Distinct Disordered Forms of Promethazine Hydrochloride: A Case of

Nov 15, 2012 - Gheorghe Borodi, Mihaela M. Pop,* Oana Onija, and Xenia Filip. National Institute for Research and Development of Isotopic and Molecula...
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Distinct Disordered Forms of Promethazine Hydrochloride: A Case of Intergrowth of Polymorphic Domains? Gheorghe Borodi, Mihaela M. Pop,* Oana Onija, and Xenia Filip National Institute for Research and Development of Isotopic and Molecular Technologies, P.O. Box 700, Cluj-Napoca R-400293, Romania S Supporting Information *

ABSTRACT: Determination of the first crystalline structures of the antihistaminic drug promethazine hydrochloride (PTZ) by single crystal X-ray diffraction revealed a possible case of intergrowth of polymorphic domains that requires further experimentation for confirmation. The two crystal structures of PTZ are characterized by high similarity of both molecular conformation and crystal packing and slight variations of the unit cell parameters induced by two distinct disorder levels in the PTZ aliphatic chain. These unit cell variations lead to small displacements of the molecules in the crystal structures and, consequently, to slight energy, density, and melting point differences between the forms. Although highly similar, the two crystalline forms of PTZ are clearly distinct disordered forms: they were repeatedly and reproducibly obtained, no intermediate disorder levels were found so far, and solvent-mediated transformation between them was evidenced by slurry experiments. In addition, the two distinct disorder levels were confirmed by solid-state nuclear magnetic resonance. Our study emphasizes the benefit of single-crystal structure data for the judgment of the phase purity and of solid forms exhibiting subtle structural differences. The newly discovered effect of disorder on the unit cell dimensions contributes to understanding the similarity limits between distinct disordered forms and, consequently, may provide important clues for crystal structure prediction.

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Similar to other phenothiazines derivatives, PTZ is oxygen sensitive, and this oxidative-degradation is observed by the appearance of coloration of the drug in the solid-state and in solution.4 Promethazine is available worldwide, in some countries as over the counter medicine, and in some only by prescription. It is available in the form of an injection, oral liquid, and tablet. Promethazine hydrochloride undergoes hepatic first pass metabolism, leading to a low oral bioavailability of approximately 24%.5 Recently, there is increasing interest in other novel formulations of the drug,6−8 including alternative administration routes such as transdermal and nasal formulations.9,10 Despite the numerous formulation activities involving PTZ,11−14 a careful literature and Cambrige Structural Database15 search showed that no crystal structure was reported so far. Moreover, there is no information available on the polymorphic forms of the API. A PDF-416 search on solid forms of PTZ revealed only two entries (1766 and 1704),17,18 and in the literature there are also few powder X-ray diffraction (PXRD) patterns reported.7,10 None of the PXRD patterns found is indexed, and therefore, it can be concluded

tudy of crystalline forms including polymorphs, hydrates/ solvates, salts, and cocrystals of active pharmaceutical ingredients (APIs) is crucial for selecting the most adequate solid form for development into a drug product.1 In particular, the investigation of drug polymorphism is of great interest to the pharmaceutical community, being a mandatory step in any formulation study according to the international official standards.2 Polymorphs are different crystalline forms that may have substantially different physicochemical properties affecting key properties of the drug, such as solubility, bioavailability, morphology, stability, shelf life, etc. It is, therefore, essential to understand the solid-state behavior of the API and to select the optimal solid form for development. Promethazine hydrochloride (PTZ), (RS)-dimethyl [1methyl-2-(phenothiazone-10-yl) ethyl] amine hydrochloride (Figure 1 and Supporting Information Scheme S1), is a phenothiazine derivate available as a medicine since its introduction in 1946. Owing to its antihistaminic, anticholinergic, sedative, and antiemetic effects, promethazine hydrochloride is widely used in a variety of clinical situations, including treatment of allergies, adjunct to anesthesia, motion sickness, insomnia, and as a preoperative sedative. The molecular structure of PTZ contains a charged aliphatic chain with a chiral carbon. The enantiomers of promethazine have been resolved and have similar antihistaminic and other pharmacologic properties.3 © 2012 American Chemical Society

Received: July 9, 2012 Revised: November 2, 2012 Published: November 15, 2012 5846

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Figure 2. Promethazine molecular conformations in Form 1 (red) and Form 2 (green). The discrete positional disorder and H atoms are omitted for clarity. The N−H···Cl hydrogen bond is included.

Figure 1. Promethazine molecule and numbering scheme in Form 1 and Form 2. The discrete positional disorder and H bonding are included. The H atoms are omitted for clarity.

that there is no evidence that a PTZ drug substance is obtained as a single solid form. In order to elucidate the solid-state behavior of PTZ, we carried out a crystallization study followed by the determination by single crystal X-ray diffraction (SCXRD) of the first crystal structures of PTZ. The crystalline materials of two novel crystal structures were obtained by controlled recrystallization in tetrahydrofuran and acetonitrile. Both forms crystallize in the monoclinic P21/c space group with one promethazine cation and one Cl anion in the asymmetric unit and with unit cells containing two molecules of each promethazine enantiomer.31 Crystallization of the PTZ forms in a centrosymmetric space group and the presence of enantiomeric molecules of opposite chirality in the unit cell show that both forms are racemic compounds. Currently, the polymorphism in molecular crystals is divided into two categories: conformational and packing polymorphism. In the former, conformationally flexible molecules adopt more than one conformation in the solid state.19−21 Packing polymorphism arises from different possible packing arrangements of conformationally rigid molecules.22 Interestingly, the crystal structures 1 and 2 of PTZ are highly similar with respect to both molecular conformation (Figure 2) and crystal packing (Figure 3). Promethazine cations interact with Cl anions via N2− H2···Cl1 hydrogen bonds and the PTZ molecular conformation is further stabilized by a C15−H15C ··· N1 intramolecular hydrogen bond (Figure 1 and Supporting Information Table S1). In both forms, promethazine molecules show positional disorder at the chiral C14 and the N2 atom of the aliphatic chain (Figure 1). After refinement, the relative occupancies of the C14 and N2 split atomic sites are similar in each crystal form. The positional disorder is slightly more pronounced in Form 1 than in Form 2 (relative occupancies of the split positions of 0.7 and 0.3 compared to 0.9 and 0.1 in Form 2; Supporting Information CIF files). Crystal packing of both forms consists of alternating double layers of PTZ molecules and Cl atoms, which run parallel to the

Figure 3. Crystal packing overlap for Forms 1 (red) and 2 (green). View along the b-axis.

bc-plane. The PTZ intermolecular layers are stabilized by π−π and C−H···π interactions between the benzene ring systems (Supporting Information Tables S2 and S3). The crystal structures do not contain voids to accommodate for water or solvent molecules. The molecular conformations of the PTZ molecules in Forms 1 and 2 are basically the same (Figure 2). Also, the hydrogen bonds and the overall crystal packing are highly similar in the two crystal structures (Figure 3 and Supporting Information Table S1). The only difference between the structures of Forms 1 and 2 is the extent of the positional disorder, leading to a slight variation of two unit cell parameters and of the unit cell volume: (Δa ∼ 0.1 Å and Δβ ∼ 1°; the differences Δb, Δc < 0.03 Å; unit cell volume difference of ∼2 Å3). As a result, there are small displacements of the PTZ molecules from one crystal structure to another. These molecular displacements generate small differences in the π−π and C−H···π interactions (differences between the benzene ring distances of 0.04 Å and between the ring slippage distances of 0.1 Å; Supporting Information Table S2) and the Cl···Cl intermolecular distances and angles (Figure 4). To visualize the differences between the crystal structures 1 and 2, we represented the extended crystal packing of the two forms 5847

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with the best possible overlap of the PTZ molecules in the unit cell (see Abstract, view along the b-axis). In this way, the small packing differences become more evident in the neighboring unit cells of the two crystals. We carried out the crystal structure determination of Form 1 at 100 K (Supporting Information CIF files) to estimate the extent of the similarity between Forms 1 and 2 in relation to the effect of temperature on the crystal structure of Form 1. We used the program XPac23 to compare the dissimilarity factors24 of the Forms 1 and 2 pair at room temperature with the one of Form 1 at room temperature and 100 K. Although the XPac analysis clearly reflects high 3D similarity between the studied crystal structure pairs, the subtle structural differences between Forms 1 and 2 are clearly larger than the temperature effect obtained for Form 1 (the dissimilarity factor for Forms 1 and 2 is almost double than in the case of Form 1 structures at room temperature and 100 K; Supporting Information Table S4). Also noticeable is the fact that the crystal structure of Form 1 at low temperature showed the same degree of positional disorder as the crystal structure determined at room temperature, indicating the presence of a stable disorder level with the temperature change (Supporting Information CIF files). Considering the recent debates in evaluating if similar crystal structures are in fact distinct solid phases and therefore real polymorphs,25,26 we carried out a detailed study of the PTZ crystal structures from the reproducibility by recrystallization and the solid-state properties point of view. The phase purity of the bulk samples of Forms 1 and 2 and the agreement with the crystal structures obtained were established by PXRD (Figure 5). Despite the high similarity between the crystal structures of Forms 1 and 2, there are noticeable differences in their PXRD patterns (Supporting Information Figure S1). The PXRD and unit cell differences between the forms are consistently present in multiple recrystallized materials obtained as powders and single-crystals (Supporting Information Figure S2 and CIF files), suggesting two stable, well-defined levels of disorder in the PTZ forms. Further, the powder diffraction pattern of the

Figure 4. Cl atom layers in the structures of Forms 1 (a) and Form 2 (b). A slice parallel to the bc-plane is marked in red.

Figure 5. PXRD patterns of Form 1 and Form 2 versus the calculated patterns. 5848

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Figure 6. 13C CP-MAS NMR spectra of promethazine HCl: (a) Form 1; (b) Form 2. The lines marked with * are side bands.

Figure 7. DSC thermograms (heating rate 10 °C/min) of Forms 1 and 2.

PTZ starting material was compared to the calculated patterns of Forms 1 and 2, indicating that the starting material is consistent with a mixture of the two forms (Supporting Information Figure S3). Similarly, the PXRD pattern reported in the PDF4 database18 is also not polymorphically pure, which might explain the absence of the indexing information, i.e. the unit cell parameters. A series of spectroscopic techniques were applied to further characterize the two crystal structures of PTZ. Raman and near infrared techniques proved not to be sensitive to the slight structural differences between the PTZ crystal structures (Supporting Information Figures S5 and S6). On the other hand, differences are detected in the 13C CP-MAS spectra of Forms 1 and 2 (Figure 6).

The assignment of the resonances to the chemically distinct carbon sites of PTZ was done by DFT chemical shielding computations in full crystals (Supporting Information Tables S5 and S6). In both forms, C15, C13, C14, C7, and C1 atoms are represented by single resonances, whereas the other carbons have overlapped lines. For the aliphatic carbons C13, C14, and C15, the presence of a less intense second resonance (labeled with C13A, C14A, and C15A) is most probably related to the local disorder, specifically present in both forms. In order to confirm that, the NMR chemical shifts were computed27 on two crystal structures of each form, corresponding to each disorder position of the C14/C14A and N2/N2A atoms. Prior to the chemical shift calculations, a geometry optimization of the crystal structures with fixed unit cell parameters was carried out and the occupancy factor was considered equal to 1 for 5849

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each disorder position. The experimental 13C chemical shifts for C13, C14, and C15 atoms are correlated with the computed values for all four molecular structures defined according to the positional disorder of Forms 1 and 2 (Supporting Information Tables S5 and S6). The major difference between the ss-NMR spectra of Forms 1 and 2 is the ratio between the C13/C13A, C14/C14A, and C15/C15A line intensities (a ratio of about 3 for Form 1 and 6.5 for Form 2). These NMR intensity ratios translated to occupancy factors would result in 75/25 for Form 1 and 87/13 for Form 2, which is in agreement with the results obtained from single-crystal diffraction (70/30 for Form 1 and 90/10 for Form 2). Consequently, the ss-NMR results clearly evidence the two distinct molecular conformations related to the positional disorder present in Forms 1 and 2. Moreover, the ratios between the two molecular conformations in the two forms is consistent with the occupancy factors obtained from single-crystal diffraction. In addition, DSC analysis shows differences in the melting points and melting enthalpies of Forms 1 and 2 (Figure 7), which corroborates with the presence of two distinct disordered forms. To understand the thermodynamical stability of the two forms, we carried out slurry experiments at room temperature in THF, acetonitrile, and ethyl acetate followed by PXRD analyses. These experiments showed that Form 1 transformed into Form 2 within one week (Supporting Information Figures S2 and S4), and consequently, Form 2 is more stable at room temperature. The relative stability between the two forms is further corroborated by lattice energy calculations27 (Supporting Information Tables S7 and S8). The (absolute) energies per molecule in the two crystal structures are −417.1 kcal mol−1 for Form 1 and −418 kcal mol−1 for Form 2, indicating that the two crystal forms of PTZ have energies within a narrow range (∼0.9 kcal mol−1). Furthermore, the calculated density of Form 2 is slightly higher than that of Form 1 (1.2579 g/cm3 for Form 2 versus 1.2566 g/cm3 for Form 1), also corroborating with the fact that Form 2 is the thermodynamically more stable form. In summary, PTZ exhibits two distinct disordered forms characterized by high similarity of both molecular conformation and crystal packing and slight variations of the unit cell parameters. These unit cell variations generated by two distinct disorder levels lead to small displacements of the molecules in the crystal structures and, consequently, to slight energy, density, and melting point differences between the forms. On the basis of the characteristics of the PTZ disordered forms, we could consider them as intermediate structures between two reference points representing two hypothetical pure, nondisordered polymorphs (polymorph 1 with the C14A/N2A atomic sites and the more stable polymorph 2 with the C14/N2 molecular conformation). In that case, Forms 1 and 2 of PTZ would represent an intergrowth of polymorphic domains, as in aspirin.28 However, unlike the case of aspirin, neither variable disorder levels nor the hypothetical polymorphs have been identified so far (in multiple recrystallization experiments). Moreover, transformation between the two distinct disordered forms was evidenced by slurry experiments, and although expected, further transformation into the hypothetical nondisordered polymorph 2 could not be achieved. Therefore, future experimentation to evidence other disorder levels and the hypothetical polymorphs will probably answer the question if Forms 1 and 2 are indeed characterized by an intergrowth of polymorphic domains or if they represent a borderline example of polymorphism.

Our study emphasizes the benefit of single-crystal structure data for the judgment of the phase purity and of solid forms exhibiting only weak energetical and structural differences. The increasing importance of the phenomenon of polymorphism in the pharmaceutical field led to improvements in the theoretical and computational methods for prediction of crystal structures that are within the energy range of possible polymorphism.29,30 Selecting feasible structures from the computed crystal energy landscape remains a difficult task because many low-energy structures can be alternative polymorphs. In this context, the newly discovered effect of disorder on the unit cell dimensions contributes to understanding the similarity limits between distinct disordered forms and, consequently, may provide important clues for crystal structure prediction.

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ASSOCIATED CONTENT

S Supporting Information *

Experimental details, lattice energy, NMR chemical shifts calculations, hydrogen bonding and ring interactions, XPac analysis, X-ray crystallographic information files (CIF), 13C CPMAS, Raman and near infrared spectra for forms 1 and 2; and powder X-ray diffraction patterns from the recrystallization and slurry experiments. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Address: 65-103 Donath Street, 400293 Cluj-Napoca, Romania. Phone: (+4)0264-584037. Fax: (+4)0264-420042. Web: www.itim-cj.ro. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by ANCS, Project POSCCE ID536. REFERENCES

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(16) International Centre for Diffraction Data (ICDD), Powder Diffraction File, PDF-4/Organics 2012, ORGD120135-5045. (17) DeLeenheer, H. J.Assoc. Off. Anal. Chem. 1971, 54, 625. (18) Bernstein, J.; Zevin, L. ICDD Grant-in-Aid; Ben-Gurion University of the Negev: Beer-Sheva, Israel, 1990. (19) Yu, L.; Reutzel-Edens, S. M.; Mitchell, C. A. Org. Process Res. Dev. 2000, 4, 396−402. (20) Roy, S.; Aitipamula, S.; Nangia, A. Cryst. Growth Des. 2005, 5, 2268−2276. (21) Reutzel-Edens, S. M.; Bush, J. K.; Magee, P. A.; Stephenson, G. A.; Byrn, S. R. Cryst. Growth Des. 2003, 3, 897−907. (22) Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Laus, G.; Wieser, J.; Griesser, U. J. New J. Chem. 2008, 32, 1677−1685. (23) Gelbrich, T.; Hursthouse, M. B. CrystEngComm 2005, 7, 324− 336. (24) Fabbiani, F. P. A.; Dittrich, B.; Florence, A. J.; Gelbrich, T.; Hursthouse, M. B.; Kuhs, W. F.; Shankland, N.; Sowa, H. CrystEngComm 2009, 11, 1396−1406. (25) Vujovic, D.; Nassimbeni, L. R. Cryst. Growth Des. 2006, 6, 1595−1597. (26) Threlfall, T. L.; Gelbrich, T. Cryst. Growth Des. 2007, 7, 2297− 2297. (27) Accelrys Software Inc. Materials Studio, Release 5.5; Accelrys Software Inc.: San Diego, CA, USA, 2010; http://accelrys.com/ products/materials-studio/. (28) Bond, A. D.; Boese, R.; Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 618−622. (29) Price, S. S. Acc. Chem. Res. 2009, 42 (1), 117−126. (30) Montis, R.; Hursthouse, M. B.; Chan, H. C. S.; Kendrickb, J.; Leusen, F. J. J. CrystEngComm 2012, 14, 1672−1680. (31) Crystal data. Form 1-THF-CL: C17H21N2S·Cl, Mr = 320.87, monoclinic, P21/c, a = 14.9293(6) Å, b = 8.3361(2) Å, c = 15.5173(6) Å, β = 118.565(5)°, V = 1696.09(10) Å3, Z = 4, Dc = 1.2566 g/cm3, μ = 3.089 mm−1, θmin = 3.37°, θmax = 72.5°, R1(wR2) = 0.0761 (0.2726) for 3318 observed independent reflection (Rint = 0.0413). Form 2ACN-CL: C17H21N2S.Cl, Mr = 320.87, monoclinic, P21/c, a = 14.8123(8) Å, b = 8.3170(2) Å, c = 15.5334(8) Å, β = 117.696(7)°, V = 1694.37(13) Å3, Z = 4, Dc = 1.2579 g/cm3, μ = 3.092 mm−1, θmin = 3.37°, θmax = 70.85°, R1(wR2) = 0.0613 (0.1895) for 3234 observed independent reflections (Rint = 0.0319). Form 1-cryo: C17H21N2S.Cl, Mr = 320.87, monoclinic, P21/c, a = 14.8724(8) Å, b = 8.2589(3) Å, c = 15.3578(8) Å, β = 118.665(7)°, V = 1655.19(14) Å3, Z = 4, Dc = 1.285 g/cm3, μ = 3.165 mm−1, θmin = 3.39°, θmax = 72.45°, R1(wR2) = 0.0624 (0.2174) for 3227 observed independent reflections (Rint = 0.0392).

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