Assembling the puzzle of Apixaban solid forms - ACS Publications

Article Cite This: Mol. Pharmaceutics 2018, 15, 1909−1916

Assembling the Puzzle of Apixaban Solid Forms Rafael Barbas, Cristina Puigjaner,* and Rafel Prohens* Unitat de Polimorfisme i Calorimetria, Centres Científics i Tecnològics, Universitat de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain S Supporting Information *

ABSTRACT: An in-depth analysis of the solid forms of the anticoagulant drug Apixaban (APX) has been conducted to sort out the confusion in the scientific and patent literature regarding the solid forms landscape. The nomenclature employed and the accompanying characterization data are often unclear and incomplete, leading to a situation in which apparently the same form has been reported by different authors or claimed by different inventors. A comprehensive solid forms screen and a full and careful comparison with the literature data has been performed to draw a reliable picture of the solid forms landscape of APX. KEYWORDS: polymorphism, patents, pharmaceutical drugs, powder X-ray diffraction

1. INTRODUCTION Recent surveys1,2 have indicated that polymorphism of molecular compounds is quite common, a fact that is of particular relevance in the pharmaceutical industry due not only to the impact on the physicochemical properties but also to the implications in the intellectual property of active pharmaceutical ingredients (APIs). According to current estimates based on the results of contracted experimental solid forms screens, about 90% of organic compounds exist in multiple crystalline forms (including polymorphs and solvates) with half of them being polymorphic.3 Thus, solid form screening, the activity of generating, isolating, and analyzing different solid forms on an API, has become an integral part in the development of a drug with great resources spent in early stages of the drug discovery process with the aim to explore a broad expanse of the solid form landscape. The motivation for this survey of the landscape is meant to reveal the form that is best suited for ultimate production and formulation, and to ensure that the intellectual property rights have been sufficiently protected. The exploration of the crystal form landscape often continues throughout the lifetime of an API, in some cases leading to alterations and improvements or even new formulations with the potential of extending the patent protection of the drug.4 While every drug involves different chemistry and different solid state landscapes, the case of Cefdinir with a variety of hydrated and anhydrous forms described in nine patents provides an example of the history of an API and the intellectual property associated with it.5 For materials that exhibit multiple solid forms a recurring problem is the lack of consistency in the labeling and characterizing of those forms. With regard to the intellectual property aspects of those forms, this situation can lead to considerable difficulty in searching and interpreting the prior art for any individual form, a factor that may determine its © 2018 American Chemical Society

patentability. This inconsistency arises in nomenclature, at least, from the lack of an accepted standard notation (Arabic or Roman numerals, lower or upper case Latin or Greek, etc.).6 Furthermore, the often extended time frames in publishing can lead to overlapping and or conflicting labeling of forms. The situation is often further complicated by the provision of minimal characterizing data for solid forms, thus providing insufficient information (i.e., sparse data and/or poor figures) for comparison and determination of identity of forms or lack thereof. Solid forms are treated as inventions defined by parameters. According to ICH (formerly the International Conference on Harmonisation and superseded by the International Council for Harmonisation), the leading platform for global pharmaceutical regulatory harmonization, in particular the Q6 A.3.3.1 guideline,7 the analytical techniques commonly used to determine the existence of multiple solid forms are X-ray powder diffraction (XRPD), thermal analysis procedures (i.e., DSC, TGA, and DTA), solid state IR, Raman spectroscopy, solid state NMR, and optical microscopy. No details are provided about how to perform the characterization and comparison among the different forms, but the implied assumption is that a person of skill in the art in preparing and characterizing solid forms knows how to employ these analytical techniques and interpret the data from them. Solid forms may be recognized and characterized by any combination of these techniques, leading to a variety of actual patent claims, and the situation for every compound is unique.8 As a result of this situation, for many compounds, especially those that command a significant market, one can find literature Received: January 22, 2018 Accepted: March 27, 2018 Published: March 27, 2018 1909

DOI: 10.1021/acs.molpharmaceut.8b00060 Mol. Pharmaceutics 2018, 15, 1909−1916

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Molecular Pharmaceutics

solution of 20 mg of APX in 2 mL of ACN at 70 °C. A solid precipitated after several seconds. Water content has been determined by TGA analysis (4.7% weight loss),16 and its XRPD has been indexed (see SI). 2.1.4. Hydrate Form IV. Obtained by slow evaporation during 9 days of a solution of 20 mg of APX in 0.05 mL of formic acid at 25 °C and also by addition all at once without stirring of 0.2 mL of DIE as antisolvent to a solution of 40 mg of APX in 0.1 mL of formic acid at 25 °C. A solid precipitated after several seconds. Water content has been determined by TGA analysis (5.6% weight loss)16 and its XRPD has been indexed (see SI). 2.1.5. Hydrate Form V. Obtained in most of the screening methodologies applied using acetic acid as solvent; for example, 40 mg of APX were dissolved in 0.2 mL of acetic acid at 25 °C, 0.4 mL of H2O or 0.4 mL of DIE were added all at once without stirring, and a solid precipitated after several seconds. Alternatively, form V was obtained by rapid cooling of a solution of 20 mg of APX in 1 mL of THF at 70 °C. Once the solid was dissolved, the solution was cooled down by immersing in an ice−water bath. After 1 h the solution was kept at 8−10 °C, and after 1 day, a solid was obtained. Water content has been determined by TGA analysis (5.8% weight loss),16 and its XRPD has been indexed (see SI). 2.1.6. Hemichloroform Solvate Form VI. Obtained by evaporation overnight of a solution of 20 mg of APX in 0.4 mL of chloroform at 25 °C and by fast cooling rate crystallization of 50 mg of APX in 1.2 mL of chloroform at 50 °C. Once the solid was dissolved, the solution was cooled down quickly inside an ice−water bath; after 1 h the solution was kept at 8−10 °C, and a solid precipitated after 8 days. Solvent content was determined by TGA analysis (19.1% weight loss) and 1 HNMR (DMSO-d6) (APX/chloroform 1:0.5 molar ratio). Its XRPD has been indexed (see SI). 2.1.7. Hemidimethoxyethane Solvate Form VII. Obtained by slurring 20 mg of APX in 2 mL of DME at 25 °C overnight, after heating the solution at 85 °C. Solvent content has been determined by TGA analysis (8.5% weight loss) and 1HNMR (DMSO-d6) (APX/dimethoxyethane 1:0.5 molar ratio). Its XRPD has been indexed (see SI). 2.1.8. Hemibenzyl Alcohol Solvate Form VIII. Obtained by evaporation at 25 °C of a solution of 20 mg of APX in 0.05 mL of benzyl alcohol after 2 days and also by addition all at once, without stirring, of 0.6 mL of DIE as antisolvent to a solution of 120 mg of APX in 0.3 mL of benzyl alcohol at 25 °C and subsequent cooling to 8−10 °C during 1 day (CCDC: 1523674).15 2.1.9. DMSO Solvate Form IX. Obtained in most of the screening methodologies applied using DMSO, for example, after overnight crystallization of a solution of 20 mg of APX in 1 mL of DMSO. Its XRPD has been indexed (see SI). 2.1.10. Isopropanol Solvate Form X. Obtained by slow diffusion of IPA as antisolvent into a solution of 120 mg of APX in 0.3 mL of benzyl alcohol at 25 °C (CCDC: 1523673).15 2.1.11. Amorphous Form XI. It was obtained in situ by quenching from the melt a sample of APX in a DSC experiment (glass transition 120 °C, ΔCp = 0.360 J/gK, see SI), but it has not been isolated. 2.2. Methods. 2.2.1. X-ray Powder Diffraction (XRPD). Xray powder diffraction patterns were obtained on a PANalytical X’Pert PRO MPD diffractometer in transmission configuration using Cu Kα1+2 radiation (λ = 1.5418 Å) with a focalizing elliptic mirror and a PIXcel detector working at a maximum

references and patents describing and claiming many solid forms of an API. Some recent examples include Sertraline HCl, which has been reported in several patents to exist at least as 17 polymorphs, four solvates, and six hydrates;9 the calcium salt of Atorvastatin with at least 60 forms patented10 and a total of 78 forms reported;11 Aripiprazole with more than 20 patents and applications claiming polymorphic, solvated, and amorphous forms;12 Sulfathiazole with five polymorphs, an amorphous form, and over one hundred solvates identified;13 or Axitinib with 60 solvates or polymorphs of solvates and five anhydrous forms.14 Moreover, these documents containing scientific and/ or technical information do not always lead to clarification of the solid form landscape but rather often compound the confusion. In the present article we have analyzed the typically confusing case of APX (Figure 1). This compound, under the

Figure 1. Chemical structure of APX.

trade name of Eliquis, is an anticoagulant drug used for reducing the risk of strokes first produced by Bristol-Myers Squibb and Pfizer in 2011. We have conducted an analysis of the 24 different patents claiming solid forms of APX showing that a variety of nomenclature combined with often scanty and inconsistent characterization data have apparently led to the same form being claimed in different patent applications. This realization prompted us to perform a comprehensive solid forms screen and a full evaluation and comparison with the relevant patent literature in order to assemble all the pieces of the solid forms puzzle of APX. In the course of this investigation we have obtained additional new benzyl alcohol and isopropanol solvates; their crystal structures analysis are the subject of another paper.15

2. MATERIALS AND METHODS 2.1. Synthesis of the Different Crystal Forms. 2.1.1. Anhydrous Form I. Obtained in most of the screening methodologies applied (mp 238 °C); for example, by slow crystallization from a solution of 20 mg of Apixaban in 2 mL of THF at 66 °C. Once the compound was dissolved, the heater was switched off and the solution was cooled down to 25 °C inside the heating block. Crystals were obtained after 1 day. 2.1.2. Anhydrous Form II. Obtained always as a mixture with Form I, when heating Forms III, V, VI, or VIII at 210 °C in a DSC pan. Its XRPD is shown in the Supporting Information (SI). Melting point has been deduced from desolvation of some hydrates and solvates in the DSC pan (mp 234 °C), Figure 3. 2.1.3. Hydrate Form III. Obtained by fast cooling rate crystallization: 20 mg of APX were dissolved in 1 mL of dichloromethane at 35 °C, and the solution was cooled down quickly inside an ice−water bath. Form III precipitated after some seconds. Alternatively, Form III was obtained by adding all at once without stirring 4 mL of pentane as antisolvent to a 1910


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Molecular Pharmaceutics detector’s active length of 3.347°. Flat geometry has been used for routine samples sandwiched between low absorbing films (polyester of 3.6 μm of thickness) measuring 2theta/theta scans from 2 to 40° in 2θ with a step size of 0.026° and a measuring time of 80−300 s per step. 2.2.2. Indexing and Space Group Determination by XRPD. Powder diffraction diagrams have been indexed by means of Dicvol04,17 and the space groups have been determined from the systematic absences, which are confirmed through the pattern matching procedure by means of FullProf.18 2.2.3. Differential Scanning Calorimetry (DSC). Differential scanning calorimetry analyses were carried out by means of a Mettler-Toledo DSC-822e calorimeter. Experimental conditions: aluminum crucibles of 40 μL volume, atmosphere of dry nitrogen with 50 mL/min flow rate, heating rate of 10 °C/min. The calorimeter was calibrated with indium of 99.99% purity. 2.2.4. Thermogravimetric Analysis (TGA). Thermogravimetric analyses were performed on a Mettler-Toledo TGA851e thermobalance. Experimental conditions: alumina crucibles of 70 μL volume, atmosphere of dry nitrogen with 50 mL/min flow rate, and heating rate of 10 °C/min.

Table 1. Bibliographic Precedents: Chronological Classification According to Their International Publication Date form(s)a

patent/article WO2007001385

19

N-1, H2-2

20

DMF-5, FA-2

US20070203178

3. RESULTS AND DISCUSSION 3.1. Bibliographic Precedents. An extensive literature survey was conducted for APX. Previous reports on the crystal polymorphism of APX are listed chronologically in Table 1, according to their international publication date. In particular, 24 patents and two articles were published from 2007 to 2015, and 49 crystal forms were reported. This survey shows that different nomenclature systems have been used (Roman numbers, Latin or Greek letters, and others) with an inconsistent labeling of polymorphs and solvates. Several analytical techniques were used to characterize the different crystal forms (cell parameters, DSC, TGA, X-ray diffractogram, and XRPD 2θ peak list). 3.2. Solid Forms Screening of APX. Aiming to produce the reported forms of APX and to search for potential new solid forms, a comprehensive polymorph/solvate screen has been conducted by using different combinations of solvents at several concentrations and temperatures, with variable cooling rates, in both thermodynamic and kinetic conditions (Table 2). A summary with the details of all experimental conditions can be found in the SI. The analysis of all isolated solids showed experimental evidence for up to 13 different crystal forms. However, we could only characterize ten in pure form: one anhydrous (Form I), three hydrates (Forms III, IV, V), five solvates (chloroform, Form VI; dimethoxyethane, Form VII; benzyl alcohol, Form VIII; DMSO, Form IX; isopropanol, Form X), and one amorphous (Form XI). All crystal forms were characterized by means of X-ray powder diffraction, DSC, and TGA. The X-ray powder diffractograms of the different crystal forms obtained are shown in Figure 2. Their XRPD diagrams were indexed with DICVOL06, the space groups were deduced from the systematic absences, and the most probable space group in each case is suggested. The cell and space groups were validated with Le Bail fit of the data using FullProf (see SI). The crystal structures of Form I and the two solvates with benzyl alcohol and isopropanol (Forms VIII and X, respectively) were solved at 100 K.15 Unit cell parameters of the different forms are shown in Table 3. In all hydrates/solvates the DSC thermograms show a very similar pattern of desolvation/melting on heating followed by

IPCOM000216217D21 WO201216836422

I, II α

IPCOM000227611D23 WO201311932824

“form”b I, II, III, DF-1

IPCOM000216902D25 CN10336039126

A, B, C, D β

US904547327

amorphous

CN10353979528 CN10383375529

I, II, III, IV, V, amorphous B

WO201405643430

I

EP2752414

a

31

characterization peak list, cell parameters peak list, cell parameters, DSC, TGA peak list peak list, X-ray diffractogram, DSC peak list peak list, X-ray diffractogram X-ray diffractogram peak list, X-ray diffractogram, DSC X-ray diffractogram, DSC peak list, X-ray diffractogram, DSC peak list, X-ray diffractogram peak list, X-ray diffractogram, DSC peak list, X-ray diffractogram, DSC peak list, X-ray diffractogram, DSC X-ray diffractogram peak list, X-ray diffractogram, DSC,TGA peak list, X-ray diffractogram, DSC,TGA peak list, X-ray diffractogram, DSC peak list, X-ray diffractogram, DSC peak list peak list, X-ray diffractogram, DSC X-ray diffractogram cell parameters peak list, X-ray diffractogram, DSC X-ray diffractogram, DSC,TGA peak list, X-ray diffractogram

A, H-3

WO201410891932

M, S, N

WO201411195433 CN10408654434

“form” monohydrate

WO201417337735

AP3, AP4, AP5

WO201420327536 WO201502190237

“form”, amorphous A

CN10465007438 CN10467223339

“form” γ

US2015001838640 Wang et al.41 CN10478844842

amorphous N-1 X

Solanki et al.43

N-1, H2-2, α

CN10491014744

I, II

Nomenclature used in each patent. nomenclature.

b

year 2007 2007 2012 2012 2013 2013 2013 2013 2013 2014 2014 2014 2014 2014 2014 2014 2014 2014 2015 2015 2015 2015 2015 2015 2015 2015

“form” means unspecific

crystallization and subsequent melting of the anhydrous forms II and I (Figure 3). Three additional solid forms were detected during the screening (Forms II, XII, and XIII). However, they could not be isolated in pure form for additional characterization. Anhydrous Form II was observed as a mixture with Form I when heating Form III, V, VI, or VIII at 210 °C in a DSC pan. Form XII and Form XIII were obtained each as a mixture with Form III in some of the screening methodologies applied in dichloromethane and ACN, respectively. In both cases, the mixtures converted to pure Form III after 2 months at 25 °C, as determined by XRPD. 1911


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Molecular Pharmaceutics Table 2. Screening of APX No. of experiments

No. of solids

solubility study

30

30

evaporations at 25 °C crystallizations from 25 to 0 °C

6 6

5 5

crystallizations at slow cooling rate

10

7

crystallizations at medium cooling rate

10

7

crystallizations at fast cooling rate crystallizations by antisolvent diffusion

10 32

6 15

precipitations by adding antisolvent at 25 °C

41

33

precipitations by adding antisolvent at high temperature (35−70 °C depending on the solvents used) quenching from the melt

28

20

1

1

methodology

a

form obtained (according to XRPD) form I, form III, form IV, form V, form VII, form VIII, form IX, mixture form III + form VI, mixture form III + form XIII, mixture form III + form XII form V, form VI, mixture form I + form IX form V, form IX, mixture form III + form VI, mixture form III + form XIII form I, form V, form VI, mixture form I + form IX, mixture form III + form XIII, mixture form III + form XII form I, form VI, mixture form I + form IX, mixture form III + form XIII, mixture form III + form XII form I, form III, form V, form VI, form IX form I, form V, form VI, mixture form III + form VI, mixture form III + form XIII form I, form III, form IV, form V, form VI, form VIII, form IX, mixture form I + form IX, mixture form III + form VI form I, form V, form IX, mixture form I + form V, mixture form I + form III, mixture form III + form VI, mixture form III + form XII form XIa

The amorphous form obtained in the DSC experiment has not been isolated, so its XRPD has not been measured.

Figure 2. Experimental XRPD of the crystalline forms of APX. Calculated XRPD from Form X crystal structure is also shown.

Table 3. Unit Cell Parameters of APX Crystal Forms form a

I Ib III IV V VI VII VIIIa IX Xa

a (Ǻ )

b (Ǻ )

c (Ǻ )

β (deg)

V (Å3)

Z

probable space group

10.0987(6) 10.2208(4) 29.525(3) 13.1394(5) 13.1048(4) 13.3594(8) 40.262(3) 6.2826(4) 32.245(2) 6.2840(2)

13.7383(10) 13.8422(6) 13.8654(7) 30.478(2) 30.594(2) 32.295(3) 11.676(1) 30.485(2) 13.8573(6) 30.4486(14)

15.7097(12) 15.7529(6) 5.9685(4) 6.2414(3) 6.2086(3) 6.1752(4) 5.3496(4) 14.0978(8) 6.0127(3) 12.8641(6)

93.716(3) 92.927(3) 90 91.270(2) 90.977(2) 89.973(9) 92.129(2) 114.198(3) 90 92.231(2)

2175.0(3) 2225.79(15) 2443.4(4) 2498.8(2) 2488.8(2) 2664.3(4) 2513.1(3) 2462.8(3) 2686.6(2) 2459.54(18)

4 4 4 4 4 4 4 4 4 4

P21/n P21/n Pnn2c P21/n P21/n P21/n P21/n P21/c Pna21c P21/n

a

Cell parameters obtained from single crystal determinations at 100 K. bCell parameters reported39 from single crystal determination at 293 K. cThe probable space groups of both orthorhombic cells with Z value of approximately 4 (assuming a density value of 1.4) have been suggested taking into account that the multiplicity cannot be 8 as the molecule is not symmetric and the asymmetric unit cannot contain only 1/2 molecule. Pnn2 has been suggested instead of Pnnm, and Pna21 has been suggested instead of Pnam.

3.3. Analysis of APX Solid Forms Patents. The main objective of this research is to clarify the IP landscape of APX. As it has been stated in the introduction, different combinations

of characterization data have been used in the extensive body of patents that protects the IP of pharmaceutical compounds. Thus, an initial search of the parameters used in the claims of 1912


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Figure 3. DSC of benzyl alcohol solvate Form VIII.

Figure 4. Assignment of peaks following a ±0.2° 2θ deviation criterion.

Table 4. Patents Describing Form I of APX characterization

a

a

patent

form

WO2007001385 WO2014108919 CN103539795 WO2014056434 WO2015021902 CN103539795 WO2014111954 CN104788448

N-1 M I I A III “form” X

cell parameters

No. of peaks reported (2θ)

X-ray diffractogram

DSC (°C)b

yes no no no no no no no

6 8 18 14 6 20

no yes yes yes yes yes yes yes

no 237 238 237 237 no no 237

11

Form I claimed no yes yes yes yes yes no yes

(peak (peak (peak (peak (peak

list list list list list

and and and and and

referral referral referral referral referral

to to to to to

an an an an an

XRPD XRPD XRPD XRPD XRPD

figure) figure) figure) figure) figure)

(peak list)

Nomenclature used in the patent. bMelting point.

forms, and it is our chosen data for comparison of the different forms. 3.3.1. Initial Considerations. A detailed analysis of the X-ray powder diffractograms found in the different patents has been performed. First, a simulated XRPD pattern of each crystal form has been represented according to the peak lists reported and their estimated relative intensities. Since some experimental issues can affect the analysis of the powder and the relative

those patents covering the different solid forms of APX was conducted. The full body of patents is listed in Table 1 where the parameters used to characterize each form are listed. The large body of APX patents shows a combination of parameters used from X-ray diffractograms, X-ray diffraction peak lists (2θ), DSC, and TGA thermograms. Since the XRPD pattern is directly related to the crystalline structure of a solid form, it is considered the gold standard for fingerprinting of different solid 1913


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Figure 5. XRPD experimental pattern of Form I (black) compared to simulated diffractograms from peak lists reported in published patents: Form N-1 WO2007001385, Form M WO2014108919, Form I (green) and Form III CN103539795, Form I (brown) WO2014056434, Form A WO2015021902, and Form X CN10478848. Simulated diffractogram of “form” (WO2014111954) is missing due to the lack of X-ray peak list since only the XRPD pattern is shown in its patent.

Figure 6. XRPD experimental pattern of Form I compared to the combined simulated pattern from reported peak lists of seven patents.

position of each XRPD peak, such as the instrument used, the diffractometer configuration (reflection, transmission, or capillary geometry), the radiation (λ), particle size, preferential orientation, measurement time per step, or amount of sample, the acceptable relative standard deviation for 2θ is ±0.2° according to the United States Pharmacopeia (USP),45 which means that peak shifts greater than 0.2° at a given 2θ angle are suggestive of a different crystalline structure. As an example of application of this criterion, the three sets of peaks shown in Figure 4 (which correspond to six different reported forms) were considered to belong to the same X-ray pattern since the deviation in each set of peaks was less than ±0.2° 2θ. It must be noted that XRPD patterns extracted from the patents have significant differences of scale, width peak, and intensities. These differences have increased the difficulty encountered during our peaks assignment. 3.3.2. Classification of the Different Forms of APX. Crystal forms N-1 and H2-2 were first reported in patent WO2007001385 in 2007. In this patent, their cell parameters and six diffraction peaks (2θ) were described. Once compared to our own data, we assigned our experimental Form I to Form N-1 due to the coincidence between their cell parameters. A careful analysis of the diffractograms reported in the different

patents suggested that eight patents could have reported the same crystal Form I (Table 4, Figure 5). A remarkable coincidence was observed between our experimental pattern of Form I and a full pattern created as a result of combining in one single simulated diffractogram all XRPD peak lists corresponding to those seven patents (Figure 6). However, additional peaks at 5.4° and 10.9° 2θ observed in the case of the named Form III reported in patent CN103539795 suggest the presence of another crystal form obtained concomitantly in that particular case. Moreover, the presence of additional low intensity peaks in the experimental pattern of Form I (and not present in the simulated pattern) was not surprising as the peak lists of the patented forms were not complete, and only the most intense or significant peaks were presumably reported. So, we conclude that all these reported forms are Form I. The same careful inspection and comparison procedure of the different diffractograms has been carried out with all the other forms with similar results. Our analysis suggests that Form II could have been claimed by up to two patents, Form III by up to ten patents, Form V by up to four patents,46 Form VI by up to one patent, Form IX by up to two patents, and Form XIII by up to three patents. Five new forms have been 1914


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(4) Gaudry, K. S. Evergreening: a common practice to protect new drugs. Nat. Biotechnol. 2011, 29 (10), 876−878. (5) Cabri, W.; Ghetti, P.; Pozzi, G.; Alpegiani, M. Polymorphism and patent, market, and legal battles: Cefdinir case study. Org. Process Res. Dev. 2007, 11 (1), 64−72. (6) Bernstein, J. Polymorphism in Molecular Crystals: IUCr Monographs on Crystallography 14; Oxford University Press: Oxford, 2002. (7) Guideline Specification Q6A; International Conference on Harmonization (ICH), Geneva, 1999. (8) Bernstein, J. Structural chemistry, fuzzy logic, and the law. Isr. J. Chem. 2017, 57, 124−136. (9) Almarsson, O.; Hickey, M. B.; Peterson, M. L.; Morissette, S. L.; Soukasene, S.; McNulty, C.; Tawa, M.; MacPhee, J. M.; Remenar, J. F. High-throughput surveys of crystal form diversity of highly polymorphic pharmaceutical compounds. Cryst. Growth Des. 2003, 3 (6), 927−933. (10) Censi, R.; Di Martino, P. Polymorph impact on the bioavailability and stability of poorly soluble drugs. Molecules 2015, 20 (10), 18759−18776. (11) Jin, Y. S. Ph.D. Thesis from Martin-Luther Universitat HalleWittenberg, Germany, 2012. (12) Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Tessadri, R.; Wieser, J.; Griesser, U. J. Conformational polymorphism in aripiprazole: preparation, stability and structure of five modifications. J. Pharm. Sci. 2009, 98, 2010−2026. (13) Bingham, A. L.; Hughes, D. S.; Hursthouse, M. B.; Lancaster, R. W.; Tavener, S.; Threlfall, T. L. Over one hundred solvates of sulfathiazole. Chem. Commun. 2001, 7, 603−604. (14) Campeta, A. M.; Chekal, B. P.; Abramov, Y. A.; Meenan, P. A.; Henson, M. J.; Shi, B.; Singer, R. A.; Horspool, K. R. Development of a targeted polymorph screening approach for a complex polymorphic and highly solvating API. J. Pharm. Sci. 2010, 99 (9), 3874−3886. (15) Barbas, R.; Puigjaner, C.; Font-Bardia, M.; Bauza, A.; Frontera, A.; Prohens, R. Manuscript in preparation. (16) In absence of the crystal structures, the water stoichiometry of the hydrates could not be assessed. (17) Boultif, A.; Louër, D. Indexing of powder diffraction patterns for low-symmetry lattices by the successive dichotomy method. J. Appl. Crystallogr. 1991, 24, 987−993. (18) Rodriguez-Carvajal, J. Recent advances in magnetic structure determination by neutron powder diffraction. Phys. B 1993, 192, 55− 69. (19) Shapiro, R.; Rossano, L. T.; Mudryk, B. M.; Cuniere, N.; Oberhlozer, M.; Zhang, H.; Chen, B. Process for preparing 4,5dihydro-pyrazolo[3,4-C]pyrid-2-ones. WO2007/001385A2 (filed 27 September 2005, priority United States US US20040613938P filed 28 September 2004). (20) Malley, M. F.; Pommier, C. J. Crystalline solvates of Apixaban. US20070203178 (filed 23 February 2007). (21) Solid state forms of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-C]pyridine-3-carboxamide Publication number IPCOM000216217D. Publication date: 25 March 2012, example 1 and example 2. (22) Vladiskovic, C.; Attolino, E.; Lombardo, A.; Tambini, S. Apixaban preparation process. WO2012168364 (filed 7 June 2012, priority Italy MI20111047A1 filed 10 June 2011). (23) Solid state forms of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-C]pyridine-3-carboxamide. Publication number IPCOM000227611D. Publication date: 9 May 2013, example 1 and example 2. (24) Cohen, M.; Yeori, A.; Mittekman, A.; Erhlich, M. Solid state forms of Apixaban. WO2013119328 (filed 28 December 2012, priority US201261595799 filed 2 February 2012). (25) Solid state forms of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-C]pyridine-3-carboxamide. Publication number IPCOM000216902D. Publication date: 23 April 2012, example 1, example 2, example 3 and example 4.

discovered during our solid forms screen (Forms IV, VII, VIII, IX, and XII). Another reported crystal form (Form XVI), which we did not obtain in the course of our polymorph screen, has been also claimed by two patents. Moreover, four patents claimed amorphous forms, and there are nine additional claimed different forms. All this information is organized in Table 22 of the Supporting Information, which shows a landscape of at least 23 different crystal forms of APX (peak lists of all forms are also shown).

4. CONCLUSIONS The thorough analysis conducted on the patents reporting 49 solid forms of APX together with the comprehensive polymorph screen performed in this case study highlights some of the chaos that has developed in solid form patent applications of APIs in the last decades. It makes clear that nomenclature employed is chaotic, and often confusing, and different combinations of characterization data have been used in the extensive body of the patents, resulting in the same form being claimed by different patents. All the previous information has been collected, ordered, and compared with our own data obtained during the screening. A careful analysis has allowed assembling the APX solid forms puzzle, which now consists of a landscape of at least 23 different crystal forms. Therefore, in view of the lack of simple and general worldwide rules for patent application filing of solid forms, clear guidelines could avoid situations similar to the case of Apixaban or Cefdinir, among many others, and this would help authors and inventors to better evaluate the prior art. Although every case is unique, according to our experience, we believe that an open debate could generate useful discussions that address this ubiquitous problem in the pharmaceutical industry.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.8b00060. Bibliographic patent precedents; screening of APX; summary of solid forms of APX with comparison of XRPD peak lists; characterization of the solid forms: DSC (anhydrous), TGA (hydrates/solvates), XRPD, and Le Bail fit of the data (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*Tel: + 34 93 4034656. Fax: + 34 93 4037206. E-mail: rafel@ ccit.ub.edu. *E-mail: [email protected]. ORCID

Rafel Prohens: 0000-0003-0294-1720 Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Bernstein, J. Polymorphism − A perspective. Cryst. Growth Des. 2011, 11, 632−650. (2) Cruz-Cabeza, A.; Reutzel-Edens, S.; Bernstein, J. Facts and fictions about polymorphism. Chem. Soc. Rev. 2015, 44, 8619−8635. (3) Stahly, G. P. Diversity in single- and multiple-component crystals. The search for and prevalence of polymorphs and cocrystals. Cryst. Growth Des. 2007, 7 (6), 1007−1026. 1915


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reported in this patent (0.50 and 0.65, respectively) show that its true stoichiometry is APX/water 1:1.15.

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Assembling the puzzle of Apixaban solid forms - ACS Publications

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