Communication pubs.acs.org/crystal
Procainium Acetate Versus Procainium Acetate Dihydrate: Irreversible Crystallization of a Room-Temperature Active Pharmaceutical-Ingredient Ionic Liquid upon Hydration O. Andreea Cojocaru, Steven P. Kelley, Gabriela Gurau, and Robin D. Rogers* Center for Green Manufacturing and Department of Chemistry, The University of Alabama, Tuscaloosa, Alabama 35487, United States S Supporting Information *
ABSTRACT: Anhydrous procainium acetate is a room temperature ionic liquid (Tg = −25 °C); however, in the presence of water, this salt forms a crystalline dihydrate (Tm = 52 °C) that cannot be dehydrated without decomposition. Unintended crystallization of any active pharmaceutical ingredient can dramatically alter its solubility and bioavailability, making it essential that ionic liquid APIs be carefully studied for their crystallization behavior.
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salts which are likely unstable in the absence of water but have nevertheless been frequently reported as pure ILs.9 While the deliquescence of crystalline ILs is well-known, organic salts in general are characterized by a tendency to form stoichiometric, crystalline hydrates (although deliquescence is also common). The prevalence of crystalline salt hydrates can be inferred from a simple search of the Cambridge Structural Database (CSD).10 Of 148640 crystal structures, which contain at least two discrete ions (including metal complex ions), 41930 of them (approximately 28%) contain a water molecule as well. Conversely, 41930 of the 94415 structures (approximately 44%) which contain a water molecule also contain ions, although structures containing discrete ions comprise only about 24% of all structures in the CSD. This pronounced tendency to form hydrates distinguishes ionic crystals from molecular crystals and cocrystals.11 One important consequence of this is that moisture from the air can result in crystallization of an amorphous solid or the transition from one crystalline form to another.12 This behavior appears underreported in ILs, but there are literature examples that suggest some ILs are similar to higher melting salts in their tendency to form crystalline hydrates.13 Water has even been argued to be an integral constituent in the structure of some inorganic ILs.14 There is at least one room-temperature IL, 1dodecyl-3-methylimidazolium chloride (technically a liquid
ost active pharmaceutical ingredients (APIs) are solids at room temperature, which may lead to possible concerns related to poor aqueous solubility or polymorphism.1 For ionizable (i.e., Brønsted acidic or basic) APIs, these properties can be adjusted without changing the biological activity by making salts of the API with different (usually biologically inactive) counterions.2 To avoid the problems associated with solid APIs altogether, our research group and others have advocated designing API salts with melting points below ambient or at least body temperatures.3 While these lowmelting API compounds are usually described as ionic liquids (ILs, salts that melt below 100 °C but here below body temperature4), the goal behind their design is to reduce or eliminate the melting point of a particular compound (the API) and not necessarily to produce an ideal ionic liquid. Thus, research at the interface of APIs and ILs has produced many liquids with properties that differ from “normal” ionic or molecular liquids.5 ILs are commonly hygroscopic; even water-immiscible ILs will rapidly reach saturation upon absorbing moisture from the atmosphere.6 This is a problem because small changes in water content can significantly affect the properties of an IL, including melting point.7,8 In some cases, this can result in the misidentification of a compound as a room-temperature IL. Many ILs which form crystalline solids at room temperature, such as imidazolium salts of inorganic anions, are deliquescent, while others may remain in a supercooled liquid state once dried.8 Other compounds have been misidentified as pure ILs due to the influence of water, such as imidazolium hydroxide © 2013 American Chemical Society
Received: May 3, 2013 Revised: June 18, 2013 Published: June 21, 2013 3290
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crystal between −2 and 108 °C),15 for which a roomtemperature crystalline hydrate has been reported.16 Supercooled 1-butyl-3-methylimidazolium chloride has been reported to crystallize on exposure to water vapor at room temperature, although it does not form a crystalline hydrate.8 Since ILs are not intrinsically immune to forming crystalline hydrates, there is a need to examine the less well-studied APIbased ILs for the same water-induced crystallizations that are commonly observed in their higher-melting counterparts. In this paper, we show that procainium acetate, a roomtemperature IL composed of pharmaceutically acceptable ions, can be prepared only through a solventless route (Scheme 1, path A) and that the crystalline procainium acetate dihydrate
solid precipitate formed at this step; however, since that was not observed here, excess water was removed by rotary evaporation at 50 °C. The resulting yellow oil was isolated and allowed to stand for ∼2 weeks at room temperature in a sealed vial, after which single crystals suitable for X-ray analysis formed. The melting point of the crystalline material was determined by DSC to be 52 °C (Figure S6 of the Supporting Information), close to that of the solid reported in the patent. It should be noted that supercooling is common among ILs, and in the absence of an observed melting point, care should be given to explore such behavior. For example, 1-butyl-3methylimidazolium chloride can be supercooled to room temperature and will crystallize as the anhydrous salt upon exposure to water.8 However, here we have only been able to observe the formation of hydrated crystals from the anhydrous liquid. Single crystal X-ray diffraction confirmed the crystalline salt to be procainium acetate dihydrate, not anhydrous procanium acetate as claimed in the patent. The asymmetric/formula unit is shown in Figure 1 with the shortest intermolecular contacts
Scheme 1. Synthesis of Procainium Acetate (Path A) and Procainium Acetate Dihydrate (Path B)
Figure 1. 50% probability ellipsoid diagram of the asymmetric unit of the crystal structure of procainium acetate dihydrate.
is isolated when the same reaction is conducted in aqueous solution (Scheme 1, path B). This is the first report of an APIIL showing a behavior common to other API salts: transitioning from an amorphous (in this case, liquid) phase to a crystalline phase upon hydration. The solventless synthesis of procainium acetate (Scheme 1, path A) was conducted by adding glacial acetic acid dropwise to procaine free base. After each addition of a few drops at a time, the vial was closed (screw top), and the reaction mixture was stirred for a few minutes. After the complete addition of one equivalent of acetic acid, the mixture was stirred (with the evolution of heat) for 10 min, when it became a viscous gel. The solution was then stirred with heating (50 °C) for approximately 12 h, yielding a light yellow oil (quantitative). Differential scanning calorimetry (DSC) of procainium acetate indicated no melting or freezing events and only a glass transition at Tg = −25 °C (Figure S6 of the Supporting Information). When stored in the absence of moisture, the liquid state persisted indefinitely; however, the liquid was observed to crystallize upon exposure to ambient air. When checking the results of our synthesis against the literature, we found that procainium acetate had been reportedly synthesized in a 1935 patent as a solid with a melting point of 56 °C.17 A second procedure (path B) based on the patent was developed as follows. Procaine free base was warmed to a temperature of 75 °C, to which a solution of glacial acetic acid in warm water (∼50 °C) was added. The mixture was stirred for ∼20 min and then allowed to stand until cool, resulting in a yellow solution. The patent reported that a
displayed as dashed lines. The acidic hydrogen atom was located from the difference map within bonding distance to the amine (N2), and the carboxylate C−O bond distances (O3, O4) were both intermediate and equivalent, indicating ionization. Powder X-ray diffraction of the bulk solid was compared to the diffraction pattern calculated from the single crystal structure and confirmed that the bulk solid is indeed the dihydrate (Figure S5 of the Supporting Information). It is clear from the crystal packing (Figure 2, bottom) that water plays an important role in enabling procainium acetate to crystallize, overcoming the very features of the ions which lead to IL behavior. Overall packing is defined by alternating cationic and anionic layers, with the water molecules residing exclusively in the anionic layer where they form an elaborate hydrogen-bonded network with the anions (Figure 2, top). This network is composed of 16-membered rings connected to each other in two dimensions (organic hydrates often form such complex, extensive networks18). The cations interact with the anionic layer through strong hydrogen bonds from the amide and ammonium groups, and they interact with other cations through weak hydrogen bonds and π−π interactions. In addition to the size mismatch between the ions, procainium has two highly polar groups on either end with a low charge, π-rich portion in the middle. Water facilitates packing in light of these size and shape mismatches by helping to space out the anions and serving as an extra hydrogen bond acceptor for the polar ends of the cation. This also enables the 3291
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investigate this, the light yellow crystalline solid obtained from path B was heated at 50 °C under high vacuum. The 1H NMR spectrum of the powder after heating showed the ratio between the procainium and acetate peak integrals decreased, corresponding to a change in the cation−anion ratio of 1:1 to a ratio of 1:0.83 or less, while the ratios of the peak integrals for different positions on the procaine molecule were mostly preserved (Figure S7 of the Supporting Information). This indicates that acetic acid was volatilized, leaving procaine free base. While the full role water may play on the properties of APIILs is not yet predictable, interactions with water should be carefully studied and, where possible, controlled. For the procainium acetate system, water not only enables the liquid salt to crystallize as a hydrate but also complicates studying the crystallization of the anhydrous compound. Without an identifiable melting point for anhydrous procainium acetate, it is impossible to absolutely prove whether the liquid is thermodynamically stable or supercooled, and thus is subject to possibly crystallizing over time at an inopportune moment. This highlights the challenge of studying the many ILs, which do not crystallize on cooling to their glass transitions; how does one prove a negative? That is how does one prove that there is indeed no melting or crystallization event? In the field of APIILs, it may be preferable for the compounds to have melting points but melting points suitable to the intended use (e.g., melting below body or ambient temperatures.) Here, we have shown that anhydrous procainium acetate can only be isolated as a room-temperature IL if care is taken to exclude moisture, since exposure to water leads directly to crystallization of a dihydrate, an apparently unusual case where adding water causes a noncrystallizing IL to crystallize. These findings are relevant as many ILs are synthesized in solution under the assumption that the resultant IL will be nonvolatile, and the solvent can be removed with heat and reduced pressure. Volatility, however, is well-known trait among protic and less fully ionized ILs,19 and decomposition of API-ILs at low pressure may turn out to be more common than expected. On the other hand, even if care is taken to avoid hydrate formation, a liquid may be isolated which can crystallize on hydration.
Figure 2. Basic unit of the procainium acetate dihydrate anion−water hydrogen bond network (top left), the interconnection of these units to form the two-dimensional hydrogen-bonded sheets (top right), and packing down the b axis (bottom), showing the alternating cationic and anionic layers.
cations to pack with the long axes of the molecules parallel so that the aromatic portions of neighboring molecules can interact. Thermogravimetric analysis (TGA) of both procainium acetate and procainium acetate dihydrate (Figure 3) revealed
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ASSOCIATED CONTENT
S Supporting Information *
Materials and methods, synthesis and characterization of the compounds, additional packing diagrams for procainium acetate dihydrate, Fourier transform infrared spectroscopy of both anhydrous procainium acetate and procainium acetate dihydrate, calculated versus measured powder X-ray diffractograms of procainium acetate dihydrate, differential scanning calorimetry, and a procedure for dehydration of procainium acetate dihydrate are available. This material is available free of charge via the Internet at http://pubs.acs.org.
Figure 3. Comparison of TGA profiles for procainium acetate dihydrate (red) and procainium acetate (blue) from 25 to 600 °C with a 30 min isotherm at 75 °C. Inset: close-up of TGA profiles at lower temperatures (25−250 °C).
signs of decomposition at only slightly elevated temperatures, with procainium acetate dihydrate showing a more steep mass loss at the very start of the measurement and greater mass loss than the anhydrous compound after a 30 min isotherm at 75 °C (4.9% for procainium acetate vs 16.7% for procainium acetate dihydrate). The TGA traces of the two salts become similar once approximately 20% and 30% of the masses of the anhydrous salt and the dihydrate are lost, respectively, corresponding to the loss of acetic acid from the anhydrous salt and the loss of two water molecules and one acetic acid molecule from the dihydrate. The TGA results suggested that anhydrous procainium acetate cannot be prepared from the dihydrate, and to
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. 3292
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS S.P.K. is supported by a U.S. Department of Energy Nuclear Energy University Programs Graduate Research Fellowship (Grant DE-NE0000366).
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REFERENCES
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