Article pubs.acs.org/OPRD
Efficient Purification of an Active Pharmaceutical Ingredient via Cocrystallization: From Thermodynamics to Scale-Up Pascal Billot,*,† Patrik Hosek,† and Marc-Antoine Perrin‡ †
Chemical Development/Physical Quality, ‡Analytical Sciences/Solid State, Sanofi R&D, LGCR, 9 quai Jules Guesde, 94403 Vitry sur Seine cedex, France ABSTRACT: Cocrystallization as a purification step was the only way to isolate an active pharmaceutical ingredient with acceptable chemical and physical specifications. The process design controlling chemical quality and polymorphism issues is described, from the thermodynamics of cocrystal formation and cleavage, to microscale data acquisition, to laboratory scale-up and transfer to the pilot plant.
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INTRODUCTION Cocrystals are becoming popular in the pharmaceutical industry as they can offer advantages over the use of the active pharmaceutical ingredient (API)1−3 by itself. Pharmaceutical companies now consider the possibilities of cocrystals early in the development of their APIs. Similar to salts, the investigation of cocrystals can multiply the number and diversity of solid form choices and thus increases the probability of identifying suitable development candidates for APIs that present solubility, bioavailability,4 or stability issues. As a means to improve unit operations such as purification or racemic resolution,5 the application of cocrystal intermediates might also be envisaged. Publications citing such applications are not numerous. Examples are thus far limited to the extraction of cinnamic acid from a fermentation broth6 and to the feasibility of purifying synthetic mixtures by forming a cocrystal of the major component7 or a cocrystal of the impurity.8 The design of scalable cocrystal processes which give high cocrystal purity and good yields is often not obvious. This contribution presents the application of cocrystals to the purification of SAR1 (Figure1), a SRC kinase inhibitor selected
RESULTS AND DISCUSSION Background. Crude SAR1 is obtained after three concatenated (nonisolated) steps as a dark-brown solution in chlorobenzene. SAR1 represents only 60% of the dry concentrate. The remaining material consists of organic impurities, only a few of which have been identified. All previous purification attempts, either by chromatography or by impurity adsorption (charcoal, alumina, or silica) followed by repeated recrystallizations in multiple solvents, were inadequate. The product was isolated at best in 90% purity with a dark-brown color. From the polymorphism study (Figure 2) it was shown that this API readily forms solvates (propanol, N,N-dimethylaceta-
Figure 2. Relationship between crystalline forms of SAR1.
mide, N-methyl-2-pyrrolidone, DMSO, methyl isobutyl ketone, acetone, DMF, methyl-THF, DME, hexafluoroisopropanol) as well as one heterosolvate (methyl propyl ketone/water). The first strategy to purify the substance was thus to prepare initially a crystalline solvate and then to desolvate it to the thermodynamically stable form (named anhydrous 1) by drying. Unfortunately for this strategy, solvates that had been easily obtained from a pure API feedstock were subsequently difficult to crystallize from the crude API solution, with the exception of the acetone and DMSO solvates. As is often the case, probably the numerous impurities in the crude APIs inhibited nucleation and growth of solvates. Crystallizations were very slow even after seeding, and yields were low in the
Figure 1. Structure of SAR1.
for treatment of acute myeloid leukemia. This specific example is interesting due to the numerous constraints imposed by the chemistry leading to the active molecule and to its very rich population of pseudopolymorphs. These issues left little design space in which to maneuver. Knowledge of phase behavior as described in ternary phase diagrams9 aided in the choice of the cocrystal coformer and the solvent necessary to cleave the cocrystal and to return to the API. In addition, acquiring a knowledge of the system’s thermodynamics aided in accelerating the laboratory-scale development and transfer to the pilot plant. © XXXX American Chemical Society
Special Issue: Polymorphism and Crystallization 2013 Received: August 2, 2012
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dx.doi.org/10.1021/op300214p | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
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For a successful crystallization processes we knew that (1) formation of the cocrystal would be favored under conditions offered by congruent cocrystal solubility, i.e. a symmetrical phase diagram with similar solubilities, ideally 1:1 molar ratio, for API and coformer (left diagram in Figure 5) and (2) that disassociation of the cocrystal to liberate SAR1 would be favored under conditions described by the opposite phase diagram: ideally no existence domain for the cocrystal (eutectic diagram, cocrystal is metastable) i.e. big differences in solubilities (right diagram) and at least a diagram with noncongruent solubility for the cocrystal Solubilities of already known coformers and of the API were measured in solvents where the API is not prone to crystallize as a solvate (Table 1). Given that the crude API was already available as a solution in chlorobenzene, this narrowed the list of coformers to benzoic acid as it was among the only acids to be soluble in chlorobenzene. To cleave the cocrystal and return to the API anhydrous 1 form, an ideal solvent would readily solubilize benzoic acid and additionally provide a high molar solubility ratio between the acid and API. As Table 2 indicates, the best solvent candidates for cleavage were isopropanol, methyl tert-butyl ether (MTBE), and acetonitrile. Feasibility Test with Pure and Crude API. We first confirmed the existence of the benzoic cocrystal with pure API by crystallization in CH2Cl2 as this solvent presents a more symmetrical phase diagram. Thus, API (1 g) and one equivalent of benzoic acid were dissolved in CH2Cl2 (5 vol) at room temperature. After a few minutes a solid crystallized, and after 2 h at room temperature the crystals were isolated by filtration in about 67% yield. The XRPD pattern of the cocrystal was identical to that seen from the comilling experiment with benzoic acid and different from XRPD patterns of the starting materials (Figure 6). Feasibility was then verified with pure API in chlorobenzene. The API and one equivalent of benzoic acid were added to chlorobenzene (5 vol) at room temperature. The resulting suspension was heated to 80 °C (no dissolution) and cooled to room temperature. The suspension was filtered after 2 h with a yield of 79%. XRPD of the isolated solid corresponded to the cocrystal. When phase diagrams are with noncongruent cocrystal solubility, crystallization should be done with an excess of coformer or API, depending on the diagram shape.11 These two trials showed that even when the molar ratio between acid and API are close to 60 the phase diagram remains symmetrical (congruent solubility) and crystallization can be successful starting with components in the cocrystal molar ratio.
range of 10−20%. Powder colors were greatly improved from dark brown to light yellow, and after drying (40 °C/30 mbar) chemical purities were around 95%. It was impossible, however, to get an API within International Conference on Harmonization (ICH) residual solvent specifications as the solvates liberated solvent at temperatures higher than 100 °C often with concomitant melting followed by degradation (Figure 3).
Figure 3. Superposed DSC and TGA (dotted line) of the DMSO solvate.
It was presumed that an aminopyrimidine motif present in SAR1, a well-known motif for cocrystal formation, would form two hydrogen bonds with acid coformers (Figure 4), thus providing a good driving force for nucleation and growth.
Figure 4. Possible hydrogen bonds with an acid coformer.
A limited cocrystal screening was done. Five hits were found with oxalic, malonic, fumaric, succinic, and benzoic acids. By Design Approach. Important points to take under consideration for the purification of raw API via a cocrystal include the cocrystal feasibility, necessity to obtain only anhydrous form 1 after cocrystal cleavage, the amount of residual solvent and residual coformer in the cleaved product, and for this molecule in particular, the potential for undesired cleavage of the urea function.
Figure 5. (a) Phase diagram with congruent solubility, (b) noncongruent solubility, (c) no existence domain for the cocrystal. B
dx.doi.org/10.1021/op300214p | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Article
Table 1. Approximate solubilities of API and coformer at room temperature (g/L solvent) chlorobenzene CH2Cl2 alcohols ethylacetate toluene alkanes MTBE acetonitrile 2-butanone (MEK)
API
benzoic acid
succinic acid
fumaric acid
malonic acid
oxalic acid
5 20
