 1.4797 (16) | H12—H13 | 1.579 (4) |
| C8—C7 | 1.3908 (16) | H13—C18 | 0.9697 (17) |
| C8—C9 | 1.4109 (16) | H13—H12 | 1.579 (4) |
| C9—C3 | 1.4418 (16) | C19—O1 | 1.2020 (16) |
| C9—C4 | 1.4099 (16) | C19—O2 | 1.3473 (16) |
| C9—C8 | 1.4109 (16) | C19—C18 | 1.5284 (16) |
| C10—C1 | 1.3278 (16) | C20—H14 | 0.9600 (17) |
| C10—H4 | 0.9297 (17) | C20—H15 | 0.9601 (17) |
| C10—C11 | 1.4583 (16) | C20—H16 | 0.9602 (17) |
| H4—C10 | 0.9297 (17) | H14—C20 | 0.9600 (17) |
| C11—C10 | 1.4583 (16) | H14—H15 | 1.568 (12) |
| C11—C12 | 1.3918 (16) | H14—H16 | 1.566 (12) |
| C11—C16 | 1.4392 (16) | H15—C20 | 0.9601 (17) |
| C12—C11 | 1.3918 (16) | H15—H14 | 1.568 (12) |
| C12—H5 | 0.9302 (17) | H15—H16 | 1.569 (4) |
| C12—C13 | 1.3715 (16) | H16—C20 | 0.9602 (17) |
| H5—C12 | 0.9302 (17) | H16—H14 | 1.566 (12) |
| C13—C12 | 1.3715 (16) | H16—H15 | 1.569 (4) |
| | | |
| H17—O2—C19 | 106.8 (14) | H5—C12—C13 | 119.0 (4) |
| C2—C1—C8 | 106.1 (2) | C12—C13—H6 | 119.5 (5) |
| C2—C1—C10 | 121.5 (2) | C12—C13—C14 | 120.7 (3) |
| C8—C1—C10 | 131.9 (4) | H6—C13—C14 | 119.6 (4) |
| C1—C2—C3 | 109.5 (3) | C13—C14—C15 | 119.5 (2) |
| C1—C2—C17 | 123.8 (4) | C14—C15—H7 | 120.2 (3) |
| C3—C2—C17 | 125.2 (3) | C14—C15—C16 | 118.7 (3) |
| C2—C3—C9 | 109.0 (2) | H7—C15—C16 | 120.3 (5) |
| C2—C3—C18 | 128.1 (3) | C11—C16—C15 | 122.0 (3) |
| C9—C3—C18 | 122.9 (3) | C11—C16—H8 | 118.8 (5) |
| H1—C4—C5 | 122.9 (3) | C15—C16—H8 | 119.1 (3) |
| H1—C4—C9 | 120.9 (5) | C2—C17—H9 | 109.5 (4) |
| C5—C4—C9 | 116.0 (3) | C2—C17—H10 | 109 (3) |
| F1—C5—C4 | 114.1 (4) | C2—C17—H11 | 109.5 (19) |
| F1—C5—C6 | 118.9 (3) | H9—C17—H10 | 109.4 (17) |
| C4—C5—C6 | 126.3 (3) | H9—C17—H11 | 109.4 (16) |
| C5—C6—H2 | 121.8 (4) | H10—C17—H11 | 109.5 (13) |
| C5—C6—C7 | 115.8 (2) | H10—H9—H11 | 60.0 (5) |
| H2—C6—C7 | 121.9 (5) | H9—H10—H11 | 60.0 (12) |
| C6—C7—H3 | 118.9 (5) | H9—H11—H10 | 60.0 (8) |
| C6—C7—C8 | 121.7 (2) | C3—C18—H12 | 109.1 (4) |
| H3—C7—C8 | 118.9 (3) | C3—C18—H13 | 109.3 (4) |
| C1—C8—C7 | 134.2 (3) | C3—C18—C19 | 111.6 (3) |
| C1—C8—C9 | 106.0 (3) | H12—C18—H13 | 109.0 (4) |
| C7—C8—C9 | 118.7 (3) | H12—C18—C19 | 108.8 (4) |
| C3—C9—C4 | 130.0 (3) | H13—C18—C19 | 109.1 (4) |
| C3—C9—C8 | 109.2 (3) | O1—C19—O2 | 121.0 (5) |
| C4—C9—C8 | 120.3 (3) | O1—C19—C18 | 112.9 (4) |
| C1—C10—H4 | 113.0 (5) | O2—C19—C18 | 123.4 (4) |
| C1—C10—C11 | 132.4 (3) | H14—C20—H15 | 109.5 (12) |
| H4—C10—C11 | 113.1 (3) | H14—C20—H16 | 109.3 (12) |
| C10—C11—C12 | 125.4 (3) | H15—C20—H16 | 109.5 (4) |
| C10—C11—C16 | 117.9 (3) | H15—H14—H16 | 60.1 (5) |
| C12—C11—C16 | 116.4 (3) | H14—H15—H16 | 59.9 (3) |
| C11—C12—H5 | 119.0 (5) | H14—H16—H15 | 60.0 (3) |
| C11—C12—C13 | 122.0 (3) | | |
Experimental details
| Crystal data |
| Chemical formula | C20H17FO3S |
| Mr | 356.41 |
| Crystal system, space group | Monoclinic, P21/c |
| Temperature (K) | 293 |
| a, b, c (Å) | 12.6858 (3), 8.1894 (2), 17.7934 (5) |
| β (°) | 106.011 (3) |
| V (Å3) | 1776.83 (6) |
| Z | 4 |
| Radiation type | Co Kα, λ = 1.78892 Å |
| Specimen shape, size (mm) | ?, ? × ? × ? |
| |
| Data collection |
| Diffractometer | Stoe Stadi-P
diffractometer |
| Specimen mounting | ? |
| Data collection mode | ? |
| Scan method | Step |
| 2θ values (°) | 2θmin = 2.126 2θmax = 70.116 2θstep = 0.01 |
| |
| Refinement |
| R factors and goodness of fit | Rp = 0.038, Rwp = 0.051, Rexp = 0.031, R(F2) = 0.07490, χ2 = 2.789 |
| No. of data points | 6800 |
| No. of parameters | 150 |
| No. of restraints | 145 |
| H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
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