X-ray diffraction data of tibolone Δ4 isomer (isotibolone)

X-ray diffraction data of tibolone �4 isomer „isotibolone…Selma Gutierrez Antonio,1,a� Fabio Furlan Ferreira,2 Gabriel Lima Barros Araujo,3

Jivaldo do Rosario Matos,4 and Carlos de Oliveira Paiva-Santos1

1Departamento de Físico Química, Instituto de Química, Universidade Estadual Paulista, Caixa Postal 355,14801-970 Araraquara, SP, Brazil2Laboratório Nacional de Luz Síncrotron, Caixa Postal 6192, 13083-970 Campinas, SP, Brazil3Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo,05508-900 São Paulo, SP, Brazil4Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, Av. LineuPrestes, 748, Sala 0801, 05508-900 São Paulo, SP, Brazil

�Received 28 July 2009; accepted 15 September 2009�

Tibolone is used for hormone reposition of postmenopause women and isotibolone is considered themajor degradation product of tibolone. Isotibolone can also be present in tibolone API raw materialsdue to some inadequate synthesis. Its presence is then necessary to be identified and quantified in thequality control of both API and drug products. In this work we present the indexing of an isotiboloneX-ray diffraction pattern measured with synchrotron light ��=1.2407 Å� in the transmission mode.The characterization of the isotibolone sample by IR spectroscopy, elemental analysis, and thermalanalysis are also presented. The isotibolone crystallographic data are a=6.8066 Å,b=20.7350 Å, c=6.4489 Å, �=76.428°, V=884.75 Å3, and space group P21, �o=1.187 g cm−3,Z=2. © 2009 International Centre for Diffraction Data. �DOI: 10.1154/1.3257612�

Key words: isotibolone, hormone, indexing, X-ray powder diffraction, synchrotron radiation

I. INTRODUCTION

Tibolone �IUPAC name �7� ,17��-17-hydroxy-7-methyl-19-nor-17-pregn-5�10�-en-20-yn-3-one, C21H28O2� isa synthetic steroid used to relieve hypo-oestrogenic symp-toms and protect against bone loss in postmenopausalwomen. This steroid is considered an unstable substance dueto isomerization into a compound known as isotibolone �iso-mer �4 or Org OM38� �Figure 1� and great effort has beencarried out by pharmaceutical industries in order to reduceisotibolone to desired levels during its synthesis �Kirchholteset al., 2000�. The isomer is formed at high-temperature ex-posure and/or acidic conditions. The isomerization mecha-nism involves the rearrangement on the A-ring of the doublebound from carbon atoms 5–10 to 4–5 �Boerrigter et al.,2002�.

Another problem, according to the patent EP 1121375B1 �Kirchholtes et al., 2000�, is that the isotibolone contentincreases during the dosage unit preparation. According toexample 2 of the cited patent, tibolone containing less than0.1% isotibolone has been prepared. However, the content ofisotibolone in the freshly prepared pharmaceutical formula-tion was already 0.4% and 1.6% after 6 months �Van Engel-gem and Marechal, 2005�. The end of shelf-life specificationwith respect to the amount of isotibolone formed during stor-age is 5% and a minimum acceptable shelf-life period forthese dosage units is 1 yr �Kirchholtes et al., 2000�.

X-ray powder diffraction and the Rietveld method arepowerful tools for the characterization of pharmaceuticalsand have been successfully used in the analysis of carbam-azepine �Iyengar et al., 2001�, D-Mannitol �Botez et al.,2003�, and paracetamol �Dong et al., 2008� among others.However, the Rietveld method requires the knowledge of the

a�Author to whom correspondence should be addressed. Electronic mail:

337 Powder Diffraction 24 �4�, December 2009 0885-7156

crystal structure of all crystalline phases present in the pow-der. Recently, Scarlett and Madsen �2006� proposed amethod for the quantitative phase analysis in which onlypartial or no crystal structure is required, although it requiresthe pattern decomposition, and, when the unit cell param-eters are known, it is possible to correct for the effects ofpreferred orientation, which is very common with pharma-ceuticals. The method can provide the same result of theRietveld method. Thus, the indexing of powder X-ray dif-fraction of drugs is very important for the research and qual-ity control of pharmaceuticals compounds even when thecrystal structure is not known. This work aims to character-ize an isotibolone sample obtained by isomerization of thecommercial tibolone sample in strong acid media and it alsopresents the indexing of isotibolone.

II. EXPERIMENTAL

The tibolone sample was kindly donated by a Brazilianpharmaceutical company. The isotibolone sample was ob-tained by isomerization of the commercial tibolone sample instrong acid media. The characterization of the isotibolonesample was carried out by elemental analysis �EA� and ther-mal analysis �TG/DSC� and FTIR spectroscopy.

A. Elemental analysis

Carbon and hydrogen contents were determined by el-emental analysis using a Perkin Elmer CHN Analyzer�Model 2400�. The accuracy of the analyses was + /−0.3%absolute.

B. Infrared spectroscopy

The IR absorption spectra of the isotibolone were ob-tained at room temperature in the range 4000 to 400 cm−1 inKBr pellets using a Nicolet spectrophotometer, model Magna

337/2009/24�4�/337/6/$25.00 © 2009 JCPDS-ICDD

C. Thermal analysis

Differential scanning calorimetry �DSC� curves were ob-tained in a DSC-50 cell �Shimadzu� using aluminum cru-cibles with about 2 mg of samples under a dynamic nitrogenatmosphere �50 mL min−1� and a heating rate of10 °C min−1 in the temperature range from 25 to 600 °C.The DSC cell was calibrated with indium �mp 156.6 °C;�Hfus=28.54 J g−1� and zinc �mp 419.6 °C�. The purity ofisotibolone sample was determined by DSC using a heatingrate of 2 °C min−1 from TA-50WSI Shimadzu Purity Deter-mination Analysis software. TG/DTG curves were obtainedwith a thermobalance model TGA 51 �Shimadzu� in the tem-perature range 25 to 900 °C, using platinum crucibles with�20 mg of samples, under dynamic nitrogen atmosphere�50 ml min−1� and a heating rate of 10 °C min−1.

D. X-ray powder diffraction

Synchrotron X-ray powder diffraction data for thesample were collected at the D12A-XRD1 beamline of theBrazilian Synchrotron Light Laboratory �LNLS� in Campi-nas, Brazil. X-rays of �=1.2407 Å wavelength were se-lected by a double-bounced Si�111� monochromator withwater refrigeration in the first crystal and the second one bentfor sagittal focusing �Ferreira et al., 2006�. The beam can bevertically focused or collimated by a bent Rh-coated ultra-low-expansion glass mirror placed before the monochro-mator, which also provides filtering of high-energy photons�third- and higher-order harmonics�. The beam was vertically

Figure 1. Isotibolone �C21H28O2� molecular structure showing standard car-bon numbering and ring identification �Boerrigter et al., 2002�.

Figure 2. The IR spectrum of isotibolone sample.

338 Powder Diffr., Vol. 24, No. 4, December 2009

focused in the sample’s position on a spot of�1 mm �vertical�� �3 mm �horizontal�. The experimentwas performed in the vertical scattering plane, i.e., perpen-dicular to the linear polarization of the incident photons. Val-ues of the X-ray wavelength used in this study and the zero-point displacement were determined from several reflectionsof an external SRM660a lanthanum hexaboride �LaB6� stan-dard �NIST�. The diffracted beam was analyzed using aGe�111� crystal analyzer and detected using a NaI�Tl� scin-tillation counter with a pulse-height discriminator in thecounting chain. The incoming beam was also monitored by ascintillation counter to normalize the decay of the primarybeam.

The isotibolone was loaded to fill about 5 cm in a0.7-mm diameter borosilicate glass capillary and data wererecorded at room temperature for �10 s at each 2� in stepsof 0.005° from 2° to 39.7°.

94 peaks were automatically found using the peak searchprocedure of the program TOPAS ACADEMIC V4.1 �Coelho,2007�. All peaks were fitted using the Thompson–Cox–Hastings pseudo-Voigt profile function �Thompson et al.,1987� and then used for the indexing. The indexing was donethrough the iterative method �Coelho, 2003� with zero-errorcorrections �Coelho, 2007�. The NBS�AIDS83 �Mighellet al., 1981� program was used for analysis of the powderpattern after indexing, which gave F�30�=609.71, M�20�=519.96, and the average difference absolute between2��obs�s and 2��calc�s of all 94 peaks ��2��=0. The solu-tion was subsequently used for the pattern decompositionusing the Pawley method �Pawley, 1981�. The backgroundwas fit using a 16-term Chebyschev polynomial. The peakprofile was modeled by the double-Voigt approach �Balzarand Ledbetter, 1993; Coelho, 2007� with anisotropic Lorentzand Gauss broadening terms adjusted for independent familyplanes �h00�, �0k0�, �00l�, �hk0�, �h0l�, �0kl�, and �hkl�. Theasymmetry was corrected by the model of Cheary and Co-elho �Cheary and Coelho, 1998a; Cheary and Coelho,1998b�.

III. RESULTS AND DISCUSSIONA. Infrared spectroscopy and thermal analysis

Analytical data for percentages of C and H in isotibolone�calc./found� are as follows: %C �80.7/80.5�, %H �9.0/8.6�.

Figure 3. DSC and TG curves obtained in dynamic nitrogen atmosphere andheating rate of 10 °C min−1 of isotibolone sample.

The results are in good agreement with the calculated values.

338Antonio et al.

TABLE I. Observed and calculated Bragg peak positions �2�o, 2�c in degrees�, observed and calculated interplanar distances �do and dc in �, relativeintegrated intensities �I100�, Miller indexes �hkl� and difference in Bragg peak positions ��2��. The 2�o and do fields for the observed reflections not used inthe indexing are left blank.

do dc I100 h k l 2�o 2�c �2�

1 10.3692 10.3675 3 0 2 0 6.860 6.861 0.0012 6.6161 6.6165 46 1 0 0 10.761 10.760 �0.0013 6.3036 6.3034 70 1 1 0 11.296 11.296 0.0004 6.2687 6.2688 38 0 0 1 11.359 11.359 0.0005 6.0006 6.0006 6 0 1 1 11.868 11.868 0.0006 5.5776 5.5775 3 �1 2 0 12.772 12.772 0.0007 5.3644 5.3644 32 0 2 1 13.281 13.282 0.0008 5.2007 5.2006 5 1 0 1 13.702 13.702 0.0009 5.1841 5.1838 4 0 4 0 13.746 13.747 0.00110 5.0444 5.0444 100 1 1 1 14.128 14.128 0.00011 4.7794 4.7795 13 1 3 0 14.916 14.916 0.00012 4.6479 4.6485 48 1 2 1 15.340 15.338 �0.00213 4.6434 6 0 3 1 15.35514 4.1555 4.1556 4 1 3 1 17.171 17.171 0.00015 4.0967 4.0960 6 �1 0 1 17.420 17.423 0.00316 4.0806 4.0806 15 �1 4 0 17.489 17.489 0.00017 4.0185 4.0184 4 �1 1 1 17.761 17.762 0.00118 3.9947 3.9949 16 0 4 1 17.868 17.867 �0.00119 3.8095 3.8095 2 �1 2 1 18.744 18.744 0.00020 3.6714 1 1 4 1 19.45621 3.5237 3.5237 12 �1 3 1 20.280 20.280 0.00022 3.5139 3.5139 4 1 5 0 20.337 20.337 0.00023 3.4582 3.4587 4 0 5 1 20.669 20.665 �0.00324 3.4558 1 0 6 0 20.68325 3.3076 3.3083 1 2 0 0 21.620 21.616 �0.00426 3.2668 3.2669 3 2 1 0 21.894 21.893 �0.00127 3.2585 3.2584 6 2 0 1 21.951 21.951 0.00028 3.2423 3.2424 5 1 5 1 22.061 22.061 0.00029 3.2187 3.2189 9 2 1 1 22.225 22.224 �0.00230 3.2142 3.2138 2 �1 4 1 22.257 22.259 0.00331 3.1517 3.1517 1 2 2 0 22.704 22.704 0.00032 3.1331 3.1344 1 0 0 2 22.841 22.831 �0.01033 3.1312 1 1 0 2 22.85534 3.1084 3.1085 3 2 2 1 23.024 23.024 �0.00135 3.0992 2 0 1 2 23.09436 3.0972 3.0961 2 1 1 2 23.109 23.117 0.00937 3.0632 3.0632 3 1 6 0 23.369 23.369 0.00038 3.0263 3.0264 1 0 6 1 23.658 23.657 �0.00139 3.0003 1 0 2 2 23.86640 2.9981 2.9974 4 1 2 2 23.884 23.889 0.00541 2.9839 2.9840 1 2 3 0 23.999 23.998 �0.00142 2.9473 2.9473 5 2 3 1 24.301 24.301 0.00043 2.9142 2.9142 5 �1 5 1 24.582 24.582 0.00044 2.8783 2.8783 2 1 6 1 24.894 24.893 0.00045 2.8534 2.8546 1 0 3 2 25.114 25.104 �0.01146 2.8521 1 1 3 2 25.12647 2.7885 2.7887 1 �2 4 0 25.708 25.706 �0.00248 2.7587 2.7587 4 2 4 1 25.991 25.991 0.00049 2.7036 1 �1 7 0 26.53150 2.6816 2.6822 1 0 4 2 26.752 26.746 �0.00651 2.6802 1 1 4 2 26.76752 2.6782 1 0 7 1 26.78753 2.6779 1 �2 0 1 26.79054 2.6559 1 �2 1 1 27.01655 2.6413 2.6413 1 �1 6 1 27.168 27.168 0.00056 2.6059 1 �1 0 2 27.54457 2.6004 2.6003 2 2 0 2 27.604 27.605 0.00158 2.5925 2.5928 1 �2 2 1 27.689 27.686 �0.00359 2.5919 1 0 8 0 27.696

339 339Powder Diffr., Vol. 24, No. 4, December 2009 X-ray diffraction data of tibolone ...

TABLE I. �Continued.�

do dc I100 h k l 2�o 2�c �2�

60 2.5862 1 �2 5 0 27.75961 2.5857 2.5856 9 �1 1 2 27.764 27.765 0.00162 2.5799 2.5801 2 2 1 2 27.827 27.825 �0.00263 2.5738 2.5739 1 1 7 1 27.894 27.893 �0.00164 2.5617 2.5621 1 2 5 1 28.029 28.024 �0.00465 2.5273 2.5273 7 �1 2 2 28.419 28.419 �0.00166 2.5220 2.5222 3 2 2 2 28.479 28.477 �0.00267 2.5005 1 0 5 2 28.73068 2.4996 2.4989 1 1 5 2 28.740 28.749 0.00969 2.4970 1 �2 3 1 28.77070 2.4384 1 �1 3 2 29.47871 2.4338 1 2 3 2 29.53572 2.4134 2.4133 6 1 8 0 29.791 29.791 0.00073 2.4003 1 �1 7 1 29.95774 2.3953 2.3952 4 0 8 1 30.021 30.022 0.00175 2.3898 2.3898 3 2 6 0 30.091 30.092 0.00076 2.3792 2.3792 1 �2 4 1 30.228 30.229 0.00177 2.3709 2.3708 1 2 6 1 30.337 30.339 0.00178 2.3283 1 �1 4 2 30.90679 2.3243 1 2 4 2 30.96180 2.3217 1 0 6 2 30.99681 2.3204 1 1 6 2 31.01482 2.3199 2.3197 2 1 8 1 31.020 31.022 0.00383 2.2526 1 3 0 1 31.97284 2.2497 2.2496 1 �2 5 1 32.014 32.015 0.00085 2.2392 2.2394 1 3 1 1 32.168 32.165 �0.00386 2.2068 1 2 7 0 32.65387 2.2066 2.2064 1 �1 5 2 32.657 32.659 0.00288 2.2055 1 3 0 0 32.67389 2.2026 2.2030 1 2 5 2 32.718 32.711 �0.00790 2.2012 1 3 2 13 32.73991 2.1931 1 �3 1 0 32.86392 2.1918 1 2 7 1 32.88393 2.1905 2.1902 4 �1 8 1 32.903 32.908 0.00494 2.1758 2.1758 2 1 9 0 33.132 33.133 0.00095 2.1625 2.1625 1 0 9 1 33.342 33.342 0.00096 2.1573 2.1572 1 3 2 0 33.424 33.425 0.00197 2.1524 2.1529 1 0 7 2 33.502 33.495 �0.00798 2.1518 1 1 7 2 33.51299 2.1420 2.1422 1 1 0 3 33.670 33.667 �0.002

100 2.1417 1 3 3 1 33.675101 2.1308 1 1 1 3 33.852102 2.1168 2.1168 2 �2 6 1 34.083 34.084 0.001103 2.1064 1 1 9 1 34.256104 2.1011 1 3 3 0 34.345105 2.0979 1 1 2 3 34.400106 2.0899 2.0896 1 0 0 3 34.535 34.541 0.006107 2.0807 1 �1 6 2 34.694108 2.0789 2.0791 2 0 1 3 34.724 34.721 �0.003109 2.0778 1 2 6 2 34.743110 2.0735 1 0 10 0 34.818111 2.0659 2.0659 1 3 4 1 34.950 34.949 �0.001112 2.0484 2.0484 1 0 2 3 35.258 35.258 0.000113 2.0480 1 �2 0 2 35.265114 2.0462 1 1 3 3 35.298115 2.0437 2.0435 1 3 0 2 35.342 35.346 0.004116 2.0403 1 �2 8 0 35.403117 2.0383 2.0381 1 �2 1 2 35.438 35.442 0.004118 2.0337 2.0336 2 3 1 2 35.521 35.523 0.002119 2.0297 2.0295 1 3 4 0 35.595 35.598 0.004

340 340Powder Diffr., Vol. 24, No. 4, December 2009 Antonio et al.

The isotibolone IR spectrum is shown in Figure 2. Thestrongest band in the spectrum at 1661 cm−1 is assigned tothe carbonyl stretching vibration band C=O due to conjuga-tion of the carbonyl group with carbon-carbon double bonds.In the 3200 to 3450 cm−1 region, the 3251 and 3404 cm−1

bands are attributed to �C–H and OH stretching, respec-tively. No strong hydrogen bonds are present in the crystalstructure of isotibolone crystals according to the IR spectraldata obtained, since no broad and intense absorption wasobserved in the considered spectral window.

TABLE I. �Continued.�

do dc I100 h

120 2.0284 1 2121 2.0086 2.0092 1 �2122 2.0080 1 �1123 2.0050 2.0049 1 3124 2.0002 1 0125 1.9974 1 0126 1.9966 1 1127 1.9901 1 2128 1.9866 1.9865 2 �2129 1.9810 1 2130 1.9798 1 1131 1.9791 1.9794 1 3132 1.9786 1 1133 1.9681 1.9686 1 0134 1.9633 1.9636 1 �2135 1.9596 1 3136 1.9565 1 �1137 1.9554 1.9544 1 2138 1.9542 1 2139 1.9474 1.9473 1 �3140 1.9427 1 �3141 1.9381 1 0142 1.9342 1 �3143 1.9260 1.9261 1 1144 1.9124 1 2145 1.9094 1 �3146 1.9047 1 �2147 1.9033 1 1148 1.9011 1 3149 1.8907 1.8906 2 2150 1.8871 1 3151 1.8812 1.8812 1 2152 1.8705 1.8705 1 �1153 1.8702 1 �3154 1.8661 1 0155 1.8628 1.8630 2 �1156 1.8624 1 �2157 1.8592 1 �3158 1.8579 1 2159 1.8568 1.8564 1 0160 1.8557 1 1161 1.8499 1.8500 1 �1162 1.8408 1.8408 1 �1163 1.8377 1 �1164 1.8363 1 �2165 1.8357 1 2166 1.8334 1.8330 1 3

The thermoanalytical profile obtained using a heating

341 Powder Diffr., Vol. 24, No. 4, December 2009

rate of 10 °C min−1 for isotibolone is presented in Figure 3.The DSC curve of isotibolone presents a sharp endothermicpeak that corresponds to melting in the range of 190 to210 °C �Tonset=194.2 °C; �H=108.2 J g−1�. TG/DTGcurves indicated that the thermal decomposition process ofisotibolone occurs in three stages in the following tempera-ture ranges and weight losses: 212 to 350 °C ��m=18.2%�,350 to 526 °C ��m=47.2%�, and 526 to 656 °C ��m=34.3%�. No thermal decomposition �weight loss� was ob-

k l 2�o 2�c �2�

8 1 35.6172 2 35.980 35.970 �0.0109 1 35.9912 2 36.047 36.049 0.0023 3 36.1378 2 36.1898 2 36.2040 3 36.3277 1 36.392 36.395 0.0031 3 36.4994 3 36.5225 1 36.536 36.530 �0.007

10 0 36.54510 1 36.747 36.737 �0.0103 2 36.839 36.834 �0.0063 2 36.9127 2 36.9722 3 36.995 37.014 0.0197 2 37.0185 0 37.151 37.155 0.0040 1 37.2454 3 37.3371 1 37.415

10 1 37.580 37.579 �0.0013 3 37.8572 1 37.9184 2 38.0155 3 38.0464 2 38.0919 0 38.309 38.311 0.0026 1 38.3859 1 38.510 38.510 0.0000 3 38.740 38.738 �0.0023 1 38.7455 3 38.8341 3 38.906 38.902 �0.0048 1 38.9146 0 38.9854 3 39.0129 2 39.036 39.046 0.0109 2 39.060

10 1 39.189 39.186 �0.0022 3 39.389 39.389 0.0008 2 39.4595 2 39.4908 2 39.5035 2 39.556 39.563 0.008

served during the melting process. After melting, the thermal

341X-ray diffraction data of tibolone ...

decomposition processes were indicated by a DSC curve asexothermic events �Tpeaks=295, 326, and 463 °C�. FromDSC curves obtained under 2 °C min−1 it was possible todetermine the purity of this sample in 98.7%.

B. Indexing of isotibolone X-ray powder pattern

The higher figure of merit �Coelho, 2003� obtained in theindexing was 176.93 for a monoclinic P21 space group withunit cell parameters a=6.8066 Å, b=20.7350 Å,c=6.4489 Å, �=76.428°, and V=884.75 Å3. After the unitcell refinement through the Pawley method, the cell param-eters were determined to be a=6.8066�2� Å,b=20.7351�5� Å, c=6.4490�2� Å, �=76.430�1�°, andV=884.77�4� Å3. The agreement factors after Pawley re-finement were the following: Rwp=5.992%, 2=1.389,weighted Durbin–Watson d statistic=1.228, and RBragg=0.290%. The list of peaks, with observed and calculated 2�and interplanar distances, together with the I100 is presentedin Table I. The observed and fitted diffractograms for thePawley refinement are shown in Figure 4. In this figure it ispossible to verify that all observed peaks were fitted and noother phase than isotibolone is present in the analyzed pow-der.

IV. CONCLUSIONS

The isotibolone was characterized by elemental analysis,IR spectrum, and TG/DTG and DSC. All characterizationdata indicate good sample quality obtained by isomerizationof tibolone. The isotibone sample was indexed as monoclinicP21 with refined unit cell parameters a=6.8066�2� Å,b=20.7351�5� Å, c=6.4490�2� Å, �=76.430�1�°,V=884.77�4� Å3, � =1.187 g cm−3, and Z=2.

Figure 4. Plot of indexing of isotibolone sample.

o

342 Powder Diffr., Vol. 24, No. 4, December 2009

ACKNOWLEDGMENTS

The authors gratefully acknowledge the financial supportof Brazilian agencies FAPESP, CNPq, CAPES, and theLNLS �Brazilian Synchrotron Light Laboratory� for beamtime.

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