New Category for Active Pharmaceutical Ingredients, a Low Molecular

Article pubs.acs.org/crystal

New Category for Active Pharmaceutical Ingredients, a Low Molecular Weight Organogelator: Crystal Structure of Atorvastatin Calcium and Its Unusual Phase Transition Behavior during Dissolution Bishal Raj Adhikari,† Daeyoung Kim,‡ Jae Ho Bae,† Jisun Yeon,† K. C. Roshan,† Sung Kwon Kang,‡ and Eun Hee Lee*,† †

College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong 30019, Republic of Korea Department of Chemistry, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea

‡

S Supporting Information *

ABSTRACT: A gel is presented which represents a new category of pharmaceutical active ingredient in addition to the conventional crystalline and amorphous forms. The crystal structure of atorvastatin calcium ethylene glycol solvate suggests atorvastatin calcium to be a low-molecular weight organogelator that forms organogels with a wide variety of alkyl alcohols. Metal ion driven ionic interactions based on the amphiphilic nature of atorvastatin calcium leads to a lamellar type packing structure. Like ethylene glycol in its solvated form, alkyl alcohols, ranging from ethanol to octanol, can interact with the metal ions, and/or occupy the void spaces within that lamellar structure, thereby forming organogels featuring highly varying solubilities and unusual phase transition behaviors. An in situ dissolution study identified changes in the amounts/ratios of solvents in the atorvastatin calcium organogels without any significant structural changes, indicating that simultaneous solvent exchange is the mechanism of phase transition during dissolution. The presented low molecular gelator system may also be observed with the other statins that share common structural features with atorvastatin calcium as well as with other pharmaceutical materials. Thus, we propose a new form of active pharmaceutical ingredient, a gel. Since gels show important pharmaceutical properties quite distinct from those of crystalline or amorphous forms, they deserve special attention.

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INTRODUCTION Gels forming a continuous macroscopic structure consist of at least two components, namely, a gel skeleton body and liquids such as water or organic solvents. According to the classification system by Flory, four types of gel exist: (1) ordered, lamellar gels, (2) covalently formed polymer networks, (3) polymer networks via physical aggregation of polymer chains, and (4) particulate disordered gels.1 Unlike chemical gels, which are linked via covalent bonds, low molecular weight hydrogels/ organogels are physical gels linked via hydrogen bonds or van der Waals interactions.2,3 Although predicting which molecular structures will form gels is not yet possible, those that do commonly feature one or more of the following: (1) fatty acid derivatives, (2) steroid derivatives, (3) anthryl derivatives, (4) gelators containing steroidal and condensed aromatic rings, (5) amino acid-type organogelators, and (6) organometallic structures.3 Gels are easily recognized by visual observation; a gel will remain on the bottom of a vial when turned upside-down.4−7 They may also be recognized by their mechanical properties through oscillation stress relaxation, steady shear, and creep © XXXX American Chemical Society

experiments; by their thermodynamic properties through calorimetric methods; through spectroscopic methods, such as fluorescence, NMR, and IR; by their structural features through small angle neutron scattering (SANS), small-angle Xray scattering, or wide-angle X-ray diffraction; by microscopic observations such as the polarized optical microscopic method or SEM; or through molecular dynamics simulations.2,4,8−12 Statins such as atorvastatin, rosuvastatin, cerivastatin, etc. are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) inhibitors, which are widely used to treat hypercholesterolemia.13 The HMG-like moiety shared by the statins binds to the active site of HMGR via hydrogen bonds and ionic interactions, and their hydrophobic groups reside in the hydrophobic pocket of the enzyme.14 Type 1 and type 2 statins are differentiated by the groups linked to their HMGlike moiety. Statins can be classified by solid state characterization (Figure 1). One group of statins has a long 3,5-dihydroxyheptanoic acid Received: September 22, 2016

A

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Figure 1. Molecular structures of statins: (a) simvastatin, (b) lovastatin, (c) fluvastatin sodium, (d) cerivastatin sodium, (e) rosuvastatin calcium, (f) pravastatin sodium, and (g) atorvastatin calcium, and optical images of (h) form VII ethanolate and (i) form VII octanolate.

solvates of atorvastatin calcium because their patterns are not readily discernible. This peculiar property of atorvastatin calcium seems related to its formation of a large number of solvates, many of which have been patented. The literature includes more than 70 different solvates of atorvastatin calcium, including many that have been patented. There have been attempts to obtain the local structure of atorvastatin calcium using 13C solid-state NMR,44 solid-state 19F magic angle spinning (MAS) NMR,45 and a combination of 13C, 19F, and 15N magic angle spinning NMR using a density function theory calculation for structure optimization.46 However, to our knowledge, single crystal X-ray data of atorvastatin calcium has not yet been successfully recorded. We successfully obtained the single crystal X-ray structure of the ethylene glycol solvate of atorvastatin calcium. Although the crystal structure of the ethylene glycol solvate of atorvastatin calcium does not unambiguously relate to gel structures, it can nevertheless provide insight concerning them.47 In addition, the solid state characterization of atorvastatin calcium organogels containing different alkyl alcohols was conducted, and to better understand their unusual phase transition behaviors during dissolution, their in situ dissolution behaviors were investigated.

moiety chain in the HMG-like moiety, while the other has a 4hydroxy-6-oxotetrahydro-2H-pyran moiety ring structure instead. Statins that have the long chain, the 3,5-dihydroxyheptaonic acid moiety, are commercially used in salt forms such as the calcium salts of atorvastatin15−33 and rosuvastatin,34 and the sodium salts of pravastatin,35 fluvastatin,36−38 and cerivastatin.39 Other statins, such as simvastatin and lovastatin, are used in nonsalt forms. Those used in salt form share a unique property; some of their salt powder patterns may be neither crystalline nor amorphous. Some of their powder patterns feature not only sharp and intense diffraction peaks at low angle 2θ but also an amorphous-like halo at high angle 2θ similar to the powder patterns observed in gels or liquid crystalline materials. Otherwise, their patterns are typical of what are referred to as low crystallinity materials. These low crystallinity materials are typically avoided during the drug development process because they are considered difficult to handle and produce consistently. We chose to research atorvastatin calcium, which holds many records as a pharmaceutical compoundbeing the best-selling medication, with a revenue of $12.4 billion dollars in 2008; having one of the highest numbers of polymorphs/solvates; being the subject of the most patents regarding its polymorphs/ solvates; and, at least in the authors’ opinion, being the most difficult to characterize and the most difficult from which to obtain a single crystal suitable for single crystal X-ray analysis. Attempts to obtain a form with physicochemical properties suitable for drug development have been undertaken because the commercially available form, the trihydrate form, shows low solubility and low bioavailability.40,41 Nevertheless, the characterization of the various forms of atorvastatin calcium has proved challenging.42,43 Powder X-ray diffraction (PXRD), the most commonly used solid state characterization method for polymorphs/solvates/amorphous active pharmaceutical ingredients (APIs) has not been easy to apply to the different

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EXPERIMENTAL SECTION

Materials. Atorvastatin calcium was purchased from Cangzhou Senary Chemical S. & T. Co., Ltd. (Hebei, China). Methanol, npropanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, and n-octanol was obtained from Sigma-Aldrich (St. Louis, MO), and ethanol from Pharmco (Brookfield, CT). Water was double-distilled and filtered through a Milli-Q ultrapure water purification system (Billerica, MA). Preparation of Atorvastatin Calcium Anhydrous Form. Atorvastatin calcium in its anhydrous form was prepared by heating approximately 5 g of atorvastatin calcium form I trihydrate at 150 °C for 3 h. Thermogravimetric analysis (TGA) was conducted to confirm the complete removal of water. B

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Figure 2. (a) Coordination motif of the ethylene glycol solvate of atorvastatin calcium composed of four molecules of atorvastatin, two calcium ions, and two ethylene glycol molecules, and (b) packing diagram of the ethylene glycol solvate of atorvastatin calcium forming lamellar arrangements. For clarity of presentation, two atorvastatin benzene rings are displayed in space-filling mode. In-Situ Dissolution Measurements of Atorvastatin Calcium Organogels. Excessive amounts of atorvastatin organogels were placed in a 500 mL beaker containing a magnetic stir bar and stirred at 200 rpm. A portion of the solution containing solids was taken at predetermined time intervals (5, 15, 30, 60, 120, 180, and 360 min) and filtered using a nylon filter of 0.2 μm pore size. Approximately 250 mg of solid was vacuum-dried at 40 °C for an appropriate time, and the dried solids were then used for PXRD, TGA, and Karl Fischer titration. The amounts of total solvents were measured by TGA, and the mass fraction of water to total solvent was measured by Karl Fischer titration. Vapor Sorption Experiments. The atorvastatin calcium organogels were exposed to differing relative humidity conditions for different durations (25 °C/52% RH for 7 days and 25 °C/97% RH for 2 days) to obtain organogels with 68% and 89% overall solvent water concentrations (w/w %), respectively, and then analyzed using PXRD, TGA, and Karl Fischer titration. In-situ dissolution measurements were performed to evaluate the solubilities of the organogels. Powder X-ray Diffraction (PXRD). The powder patterns of the atorvastatin calcium organogels were evaluated using a D8 ADVANCE with Davinci (Bruker AXS Inc., GmbH, Germany) using Cu Kα radiation and equipped with a high speed LynxEye detector. Samples were analyzed over a 2θ range of 4−25° with increments of 0.02° at a rate of 6°/min. The data were analyzed using DIFFRACplus Eva (Bruker AXS Inc.). For the in situ dissolution measurements, the organogels were prepared in two different ways. Their powder patterns were measured not only immediately after filtering them from the solution but also after vacuum-drying them. The temperature and duration of the vacuum-drying were varied depending on the properties of organogels themselves. Differential Scanning Calorimetry (DSC). Thermal analysis was conducted using a Q2000 DSC (TA Instruments, New Castle, DE, USA). The temperature scale and heat flow were calibrated by measuring the onset temperature and the enthalpic response of an indium standard. Low mass sample pans were used, and the samples were heated from 0 to 175−200 °C at a rate of 20 °C/min. The data were acquired and analyzed using Universal Analysis 2000 software v. 4.1D (TA Instruments). Thermogravimetric Analysis (TGA). Changes in the weights of atorvastatin calcium organogels were measured using the TA Instruments thermogravimetric analysis system (TGA Q50 Thermog-

ravimetric Analyzer; TA Instruments, New Castle, DE). A sample weighing approximately 10 mg was placed on a sample pan, and the heating rate was 20 °C/min, from room temperature to 180−200 °C. Data were acquired and analyzed using Universal Analysis 2000 software v. 4.1D (TA Instruments). Karl Fischer Titration. The volumetric water content determination was performed using a Metrohm 870 KF Tritino Plus autotitrator (Herisau, Switzerland). The instrument was calibrated using the Hydranal water standard (1 g contains 10.0 mg of water). Methanol was used as the titration medium, and the titration was performed in triplicate using 50−100 mg of sample. Hot-Stage Microscopy (HSM). The ethylene glycol solvate of atorvastatin calcium was placed in a Linkam THMS350/600/720 (Linkam Scientific Instruments Ltd., Surrey, UK) hot stage under a polarizing optical microscope, NIKON Eclipse LV100POL (NIKON, NY, USA) equipped with a Nikon DS-Fi1 camera and Nikon NISElements BR software (ver. 4.00.06). The heating rate was controlled by Linksys32 software (Linkam Scientific Instruments Ltd.) and set at 20 °C/min, from room temperature to 350 °C. X-ray Data Collection and Structure Determination. X-ray intensity data were collected on a Bruker SMART APEX-II CCD diffractometer using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å) at temperatures of 296 and 123 K. The structures were solved by applying the direct method using SHELXS-2013 and refined by full-matrix least-squares on F2 using SHELXL-2013.30 All nonhydrogen atoms were refined anisotropically. Amine H atoms were located from the difference map and refined freely (refined distances; N−H = 0.73(3) and 0.96(2) Å). Other H atoms were positioned geometrically and refined using a riding model, with C−H distances = 0.93−0.98 Å. The isotropic displacements, Uiso, of the hydrogen atoms were constrained to 1.2Ueq of the carrier C atom on aromatic and methylene moieties and 1.5Ueq of the carrier C atom on methyl groups.

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RESULTS AND DISCUSSION Crystal Structure Analysis and Desolvation Behavior of the Ethylene Glycol Solvate of Atorvastatin Calcium. The ethylene glycol solvate of atorvastatin calcium crystallizes in the monoclinic crystal system in the space group P21 (see Supporting Information Table S1). The unit cell length parameter b is 69.16 Å, which corresponds to a 2θ value of C

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Figure 3. Micrographs of the ethylene glycol solvate of atorvastatin calcium under a hot-stage microscope at room temperature, 153 °C and 173 °C (top). Proposed structure of the helical strands upon desolvation (bottom).

Figure 4. (a) Powder patterns of atorvastatin calcium slurried in various alkyl alcohols and (b) maximum solubilities of atorvastatin calcium organogels shown during dissolution.

2.55° for the (0 2 0) face. The coordination motif of the ethylene glycol solvate of atorvastatin calcium consists of four atorvastatin calcium molecules with two calcium ions and two ethylene glycol molecules (Figure 2a). Each calcium ion is coordinated by three atorvastatin calcium molecules via a total of one hydroxyl and three carboxylic acids, and by two ethylene glycols via a total of four hydroxyls. The nearly octahedral coordinates are completed by the two molecules of ethylene

glycol. The carboxylic acid oxygens of two out of the four atorvastatin molecules in the asymmetric unit are shared by two different calcium ions, an arrangement that connects the two calcium ions making a coordination motif. The additional ethylene glycol molecules occupying the void spaces of the unit cell are removed for clarity and squeezed out during the structural refinement processes. D

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Figure 5. An in situ dissolution study of organogels containing different alcohols showing gradual decreases in the intrinsic solubilities of atorvastatin calcium organogels during dissolution.

organogels are strong enough to hold a magnetic stir bar even when inverted (Figure 1). The eight organogels’ similar powder patterns (Figure 4a) indicate their structural similarity, but the significant differences in both their maximum solubilities (Figure 4b) and thermal behaviors (see Supporting Information Figures S1 and S2) are notable. Typically, the heats of fusion of crystalline materials are more than 80 J/g, but those of the organogels ranged from 10 to 55 J/g. The solubilities of the organogels are significantly higher than that of commercially available form I and vary widely in spite of structural similarities. The n-propanol organogel of atorvastatin calcium showed the highest solubility (687.8 ± 15.5 μg/mL), and the solubilities of the organogels decreased with the length of the carbon atom chain of the alcohol. The powder patterns of the heptanol and octanol forms, labeled as form E, resemble those of amorphous materials. It was difficult to remove the residual solvent from these forms after slurrying, and this might explain their increased solubility despite their long alkyl chains. In-situ Dissolution Measurements. Monitoring the dissolution behavior of the organogels in situ by PXRD, TGA, and Karl Fischer titration allowed it to be better understood. The powder patterns of the organogels during dissolution do not show any significant structural changes (see Supporting Information Figures S3−S9). However, as solubility decreased across the organogels, there was a gradual change in the mass percentage of water to total solvent (see Supporting Information Figure S10). Figure 5a shows the gradual decrease in solubilites over time, and Figure S10 shows the gradual decrease in the mass percentage of the respective alcohol to total solvent, in other words, gradual increase in the mass percentage of water to total solvent. The decrease in the mass percentage of the respective alcohol to total solvent was calculated by subtracting the mass percentage of water from mass fraction of the total solvents. The normal phase transitions of APIs in solution occur via dissolution of the metastable form, followed by crystallization of the stable one.49,50 However, the in situ dissolution study of organogels suggests an unusual phase transition−simultaneous solvent exchange without significant corresponding structural changes, a dissolution behavior that may be unique to organogels. Vapor Sorption Study of the Organogels. A vapor sorption study was performed to confirm simultaneous solvent

Atorvastatin molecules exhibit an amphiphilic nature; hydrophilic hydroxyl and carboxyl group moieties are attached to an alkyl chain and a bulky hydrophobic moiety is composed of three benzene rings. Typically, amphiphilic molecules consist of a hydrophilic moiety attached to long (>C18) hydrophobic alkyl chain(s) and come together to form membrane-like structures with the hydrophilic moiety forming the outer layer. However, in the case of atorvastatin calcium, the hydrophobic moiety is bulky and forms the outer layer of the lamellar structure, with the hydrophilic metal ion coordination residing in the center (Figure 2b). The ethylene glycol solvate of atorvastatin calcium was a rodshaped crystal, but the rod-shaped crystals were transformed into helical strands upon desolvation. Figure 3 shows the helical strands observed under a hot-stage microscope upon heating, along with their proposed structure constructed by translating one of the molecular strands along the b axis. This type of helical strand was often observed upon the desolvation/ dehydration of hydrogels to form so-called xerogels.3,48 Atorvastatin Calcium Organogels. Atorvastatin calcium forms organogels with a wide variety of alkyl alcohols. The powder patterns of the organogels along with the calculated powder pattern of the ethylene glycol solvate of atorvastatin calcium are shown in Figure 4a. The powder patterns of the atorvastatin calcium organogels seem to belong to neither the conventional crystalline nor the conventional amorphous forms. The powder patterns of the organogels have broad but distinct diffraction peaks at low angle 2θ and an amorphous-like halo at high angle 2θ. The diffraction peaks of the (0 2 0), (0 4 0), (0 6 0), and (0 8 0) faces are distinct, as expected from the lamellar structure of the solvate. Despite numerous attempts, only the ethylene glycol solvate yielded a single crystal suitable for single crystal X-ray analysis. In that X-ray analysis derived structure, one ethylene glycol molecule provided two coordination bonds to the calcium ion via its two hydroxyl end groups connected by its ethyl moiety. However, replacing one ethylene glycol molecule with two alkyl alcohol molecules would increase the flexibility of the structure and could thereby result in gel formation. Representative pictures of the atorvastatin calcium organogels formed by slurrying anhydrous atorvastatin calcium in alkyl alcohols ranging from ethanol to n-octanol are shown in Figure 1h (VII ethanolate) and Figure 1I (VII octanolate). The E

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systems.51−55 Also, crucial is the clear classification of physical forms for reasons related to both regulation and intellectual property. For example, salts are regarded as new APIs, while cocrystals are regarded as “API-excipient” molecular complexes.56 The data required for New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) differ widely depending on which category the API belongs to.57 We report the crystal structure of atorvastatin calcium ethylene glycol solvate for the first time. Related to the crystal structure, we suggest atorvastatin calcium as a low-molecular weight organogelator that forms organogels with a wide variety of alkyl alcohols and report its unusual phase transition behavior during dissolution. We believe that the low molecular gelator system may also be observed with other statins sharing common features, such as metal ions and a 3,5-dihyroxyheptanoic acid moiety, as well as with other pharmaceutical materials. Therefore, we suggest that for pharmaceutical active ingredients, in addition to the crystalline and amorphous categories, a new gel category is necessary. Special attention is required for gel-type materials since their physicochemical properties and dissolution behaviors, and possibly other important pharmaceutical properties, can differ widely from those of known pharmaceutical forms such as amorphous or crystalline solids.

exchange as a mechanistic explanation for the solubility decrease during dissolution. The ethanolate organogels containing 39%, 68%, and 89% water to total solvent were prepared by storing them to different storage conditions (Table 1). The powder patterns of the ethanolate organogels Table 1. Mass Percentage of Water to Total Solvent in the Ethanolate Organogel and the Solubility of the Ethanolate Organogel after Exposing It to Different Storage Conditions sample no.

mass percentage of water to total solvent (w/w %)

max. solubility during dissolution (μg/mL)

storage conditions before measurements

1 2

39 68

619.71 ± 22.61 563.49 ± 23.10

3

89

418.46 ± 21.13

initial sample 52% RH at r.t. for 7 days 97% RH at r.t. for 3 days

containing different weight percentage of water to total solvent are similar to each other meaning that the weight percentage of water to total solvent did not alter overall structure of the ethanolate organogels (see Supporting Information Figure S11). However, the maximum solubilites of the organogels were quite different depending on the amounts of mass percentage of water to total solvents (Table 1, Figure 6). Similar to the in situ dissolution measurements study, as the mass percentage of water to total solvent in the organogels obtained from the vapor-sorption study increased, the maximum solubility of the organogels decreased (Figure 6). It can be concluded that in addition to the type of solvents, the amounts of mass percentage of water to total solvents determine the solubilities of the organogels and the simultaneous solvent exchange occurred during dissolution could be the possible mechanism of decrease in solubility during dissolution of the organogels.

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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.6b01394 Thermal analysis and powder patterns measured during the in situ dissolution measurements are shown in Figures S1−S9 and Tables S1−S2. The powder patterns of the ethanolate organogels containing various amounts of water are shown in Figure S10 (PDF)

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CONCLUSION Information regarding the solid state properties, solubilities, and stability/phase transitions of APIs is crucial to the drug development process due to the differing solubilities, stabilities, bioavailabilities, and manufacturabilities of different polymorphs, solvates, amorphous forms, or multicomponent

Accession Codes

CCDC 1497572 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge

Figure 6. An in situ dissolution study of Form VII ethanol organogels containing different mass percentage of water to total solvent prepared by exposing them to different storage conditions. The maximum solubilities vary depending on the mass percentage of water to total solvent in the organogels. F

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Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: (+82) 44-860-1606. Tel: (+82) 44-860-1620. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by a grant (14172MFDS189) from the Ministry of Food and Drug Safety in 2014 and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2016R1A1A1006429).

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