Article pubs.acs.org/OPRD
Control of Crystal Modification and Crystal Shape by Control of Solid−Solid Transitions during Crystallization and Drying: Two Industrial Case Studies‡ Fabrice Dufour,* Benjamin Stichel, and J. Ian Grayson Business Line Health Care, Evonik Industries AG, Rodenbacher Chaussee 4, Building 915, 63457 Hanau-Wolfgang, Germany S Supporting Information *
ABSTRACT: Crystallization and drying are the final steps in the manufacture of most drug substances that determine their final features and may also impact the manufacture of the formulated drug product. It is important to understand and control the mechanisms involved in the crystallization and drying processes to avoid handling and formulation problems, and this is illustrated with two examples of large-scale processes. In the first, a solid−solid phase transition between two very similar crystalline forms was shown to lead to dramatic particle size reduction and consequent processing issues; the unwanted phase transition was avoided by careful choice of crystallization conditions. In the second, control of the drying conditions allowed a rapid solid−solid phase transition of a mixed solvate into a stable anhydrous form.
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INTRODUCTION Crystallization is one of the most common processes in chemistry. A typical manufacturing process for an active pharmaceutical ingredient (API) may contain five or more separate crystallization steps. Every process chemist regularly encounters problems with the behavior of a compound in the solid state and not just at the research or process development stage1 but even when the process is in routine production. In an extreme case, the appearance or disappearance of a polymorph during production has led to the withdrawal of a product from the market.2 Many of the characteristics and properties of the final solid material, such as crystal form, particle size distribution, solubility and bulk density and its processing and formulation properties,3 including filtration, drying, compaction and granulation, are strongly influenced by the initiation of the crystallization process. This has led to an increased effort to achieve a better understanding and control of the mechanisms of crystallization,4 polymorphism5−7 and solvent-mediated phase transitions.4,5,8 In spite of this increased effort in understanding the crystallization process, it has been pointed out that relatively little emphasis has been placed on the importance of the drying process in determining the final solid properties of a pharmaceutical product.9 Kougoulos et al.10 and Kontcho Kom et al.11 have studied the influence of parameters such as the type of dryer, mixing rate, temperature and residual moisture on the bulk powder properties of pharmaceuticals. Cypes et al.12 described a technical solution to prevent dehydration of a monohydrate form during a drying process at the 30 kg scale. Feth et al. have described the process development of the drying of a nonstoichiometric hydrate, which is subject to several possible phase transitions.13 Other investigations have focused on the improvement of heat transfer and overall drying rate, taking into account the kinetics of desolvation.14 The recent development of process analytical technologies such as FBRM, IR and Raman spectroscopy, have not only helped significantly in the understanding, monitoring © 2013 American Chemical Society
and scale-up of crystallization processes, but are also being widely used to monitor solid-state process including drying, granulation, coating and extrusion.15,16 We present here two case studies on the optimization of crystallization and drying process for an API and for an intermediate, both of which are routinely manufactured at the multitonne scale at Evonik. Both cases involve complex systems undergoing rapid solid-phase transitions, which made the characterization and understanding of the solid-state behavior difficult. Analysis of the industrial process using PAT as well as traditional methods such as X-ray powder diffraction (XRPD), phase diagrams and DSC led to the development of improved processes, which gave a more consistent product form at production scale.
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CONTROL OF CRYSTAL MORPHOLOGY BY MEANS OF CONTROL OF SOLID−SOLID TRANSITIONS DURING CRYSTALLIZATION KAAD17 is a potassium salt of an amino acid derivative used in the synthesis of an API, which has been manufactured for many years at Evonik’s site in Hanau (Germany). The product is isolated by crystallization from ethanol containing a small amount of water. The process was reinvestigated because of continuing inconsistency in stirring, centrifugation and drying behavior and variation in the solid-state properties of the product. Some of these occurred on a prime batch and others only when the mother liquors were recycled, as listed below. (1) Formation of a product crust on the vessel wall although batches were seeded in order to favor a smoother crystallization. This led to poor heat transfer and required reheating to remove the crust. Special Issue: Polymorphism and Crystallization 2013 Received: November 16, 2012 Published: February 12, 2013 568
dx.doi.org/10.1021/op300333h | Org. Process Res. Dev. 2013, 17, 568−577
Organic Process Research & Development
Article
corresponding to the production batch in the range 50−55 °C, which is believed to correspond to the presence of the LT form at 55 °C. However filtration of a sample and immediate XRPD analysis showed only the first peak of the LT form at 4.9°, with the rest of the pattern corresponding to the monohydrate (see Supporting Information). We surmise that the LT form is either an anhydrous phase or an ethanol solvate. HT Form. The HT form was obtained by reslurrying the monohydrate in ethanol at 50 °C. The first peak of its XRPD pattern has also been observed in some wet samples, after washing with ethanol, but disappears on standing. The HT form is most probably an ethanol solvate.18 M′ Form. The M′ form is key to understanding the crystalline behavior of KAAD. It has an XRPD pattern similar to the monohydrate form, but always exhibits a lower crystallinity, and shows two additional peaks at 23° and 24.5°, which are not indexed by the monoclinic unit-cell found for the monohydrate. A reasonable triclinic unit-cell was found by powder indexing, which could index all the peaks of the experimental XRPD pattern with a figure of merit 10 (Table 1 and Figure 2). The DSC analysis of this form showed a symmetrical dehydration peak at 80−90 °C and two melting peaks at 175 and 180 °C, due either to a recrystallization process during the first melting event or to the formation of two separate anhydrous forms during the DSC experiment (see Supporting Information). In addition a variable loss of mass (4−12%) was observed during DSC experiments. A rapid phase transition from M′ to monohydrate was observed during stirring of the suspension at 20−25 °C following crystallization (Figure 3). An exothermic event several hours into the stir period was found to correspond to a spontaneous conversion of the M′ form (large needles) to the monohydrate (small crystals). XRPD data confirmed identity of the forms. The FBRM analysis confirmed that the crystal size reduction was not a result of continuous mechanical attrition due to stirring but occurred exactly during the exothermic event (see Supporting Information). We concluded that a phase transition occurred between two separate crystalline phases: the M′ form and the monohydrate.
(2) A much thicker product suspension was sometimes obtained during liquor recycle batches, leading to plugging, and to a requirement for additional solvent. (3) Long centrifugation times (by a factor of 2−3) were routinely observed for prime and for some recycle batches. (4) Large hard agglomerates formed during drying, leading to longer drying times, particularly for prime batches. This led to variable product bulk density, dissolution rates and reaction times in the subsequent process stage. Five different crystalline forms were detected during the investigation and are differentiated by their XRPD patterns (Figure 1). Each phase is reproducible in different experiments,
Figure 1. XRPD patterns of the five observed crystalline forms of KAAD.
and each is considered to be a single phase. As some of the phases are unstable and convert into the more stable monohydrate and M′ forms, it was not possible to completely characterize all the forms observed. Monohydrate. (M Form). This was detected by drying the wet product in air, and has been characterized by DSC (loss of mass 7.5%), TG (loss of mass 7.3%) and KF (water content 7.5%), all corresponding to a theoretical monohydrate containing 7.4% water. DSC shows a broad peak at Tonset 84 °C, transforming to an anhydrous phase with mp 174 °C (see Supporting Information). Powder indexing of the XRPD pattern gave a solution with a monoclinic unit cell and with a good figure of merit (Table 1). Anhydrous Form. The anhydrous form was detected in the industrially dried product and also by dehydration of the monohydrate at 90 °C under vacuum in the laboratory. DSC shows a single melting peak with Tonset 172 °C. LT Form. The LT form was obtained by reslurrying the monohydrate in pure ethanol at 20 °C. If small amounts of water (1%) are present in the system, however, it is transformed within minutes to the monohydrate or the M′ phase after filtration. Indeed, a visual change of the suspension aspect and a change of crystal shape were reproducibly and reversibly observed on heating and cooling a suspension
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HETEROGENEOUS EQUILIBRIA The isothermal section of the ternary system KAAD/water/ ethanol at 20 °C was investigated. KAAD is not chemically stable in water and only the ethanol-rich region could be investigated (Figure 4). The stability domain of the monohydrate was identified, but because of the lability of the LT and HT forms, it was difficult to identify reliably which other solid phases were in equilibrium with the saturated solutions in the ethanol-rich region. For simplicity it is assumed that the LT form is actually the only equilibrium solid phase in the ethanol-rich region at the temperature studied; the observed M′ phase results from rapid phase transition of the LT form after sampling. In accordance with Landau and Palatnik’s contact rule19 a 3-phase domain containing LT, monohydrate and a 2-fold saturated liquid in equilibrium was deduced and drawn between the two 2-phase domains of LT
Table 1. Powder indexes of the monohydrate and the M′ form XRPD pattern
crystal system
a (Å)
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å3)
probable space group
# of exp peak
figure of merit
M M′
monoclinic triclinic
13.90 13.82
4.44 10.49
9.86 8.66
90 70.4
92.5 92.4
90 93.2
609 1182
P21 P1̅
20 20
21.4 10.2
569
dx.doi.org/10.1021/op300333h | Org. Process Res. Dev. 2013, 17, 568−577
Organic Process Research & Development
Article
Figure 2. Comparison of the powder indexing solutions with the experimental XRPD patterns for the monohydrate form (top) and the M′ form (bottom). The green and blue lines below correspond to the theoretical and experimental peak positions respectively.
Figure 3. Profile of a recrystallization experiment showing a spontaneous exothermic event ∼7 h into the stir period, together with pictures of the suspension before and after the exotherm.
and monohydrate respectively. The possibility that the actual stable equilibrium contains a nonstoichiometric hydrate, M′, can, however, not be excluded. The representative compositions of the crystallization solutions from production campaign 17 were plotted on this
phase diagram (green triangles in Figure 4). It is clear that the composition of the production batches is very close to the phase boundary where the monohydrate is not the only solid phase in stable equilibrium with the saturated solution. This is particularly true for the prime batches. 570
dx.doi.org/10.1021/op300333h | Org. Process Res. Dev. 2013, 17, 568−577
Organic Process Research & Development
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the suspension was heated again to 50 °C for 2 h (below the transition temperature to the LT form) at a moderate stirring rate, and then cooled down to 20 °C within 4h. The ripening at 50 °C led to an improved crystal form with agglomerates of larger needles (Figure 5). This was reproducibly achieved, both for prime batches and with recycled mother liquors, at laboratory and production scale (see Supporting Information). XRPD analysis of the solid product isolated from the optimized process showed some interesting differences between the laboratory and the plant results. In production batches, we routinely only isolated the monohydrate form. However, reproduction of the optimized process in the laboratory showed the M′ form as the isolated product, with a water content from 5.5−7.1%, despite milder drying conditions. We were pleased to see that no amorphous material was obtained either in the plant or laboratory runs (see Supporting Information). The apparent higher stability of the M′ form could be because of the improved crystallinity achieved by the new crystallization conditions, some crystal defects being required to trigger the transition.20 Another hypothesis is that the modified crystal morphology (as suggested by different orientation effects and relative intensities of the diffraction peaks) impairs the diffusion kinetics of the solvent molecules in the crystal structure and precludes it from achieving the required exact composition of the monohydrate. It has, however, been assumed that the M′ form and the monohydrate are distinct phases because of the exothermic phase transition observed in the stirred suspension, which is accompanied by a change from the triclinic to the monoclinic crystal form with improved crystallinity. On the other hand, based solely on the XRPD patterns, M′ and the monohydrate could be considered as the same crystal form with modified relative intensities due to different crystallinity and defect concentration, different crystal shapes and texture effects. That apparently different “XRPD polymorphs” actually correspond to the same phase with different morphologies has already been pointed out by Gavezzotti.21 By considering the M′ form as a defect version of the monohydrate, the phase transition would consist in rebuilding the initial form in a more ordered way, an unprecedented type of spontaneous recrystallization of a poorly ordered crystal structure. A simpler explanation is that M′ and the monohydrate are actually two distinct phases of almost identical XRPD patterns despite significant structural differences. These process changes (see Experimental Section) had a major impact on the whole manufacturing process. Because of the higher water content required for the solution before crystallization, distillation of the mother liquors and addition of
Figure 4. Ethanol-rich region of the isothermal section of the KAAD/ ethanol/water ternary system at 20 °C.
On the basis of these observations, we postulate the following sequence of events during the crystallization process. In a mixture containing ∼3% water, the LT form is the first crystalline phase formed on cooling (at ∼55 °C). This then transforms to the M′ form, which has a structure able to contain ethanol and water over a range from 0.5 water and 0.5 ethanol, down to 1.0 water. This fits the loss on drying range observed in the DSC. When the composition of the crystals exactly fits that of the monohydrate, a reordering of the solid phase into the more stable monohydrate of higher (monoclinic) symmetry becomes possible. This results in the more crystalline small bent needles of monohydrate observed, and leads to mixtures which are difficult to stir.
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PROCESS OPTIMIZATION The aim of the optimization was to control the crystallization process in order to avoid the dramatic crystal size reduction induced by the M′ to monohydrate phase transition. This involved reproducibly producing crystals of the monohydrate, but of a size and shape which would ensure improved stirring, centrifugation and drying properties. The water content of the solution before crystallization was adjusted to 5.0−6.0%, (the compositions of actual plant batches run using this optimized process are indicated by red diamonds in Figure 4). After crystallization by rapid cooling to 40 °C under vigorous stirring,
Figure 5. Photographs of the monohydrate crystals obtained with the old crystallization process (left), and with the new crystallization process, before (middle) and after (right) the ripening period at 50 °C and cooling to 20 °C. 571
dx.doi.org/10.1021/op300333h | Org. Process Res. Dev. 2013, 17, 568−577
Organic Process Research & Development
Article
the formation of an amorphous product during storage of the wet product (as filtered, or acetone washed), during drying, or because of drying under the conditions of the XRPD experiment. H1 Form. This is present in the wet product obtained under plant crystallization conditions, and is the most stable form under the final conditions of the crystallization. However on isolation and storage, either in the presence of the mother liquors or of an acetone wash, or when allowed to dry in air, it converts into forms H2, H3, or a mixture of both. XRPD patterns of an acetone-washed plant sample dried in air over 12 days under ambient conditions show the conversion of H1 into H3 together with some H2 (Figure 7).
fresh ethanol for the next batch were reduced to the minimum required to attain 5−6% water in the crystallization solution. In addition, milder drying conditions were applied to dry the product only to the monohydrate stage (at 60 °C) rather than to the anhydrous form (at 90 °C), once it had been shown that KAAD monohydrate could be used in the next stage of the process. Some of the modifications to the production process, which resulted in a reduction in production costs of 20%, are shown in Table 2. Table 2. Comparison of the original and optimized crystallization processes for the manufacture of KAAD initial (campaign 17) percentage of batches with stirring/ transfer problems centrifugation time LOD of the wet product drying time amount distilled to recycle the liquors average ethanol usage/batch yield crystallization time
optimized (campaign 18)
30%
0
16.5 h 35% 54 h 3000 L 3750 L 92% 8h
8.5 h 26% 19 h 1500 L 1900 L 92% 12 h
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CONTROL OF CRYSTAL MODIFICATION BY MEANS OF CONTROL OF THE SOLID−SOLID TRANSITION DURING DRYING CASAD17 is a metal salt of an amino acid derivative, an API in routine production at Evonik at a multitonne scale. The salt is isolated by crystallization from an acetone−water mixture at 20−25 °C, centrifuged, and washed with acetone. It is dried under vacuum at a maximum temperature of 75 °C, to a residual water level of
