Solution versus Crystal Hydration: The Case of γ-Amino Acid

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Solution versus Crystal Hydration: The Case of γ‑Amino Acid Pregabalin Rene ́ R. E. Steendam,* U. B. Rao Khandavilli, Leila Keshavarz, and Patrick J. Frawley Synthesis and Solid State Pharmaceutical Centre (SSPC), Bernal Institute, University of Limerick, Castletroy, Limerick, Ireland

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S Supporting Information *

ABSTRACT: Understanding the link between solution chemistry and nucleation is essential to control crystallization processes, in particular regarding pharmaceutical compounds. In the present work, the link between the solution hydration state and crystallization of the γ-amino acid pregabalin is presented. Pregabalin is a blockbuster pharmaceutical drug having broad therapeutic effects. Using induction time experiments in combination with the classical nucleation theory, we show that the ease of nucleation increases with solubility and water fraction of the solvent. Water was found to enhance both the kinetic and thermodynamic processes of forming a nuclei. As a result, larger clusters which represent the hydrate form were measured using dynamic light scattering in pure water. Once in the solid state, the hydrate form of pregabalin was found to be physically unstable, as it rapidly converted back into its anhydrate form, as rationalized using in-line Raman spectroscopy. Thus, the hydration and nucleation of pregabalin in solution is highly favored, as opposed to the solid-state situation, where the anhydrate is the stable form. Despite these differences, a solution− crystallization link could still be established in our work. Knowledge of the solution chemistry and structural landscape of pharmaceutical compounds is essential for the development of manufacturing routes and patent protections, and we foresee that the presented approach can be used to further reveal relationships among self-association in solution, crystallization, and hydration of a wide range of organic compounds.

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first time. The blockbuster pharmaceutical drug pregabalin was investigated, as it remains unclear how the crystallization of this amino acid is influenced by the nature of the solvent. Pregabalin is commercialized by Pfizer under the trade name Lyrica16 and is ranked among the top 20 prescription medications.17 Pregabalin has broad therapeutic effects, as it is used for the treatment of epilepsy,18 generalized anxiety disorder,19 and many pain-related causes, including neuropathic pain,20 fibromyalgia,21 and postsurgical pain.22 The molecular structure of pregabalin is part of the γ-aminobutyric acid family, where the marketed (S)-(+) enantiomer exhibits the desired pharmacological activity (Figure 1).23 Parallel to the present work, the crystal structures of two similar metastable hydrate forms of pregabalin were elucidated in addition to the stable anhydrate form.24 The hydrates are enantiotropically related to each other by temperature, and their molecular packings are virtually the same. The presence

INTRODUCTION Nucleation is the first and most elusive step of crystallization which determines many product aspects, including crystal shape, crystal size distribution, and polymorphism.1 A key parameter in crystal nucleation is solution chemistry, as it affects the nucleation process in three ways. First, solute molecules must break solvent−solute interactions through desolvation before attaching to a growing nucleus.2 Desolvation of organic molecules generally becomes more difficult for solvents that bind more strongly to solute molecules.3−6 For example, solvents with higher polarity lead to stronger interactions with polar solute molecules, resulting in higher solubilities and higher nucleation barriers.7 For electrolytes in aqueous solutions, the difficulty of nucleation (i.e., effective interfacial energy) decreases with increasing solubility.8 Second, solvents influence the structuring of solute molecules into clusters and as such often define the configuration of the crystal structure.9−13 As a result, different polymorphic forms of the same compound may be formed depending on the solvent. Finally, solvent molecules may be incorporated in the crystal structure to form solvates. Among solvate formation, the incorporation of water into the crystal structure is most often encountered, as about one-third of small organic molecules form hydrates.14 Knowledge of hydration and dehydration is essential, as the bioavailability of pharmaceuticals strongly depends on the hydration state.15 Herein, the link among solution chemistry, hydration, and crystallization of a small organic molecule is revealed for the © XXXX American Chemical Society

Figure 1. Molecular structure of the zwitterion pregabalin. Received: February 26, 2019 Revised: May 2, 2019 Published: June 24, 2019 A

DOI: 10.1021/acs.cgd.9b00253 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Table 1. Overview of Solution Properties and Estimated Parameters Derived from the Nucleation Kinetic Data, Including Mole Fraction of Water x, Mass Fraction of Water xm, Supersaturation Ratio S, Solubility C*, Growth Time of a Nucleus tg, and Effective Solid−Liquid Interfacial Energy γef γef (mJ/m2)b

solvent

x

xm

S

C* (mg/g)a

tg (s)

water water/methanol water/methanol water/2-propanol methanol

1.000 0.727 0.544 0.454 0.000

1.000 0.600 0.400 0.200 0.000

1.2−1.3 1.4−1.5 1.5−2.0 2.2−2.6 2.8−3.4

32.6 17.7 16.2 4.95 5.54

100−430 270−1660 200−2900 1300−4400 1030−7400

1.01 1.54 1.41 1.95 2.63

± ± ± ± ±

0.34 0.17 0.20 1.17 0.48

a

Solubility of the anhydrate form calculated using literature data.25 b95% confidence limits are shown. Solid-State Characterization. The polymorphic nature of the solids produced from the induction time experiments were established through X-ray powder diffraction (XRPD) measurements. Samples of the solids were gently ground into a fine powder and measured on a PANalytical EMPYREAN diffractometer using Bragg−Brentano geometry and an incident beam of Cu Kα radiation (λ = 1.5406 Å). Scans were performed at room temperature on a spinning silicon sample holder with a step size of 0.013° 2θ and a step time of 68 s. An XPRD pattern from a reported single X-ray structure (CSD code CIDDEZ) of pregabalin was used as a reference.27 Single-crystal data of the anhydrate (CSD code CIDDEZ) as well as the two similar hydrate forms (CCDC numbers 1879470 and 1879471)24 was used to illustrate the proposed dehydration mechanism, as shown in Figure 5. Crystallization Monitored through Raman Spectroscopy. Cooling crystallization experiments in each tested solvent composition were carried out in magnetically stirred 25 mL glass reactors in a Mettler Toledo Easymax workstation. A Kaiser Raman Rxn2 analyzer in combination with an Invictus 785 nm laser, a CCD camera (DV420-OE) based detector, and an immersion probe (i.d. 1/4 in.) was used to measure in-line Raman spectra. The data were collected and analyzed using Mettler Toledo iC Raman software. The suspensions were stirred at 200 rpm, and the temperature of the stirred suspensions was increased to T = 60 °C, where it remained for 1 h to ensure complete dissolution of the solids. Once the sample was dissolved, the solution temperature was reduced to T = 5 °C at a rate of 4 °C/min, during which crystallization occurred. The suspension was stirred for an additional 20 h at temperature T = 5 °C. Supersaturation ratios S = 1.26, 2.37, 2.29, 4.45, and 3.96 were used in combination with water, water/methanol (x = 0.544), water/ methanol (x = 0.727), water/2-propanol (x = 0.454), and methanol, respectively. The reported solubility data were used to calculate the required supersaturation ratios at temperature T = 5 °C.25 In the present study, the solubility data of the anhydrate were used for all solvent mixtures, whereas solubility data of the hydrate should be used in the experiments where the hydrate was formed. However, in our attempts involving in-line Raman spectroscopy, we were not able to measure the solubility of the hydrate, as it rapidly converted back to its anhydrate form. The hydrate form is metastable and should therefore have a higher solubility than the anhydrate. Yet, the S range required for the crystallization of the hydrate in water was low, as it ranged between 1.2 and 1.3. A higher solubility of the hydrate would lead to lower calculated S values that would have to range between 1.1 and 1.2. Accordingly, it can be assumed that such a small difference in S would not significantly affect the estimated nucleation data. Dynamic Light Scattering (DLS). The sizes of the molecular aggregates and clusters were measured using DLS. Suspensions having a total concentration of 40 mg/mL of pregabalin were prepared in water and the water/methanol solvent mixtures. The suspensions were heated to a temperature T = 60 °C for 1 h to ensure complete dissolution. The solid-free solutions were filtered using 0.2 μm syringe filters and were collected in disposable cuvettes. The cuvettes were placed in a Malvern Zetasizer ZSP Nano instrument. The solution was brought to a fixed temperature of T = 50 °C, which represents supersaturated conditions for the solutions in water and water/ methanol. Each sample was subjected to 10 consecutive runs, and each run consisted of 10 consecutive measurements. The resulting

of water in the solid phase significantly affects the material properties of pregabalin, as anhydrate crystals are brittle as opposed to the flexible hydrate crystals.

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EXPERIMENTAL SECTION

Materials. (S)-3-(Aminomethyl)-5-methylhexanoic acid, which is also known as pregabalin (>97%, NMR), was obtained from Fluorochem. The solvents 2-propanol (99%, GC) and methanol (99%, GC) were obtained from Sigma-Aldrich and were used as received. Milli-Q deionized water was prepared in our own laboratory using a Millipore water purification system. Induction Time Measurements. Induction times were recorded using a Crystal16 (Technobis) instrument. A 6 g stock solution was prepared for each supersaturation ratio S. The supersaturation ratio S was calculated as S = C/C*, in which C is the total concentration of solute in solvent and C* is the equilibrium solubility at a fixed temperature T. Solubility data from the literature were used to calculate the required amount of solute and solvent for each supersaturation ratio S.25 The stock solution was heated to a temperature of 60 °C, where it remained for 30 min to ensure complete dissolution of the solute. A micropipet was used to transfer 1.2 mL of stock solution to each HPLC vial. The caps of the HPLC vials were tightly sealed and wrapped with cling film to reduce the possibility of solvent evaporation. The HPLC vials were placed in the Crystal16 instrument, and constant magnetic stirring using a bottom stirrer bar was set at 900 rpm. The set temperature was first sufficiently reduced to facilitate crystallization of all vials. Subsequently, the set temperature was increased at a rate of 5 °C/ min to a temperature that was 10 °C higher than the theoretical solubility temperature. After 30 min, the temperature was reduced to the crystallization temperature at a rate of 5 °C/min in order to create the desired fixed supersaturation ratio S. The time when constant temperature was reached was taken as the start time t0. The time when crystallization started, as indicated by a decrease in transmissivity of the solution, was taken as the detection time tD of crystallization. The time difference between the detection time tD and the start time t0 was used as the induction time t. For experiments involving short induction times of 15000 s or lower, the software was programmed to start a new experiment once the transmissivity of the vials was reduced to less than 90%. For experiments involving long induction times of 15000 s or longer, the software was programmed to start a new experiment after 15000 s. This way, between 50 and 160 induction times were recorded for each supersaturation ratio S in each solvent system. Each induction time distribution was fitted to eq 1 derived from the CNT. Parameters A and B for interface-transfer-controlled and volume-diffusion-controlled nucleation were obtained from a linear fit of a plot of ln(J/S) versus 1/ln2 S and ln(J/S ln S) versus 1/ln2 S, respectively.26 The effective solid−liquid interfacial energies (γef) needed to create a nucleus in solution were calculated using eq 2 using the molecular volume (v) of the solid state of pregabalin. For the experiments in which water was part of the solution (i.e., x > 0), the molecular volume of the unit cell of the hydrate was used (i.e., v = 1.11 × 10−27 m3) in eq 2. For the anhydrous experiment in methanol (i.e., x = 0), the molecular volume of the unit cell of the anhydrate was used (i.e., v = 9.41 × 10−28 m3) in eq 2. B

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bimodal size distributions consisted of monomers with mean sizes of about 1 nm in diameter and larger clusters with mean sizes larger than 1000 nm in diameter. The measured sizes fluctuated over time but did not consistently increase or decrease in size. The average sizes were taken over 10 runs, and the 95% confidence intervals were calculated. Fresh samples were prepared and measured to show that this procedure is reproducible. The solubility of pregabalin in water/2propanol (x = 0.454) and methanol is about 12 mg/mL at the temperature T = 50 °C. Due to the low solubility, it was not possible to measure the cluster sizes in water/2-propanol (x = 0.454) and methanol.

where P is the probability that at least one nucleus has formed. The probability of nucleation depends on the nucleation rate J, the volume of the solution V, the time t required to detect the onset of crystallization, and the growth time tg of a nucleus. The growth time tg of a nucleus in water, as indicated by the shortest crystallization time in Figure 2, is short and very similar across a narrow supersaturation ratio range of S = 1.2− 1.3 (Table 1). A significantly higher and wider supersaturation range was needed to obtain different probability distributions for each of the other solvent systems (see the Supporting Information). The supersaturation ratios S and supersaturation ratio range required to induce crystallization both increased with decreasing mole fraction x of water (Table 1). Thus, it becomes more difficult for pregabalin to crystallize when the mole fraction x of water in the solvent is reduced. This trend is also reflected in the estimated effective solid−liquid interfacial energies γef shown in Table 1, which were determined using CNT eq 2

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RESULTS AND DISCUSSION The aqueous alcohols shown in Table 1 consist of different mole fractions x of water and were selected to study the crystallization kinetics and thermodynamics in relation to the hydration of pregabalin. In total, more than 1800 crystallization experiments were conducted and the resulting data were correlated with classical nucleation theory (CNT) expressions according to literature procedures.26,28,29 A previous study25 showed that the solubility of pregabalin increases with increasing water fraction x, which is common for amino acids.30 Figure 2 shows the probability P of crystallization of pregabalin in water as a function of time t for different

yef =

27k3T 3B 4c 3v 2

(2)

where B is the thermodynamic parameter for heterogeneous nucleation, c the shape factor for spheres (i.e., c = (36π)1/3), and v the molecular volume of the crystalline phase of pregabalin. Typically, the effective solid−liquid interfacial energy γef of organic compounds increases with solubility C* and solvent polarity, as solute molecules experience more difficulty in undergoing desolvation when the solute−solvent interactions are stronger.7 On the other hand, an inverse relationship between the interfacial energy γef and solubility is characteristic for inorganic electrolytes in aqueous solutions.8 In our experiments, the organic compound pregabalin was used, which is a zwitterion and therefore an electrolyte in aqueous solutions. As a result, pregabalin mirrors the properties of inorganic electrolytes in aqueous solutions and follows an inverse relationship between the interfacial energy γef and solubility (Table 1). In addition to the interfacial energy−solubility link, an inverse relationship between the mole fraction x of water and the effective solid−liquid interfacial energies γef was apparent (Table 1). The link between the mole fraction of water x and the crystallization of pregabalin was further elucidated using the estimated kinetic A and thermodynamic B parameters, as obtained from CNT eq 3 for surface-transfer-limited nucleation. The analogous volume-diffusion controlled nucleation expression provided similar values (see Supporting Information).

Figure 2. Probability P distributions for the crystallization of pregabalin in water as a function of time t measured for supersaturation ratios S = 1.21 (red ●), 1.23 (green ■), 1.24 (blue ▲), 1.25 (black ▼) ,and 1.27 (orange ⧫). The lines are fits of eq 1 to the data.

i B y J = AS expjjj− 2 zzz ln S{ k

supersaturation ratios S. In general, the probability P of crystallization of pregabalin in water sharply increased with increasing supersaturation ratio S. The probability distribution for supersaturation S = 1.23 appeared to be an outlier, as it overlaps with data for S = 1.25. This outlier may have resulted from weighing errors and/or heterogeneous particles. Such small variations would significantly affect the nucleation probability P, as small changes in supersaturation ratio S lead to significantly different induction times. Each probability distribution was fitted to the following equation derived from the CNT P(t ) = 1 − exp( −JV (t − tg))

3

(3)

The dependence of the thermodynamics and molecular kinetics on the mole fraction of water x and supersaturation ratio S of pregabalin is clearly shown in Figure 3. Kinetic parameter A was used to determine the molecular kinetics (zf *C0 = ASavg), which according to the CNT accounts for the statistical process of a building unit attaching to a nucleus and depends on the Zeldovich factor (z; i.e. the probability of a cluster larger than the critical size to decay), the attachment frequency f * of building units to a nucleus, and the concentration of nucleation sites C0.31 Figure 3 shows that

(1) C

DOI: 10.1021/acs.cgd.9b00253 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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crystals, showing that the same anhydrate crystal structure was reproducibly isolated as the stable form in all crystallization experiments. The hydrate form of pregabalin is highly metastable under atmospheric conditions but could be formed initially upon nucleation. In our work, in-line Raman spectroscopy was used to measure the formation of the hydrate form. Figure 4 shows

Figure 3. Number of molecules in the critical nucleus (n*= 2B/ln3 S) of pregabalin versus supersaturation ratio S for solvents water (green ⧫), water/methanol (x = 0.727, purple ▶), water/methanol (x = 0.544, orange ■), water/2-propanol (x = 0.454, red ▼), and methanol (blue ●). The open symbols represent the molecular kinetics (zf*C0 = ASavg). The horizontal axis at the top shows the order of the mole fraction of water x. 95% confidence bands are shown.

the molecular kinetics increase with an increasing water fraction x in the solvent, which may be due to the enhanced polarity of solute−water units that could improve the attachment process to form a nucleus. The effect of water on the self-association of pregabalin wins out over the effect of supersaturation. The thermodynamic parameter B was used to determine the number n* of molecules in the critical nucleus (n*= 2B/ln3 S). Figure 3 shows that a large number n* of molecules make up the nuclei in pure water, which required comparatively small supersaturation ratios S of about 1.25 to be formed. On the other hand, a small number of molecules in the critical nuclei size in pure methanol required comparatively high supersaturation ratio S values of about 3 to be formed. In the water− alcohol mixtures, the number n* of molecules in the critical nucleus appears to be an average of small and large nuclei sizes, depending on the amount of water in the solvent. The large number of molecules in the critical nucleus in water could be due to the formation of large hydrogen-bonded pregabalin−water networks and clusters. The resulting large cluster sizes in water and smaller cluster sizes in water/ methanol solvents were measured using dynamic light scattering (DLS). The solubility of pregabalin in water/2propanol (x = 0.454) and methanol was too low for DLS measurements. At a temperature of 50 °C, the solubility of pregabalin in water and in the water/methanol solvent is equal.25 Under these conditions, DLS experiments showed that the nuclei in water, water/methanol (x = 0.727), and water/ methanol (x = 0.273) have average diameters of approximately 1755 ± 133, 1144 ± 110, and 1162 ± 199 nm, respectively. Thus, both the CNT and DLS measurements show that the water fraction in the solution significantly influences the formation of nuclei. The link between the amount of water in solution and the nucleation data may be the result of the crystallization of the hydrate and anhydrate forms of pregabalin. However, X-ray powder diffraction (XRPD) was used to analyze the product

Figure 4. Raman spectra as a function of time during the hydrate-toanhydrate transition of pregabalin in water at a temperature of 5 °C. The start of the transition is indicated by the line at 50 min.

the Raman spectra of pregabalin as a function of time during the hydrate to anhydrate transition in water in the spectral region 840−790 cm−1. The anhydrous starting material was characterized by an intense peak at 824 cm−1 and a smaller peak at 810 cm−1. This peak pattern was also observed for the molecularly similar anhydrous amino acid L-leucine.32 For Lleucine, these peaks were observed at 848 and 836 cm−1 and were assigned to the out-of-plane vibration of the carboxylate group and the rocking motions of the methyl groups.32 On the basis of the peak assignment of L-leucine, it was possible to rationalize the observed Raman spectra of pregabalin. The solution state of pregabalin in water was characterized by a single broad peak at 810 cm−1. Water forms hydrogen bonds with the carboxylate group of pregabalin hydrate, and the absence of the 824 cm−1 peak may therefore result from water inhibiting the carboxylate out-of-plane vibration. As such, the peak at 810 cm−1 most likely results from the rocking motions of the methyl groups. The peak at 810 cm−1 started to slowly reduce in height, which was attributed to the nucleation of the hydrate. The out-of-plane vibration of the carboxylate group emerged after 50 min and points to the start of the transformation of the hydrate into the anhydrate form (Figure 3). The transition to the anhydrate typically started within 50 min after the formation of the hydrate. Over time, the peak at 824 cm−1 increased in height until the peak ratio between 824 and 810 cm−1 remained the same, indicating the complete transformation of the hydrate. The hydrate-to-anhydrate transition of pregabalin in water took 100 min to complete, which was significantly slower than the 25 min transition in water/methanol solvent mixtures. The D

DOI: 10.1021/acs.cgd.9b00253 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Figure 5. Schematic illustration of the proposed irreversible transition of the pregabalin hydrate crystal structure into the interlocked anhydrate form.

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poor solubility of pregabalin in methanol and the water/2propanol (x = 0.454) mixture prevented us from recording Raman spectra in those solvents.25 The transition of the hydrate into the anhydrate form was found to be irreversible at room temperature. Figure 5 schematically shows a proposed mechanism by which this irreversible transition may occur. In the solid-state structure of the hydrate form, the ammonium and carboxylate groups of pregabalin bind with water to make up a bilayer where the apolar aliphatic chains point outward. The resulting cavities in the bilayer between the aliphatic chains are too small to accommodate the aliphatic chains of a second layer. When water is removed from the hydrate, one row of pregabalin molecules in the bilayer rotate to facilitate the strong intermolecular hydrogen bonds between the ammonium and carboxylate groups. This twist in molecular orientation leads to a larger cavity between the aliphatic chains, which is large enough to accommodate the aliphatic chains of a second bilayer to stabilize the structure. The resulting final interlocked structure prevents water from going into the crystal lattice, making the hydrate to anhydrate transition irreversible in the solid state. The difference in size between the compact anhydrate and the larger hydrate is in agreement with our crystallization experiments (Figure 3) and DLS measurements.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.9b00253.

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Typical XRPD spectrum of the obtained pregabalin crystals, probability distributions as a function of induction times of pregabalin in different solvent systems, plot of ln(J/S) versus 1/ln2 S for different solvent systems, and estimated values for the kinetic and thermodynamic parameters for interface-transfer-controlled nucleation and volume-diffusion-controlled nucleation (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail for R.R.E.S.: [email protected]. ORCID

René R. E. Steendam: 0000-0002-3363-4160 U. B. Rao Khandavilli: 0000-0003-1823-3630 Leila Keshavarz: 0000-0002-1218-9352 Patrick J. Frawley: 0000-0001-7066-0942 Notes

The authors declare no competing financial interest.

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CONCLUSIONS

ACKNOWLEDGMENTS This research has been conducted as part of the Synthesis and Solid State Pharmaceutical Centre (SSPC) and funded by Science Foundation Ireland (SFI) under Grant 12/RC/2275. We thank Danny Stam and Technobis for providing us a Crystal16 instrument for the induction time measurements.

We have demonstrated that the interfacial energy of pregabalin is inversely related to the solubility and the water fraction of the solvent. In solution, pregabalin forms large hydrate clusters preferentially over smaller anhydrate clusters. On the other hand, crystallization of pregabalin revealed that the hydrate is highly metastable in crystalline form, as it rapidly and irreversibly transforms back to its anhydrate form. Such a stark difference between solution chemistry and crystallization may be present in many other crystallization systems, which may hinder research linking solution chemistry to crystallization. However, we show that a solution−crystallization link could still exist in such contrasting cases and we foresee that the approach presented can be used to further reveal relationships among self-association in solution, crystallization, and hydration of a wide range of organic compounds. Such knowledge of the solution chemistry and structural landscape of pharmaceutical compounds is essential for the development of manufacturing routes and patent protections.

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REFERENCES

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DOI: 10.1021/acs.cgd.9b00253 Cryst. Growth Des. XXXX, XXX, XXX−XXX