Formation of Piroxicam Polymorphism in Solution Crystallization

Article pubs.acs.org/crystal

Formation of Piroxicam Polymorphism in Solution Crystallization: Effect and Interplay of Operation Parameters Thomas B. Hansen* and Haiyan Qu

Downloaded by CENTRAL MICHIGAN UNIV on September 14, 2015 | http://pubs.acs.org Publication Date (Web): August 13, 2015 | doi: 10.1021/acs.cgd.5b01016

Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark ABSTRACT: Recently, new insights into crystallization prior to actual nucleation have shown interesting results for drugs showing differences in hydrogen bonding or orientation in various polymorphic forms. On the basis of this concept, piroxicam was chosen as a model compound because the two common forms, I and II, show hydrogen bonding between different parts of the molecules and differences in the orientation of molecules in the crystal lattice. The goal of this work is to explore how various methods of controlling polymorphism during production could be employed. The mechanisms behind the nucleation were also explored, and new insights into polymorphic control are documented and discussed. The crystal landscape was mapped for cooling crystallization of piroxicam from acetone/water mixtures (0.5 K/min) and for antisolvent crystallization from acetone with water as the antisolvent. Varying cooling rates and the use of seeding were used to determine if the system was controlled by a single nucleation event or if the initial form was not the determining factor for the produced form. Finally, the use of soluble additives have previously been found to impact the polymorphic form and was thus employed to impact the nucleation rate as well as the formation of the solid forms in batch cooling crystallization. molecules prior to actual nucleation.3 Alternatively, nucleation of a specific polymorph can be promoted by the presence of an ordered surface, either of a crystalline solid or of a polymer.4,5 The effectiveness of this approach fits with the greater importance of single nucleation events that were recently found to be more common than previously thought.6 Different excipients are commonly used in the production of pharmaceutical products as fillers, coatings, or stabilizers. With respect to the effective production and control of a specific polymorph in the pharmaceutical industry, it is particularly important to gain a comprehensive understanding of the effects of these excipients upon the formation of the crystal structure of the API. On one hand, this will allow the strategy of using the excipients to inhibit undesired or promote desired crystal forms during nucleation and crystal growth as a control of the crystallization process.7−11 On the other hand, this leads to the risk of an excipient impacting polymorphism in an undesired fashion, during either production or storage. The solute molecules may present in different configurations in different solutions, and thus, the impact of solvents and soluble additives on the nucleation of polymorphs can be more significant for the polymorphic system in which different solid forms possess different intermolecular hydrogen bonding and/ or show completely different orientations of the molecules in the unit cell.12,13 Kulkarni et al.12 have reported the link

1. INTRODUCTION With the increasing number of drug candidates with poor water solubility, crystallization of active pharmaceutical ingredients (APIs) and especially control of the polymorphism have become important challenges in the pharmaceutical industry.1 One efficient method for developing the formulation of poorly water-soluble drugs is to first explore the solid form landscape of the API and subsequently select the form with the optimal properties for product development. However, selecting the desired form, which is often a metastable form with a higher solubility, makes it necessary to design the crystallization processes that lead to the formation of the pure target form without any contamination of other polymorphs. Even a small amount of an undesired crystal form may catalyze the unexpected solid phase transformation in the downstream processing as well as in storage and thereby lead to serious problems related to the altered bioavailability of the product. As a consequence, the in-depth understanding of the effects of the operation parameters and the interplay of the parameters on the formation of the different polymorphs of an API during crystallization is of paramount importance in the design and development of a robust crystallization process. It is generally accepted that the formation of the different polymorphs starts from the nucleation stage, where blocks are added to clusters.2 The building blocks are not necessarily seen as just one drug molecule, and two or more molecules might therefore be self-associated prior to cluster formation. The impact of solvents or soluble additives may in such cases be due to the formation of a preferred association between API © 2015 American Chemical Society

Received: July 17, 2015 Revised: August 1, 2015 Published: August 4, 2015 4694

DOI: 10.1021/acs.cgd.5b01016 Cryst. Growth Des. 2015, 15, 4694−4700


Crystal Growth & Design

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operation of crystallization processes of APIs that are capable of forming different solid forms.

between the solvent and the nucleation of isonicotinamide (INA) polymorphs. The solvent in which the INA molecules present in a head-to-tail chain configuration promoted the nucleation of the polymorphic modification of INA with a similar molecular configuration in the crystal structure. However, such a configuration of the solute molecules in solution is not stable and can change with various parameters, such as the solute concentration, the temperature, the presence of seed crystals or additives, and the operating mode of crystallization. Therefore, the effects of solvents on polymorphism nucleation and the interplay between the operation parameters in different crystallization processes need to be thoroughly investigated to establish a feasible strategy for polymorphism control during crystallization processes. In this work, piroxicam, which is a nonsteroidal antiinflammatory drug (NSAID), has been chosen as a model compound. It has been reported that piroxicam can form four anhydrous polymorphs and one monohydrate.14−16 Among the four polymorphs, forms I and II can be produced by simple crystallization from solution, whereas forms III and IV can be prepared by melt/quench cooling or by spray drying from amorphous piroxicam.17 As shown in Figure 1, the two

2. EXPERIMENTAL METHODS 2.1. Materials and Equipment. Piroxicam form II was purchased from Afine Chemicals Limited (Zhejiang, China). Form I was purchased from Chr. Olesen Pharmaceuticals A/S (Gentofte, Denmark). The monohydrate form was created by suspending form II in a 70 mol % ethanol/water mixture for 48 h, filtering it, drying it, and using Raman spectroscopy to confirm complete transformation. All solid forms have been confirmed by X-ray powder diffraction.14−16 Raman spectroscopy was used in this work to identify the solid forms of the crystals produced in the experiments; it was deemed sufficient because clear differences in the Raman spectra of the different forms have been shown in previous work.20 The additives, polyvinylpyrrolidone (PVP) K25 and polyvinylpyrrolidone (PVP) K90, were purchased from BASF. Vinylpyrrolidonevinyl acetate copolymer (Kollidone VA64), polyethylene-propylene glycol copolymer (poloxamer F68), poly(ethylene oxide) (PEO), methylcellulose (MC), ethylcellulose (EC), hydroxypropyl cellulose (HPC), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), and poly(methacrylic acid-co-methyl methacrylate) 1:1 Eudragit L100 were bought from Sigma-Aldrich Chemical Co. Hydroxypropyl methylcellulose (HPMC, hypromellose, 15 mPa) and hydroxypropyl methylcellulose (HPMC, hypromellose, 50 mPa) were obtained from Shin-Etsu. Ethanol (anhydrous, 99.9 vol % purity) was from Kemetyl A/S (Køge, Denmark). Acetone CHROMASOLV HPLC (>99.8%) from Sigma-Aldrich and deionized water were used as the solvent and antisolvent. 2.2. Raman Spectroscopy. A Bruker MultiRAM FT-Raman instrument with a 1064 nm laser, operating at 500 mW with 120 scans, was used to collect Raman spectra for the majority of the samples. For experiments with a very low yield of crystals, a Bruker Senterra Dispersive Raman microscope with a 785 nm laser operating at 100 mW with a 5 s integration time and two scans was used. As shown in Figure 2, the Raman spectra of the various forms showed enough differences to distinguish among form I, form II, and

Figure 1. Piroxicam form I (left) and form II (right), showing differences in orientation and hydrogen bonding.

polymorphs of piroxicam, forms I and II, have different intermolecular hydrogen bonding networks and show different molecular orientations. Form I shows a head-to-head configuration, whereas form II shows a head-to-tail configuration. The effects of different soluble additives on the formation of piroxicam forms I and II have been studied in our previous work.18,19 It has been discovered that the additives with partial Hansen solubility parameters δT and δh similar to those of piroxicam will be more likely to affect the nucleation of the different polymorphs. On the other hand, the additives with δh values similar to that of the solvent will have more interaction with the solvent and thus be more likely to affect the nucleation of the monohydrate if water is present. The objective of this work is to gain a more in-depth understanding of the formation of piroxicam solid forms in both cooling and antisolvent crystallizations. The effects of different operation parameters, such as solvent, temperature, solute concentration, the presence of certain soluble additives, polymorphic seeding, and furthermore the interplay of the operation parameters on the crystallization of piroxicam, have been investigated. A solid form landscape of piroxicam has been established to show the link between the operation parameters and the crystal structure of the product. The obtained results demonstrated the complex nature of the nucleation of a polymorphic system, which leads to a significant challenge in the design and

Figure 2. Raman spectra of anhydrous form I, form II, and the monohydrate of piroxicam.

the monohydrate. In experiments conducted with acetone/water mixtures, it was often found that several forms coexisted, and Raman mapping was therefore utilized in a 4 × 4 grid spread over a large area of the filtered crystals. Although differences in the spectra were enough to do a basic visual determination of the forms, we decided to use MCR-ALS21 to combine and analyze multiple spectra. This also made it more feasible to run a large number of experiments without having a large manual workload in interpreting spectral results. By using such an analysis method, a more precise quantitative measurement of the composition of the mixture of different forms was also achieved, making it possible to better detect impacts that changed only the composition of the mixture slightly. 4695




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MCR-ALS is an offshoot of PCA, and like PCA, the goal is to describe a given data set, D, by a combination of matrices C and S and the error matrix E (D = CST + E). However, instead of each component representing the most mathematical variance, the goal of MCR-ALS is to have each component represent an actual chemical compound; thus, the loadings in MCR-ALS represent concentration profiles (C) for each compound, and the scores (S) represent the response, in this case Raman spectra for each crystal form.22 Similar to PCA, data matrix D is sought to be reconstructed from the concentration and spectra. In short, scores in PCA are similar to a standard spectral matrix and loadings are similar to the concentration matrix used in MCR-ALS. MCR-ALS for analysis of Raman data in crystallization has previously been used successfully by the authors.20 In this case, however, the standard spectra for all relevant forms could be used as input for the analysis. The collected Raman spectra and standard spectra of form I, form II, and the monohydrate were combined into a single matrix for results and one for the standards. MCR-ALS23,21 with non-negative constraints for spectra and concentrations and closure for a concentration set to 100 were used to quantify the composition of the solid mixture. A value of 100 for concentration was used to easily translate into the percentage of each form present in a given sample. Results were then averages for all of the spectra to quantify a single composition profile for each experiment. 2.3. Nucleation Kinetics Characterized by Metastable Zone Width Measurement. The effects of the additives on the nucleation kinetics of the polymorphs of piroxicam have been investigated by measuring the metastable zone width (MSZW) of piroxicam solutions with and without the additives. Experiments were conducted using a Mettler Toledo Easymax 102 Advanced Synthesis Workstation, fitted with two 100 mL glass reactors, a magnetic stirring crossbar, and a separate temperature probe for each reactor. The setup was controlled using the iControl software package and using N2 as the purge gas. The MSZW experiments were shielded from sunlight, and backlight LEDs of the Easymax system were only used periodically to check the turbidity of the solution to prevent any degradation of the API. An ethanol/water mixture containing 70 mol % ethanol has been used as the solvent. Piroxicam solutions saturated at 37 °C were prepared by mixing 50 g of solvent and an appropriate amount of pirxociam in the reactor. For the experiments with additives, the solvent and additives were mixed with an additive concentration of 5 μg/mL solvent. After the additive dissolved in the solvent, piroxicam was added to the solution. The solution was heated to 45 °C at a heating rate of 1 K/min and was kept at 45 °C for 10 min to achieve thorough dissolution of piroxicam crystals. The solution was then cooled at a rate of 0.5 K/min. The MSZW was characterized by the onset of nucleation, which was denoted by a sudden change in the turbidity of the solution observed with the naked eye. Approximately 1 min after nucleation happened, the suspension was filtered and the crystal form was determined using Raman spectroscopy. 2.4. Crystal Landscape of Piroxicam in Acetone/Water Mixtures. Formation of the piroxicam polymorphs in pure acetone and acetone/water mixtures (down to 80 wt % acetone) was investigated by performing cooling crystallizations with different initial concentrations of piroxicam. The experiments were conducted in the same Mettler Toledo Easymax 102 Advanced Synthesis Workstation used for MSZW experiments. Piroxicam solutions saturated at different temperatures were prepared and heated to 50 °C and kept for 1 h to achieve thorough dissolution of the piroxicam crystals. Cooling was performed at a rate of 0.5 K/min until the solution became turbid. The temperature at this turbid point was recorded and was considered as the nucleation point. After sufficient crystals had formed in the suspension (approximately 10 min), cooling was stopped and the suspension was filtered. The separated crystals were kept in a fume hood for 2 h and then brought to Raman for analysis. The effects of selected additives on the formation of piroxicam polymorphs have been studied by performing the cooling crystallization with additives at a concentration of approximately 200 μg/mL solvent. The feasibility of directing the formation of piroxicam polymorphs using polymorphic

seeding was investigated with a seeding load of 5% (defined as the seed mass per solute in solution). 2.5. Solubility of Piroxicam in Acetone/Water Mixtures and Antisolvent Crystallization of Piroxicam. The solubility of piroxicam form II in acetone/water mixtures has been measured using a gravimetric method. It was observed that the solubility of piroxicam decreases significantly with an increasing water concentration, which suggested the feasibility of performing antisolvent crystallization by using water as the antisolvent. Piroxicam/acetone solutions saturated at 45, 35, and 25 °C were prepared by mixing 200 g of acetone with appropriate amounts of piroxicam. The solution was heated to 5 °C above the saturation temperature for 30 min to achieve thorough dissolution of the crystals. Then the solution was transferred to a 1 L glass reactor equipped with an overhead impeller, and the antisolvent crystallization started. A peristaltic pump was used to transfer water to the reactor at a rate of 9 or 25 g/min. The experiment ended when the acetone fraction in the solvent reached 30 wt %. When the solution suddenly became turbid, the time was recorded and then the amount of water fed to the system could be calculated. After filtration and drying, the produced crystals were analyzed via Raman spectroscopy. The effect of polymorphic seeding was studied by adding 5 mg of seeds to the solution before nucleation occurred.

3. RESULTS AND DISCUSSION 3.1. Effects of the Additives on the Nucleation of Piroxicam. In a previous study, we have investigated the effects of additives on the crystallization of piroxicam solid forms in evaporative crystallization from ethanol/water mixtures.18,19 It has been discovered that the additives with partial Hansen solubility parameters δT and δh similar to those of piroxicam will be more likely to affect the nucleation of the different polymorphs. On the other hand, the additives with partial Hansen solubility parameter δh similar to that of the solvent will have more interaction with the solvent and thus be more likely to affect the nucleation of the monohydrate. In this work, the effects of the additives on the nucleation of piroxicam were further studied by performing the metastable zone width (MSZW) measurement in a solvent of an ethanol/water mixture with 70 mol % ethanol. The MSZWs without and with additives are shown in Figure 3 together with the solid forms of

Figure 3. Metastable zone width of piroxicam with and without additives. Data for the solid form of the nucleated crystals are also shown (II+MH had spectra showing a mix of form II and monohydrate). Average of blank samples shown by a horizontal line.

the nucleated crystals. As shown in Figure 3, without any additives, nucleation of form II occurred at a temperature of around 27−28 °C, which corresponds to a MSZW of 9−10 °C. The presence of PVP K25 and PVP K90 retarded the nucleation; form II nucleated out at a temperature of around 22−25 °C, which led to a wider MSZW of 15−12 °C. The presence of HPMC (15) and HPMC (50) also slightly 4696




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Figure 4. Overview of solubility and nucleation points with respect to the polymorphs.

production chain, a solvent that can provide a higher solubility of piroxicam is preferred. The solubility of piroxicam in acetone and acetone mixtures is much higher than that in ethanol/water mixtures; therefore, the piroxicam crystal form landscape in cooling crystallization from acetone and acetone/water mixtures was established. By establishing this landscape, we aim to gain insight into the effects of various operation parameters and their interplay on the formation of the crystal forms of piroxicam. The onsets of nucleation of the crystal forms of piroxicam in the cooling crystallization from acetone and the acetone/water mixture with 96 wt % acetone are shown in Figure 4. Remarkably, the polymorphism of piroxicam crystallized from the solution seems to depend more on the initial concentration of piroxicam in solution rather than the temperature of nucleation. In the cooling crystallization from piroxicam solutions with a higher concentration (e.g., saturated at 45 and 40 °C), form II was crystallized out, whereas the cooling crystallization performed in low-concentration solutions yielded pure form I. The mixture of form I and form II was produced in the experiments with intermediate solute concentrations. As shown in Figure 4, the same dependency, of the polymorphism of piroxicam, on solute concentration was observed for the crystallization from both acetone and from the acetone/water mixture. To further verify the contribution of the solute concentration and temperature of nucleation on the polymorphism, fast-cooling crystallizations have been performed from both solvents. It can be seen from Figure 4 that nucleation in these fast-cooling crystallizations occurred at a temperature similar to the nucleation temperature of the crystallization from which a mixture of form I and form II was produced. However, the polymorphism of the nucleated crystals from these fast-

inhibited the nucleation of form II, which is denoted by the widening of the MSZW in the presence of these two additives. The solid form of the nucleated crystals analyzed via Raman spectroscopy showed that a mixture of form II and the monohydrate has been produced in the presence of PVP VA64. This observation suggested that PVP VA64 could have promoted the nucleation of the monohydrate. Although variations in the MSZW are often seen, it has also been found that the MSZW is not volume-independent.24 A larger volume will lead to a smaller variation in the measured MSZW; the use of 100 mL reactors therefore lowers the chance that variations are due to the random nature of crystallization but are in fact linked to controlled experimental changes. One of each of the experiments with Soluplus and HPC as the additive yielded Raman spectra showing small amounts of the monohydrate; however, most of the collected spectra from the samples showed pure form II, and only a few spectra showed the slight formation of monohydrate. Because this was present in only one of the runs for each of the two additives, and that the slight monohydrate signal was not present in the majority of the spectra, we concluded that the small amounts of monohydrate in the two experiments were due to either poor filtration, leaving enough water with the sample to promote the transformation, or a slight uptake of moisture from the atmosphere before Raman measurements were performed. 3.2. Piroxicam Crystal Form Landscape in Cooling Crystallization from Acetone and Acetone/Water Mixtures. The solubilities of piroxicam in ethanol and ethanol/ water mixtures are rather low; the ethanol/water mixture with 80 mol % ethanol provided the highest solubility of piroxicam, which is ∼3.19 mg/g of solvent. For a crystallization process of piroxicam aiming at separation and purification in the 4697




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Figure 5. Crystal landscape for piroxicam in cooling crystallization from acetone/water mixtures. Circles depict points at which excipients were tested.

monohydrate in the cooling crystallization performed with the intermediate solute concentrations. The effects of the additives have been explored by comparing the composition of the crystals produced via the cooling crystallization. As shown in Figure 6, the effects of PVP K25, PVP K80, and PEO 3350

cooling crystallizations remained as form II, which is the same as the polymorphism of the crystals produced with slow cooling. This observation suggested that the solute concentration played a very important role in the formation of the polymorphs. As shown in Figure 1, the two polymorphs of piroxicam, form I and form II, have different intermolecular hydrogen bonding networks and show different molecular orientations. Form I shows a head-to-head configuration, whereas form II shows a head-to-tail configuration. It has been reported that for a polymorphic system in which different polymorphs possess different molecular orientations in the unit cell, the solvent may influence the nucleation of the polymorphs through their impact on the self-association of the solute molecules in the solution.12,13 Kulkarni et al.12 have reported the link between the solvent and the nucleation of isonicotinamide (INA) polymorphs. The solvent in which the INA molecules present in a head-to-tail chain configuration promoted the nucleation of the polymorphic modification of INA with a similar molecular configuration in the crystal structure. However, our observation in this work has suggested that the solvent effects in such a molecule orientation distinguishable polymorphic system are more complicated than what has been denoted in the literature, perhaps because of the metastable nature of the self-association of the solute molecules in the solution. The changes in the environment, such as the solute concentration, may change the predominant configuration of the molecular associations and therefore may change the polymorphism of the crystallized API crystals. A complete crystal form landscape of piroxicam in cooling crystallization from different acetone/water mixtures is shown in Figure 5. It can be seen in Figure 5 that it was possible to obtain anhydrous form I, form II, and the monohydrate by varying only the concentration of API and solvent composition. The formation of the monohydrate became dominant when the water concentration in the solvent was >10 wt %. It can also be observed in Figure 5 that a boundary layer exists between the areas of pure polymorphism, where a mixture of form I and form II was obtained. It has been found in our previous studies18,19 that certain additives could affect the nucleation of the solid forms of piroxicam in an evaporative crystallization from an ethanol/ water mixture. We decided to investigate the effects of these additives (PVP K25, PVP K90, PEO3350, HPMC 15, and HPMC 50) on the formation of the polymorphs and

Figure 6. Effects of additives on the formation of piroxicam crystal forms in cooling crystallization from acetone and an acetone/water mixture with 96 wt % acetone.

are very limited, and the amounts of monohydrate predicted from the model are small enough that noise in the spectra may account for it. None of the additives show any significant effect on the crystal forms produced when the solvent is an acetone/ water mixture even though an effect was found in ethanol/ water solvent. HPMC 15 shows no impact compared to that of the blank samples. However, HPMC 50 shows a very clear change favoring the creation of form I, completely eliminating form II from the nucleation and greatly impeding the growth of the monohydrate. The same is seen for HPC where no form II is present in the produced crystals; however, the amount of monohydrate is not affected in the same way as seen with HPMC 50. It has been reported that the nucleation of a polymorphic system may follow the single-crystal nucleation mechanism;25 the first-born nucleus will induce the secondary nucleation, and the polymorphism of the crystal products is determined by the polymorphism of the first-born nucleus. It can be expected that in such a system, mostly a pure crystal form instead of a mixture of several forms will be produced from the crystallization, although the reproducibility of the 4698



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higher feed rates allowed for the generation of a greater supersaturation before nucleation (shown in Figure 7). However, although the nucleation occurred at a solvent composition at which the piroxicam monohydrate is more stable than the anhydrous forms, all of the antisolvent experiments produced form I regardless of the feed rate. A very small amount of monohydrate appeared in the products from the runs at 45 °C, and it might be caused by the slight transformation from form I to monohydrate. This behavior has been documented in ethanol/water mixtures.20 The use of form II as seed crystals showed no impact on the created form in any of the experiments, indicating that the initial crystal form exerted very minor effects on the crystallization of the solid forms. It has been observed that the nucleation of the monohydrate was dominating in the cooling crystallization if the water concentration in solvent was >10 wt %. This result highlighted the complex nature of the nucleation of polymorphic and anhydrate/hydrate systems; although the relative stability of the polymorphs and the hydrates is determined by the temperature and solvent composition, the operating mode of the crystallization process may affect the nucleation kinetics and mechanisms of the solid forms and thus may change the form of the crystalline products.

crystal form from batch to batch might be poor because of the random primary nucleation of the first crystal. The observations from this work suggested that the piroxicam nucleation did not follow the single-crystal nucleation mechanism. One of the most effective ways of controlling polymorphism crystallization is polymorphic seeding. In this work, the feasibility of using polymorphic seeding to control the polymorphism of the crystal products was studied. The polymorphic seeding strategy (shown in Table 1) has been


Table 1. Overview of the Results of Polymorphic Seeded Crystallization API concentration

acetone concentration (%)

blank run form

45 45 15 15 25

96 100 96 100 96

25

96

form II form II form I form I forms I and II forms I and II

seed used form form form form form

produced form

I I II II I

form I form I mixture form II form I

form II

form II

4. CONCLUSION In previous work,20 it was found that various additives would impact the crystal form of piroxicam during evaporative crystallization from an ethanol/water mixture. In this study, it has been shown that effects are also seen in other solvent systems under different operating conditions. For cooling crystallizations from a 70 mol % ethanol/water mixture, it was found that several of the tested additives increased the MSZW by up to 5 °C; however, only PVP VA64 showed a slight impact on the crystal form, forming a mixture of form II and the monohydrate. Studies of the crystal landscape in acetone/water mixtures proved to be a complex system with both forms I and II as well as the monohydrate at higher water contents. In general, form II was encountered at high API concentrations, form I was found at low API concentrations, and the monohydrate was found when the level of water in the solvent increased above 10%. A clear boundary layer between these sections of the landscape was also found where two forms would be competing during nucleation. With this in mind, seeding experiments were planned for this boundary layer and a clear effect was seen, showing that control of the produced form could be achieved through simple cooling crystallization with polymorphic seeding. With regard to additives, six additives were selected for further studies. PVP K25, PVP K90, and PEO 3350 were tested where form I and II were competing with the last two showing a slight change toward more form II and less form I present. For the other three, HPMC 15, HPMC 50, and HPC, the effects were more pronounced. HPMC 50 and HPC both showed the elimination of form II from the crystals, and HPMC 50 also showed an almost complete lack of monohydrate. HPMC 15 did not show a significant effect on polymorphism formation. The interplay of solute concentration, cooling rate, and nucleation temperature in the cooling crystallization of pirxociam from acetone and an acetone/water mixture was studied. The results showed that the cooling rate as well as the nucleation temperature had no effect on the formation of the

designed on the basis of the crystal form landscape of piroxicam shown in Figure 5. Form I seed crystals (5% of the solute concentration in the initial solution) were added to the crystallizations that yielded form II in the nonseeded crystallizations, and vice versa for the utilization of form II seed crystals. At a concentration of 25 mg/g in 96% acetone, a mixture of the two forms was normally obtained from nonseeded crystallization, and thus, seeding with both form I and form II was conducted. It was found that for most experiments the produced form was changed on the basis of the seeding form; that is, seeding with form I gave form I, and similar seeding with form II yielded form II (shown in Table 1). However, for the experiments in 96% acetone with initial concentrations of 15 mg/g with seeding of form II, a mixture of form II and form I was produced. This probably indicated that under this operation condition, the formation of form I cannot be circumvented completely simply by seeding. 3.3. Antisolvent Crystallization of Piroxicam from an Acetone Solution. As shown in Figure 7, the solubility of piroxicam decreases sharply as the water concentration in the solvent increases, which suggested the feasibility of using water as the antisolvent to conduct antisolvent crystallizations. Different feeding rates of water were tested, and as expected,

Figure 7. Solubility of piroxicam in acetone/water mixtures and the onset of nucleation in antisolvent crystallization. 4699




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(9) Qu, H.; Louhi-Kultanen, M.; Kallas, J. Cryst. Growth Des. 2007, 7, 724−729. (10) Otsuka, M.; Ohfusa, T.; Matsuda, Y. Colloids Surf., B 2000, 17, 145−152. (11) Raghavan, S.; Trividic, A.; Davis, A.; Hadgraft, J. Int. J. Pharm. 2001, 212, 213−221. (12) Kulkarni, S. A.; McGarrity, E. S.; Meekes, H.; ter Horst, J. H. Chem. Commun. 2012, 48, 4983−4985. (13) Li, J.; Bourne, S. A.; Caira, M. R. Chem. Commun. 2011, 47, 1530−1532. (14) Kojić-Prodić, B.; Ruż’ć-Toroš, Ž . Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1982, 38, 2948−2951. (15) Reck, G.; Dietz, G.; Laban, G.; Günther, W.; Bannier, G.; Höhne, E. Pharm. 1988, 43, 477−481. (16) Bordner, J.; Richards, J. A.; Weeks, P.; Whipple, E. B. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1984, 40, 989−990. (17) Naelapäa,̈ K.; van de Streek, J.; Rantanen, J.; Bond, A. D. J. Pharm. Sci. 2012, 101, 4214−4219. (18) Liu, G.; Hansen, T. B.; Qu, H.; Yang, M.; Pajander, J. P.; Rantanen, J.; Christen-sen, L. P. Chem. Eng. Technol. 2014, 37, 1297− 1304. (19) Hansen, T. B.; Nielsen, P.; Qu, H. BIWIC 2014. 21st International Workshop on Industrial Crystallization; 2014; Vol. 21, pp 114−121. (20) Liu, G.; Qu, H.; Yang, M.; Pekka Pajander, J.; Rantanen, J.; Christensen, L. P. Chem. Eng. Technol. 2014, accepted for publication, BIWIC Special Issue. (21) Jaumot, J.; Gargallo, R.; de Juan, A.; Tauler, R. Chemom. Intell. Lab. Syst. 2005, 76, 101−110. (22) Tauler, R.; Smilde, A.; Kowalski, B. J. Chemom. 1995, 9, 31−58. (23) de Juan, A.; Tauler, R. Crit. Rev. Anal. Chem. 2006, 36, 163−176. (24) Kadam, S. S.; Kulkarni, S. A.; Coloma Ribera, R.; Stankiewicz, A. I.; ter Horst, J. H.; Kramer, H. J. M. Chem. Eng. Sci. 2012, 72, 10−19. (25) Kadam, S. S.; Kramer, H. J. M.; ter Horst, J. H. Cryst. Growth Des. 2011, 11, 1271−1277. (26) Davey, R. J.; Schroeder, S. L. M.; ter Horst, J. H. Angew. Chem., Int. Ed. 2013, 52, 2166−2179.

polymorphism of the crystallized piroxicam. All fast cooling rate runs showed no change in the produced crystals based on the initial concentration and solvent composition. This gives a clear indication that the API concentration prior to nucleation is a dominating factor in determining the produced polymorph. On the basis of the self-association discussed by Davey, Schroeder, and Horst,26 specific building units (BU) may be formed prior to nucleation. These units may consist of several molecules arranged in a specific manner. Assuming this is the case for piroxicam, there would be two types of BU, one for each of the two forms, form I and form II. If the numbers of molecules present in each of the two BUs were different, this might explain the impact of concentration. In high-concentration systems, a BU consisting of several molecules would be encountered more often than in low-concentration systems. However, confirming such a mechanism requires extensive investigation of solute−solvent interaction at various concentrations using a variety of measuring techniques.26 With the rapid decrease in the solubility of piroxicam as the water content of the solvent increased, antisolvent crystallization was deemed feasible. The results showed no impact on the produced form as a function of temperature, solute concentration, or solvent composition when nucleation occurred. Form I was crystallized out from all experiments regardless of the different operation parameters. Even when seeding with form II was employed, none of the investigated systems deviated from the nonseeded results in any way. It should be noted that form I is not stable in the used solvents, and therefore, transformation into the monohydrate form is to be expected if samples are left in suspension for extended periods.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the students in the course of “Crystallization and Processing of Pharmaceuticals” in the Department of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, for their contributions to laboratory work and M.Sc. Peter Hallberg Nielsen for his contributions during his master’s thesis.

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REFERENCES

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