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Effect of Additives on the Transformation Behavior of L-Phenylalanine in Aqueous Solution Rajeev Mohan,† Kee-Kahb Koo,‡ Christine Strege,§ and Allan S. Myerson*,| Andrx Pharmaceuticals, Inc., 4955 Orange Drive, Fort Lauderdale, Florida 33314, Department of Chemical Engineering, Sogang University, Seoul 121-742, Korea, Institut fur Verfahrenstechnik TVT, Martin-Luther-Universita¨ t, Halle D-06099, Germany, and Department of Chemical Engineering, Illinois Institute of Technology, 3301 S. Dearborn, Chicago, Illinois 60616
The solution-mediated transformation of anhydrous L-phenylalanine in a saturated solution of monohydrate L-phenylalanine has been studied and the transformation rate quantified using the powder X-ray diffraction technique. It has been demonstrated that the anhydrous form is not stable below 37 °C (transition point) in the presence of additives, as previously reported (Sato, T.; Sano, C. European Patent 0703214A2, 1995), and that the additives (ammonium sulfate and dextrose) affect only the transition rate but not the thermodynamic stability or the transition point. 1. Introduction and Background Polymorphism is the phenomenon of a chemical species having more than one possible crystal structure. Numerous organic materials including amino acids and pharmaceutical and food substances are known to have polymorphs. In addition, many of these materials can crystallize as hydrates or solvates where solvent is present as an integral part of the crystal lattice. Solvates and hydrates of a given compound are often called pseudopolymorphs. The crystallization of polymorphs/ pseudopolymorphs occurs as a result of different molecular conformations or packings. It is a function of crystal growth conditions such as temperature, pressure, impurity content, and growth rate, along with intra/intermolecular forces and interactions of the solute with solvents and additives. In many cases, crystallization leads to the formation of a metastable polymorph, which will eventually transform into a more stable form. This transformation can occur in solution or in a dry state. The transformations from one polymorph to another are usually rapid when crystals are suspended in solutions and are termed solution-mediated transformations. Solution-mediated transformations have been reported for stearic acid,2,3 magnesium phosphate hydrate,4 L-glutamic acid,5 theophylline,6 carbamazepine,7 ammonium nitrate,8 calcium sulfate,9 and calcium phosphates.10 The phase transformations of several organic and inorganic hydrate salts have been studied.11,12 These studies indicate that the stable crystals grow, whereas the less stable crystals dissolve. Typically, for a given substance, there exists a transition temperature below which one polymorph is stable and above which another form is stable. Reversible transformations between these forms can be effected by temperature manipulations. Sometimes transformation is not certain even though a system * Corresponding author. Tel.: + 1-(312)-567-3163. Fax: + 1-(312)-567-7018. E-mail address:
[email protected]. † Andrx Pharmaceuticals, Inc. ‡ Sogang University. § Martin-Luther-Universita ¨ t. | Illinois Institute of Technology.
enters a condition that will theoretically allow it. Transformation can only be ensured if a more stable solid phase is already present, is introduced (by seeding), or makes its appearance by nucleation. The rate of transformation can also be affected by the addition of additives or specific impurities.13 Materials crystallizing in different polymorphs show a wide range of physical and chemical properties, including different melting points, spectral properties, thermal conductivities, heat capacities, and densities.14-24 For example, the most stable structure has the lowest solubility and the lowest dissolution rate. Polymorphism is particularly important in pharmaceutical industries, where the polymorph present can alter the dissolution rate, bioavailability, chemical stability, and/or physical stability. Furthermore, during the manufacturing process of dosage forms or the storage of products, phase transition has been frequently observed.19,25-27 Because of the different properties of polymorphs, it is advantageous to choose the proper polymorph for the desired application. Several factors need to be addressed, including the number of polymorphs; the solubilities of the different forms; the methods for preparing pure stable forms; the methods for preventing the transformation of forms during several unit operations such as drying, grinding, or tableting, etc.; and the chemical and physical stabilities of each form. Haleblain and McCrone17 reviewed the numerous activities that require the consideration of polymorphism. Crystal habit plays an important role during downstream processing. Platelike forms of tolbutamide cause powder bridging and capping problems during tableting.28 In suspensions, it has been shown that transformation of a material to a stable form results in caking. This was due to the growth of crystals of the stable form with the concurrent dissolution of crystals of a less stable form.29 The dissolution and bioavailability due to different polymorphs has been well-documented.30,31 Therefore, it is necessary to control conditions to obtain the desired polymorph and, more importantly, to prevent the transformation of the desired form to another polymorph. Several analytical methods have been used to study polymorphism.17,20,32 Infrared spectroscopy, high-resolu-
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tion NMR spectroscopy,33 Raman spectroscopy,34 differential scanning calorimetry and differential thermal analysis,19,35,36 and X-ray diffraction methods37,38 are the main approaches. The X-ray diffraction technique has a high degree of accuracy and almost never fails because of its outstanding ability to detect differences in crystal structures. An important technique for measuring the different amounts of polymorphs present in a system is quantitative X-ray diffraction. The quantitative X-ray diffraction technique has been applied in many areas, such as the analysis of mine dust, quartz,39,40 heavy metal carbides,41 inorganic compounds,42-44 organic compounds,45,46 and pharmaceutical systems.7,38 L-Phenylalanine, an essential amino acid and a pharmaceutical and food intermediate, exhibits pseudopolymorphism. It can exist in two different crystalline states: a monohydrate (monoclinic, a ) 13.598 Å, b ) 10.229 Å, c ) 6.484 Å, Z ) 4, space group P2221) and an anhydrous form (orthorhombic, a ) 13.598 Å, b ) 14.468 Å, c ) 9.169 Å, Z ) 8, space group P2221). The transition point was reported to be 37 °C in water. The needle-shaped monohydrate is stable below the transition point, and the anhydrous form, which resembles flakes, is stable above the transition point. The anhydrous form of L-phenylalanine is desirable for industrial purposes because of its ease of downstream processing such as solid/liquid separation and drying. It has been reported that the stable anhydrous form can be obtained in the hydrate region through the addition of certain additives.1 In this study, we report the results of experiments undertaken to elucidate the solution-mediated phase transformation of anhydrous L-phenylalanine into monohydrate. Experiments were also performed to determine the effect of additives on the transformation rates of anhydrate to monohydrate below the transition point. The results could provide some insight into the process development of L-phenylalanine crystallization from aqueous solution. 2. Experimental Section 2.1. Materials. L-Phenylalanine anhydrate (assay, formula >99%), purchased from Aldrich Chemical Co., was used without further purification. The monohydrate form of L-phenylalanine was obtained by recrystallization. A saturated solution of anhydrate was prepared at 60 °C and then quenched in a thermostat maintained at 5 °C. After 24 h, crystals of the monohydrate formed;47 they were filtered using a mechanical vacuum pump, dried for 24 h at 30 °C, and then stored at room temperature. The crystal structure was confirmed using powder X-ray diffractometry (PXRD; Rigaku, Miniflex). Analysis of the X-ray pattern indicated that the drying process did not result in any dehydration of the monohydrate crystals. Several additives, both electrolytes and nonelectrolytes such as ammonium sulfate [(NH4)2SO4], sodium chloride (NaCl), aluminum sulfate [Al2(SO4)3], potassium aluminum sulfate dodecahydrate [KAl(SO4)2‚ 12H2O], dextrose (C6H12O6), and sucrose (C12H22O11), were selected to study their effects on both solubility and the transformation rate of L-phenylalanine anhydrate to the monohydrate form. 2.2. Solubility Measurements. The solubilities of the two forms of L-phenylalanine in water, at different temperatures, were determined by a gravimetric technique. A known amount of L-phenylalanine was added to 50 g of water in an equilibrium cell. A Scientech
microbalance, with a precision of (0.0001 g, was used to weigh the samples. The equilibrium cell was placed in a double-jacketed cylinder maintained at the desired temperature by a thermostat (Polyscience). The solution was agitated using a magnetic bar for 5 h. The solid phase was later filtered using a mechanical vacuum pump. The sample was dried in a vacuum oven at 30 °C for 24 h. The solubility was calculated by subtracting the weight of the dried solid from the original weight of L-phenylalanine added. The crystal structures of the solid samples were examined using PXRD patterns to ensure the no phase transformation occurred. 2.3. Transformation Kinetic Studies. The phase transformation study of the anhydrate form of Lphenylalanine into monohydrate was performed isothermally under ambient pressure at three different temperatures of 5, 15, and 30 °C. The experiments were carried out using the following procedure: An excess amount of monohydrate was dissolved in distilled water at the desired temperature for 24 h. The solution was filtered to prepare a saturated solution of monohydrate. The saturated solution was sealed in a 500-mL glass cylinder and was then heated to a temperature a few degrees higher than the saturation temperature. The solution was maintained at this temperature for 30 min to ensure that any clusters or nuclei that might have been produced during filtration were dissolved. In each experimental run, 10 glass test tubes (50 mL) containing the saturated solution (40 g) of monohydrate with anhydrate powder (0.2 g) were prepared. These tubes were immediately placed in a constant-temperature bath maintained at the desired temperature and agitated (fixed speed) by a magnetic bar. Samples were removed at the desired time intervals, and the solid phase was filtered with a mechanical vacuum pump. The physically adsorbed water was removed by drying the sample for 24 h at 30 °C. Finally, the crystal structure of the dried sample was examined using PXRD to enable the calculation of the degree of phase transformation. The effect of the drying process on the transformation rate was examined by wetting anhydrous crystals and drying them for 24 h at 30 °C. Analysis of these samples by X-ray diffraction showed no measurable transformation. 2.4. Powder X-ray Diffractometry. The PXRD technique was employed to quantify the relative amounts of the anhydrate and monohydrate forms present in mixtures. The method is based on the differences between the powder diffraction patterns of the two forms of L-phenylalanine. Unlike the Karl Fischer and drying methods, the X-ray method can distinguish between absorbed moisture and water of crystallization. The measurements were carried out under the following conditions: Ni-filtered Cu KR (λ ) 0.15418 nm) radiation; voltage, 30 kV; current, 15 mA; receiving slit, 0.3 mm; scan step, 0.05°; scanning speed, 1°/min; and detector, scintillation counter. The areas of all peaks (2θ ) 4-40°) of the anhydrate and the monohydrate were utilized for calculation purposes. 2.5. Optical Microscopy. Crystals of L-phenylalanine hydrate and anhydrate were observed using an optical microscope (Nikon, F-II) and recorded with a camera (Nikon, FX-35A). Along with the crystal shape and size, the microphotographs were useful for checking the crystal quality, including solvent inclusions. 2.6. Calculation Curve for Degree of Transformation. The anhydrate conversion or the monohydrate
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Figure 1. Typical PXRD patterns for a number of standard mixtures of anhydrate (A) and monohydrate (H) forms.
content of the sample collected with time was measured on the basis of the area ratio of the PXRD peaks of the two crystal forms. Known quantities of standard samples were prepared by physically mixing the anhydrate and monohydrate forms of L-phenylalanine in various ratios in a mortar and pestle. The PXRD patterns of the standard samples were measured for a number of samples. Figure 1 shows typical PXRD patterns for a number of standard mixtures of different compositions (0, 20, 50, 70, and 100 wt % of the anhydrous form). As can be seen in Figure 1, five peaks in the pure anhydrate PXRD patterns (2θ ) 5.7, 17.1, 22.8, 28.6 and 34.5°) can be separated from peaks of the pure monohydrate. Therefore, the ratio of the area of five characteristic peaks for the anhydrate to the total area of all peaks for a mixture of the two forms was chosen for use in the construction of a standard chart for determining the extent of phase transformation. In this way, a calculation chart for the degree of anhydrate conversion into monohydrate was prepared as shown in Figure 2. 3. Results and Discussion 3.1. Solubilities. The solubilities of the two forms of in water, in the temperature range of 15-50 °C, are shown in Figure 3. In the present L-phenylalanine
Figure 2. Calculation chart for the degree of conversion of anhydrate (A) into monohydrate (H) form.
experimental range, the data were regressed by the least-squares method to the following equations
S ) 2.043 + 2.394 × 10-2T + 4.211 × 10-4T 2 (anhydrate) S ) 1.949 +5.169 × 10-3T + 9.900 × 10-4T 2 (monohydrate) where S is the solubility (g of L-phenylalanine/100 g of H2O) and T is the temperature (°C). The average
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Figure 3. Solubilities of the two forms of anhydrous and monohydrate.
L-phenylalanines
Figure 4. Effect of various additives on the solubility of phenylalanine (anhydrate).
L-
absolute deviations between the experimental data and the calculated values were 0.22% for the anhydrate and 0.29% for the monohydrate. On the basis of the experimental data and regression, it was found that the solubility curves showed an enantiotropic nature and that the transition point between these two forms is about 37 °C, which quantitatively agrees with the previous data.1 The effect of additives on the solubility of the anhydrate of L-phenylalanine is shown in Figure 4. The additives used in the present experiments were chosen on the basis of previous research.1 The amount of additives added was 10 g/100 g of H2O. Some electrolytes, such as ammonium sulfate and sodium chloride, tend to lower the solubility of anhydrate. Other electrolytes, such as aluminum sulfate and potassium aluminum sulfate dodecahydrate, increase the solubility to a large extent. In aqueous solutions, L-phenylalanine is doubly charged and is known as a zwitterion. The charges at the ends of the molecule form a strong dipole. Thus, complex interactions among zwitterions of Lphenylalanine, water molecules, and ions of electrolytes seem to strongly affect the solubility. As expected, nonelectrolytes (dextrose and sucrose) were found to have a negligible effect on the solubility of the anhydrate in water. 3.2. Solution-Mediated Transformation. Transformation studies were carried out to determine whether the two forms could be crystallized in the temperature region where they are unstable (the anhydrous form is unstable below 37 °C, and the monohydrate is unstable above 37 °C). A saturated solution of L-phenylalanine in water at 40 °C was cooled to 32.5 °C (the region where the hydrate is stable). The solid was filtered and dried for 12 h. It was found that the crystals were in the form of needles, indicating the presence of the monohydrate
form. The experiments were repeated with ammonium sulfate and dextrose as additives (additive concentration of 10 g/100 g of water). The saturated solution was cooled from 40 °C to 32.5 °C in the first set of experiments and to 35.9 °C in the second set of experiments. In all of the experiments, the precipitated crystals were found to be needles. Anhydrate L-phenylalanine, with a flakelike morphology, was precipitated when the solutions were crystallized at temperatures above 37 °C. Figure 5 shows typical microphotographs of anhydrate L-phenylalanine transforming into the monohydrate form after 5 and 20 h at a temperature of 26.5 °C. After 5 h, the monohydrate crystals began to form on the anhydrate (Figure 5, top). It can be seen that the process is completed after 20 h. This is confirmed by the presence of only the needlelike structure of the monohydrate in the bottom image in Figure 5. The transformation rates of anhydrate in the saturated solution of monohydrate were measured for the pure system at 5, 15, and 30 °C, as shown in Figure 6. Solution-mediated transformation proceeds so that the two processes, the dissolution of the metastable form and the recrystallization of the stable form, occur simultaneously. When the metastable phase is within the metastable zone width of the stable phase, there will be an induction time of nucleation for the stable phase. If the metastable phase is outside the metastable zone width, the stable form will be produced without an induction time. In this sense, the initial conditions of all of our experimental runs seem to be within the metastable zone width of the stable phase.49 At 30 °C, the induction time was about 22 h, and the phase transformation process was completed in 60 h. At 15 °C, the monohydrate crystals were formed after an induction time of 3 h. The phase transformation process was completed in approximately 10 h. It is interesting to note that the induction time is much longer and the transformation rate is much slower at 30 °C than at 15 °C. This result can be explained by the fact that the free energy difference between the two crystal structures, given by the solubility difference, plays a major role in phase transformation kinetics rather than the kinetic effect activated by increasing temperature. Figure 7 illustrates the transformation process of the anhydrate form of L-phenylalanine at 15 °C. The PXRD patterns of the samples obtained at different times clearly indicate the transformation occurring in the solution. From Figure 3, the solubility differences between the two forms are approximately 0.25 g/100 g of H2O at 15 °C and 0.15 g/100 g of H2O at 30 °C. This change in solubility differences (0.1 g/100 g of H2O) is expected to be the major driving force for the phase transformation. Hence, it can be expected that, as the operating temperature of the transformation study approaches the transition point, the system will achieve an equilibrium state where the transformation rates of the two modifications will be equal to each other. The results at 5 and 15 °C can be interpreted similarly. The solubility differences at 5 and 15 °C seem to be almost the same, and the temperature effect on the transformation kinetics is negligible. Therefore, the phase transformation kinetics at 5 and 15 °C are similar, as shown in Figure 6. 3.3. Effect of Additives on Phase Transformation at 15 °C. Figure 8 shows the effect of additives on the phase transformation of L-phenylalanine at 15 °C. This
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Figure 5. Microphotographs of transformation process of L-phenylalanine anhydrate at 26.5 °C after 5 and 20 h. After 5 h (top), the needles of monohydrate begin to form on the anhydrous flakes. After 20 h (bottom), only needles of monohydrate can be seen, indicating complete transformation.
figure clearly demonstrates that the additives selected in the present experiments, ammonium sulfate and dextrose, tend to lower the transformation rate of L-phenylalanine. However, the interaction mechanisms of the additives in aqueous solutions of L-phenylalanine seem to be quite different. When the electrolyte ammonium sulfate was added in the amount of of 0.5 g/100 g of H2O, the transformation was not observed to take place until at least 9 h had elapsed. In addition, the total time for the complete conversion of the anhydrate form was 19 h. Compared with the pure system, the induction time of nucleation increased by a factor of 3, and the total transformation time increased by a factor of 2. The reduction in
solubility due to ammonium sulfate has been attributed to the inhibition of molecular interactions between L-phenylalanine and water molecules. This results in a slowing of the transformation rate. Information on the structural details of L-phenylalanine in the solution and on their interactions with water and additive molecules might be required to understand quantitatively the distinct behavior of transformation of L-phenylalanine with electrolytes. At a dextrose concentration of 0.5 g/100 g of H2O, no change was observed in the transformation kinetics compared with those of a pure system. However, on increasing the concentration of dextrose to 5 g/100 g of H2O, it was found that the phase transformation rate
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dextrose does not affect the solubility. From these observations, it can be concluded that long-chain molecules of dextrose hampering the mass transfer of the L-phenylalanine molecules in the solution or at the interface of monohydrate crystals might be responsible for slowing the transformation rate of the anhydrate. 4. Conclusions
Figure 6. Transformation rates of anhydrate L-phenylalanine to the monohydrate form at 5, 15, and 30 °C.
The distinctly different PXRD patterns of the two forms of L-phenylalanine have allowed us to quantitatively determine the phase transformation rate of the anhydrate form into the monohydrate from a saturated solutions of monohydrate. Shorter induction times and higher transformation rates at 5 and 15 °C, compared to 30 °C, implies that a major factor affecting the phase transformation kinetics is the solubility difference between the two forms at a given temperature rather than the reaction kinetics. It has been demonstrated that the anhydrous form is not stable below 37 °C in the presence of additives, as had previously been reported.1 In addition, the additives result in a decrease in the transformation rate of the anhydrous form to the hydrate. The lowering of the transformation rate was attributed to a reduction of the solubility of anhydrous L-phenylalanine in the case of ammonium sulfate and to the inhibition of the mass transfer of L-phenylalanine to the crystal surface of monohydrate formed in the solution as a result of the addition of dextrose. Literature Cited
Figure 7. PXRD patterns showing transformation of anhydrate L-phenylalanine at 15 °C. The peaks of interest represent 2θ ) 5.7, 17.1, 22.8, 28.6, and 34.5°.
Figure 8. Effect of additives on the transformation rates of anhydrate L-phenylalanine at 15 °C.
considerably slowed. At a reaction time of 20 h, 80% of the phase transformation was completed, as can be seen in Figure 7. However, the induction time with the addition of dextrose is similar to that of pure system as
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Received for review June 19, 2001 Revised manuscript received October 1, 2001 Accepted October 5, 2001 IE0105223
