DOI: 10.1021/cg100451q
Formation of Cocrystals from Stoichiometric Solutions of Incongruently Saturating Systems by Spray Drying
2010, Vol. 10 3302–3305
Amjad Alhalaweh and Sitaram P. Velaga* Department of Health Sciences, Lulea University of Technology, Lulea S-971 87, Sweden Received April 5, 2010; Revised Manuscript Received June 1, 2010
ABSTRACT: Spray drying is a well established technique for material processing and scale-up. This study investigated the formation of pharmaceutical cocrystals by spray drying. The cocrystal formation mechanisms in spray-drying and solution methods, based on triangular phase diagrams, are discussed. The solvent evaporation of stoichiometric solutions of incongruently saturating cocrystals resulted in a mixture of phases, as dictated by the thermodynamic phase diagram. In contrast, spray drying of similar solutions of incongruently saturating systems generated pure cocrystals. It is thus suggested that the formation of cocrystals by spray drying could be kinetically controlled and/or mediated by the glassy state of the material. Pharmaceutical cocrystals can improve drug physicochemical and mechanical properties as well as in vivo performance and, hence, are a potential new alternative in the selection of optimal solid forms in drug product development.1,2 Traditionally, cocrystal screening has been based on empirical methods such as solvent evaporation, crystallization from melts, and grinding.3-6 An understanding of the role of thermodynamics and solution chemistry in cocrystal formation has led to rational and efficient cocrystal screening methods such as reaction crystallization and slurry crystallizations.7-10 Other methods, such as supercritical fluid crystallization (SCF) and twin screw extrusion, have also been used recently in the preparation of cocrystals.11,12 The cocrystal eutectic points or transition concentrations, where two solid phases coexist in equilibrium with a liquid phase, define the thermodynamically stable regions of the cocrystal in relation to its pure components in phase diagrams [i.e., phase solubility diagrams (PSD) or ternary phase diagrams (TPD)].7,13 Thus, information on the relevant eutectic points could guide cocrystal synthesis in solution-based methods and the selection of optimal cocrystals for further development. In addition, the relationship between the concentrations of cocrystal components at the eutectic point and the solubility of the individual components can be used to identify whether the cocrystal will be congruently or incongruently saturating in a particular solvent and at a particular temperature.7,13 Accordingly, a congruently saturating cocrystal is thermodynamically stable during slurrying and can be readily formed by slurrying a stoichiometric ratio of cocrystal components. On the other hand, an incongruently saturating cocrystal transforms during slurrying, resulting in a less soluble solid form. These principles were applied in sorting the model cocrystal systems in this study. The scalability of a crystallization process is a vital issue in determining the utility of cocrystals in product development. Unfortunately, not all screening methods are suitable for cocrystal scale-up. Furthermore, the development of a scale-up crystallization process is essentially more complex for cocrystals than for single component crystals. With knowledge of the phase solubility behavior, slurry-based crystallization methods have been developed for the scale-up of carbamazepine-nicotinamide and caffeine-glutaric acid (CAF-GLT) cocrystals.14-16 However, these methods are vastly nonstoichiometric, and the generation of pure cocrystalline material requires careful control of thermodynamic and kinetic factors. In addition, these are noncontinuous batch crystallization methods. Recently reported *To whom correspondence should be addressed. E-mail: sitaram.velaga@ ltu.se. Telephone: þ46-920-493924. pubs.acs.org/crystal
Published on Web 06/16/2010
SCF and twin screw extrusion methods could be suitable for scale-up production after considerable optimization. Thus, the need for techniques that can overcome these challenges in the preparation and scale-up of cocrystals has encouraged us to test cocrystallization by spray drying. Spray drying is a method of producing dry powders from a solution or a suspension by rapidly evaporating the solvent in a fraction of a second with a hot air stream.17,18 This is one of the preferred technologies for material processing and scale-up in the pharmaceutical and food industries because it is a fast, continuous, and one-step process. The technique has been used for engineering particles with the distinctive physical properties (i.e., shape, size, density, and surface properties) required to tackle various drug delivery challenges. Although the solid-state nature of the spray-dried materials is often amorphous due to rapid solidification, few drug materials are produced in crystalline forms (polymorphs or solvate/hydrate).19,20 The rapid supersaturation of the solution and change in temperature are considered to be critical factors in the generation of polymorphs or metastable crystalline forms by spray drying.20 Thus, spray drying appears to offer a unique environment for the synthesis and scale-up of cocrystals. These merits or features of spray drying were additional motivations for this study. In the study, we set out to investigate the cocrystallization of incongruent and congruent cocrystal systems by spray drying and to understand the role of thermodynamic and kinetic factors in the formation of cocrystals by this technique. The cocrystallization pathways in spray drying in relation to the solvent evaporation method are discussed. To the best of our knowledge, the formation of cocrystals using spray drying has not been systematically studied to date. The model cocrystals used in the study are listed and abbreviated in Table 1.21-24 The saturation conditions of these cocrystals at room temperature (23-24 °C) was verified by slurrying a stoichiometric mixture of cocrystal components in the respective solvents. The saturation condition of the cocrystals was also verified at a temperature equivalent to the outlet temperature in the spray-drying process by slurrying them in the same solvents. The stoichiometric solutions of drug and coformer were subjected to solvent evaporation crystallization at room temperature and spray drying. The solid phases resulting from different methods were analyzed by powder X-ray diffraction (PXRD). Thermal analysis of the solids was also performed when appropriate. All the corresponding experimental data and analysis including tables and figures are presented in the Supporting Information. Spray-dried particles of carbamazepine-glutaric acid (CBZ-GLT) cocrystals, processed under both congruent and incongruent r 2010 American Chemical Society
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conditions, were examined by scanning electron microscopy (SEM). A schematic TPD was used to illustrate the crystallization pathways of congruently and incongruently saturating cocrystals in solvent evaporation and spray-drying methods (Scheme 1). A summary of the resulting solid phases from the solvent evaporation and spray-drying methods, as confirmed by PXRD, is presented in Table 2. The PXRD patterns of the CBZ-GLT system are presented as an example in Figure 1. In general, the X-ray diffraction peaks of spray-dried cocrystals were broader and lower in intensity than those prepared from other crystallization methods. This may be due to crystal imperfections, as demonstrated for spray-died particles earlier.19,25 Under incongruent saturation conditions, a mixture of cocrystals and cocrystal components was crystallized using the solvent evaporation method (Table 2). These results are quite understandable if we
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consider the thermodynamic pathway in the TPD for an incongruent system (Scheme 1a). The stoichiometric solution of drug and coformer supersaturates with respect to drug as it passes the region (L þ D) and with respect to drug and cocrystal in the region (L þ D þ D-C), leading to the precipitation of a mixture of phases. However, it is possible to generate pure cocrystals using solvent evaporation under these conditions through nucleation
Table 1. Model Cocrystals Used in This Study, with Their Stoichiometries cocrystal
abbreviations
stoichiometry
ref
carbamazepine-glutaric acid theophylline-nicotinamide urea-succinic acid caffeine-glutaric acid caffeine-oxalic acid indomethacin-nicotinamidea
CBZ-GLT THF-NIC URE-SUC CAF-GLT CAF-OXA IND-NIC
1:1 1:1 1:1 1:1 2:1 1:1
9 21 23 22 22 24
a The existence of IND-NIC cocrystals was indicated, but they were not thoroughly characterized. We have fully characterized 1:1 IND-NIC cocrystals by high performace liquid chromatography, DSC, PXRD, Raman, and solution NMR spectroscopy; data are presented in the Supporting Information.
Figure 1. PXRD patterns of (a) reference cocrystalline material of CBZ-GLT, and solid phases resulting by subjecting stoichiometric solutions of CBZ-GLT to solvent evaporation under (b) a congruently saturating condition (ethyl acetate) and (c) an incongruently saturating condition (ethanol) and to spray drying under (d) a congruently saturating condition (ethyl acetate) and (e) an incongruently saturating condition. Observe the additional peaks in pattern c.
Scheme 1. Ternary Phase Diagram (TPD) for (a) Incongruently Saturating and (b) Congruently Saturating Systemsa
a
L, D, C, and D-C indicate liquid phase, drug, coformer, and cocrystal solid phases, respectively (slightly modified from ref 7).
Table 2. Saturation Conditions for Different Cocrystals at Room and Spray-Drying Outlet Temperatures, along with the Solid Phases Resulting from Solvent Evaporation and Spray-Drying Methods cocrystal system
solvent
cocrystal saturation condition at room temperaturea
cocrystal saturation condition at the spray-drying outlet temperatureb
CBZ-GLT THF-NIC URE-SUC CAF-GLT
ethanol ethanol water water
incongruent incongruent incongruent incongruent
incongruent incongruent incongruent incongruent
IND-NIC CAF-OXA CBZ-GLT IND-NIC
methanol methanol ethyl acetate ethyl acetate
incongruent congruent congruent congruent
incongruent incongruent congruent congruent
solvent evaporationc
spray dryingc
CBZ form III, GLT, cocrystal THF, NIC, cocrystal, 2:1 cocrystal, SUC CAF monohydrate, GLT, cocrystal form I and form II IND solvate, NIC, cocrystal cocrystal cocrystal cocrystal
cocrystal cocrystal cocrystal cocrystal form Id amorphous cocrystal cocrystal amorphous
a Determined by slurrying the stoichiometric mixture of cocrystal components at room temperature; different solid phases were formed in the case of incongruent systems (Supporting Information, S4). This was a complementary experiment to slurrying the cocrystals. b Determined by slurrying the cocrystals at the spray-drying outlet temperature; different solid phases were formed in the case of incongruent systems (Supporting Information, S4). Spray-drying outlet temperatures were different for different systems in the spray-drying process (Supporting Information, S2). c The concentrations of the starting solutions were identical; the details are presented in the Supporting Information, S2. d Metastable polymorph of 1:1 CBZ-GLT cocrystals (refs 16 and 22).
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Figure 2. SEM pictures of spray-dried cocrystals of CBZ-GLT under (a) a congruently saturating condition (ethyl acetate) and (b) an incongruently saturating condition (ethanol).
control. Notably, slurrying of the respective stoichiometric component mixtures of these systems did not result in pure cocrystals (Table 2). On the other hand, under congruent conditions, uniform cocrystals were formed using the solvent evaporation method. This result can be explained by the TPD for congruently saturating cocrystals, as shown in Scheme 1b. The stoichiometric ratio line (i.e., dashed line) crosses the region (D-C þ L), where the cocrystal is a thermodynamically stable solid phase. Therefore, evaporation of a stoichiometric solution of cocrystal components usually leads to the formation of cocrystals. Also, pure cocrystals were obtained from slurrying stoichiometric component mixtures of these congruent systems (Table 2). Interestingly, spray drying of stoichiometric solutions of cocrystal components under incongruent conditions resulted in pure cocrystals of CBZ-GLT, THF-NIC, URE-SUC, and CAF-GLT (Table 2). However, for the IND-NIC system, the amorphous material that was formed crystallized to cocrystals on storage (see the Supporting Information). Clearly, in contrast to the solvent evaporation method, spray drying generated pure cocrystals under incongruent conditions. This is contrary to what one would expect, since spray drying is a rapid evaporation process. However, the operating temperature can have a major influence on the solubilities of the cocrystals and their components, thus eventually altering the stability domains beween the phases. Indeed, the slurry experiments at the outlet temperatures confirmed that the cocrystals were still incongruently saturating in the respective solvents. This ruled out the possibility of switching the order of thermodynamic stability for cocrystals and their pure components at the outlet temperatures of spray drying (see the Supporting Information). For instance, the order of stability was changed in the case of CAF-OXA cocrystals; a congruently saturating system in methanol at room temperature became incongruently saturating at the outlet temperature (Table 2). The spray-drying results of the CBZ-GLT and IND-NIC systems under congruent saturation conditions were similar to those under incongruent conditions (Table 2). Further, the morphology of the particles of CBZ-GLT cocrystals generated by spray drying under either incongruent or congruent conditions was similar (Figure 2). A detailed discussion of cocrystal particle characteristics is out of the scope of this article. Indeed, particle engineering and cocrystal particle characteristics are the topics of our ongoing research work. A very few single-component and multicomponent systems have been spray dried into partially or highly crystalline forms from solutions.19 Most of the literature in this area focuses on studying the effect of the processing conditions on the solid-state properties of the final product rather than on understanding the mechanisms behind the formation of the crystalline phase.26,27 Indeed, the precipitation mechanisms in spray drying are difficult to describe, as nucleation and growth processes are inaccessible experimentally.28 However, based on kinetic models, the crystal-
Alhalaweh and Velaga lization of materials using the spray-drying technique is thought to be a two-stage process: from a liquid to an amorphous or partially crystalline solid in the first stage and from an amorphous to a crystalline phase in the second.29 While it is difficult to propose a mechanism of cocrystal formation in spray drying, we have tried to rationalize the results. Cocrystals could preferentially nucleate and grow in highly supersaturated regions for the drug because of rapid solvent evaporation from the droplets, the presence of coformer, and/or an interaction between the drug and the coformer in the liquid phase. It could also be possible that, during spray drying, droplets containing the stoichiometric ratio of cocrystal components solidify and the system very quickly reaches the point D-C in the phase diagram, irrespective of the cocrystal saturation condition (Scheme 1a or b). This solid would comprise an intimate mixture of drug and coformer that instantaneously crystallizes to form cocrystals. However, some systems can result in an amorphous state, since the material crystallization propensity in the spraydrying process also depends on the processing conditions and material properties, e.g. the glass transition temperature. We are currently studying the influence of processing conditions and glass transition temperature of the components on the solid phase outcome in the spray drying. The formation of cocrystals via an amorphous or disordered state has also been proposed in solidstate grinding.4,30 These results suggest that spray drying is not limited by thermodynamic phenomena in the formation of cocrystals from solutions of stoichiometric components. In other words, cocrystal formation during spray drying defies the confinement of the stability zone in the phase diagram. Therefore, spray drying can have significant advantages in scale-up operations over equilibrium methods, which require a thorough understanding of phase behavior and considerable effort in optimization and control of the process. Remarkably, the 1:1 URE-SUC cocrystal was discovered and consistently generated in pure form by spray drying but not by slurry or reaction crystallization methods.22 Furthermore, a metastable form of the CAF-GLT cocrystal, i.e. Form I, was generated by spray drying, reiterating our explanation of kinetic control in the cocrystal formation by spray drying. These results suggest that spray drying could be used for preparing metastable polymorphs or stoichiometrically diverse cocrystals. The findings of this study were as follows: (1) pure cocrystals or even new cocrystals can be generated simply by spray drying; (2) the formation of cocrystals under incongruent saturation conditions in spray-drying processes undermines the importance of thermodynamic phenomena; (3) spray drying is a suitable technology for the preparation and scale-up of cocrystals. More studies are essential to better elucidate cocrystal formation mechanisms in the spray-drying process. Acknowledgment. The authors wish to thank Kempestiftelserna for an instrument grant. S.P.V. is grateful for the project grant from the Swedish Research Council. We thank Dr. Scott Childs for the solution NMR work and for comments on the manuscript. Supporting Information Available: Characterization and confirmation of 1:1 IND-NIC cocrystals, determination of cocrystal saturation conditions, method of preparation of cocrystals, solidstate characterization, and analysis of different solid phases. This material is available free of charge via the Internet at http://pubs. acs.org.
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