Communication pubs.acs.org/crystal
New Insights into the Preparation of the Low-Melting Polymorph of Racemic Ibuprofen P. Andrew Williams, Colan E. Hughes, and Kenneth D. M. Harris* School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, Wales, U.K. S Supporting Information *
ABSTRACT: Recently, a second crystalline polymorph (Form II) of racemic ibuprofen was reported to be obtained by crystallization from the supercooled liquid state. The reported procedure involved a temperature schedule that included the requirement to quench the sample to a temperature (168 K) significantly below the glass-transition temperature (228 K) followed by annealing at a temperature (typically 258 K) above the glass-transition temperature. In the present work, we show (by differential scanning calorimetry and in situ, variabletemperature powder X-ray diffraction) that Form II of racemic ibuprofen can be prepared by crystallization from the supercooled liquid at temperatures as high as 273 K, without the requirement for low-temperature quenching and without the requirement for the material to pass below the glass-transition temperature. Our results lead to a new interpretation of the experimental conditions for producing Form II of racemic ibuprofen and remove racemic ibuprofen from the set of crystalline materials that are obtained only via low-temperature quenching of a supercooled liquid.
1. INTRODUCTION Ibuprofen [2-(p-isobutylphenyl)propanoic acid; Scheme 1] is recognized by the World Health Organization1 as one of the three essential nonopioid analgesics, nonsteroidal anti-inflammatory medicines, and antimigraine medicines. It is most commonly marketed as the racemic acid form (as shown in Scheme 1), although it is sometimes marketed as a salt (of which the sodium salt2 and the lysine salt3 have been widely studied and have been shown to exhibit polymorphism). Only the S (+) enantiomer of ibuprofen is biologically active, but enzymatic inversion converts the R (−) enantiomer to the active S enantiomer.4 In pharmaceutical applications of crystalline materials, it is often crucial to understand the diversity of polymorphic forms5
In common with several other important medicines that exhibit polymorphism in their pure form (including aspirin6 and paracetamol7), two polymorphs of racemic ibuprofen have been reported to date. The first discovered polymorph (Form I) has a melting temperature of 349 K, and the crystal structure was first reported in 1974.8 Recently, a second polymorph (Form II) was discovered,9 and its crystal structure has since been determined.10 A metastable amorphous form of racemic ibuprofen is also known, with a glass-transition temperature of 228 K.11 While the low melting temperature (290 K) of Form II would seem to preclude its use in medication and suggests that it is metastable relative to Form I, the discovery of polymorphism for the pure racemic acid, together with the existence of the metastable amorphous form, indicate that the polymorphic landscape of ibuprofen is only partially understood. Given the worldwide importance of this drug, consolidation of our understanding of these phenomena could have significant consequences. In this paper, we focus on racemic ibuprofen in the acid form, which we refer to as rac-ibuprofen. In previous studies,9 Form II of rac-ibuprofen was discovered in differential scanning calorimetry (DSC) experiments in which molten rac-ibuprofen was quenched rapidly to 143 K and maintained at this temperature for a period of time, followed by annealing at 258 K. It was stated that the initial stage of quenching the sample to 168 K (i.e., 60 K below the glass-transition temperature) or
Scheme 1
that are available to a given drug molecule, as different polymorphs can have significantly different solid-state properties and hence different performance in therapeutic applications. Thus, an important aspect of pharmaceutical research is the discovery, structural characterization, and physicochemical understanding of the full range of polymorphic forms that are accessible to a given drug molecule, as well as the development of reliable and reproducible procedures for preparing each specific polymorph. © 2012 American Chemical Society
Received: May 3, 2012 Revised: October 23, 2012 Published: November 6, 2012 5839
dx.doi.org/10.1021/cg300599q | Cryst. Growth Des. 2012, 12, 5839−5845
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Communication
Figure 1. Examples of DSC data (with exotherms shown as positive peaks) for rac-ibuprofen, demonstrating different outcomes in the final heating stage. Forms I and II are identified from their melting behavior, indicated by endothermic (negative) peaks with onset temperatures at 349 K (Form I) and 289 K (Form II). The broad exothermic (positive) peak in the region 310−345 K arises from crystallization of Form I. In part a, the initial formation of Form II is observed from its melting endotherm at 289 K, with further heating leading to crystallization of Form I and subsequent melting at 349 K (results from experiment A). In part b, only crystallization and subsequent melting of Form I are observed (results from experiment K). In part c, only the melting of Form II is observed (results from experiment I; in this case, the melting endotherm is very small and is shown expanded in the inset with the baseline in red and the intercept line indicating the onset temperature in green). In part d, no events are observed in the final heating stage (even when the DSC data are expanded in the vicinity of 289 K as shown in the inset), indicating that no crystalline phases are produced (results from experiment H).
chloroform other than rac-ibuprofen. This assignment was confirmed by gas chromatography on a solution in chloroform, which indicated that there were no detectable impurities (purity greater than 99%). Powder XRD confirmed that the only crystalline phase present in the product was Form I of racibuprofen. From eight independent DSC measurements (using the instrumentation specified below), the melting temperature (taken from the onset of the melting endotherm in the DSC data) and melting enthalpy were determined to be 347.15(10) K and 25.96(45) kJ mol−1, respectively. For comparison, values of the melting temperature reported in previous literature (for those cases quoting peak onset values from DSC measurements) are (71.7 ± 0.2) °C15b (≈344.8 K), 74.685 °C15a (≈347.84 K), and (348.35 ± 0.11) K,15c and reported values of melting enthalpies are (25.8 ± 0.5) kJ mol−1 from DSC, 9 (27.2 ± 0.4) kJ mol −1 from DSC, 15b 23.33 kJ mol−1 from DSC,15a (25.04 ± 0.10) kJ mol−1 from DSC,15c and 26.65 kJ mol−1 from adiabatic calorimetry.15c DSC measurements were carried out on a TA Instruments Q100 using sealed aluminum pans for samples of rac-ibuprofen with mass in the range 3.2 mg to 4.9 mg. All heating was carried out at 10 K min−1, and all cooling was carried out at 20 K min−1. As discussed in more detail in section 3.1, the temperature schedule in the general procedure for exploring the formation of Form II of rac-ibuprofen involved three stages, which are referred to consistently throughout this paper as “quenching”, “annealing”, and “final heating”. Quenching refers
lower temperature is a prerequisite for obtaining Form II, which was interpreted in terms of nucleation of Form II occurring in the low-temperature regime. Similar preparations of other crystalline phases by quenching a supercooled liquid below the glass-transition temperature have been reported, including 3,3′dimethoxy-4,4′-bis(2,2-diphenylvinyl)biphenyl,12 m-toluidine,13 and o-benzylphenol.14 In the case of m-toluidine, this procedure represents the only known route for obtaining a particular polymorph (the β polymorph). In the present work, we investigate the experimental conditions required for obtaining Form II of rac-ibuprofen, with particular interest in assessing the reported necessity of low-temperature quenching and exploring the highest temperature at which Form II may be obtained.
2. EXPERIMENTAL SECTION The sodium salt of rac-ibuprofen (purchased from Fluka; purity 99.5%) was converted into the acid form by dissolution in water followed by addition of hydrochloric acid, leading to precipitation of the acid (which has a low solubility in water). The acid was then extracted with chloroform, washed with water to remove any residual salt, and then crystallized by evaporation of the chloroform at ambient temperature. The purity of the sample of rac-ibuprofen was assessed by solution-state 1H NMR, powder X-ray diffraction (XRD), gas chromatography, and melting point analysis. Solution-state 1H NMR showed no evidence of any component soluble in 5840
dx.doi.org/10.1021/cg300599q | Cryst. Growth Des. 2012, 12, 5839−5845
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Communication
to rapid cooling of the molten sample to a temperature below the glass-transition temperature. Annealing refers to holding the sample at a temperature above the glass-transition temperature for a period of time. Final heating refers to the last stage of the procedure, following annealing, in which the temperature is increased in order to identify the crystalline polymorphs present from their melting behavior. As discussed below, in some of our experiments, the quenching step was omitted from the temperature schedule. Variable-temperature powder XRD experiments were carried out on a Bruker D8 instrument (Cu Kα1; germanium monochromated; reflection geometry; Våntec detector; Oxford Cryosystems Phenix temperature controller). For these studies, a sample of Form I of rac-ibuprofen (mass of sample ca. 11 mg) was placed in an indentation in a copper disk, which was heated (ex situ) on a hot plate to ca. 373 K to melt the sample. The molten sample of rac-ibuprofen in the copper disk was then transferred to the powder X-ray diffractometer, cooling to near ambient temperature while being transferred. The sample chamber in the cryostat was evacuated and cooled to the target temperature at the maximum possible rate (average rate of cooling estimated to be ca. 2 K min−1). After the target temperature was reached, the powder XRD pattern was recorded repeatedly as a function of time. The total time to record each powder XRD pattern was either 44 or 88 min, which defines the time-resolution of the powder XRD study. The powder XRD data were recorded in the range 4° ≤ 2θ ≤ 43° with a step size of 0.016° and a time per step of either 1 or 2 s. In the low-temperature powder XRD data recorded in the present work, the background at low diffraction angle (2θ < 10°) is very high, which is an unavoidable feature of data recorded using the cryostat employed in our lowtemperature powder XRD experiments. For this reason, the powder XRD data shown here are plotted from a starting angle of 2θ = 10°. As discussed in more detail below, we emphasize that Forms I and II of rac-ibuprofen are clearly distinguished from each other by unique characteristic peaks in the region 2θ > 10°. For these powder XRD data, the variation of the relative amounts of the two polymorphs present as a function of time was assessed by integration of a set of peaks characteristic of each polymorph (in a region for which no peak from the other polymorph was present). For Form II, the selected peaks were between 20.7° and 21.4°. For Form I, the selected peaks were between 19.1° and 19.8°. The comparatively low quality of the powder XRD data did not permit quantification of the relative amounts of the two polymorphs by Rietveld refinement. However, the use of peak integrals provides a reasonable means of assessing the relative amounts of two phases under circumstances in which the degree of preferred orientation does not change significantly as a function of time.
Table 1. Experimental Conditions in the DSC Studies on rac-Ibuprofen and the Results Obtained Concerning the Presence or Absence of Form II and Form I Determined from the Final Heating Stagea quenching A B C D E F G H I J K L M N
annealing
result from final heating
T/K
time/h
T/K
time/h
Form II
Form I
143 143 143 193
1 0 0 0
258 258 258 258 258 258 258 258 258 243 243 273 273 273
3 3 3 3 6 3 3 1 1 3 3 12 3 3
70% 100%
