Two orthorhombic polymorphs of hydromorphone

Conditions to obtain two polymorphic forms by crystallization from solution were determined for the analgestic drug hydromorphone. In both polymorphs, the hydromorphone molecules adopt very similar conformations with some small differences observed only in the N-methyl amine part of the molecule. The crystal structures of both polymorphs feature chains of molecules connected by hydrogen bonds


Chemical context
Drug polymorphism has been the subject of hundreds of publications and numerous excellent reviews (Byrn et al., 1999;Grant, 1999;Singhal & Curatolo, 2004;Vippagunta et al., 2001). It is well established that polymorphs with different stability may have different solubility and dissolution rates, which can affect the bioavailability. The semi-synthetic opiate drug hydromorphone is a potent derivative of morphine and despite poor bioavailability (Parab et al., 1988) is commonly used to treat moderate to severe pain in the treatment of cancer (Sarhill et al., 2001). To improve bioavailability of this compound a polymorph screen was performed that resulted in two solvent-free forms, designated as form I and form II.

Structural commentary
The molecular structure of hydromorphone in both polymorphs is nearly identical (Fig. 1) with some deviations found only for the N-methyl amine part of the piperidine fragment (Fig. 2). For example the C10-C11-N12-C13 torsion angle is 178.5 (2) for form I and 169.5 (2) for form II. The adopted Molecular structure and atom-numbering scheme for hydromorphone in the crystals of form I (left) and form II (right). Displacement ellipsoids are shown at the 50% probability level.

Figure 2
Superposition of the hydromorphone molecules from two polymorphic forms (red form I, blue form II) generated by fitting of the aromatic ring.

Figure 3
Crystal packing diagram of form I, viewed along the a axis. Hydrogen bonds are shown as blue lines.

Figure 4
Crystal packing diagram of form II, viewed along the a axis. Hydrogen bonds are shown as blue lines. group donates a hydrogen atom which is accepted by the free electron pair of the N atom (Fig. 5, Table 1). In the crystals of form II, intermolecular hydrogen bonds also generate a chain of molecules that propagates along the a axis; however, adjacent molecules along this chain are related by a 2 1 symmetry axis. The molecules are connected by O-HÁ Á ÁO hydrogen bonds with the hydroxyl group as donor and the etheric O atom as acceptor (Table 2). These chains form a zigzag pattern, as illustrated in Fig. 6. The packing arrangement of molecules in form II is more dense than in polymorph I, as indicated by the Kitajgorodskij (1973) packing coefficients of 0.71 and 0.69, respectively.

Synthesis and crystallization
10.8 mg of hydromorphone was dissolved in 1.8 mL THF/ acetone (1/1, v/v) and left to evaporate slowly under ambient conditions. After several days, colorless prism-like crystals of form I (m.p. 549.8 K) appeared that were used for diffraction studies. Crystals of form II were obtained in the following way: 19.7 mg of hydromorphone was suspended in 0.3 mL of 50/50 mixture of ethanol and toluene. The suspension was heated to 333 K and stirred for about one h until it became clear. Subsequently, the vial was cooled rapidly to 278 K and colorless block-like crystals (m.p. 550.2 K) precipitated that were used for diffraction studies.

Refinement
The H atoms from the methyl group in form II were included from geometry and their isotropic displacement parameters refined. The remaining H atoms were found in a Fourier difference map and freely refined. The absolute configuration of hydromorphone was known from the synthetic route.  Table 1 Hydrogen-bond geometry (Å , ) for (I). Symmetry code: (i) x þ 1; y; z.

Figure 5
The chain of molecules running along the a axis formed by O-HÁ Á ÁN hydrogen bonds in form I.

Figure 6
The zigzag chain of molecules running along the a axis formed by O-HÁ Á ÁO hydrogen bonds in form II.
absence of significant anomalous scattering effects, Friedel pairs were merged. Crystal data, data collection and structure refinement details are summarized in Table 3.

e]isoquinolin-7-one]
Crystal data where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.005 Δρ max = 0.19 e Å −3 Δρ min = −0.17 e Å −3 Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.