Crystal Engineering of Isostructural Quaternary Multicomponent

Jun 27, 2012 - A crystal engineering strategy that involved data mining of existing crystal ..... Bernard Omondi , Andreas Lemmerer , Manuel A. Fernan...
0 downloads 0 Views 3MB Size
Download PDF
Article pubs.acs.org/crystal

Crystal Engineering of Isostructural Quaternary Multicomponent Crystal Forms of Olanzapine Published as part of the Crystal Growth & Design virtual special issue In Honor of Prof. G. R. Desiraju Heather D. Clarke,† Magali B. Hickey,*,‡ Brian Moulton,† Jason A. Perman,† Matthew L. Peterson,§ Łukasz Wojtas,† Ö rn Almarsson,‡ and Michael J. Zaworotko*,† †

Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, CHE205, Tampa, Florida 33620, United States Alkermes, Inc., 852 Winter Street, Waltham, Massachusetts 02451, United States § Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02412, United States ‡

S Supporting Information *

ABSTRACT: Pharmaceutical cocrystals have gained increased attention at least in part because of their potential for enhancing physicochemical and biopharmaceutical properties of existing drugs. As a result, design, screening, and large-scale preparation of pharmaceutical cocrystals have been emphasized in recent research. The design of pharmaceutical cocrystals has focused primarily on determining the empirical guidelines regarding the hierarchy of supramolecular synthons. However, this approach is typically less predictive when considering drugs that are complex in nature, such as those having a multiplicity of functional groups and/or numerous degrees of conformational flexibility. In this manuscript, we report a crystal engineering design strategy to facilitate the synthesis of multicomponent crystal forms of the atypical antipsychotic drug olanzapine, marketed as a drug product under the trade name Zyprexa. Comprehensive analysis and data mining of existing crystal structures of olanzapine were followed by grouping into categories according to the crystal packing exhibited and systematically using this information to crystal engineer new compositions. This approach afforded isostructural, quaternary multicomponent crystal forms of olanzapine composed of a stoichiometric ratio of four molecular components: olanzapine; a cocrystal former; water; solvent (isopropylacetate). To our knowledge this study is unprecedented in that the observed quaternary structures can be classified as solvates, hydrates, or cocrystals.

■

patent coverage.9,10 Most importantly, pharmaceutical cocrystals can enhance physicochemical properties of APIs such as solubility,11 stability,12 and mechanical properties13 while preserving the intrinsic activity and efficacy of the drug molecule. In addition, pharmaceutical cocrystals have been incorporated with other techniques used to modulate physicochemical properties as noted in the examples of nanocrystalline cocrystals14 and cocrystals of salts.15 It should also be noted that there has been a concurrent rise in patent activity concerning pharmaceutical cocrystals,16 and regulatory bodies are developing guidelines that address approval of pharmaceutical cocrystals in drug products.7b,17 That pharmaceutical cocrystals are amenable to design using crystal engineering strategies can be attributed to the exterior functional groups of APIs that readily engage in supramolecular synthons, especially hydrogen bonded supramolecular synthons, with a wide variety of pharmaceutically acceptable cocrystal formers. However, design remains a challenge for

INTRODUCTION Crystal engineering1,2 has matured into a well-recognized aspect of solid-state chemistry and is focused on the design of novel compositions of crystalline solids with controllable structure and tunable physicochemical properties. The relevance of crystal engineering to pharmaceutical science is high as the selection of a suitable crystal form of an active pharmaceutical ingredient (API) is particularly relevant to oral drug delivery3 and may profoundly influence the development and performance of the API in a drug product. Crystal forms of APIs have spanned polymorphs,4 solvates,5 hydrates,6 and more recently, pharmaceutical cocrystals.7,8 Pharmaceutical cocrystals can be defined as multiple component crystals in which at least one component is molecular and a solid at room temperature (the cocrystal former) and forms a supramolecular synthon with a neutral (i.e., cocrystals of neutral molecules) or charged API (i.e., cocrystals of salts). Pharmaceutical cocrystals have emerged as a new paradigm in pharmaceutical solid form selection since their modularity means that they diversify the range of crystal forms exhibited by APIs, allowing opportunities for improved performance characteristics and extension of product life and © 2012 American Chemical Society

Received: May 24, 2012 Revised: June 25, 2012 Published: June 27, 2012 4194

dx.doi.org/10.1021/cg3007052 | Cryst. Growth Des. 2012, 12, 4194−4201

Crystal Growth & Design

Article

those APIs that possess multiple functional groups.18 In addition, the design or engineering of compositions with more than two unique components is challenging because of the functional diversity introduced by each component and poor ability to predict interactions that direct crystal packing. It should therefore be unsurprising that examples of fourcomponent cocrystals are rare.19 Olanzapine (2-methyl-4-(4-methyl-l-piperazinyl)-10H-thieno-[2,3b][1,5]benzo-diazepine), a BCS20 class II (low solubility, high permeability) API, represents an excellent crystal engineering target and is a widely prescribed atypical antipsychotic drug marketed under the trademark name Zyprexa by Eli Lilly and Company. The drug product is effective in treating psychiatric disorders such as schizophrenia and manic episodes associated with bipolar disorder.21 Olanzapine has been shown to reduce positive (hallucinations and delusions), negative (social and emotional withdrawal), and cognitive symptoms in acute and relapsing schizophrenics.22 Crystal forms of olanzapine are well studied and include six anhydrous polymorphs,23−27 three polymorphic dihydrates,28 two polymorphic sesquihydrates, several solvated forms,29 mixed solvates and hydrates,30 salts and an amorphous form.31 Reutzel-Edens et al. addressed the polymorphism of olanzapine dihydrate and the structural relationship between the anhydrates and hydrates.32 Nangia et al. showed that the solubility of olanzapinium monomaleate and dimaleate salts in water at 37 °C was 225−550 times greater than that of the free base form of olanzapine.33 Isostructural cocrystals, that is, crystal forms that exhibit the same or similar crystal structure,34 have been reported in the literature.35 These crystal forms, primarily binary cocrystals, are generally designed by interchanging structurally equivalent functional groups such as chloride/methyl,36 Br/I,35d or CH/ N.35g However, the design and synthesis of isostructural olanzapine cocrystals that contain four distinct molecular entities including a solvate and a water molecule represent a significant crystal engineering challenge. Indeed, it has been shown recently that even subtle changes in the chemical composition of the API, for example, swapping a sodium for a potassium cation, can result in significant and unpredictable changes in both packing arrangement and physicochemical properties of the salt.37 Furthermore, hydrates are known to be promiscuous in terms of their crystal packing because water molecules can typically adopt multiple supramolecular synthons.38,39 However, the design of isostructural cocrystals based on the analysis of existing crystal forms offers a tractable crystal engineering opportunity that could facilitate the systematic fine-tuning of API physicochemical properties.40 This article illustrates such a situation by presenting a design strategy to construct multicomponent crystal forms of olanzapine a priori from the systematic analysis of existing crystal structures, thereby affording multicomponent compositions of olanzapine with four unique molecular components in a stoichiometric ratio.

■

Scheme 1. Molecular Structures of Olanzapine and the Cocrystal Formers Used Herein

solution) and nicotinamide (37.6 μL of a 20 mg/mL stock solution) were added to a glass vial and the solvent was evaporated under nitrogen flow. Isopropyl acetate was added to the mixture and the sealed vial was heated at 70 °C for 2 h before being cooled at 5 °C for 24 h. The solution was then concentrated to 50 μL total volume, recapped, and left at 5 °C for an additional 24 h. Large yellow plates of OLANAM·IPA·4H2O were harvested and allowed to dry at ambient conditions. Olanzapine·Salicylamide Isopropylacetate Tetrahydrate OLASAM·IPA·4H2O. Olanzapine (7.5 mg, 0.024 mmol) and salicylamide (5.1 mg, 0.037 mmol) were dissolved in 1 mL of isopropyl acetate and heated at 90 °C until the solids had dissolved. The vial was loosely covered with aluminum foil and the solution was allowed to slowly evaporate at 5 °C. After three days, large yellow plates of OLASAM·IPA·4H2O were collected by filtration and dried at room temperature. Olanzapine·p-Hydroxybenzamide Isopropylacetate Tetrahydrate, OLAPHBNZ·IPA·4H2O. Olanzapine (7.5 mg, 0.024 mmol) and p-hydroxybenzamide (7.0 mg, 0.051 mmol) were dissolved in 1 mL of isopropyl acetate and heated at 90 °C until the solids had dissolved. The loosely covered with aluminum foil vial was allowed to slowly evaporate at 5 °C. After 11 days, yellow plates of the OLAPHBNZ·IPA·4H2O were collected by gravimetric filtration and dried at room temperature. CSD Analysis. A CSD survey was conducted to investigate the number of crystal forms that contain four distinct chemical entities. The parameters used to define the search was as follows: number of chemical units = 4, 3D-coordinates present, no ions, only organics, R ≤ 7.5%. Powder X-ray Diffraction (PXRD). Bulk samples were analyzed by PXRD using a Bruker AXS D8 powder diffractometer. Experimental conditions: Cu Kα radiation (λ = 1.54056 Ǻ ); 40 kV; 30 mA; scanning interval 3−40° 2θ; time per step 0.5 s. The experimental PXRD patterns and calculated PXRD patterns from single crystal structures were compared in order to confirm whether or not the composition of the bulk materials was consistent with that of the single crystal used for single crystal X-ray crystallography. Single Crystal X-ray Diffraction Analysis. Single crystal X-ray data were collected using a Bruker-AXS SMART-APEXII CCD

EXPERIMENTAL SECTION

Olanzapine was obtained from Alkermes Inc. and used without further purification. Reagents were purchased from commercial vendors and used without further purification. Solvents were purchased from commercial vendors and distilled before use. Resulting cocrystals were analyzed by powder X-ray diffraction (PXRD) and single crystal X-ray analysis where applicable. Olanzapine·Nicotinamide Isopropylacetate Tetrahydrate, OLANAM·IPA·4H2O. Olanzapine (40 μL of a 25 mg/mL stock 4195

dx.doi.org/10.1021/cg3007052 | Cryst. Growth Des. 2012, 12, 4194−4201

Crystal Growth & Design

Article

diffractometer using Cu Kα radiation (λ = 1.54178 Å) for OLASAM·IPA·H2O and Mo Kα radiation (λ = 0.71073 Å) for OLANAM·IPA·4H2O. Indexing was performed using APEX241 (difference vectors method). Data integration and reduction were performed using SaintPlus 6.01.42 Absorption corrections were performed by a multiscan method implemented in SADABS.43 Space groups were determined using XPREP implemented in APEX2. The structures were solved using SHELXS-97 (direct methods) and refined using the SHELXL-97 (full-matrix least-squares on F2) contained in the APEX2 and WinGX v1.70.0144−47 [4,5,6,7] program packages. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms of water molecules and −NH groups of OLANAM·IPA·4H2O were located via Fourier difference map inspection and included in the refinement process using distance restraints (DFIX) with isotropic thermal parameters: Uiso(H) = 1.5Ueq(−NH, −OH). All remaining hydrogen atoms were placed in geometrically calculated positions and included in the refinement process using a riding model with isotropic thermal parameters: Uiso(H) = 1.2Ueq(−CH, −CH2), Uiso(H) = 1.5Ueq(−OH, −CH3). Hydrogen atoms of water molecules and −NH groups for OLASAM·IPA·4H2O were located via Fourier difference map inspection and included in the refinement process using distance restraints (DFIX, SADI) with isotropic thermal parameters: Uiso(H) = 1.5Ueq(−NH,−OH). All remaining hydrogen atoms were placed in geometrically calculated positions and included in the refinement process using a riding model with isotropic thermal parameters: Uiso(H) = 1.2Ueq(−CH, −CH2), Uiso(H) = 1.5Ueq(−OH, −CH3). Crystallographic data and hydrogen bonding tables are in Supporting Information.

SAM molecules form amide homodimers along the b axis (Figure 2a,b). Olanzapine molecules are aligned in a

Figure 2. Crystal packing viewed along the b axis of (a) OLANAM·IPA·4H2O and (b) OLASAM·IPA·4H2O reveals that the tetrameric catemers of water molecules are terminated by the cocrystal former (NAM or SAM) which in turn forms dimers to propagate the structure. In each case, two olanzapine molecules are omitted for the sake of clarity.

herringbone pattern and are stacked in an eclipsed fashion (Figure 3a,b). Single crystals suitable for X-ray structure

■

RESULTS Crystal Structures of OLANAM·IPA·4H2O and OLASAM·IPA·4H2O. OLANAM·IPA·4H2O and OLASAM·IPA·4H2O crystallize in the monoclinic space group P21/c, and each cocrystal was found to contain two independent OLA molecules, four independent water molecules, an independent isopropyl acetate molecule, and one independent molecule of the cocrystal former (NAM or SAM). The crystal structures of OLANAM·IPA·4H2O and OLASAM·IPA·4H2O exhibit twodimensional hydrogen-bonded networks in which four water molecules hydrogen bond to self-assemble into a tetrameric catemer. This tetrameric catemer in turn interacts with four OLA molecules by donating four hydrogen bonds and accepting two hydrogen bonds (Figure 1a,b). The isopropyl acetate molecules and the NAM/SAM cocrystal formers terminate the tetrameric catemer of water molecules via OH···O and NH···O hydrogen bond interactions. NAM/

Figure 3. Crystal packing of (a) OLANAM·IPA·4H2O and (b) OLASAM·IPA·4H2O reveals the herringbone pattern of pairs of olanzapine molecules that are hydrogen bonded to tetramers of water molecules. NAM, SAM, and isopropyl acetate molecules are omitted for the sake of clarity.

determination were not obtained for OLAPHBNZ·IPOAc·4H2O. However, the PXRD pattern of OLAPHBNZ·IPOAc·4H2O is a close match to that of OLANAM·IPA·4H2O and OLASAM·IPA·4H2O (see Supplementary Information).

■

DISCUSSION A typical first step in the crystal engineering of cocrystals is analysis of the crystal packing and hydrogen bonding patterns exhibited in existing crystal structures of the target molecule(s) and/or related molecules. Analysis of the crystal structures of olanzapine that have been deposited in the CSD reveals several polymorphs of the anhydrate; three polymorphs of olanzapine dihydrate; two polymorphs of olanzapine sesquihydrate; methanol and dichloromethane solvates; four mixed solvates and hydrates; and benzoate, nicotinate, and maleate salts (Table 1). Inspection of the crystal packing in these previously published crystal forms of olanzapine reveals that each crystal form contains pairs of olanzapine molecules which adopt mirror-related conformations.48 In olanzapine anhydrate, these pairs are connected by NH···N hydrogen bond interactions (Figure 4). However in the solvated and salt forms of olanzapine, the NH···N interaction is disrupted by solvent molecules or anions that link pairs of olanzapine molecules. Several of these crystal forms are isostructural and they can be categorized according to their crystal packing arrangements and crystallographic unit cell parameters, which we herein denote as packing types A, B, C, and D (Tables 2−5). Packing

Figure 1. Crystal packing viewed along the a axis of (a) OLANAM·IPA·4H2O and (b) OLASAM·IPA·4H2O reveals a tetrameric catemer of water molecules that is hydrogen bonded to four OLA molecules. The tetrameric catemer offers four hydrogen bond donors and two hydrogen bond acceptors to complement a pair of olanzapine molecules. Isopropyl acetate and the cocrystal former (NAM or SAM) hydrogen bond to each side of the tetrameric catemer. 4196

dx.doi.org/10.1021/cg3007052 | Cryst. Growth Des. 2012, 12, 4194−4201

Crystal Growth & Design

Article

and offer the same number of hydrogen bond donors and acceptors similar to supramolecular synthon 1 to match a pair of olanzapine molecules. In the methanol solvate (UNOGOT), a pair of methanol molecules lies between the pairs of olanzapine molecules and hydrogen bonds to four olanzapine molecules via NH···O and OH···O interactions. Packing type C is exhibited in four crystal forms of olanzapine: AQOMEY (sesquihydrate form I), AQOMAU02 (dihydrate form E), CAYTUS (DMSO solvate), and ELEVOG (methanol monohydrate). In a manner similar to packing types A and B, the solvent molecules occupy sites between the pairs of olanzapine molecules, and in turn they form hydrogen bonds to four adjacent olanzapine molecules. Supramolecular heterosynthon 2 is also observed in the hydrated crystal forms. The difference between packing types B and C is the orientation of adjacent sheets, which are stacked in a staggered fashion in type C (Figure 8). Packing type D is exhibited in salts of olanzapine with benzoate (JIXROY) and nicotinate (TAQNUV) anions. Analysis of the crystal structures reveals alignment of pairs of olanzapine molecules along the c axis (Figure 9). The pairs of olanzapine molecules are connected via charge-assisted hydrogen bonds formed between the carboxylate moiety of the benzoate and nicotinate anions and the ammonium moiety of the olanzapine cation. Crystal Engineering of Isostructural Cocrystals of Olanzapine. The formation of centrosymmetric pairs of olanzapine molecules is observed in all previously reported crystal forms of olanzapine. Analysis of these crystal forms reveals that solvent molecules arrange themselves between pairs of olanzapine molecules and hydrogen bond to four olanzapine molecules irrespective of the solvent molecule. It has been asserted that water molecules are promiscuous in terms of the supramolecular synthons they exhibit, as well as resulting structural stability and stoichiometry.38 For example, gallic acid monohydrate, the first tetramorphic hydrate for which fractional coordinates have been determined for all four polymorphs, exhibits different supramolecular synthons and crystal packing in each polymorph.39 In contrast, analysis of the polymorphic forms of olanzapine dihydrate for which

Table 1. REFCODES for Crystal Structures of Olanzapine Deposited in the CSD anhydrate UNOGIN UNOGIN01 solvates UNOGOT (methanol) WEXQAS (dichloromethane)

dihydrate AQOMAU AQOMAU01 AQOMAU02 hydrates of solvates CAYTUS (DMSO monohydrate) ELEVOG (methanol monohydrate) WEXPUL (butan-2-ol monohydrate) WEXQEW (ethanol dihydrate)

sesquihydrate AQOMEY AQOMEY01 salts JIXROY (olanzapinium benzoate) TAQNUV (olanzapinium nicotinate) AMIYUR (olanzapinium maleate (1:1)) AMIZAY (olanzapinium maleate (1:2))

type A is exhibited in the crystal structure of olanzapine dihydrate form D (AQOMAU, Figure 6). In packing type A, supramolecular heterosynthon 1 (Figure 5a) is observed whereby the water molecules are arranged as a cyclic tetramer between pairs of olanzapine molecules, thereby offering four hydrogen bond donors and two hydrogen bond acceptors. The number of hydrogen bond donors and acceptors in the cyclic and linear tetramers of water molecules is complementary to a pair of olanzapine molecules since olanzapine possesses one hydrogen bond donor and two hydrogen bond acceptors. The pairs of olanzapine molecules form a herringbone pattern and the sheets are eclipsed with respect to each other (Figure 6b). Packing type B is exhibited in three isostructural crystal forms of olanzapine: AQOMAU01 (dihydrate form B), AQOMEY01 (sesquihydrate form II), and UNOGOT (methanol solvate). Packing type B exhibits a three-dimensional network in which the solvent molecules lie between pairs of olanzapine molecules and hydrogen bond to four olanzapine molecules (Figure 7). In all three type B crystal forms, pairs of olanzapine molecules are aligned along the crystallographic a axis in a herringbone pattern to form sheets that are stacked in an eclipsed manner. Supramolecular heterosynthon 2 (Figure 5b) is observed in the hydrated crystal forms AQOMAU01 and AQOMEY01 with the water molecules arranged as a catemer

Figure 4. Crystal packing of olanzapine anhydrate form I reveals pairs of olanzapine molecules sustained by NH···N hydrogen bond interactions along the c axis. 4197

dx.doi.org/10.1021/cg3007052 | Cryst. Growth Des. 2012, 12, 4194−4201

Crystal Growth & Design

Article

Table 2. Crystal Forms of Olanzapine That Exhibit Packing A REF CODE

compound

a (Å)

b (Å)

c (Å)

α (°)

β (°)

γ (°)

volume

space group

AQOMAU

dihydrate

9.927(5)

10.095(5)

10.514(6)

84.71(1)

62.66(