Solid State Characterization and Crystal Structure from X-ray Powder Diffraction of Two Polymorphic Forms of Ranitidine Base

Solid State Characterization and Crystal Structure from X-Ray Powder Diffraction of Two Polymorphic Forms of Ranitidine Base HE´CTOR NOVOA DE ARMAS,1,2 OSWALD M. PEETERS,2 NORBERT BLATON,2 ELKE VAN GYSEGHEM,3 JOHAN MARTENS,4 GERRIT VAN HAELE,5 GUY VAN DEN MOOTER3 1 Johnson & Johnson, Pharmaceutical Research and Development, A Division of Janssen Pharmaceutica NV, Pharmaceutical Sciences Department, Turnhoutseweg 30, B-2340 Beerse, Belgium 2

Laboratory for Biocrystallography, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, O & N2 Campus Gasthuisberg, Herestraat 49 - bus 822, B-3000 Leuven, Belgium 3

Laboratory for Pharmacotechnology and Biopharmacy, Faculty of Pharmaceutical Science, Katholieke Universiteit Leuven, O & N2 Campus Gasthuisberg, Herestraat 49 - bus 921, B-3000 Leuven, Belgium 4

Centre for Surface Chemistry and Catalysis, Katholieke Universiteit Leuven, Kasteelpark Arenberg 23 - bus 2461, B-3001 Heverlee, Belgium 5

Corden PharmaChem NV, Industriezone Roosveld 2, B6 B-3400 Landen, Belgium

Received 8 January 2008; revised 20 February 2008; accepted 27 February 2008 Published online 4 April 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21395

ABSTRACT: Ranitidine hydrochloride (RAN-HCl), a known anti-ulcer drug, is the product of reaction between HCl and ranitidine base (RAN-B). RAN-HCl has been extensively studied; however this is not the case of the RAN-B. The solid state characterization of RAN-B polymorphs has been carried out using different analytical techniques (microscopy, thermal analysis, Fourier transform infrared spectrometry in the attenuated total reflection mode, 13C-CPMAS-NMR spectroscopy and X-ray powder diffraction). The crystal structures of RAN-B form I and form II have been determined using conventional X-ray powder diffraction in combination with simulated annealing and whole profile pattern matching, and refined using rigid-body Rietveld refinement. RAN-B form I is a monoclinic polymorph with cell parameters: a ¼ 7.317(2), b ¼ 9.021(2), ˚ , b ¼ 95.690(1)8 and space group P21/c. The form II is orthorhombic: c ¼ 25.098(6) A ˚ with space group Pbca. In RAN-B polya ¼ 31.252(4), b ¼ 13.052(2), c ¼ 8.0892(11) A morphs, the nitro group is involved in a strong intramolecular hydrogen bond responsible for the existence of a Z configuration in the enamine portion of the molecules. A tail to tail packing motif can be denoted via intermolecular hydrogen bonds. The crystal structures of RAN-B forms are compared to those of RAN-HCl polymorphs. RAN-B polymorphs are monotropic polymorphic pairs. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:146–158, 2009

Keywords: crystal structure; X-ray powder diffractometry; ranitidine base; ranitidine hydrochloride; crystallography; polymorphism; characterization; calorimetry; FTIR-ATR; 13C-CPMAS-NMR

This article contains supplementary material, available at www.interscience.wiley.com/jpages/0022-3549/suppmat. Correspondence to: He´ctor Novoa de Armas (Telephone: 3214-608733; Fax: 32-14-607083; E-mail: [email protected])

146

Journal of Pharmaceutical Sciences, Vol. 98, 146–158 (2009) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

SOLID STATE CHARACTERIZATION OF RANITIDINE BASE POLYMORPHS

INTRODUCTION Ranitidine hydrochloride (RAN-HCl, N-[2[[[5[(dimethylamino)methyl]-2-furanyl]-methyl] thio]-ethyl]-N0 -methyl-2-nitro-1,1-ethenediamine hydrochloride, C13H22N4O3SHCl) belongs to a general class of anti-ulcer drugs and is one of the most frequently prescribed drugs in North America and Europe. This drug is used to block acid production in the stomach, which is implicated in indigestion, acid reflux, heartburn, ulcers, and in the Zollinger–Ellison syndrome. RAN-HCl works by blocking the histamine H2 receptor in the gut that stimulates stomach acid secretion providing a more favorable stomach pH through higher acidity.1 RAN-HCl is the product of reaction between HCl and ranitidine base (RAN-B, Scheme 1). RAN-B is a pale-yellow to off-white powder with two pKa values2 (pKa1 ¼ 8.20 and pKa2 ¼ 2.30), which means that it can react with more than one proton. During HCl addition reaction, the first HCl molecule reacts with the nitrogen of the dimethylamino group, then as the pH decreases, the second HCl molecule reacts with the ethenediamine where the C-protonation rather than the N-protonation occurs.3 RAN-HCl has two known polymorphic forms and also several pseudopolymorphic forms or solvates.4 This drug was developed in the late 1970s by Allen and Handbury Ltd., part of the Glaxo group (nowadays Glaxo SmithKline, Brentford, Middlesex, UK). The Glaxo group disclosed a RAN-HCl production method (Example 32 of US patent 4,128,658), which led to the formation of form I RAN-HCl,5 commercialized as Zantac1. Several years later, the Glaxo group issued a patent6 for the production of a new polymorphic

Scheme 1. DOI 10.1002/jps

147

form of RAN-HCl which was designated as form II. They claimed that the new form did not have the disadvantages of original form I, namely, poor filtration and drying characteristics. In 1997, after the expiration of the 1978 patent to produce form I, Canadian generics manufacturer Novopharm, Geneva Pharma (a Novartis group company), Roxane (part of Boehringer Ingelheim) and Torpharm filed abbreviated new drug applications (ANDAs) for the RAN-HCl form I.7–11 The Glaxo group patent and the reissued work of Murthy and coworkers in 20028 suggest that an important requirement for obtaining form I is to keep the amount of water to a minimum (less than 0.5 wt%) while the presence of water leads to the formation of form II. Mirmehrabi et al.12 suggest that significant amounts of strongly polar solvents such as methanol would favor the production of form II, while anhydrous less polar or nonpolar solvents will promote production of form I. From the analysis of the crystal structure of form II, they suggested the importance of intramolecular hydrogen bonding on the crystal growth of these forms. In anhydrous less polar or nonpolar solvents the intramolecular hydrogen bonds are expected to be strong leading to form I, where crystal growth is restricted (crystals of 1–10 mm were obtained). In this matter, they suggested that the nitroethenediamine moiety in RAN-HCl could exist as different tautomeric forms, demonstrating that RAN-HCl form II could exist as a mixture of the enamine and the nitronic acid tautomers (Scheme 1). RAN-HCl form I crystal structure13 was solved using single crystal X-ray diffraction at low temperature (T ¼ 100 K), in order to reduce the disorder in the tail of the molecule. The first known crystal structure of a RAN-HCl polymorph was solved by single crystal X-ray diffraction for the form II polymorph.14 This crystal structure shows conformational disorder in the nitroethenediamine moiety. The structural results show 50% occupancy in each of the two sites for the two nitrogens of the nitro and enamine groups, one carbon, and two oxygen atoms. Stephens and coworkers15 redetermined the crystal structure of RAN-HCl form II using high resolution X-ray powder diffraction (from synchrotron radiation data) combined with simulated annealing. They suggested the possibility of using these methods to reveal the conformational disorder shown by the previous single crystal study. However, this disorder is from a configurational nature and JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

148

DE ARMAS ET AL.

not conformational as suggested by Mirmehrabi et al.12 Detection of RAN-HCl form I or form II in polymorphic mixtures of both forms has been carried out in our laboratories and it is of high importance for the manufacturing of the licensed RAN-HCl polymorph of a company (Corden PharmaChem, N.V., Belgium (Cambrex Profarmaco Landen N.V., Personal Communication)). RAN-B, the starting material to obtain the RANHCl, can exist also as two polymorphic forms, of which, to the best of our knowledge, neither the solid state characterization nor the crystal structures have been reported. Single crystal X-ray diffraction is the ideal technique for determining the three-dimensional structure of organic compounds in the crystalline state. Unfortunately, the necessary prerequisite to obtain crystals suitable for X-ray diffraction analysis is not always met for all compounds and some materials are only available as polycrystalline powders. In recent years, a considerable progress has been made in the techniques for solving crystal structures of relatively complex organic molecular structures from X-ray powder diffraction (XRPD) data by modeling the structure in direct space (global optimization) using, among others, Monte Carlo simulated annealing (SA).16,17 This makes the XRPD structure determination ideal for solving unknown packing of molecules whose conformations are largely predictable.18 In this article, optical microscopy, thermal analysis (DSC, TGA), Fourier transform infrared spectrometry (FTIR) in the attenuated total reflection (ATR) mode (FTIR-ATR), 13C-CPMASNMR spectroscopy and X-ray powder diffraction (XRPD) have been used to characterize RAN-B polymorphic forms I and II. Conventional XRPD data in combination with real space techniques (SA and whole profile pattern matching implemented in the DASH structure solution package),19 and the Rietveld method20 for refinement have been used to solve the crystal structure of RAN-B polymorphs, the starting material of the well known RAN-HCl drug.

EXPERIMENTAL Materials The samples of RAN-B form I and II (batch 105095-R1 for form I and 105094-R2 for form II) JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

are white to slightly beige crystalline powders, and were supplied by Corden PharmaChem (Cambrex Profarmaco Landen N.V., Belgium). The quality control of this sample was guaranteed and certified by its producers. The samples complied with all the necessary standards of quality control required by Corden PharmaChem. XRPD analysis, as part of the quality control process, indicated unequivocally which polymorphic form was present and used for each of the other analysis. All attempts to prepare single crystals from RAN-B form I and II by using several polar and nonpolar solvents (and their combinations), failed.

Hot Stage Microscopy (HSM) The particle size, habit, and crystallinity of the samples were examined with an Olympus BX51 Hot-stage (optical) microscope (Olympus Optical Co., Ltd., Tokyo, Japan). This polarizing optical microscope was equipped with a LINKMAN THMS600 hot stage (Linkam Scientific Instruments Ltd., Surrey, UK) and LINKMAN TMS94 programmable temperature controller.

Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) DSC measurements were carried out using a Q1000 DSC (TA Instruments, Crawley, West Sussex, UK) equipped with a refrigerated cooling system (RCS). Data were analyzed mathematically using Thermal Solutions software (TA Instruments).21 Dry nitrogen (5.5, Messer N.V., Machelen, Belgium) at a flow rate of 50 mL/min, was used as the purge gas through the DSC cell. TA Instruments aluminum open pans were used for all calorimetric studies. The mass of the empty sample pan was matched with the mass of the empty reference pan within 0.1 mg, the sample mass varied from 4 to 7 mg. The temperature scale and the enthalpic response were calculated with an Indium standard. Validation of temperature and enthalpy using the same standard materials showed that deviation of the experimental from the reference value was < 0.5 K for the temperature measurement, and <1% for the enthalpic response. The DSC thermograms were measured with a heating rate of 0.58C/min and recorded from room temperature (RT). Thermogravimetric analysis was performed with a TA Instruments Q500 (TA Instruments, DOI 10.1002/jps

SOLID STATE CHARACTERIZATION OF RANITIDINE BASE POLYMORPHS

New Castle, DE). Approximately 10 mg of sample was weighed in an aluminum pan of 30 ml and heated from room temperature at a heating rate of 208C/min. The end point was set at 3008C or after a weight loss of 20% was reached. Fourier Transform Infrared Spectrometry (FTIR) in the Attenuated Total Reflection (ATR) Mode (FTIR-ATR) The samples were analyzed using a Thermo Nexus 670 FTIR spectrometer (Thermo Fisher Scientific Inc., Waltham, MA) in the 400– 4000 cm1 range with a resolution of 1 cm1 and 32 scans per spectrum, in absorbance and transmittance modes, as a function of wave number. The samples were analyzed using a Harrick Split Pea with Si crystal microATR accessory. A DTGS detector type with KBr windows and Ge on KBr as beam splitter was used. A baseline correction has been performed through a polynomial fit through low-absorption regions of the collected spectra. 13

C-CPMAS-NMR

The samples of RAN-B form I and II were characterized by means of 13C MAS NMR spectroscopy. The spectra were recorded on a Bruker AMX300 spectrometer (Bruker BioSpin, Rheinstetten, Germany) at 300 MHz equipped with a Bruker 7 T 15 cm supercon vertical magnet (7.0 T). The samples were packed in 4 mm ZrO2 rotors and allowed to spin before each experiment in order to stabilize the sample packing and improve the field homogenization. The crosspolarization with magic angle spinning (CPMAS) was applied at a spinning frequency of the rotor of 6 kHz. 11150 scans were accumulated with a recycle delay of 5 s. Chemical shifts are expressed in parts per million (ppm) and referred to the resonance signal of tetramethylsilane.

X-Ray Powder Diffraction (XRPD) Powder X-ray diffraction patterns of both polymorphic forms of RAN-B were recorded on a BRUKER D8 VARIO/VANTEC powder X-ray diffractometer (Bruker AXS, Karlsruhe, Germany). The instrument was operated at 40 kV and 40 mA (Cu Ka1 radiation; exit slit 1.2 mm, 2.5 mm soller slit). The diffractometer was equipped with a Johannson type curved Ge(1 1 1) focusing primary DOI 10.1002/jps

149

monochromator and a VANTEC position sensitive detector (38 window configured). The instrument was calibrated employing a quartz standard. Sealed boron-glass capillaries of 0.3 mm inner diameter by 30 mm long were filled with RAN-B powder of each polymorph. Data were collected in transmission geometry over the 2u range of 2–608, with a step size of 0.0088 and as counting time 8 s/ step for a total of 16.7 h of recording time per diffractogram of each RAN-B form. Throughout the experiments, the ambient temperature was maintained at 298(1) K. The intensities of the diffraction lines were measured as peak heights above background and expressed as a percentage of the strongest line using the WinPLOTR program of the FullProf.2k suite of programs (version 3.20).22

X-Ray Powder Diffraction (XRPD) Structures Solution and Refinement The determination of the cell dimensions is the first step in structure determination by XRPD. The ultimate confirmation of the right cell determination, obtained from the indexing of the powder pattern, is the successful crystal structure solution and refinement. From the initial analyses of the powder diffractograms of RAN-B crystalline phases, and using the dichotomy method of the program DICVOL04,23,24 a monoclinic cell was found for RAN-B form I: ˚ , b ¼ 95.718. a ¼ 7.355, b ¼ 9.064, c ¼ 25.225 A From the calculated density (Dx ¼ 1.402 Mg/m3, derived from the experimental determination of the cell constants, after indexing of the experimental powder diffractogram) of the powder specimen of this form, we could conclude that four molecules should be present in the unit cell (Z ¼ 4). The space group was obtained from the analysis of systematic absences in the powder pattern: P21/c (No. 14). For RAN-B form II an orthorhombic cell was found: a ¼ 31.328, ˚ . From the calculated b ¼ 13.086, c ¼ 8.111 A density (Dx ¼ 1.409 Mg/m3) of the powder specimen of this polymorphic form, it could expect that eight molecules should be present in the unit cell (Z ¼ 8). The space group deduced for RAN-B form II was Pbca (No. 61). The correctness of the space groups was confirmed by the successful structure solution and refinement of the crystal structures presented in this work. The structure of both RAN-B polymorphs was solved employing the program DASH,18,19 which JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

150

DE ARMAS ET AL.

Scheme 2. utilizes a Monte Carlo/Simulated Annealing (SA) technique.16 The RAN-HCl form I, retrieved from the Cambridge Structural Database (CSD, version 5.28, reference code: TADZAZ01),25 was used as initial molecular model. During the global optimization in the SA and for each polymorph structure determination, sixteen degrees of freedom were defined: free location and orientation of the whole RAN-B molecule (one rigid body) plus an internal coordinate description of the molecule by torsional freedom on ten torsional angles (denoted as t1, . . ., t10, see Scheme 2), excluding H-atoms. In DASH the SA control parameters were set to default values: 20 runs with 1  107 SA moves per run were implemented for each structure determination. The structure of the best solution (i.e., that with favorable x2profile =x2Pawley ratio, which is an indication that the structure obtained in the SA procedure) is in the global minimum. Details on how these values are calculated can be found in the DASH users’ manual.19 DASH had x2 ratio of five for RAN-B form I and six for RAN-B form II, respectively (favorable values for this ratio are between 2 and 10). On the other hand, the lack of unrealistic close contacts and the presence of a realistic network of hydrogen bonds suggesting that the solution is correct. The refinement was performed by the Rietveld method20 as implemented in the DASH program. The background level was modeled by a polynomial function, while systematic errors were corrected with the aid of sample displacement angular shifts. In the final cycles the peak shapes were described by a pseudo-Voigt function. A global isotropic temperature factor parameter was refined for all non-H-atoms (U ¼ 0.09(1) for both crystal structures of RAN-B forms I and II). Scattering parameters were taken from the internal library of the program DASH. The unit cell parameters obtained after Rietveld refinement were: Form I: a ¼ 7.317(2), b ¼ 9.021(2), JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

˚ , b ¼ 95.690(1)8, V ¼ 1648.34(3) A ˚3 c ¼ 25.098(6) A and form II: a ¼ 31.252(4), b ¼ 13.052(2), ˚ , V ¼ 3299.72(3) A ˚ 3. The final c ¼ 8.0892(11) A agreement factors at convergence were: for the RAN-B form I structure: Rp ¼ 5.09, Rwp ¼ 7.37%, for the RAN-B form II structure: Rp ¼ 4.63, Rwp ¼ 6.22%. Figure 5 shows the final Rietveld refinement plots and the very good agreement

Figure 1. Optical micrographs showing the morphological differences between RAN-B polymorphs particles: RAN-B form I (A), RAN-B form II (B). DOI 10.1002/jps

SOLID STATE CHARACTERIZATION OF RANITIDINE BASE POLYMORPHS

151

onset at 73.50  0.078C and melting enthalpy of 105.10 J/g corresponds to RAN-B form I. RAN-B form II shows a typical melting onset at 77.69  0.078C and a melting enthalpy of 112.37 J/g (Tab. 1). For form II, the purity was determined by DSC as 98.6% while for RAN-B form II it was 97.8%. Both polymorphs start to decompose at 2008C, as shown by the substantial loss of weight in the TGA (TGA plots are added as supplementary material). Contrary to what is observed in the thermodynamic behavior of the RAN-HCl polymorphs12 and according to the Burger and Ramberger polymorphic rules (e.g., entropy of fusion rule), the RAN-B polymorphs are monotropic pairs (Tab. 1). However, no solid–solid transitions were observed from RT until decomposition of the sample (Fig. 2). FTIR-ATR

Figure 2. DSC traces of RAN-B forms I (A) and II (B), respectively. RAN-B polymorphs form a monotropic system (see Tab. 1).

between the observed (obtained from XRPD experiment) and calculated (obtained from the structure solution and refinement) diffraction patterns of each crystal structure of the RAN-B polymorphs.

RESULTS AND DISCUSSION Thermal Behavior of Ranitidine Polymorphs Figure 1 shows the morphology of the powder particles of RAN-B polymorphs. The particles in RAN-B form I (Fig. 1A) were block-like microcrystals while in RAN-B form II (Fig. 1B) the particles appear thinner and more elongated. Figure 2 shows the DSC traces of RAN-B forms I and II, respectively. A melting peak with melt

Spectra from pure forms of each polymorph are very similar. RAN-B form I can be differentiated from RAN-B form II by the peaks at 600 and 990 cm1. RAN-B form II shows a doublet at 1360 and 1370 cm1 while for form I just a singlet appears at 1370 cm1. The FTIR-ATR spectra are reported as supplementary material. 13

C-CPMAS-NMR

The 13C-CPMAS-NMR spectra of RAN-B polymorphs are shown in Figure 3 and chemical shifts are presented in Table 2. The peak shifts show the differences between the two polymorphic forms. In the RAN-HCl form I spectrum reported by Mirmehrabi et al.,12 a singlet is observed at about 100 ppm (corresponding to carbon atom where the nitro group is attached) indicative of order, while in the RAN-HCl form II spectrum a doublet indicative of tautomerism is observed. Contrary to what is observed in the NMR spectra of RAN-HCl polymorphs, in the spectra of RAN-B polymorphs (Fig. 3A and B) no differences are observed at about 100 ppm. This is an indication that in RANB polymorphs no mixture of tautomers can be

Table 1. Temperature, Enthalpy, and Entropy of Melting of RAN-B Polymorphs Heating rate (8C/min)

Form

Tmelt (8C)

DHmelt (J/g)

DSmelt (J/g 8C)

Comparison

0.5 0.5

I II

73.50 (5) 77.69 (7)

105.10 (6) 112.37 (7)

1.42 (6) 1.44 (7)

Tmelt.I < Tmel.II DSmelt.I < DSmelt.II

The values in parenthesis correspond to the standard deviations from four measurements. DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

152

DE ARMAS ET AL.

Figure 3. 13C-CPMAS-NMR spectra of RAN-B forms I (A) and II (B), respectively. Chemical shifts are presented in Table 2.

expected. It is worthwhile to mention that the presence of one or other tautomer can only be confirmed by structure determination using X-ray crystallographic methods.

Crystal Structures of RAN-B Form I and II and Comparison to that of RAN-HCl Forms Figure 4 shows the X-ray powder diffraction patterns of RAN-B polymorphs. RAN-B form I crystallizes in a monoclinic crystal system with four molecules in the unit cell, while RAN-B form II crystallizes in the orthorhombic crystal system with eight molecules in the unit cell. Table 3 presents the most relevant crystallographic data for the crystalline forms of RAN-B and RAN-HCl. ˚ 3) is The unit cell volume of form II (3299.72(3) A practically the double of that of the form I ˚ 3). In both polymorphs the mole(1648.34(3) A cules, as a whole, adopt an eclipsed conformation (i.e., neither fully folded nor fully extended), similar to the conformation found in RAN-HCl, forms I and II. Figure 6 shows the molecular conformations of the RAN-B polymorphs, as well as the conformation of the previously studied RAN-HCl forms for comparison. The enamine JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

Figure 4. X-ray powder diffraction patterns of RANB forms I (A) and II (B), used in the structure determination by XRPD.

portion of the ranitidine molecule can exist in two possible configurations with respect to the double bond C11–C13 (E and Z arrangements), in which the methylamino and the nitro substituents are cis and trans to each other, respectively. The Z configuration was adopted in both structures of RAN-B polymorphs, as in the crystal structure of RAN-HCl form I.13 This arrangement in the crystal structure is different to that of the ranitidine hydrogen oxalate26 that displays the E configuration. In RAN-HCl form II, Ishida et al.14 report that both configurations (E and Z) are present and they were found to be disordered. However, other authors interpret the crystal structure of RAN-HCl form II as a mixture (1:1) of the enamine and the nitronic acid tautomers.12 In solution, the existence of an equimolar mixture of E/Z enamine isomers has been reported.3 This interconversion in solution is facilitated by the p-delocalization over the enamine system. In RAN-B polymorphs the nitro group is involved DOI 10.1002/jps

SOLID STATE CHARACTERIZATION OF RANITIDINE BASE POLYMORPHS

153

Figure 5. Observed (crosses) and calculated (solid line) profiles for the Rietveld refinement of RAN-B forms I (A) and II (B). The difference plots are on the same intensity scale. The high 2u angle region, between 408 and 608, is zoomed in a separated plot.

DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

154

DE ARMAS ET AL.

Figure 5. (Continued)

in a strong intramolecular hydrogen bond involving the atoms N2 (as donor) and O2 (as acceptor): ˚ , angle: 1368; RAN-B form I: O2  N2 ¼ 2.596 A ˚ , angle: 1368. RAN-B form II: O2  N2 ¼ 2.603 A The same kind of intramolecular interaction is present in RAN-HCl form I and it is responsible for the E/Z configurations being favored in the solid state. Figure 7 shows the packing diagram of both RAN-B forms in the solid state. In the RAN-B form II the O2 atom is also involved in an intermolecular hydrogen bond with the N3 of the neighboring molecule. The molecules are held together in

Table 2. 13C-CPMAS-NMR Peak Assignment (ppm) of RAN-B Polymorphs Carbon

Form I

Form II

C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13

148.91 111.86 111.61 157.15 54.94 26.69 29.77 32.10 41.70 44.63 157.15 25.27 98.11

147.54 106.70 113.22 155.99 56.21 27.24 29.67 33.66 37.76 45.14 157.05 25.42 98.77

Atomic numbering is shown in Scheme 2. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

the crystal by this intermolecular interaction ˚ , angle: 1458) (RAN-B form II: O2  N3 ¼ 2.859 A forming one-dimensional infinite chains of molecules running perpendicular to the ac plane of the unit cell along the base vector (0 1 0) in a tail to tail fashion. In RAN-B form I, the oxygen (O3) of the nitro group is involved in an intermolecular hydrogen bond that held the molecules forming one-dimensional infinite chains running perpendicular to the bc plane of the unit cell and along the base vector (1 0 0) in a tail to tail fashion (RAN˚ , angle: 1418). In both B form II: O3  N3 ¼ 2.725 A polymorphs of RAN-B the tail to tail packing motif can be denoted, using graph set analysis, as infinite C(6) chains, but a different (donor) oxygen of the nitro group is involved in it (O3 in form I and O2 in form II). The packing of the molecules in RAN-HCl form I is in a head to tail fashion through a hydrogen bond that involve the two different Cl anions and the nitrogen atoms N1 of the dimethylamino at the head and the N3 of the methylamino at the tail of the molecule. A tail to tail motif is present in RAN-HCl form II, as well as the interaction between the Cl anions and the N1 atom of the dimethylamino at the head of the molecule. The O3 atom in RAN-B form II is involved in the only weak interaction of the type C–H  O present in this structure, while in RANB form I both oxygens of the nitro group are involved in weak interactions of this nature. This kind of C–H  O interactions has also been observed in the crystal structures of ranitidine hydrogen oxalate and RAN-HCl forms I and II. DOI 10.1002/jps

SOLID STATE CHARACTERIZATION OF RANITIDINE BASE POLYMORPHS

155

Table 3. Most Relevant Crystallographic Data for the Crystalline Forms of RAN-B and RAN-HCl RAN-B form I Species method Powder diffraction Formula C13H22N4O3S MW 314.41 Crystal system Monoclinic Space group P21/c Unit cell dimensions ˚) a (A 7.317(2) ˚) b (A 9.021(2) ˚) c (A 25.098(6) b (8) 95.690(1) ˚ 3) V (A 1648.34 Z 4 Dcal (Mg/m3) 1.267

RAN-B form II

RAN-HCl form I13

RAN-HCl form II14

Powder diffraction C13H22N4O3S 314.41 Orthorhombic Pbca

Single-crystal diffraction C13H23N4O3SþCl 350.86 Monoclinic P21/n

Single-crystal diffraction C13H23N4O3SþCl 350.86 Monoclinic P21/n

31.252(4) 13.052(2) 8.0892(11) 90.00 3299.72 8 1.266

12.1918(6) 6.5318(3) 22.0382(3) 93.985(3) 1750.76(13) 4 1.331

7.208(2) 12.979(7) 18.807(1) 95.06(2) 1752.73 4 1.329

The existence of these weak interactions27,28 is facilitated by the presence of the adjacent activating groups NO2, as well as the NHþ and Cl ions in the RAN-HCl forms.

Figure 8 shows the superposition by the furyl ring of the molecules of RAN-B polymorphs. In RAN-B form I this ring forms an angle of 79.0(1)8 with the plane through the atoms of the 2-

Figure 6. Conformation of RAN-B polymorphs: form I (A), form II (B), and those of RAN-HCl form I (C) and the two possible tautomers of form II (enamine (D), and nitronic acid (E)), respectively. The strong intramolecular hydrogen bond characteristic of this family of compounds and responsible for the E/Z configurations to be favored in the solid state is denoted as dashed lines. DOI 10.1002/jps

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

156

DE ARMAS ET AL.

Figure 7. Packing of RAN-B molecules in the crystal: projection of form I molecules onto bc plane (A); projection of form II molecules onto ac plane (B). Packing of RAN-HCl molecules is also shown for comparison: projection of RAN-HCl form I molecules onto bc plane (C); projection of RAN-HCl form II molecules onto bc plane (D). Hydrogen bonds involving the nitro group at tail of the molecule have been highlighted for each case. The molecules in both forms of RAN-B follow the same tail to tail packing pattern, as in RANHCl of form II. In RAN-HCl form I the molecules are packed in a head to tail fashion.

ethylamino-2-methylamino-1-nitroethylene moiety, which is closer to the value of 75.2(1)8 observed in ranitidine hydrogen oxalate than in RAN-HCl form I (69.5(1)8) and than in the disordered RAN-HCl from II (63.4(1)8). In the RAN-B form II, the furyl ring forms an angle of 22.2(1)8, closer to the plane of the tail of the molecule and resembling a step-like conformation linked by the bonds C8–S1–C9 (bond angle rather orthogonal of 102.0(2)8). The least-square plane through the nine atoms of the enamine moiety (C10 to O3) indicates that they are in a plane with a root mean square deviation (r.m.s.d.) of the ˚ , and atoms from the best plane being 0.038(2) A ˚ with a maximum of 0.072(2) A for N3 and a ˚ for C12. For the RAN-B minimum of 0.003(2) A form II, the nine atoms of the enamine moiety are also in a plane with r.m.s.d. of the atoms from the ˚ . The N3 deviates most best plane being 0.037(2) A ˚ ), while N2 deviates from the best plane (0.093(2) A ˚ the least (0.002 A). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

This crystal structure determination of RAN-B polymorphs reveals the same strong intramolecular hydrogen bond present in RAN-HCl polymorphs. This is the intramolecular hydrogen bond at the nitroethenediamine that plays a role in the formation of one or the other RAN-HCl polymorph. It has been reported by Mirmehrabi et al.12 that RAN-HCl form I or form II production is related to the polarity of the crystallization media (by the interference of the polarity of the solvent and the absence of water, <0.5 wt%). According to these authors, the intramolecular hydrogen bond present in RAN-HCl is expected to be weakened or disrupted in aqueous and/or more polar solvents leading to the formation of the RAN-HCl form II. According to this, obtaining either RAN-HCl form I or II does not depend on the starting product (RAN-B form I or II polymorphs) but on the control of the polarity of the crystallization medium and on the absence or the limited amount of water present. DOI 10.1002/jps

SOLID STATE CHARACTERIZATION OF RANITIDINE BASE POLYMORPHS

157

via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44-1223-336033.

ACKNOWLEDGMENTS

Figure 8. Projections of the superimposition, by the furyl ring, of the solid state conformations of RAN-B polymorphs. The least-square plane through the nine atoms of the enamine moiety indicates that they are in a plane, in both crystalline forms.

CONCLUSIONS The two polymorphs of ranitidine base (RAN-B) have been characterized by different techniques inherent to the solid-state analysis. Their crystal structures have been determined by conventional X-ray powder diffraction and compared to the previously reported crystal structures of the two hydrochloride forms (RAN-HCl). In RAN-B polymorphs, the nitro group is involved in a strong intramolecular hydrogen bond responsible for the existence of a Z configuration in the enamine portion of the molecules. This intramolecular hydrogen bond is also present in the crystal structures of RAN-HCl polymorphs and plays a key role in the formation of one or the other RANHCl form. The 13C-CPMAS-NMR spectra of RAN-B polymorphs show no indication of tautomerism as it is the case of RAN-HCl. In RAN-HCl, the enamine portion of the ranitidine molecule exist in two possible configurations with respect to the double bond C11–C13 (E and Z arrangements). In RAN-B polymorphs, a tail to tail packing motif can be denoted via intermolecular hydrogen bonding, showing a different packing than in RAN-HCl form I. From the thermodynamic point of view, the two RAN-B polymorphs form a monotropic system, however no solid–solid transition was observed during the DSC experiments. CCDC 664730 and 664731 contains the supplementary crystallographic data for this article. These data can be obtained free of charge DOI 10.1002/jps

We wish to thank Corden PharmaChem N.V., Belgium (formerly Cambrex Profarmaco Landen N.V.) for kindly supplying us with the ranitidine base samples. Bruker AXS GmbH (Karlsruhe, Germany) is acknowledged for their help in XRPD data collection at its application labs. We thank Dr. K. Houthoofd (Centre for Surface Chemistry and Catalysis, KU Leuven, Belgium) for recording the 13C-CPMAS-NMR spectra. We are grateful for the useful revisions and comments of the referees and those of Prof. H. Brittain. The authors acknowledge financial support from FWO-Vlaanderen (G.0614.07).

REFERENCES 1. Martindale W. 1996. The Extra Pharmacopoeia, 31st edition; Reynolds JEF, editor. London: The Pharmaceutical Press. 2. Dumanovic D, Juranic I, Dzeletovic D, Vasic VM, Jovanovic J. 1997. Protolytic constants of nizatidine, ranitidine and N,N(-dimethyl-2-nitro-1,1ethenediamine, spectrophotometric and theoretical investigation. J Pharm Biomed Anal 15:1667–1678. 3. Cholerton TJ, Hunt JH, Klinkert G, Smith MM. 1984. Spectroscopic studies on ranitidine: Its structure and the influence of temperature and pH. J Chem Soc Perkin Trans 2:1761–1766. 4. Madan T. 1994. Preparation and characterization of ranitidine-HCl crystals. Drug Dev Ind Pharm 20: 1571–1588. 5. Price BJ, Clitherow JW, Bradshaw J. 1978. Aminoalkyl furan derivatives. US patent 4,128,658. 6. Crookes DJ. 1985. Aminoalkyl furan derivatives. US patent 4,521,431. 7. Khanna JM, Kumar N, Khera B, Khanna M. 1997. Process for the manufacture of form 1 ranitidine hydrochloride. US patent 5,621,120. 8. Murthy K, Radatus BK, Sidhu KPS. 1995. reissued 2002. Process for production of an improved form of form 1 ranitidine hydrochloride having improved filtration and drying characteristics. Canadian patent 2120874. 9. Ngooi TK, McGolrick JD, Antczak C, Tindall JLA. 1994. Preparation of form 1 ranitidine hydrochloride. US patent 5,338,871. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

158

DE ARMAS ET AL.

10. Ngooi TK, Antczak C, Tindall JLA, McGolrick JD. 1998. Preparation of form 1 ranitidine hydrochloride. Canadian patent 2099530. 11. Schickaneder H., Nikolopoulos A, 1997. Process for preparing form 1 ranitidine hydrochloride. US patent 5,663,381. 12. Mirmehrabi M, Rohani S, Murthy KSK, Radatus B. 2004. Characterization of tautomeric forms of ranitidine hydrochloride: Thermal analysis, solid-state NMR, X-ray. J Cryst Growth 260:517–526. 13. Hempel A, Camerman N, Mastropalo D, Camerman A. 2000. Ranitidine hydrochloride, a polymorphic crystal form. Acta Crystallogr C56:1048–1049. 14. Ishida T, In Y, Inoue M. 1990. Structure of ranitidine hydrochloride. Acta Crystallogr C46:1893–1896. 15. Huq A., Stephens PW. 2003. Subtleties in crystal structure solution from powder diffraction data using simulated annealing: Ranitidine hydrochloride. J Pharm Sci 92:244–249. 16. David WIF, Shankland K, Shankland N. 1998. Routine determination of molecular crystal structures from powder diffraction data. Chem Commun (Cambridge) 8:931–932. 17. Pagola S, Stephens PW, Bohle DS, Kosar AD, Madsen SK. 2000. The structure of malaria pigment, b-haematin. Nature (London) 404:307–310. 18. Florence AJ, Shankland N, Shankland K, David WIF, Pidcock E, Xu X, Johnston A, Kemmedy AR, Cox PJ, Evans JSO, Steele G, Cosgrove SD, Frampton CS. 2005. Solving molecular crystal structures from laboratory X-ray powder diffraction data with DASH: The state of the art and challenges. J Appl Crystallogr 38:249–259.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 1, JANUARY 2009

19. David WIF, Shankland K, Cole J, Maginn S, Motherwell WDS, Taylo R. 2001. DASH user manual. Cambridge, UK: Cambridge Crystallographic Data Centre. 20. Young RA. 1993. The Rietveld method. Oxford (UK): Oxford University Press. 21. Universal Analysis, TA Instruments software. TA Instruments, Inc. New Castle, Delaware (USA). 22. Rodrı´guez-Carvajal J. 2005. FullProf, version 3.20, LLB. France: CEA/Saclay. 23. Boultif A., Loue¨r D. 1991. Indexing of powder diffraction patterns for low-symmetry lattices by the successive dichotomy method. J Appl Crystallogr 24:987–993. 24. Boultif A. Loue¨r D. 2004. Powder pattern indexing with the dichotomy method. J Appl Crystallogr 37:724–731. 25. Allen FH. 2002. The Cambridge Structural Database: A quarter of a million crystal structures and rising. Acta Crystallogr B58:380–388. 26. Kojic´-Prodic´ B, Ruzˇic´-Torosˇ Zˇ, Toso R. 1984. Structure of a new H2-receptor antagonist, 2-(2{[5-(dimethylammoniomethyl)-2-furyl]methylthio} ethylamino)-2-methylamino-1-nitroethylene hydrogen oxalate (ranitidine hydrogen oxalate). Acta Crystallogr C46:1837–1840. 27. Steiner T. 1998. Donor and acceptor strengths in CH-O hydrogen bonds quantified from crystallographic data of small solvent molecules. N J Chem 22:1099–1103. 28. Desiraju GR. 2005. C–HO and other weak hydrogen bonds. From crystal engineering to virtual screening. Acc Chem Res 2995–3001.

DOI 10.1002/jps