Formulation of Liquid Propofol as a Cocrystalline Solid - Crystal

R.; Thakur , T. S.; Thaper , R. K.; Thomas , S. P.; Tothadi , S.; Vangala , V. R.; Variankaval , N.; Vishweshwar , P.; Weyna , D. R.; Zaworotko , ...
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Formulation of Liquid Propofol as a Cocrystalline Solid Scott C. McKellar,† Alan R. Kennedy,‡ Neil C. McCloy,† Eileen McBride,† and Alastair J. Florence*,† †

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, U.K. WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow, G1 1XL, U.K.

‡

S Supporting Information *

ABSTRACT: This work details a crystal engineering strategy to obtain a novel solid form of the liquid drug molecule propofol using isonicotinamide as a cocrystal former. Knowledge of intermolecular hydrogen bonded supramolecular synthons has been exploited to select a potential cocrystal former based on the likely growth unit formed. The structure of the cocrystal, solved using single-crystal X-ray diffraction, is reported, confirming the molecular packing and key intermolecular interactions adopted in the novel solid form. The potential to enhance a drug’s properties is demonstrated by an increased melting point compared to the native drug form, such that the liquid drug becomes a stable solid at room temperature. Unusually, the propofol/isonicotinamide complex has three structurally similar, temperature-dependent polymorphs, and the crystal structure of each form is reported herein.

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INTRODUCTION Over the past two decades, there has been a vast increase in the amount of research devoted to crystal engineering,1,2 where complementary supramolecular synthons between molecules are exploited to “tailor the chemical and/or physical properties of crystalline solids through crystal design at the molecular level”.3 The relevance of crystal engineering to pharmaceutical science has been illustrated more recently for active pharmaceutical ingredients (APIs) with significant improvements in key physicochemical properties such as solubility and dissolution rates having been demonstrated following cocrystallization with a water-soluble and pharmaceutically acceptable cocrystal former.4−9 As in salt selection, the synthesis of pharmaceutical cocrystals is noncovalent and provides a route to optimize important physicochemical attributes without altering the pharmacological activity of the API.8,10 Solid dosage forms comprising a crystalline form of the API are typically the preferred medium to deliver a drug to patients.5 From a manufacturing perspective, crystallization offers a cost-effective way to purify and isolate API molecules in a reproducible form with well-defined attributes. The crystalline form of the API provides a stable and convenient way to identify, transport, and store the molecule before manufacture of the final drug product. Solid oral dosage formulations also improve patient compliance, when compared to liquid or injectable forms.11 In this report, we describe a simple crystal engineering approach to obtain a novel solid form of the liquid anesthetic drug molecule propofol (2,6-diisopropylphenol (PRO); Scheme 1) using isonicotinamide (ISN; Scheme 1), based on the fact that ISN is a widely used cocrystal former12−15 and forms hydrogen-bonded cocrystals with phenolic compounds.16 The motivation for this work was to investigate whether cocrystallization could be used to convert © 2014 American Chemical Society

Scheme 1. Molecular Structures of (a) Propofol (PRO), (b) Isonicotinamide (ISN), (c) Nicotinamide (NIC), (d) Isonicotinic Acid, and (e) Nicotinic Acid

PRO, which is a liquid at room temperature, to a stable crystalline solid. Though ISN is not currently a Generally Recognized as Safe (GRAS) substance, its structural similarity to nicotinamide, a GRAS vitamin, has seen it recognized as being pharmaceutically acceptable.7,17 PRO has interesting structural characteristics for Received: January 28, 2014 Published: February 27, 2014 2422

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an intravenous anesthetic18 and as a model compound for cocrystallization. It is an ortho disubstituted phenol, with the hydroxyl the sole functional group, hindered by two isopropyl substituents. The high lipophilicity (logP = 4.16)19 results in a low aqueous solubility (0.84 mM).20 Salt formation in solution is unsuitable as the ionizable hydroxyl group has a pKa of 11.18 Accordingly, PRO is formulated as an oil-in-water emulsion for delivery, but this has associated problems including instability,21 pain on injection,22 and hyperlidemia.23 PRO prodrugs24 and cyclodextrin encapsulation25 have both been investigated as emulsion alternatives, but the former does not appear to be as effective an anesthetic, while the latter’s effect seems uncertain and has possible adverse side effects.18 It is therefore of interest to also investigate whether cocrystal formation offers a potential alternative route to enhancing the physical properties of this important API. In this work, the robust and directional O−H···Naromatic heterosynthon26−30 is exploited, specifically in the context of phenol/ISN adducts as reported by Vishweshwar et al.16 On the basis of this, it was proposed that PRO would hydrogen bond to ISN via motif I and that the structure would be extended via R22(8) amide···amide homosynthon dimers between ISN molecules (motif II), as illustrated in Scheme 2.

been demonstrated as a useful tool to guide the selection of suitable coformers and aid the design of novel cocrystals. For more extensive studies, the reliability of cocrystal design has been refined with a range of successful computational approaches to cocrystal prediction and analysis, such as electrostatic potential surface characterization and lattice energy matching of coformers,31,32 while binary and ternary phase diagrams have been shown to be useful tools in understanding cocrystal formation.33 Shape complementarity between coformers is also an important consideration.34 While valuable insights can be gained from these recent advances in structure prediction, it is essential to test the design experimentally since consideration of important factors such as functional group competition, relative bond strength, and molecular packing is generally more arbitrary. PRO was cocrystallized with ISN to produce a novel crystal structure (PRO/ISN in a 3:2 ratio), solved using single-crystal X-ray diffraction (XRD). In addition to using ISN, unsuccessful attempts were made to obtain a PRO cocrystal with NIC, nicotinic acid, and isonicotinic acid and are discussed below. There has been some debate around the nomenclature and definition of cocrystals,35 which is worth highlighting for the PRO/ISN complex because PRO is a liquid at room temperature (18 °C melting point). A cocrystal is a chargeneutral, multicomponent system in which neither “target” species is a solvent molecule. Regarding the definition of what constitutes the target species, Aakeröy and Salmon argue that both cocrystal components should be solid at room temperature36 to differentiate them from solvates. However, Stahly argues that the properties of the starting components should not be important37 since Aakeröy’s definition excludes crystal structures where one component is a gas or liquid by intent.38 We advocate the use of the term cocrystal in the instance of PRO/ISN since the element of design is not limited purely to solid starting materials and here is applied with the intention of producing a multicomponent crystalline solid product. Though crystal engineering principles have been previously performed using liquids,39,40 studies of liquid APIs for healthcare applications are rare in the literature with the only example foundin which one component is naturally solid and the other naturally liquidbeing carbamide peroxide.41 This comprises urea and hydrogen peroxide in solid crystalline form for use as a whitening agent in toothpaste. An attempt to assess the intrinsic aqueous dissolution rate of the cocrystal compared with the pure liquid was carried out. Preliminary results indicate that compared to raw PRO in its normal liquid state at room temperature, the intrinsic aqueous dissolution rate of PRO from PRO/ISN is enhanced as a direct result of cocrystal formation. Full details of the measurements, methodology, and results can be found in the Supporting Information.

Scheme 2. Examples of Potential Hydrogen Bonded Supramolecular Synthons (Motifs I−IV) within a PRO/ISN Cocrystal

Further structural possibilities exist and include OH···OC and HO···HN interactions between the hydroxyl group and the amide dimer (motifs III and IV; Scheme 2), although these heterosynthons are less frequently observed within structures that have been reported. A Cambridge Structural Database (CSD) search (ConQuest v1.14) reveals the presence of motifs III and IV in 121 and 83 crystal structures, respectively, compared with over 2000 containing motif I and over 1400 containing motif II. Motifs I and II can be considered the most likely synthons to occur in a potential PRO/ISN structure. These basic structural assumptions of ISN as a coformer can also be applied, by consideration of size, shape, and available hydrogen bond donors and acceptors, to the structurally similar GRAS coformers: nicotinamide (NIC), nicotinic acid, and isonicotinic acid (Scheme 1). While the synthon-based approach to crystal engineering is not an ab initio predictive tool for cocrystal formation, it has

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MATERIALS AND METHODS

Materials. PRO, ISN, NIC, nicotinic acid, isonicotinic acid, and acetonitrile (≥99.9%, CHROMASOLV gradient grade) were purchased from Sigma-Aldrich (UK) in high purity and used as received. HPLC-grade deionized water was sourced on site from a Purite Analyst water purification unit. Preparation of PRO/ISN Complex. Single crystals of the complex were grown from a solution of ISN in PRO. The crystallization was carried out in a 10 mL glass vial. Excess ISN was added to 6 mL of PRO, and the solution was stirred with a 12 mm magnetic stirrer bar at 1000 rpm at 80 °C for 20 min. The solution was filtered and cooled slowly to room temperature, yielding single crystals within a few 2423

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capillary VT-XRPD studies, the same cooling regime was again used, and data were collected in the 2−40 2θ° range with a count time of 1 s step−1. Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Thermal behavior, mass loss, and melting points with heating were monitored using simultaneous thermal analysis (STA), comprising DSC and TGA analyses with helium as a purge and protective gas. This was carried out on a Netzsch STA 449 C thermocouple, equipped with a Netzsch CC 200 liquid nitrogen supply system and a Netzsch CC 200 C control unit. The sample weight was accurately weighed to approximately 10 mg and was scanned at 10 °C min−1 over the required heating range. Data were visualized using Netzsch analysis software, Proteus version 4.3.1. DSC analysis at subzero temperatures was conducted on a Mettler Toledo DSC1 calorimeter with a Mettler Toledo liquid nitrogen cooling system and nitrogen purge gas. The sample weight was accurately weighed to approximately 20 mg and was scanned at 10 °C min−1 from 30 °C to −150 °C and then back to 30 °C. Data analysis was performed using Mettler Toledo STARe software and visualized using Microsoft Excel. Hot-Stage Microscopy. Samples were placed on a Linkham THMS600 heating block, connected to a Linkham TMS94 control unit. The experiment was carried out over a heating range of 25−160 °C at a rate of 10 °C min−1 and monitored using a Meiji polarized microscope, equipped with a JVC Digital Color Video camera. Mass Loss Measurements. An empty vial (and cap where necessary) were weighed and then approximately 50 mg of PRO/ISN was added to the vial and weighed accurately. The sample was reweighed every day for one week and weekly thereafter for one month, and the weight of the empty vial was subtracted from the weight of the vial and the sample.

minutes. The crystals did not diffract to a high angle but were of adequate quality to enable structure solution using single-crystal XRD. Polycrystalline powder samples of the cocrystal complex were produced at room temperature initially by grinding stoichiometric amounts (1:1, 1:2, 2:1 ratios) of PRO and ISN in a mortar and pestle and also with a steel ball bearing in a Retzch MM400 ball mill for 15 min at 25 Hz. Liquid PRO visibly disappeared within a few minutes of grinding as cocrystallization with ISN occurred, and cocrystal phase purity was improved at higher PRO/ISN ratios (3:1, 2:1), where PRO was in excess and could be removed by evaporation. To ensure a purephase cocrystal product, PRO/ISN powder was later synthesized by crash cooling from 100 °C to −18 °C a 50 mL saturated solution of ISN in PRO, producing an amorphous glass as the excess PRO froze. Crystallization was induced by bringing the sample back to room temperature and scratching the surface of the PRO/ISN glass, yielding a pure PRO/ISN powder. The sample was dried of the excess liquid PRO by vacuum filtration. In this fashion, the entire process of synthesizing and isolating the pure-phase cocrystal powder could be completed in less than 30 min. The above experiments were repeated using NIC, nicotinic acid, and isonicotinic acid in place of ISN, but no evidence of any cocrystal formation with PRO was detected. Single-Crystal XRD Analysis. Single-crystal diffraction data were collected at 123 K and 273 K on a Bruker Apex II CCD diffractometer using graphite monochromated Mo Kα1 radiation (λ = 0.71073 Å) and at 218 K on an Oxford Diffraction Xcalibur instrument with Cu Kα1 radiation (λ = 1.5418 Å). Samples were mounted under oil on a glass fiber situated on top of a goniometer head. Structure solution was carried out using direct methods in SHELXS-97.42 Hydrogen atom positions on hydrogen bonding and ionizable groups were located from difference maps where possible, and remaining hydrogen atoms were placed in calculated positions using a riding model. Refinement of atomic coordinates and thermal parameters was performed by fullmatrix least-squares methods on F2 within SHELXL-97 using all the unique data. The refined structures were viewed using PLATON43 and ORTEP44 within the WinGX suite of programs.45 PRO/ISN form 1 (room temperature) was collected and maintained at 273 K to prevent desolvation of the single crystal. No evidence of any phase change was found between room temperature and 273 K; thus, it follows that the crystal structure of PRO/ISN at 273 K is an accurate representation of the structure at room temperature. All final crystal structures were visualized for hydrogen bond lengths, angles, torsions, and packing arrangements using the CSD system software, Mercury version 3.1. Variable-Temperature X-ray Powder Diffraction (VT-XRPD) Analysis. Samples of PRO/ISN powder were lightly ground in an agate mortar and loaded into 0.7 mm diameter borosilicate glass capillaries. The capillaries were packed by gentle tapping to encourage powder flow. The capillaries were mounted with glass wool on a goniometer head and aligned using a microscope. The goniometer head was then mounted in a Bruker-AXS D8 Advance powder diffractometer equipped with a primary monochromator (Cu Kα1 radiation), transmission capillary geometry, and a Bruker Lynxeye position-sensitive detector. Any further alignment was then carried out as necessary on the instrument. An Oxford Cryosystems heating tube was suspended at the top of, and parallel to, the capillary. Data collection was carried out at the desired temperature (123−300 K), and the capillaries were rotated throughout the data collection to remove preferred orientation effects as much as possible. Data were collected in the 2θ range of 2−40° with a count time of 1−8 s, depending on the quality of data required. All XRPD patterns were visualized using DIFFRACplus Eva software. Variable-Temperature Diffraction Studies. To monitor changes in the diffraction pattern of single-crystal diffraction data, a PRO/ISN crystal was held stationary under a 273 K nitrogen stream and cooled in 5 K steps to 123 K. The crystal was held at each 5 K step for several minutes to allow thermal equilibration, and a single frame (30 s frame−1) was collected. The same procedure was used to heat the crystal back to room temperature. The procedure was repeated again using another crystal, but at each hold temperature, a matrix collection (30 s frame−1) was carried out to allow calculation of the unit cell. For

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RESULTS AND DISCUSSION The cocrystallization of liquid PRO and solid ISN yielded the PRO/ISN complex as a solid, crystalline off-white powder and separately as clear single crystals, as shown in Figure 1. Intriguingly, the complex displays a remarkable number of completely reversible single-crystal to single-crystal (SC-SC) phase transformations,46−48 with no damage (i.e., fracture or polycrystallinity) imparted on the crystal. There are three subtly different polymorphs of the complex that appear, disappear, and reappear as a function of temperature. Differences in crystal structure are very slight but are evidenced mainly by changes in the unit cell dimensions and crystal symmetry between the forms. In this respect, the three PRO/ISN polymorphs may be considered as belonging to the series of structures sometimes referred to as isostructural polymorphs.49 Previous discoveries of the rare phenomenon of isostructural polymorphism have shown that polymorphs can have virtually identical molecular geometries and intermolecular interactions but arise from changes in symmetry or pseudosymmetry,50 disorder,51 and/or seemingly trivial molecular rearrangements52 and are best exemplified by changes in space group or unit cell dimensions. A common feature is for one or two unit cell axes to double or triple in length with reduction in symmetry. This work is, as far as we could ascertain, the first example of a pharmaceutical cocrystal that exhibits isostructural polymorphism. Crystal Structure. The PRO/ISN crystal structure confirms the success of the design strategy, with all three forms showing the same hydrogen bonding motifs. The structures are defined by zero-dimensional PRO···ISN···ISN···PRO dimeric constructs comprising motifs I and II, as illustrated in Figure 2. In forms 1 and 3, these dimers have crystallographically imposed centrosymmetry. In form 2, only one-third of the dimers are strictly centrosymmetric. Further N−H···O−C hydrogen bonding between adjacent amide dimers extends 2424

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every second amide dimer in each ladder also forming hydrogen bonds to two “pendant” PRO molecules. These are approximately perpendicular to the plane of the ladder, lie mutually anti with respect to the [OCNH]2 ring, and correspond to motif III (Figure 3). Adjacent ladders are

Figure 3. Motifs I, II, and III in the crystal structure of form 3 PRO/ ISN, viewed down the plane of the ladder.

interdigitated and stabilized by layers of C−H···π interactions between C−H on the aromatic ring of ISN of one ladder and the aromatic ring of PRO on the other. Polymorphism. Three temperature-dependent polymorphs were identified within a lone single crystal of PRO/ISN, on cooling from room temperature to 123 K. This was initially identified by observing the diffraction pattern of a stationary crystal as the temperature was cooled at 5 K increments. On cooling form 1 (273 K) to form 2 (218 K), several new diffraction peaks appear in the pattern, consistent with a loss of crystal symmetry and/or an increase in unit cell volume or cell axis length. Between form 2 and form 3 (123 K), several diffraction peaks disappear from the pattern, implying the opposite (see Supporting Information, Figure S5). The SC-SC polymorphic transitionswhere form 1 (room temperature) converts to form 2 at ∼253 K, and form 2 to form 3 at ∼215 Kare reversible and reproducible and can be monitored using single-crystal XRD, which accordingly has been used to solve the structure of each polymorph. Figure 4 shows the change in reduced unit cell volume of PRO/ISN as a function of temperature. The reversible discontinuity in volume indicates that the polymorphs are enantiotropically related via reversible first-order phase transitions driven by small reductions in free energy. Crystallographic data for each form are shown in Table 1. The transitions between each of the forms were also monitored and confirmed using XRPD and DSC (see Supporting Information Figures S6, S7 and S8 and Table S1). Several data sets were collected before the three structures presented were deemed the best available. Note that although the polymorphic transitions were reversible in one crystal, the data presented are for three separate samples. Meaningful data for form 1 were only able to be collected up to 48 in 2θ° (Mo radiation), so no high-angle data exist. In the diffraction data for forms 1 and 3, only around one-third of all reflections are strong enough to be “observed” at the I > 2σ(I) level. The diffraction data for form 1 can be forced to index and process using the unit cell of form 3, and vice versa. However, final crystallographic models based on these “wrong” processing

Figure 1. Vials containing (a) liquid PRO and (b) solid off-white PRO/ISN powder at room temperature. (c) A 5× photomicrograph of PRO/ISN single-crystal rods at room temperature.

Figure 2. Crystal structure of form 3 PRO/ISN containing (a) motifs I and II in zero-dimensional PRO···ISN···ISN···PRO constructs and (b) one-dimensional hydrogen-bonded ladder linking constructs at the amide dimer, colored by symmetry equivalence and with hydrogen atoms omitted for clarity.

the structure in one dimension, creating a ladder where the plane of the ISN aromatic rings in each amide dimer is sequentially staggered by ∼50° with respect to the plane of the amide dimers directly above and below (Figure 2). These onedimensional ladders propagate along the crystallographic a direction and correspond to the approximately 9.8 Ǻ translation that is retained in all forms. The ladders as described above have 2:2 PRO/ISO ratios. The “extra” PRO molecules in the overall 3:2 composition of the cocrystals is accommodated by 2425

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Forms 1, 2, and 3 of PRO/ISN appear almost identical in terms of packing and molecular conformation, as shown in Figure 5 by a structural overlay of a 15 molecule cluster of each

Figure 4. Plot of reduced unit cell volume of one PRO/ISN crystal vs temperature, highlighting the reversible phase transitions at ∼253 K between form 1 (diamonds) and form 2 (squares), and 215 K between form 2 and form 3 (circles).

parameters feature extensive atomic motion, a decrease in the crystallographic R-factors and several nonpositive definite atoms. Such features in the “wrong” refinements indicate that the cells and structure solutions obtained for forms 1 and 3 are correct. The diffraction data for form 2 can only be indexed using the form 2 cell.

Figure 5. Overlay of a 15 molecule (9 PRO and 6 ISN) cluster where molecules of form 1 are colored blue, form 2 are red, and form 3 are green. Hydrogen atoms are omitted for clarity. The packing of each molecule is very similar, as indicated by a root-mean-square (rms) value of 0.11 Å between each form.

Table 1. Crystallographic Data and Structure Refinement Parameters for Forms 1−3 of PRO/ISNa empirical formula temperature (K) wavelength (Å) crystal system space group a (Å) b (Å) c (Å) α (°) β (°) γ (°) volume (Å3) Z density (g cm−3) Mu (mm−1) F(000) θ range (°) index ranges

reflections collected independent reflections restraints parameters GOF on F2 final R indices [I > 2σ(I)] R indices (all data)

Form 1

Form 2

Form 3

C48H66N4O5 273(2) 0.71073 triclinic P1̅ 9.8166(15) 15.4479(29) 17.3131(33) 114.971(7) 100.174(9) 90.326(9) 2333.12(102) 2 1.11 0.071 844 3.4−24.0 −11 ≤ h ≤ 10 −17 ≤ k ≤ 17 −19 ≤ l ≤ 19 19557 7201 [R(int) = 0.064] 7 535 0.982 R1 = 0.068 wR2 = 0.054 R1 = 0.187 wR2 = 0.209

C48H66N4O5 218(2) 1.54056 triclinic P1̅ 9.8183(4) 15.4270(6) 46.7832(17) 81.262(3) 88.059(3) 89.925(3) 6999.79(34) 6 1.11 0.563 2532 3.2−67.5 −11 ≤ h ≤ 7 −18 ≤ k ≤ 18 −56 ≤ l ≤ 56 45158 24984 [R(int) = 0.044] 0 1578 1.004 R1 = 0.074 wR2 = 0.202 R1 = 0.140 wR2 = 0.278

C48H66N4O5 123(2) 0.71073 monoclinic P21/c 9.7937(3) 15.2747(5) 31.0802(10) 90 98.472(3) 90 4598.73(21) 4 1.13 0.073 1688 3.4−26.0 −12 ≤ h ≤ 11 −18 ≤ k ≤ 18 −37 ≤ l ≤ 38 22751 9026 [R(int) = 0.077] 7 547 0.723 R1 = 0.054 wR2 = 0.115 R1 = 0.175 wR2 = 0.137

a

Since each form is defined by the same basic formula unit (3 PRO/2 ISN), the same empirical formula has been used for each form, and the number of formula units comprising the unit cell is reflected by the Z value. 2426

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motif IV (Scheme 2). In combination, these changes to motifs III and IV may correspond to changes in the position of the pendant PRO groups and thus determine our definition of homo- and heterointerdigitation. Unsuccessful Cocrystallization Attempts. After attempts at cocrystallization of PRO with NIC, nicotinic acid, and isonicotinic acid, XRPD analysis provided only the diffraction patterns for the solid starting materials, indicating only a physical mixture of PRO with each coformer. As a means of highlighting the limitations of the empirical “synthon approach” to crystal engineering, it is interesting to speculate why this was the case. A CSD search reveals that there are currently no published crystal structures of cocrystals/solvates of nicotinic acid or isonicotinic acid with phenolic or alcoholic coformers that contain motif I. Examination of the hydrogen bonding in the native crystal structures of nicotinic acid (CSD reference code NICOAC01) and isonicotinic acid (ISNICA) reveals that the molecules do not form acid···acid dimers like ISN and are instead linked by one-dimensional chains solely defined by COOH···Naromatic bonding (see Supporting Information, Figure S14). As discussed by Zaworotko and co-workers,29 the qualitative “hierarchy of supramolecular synthons” dictates that the strong COOH···Naromatic interaction is almost always more favorable than the comparatively weaker COH···Naromatic (motif I) interaction. Indeed, the authors note that in competition with alcohols, the COOH···Naromatic synthon, which defines the nicotinic acid structures, will take precedence. Therefore, each acid molecule is more likely to favor homomeric hydrogen bonding than heteromeric bonding with PRO. Nine reported cocrystals of NIC contain the COH···Naromatic synthon.53 However in each of the NIC cocrystal examples the coformer, unlike PRO, has two or more functional groups which propagate and stabilize the structure in three dimensions. The absence of a second functional group on PRO, and the resulting reduction in dimensionality that would occur in a PRO/NIC complex, may explain why NIC does not cocrystallize with PRO. By comparison to the PRO/ISN structure (Figure 2), it is also likely that the change in position of the aromatic nitrogen atom from para in ISN to meta in NIC would prevent efficient packing of the zero-dimensional constructs into a one-dimensional ladder due to a hindered environment around the terminal PRO molecules. The importance of propagation of the structure in a potential cocrystal is reflected by comparison of the native ISN and NIC crystal structures. In the crystal structures of the dimorphic NIC (NICOAM01/02), all available hydrogen bond-donating and accepting sites are used in N−H···Naromatic and CO···HN interactions, giving rise to the efficient three-dimensional packing shown in Figure S15, Supporting Information. Though the potential motif I offered to NIC by PRO is, by comparison to the existing interactions, a strong hydrogen bond, the heteromeric bonding in only one dimension, and the bulky isopropyl groups could lead to significantly less efficient packing in a potential PRO/NIC cocrystal structure than in the native structure. This is also true of forms 2−5 of the pentamorphic ISN (EHOWIH02-05). However, in the thermodynamically stable form 1 crystal structure of ISN (EHOWIH01), not all hydrogen bond-accepting atoms are used. The crystal structure is defined by two-dimensional tapes linked at the amide dimer, while adjacent pyridyl moieties interact via weaker CH···Naromatic bonds, as shown in Figure

form and as is evident from the already-described persistence of the same hydrogen bonded construct (ladders of dimers with terminal and pendant PRO molecules) through all three forms. Viewed along the length of the ladders (e.g., along the crystallographic a direction) it can be seen that each ladder is surrounded approximately hexagonally by six nearest neighbor ladders. Four of these neighboring ladders are approximately 17.31 Ǻ from the central polymer, but the other two are slightly closer, and this distance does vary slightly between the three forms. This distance corresponds to the length of the b axis and so ranges from 15.45 Å in form 1 to 15.27 Å in lowtemperature form 3. This similarity in packing again emphasizes the subtle nature of the transformation seen herea point confirmed by the DSC analyses (Figure S8, Supporting Information) where very low peak intensity prevents accurate calculation of the enthalpy values. This indicates that the enthalpy changes must be trivial by comparison to those usually associated with significant structural rearrangements that occur in polymorphic transitions. The main structural difference between the three forms seems to lie in the detail of the interdigitation of ISN between terminal PRO groups. The ISN dimers can be split into two types: those that hydrogen bond to the third, pendant PRO molecule (Type A) and those that do not interact with the pendant PRO molecules (Type B) (see Figure S9, Supporting Information). In form 1, when viewed along the a direction, the ISN molecules of Type A dimers lie between terminal PRO groups that also form part of the Type A dimers. ISN molecules of Type B dimers interdigitate only between PRO molecules from Type B dimers. This will be labeled “homointerdigitation” (see Figure S10, Supporting Information). In form 3, the opposite is true. Type A ISN molecules interdigitate between Type B PRO molecules, and Type B ISN molecules interdigitate between Type A PRO molecules. This will be called “heterointerdigitation” (see Figure S11, Supporting Information). As is appropriate to its formation in temperature ranges between the other two forms, form 2 is intermediate in structure. It features both homo- and heterointerdigitation, and it is the alteration of layers of the two interaction types along the c direction that leads to the tripling of this unit cell length. This change could be thought of as corresponding to slippage of ladders along the a direction or it could arise from changes to the hydrogen bonding nature of the pendant PRO groupsthis latter explanation would result in only small low energy shifts in position within the structure and would effectively switch which dimers interact with the PRO molecules. Examining the geometric parameters, only subtle differences between the polymorphs of PRO/ISN can be seen. Mostly these are simply consistent with contraction as a result of cooling. Such changes are generally not significant enough to warrant detailed discussion, but one of the more meaningful examples is the decrease in hydrogen bond length between pendant PRO bound via motif III to the amide dimer. The D··· A distances (OPRO···OISN) are 3.074 Å in form 1, 2.970, 2.972, and 2.975 Å, in form 2 and 2.909 Å in form 3. The corresponding distance between the same OPRO and the nitrogen atom of the ISN on the adjacent construct also decreases (3.260 > 3.174 > 3.164 Å), resulting in a weak N− H···O hydrogen bond in form 3 where the phenol group of PRO is acting as a hydrogen bond acceptor, as shown in Supporting Information, Figure S12. Though this is relatively trivial with respect to the supramolecular structure, it is worthy of mention here since this interaction is the aforementioned 2427

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S16, Supporting Information. Since PRO offers the potential for stronger hydrogen bonding interactions at the pyridyl site (motif I) in ISN, cocrystallization offers a favorable alternative to the homomeric interaction, while still maintaining a rigid dimer-linked backbone. It is also noteworthy that, in addition to considerations of the structural factors underpinning possible cocrystal formation, the crystallization conditions used in the search are also important and thus varying the experimental parameters to probe alternative outcomes of nucleation are important considerations. For example, having stirred or quiescent solutions can vary the crystalline form of carbamazepine produced from small-scale solution crystallizations.54 Also three new solvates of carbamazepine were identified from a retrospective analysis of a solution crystallization screen by attempting the recrystallizations at lower temperatures.55 Further work is ongoing to assess whether alternative crystallization conditions can potentially promote the formation of these alternate PRO cocrystal systems. Thermal Stability. DSC and TGA analyses showed that the PRO/ISN complex desolvates at 55 °C (though the onset is at 36 °C), wherein PRO reverts to its liquid form. Using hot stage microscopy, liquid PRO can be observed emanating from the PRO/ISN crystals at this temperature (see Figure S13, Supporting Information), as opposed to evaporating directly from the crystal lattice as would usually be expectedthis phenomenon of desolvation as a liquid is probably attributable to the high thermal stability of native liquid PRO (boiling point ≈ 256 °C). A rapid recrystallization of ISN ensues before both compounds evaporate (Figure S13). Clearly it is desirable for a pharmaceutical system to be stable within a significant temperature range above normal storage and transportation temperatures. To study the physical stability of the cocrystal further, a mass loss experiment was carried out under various storage conditions. Figure 6 shows the change in mass of PRO/ ISN when stored for one month: in an open vial at room temperature (RT); in a sealed vial with a hole in the lid at room temperature and at 4 °C. At 4 °C, the PRO/ISN complex is stable for 4 days before desolvating at an approximate rate of 0.02% per day, losing

0.2% over the whole month. XRPD analysis after one month showed that the sample remained as pure PRO/ISN. In the sealed vial at room temperature, the complex is stable for 4 days then desolvates at around 0.1% mass per day to 1.7% over the course of the test. In the open vial, PRO/ISN is stable for 1 day before desolvating at approximately 0.7% by mass per day over the first week and 8.6% in total over the month. XRPD analysis of the open sample after one month revealed several new lowintensity peaks in the diffraction pattern. An overlay of the new peaks were a match for those in the diffraction pattern of pure ISN (form 1), confirming that as PRO was evaporating from the complex, ISN was recrystallizing from the cocrystal complex. The stability of PRO/ISN, even at room temperature, is still a considerable improvement over native liquid PRO, which loses 32.9% of its mass over the course of a month at room temperature. Though considerably more stable at lower temperatures than at room temperature, the PRO/ISN complex is not as stable as would be desired for an alternative formulation approach.

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CONCLUSIONS We have reported a novel form of the liquid anesthetic propofol (PRO) that is solid at room temperature, with a melting point ∼50 °C higher than the starting material. The new complex was obtained by cocrystallization with isonicotinamide (ISN). Methodologically, the synthesis of both polycrystalline powder and representative single crystals was facile. Compared to most other cocrystallization studies where both reactants are solid, PRO acts as solvent and reactant. Thus, the final stoichiometric cocrystal can be obtained by dissolving and cooling ISN in PRO, as well as cogrinding stoichiometric equivalents. The PRO/ISN cocrystal displays two rare single-crystal to singlecrystal transformations which are reversible and nondestructive. The polymorphs are structurally very similar, with hydrogen bonded synthons and key packing features retained across the three forms. This is the first reported case of “isostructural” polymorphism in a pharmaceutical cocrystal. Both thermal transitions are accompanied by changes in symmetry and unit cell axes as a result of subtle changes in the molecular packing. In principle, since drug candidates are usually preferred in a solid dosage form, the results highlight the potential for cocrystallization as a tool to raise API melting point and would have potential application for other drugs, highlighting a possible route to stable, solid drug forms for liquid, lowmelting, or unstable compounds. However, for industrial application,56 it is important that other physicochemical properties of the API are optimized. This study demonstrates how crystal engineering of important drug candidates with suboptimal properties has the potential, as part of the drug development process, to aid the control and development of a solid form that best optimizes the drug properties. Often physical form selection requires a compromise between purity, form, yield, stability, and solubility; however, cocrystal formation provides an additional route to the selection and control of pharmaceutical solids and their characteristic properties. As experimental approaches continue to discover new materials with interesting and varied properties, a key requirement is to predict accurately physical properties from a knowledge of crystal structure. The advancement of crystal structure prediction methods for cocrystals57 needs to be matched by improvements in the capability to predict solubility, stability, and other physical and mechanical properties to enable

Figure 6. Mass loss of PRO/ISN powder over time in various environmental conditions (open at room temperature (circles), sealed at room temperature (squares), sealed at 4 °C (triangles)), and mass loss of liquid PRO when open at room temperature (diamonds). 2428

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a more informed first-principles approach to pharmaceutical solid selection.

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ASSOCIATED CONTENT

S Supporting Information *

Additional experimental data, figures, and tables as discussed in the text. CIF files are supplied. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Address: SIPBS, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, UK. E-mail: alastair.florence@strath. ac.uk. Tel: +44-141-548-4877. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Engineering and Physical Sciences Research Council (EPSRC) and the Glasgow Centre for Physical Organic Chemistry (GCPOC) for funding and are grateful to Dr. Isobel Fletcher (Department of Chemical and Process Engineering, University of Strathclyde) for assistance with lowtemperature DSC analysis.

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with bond distance set to VdW + 0.1 Å. The coformers in the nine reported cocrystals are as follows: 5-methylbenzene-1,3-diol (EWAQAV), 5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one (GAZWUB), ethyl paraben (GOGQID), bis(benzene-1,2,3-triol) (HEDROZ), trifluoroethanol (MOSKEL), gallic acid hydrate (MUPPAP), 4hydroxy-3-methoxybenzaldehyde (OBUBOE), 4-hydroxybenzoic acid (RUYHEZ), 3-hydroxybenzoic acid (XAQQIQ). (54) Sypek, K.; Burns, I. S.; Florence, A. J.; Sefcik, J. Cryst. Growth Des. 2012, 12, 4821. (55) Johnston, A.; Johnston, B. F.; Kennedy, A. R.; Florence, A. J. CrystEngComm 2008, 10, 23. (56) Trask, A. V. Mol. Pharmaceutics 2007, 4, 301. (57) Bardwell, D. A.; Adjiman, C. S.; Arnautova, Y. A.; Bartashevich, E.; Boerrigter, S. X. M.; Braun, D. E.; Cruz-Cabeza, A. J.; Day, G. M.; Della Valle, R. G.; Desiraju, G. R.; van Eijck, B. P.; Facelli, J. C.; Ferraro, M. B.; Grillo, D.; Habgood, M.; Hofmann, D. W. M.; Hofmann, F.; Jose, K. V. J.; Karamertzanis, P. G.; Kazantsev, A. V.; Kendrick, J.; Kuleshova, L. N.; Leusen, F. J. J.; Maleev, A. V.; Misquitta, A. J.; Mohamed, S.; Needs, R. J.; Neumann, M. A.; Nikylov, D.; Orendt, A. M.; Pal, R.; Pantelides, C. C.; Pickard, C. J.; Price, L. S.; Price, S. L.; Scheraga, H. A.; van de Streek, J.; Thakur, T. S.; Tiwari, S.; Venuti, E.; Zhitkov, I. K. Acta Crystallogr., Sect. B: Struct. Sci. 2011, 67, 535.

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