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Structural and Thermodynamic Features of Three Stable Crystal Forms of Temazepam: A Sedative Drug Published as part of a virtual special issue on Structural Chemistry in India: Emerging Themes. Ram K. R. Jetti,* Balakrishna R. Bhogala, Asha R. Gorantla, Nageswara R. Karusula, and Debashish Datta Chemical Research Division, API-R&D, R&D Center, Matrix Laboratories Limited (a subsidiary of Mylan Inc., USA), Plot No. 34A, Anrich Industrial Estate, Bollaram Village, Jinnaram Mandal, Medak District, Pin No. 502325, A.P., India

bS Supporting Information ABSTRACT: Two anhydrous crystal forms (Form X and Form VI) of temazepam were determined by single crystal X-ray diffraction and compared with the crystal structure of the literature crystal form, Form 0. All three polymorphic forms have Z0 > 1. Forms 0 and VI reveal a self-inclusion host
guest type crystal packing whereas Form X shows a layered 3D-packing arrangement. The three polymorphic forms are monotropically related, and their relative thermodynamic stability is in the following order: Form 0 > Form X > Form VI. This study further reveals the origin of the thermodynamically more stable form (Form 0) and evaluates its intriguing structural and thermodynamic features with two other stable crystal forms: Forms X and VI, respectively.

he current challenges in solid-state chemistry of drugs1 are to identify and characterize all possible solid forms/polymorphs, understand their physicochemical properties, establish thermodynamic stability, and suggest the optimal solid form for final drug development. Inefficient understanding of the solidstate properties of a drug leads to unexpected problems to produce reliably a form that has been used for pivotal clinical studies.2 Conversely, a thorough understanding of the solid-state behavior of various crystal forms has implications in candidate selection for drug development, processing, formulation, and performance of the drug products, regulatory aspects, and intellectual property. Finding the “right” solid form and developing a scalable crystallization process for its production on a large scale is critical for the success of a drug product. In this article, we discuss the solid-state development efforts in our laboratory to produce a thermodynamically stable form of an active pharmaceutical ingredient (API), temazepam. Temazepam [7-chloro-3-hydroxy-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one], a 3-hydroxybenzodiazepine drug, was one of the most popular and widely prescribed hypnotics on the market and was sold as a racemic mixture. According to the patent literature,3 three different melting points of temazepam (115
116 °C, 120
122 °C, and 158
160 °C) were observed, but there is no clear evidence of their solid state characterization. The Merck Index4 reports the melting point of temazepam as 119
121 °C, and monographs of USP (United States Pharmacopoeia)5 report its solubility, appearance, and identification by IR, but the polymorphic related information is not reported anywhere. Our interest in this drug stems from both

T

r 2011 American Chemical Society

its confusion in the literature with respect to its differences in the melting points and to identifying new solid forms of therapeutic agents and establishing their structural and thermodynamic relationships. In this context, recently, we published a patent application6a on comprehensive studies aimed at the polymorphism of temazepam, where we developed more than 10 polymorphs (see Supporting Information) and their characterization using various analytical techniques, such as powder X-ray diffractometry, DSC, TGA, and IR-spectroscopy, etc. In continuation of our work, we further investigated single crystal X-ray diffraction studies to understand the structural diversity and polymorphic purity of these forms. In this communication we report the crystal structures of two stable anhydrous polymorphs of temazepam: Form X and Form VI.6b The structural features of these crystal forms are discussed along with the literature crystal structure7 (hereafter referred to as Form 0) and also the established thermodynamic relative stability of these forms. The study of these crystal structures is interesting in terms of the awkward molecular shape of temazepam. This could be the possible reason for its existence in more than ten solid phases, including solvates (Scheme S1 of the Supporting Information).8 The molecular structure of temazepam (Scheme 1) has a sevenmembered heterocyclic ring consisting of two nitrogen atoms and two endocyclic olefin bonds in conjugation, one as part of a fused chlorobenzene ring adjacent to a phenyl substitution. It Received: November 25, 2010 Revised: March 24, 2011 Published: April 19, 2011 2039

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Scheme 1. Molecular Structure and Hydrogen Bonded Synthons of Temazepam

Figure 2. Crystal structure of Form X. (a) Synthon I between molecules of 1 and the association of molecule 2 via weak C
H 3 3 3 N, C
H 3 3 3 O, C
H 3 3 3 Cl, and C
H 3 3 3 π interactions. (b) Zigzag 2Dlayer arrangement of molecules of 2 in the xy-plane. Note the C
H 3 3 3 O chains running in opposite directions along the y-axis. (c) Zigzag 2D-parquet layer in the xy-plane, consisting of molecules of 2. (d) Alternate arrangement of 2D-layers shown in “b” and “c” in a 3D-structure along the z-axis (interlayer interactions were not shown for clarity). The independent molecules are colored differently (orange and green).

Figure 1. Crystal structure of Form 0. (a) Synthon I between molecules of 1, Synthon II between molecules of 2, and the association of molecules of 3 with the former two via a Cl 3 3 3 Cl interaction and a O
H 3 3 3 O(H) hydrogen bond. (b) Crystal packing view along the yaxis, showing a 3D brick-wall-like host arrangement (green and orange) which is occupied by guest molecules (violet). Note the symmetry independent molecules are colored differently.

also has a methyl substitution on one of the nitrogen atoms and a secondary hydroxyl group on a chiral carbon atom flanked between weak hydrogen bond acceptors, i.e., the carbonyl oxygen and sp2 nitrogen atom of the seven-membered ring (Scheme 1). Because of these geometrical and electronic effects in temazepam, the seven-membered ring adopts a boat conformation with the hydroxy group occupying the equatorial position, and the molecule overall acquired a nonplanar shape in all the crystal structures. This is the case in all benzodiazepine derivatives, resulting in an awkward molecular shape.7a Due to the imbalance in hydrogen bond donor
acceptor groups, majorly three kinds of hydrogen bond synthons are possible between the temazepam

molecules, as shown in Scheme 1. A search of the CSD9 (Cambridge Structural Database) for the OdC
CH(OH)
N moiety resulted in 15 structures (see Supporting Information); out of them, six structures have synthon I, two structures showed synthon II, and synthon III was not observed in a manual search (considered D up to 3.3 Å). These hydrogen bonds (O
H 3 3 3 O, O
H 3 3 3 N) are weak because of the poor hydrogen bond donor nature of the aliphatic hydroxy group. As there is not much barrier between such moderately weak hydrogen bonds and weak interactions such as C
H 3 3 3 O, C
H 3 3 3 N, C
H 3 3 3 Cl, C
H 3 3 3 π, and Cl 3 3 3 Cl, the latter also together competes/ coexists with the former. Therefore, temazepam exhibits polymorphism and crystallized with Z0 > 1 in the observed crystal structures (Form 0, Form X, and Form VI). Form 0 crystallizes in monoclinic space group P21/c with Z0 = 3 and has the same configuration in the asymmetric unit. All three Z0 molecules involve three different kinds of hydrogen bonds. The first one forms centrosymmetric O
H 3 3 3 N dimer synthon I, the second one forms a centrosymmetric O
H 3 3 3 O dimer synthon II, and the third one connects the former two via a Cl 3 3 3 Cl (Type-II)10 interaction and a O
H 3 3 3 O(H) hydrogen bond, as shown in Figure 1a. The overall supramolecular structure can be viewed as a self-host
guest system where the second and third Z0 molecules form a 3D brick-wall kind of host arrangement, leaving channels down to the y-axis that are occupied with molecules of the first kind (Figure 1b). The structure was further strengthen by weak intermolecular interactions:11 C
H 3 3 3 O, C
H 3 3 3 N, C
H 3 3 3 Cl, and C
H 3 3 3 π (Table S1 of the Supporting Information). Form X crystallizes in orthorhombic space group Pbca with Z0 = 2 (Figure 2a), and each temazepam molecule has a different configuration (R and S). A close inspection of this intricate 3Dstructure showed two different layered patterns. Each symmetry independent molecule forms a separate 1D-chain with their 2040

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Crystal Growth & Design screw-related molecules along the y-axis, using a C
H 3 3 3 O(H) interaction (D, 3.31 and 3.32 Å) between similar atoms (Figure S1 of the Supporting Information). The molecules from one kind of tape connect with the molecules from the inversion related tapes on both sides via centrosymmetric (O
H 3 3 3 N) dimer synthon I (Figure 2a) into a parquet floor network in the xyplane (Figure 2c). The other kind of tape does not show any connection between its symmetry related tapes but arranged into a zigzag layer in the xy-plane (Figure 2b). The O
H group in these chains is not involved in hydrogen bonding. These layers are arranged alternately along the z-axis and connected by C
H 3 3 3 O, C
H 3 3 3 N, C
H 3 3 3 Cl, and C
H 3 3 3 π interactions (Table S1 of the Supporting Information) into a 3Dstructure (Figure 2d).

Figure 3. Crystal structure of Form VI. (a) Synthon III formed between symmetry independent molecules of the same configuration (shown with R): 10 and 2. (b) Columnar arrangement of green molecules via C
H 3 3 3 O and C
H 3 3 3 π interactions. (c) View along the x-axis, showing a 3D-brick-wall-like host arrangement (orange) which is occupied by the green molecules. Note the symmetry independent molecules are colored differently.

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The single crystal X-ray diffraction of Form VI shows it crystallizes in triclinic space group P1, with Z0 = 2, and the molecules have R and S configurations (Figure 3a). The Z0 molecules of the same configuration are connected by noncentrosymmetric synthon III (Figure 3a). One of the two Z0 molecules forms a centrosymmmetric dimer consisting of C
H 3 3 3 O(H) and C
H 3 3 3 π interactions, and such dimers are connected into a 1D-columnar structure via (H2)C
H 3 3 3 O(H) and (H2)C
H 3 3 3 π interactions between inversion related molecules along the x-axis (Figure 3b). The other symmetry independent molecule forms discrete dimers with the inversion related molecule via C
H 3 3 3 O hydrogen bonds. The overall supramolecular structure can be viewed as a self-inclusion host
guest system where molecules of 2 form a 3D brick-wall kind of host arrangement, leaving channels down to the x-axis, and such channels are filled with molecules of the first kind (Figure 3c) and in turn connected by synthon III to the host. The three above crystal structures confirm that the materials are strictly racemic, and the overall molecular arrangement in the crystal lattice is schematically shown in Figure 4. The crystal packings of Forms 0 and VI have similar kinds of self-inclusion host
guest structures (Figure 4) whereas Form X forms a zigzag layered structure. The overlay of the experimental powder diffraction patterns (PXRDs) with the simulated ones (Figure S2 of the Supporting Information) shows good correlation of the crystal structures with the bulk material obtained in our patent processes.6a This further confirms the polymorphic purity of novel crystal forms, Forms X and VI. In polymorphic systems, the Z0 , crystal packing, density, and hydrogen bonding information obtained from single crystal X-ray diffraction data provides valuable insights in understanding the stability of the corresponding crystal form.12 All three polymorphic forms—Form 0, Form X, and Form VI—have Z0 values 3, 2, and 2, respectively, with the calculated densities of 1.40, 1.431, and 1.325 g cm
3 and melting points 160.7, 159.3, and 138.5 °C, respectively (Table 1). Based on these values, the

Figure 4. Schematic representation of crystallization outcomes for temazepam from solution in comparison to their lattice arrangements (four full unit cells were shown in 2D). The symbols A1, A2, and A3 signify crystallographically independent molecules for the S-enantiomer, and A1*, A2*, and A3* correspond to the R-enantiomer. Note that the different symmetry independent Z0 molecules (colored differently) play different roles in crystal packing. 2041

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Table 1. Crystal Data and Physicochemical Properties of Temazepam Polymorphs parameter

form 0

form X

form VI

solvent of crystallization

ethanol

ethanol

isopropyl ether

space group

P21/c

Pbca

P1

a (Å)

19.528(5)

13.2796(14)

9.7397(11)

b (Å)

11.328(3)

13.4955(15)

12.2026(13)

c (Å)

20.231(4)

31.687(3)

13.5162(15)

R (deg)

90

90

101.408(2)

β (deg)

107.0(1)

90

104.344(2)

γ (deg) Z0

90 3

90 2

98.815(2) 2

volume (Å3)

4279.81

5678.8(11)

1490.6(3)

Dcalc (g/cm3)

1.40

1.431

1.325

packing index (%)

68.9

69.8

64.6

melting point (°C, DSC)

160.7

159.3

138.5

heat of fusion (ΔHf, J/g)

∼93 ( 3

∼88 ( 2

∼69 ( 3

IR (ν, cm
1)

O
H

3396 and 3445

3441

3434

CdO

1687 and 1668 1.204, 1.217, and 1.235

1681 1.22

1695 and 1679 1.22 and 1.23

O
H 3 3 3 N O
H 3 3 3 O O
H 3 3 3 O
H

2.87

3.01

3.11

CdO distances (Å) H-bond (D, Å)

2.88

2.84

3.02

3.08

Form 0 is the thermodynamically more stable form with high melting point, but it is less dense than Form X and violating the density rule.13 This is not unprecedented, but it is uncommon.2a,14 This is achieved mainly due to the overall hydrogen bonding features of Form 0 over the other two forms, as discussed above (i.e., synthons I and II in Form 0 vs synthon I in Form X and synthon III in Form VI), and its auxiliary weak interactions as listed in Table 1 and Table S1 of the Supporting Information. The reason for the low density of Form 0 compared to Form X could be the three symmetry independent Z0 molecules of the same configuration (S) and their inversion related molecules (S*, i.e. corresponding to the R configuration) segregated into alternate domains12f (Figure 4), which leads to an inefficient crystal packing, whereas in the high density form, Form X, the two symmetry independent Z0 molecules of both R and S come together to form an intimate mix (Figure 4), which leads to an efficient close packing.15 Notably, the R and S molecules of Form VI, even though arranged intimately, have separate layers consisting of less common synthon III (CSD, Supporting Information) formed between same handed molecules. This could be a possible reason to have low density and melting point for Form VI among the three forms. The IR-data also supports the hydrogen bond strengths of Form 0 over the other two (see Figure S3, Table 1, and Supporting Information for details on IR-data) and validates the “infrared rule”13,16 in the estimation of the relative stability of the forms, i.e. Form 0 > Form X > Form VI. The thermodynamic stability of these crystal forms is further corroborated by lattice energy calculations17 (Supporting Information, Tables S2 and S3). The (absolute) energies per molecule in the three crystal structures are 71.08, 74.24, and 71.92 kcal mol
1, indicating that the various crystal forms of temazepam examined in this study have energies within a narrow range (∼1
3 kcal mol
1). This shows that Form 0 is the thermodynamically more stable form.

Table 2. Torsion Angles, τ1 and τ2, Corresponding to the C
C Single Bond Connecting the Substituent Phenyl Ring with the Benzodiazepine Ring in Different Polymorphs of Temazepam, and Interplanar Angles between the Two Phenyl Rings of a Molecule molecule τ1 (deg) τ2 (deg) polymorph (chirality) N4
C5
C12
C17 C11
C5
C12
C13 form 0

form X form VI

1 (S) 2 (S) 3 (S) 1 (S) 2 (R) 1 (S) 2 (R)

20.61 38.78 34.79 38.37
32.24 29.12
34.51

23.53 39.72 36.94 34.48
34.26 32.13
39.73

interplanar angle (deg) 58.64 66.81 65.99 68.85 62.28 68.55 72.03

TGA of these forms showed no significant weight loss ( Form X > Form VI, respectively. This polymorphic system shows adherence to Ostwald’s rule whereas Forms 0 and X violate the density rule. This study for the first time revealed the origin of Form 0, which is the thermodynamically more stable form, and its usage as seeds in controlling the nucleation of kinetic polymorphs (Forms X and VI) during crystallization. Form 0 is commonly present in commercial products. Form X, the second highest temperature form, is characterized by a high kinetic stability in comparison to Form VI in shelf life. Form X is also reliably produced by crystallization from solvents. Therefore, Form X is of practical pharmaceutical relevance, which may create market opportunities for alternate solid drug formulations to the marketed form.

’ ASSOCIATED CONTENT

bS

Supporting Information. Details of CSD search, hydrogen bond table, additional figures for PXRD, IR, DSC, TGA, and CIF-files. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*Telephone: (þ91) 40-3049-2054. E-mail: ram.jetti@matrixlabsindia. com.

’ ACKNOWLEDGMENT We thank Prof. G. R. Desiraju for his support in providing single crystal data and CSD search, Prashant M. Bhatt (University of Hyderabad) for structure determination, Dr. T. Tejender (IISc Bangalore) for lattice energy calculations, and Dr. Hari Babu and Sanjeev Sethi (Matrix Laboratories) for their encouragement. ’ REFERENCES (1) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid-State Chemistry of Drugs, 2nd ed.; SSCI, Inc.: West Lafayette, IN, 1999. 2043

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