Highly Crystalline Forms of Valsartan with Superior ... - ACS Publications

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Highly Crystalline Forms of Valsartan with Superior Physicochemical Stability Jian-Rong Wang, Xiaojuan Wang, Liye Lu, and Xuefeng Mei* Pharmaceutical Analytical & Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China S Supporting Information *

ABSTRACT: Single crystal structures of blockbuster antihypertensive drug Valsartan are revealed the first time in this report. Two new highly crystalline forms, named form E and an ethanol solvate form F, were discovered and fully characterized by PXRD, Raman, IR, TG, DSC, and DVS. Conformational flexibility and single crystal structures are discussed in detail. Physicochemical properties, such as hygroscopicity, chemical stability, crystallinity, and dissolution behaviors, are compared with the marketed solid-state form (amorphous state). The results show that the newly discovered highly crystalline form E presents a remarkably different dissolution behavior and superior chemical stability.

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INTRODUCTION The majority of drug products, formulated active pharmaceutical ingredients (APIs), are administered as oral solid dosage forms, such as tablets and capsules, owing to the superior chemical and physical stability in solid than in solution.1 Drugs even intended for parenteral application are also often stored under solid state and dissolved in solution prior to use. The solid APIs used in the formulation could exist in distinctive solid modifications, such as polymorphs, solvates, hydrates, salts, cocrystals, and amorphous state. Among the various solid forms, polymorphs (alternative arrangements of the same molecular entity in the crystal lattice) and solvates, especially hydrates, are universal phenomena existing in the organic small molecular-based APIs and have drawn special attention from both academic and industrial researchers.2−5 It is welldocumented that new crystal modifications may present pronounced differences in pharmaceutically relevant properties, such as hygroscopicity, stability, solubility, dissolution rates, bioavailability, and sometimes biological activities.6−8 In addition, new polymorphs are patentable and, hence, possess economic impact in terms of intellectual property protection.9 In order to achieve a reasonable shelf life and to prevent form transformation in the future manufacture processes, solid APIs are generally produced and stored under a desired solid form (e.g., in most cases) under the most thermodynamically stable and highly crystalline form. Consequently, identification and preparation of the optimum solid-state form of a drug candidate is of paramount importance in the course of the drug development process.10,11 Valsartan [(S)-2-(N-((2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)pentanamido)-3-methyl-butanoic acid] is a potent, orally bioavailable and highly selective antagonist of the angiotensin II at the AT1-receptor (Scheme 1). Formulated as the free acid in capsule and tablet dosage forms, the drug was © XXXX American Chemical Society

Scheme 1. Chemical Structure of Valsartan

originally developed by Ciba-Geigy, and later Novartis Pharmaceutical Company, for hypertension and heart failure.12,13 Valsartan was approved by the United States Food and Drug Administration (FDA) in 1996 and is sold under the trade name Diovan. The drug has been in therapeutic use for more than fifteen years, and the global sales of Diovan were approximately $5.7 billion in 2011. Despite its huge success on the market, the drug was developed under an undesired solid state with unfavorable processability and chemical stability.14−16 Valsartan was classified as a BCS class II compound with poor water-solubility at pH 4.5 or lower.17 Probably associated with its low solubility at the biological pH range, the drug’s bioavailability was reported to be less than 23% in a pivotal human study.18 The solid state form in the marketed products was found to be mostly amorphous, exhibiting great hygroscopicity and unfavorable chemical stability. In accordance with the United States Pharmacopeia (USP) drug substance specifications, the Valsartan drug substance needs Received: May 17, 2013 Revised: June 4, 2013

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dx.doi.org/10.1021/cg400762w | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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stability, and dissolution rates are compared with the commercial amorphous form.

to be stored under controlled room temperature and protected from moisture and light during storage, owing to the undesirable physicochemical properties under an amorphous state. In order to improve its chemical stability and solubility, Valsartan was extensively studied over the years by application of a variety of formulation technology, such as formation of cyclodextrin (CD) complex, solid dispersion, and other solubility enhancement techniques.17,19−21 Although multiple patents have been filed around the polymorphs of this drug over last decades,22−29 highly crystalline Valsartan material was generally believed to be difficult to make.30 With the U.S. patent no. 5399578, the synthesis and application of the Valsartan compound was disclosed. The drug substance obtained from ethyl acetate was reported to have melting intervals ranging from 105 to 115 °C. It was reported that attempts to prepare the reported solid using the same method resulted in a sticky solid and was characterized to be amorphous by PXRD analysis.28 This is further substantiated by findings of Marti et al. (WO200206253, page 2, paragraph 1) that showed that the X-ray diffraction pattern of the Valsartan free acid obtained from prior crystallization methods consists essentially of a very broad, diffused X-ray reflection and, therefore, designated as an amorphous form. Subsequently, WO2003089417 disclosed new crystalline forms of Valsartan designated as forms I and II and their preparation methods. WO2004083192 disclosed new crystalline forms of Valsartan designated as form I to form IX and methods for their preparation. 25 Subsequently, WO200410067406 claimed a novel crystal form of Valsartan with PXRD data and DSC melting onset temperature around 92 °C. It has been observed that the crystal forms claimed in WO2003089417, WO2004083192, and WO200410067406 are found to be contaminated with high contents of amorphous Valsartan. WO2007017897 A2 described novel crystalline forms of Valsartan, forms A, B, C, and D, and the processes for their preparation; more details were also given to the pharmaceutical compositions containing these polymorphs and their use in medicine. While form D was determined to contain high crystalline content (claimed to be 95−98%), forms A, B, and C were obviously mixed with a high content amorphous material, according to their broad, diffused PXRD diffraction peaks. It was not until very recently that the preparation of the highly crystalline form of Valsartan with a single crystal unit cell and some high resolution SEM pictures was disclosed in Novartis WO2012016969.29 Although the Novartis patent reported XPRD data and unit cell dimensions for the claimed new crystalline form, there was no crystal structure disclosed. In addition, there is no detailed physical characterization, dissolution, or chemical stability studies reported. The aim of this study is to provide new insight into the formation of highly crystalline Valsartan and to reveal how solid state forms affect the drug’s hygroscopicity, solubility, and chemical stability. Herein, we report the preparation of two new solid-state forms of Valsartan (forms E and F), exhibiting a highly crystalline nature with a detailed single crystal structure analysis. The highly crystalline modifications were thoroughly characterized by various analytical techniques, such as powder X-ray diffraction (PXRD), Fourier transform infrared (FT-IR) spectroscopy, and Raman spectroscopy. Accordingly, the physicochemical properties were investigated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and dynamic vapor sorption. Hygroscopicity, chemical

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EXPERIMENTAL SECTION

Materials. The marketed form of Valsartan (majority of amorphous form) was obtained from Shanghai Nuote Biological Technological Company, Ltd. with greater than 99% purity. All analytical grade solvents were purchased from Sinopharm Chemical Reagent Company, Ltd. and used without further purification. Preparation of Form E. To a 5 L round-bottom glass flask, 100 g of Valsartan powder and a 2 L solvent mixture of n-heptane and diethyl ether (v/v, 1:1) were added. The slurry was heated to 30 °C and stirred for 72 h. The mixture was cooled down to room temperature, filtered, and dried over vacuum for 4 h at room temperature to give form E (97.5 g, 97.5% yield) as a white crystalline powder. Preparation of Form F. To a 4 mL glass vial, 200 mg of Valsartan powder and a 2 mL solvent mixture of ethanol and water (v/v, 1:2) were added. The mixture was slurried at 50 °C and stirred for 3 days. The mixture was cooled down to room temperature, filtered, and dried over vacuum for 4 h at 50 °C to give form E (126 mg, 63.0% yield) as a white to off-white crystalline powder. Differential Scanning Calorimetry (DSC). Differential scanning calorimetry was performed with a PerkinElmer DSC 8500 instrument. Samples weighing 3−5 mg were heated in standard aluminum pans at scan rates of 10 and 50 °C/min, under a nitrogen gas flow of 20 mL/ min. Thermogravimetric Analysis (TGA). Thermogravimetric analysis was carried out in Netzsch TG 209 F3 equipment with a typical scan rate of 10 °C/min and a nitrogen gas purge with a flow of 20 mL/min. Intrinsic Dissolution Rate (IDR). Intrinsic dissolution experiments were carried out on a PION uDISS apparatus using a pH 4.5 acetic acid−ammonium acetate buffer as dissolution medium. For IDR measurements, 8 mg of the marketed form (amorphous material), form E, and form F were placed in the dissolution attachments and compressed to a 0.07 cm2 disc, using a press at a pressure of 120 bar and held for 3 min. The attachments were placed in 20 mL glass vessels prefilled with pH 4.5 acetic acid−ammonium acetate buffer at 25 °C and rotated at 200 rpm. The concentration of the solution was determined by USP high-performance liquid chromatography (HPLC) assay method. Confirmed by PXRD analysis, there is no form transformation observed upon compression and throughout the dissolution experiments. Equilibrium Solubility. Solubility of the marketed form, E, and F of Valsartan were measured in pH 4.5 acetate−ammonium acetate buffer solutions by slurrying the excess amounts of solids in buffer at room temperature. The concentration of the solution was determined by the USP HPLC assay method. There is no form transformation observed throughout the slurry experiments, which was confirmed by PXRD analysis. Dissolution of Capsules. Capsules containing the marketed form, E, and F of Valsartan were prepared following the marketed formulation of Diovan. Each capsule contains 80 mg Valsartan, 54 mg microcrystalline cellulose, 15 mg crospovidone, 4.5 mg magnesium stearate, and 3.5 mg colloidal silicon dioxide. The mixtures were blended evenly, and then manually filled into a size 2 hard gelatin capsule. The dissolution tests were carried out at 37 °C with a 75 rpm stirring speed, following the United States Pharmacopeia (USP) basket I method on a suitable dissolution apparatus (Dragon Lab MS-H-S10). Sample solutions were periodically drawn out and filtered through a fiber filter (pore size 0.45 um, Gelman Sciences). The concentrations of Valsartan sample solutions were determined by a UV spectrophotometer (Thermo 756 CRT) at 23 ± 1 °C. The wavelength of maximum absorbance (λmax) of Valsartan in dissolution media is 250 nm, which was used for calibration and calculation. Powder X-ray diffraction (PXRD). PXRD patterns were obtained with a Shimadzu XRD 6000 X-ray diffractometer coupled with a Cu Kα radiation tube (V = 40 kV and I = 30 mA). 2θ scanned on a range of 5−40°. All data were acquired at ambient temperature (20 °C). B



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Data were imaged and integrated with RINT Rapid and peak-analyzed with Jade 6.0 from Rigaku. Single Crystal X-ray Diffraction. Single crystal X-ray diffractions of form E (0.30 × 0.20 × 0.20 mm3) and form F (0.20 × 0.18 × 0.16 mm3) were performed on a Bruker Apex II CCD diffractometer, using Mo Kα radiation (λ = 0.71073 Å) at 100 K for form E and a Bruker Apex II CCD diffractometer, using Cu Kα radiation (λ = 1.54178 Å) at 133 K for form F, respectively. The structures were solved by direct methods and refined with full-matrix least-squares difference Fourier analysis, using SHELX-97.31 All nonhydrogen atoms were refined with anisotropic displacement parameters, and all hydrogen atoms were placed in calculated positions and refined with a riding model. Data were corrected for the effects of absorption, using SADABS. Fourier Transform Infrared (FT-IR). Fourier transform-infrared (FT-IR) spectra were collected by a Nicolet-Magna FT-IR 750 spectrometer in the range of 4000 to 350 cm−1, with a resolution of 4 cm−1 at ambient conditions. Confocal Raman Microscope. Raman spectra were recorded using a Thermo Scientific DXR Raman microscope equipped with a laser of 532 nm wavelength in the range of 3500 to 50 cm−1. Samples were analyzed directly on a glass sheet using 10 mW laser power and a 50 μm pinhole spectrograph aperture. Dynamic Vapor Sorption (DVS). Dynamic vapor sorption experiments were performed on a DVS instrument from Surface Measurement Systems, Ltd. Samples were studied over a humidity range of 0 to 95% RH at 25 °C. Each humidity step was made if less than 0.02% weight change occurred over 10 min, with a maximum holding time of 3 h. Hot-Stage Microscopy (HSM). All HSM examinations were performed on a XPV-400E Polarizing microscope and a XPH-300 hot stage coupled with a JVC TK-C9201 EC digital video recorder (Shanghai Changfang Optical instrument Company, Ltd.).

Figure 2. PXRD patterns of new crystalline forms (E and F) and the marketed form.

18.76, 26.58, and 31.36°, and form F shows unique diffraction peaks at 2θ = 8.26, 9.72, 11.94, 12.42, 14.62, 17.42, 22.72, and 24.38°. The PXRD patterns from bulk powder samples agreed well with the results calculated from single-crystal structures, which are discussed below. It was observed that form E can only be obtained when the crystallization was conducted in a particular solvent mixture under a temperature higher than 30 °C, while form F can be selectively synthesized from solvent mixtures in the presence of EtOH, under elevated temperature. Crystal Structure Analysis. Precipitation of Valsartan from a solution often leads to transparent amorphous films or loose powder. We found that highly crystalline materials can be formed only under strictly controlled crystallization conditions and with a certain combination of solvent mixtures used. Even so, obtaining suitable single crystals of Valsartan for structure determination proved challenging, due to the tendency to form tiny small crystals with extensive twinning and modest crystal quality. Despite these challenges, we were able to obtain suitable single crystals for structure determination for both forms for the first time. Single crystal structure of form E was solved and refined in an orthorhombic space group P212121. Details of data collection and structure refinement are summarized in Table 1. The unit cell contains one molecule of Valsartan in the asymmetric unit. As depicted in Figure 3a, the Valsartan molecules are connected via two distinctive hydrogen bonds, both associated with the tetrazole moiety. One hydrogen bond is generated between the carboxylic acid group and the tetrazole ring at the 2 position; another one is constructed between the valeryl carbonyl group and the tetrazole ring at the 5 position, instead (Figure 3b). The hydrogen bond distance between N5−H···O1 and N2− H···O3 were determined as 1.818 and 1.986 Å, respectively. Noticeably, the intermolecular hydrogen bonding interactions, between the carboxylic acid group and the 2 position of the tetrazole ring, connect Valsartan molecules in a head-to-tail fashion along the a axis to form an infinity left-handed helical chain structure (Figure 3c). On the other hand, the hydrogen bonds between N5−H···O1D connect adjacent independent helical chains to form a two-dimensional (2D) H-bond network architecture throughout the crystal structure (Figure 3d). Crystal structure of form F was solved and refined also in the orthorhombic, P212121 space group with one molecule of Valsartan and a molecule of ethanol solvent in the asymmetric unit (Z = 4) (Table 1). The crystal structure and packing motifs

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RESULTS AND DISCUSSION A variety of crystallization procedures and solvents were investigated in order to explore the solid-state landscape of Valsartan.32,33 Most of the crystallization experiments led to a glassy transparent film, corresponding to an amorphous state. To our surprise, a highly crystalline material, named form E, was obtained from a slurry of amorphous material in the nheptane and diethyl ether (v/v, 1:1) solvent mixture at 30 °C. The crystals exhibit plate shape with well-defined sharp edges and faceted surfaces, Figure 1. Also discovered from a slurry

Figure 1. Polarizing microscopy pictures for the highly crystalline forms E (left) and F (right).

experiment, an elongated, columnar-shaped highly crystalline material (form F) that was later found to be an ethanol solvate, was synthesized when an amorphous Valsartan powder was slurried in an ethanol and water (v/v, 1:2) mixture at 50 °C. Unlike the marketed amorphous form with broad, diffusive Xray diffractions, both forms E and F present distinctive and well-defined PXRD diffraction peaks with crystallinity of 99% or higher (Figure 2). The PXRD patterns of these two crystalline forms are visually distinguishable. Form E possesses characterization peaks at 2θ = 9.40, 10.84, 11.80, 14.02, 17.82, C



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Table 1. Crystallographic Data for E and F Valsartan

form E

form F

formula formula weight crystal system space group temperature (K) a (Å) b (Å) c (Å) α (°) β (°) γ (°) cell volume (Å3) calcd density (g/cm3) Z λ independent reflections S R1 Rint wR

C24H29N5O3 435.52 orthorhombic P212121 100(2) 7.3516(11) 16.346(2) 18.801(3) 90 90 90 2259.3 (6) 1.286 4 0.71073 3970 1.043 0.048 0.048 0.118

C24H29N5O3·C2H6O 481.59 orthorhombic P212121 133(2) 10.2475(3) 12.7244(3) 19.7838(5) 90 90 90 2579.7(1) 1.240 4 1.54178 4448 1.025 0.027 0.038 0.070

are obviously different from that of form E, mainly due to the inclusion of an EtOH molecule in the form F crystal lattice. Unlike the direct formation of hydrogen bonding in form E, the carboxylic acid and tetrazole moiety was connected by an ethanol solvent molecule through a set of intermolecular hydrogen bonding (Figure 4a). The distance between O3− H···O4 and O4−H···N2 was determined as 1.783 and 2.065 Å, respectively. A head-to-tail fashion helical structure was also constructed through the H-bonding interactions between carboxylic acid and the tetrazole group. The right-hand helix structure can be observed, viewing along the a axis (Figure 4c). The helical structures were connected through an intermolecular hydrogen bonding between the valeryl carbonyl group and the tetrazole amino group at the 5 position (Figure 4d). The distance between N5−H···O1 was measured as 1.713 Å (Table 2). A comparison of the hydrogen bond distance revealed that the interaction between the valeryl carbonyl and the tetrazole amino group in form F is the strongest hydrogen bond among all the O−H···O and N−H···O hydrogen bonds present in both crystal structures. The free rotation along C12−C13 and C15−C18 could provide conformational flexibility in the Valsartan molecular structure. The conformations of Valsartan molecules under different crystal forms are compared in Figure 5. The observed conformations of form E are significantly different from that found in the crystal structure of ethanol solvate form F. The interaction between the Valsartan molecule and the ethanol molecule lead to pronounced conformational change in crystal structure. In accordance with the single crystal data, form E (red) can be best described as a syn- configuration with the tetrazole and valine substitutions on the same side of the phenyl ring, while form F (blue) posing an anti- configuration with the two substitutions presenting on the opposite side of the phenyl ring. The torsion angles between the two phenyl rings are also different; as depicted in Figure 5, the dihedron angle between C14−C15 and C18−C19 was determined as 139.3° and 45.3° in form E and form F, respectively. The most remarkable variations between the two conformers lie in the configurations of the substituted amide moieties connected to

Figure 3. Single crystal structure of form E. (a) H-bonding between the carboxylic acid and tetrazole. (b) H-bonding network along the a axis. (c) Side view of helical chains growing along the a axis. (d) Top view of helical chains in the crystal-packing diagram.

the biphenyl ring structures, which could be best described by measuring the bond angles along the biphenyl-amide structure. The bond angles for C12−C11−N1 were determined as 115.0° and −113.8° in forms E and F, respectively. Spectroscopic Analysis. FT-IR spectroscopy is employed to obtain information pertaining to the differences in molecular conformation and hydrogen bonding in the solid state. Polymorphic structures containing strong hydrogen bonds, such as N−H···O and O−H···O hydrogen bonds, can easily be D



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Figure 5. Overlay of unique molecules in crystal structure of Valsartan form E (red) and form F (blue).

differentiated by IR spectroscopy.34 A comparison of FT-IR spectra of Valsartan solid-state forms revealed some variations in IR singles among the different forms (Figure 6). An obvious

Figure 6. Comparison of IR spectra of the Valsartan forms (inset shows the close-up of a certain region).

difference can be identified in the amide carbonyl stretching vibration region (e.g., the IR singles corresponding to carbonyl CO vibration were observed at 1734 cm−1, 1738 cm−1, and 1724 cm−1 for the marketed form and forms E and F, respectively). The observed significant blue shift of the valeryl carbonyl CO vibrational starching in form F could be caused by the strong hydrogen bonding interactions between the valeryl carbonyl group and the tetrazole amino group. The short hydrogen bond distance (measured as 1.713 Å for N5− H···O1 in the single crystal structure of form F) further supports the above argument. In addition, the strong hydrogen bonding interactions also cause an obvious blue shifting in the N−H and O−H stretching vibration in form F (e.g., the N−H and O−H vibration stretching observed at 3423 cm−1, 3430 cm−1, and 3357 cm−1 for the marketed form and forms E and F, respectively. Significant differences are also observed in the Raman spectra for the carbonyl CO stretching vibration that involved the hydrogen bonds (Figure 7). The difference in the N−H and O−H stretching vibration is not obvious in the Raman spectra of both forms E and F. However, some peak shape change and broadening (especially observed in the amorphous form) was found between the forms throughout the investigated Raman spectra range.

Figure 4. Single crystal structure of form F. (a) H-bonding intermediated by EtOH solvent molecules. (b) H-bonding network along the a axis. (c) Side view of helical chains growing along the a axis. (d) Top view of helical chains in the crystal-packing diagram.

Table 2. Hydrogen Bonding Distances and Angles for Forms E and F Valsartan

D−H···A/A···H−D

H···A (Å)

D···A (Å)

D−H···A (deg)

form E

O1···H−N5′ O3−H···N2″ O1···H−N5′ O3−H···O4 (EtOH) O4−H···N2″

1.818 1.986 1.713 1.783 2.065

2.645 2.715 2.670 2.619 2.885

160.76 147.47 176.76 173.43 165.14

form F

E



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Figure 9. DSC curves of the marketed form and forms E and F.

Moisture Sorption Analysis. Moisture uptake could have a profound impact on the crystallization process development, formulation selection, chemical, physical stability, storage conditions, and packaging material selection, etc. In order to study the vapor sorption properties of the three solid forms, dynamic vapor sorption (DVS) experiments were carried out under a closed chamber system that creates specific relative humidity and temperature environments at controlled pressure. As one would expect, the highly crystalline material of forms E and F present significant lower hygroscopicity compared with the amorphous form, Figure 10. A substantial moisture uptake

Figure 7. Comparison of Raman spectra of the Valsartan forms (inset shows the close-up of a certain region).

Thermal Analysis. A comparison of TGA thermograms of Valsartan solid-state forms is shown in Figure 8. The TGA plots

Figure 8. TG for forms E and F, indicating that F is an ethanol solvate (calculated weight loss for one molecular ethanol is 9.6%). Figure 10. Dynamic vapor sorption isotherms of Valsartan forms and amorphous at 25 °C.

for form E showed no weight loss before decomposition starting at 160 °C, indicating that the polymorph sample is free from residual solvents, while the TGA diagram for form F showed some obvious mass loss between 100 and 150 °C. The mass change of 9.63% conforms to the stoichiometric ratio of one equivalent of EtOH molecule/one mole of Valsartan (theoretical value: 9.55%, with respect to Valsartan itself). The presence of one equivalent of EtOH was also confirmed by the 1 H NMR spectrum and single-crystal structure analysis. Crystalline and amorphous forms are also analyzed by the Hyper-DSC, glass transition process were observed from 70 to 85 °C for the marketed amorphous powder, no melting events can be identified as the temperature further increased until decomposition. However, sharp endotherm peaks, indicating melting points at 130 °C (DSC onset temperature with ΔHfus = 100.1 J g−1) and 94 °C (DSC onset temperature with ΔHfus = 152.7 J g−1) can be observed in the DSC thermograms for forms E and F, respectively (Figure 9). Unlike the highly amorphous state in which Valsartan is usually prepared, the existence of clear melting endotherm behaviors for both forms E and F clearly demonstrated the highly crystalline nature of both newly discovered forms.

(more than 2% mass gain) was observed for amorphous material as the relative humidity (RH) increase up to 95%. No phase conversions were observed during the moisture sorption process, which indicate that the water is mostly absorbed on the surface of the material. However, for highly crystalline solids forms E and F, very low (less than 0.1%) affinities for water vapor were found at the humidity range, up to 70% RH (e.g., the mass gains are 0.028% and 0.074% at 60% RH for forms E and F, respectively). Overall, no more than 0.3% moisture uptake was observed for the highly crystalline forms E and F when humidity increased up to 95% RH. Intrinsic Dissolution Rate and Dissolution in Capsules. Dissolution rate is a key parameter to be considered during the course of oral dosage form development. Since a drug has to be dissolved before it can be absorbed, the dissolution profiles could have profound influence on the pharmacokinetics and pharmacodynamics properties. For a comprehensive understanding of how the solid-state forms affect the dissolution behaviors, both intrinsic dissolution rates and dissolution of drug products are investigated for forms E and F and the F



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Figure 11. Intrinsic dissolution profiles of the Valsartan drug substance in different solid-state forms (left) and dissolution profiles for capsules made from different forms in pH 4.5 acetate−ammonium acetate buffers (right).

Figure 12. Changes of Valsartan assay values during storage at (a) 80 °C/75% RH and (b) 80 °C for different solid-state forms.

substance. Gel formation is a common factor to cause dissolution slow down, and the gel formation process could be attributed to the strong interactions between amorphous material and the excipients. Physical and Chemical Stability. Due to the susceptibility to thermodegradation and moisture, the Valsartan drug substance is required to be stored under controlled room temperature conditions and protection from moisture and heat, according to USP 34. In order to compare the thermostability of Valsartan under different solid modifications, forms of the Valsartan drug substance were submitted to accelerated storage conditions at 80 °C/75% RH and 80 °C for 6 weeks. The stability samples were periodically pulled out and analyzed by HPLC and physical examination. After 2 weeks under stressed conditions, the appearance of the amorphous state and form F was found to change from white powder to a brownish color under both stressed conditions; nevertheless, no obvious color change can be identified for form E, even after 6 weeks under the same storage conditions. Ethanol solvate form F was found to be the least stable form in terms of chemical stability. As depicted in Figure 12, the assay value of Valsartan for form F was found to quickly decrease to only 70% and 51% after 6 weeks stored under 80 °C/75% RH and 80 °C, respectively. Similar trends of degradation (degrade to 70% after 6 weeks) was found for amorphous forms under 80 °C/75% RH. However, the amorphous Valsartan drug substance was fairly stable under 80 °C, and the assay value was found to be able to hold at more than 97% after 6 weeks. This observation further demonstrated that moisture uptake is one of the major factors to cause Valsartan’s degradation. To our surprise, there was no degradation product or any obvious color change observed within the polymorphic form E stressed under both conditions for 6 weeks. It was well-documented that the major degradation pathway for the Valsartan drug substance involves the breaking up of the amide bond to form impurity A and a pentanoic acid

marketed amorphous form. As depicted in Figure 11, the ethanol solvate form F and amorphous form presents similar rates of the intrinsic dissolution rates (57 and 53 μg/cm2/min for form F and amorphous, respectively). However, the pure crystalline form E possesses an obviously lower intrinsic dissolution rate (14 μg/cm2/min). This finding is conformed to a general belief that the amorphous material contains higher free energy and, hence, usually presents a greater solubility and dissolution rate than its corresponding crystalline forms. The equilibrium solubility of the marketed form and forms E and F of Valsartan were also determined as 2.06, 1.06, and 2.29 mg/ mL, respectively. Furthermore, in order to evaluate the effects of polymorphism on the dissolution behaviors of formulated drug products, three batches of Valsartan capsules were prepared in 80 mg dosages, resembling the market formulations. The drug products are made of the same formulation matrix and process procedure but with different polymorphic forms. The United States Pharmacopeia (USP) basket I method was followed, and the capsules were subjected to a dissolution test in pH 4.5 acetate−ammonium acetate buffers at 37 °C. The dissolution profiles were compared in Figure 11. Results demonstrated that the dissolution properties were significant influenced by the solid-state forms used. Noticeably, the order of dissolution rates is form E > form F > amorphous form, where form E has the fastest dissolution profile, calculated 5.5 times greater than that of the amorphous adduct. Form F also presents more than 2 times greater dissolution rates than the amorphous form under the same dissolution medium. No phase transformation (monitored by PXRD and Raman) was observed when forms E and F were slurried in the dissolution medium for 3 days. However, obvious gel formation was found in the amorphous products during the course of dissolution, which could be the reason for the explanation of why the dissolution process slows down for the capsules containing the amorphous Valsartan drug G



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impurity (Scheme 2). It is well worth noting that the hydrolysis of Valsartan requires a mole of water molecule to be Scheme 2. Degradation Pathway for Hydrolysis of Valsartan under Solid State

participating in the solid-state reaction. The superior thermal stability for polymorphic form E could attribute to the low hygroscopicity and highly crystalline nature of this particular solid-state form. Furthermore, it is a generally accepted idea that water mobility will be increased when the temperature is above the glass transition temperature Tg (in this case, Tg = 76 °C) in the amorphous form, which could lead to high chemical reactivity and thermal instability.

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CONCLUSIONS Single-crystal structures of the blockbuster antihypertensive drug Valsartan was first revealed in this study. Highly crystalline materials of Valsartan were prepared by controlling crystallization solvents and procedures. Conformational flexibility and molecular packing was illustrated by single crystal structure analysis. The new discovered polymorphic form E and ethanol solvate form F were fully characterized by PXRD, IR, and Raman spectroscopy. Thermodynamic properties, such as hygroscopicity, dissolution rates, and chemical stability of the newly discovered forms were fully investigated, and the results are compared with the marketed amorphous form. The formulated capsule containing form E exhibits more than a 5 times greater dissolution rate in a pH 4.5 acetate−ammonium acetate buffer with outstanding chemical and physical stability. Valsartan form E studied in this work exhibits superior chemical stability and significantly different dissolution behaviors, which may encourage applying this form over the current commercial amorphous form in the future development of this important antihypertensive drug.

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ASSOCIATED CONTENT

S Supporting Information *

X-ray crystallographic data in CIF format and CIF check. This material is available free of charge via the Internet at http:// pubs.acs.org.

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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 National Natural Science Foundation of China (Grant 81273479) and the Chinese Academy of Sciences for funding.

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REFERENCES

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