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Paracetamol Form II: An Elusive Polymorph through Facile Multicomponent Crystallization Routes Lynne H. Thomas,† Craig Wales,‡ Lihua Zhao,§ and Chick C. Wilson*,† †
Department of Chemistry, University of Bath, Bath BA2 7AY, U.K. School of Chemistry and WestCHEM Research School, University of Glasgow, Glasgow G12 8QQ, U.K. § NiTech Solutions Ltd, Scottish Enterprise Technology Park, Rankine Avenue, East Kilbride G75 0QF, U.K. ‡
bS Supporting Information ABSTRACT: A simple route to crystallization of the pharmaceutically important paracetamol form II is reported. The method is based around multicomponent crystallization techniques, involving various second components containing carboxylic acid groups and a range of solvents. These crystallization experiments do not produce multicomponent molecular complexes, but instead they provide the conditions in which the metastable paracetamol form II is reliably produced in 100% yields and with stability of greater than one year. To date, batches of paracetamol form II have been produced easily on the 100 mg scale with clear potential for bulk production.
C
o-crystallization is an increasingly promising approach to accessing important solid forms of, for example, pharmaceutical materials. The work reported here represents a breakthrough in using such a technique—the presence of a coforming molecule—to generate an industrially significant solid form of an important pharmaceutical molecule with favorable physical properties for its formulation and delivery (Figure 1). The selectivity and yield offered by this multicomponent route is remarkable and makes production of this desirable form routinely accessible for the first time. The range of related cocomponents capable of accessing the desired form of paracetamol is unprecedented, allowing the optimization of both comolecule and solvent in a systematic manner using a library of compounds to generate 100% yields. The generalization of this approach offers enormous potential for the facile production of similarly challenging but desirable solid forms. p-Hydroxyacetanilide (paracetamol) is an important bioactive compound and active pharmaceutical ingredient (API), previously studied intensively in the crystalline state.1 7 The metastable orthorhombic form II polymorph has been shown to be more soluble1 and more readily compressible into tablets than form I, due to the layered nature of its packing in the solidstate. These physical characteristics make it far more attractive in formulation.2 However, existing routes to selective crystallization of this phase are complex, and solid form II products from these tend to convert into form I over time;7 form II is a metastable polymorph. The favorable physical properties of form II make it desirable to find a route to selective crystallization of this polymorph that would lend itself to production on an industrial scale. We present a method for selectively controlling polymorph growth utilizing cocrystallization methodology. By introducing a second component into the crystallization environment in addition to the solvent, it is possible to selectively grow paracetamol r 2011 American Chemical Society
Figure 1. Methodology for templated selective crystallization in multicomponent solutions.
form II under ambient conditions and to 100% yields (Figure 2). Furthermore, the crystals obtained are stable for periods of greater than one year. The critical importance of generating form II at 100% is emphasized by the fact that the presence of small quantities of form I in the final product encourages the conversion of the metastable form II into the more stable form I over a period of weeks to months. The simplicity of the method and the use of ambient conditions make this a highly desirable route to the selective growth of paracetamol form II with greater potential for scale-up to industrial processes than the methods identified previously. The technique also has more general applicability in accessing elusive but valuable solid forms of active molecular ingredients. It is relatively common to use additives to encourage polymorph selection,4,8 where it is possible to engineer the polymorph obtained by considering the faces of the seeding additives.9 Co-crystallization, however, where the relative quantities of the desired material and the coformer are equal, has not generally been exploited in this manner. Conventionally, cocrystallization can be described as a deliberate attempt to bring Received: February 11, 2011 Revised: March 14, 2011 Published: March 15, 2011 1450
dx.doi.org/10.1021/cg2002018 | Cryst. Growth Des. 2011, 11, 1450–1452
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COMMUNICATION
Figure 2. Templated conversion of form I to form II paracetamol.
together different molecular species within one lattice without making or breaking covalent bonds, often forming a heteromolecular crystalline product with discrete molecules linked by intermolecular interactions (a “molecular complex”). In this manner, it has been used to vary physicochemical properties in a number of ways, including enhancing stability under humid conditions10 and enhancing solubility.11,12 It is not common for an intended cocrystallization experiment to produce selective polymorph growth, though there are examples of this often serendipitous outcome reported.3,4,13 However, to the best of our knowledge, this route has only previously led to metastable forms that convert to a more stable form with time or to mixtures of polymorphs. In the present work, paracetamol has been systematically recrystallized from solutions containing a series of monosubstituted halobenzoic acids. A number of these multicomponent recrystallizations—targeted at the production of molecular complexes of paracetamol—in fact produce, reliably and reproducibly, samples containing 100% pure paracetamol form II (along with the uncomplexed second component used in the preparation) using standard solvent evaporation under ambient conditions (Table 1). After a period of days to months, depending on the volatility of the solvent used, distinct crystals of both paracetamol form II and the pure benzoic acid were formed, which could be easily separated and identified by the crystal habit and the pink hue characteristic of the paracetamol form II crystals. The resultant materials have been fully characterized by DSC, Raman spectroscopy, and powder XRD. The production of form II is unambiguously confirmed by quantitative phase analysis of the XRD patterns within PolySNAP.14 In no case did the XRD indicate the formation of a molecular complex. Repeat experiments show consistency in the yields obtained, and recrystallizations on the 100 mg scale have been successfully performed to date. Single crystals of form II have also been produced, verified by full redetermination of the previously reported crystal structure. Moreover, very large (mm-sized) single crystals of good quality have been obtained, representing an enormous advance in the production of this previously elusive material in large quantities. Both the solvent and benzoic acid appear to have a role in templating the crystallization outcome. The 4-substituted benzoic acids (BAs) produce form II paracetamol most reliably with 100% yields obtained repeatably from 1:1 crystallizations, particularly with 4-bromoBA; the choice of solvent can also be seen to have an influence in the crystallization process. The use of the other halo-substituted BAs as coformers can also give up to 100% form II yields, but less reliably and predictably than the 4-substituted cases. Interestingly, the molar ratio of the benzoic
acid is also seen to be important, with 2:1 paracetamol to 4-bromobenzoic acid cocrystallizations also giving rise to 100% form II, while a 4:1 ratio results in a mixture. High concentrations of the benzoic acid are therefore necessary for selectively producing form II. The high selectivity achieved through the use of substituted BAs as templates for the formation of form II led us to investigate the use of a solvent containing a carboxylic acid group—acetic acid. While we observe large yields of paracetamol form II from this route, with acetic acid as solvent in excess, we have not yet been able to obtain 100% yields, with a small quantity of form I present in all samples. In these experiments, crystallization from supersaturated solutions of paracetamol in acetic acid obtained by heating results in the production of pure form I, probably due to undissolved paracetamol form I seeding the solution. Unsaturated solutions of paracetamol, in excess acetic acid, have resulted in 95% conversion to form II, but the residual presence of form I would likely result in full conversion to that form over time. The stability of form II when grown with 100% yield has been determined to be greater than a year. In cases where a mixture is formed, form II is observed to convert to form I over several months under solvent free conditions, suggesting that the II f I conversion is mediated by the presence of form I and not by the solvent as previously suggested.6 The crystallizations presented yield a form II product which is stable under grinding (during preparation for XRD); this is vital in the ability of this material to be tableted. In summary, we have identified a new route to selective polymorph growth using a comolecule to perturb the solution environment, encouraging the growth of the metastable polymorph of paracetamol. The control of polymorphism through a variety of related coformers is of particular interest given the different molecular arrangements occurring in the crystal structures of the benzoic acids. This suggests, in the first instance, that the templating occurs within the solution phase and not as epitaxial growth from a face of a benzoic acid crystal, a conclusion supported by the ease of separation of the crystals. In subsequent experiments, we have also generated 100% yields of form II when grown in combination with other carboxylic acid containing compounds such as succinic acid and fumaric acid, the crystal structures of which are quite different from those of the benzoic acids. This again suggests the templating process occurs in the solution phase. This route to selective crystallization of paracetamol form II has proven to be simple, effective, reproducible, and reliable, and it promises to yield for the first time the capability of producing large-scale quantities of this important material. 1451
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Table 1. Multicomponent Crystallization Routes to Paracetamol Form II co-former 4-BrBA
4-ClBA
4-FBA
3-BrBA
solvent
form produced
methanol
100% form II
stable for >1 year
ethanol acetone
mixture mixture
some batches 100% form II converts to form I with time
acetonitrile
100% form II
isopropanol
100% form II
methanol
majority form II
ethanol
mixture 100% form II
acetonitrile
mixture
some batches 100% form I
isopropanol methanol
100% form II mixture
some batches 100% form II
ethanol
mixture
acetone
100% form II
acetonitrile
mixture
isopropanol
100% form II
methanol
100% form I
ethanol
100% form I
acetone acetonitrile
100% form II 100% form I
isopropanol
mixture
methanol
100% form I
acetone
100% form I
3-FBA
acetone
100% form I
isopropanol
100% form II
methanol
100% form I
ethanol acetone
100% form II mixture
ethanol
100% form II
2-ClBA
2-FBA BA
some batches 100% form II
acetone
3-ClBA
2-BrBA
comment
acetone
mixture
acetonitrile
100% form I
isopropanol
100% form II
methanol
100% form I
ethanol
mixture
methanol ethanol
mixture 100% form I
acetone
100% form I
acetonitrile
100% form I
isopropanol
100% form I
converts to form I with time
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’ ASSOCIATED CONTENT
bS
Supporting Information. Details of powder patterns for form I and form II, Raman spectra for forms I and II, and crystallographic data and CIF file for paracetamol form II. This material is available free of charge via the Internet at http://pubs. acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected].
’ REFERENCES (1) Sohn, Y. T. J. Korean Pharm. Sci. 1990, 20, 97–104. 1452
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