Solubility and Dissolution Rate Enhancement of Triamterene by a

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Solubility and Dissolution Rate Enhancement of Triamterene by a Cocrystallization Method Ai-Yan Li, Lin-Lin Xu, Jia-Mei Chen, and Tong-Bu Lu Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b00439 • Publication Date (Web): 02 Jul 2015 Downloaded from http://pubs.acs.org on July 6, 2015

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Crystal Growth & Design

Submitted to Cryst. Growth Des.

Solubility and Dissolution Rate Enhancement of Triamterene by a Cocrystallization Method Ai-Yan Li,a Lin-Lin Xu,a Jia-Mei Chen,*a and Tong-Bu Lu*a,b

a

School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China

b

MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical

Engineering, Sun Yat-Sen University, Guangzhou 510275, China

* To whom correspondence should be addressed. Fax: +86-20-84112921. E-mail: [email protected]; [email protected].

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ABSTRACT: A potassium-sparing diuretic, triamterene, shows a low oral bioavailability with wide intersubject variation due to its poor aqueous solubility (45 µg/mL). To improve its solubility, a group of pharmaceutically acceptable coformers were screened with triamterene by slurry and liquid-assisted grinding methods, and DL-mandelic acid (1) and saccharin (2) successfully cocrystallized with triamterene to form one anhydrous and one monohydrate molecular salts, respectively. Both new forms were characterized by spectroscopic methods, thermal analysis, and X-ray diffraction. Their single crystal structures reveal that proton transfer from coformers to the nitrogen atom of the pyrimidine group in triamterene, and the coformer anions thus connect to the protonated triamterene by multiple hydrogen bonded heterosynthons. The apparent solubility values and intrinsic dissolution rates of 1 and 2 in simulated gastric fluid (pH 1.20) are higher than those of parent drug, indicating the solubility of triamterene can be effectively improved by cocrystallization. The exposure of 1 and 2 to 0-95% RH levels and accelerated ICH condition of 40 oC/75% RH confirm their stability and the potential of these new forms to envisage new, more efficient formulations of triamterene.

KEYWORDS: triamterene · crystal engineering · cocrystallization · DL-mandelic acid · saccharin · dissolution rate · solubility

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INTRODUCTION In pharmaceutical industry, not more than 1% of active pharmaceutical ingredients (APIs) could come to market due to the poor biopharmaceutical properties, about 40% of which are poorly water-soluble and usually restricted in oral bioavailability.1,2 A current challenge in the drug product development is to improve the solubility of poorly soluble drugs without compromising the stability and other performance characteristics. Pharmaceutical cocrystallization of APIs with other pharmaceutically accepted molecules (which are usually referred to as coformers) is one of the effective ways to amend physiochemical properties, including solubility and dissolution rates, of API molecules without altering their pharmacological behavior.3-11 Cocrystallization is a crystal engineering approach with design or synthesis of new compounds based on the use of reliable supramolecular heterosynthons.12 The presence of various functional groups in APIs may form robust supramolecular synthons such as acid···amide, acid···pyridine, amide···pyridine, etc., which offer a great opportunity for pharmaceutical cocrystallization.13-15 Triamterene (2,4,7-triamino-6-phenylpteridine, TA, Scheme 1) is a potassium-sparing diuretic and is used either alone or together with other diuretics, such as derivatives of anthranilic acid and thiazide to reduce their potassium-wasting effects.16 It is also usually administered in combination with other antihypertensive agents, such as reserpine and hydrochlorothiazide for the treatment of hypertension.17 Due to its poor aqueous solubility (45 µg/mL), TA shows low oral bioavailability with wide intersubject variation.18,19 For this reason, improving the aqueous solubility of TA is of interest for preformulation and formulation scientists. Complex formation of TA with various cyclic oligomers, including cyclodextrin, p-sulfonatocalix[6]arene, and cucurbit[7]uril, as well as solid dispersion technique has been reported to improve the solubility and bioavailability of TA.20-23

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However, the existence of toxicity or stability problems for the above TA formulations hampered them to be applied for clinical therapy.24,25 Therefore, the development of new pharmaceutical formulations of TA is highly desirable, which motivated us to explore the cocrystallization tendencies of TA in order to improve its solubility. NH2 N

N NH2

O

OH

N

N

OH NH S O O

O

NH2

Ttriamterene (TA)

Saccharin

Mandelic Acid

Scheme 1. Compounds Used in Cocrystallization

H H N R22(8) N H N N

N

N

H O R22(8) N H O

H

H N R22(8) N H O

H I

H III

II

N H O R22(8) N H O

N H O R22(8) N H N

H

H V

IV

Scheme 2. Homo- and Hetero- Hydrogen Bonded Synthons Discussed in This Study Herein we attempt to address the deficiency in solubility of TA by cocrystallization with some soluble guest molecules. To evaluate the potential for cocrystallization, the structure of TA was analyzed from a crystal engineering perspective. The crystal structure of TA (refcode FITZAJ)26 shows that the most useful hydrogen bonding group is the amino pyrimidine group (Figure S1, Supporting Information), which is known to form robust hydrogen bonded synthons with carboxylic and amide compounds (Scheme 2).15,27 Therefore,

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TA was reacted with a series of coformers, including isonicotinic acid, cinnamic acid, DL-mandelic acid, urea, saccharin and adenine. Finally, only DL-mandelic acid and saccharin (Scheme 1) could successfully cocrystallize with TA by slurry and liquid-assisted grinding methods. Mandelic acid has a long history of use in the medical community as an antibacterial.28 Saccharin is the FDA-approved GRAS (generally recognized as safe) compound.29 We employed solid-state material characterization techniques such as XRD, DSC, TG, and IR to characterize these new phases. Their crystal structures were also obtained from single crystal X-ray diffraction studies. Finally, investigation on powder dissolution, intrinsic dissolution rate and stability performance were also carried out.

EXPERIMENTAL SECTION Materials and General Methods. TA was purchased from Suizhou Hongqi Chemical Co., Ltd. All of the coformers were purchased from Aladdin reagent Inc. All other chemicals and solvents were commercially available and used as received. Elemental analyses were carried out by Elementar Vario EL elemental analyzer. The infrared spectra were recorded in the 4000 to 400 cm−1 region using KBr pellets and a Bruker EQUINOX 55 spectrometer. X-ray powder diffraction (XRPD) patterns were obtained on a Bruker D2 Advance diffractometer (Bruker, PHASER) with Cu Kα radiation (λ = 1.5418 Å) at 30 kV and 10 mA. Variable temperature X-ray powder diffraction patterns (VT-XRPD) were obtained on a Bruker D8 Advance with Cu Kα radiation (40 kV, 40 mA), with a heating rate of 10 °C/min and holding the measured temperature for 5 min for data collection. Differential scanning calorimetry (DSC) was recorded on a Netzsch DSC 200 F3 instrument and aluminum sample pans in nitrogen atmosphere, with a heating rate of 10 °C/min. Thermogravimetric (TG) analyses were recorded on a Netzsch TG-209 instrument and alumina crucible in nitrogen atmosphere,

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with a heating rate of 10 °C/min. Preparation of TA-Mandelate (1:1) (1). This material was obtained via the following two methods: (i) A 1: 1 mixture of TA (50.6 mg, 0.2 mmol) and DL-mandelic acid (30.4 mg, 0.2 mmol) with two drops of ethanol was added to a 25 mL stainless steel grinding jar. The mixture was ground with a Retsch MM200 mixer mill for 30 min at a frequency of 20 Hz. (ii) A mixture of TA (25.3 mg, 0.1 mmol) and DL-mandelic acid (15.2 mg, 0.1 mmol) was added to 3 mL of deionized water. The resulting suspension was allowed to stir at 50 °C for two days, in which the reactants slowly transformed to 1 as yellow solid. The reaction mixture was filtered and the isolated solid was dried under vacuum for 24 h. Yield: 34.2 mg, 84%. Anal. (%) Calcd for C20H19N7O3: C, 59.25; H, 4.72; N, 24.18. Found: C, 59.35; H, 4.65; N, 23.56. IR (KBr, ν): 3530 (m), 3457 (m), 3313 (m), 3068 (m), 2958 (m), 2913 (m), 1670 (s), 1622 (s), 1545 (m), 1454 (m), 1407 (m), 1286 (m), 1060 (m), 735 (m), 703 (m), 684 (m), 618 (w), 558 (m), 478 (w) cm−1. Excess of 1 was added to 2 mL of ethanol and the resulting suspension was allowed to stir at ambient temperature for 1 h and then filtered. The filtrate was left to evaporate slowly at room temperature in a sealed glass desiccator containing P2O5. After about two weeks, plate-shaped crystals of 1 were obtained. Preparation of TA-Saccharin Salt Monohydrate (1:1:1) 2. This material was obtained via the following two methods: (i) A 1: 1 mixture of TA (50.6 mg, 0.2 mmol) and saccharin (36.6 mg, 0.2 mmol) with two drops of deionized water was added to the stainless steel grinding jar. The mixture was ground for 20 min at a frequency of 20 Hz. (ii) 2 was prepared by the slurry method similar to that of 1, except using saccharin instead of DL-mandelic acid. Yield: 38.6 mg, 89%. Anal. (%) Calcd for C19H18N8O4S3: C, 50.21; H, 3.99; N, 24.66; S, 7.06. Found: C, 50.28; H, 4.04; N, 24.45; S, 7.05. IR (KBr, ν): 3613 (m), 3396 (m), 3322 (m), 2846 (m), 2723 (m), 2645 (m), 1634 (s), 1604 (s), 1512 (m), 1447 (s), 1353 (m), 1284 (m), 1050

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(m), 944 (m), 834 (w), 774 (m), 751 (m), 681 (m), 603 (m), 563 (m), 466 (w) cm−1. Single crystals of 2 were also obtained by a procedure similar to that of 1, except using mixture solvents of water and ethanol (1:4) instead of pure ethanol. After about one week, block-shaped crystals of 2 were obtained. Single Crystal X-ray Diffraction. Single crystal X-ray diffraction data of 1 and 2 were collected on an Agilent Technologies Gemini A Ultra system with graphite monochromated Cu Kα radiation (λ= 1.54178 Å). Cell refinement and data reduction were applied using the program of CrysAlis PRO.30 The structures were solved by the direct methods using the SHELX-97 program31 and refined by the full-matrix least-squares method on F2. All non-hydrogen atoms were refined with anisotropic displacement parameters. The hydrogen atoms were placed in calculated positions with fixed isotropic thermal parameters and included in the structure factor calculations in the final stage of full-matrix least-squares refinement. Crystallographic data and details of refinements of 1 and 2 are listed in Table 1, and selected hydrogen bonding distances and angles are given in Table 2. Dissolution Experiments. Concentrations of TA in HCl solution (pH 1.20) were determined by a Cary 50 UV/vis spectrophotometer at 362 nm, where DL-mandelic acid and saccharin does not absorb, and therefore, would not interfere with the determination of the concentration of TA. For experiments involving TA, 1 and 2, the absorbance values were related to solution concentrations using a calibration curve. For the powder dissolution experiments, all of the solids were milled to powders and sieved using standard mesh sieves to provide samples with approximate particle size ranges of 75-150 µm. In a typical experiment, 50 mL of HCl solution (pH 1.20) was added to a flask containing 100 mg of TA (or corresponding to, for 1 and 2), and the resulting mixture was stirred at 25°C and 500 rpm. At each time interval, an aliquot of the slurry was withdrawn

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from the flask and filtered through a 0.22 µm nylon filter. Appropriate dilutions were made to maintain absorbance readings within the standard curve. After the dissolution experiments, the pH values of the solutions were measured, and the remaining solids were filtered, dried and analyzed by XRPD. All the experiments were repeated three times to evaluate the standard deviations. Intrinsic dissolution rate (IDR) measurements were carried out on a ZQY-2 Dissolution Tester (Shanghai Huanghai Yaojian Instrument Distribution Co., Ltd). According to USP 36,32 paddle dissolution method was used to determine the intrinsic dissolution profile of solid materials at 37 ± 0.5 °C using 150 mL of HCl solution (pH 1.20) as the dissolution medium to simulate gastric fluid, and the paddle continuously rotated at 100 rpm. Each solid was compressed in a hydraulic press under 0.5 ton for 20 seconds in a die of 5 mm diameter disk. The disk was coated using paraffin wax, leaving only the surface under investigation free for dissolution. Dissolution samples were successively collected from the dissolution medium at each time interval, 2 mL of the dissolution medium was withdrawn and replaced by an equal volume of fresh medium to maintain a constant volume. The concentration of dissolved TA was determined by UV/vis spectrophotometry. Each intrinsic dissolution test lasted 60 min, after which time the disks were recovered, carefully ground and checked by XRPD. All the experiments were repeated three times to evaluate the standard deviations. Dynamic Vapour Sorption (DVS) Study. DVS measurements were performed on a DVS intrinsic instrument (Surface Measurement Systems, UK). The temperature was maintained at a constant of 25 ± 0.1 ºC. All samples were initially dried for several hours under a stream of nitrogen to establish the equilibrium dry mass. Then the relative humidity (RH) was increased in 10% RH steps to 95% RH. Finally, the RH was decreased in a similar fashion for the desorption phase. The sorption/desorption isotherms were calculated from the equilibrium

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mass values. Stability Test. Stability of 1 and 2 at accelerated ICH condition (40 °C/75% RH) was tested. Vial of each sample was subjected to the condition for durations of 1 month, 2 months, 3 months and 6 months. Upon completion of the duration allowed, the samples were immediately analyzed by XRPD.

RESULTS AND DISCUSSION Crystal Structure Analysis. The availability of single crystal X-ray structures could help identify the arrangements and interactions of TA and coformers in the crystal lattice. The crystal structure of 1 belongs to the monoclinic, P21/c space group (Table 1). The asymmetric unit contains one TA cation and one DL-mandelate anion, in which a proton transferrs from the carboxylic group of DL-mandelic acid to the pyrimidine N3 atom of TA. Protonated TA and DL-mandelate anion are connected through a charge-assistant hydrogen bonded (N3+-H3A⋅⋅⋅O2- and N6-H6B⋅⋅⋅O3) R22(8) heterosynthon (synthon IV, Scheme 2) to form a dimer (Figure 1a). Two dimers are further connected through interdimer N6-H6A⋅⋅⋅O3 hydrogen bonds to generate a tetramer. The tetramers are held together through N7-H7B⋅⋅⋅O2hydrogen bonds to form a one-dimensional (1D) chain (Figures 1b and 1c). Two adjacent chains are connected with each other via N7-H7B⋅⋅⋅O2- hydrogen bonds (Figure 1d). The crystal structure of 2 was solved in a triclinic, P-1 space group (Table 1). The asymmetric unit contains one TA cation, one saccharin anion and one water molecule, in which one TA cation is simultaneously connected to one saccharin anion through a charge-assistant hydrogen bonded (N7-H7B⋅⋅⋅N8-, N4+-H4A⋅⋅⋅O1) R22(8) heterosynthon (synthon V, Scheme 2) and one water molecule through a N7-H7A⋅⋅⋅O4 hydrogen bond to

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form a trimer (Figure 2a). The trimers are held together through N6-H6B⋅⋅⋅O1 and N5-H5B⋅⋅⋅N2 hydrogen bonds to form a 1D chain (Figures 2b and 2c). Two adjacent chains are connected with each other through O4-H3A⋅⋅⋅O3 hydrogen bonds (Figure 2d). From crystal structure analysis, we can see that two charge-assistant hydrogen bonded R22(8) heterosynthons IV and V, instead of R22(8) heterosynthons II and III as we designed (Scheme 2), are produced in 1 and 2. Thus both 1 and 2 are classified as salts since a proton transfer occurred from coformers to TA. It has been reported that ionization or salt formation is observed when ∆pKa value is greater than 3.6,33 As pKa values for TA, mandelic acid and saccharin are 7.16,34 3.41 and 1.31, respectively, both ∆pKa (∆pKa = pKa TA - pKa coformer) values for 1 and 2 are greater than 3 (3.75 and 5.85, respectively). These results also confirm the formation of salts, which corroborates with the observations from single crystal structure analysis. XRPD Analysis and Thermal Analysis. XRPD was used to check the crystalline phase purity of the bulk batch of 1 and 2. The results show that the patterns of the products are different from either that of TA or those of corresponding coformers (Figure S2, Supporting Information), indicating the formation of new crystalline phases. In addition, all the peaks displayed in the measured patterns of 1 and 2 closely match those in the simulated patterns generated from single crystal diffraction data (Figure S2, Supporting Information), confirming the single phases of 1 and 2 were formed. The thermodynamic stability of these new crystal forms was investigated by means of DSC and TG analyses (Figure 3). 1 begins to decompose at 232 °C and no evidence of a phase transformation in DSC curve is observed before decomposition (Figure 3a). In contrast, TG curve of 2 shows a weight loss of 3.89 % from 86 °C to 138 °C corresponding to loss of one crystalline water molecule (calcd 3.96%). In the same temperature range, an endothermic

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peak due to dehydration is present in the DSC curve, which is followed by an exothermic peak at 167 °C due to a further phase transformation (Figure 3b). These two heat induced phase change processes are also observed in VT-XRPD patterns at 90 °C and 170 °C, respectively (Figure S3, Supporting Information). Then 2 begins to decompose at 216 °C (Figure 3b). Dissolution Studies. The apparent solubility and dissolution rate of drugs are of paramount importance in pharmaceutical development and quality control, and higher apparent solubility and shorter dissolution time may result in greater absorption. The powder dissolution profiles of TA, 1 and 2 in simulated gastric fluid (HCl solution with pH of 1.20) are shown in Figure 4 in the form of TA concentration (µg/mL) vs. time (min). It could be found that compared with intact TA, 1 shows a comparable powder dissolution profile, whereas 2 shows a higher solubility and a faster dissolution rate. 1 and 2 reach maximum solubility (Smax) within 5 min (Figure 4a) and 2 h (Figure 4b), respectively, and then decrease slowly over time. This type of “spring and parachute effect” has been exhibited by a lot of cocrystallization systems recently.6,7 The peak TA concentrations of 1 and 2 are approximately 20% and 80% higher than that of the API alone, respectively. The supersaturated solution is formed at the initial stage of dissolution and then preserved for several hours. Such a behavior is especially favorable for pharmaceutical applications. The concentrations of all samples are gradually close to each other (Figure 4b), indicating that they all transform to a more stable form of TA. The pH values of the resulting solutions remain unchanged (1.20 ± 0.01) in all instances. As pKa value for TA is 7.16,34 it is reasonable to assert that a transition from initial phases to triamterene hydrochloride occurred at pH 1.20. XRPD analysis of the undissolved solids indicates that no XRPD peaks indicative of the starting materials were observed for TA and 1, suggesting that the phase transition process completed in these two instances. Meanwhile,

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XRPD peaks corresponding to the starting materials were observed for 2 other than those new peaks, suggesting that only part of 2 transformed to triamterene hydrochloride in 8 h (Figure S4, Supporting Information). IDR is a key physicochemical parameter commonly used to assess a possible risk of the dissolution-rate controlled absorption of a new chemical entity. Owing to its kinetic nature, IDR assumes a better correlation with in vivo drug dissolution dynamics than solubility.35 To quantitatively evaluate the impact of the solid-state modification on the dissolution rate, IDR experiments for TA, 1 and 2 were carried out. Above all, our measurement was taken under the “sink condition” (as defined in USP 36,32 the volume of medium at least three times that required in order to form a saturated solution of drug substance), which allowed the dissolution to be unaffected by previously dissolved material. The IDR profiles within the first 60 min are graphed in Figure 5. All of the samples demonstrated excellent linearity over the entire time span (60 min). The values obtained by least squares analysis of the linear regions of the dissolution profiles are provided in Table 3. From these results intrinsic dissolution rates of 0.070 and 0.111 mg/min/cm2 were obtained for 1 and 2, about 32% and 109% faster than that obtained for pure TA (0.053 mg/min/cm2). This confirms the potential of 2 to envisage more efficient formulations of TA. XRPD analysis of the solids recovered after 60 min revealed that similar phase transitions occurred for TA and 1, whereas 2 did not change during the intrinsic dissolution test (Figure S5, Supporting Information). DVS and Stability Studies. To reveal possible solid-state physical stability concerns, the influence of humidity on the stability of 1 and 2 was studied by DVS experiments. The resulting vapour sorption isotherms are shown in Figure 6. The phase transitions during the DVS experiments were confirmed by XRPD detection (Figure S6, Supporting Information). 1 and 2 exhibit similar sorption/desorption behavior with TA. As the humidity is increased up

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to 95% RH, 1 and 2 only uptake 0.12 % and 0.20% water on the surface, respectively, then they reversibly lose the absorbed water, and no hysteresis gap is observed in these two instances (Figure 6). The XRPD patterns for 1 and 2 after DVS experiment also demonstrate that they retain their crystal forms after the DVS experiments (Figure S6, Supporting Information). It should be noted that the crystalline water molecules of 2 are so stable that they can remain in the crystal lattice even at 0% RH. The stability of 1 and 2 at accelerated ICH condition (40 °C/75% RH) was also monitored for different storage time points. The results of XRPD measurements indicate that 1 and 2 retained their initial crystal form for 6 months (Figure S7, Supporting Information). It demonstrates that 1 and 2 are stable as isolated solids and their kinetic stability at 0-95% RH levels as well as accelerated ICH condition are sufficient to allow standard processing steps to be carried out.

CONCLUSIONS In this study, we investigated the cocrystallization behavior of triamterene using a crystal engineering approach, with the goal of identifying new crystal forms that could potentially be used to improve its poor solubility. One anhydrous and one monohydrate molecular salts of triamterene with DL-mandelic acid (1) and saccharin (2), respectively, were successfully prepared and fully characterized by XRD, IR, DSC, and TG measurements. The single crystal structures reveal that proton transfer from coformers to the nitrogen atom of the pyrimidine group in triamterene, and the coformer anions connect to protonated triamterene through charge-assistant hydrogen bonded heterosynthons IV and V to form dimer structures in 1 and 2, respectively. The dissolution studies demonstrate that 1 and 2 respectively show 20% and 80% higher apparent solubility, as well as 32% and 109% faster intrinsic dissolution rates in

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simulated gastric fluid (pH 1.20), compared to the free drug. The DVS measurements and accelerated ICH condition tests confirm that 1 and 2 are stable as isolated solids and the potential of these new crystal forms to envisage new, more efficient formulations of triamterene.

ASSOCIATED CONTENT Supporting Information Crystal structure of triamterene, XRPD analysis with regard to preparation, powder and intrinsic dissolution experiments, DVS, and accelerated ICH condition test, as well as VT-XRPD analysis of 2. This information is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEDGEMENTS This work was financially supported by Pearl River S&T Nova Program of Guangzhou (No. 2013J2200054), Fundamental Research Funds for the Central Universities (No. 14ykpy08), NSFC (No. 21331007), and NSF of Guangdong Province (No. S2012030006240).

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(20) Arias, M. J; Moyano, J. R; Ginés, J. M. Int. J. Pharm. 1997, 153, 181–189. (21) Chao, J.; Zhang, Y.; Fan, X.; Wang, H.; Li Y. Spectrochim. Acta A 2013, 116, 295−300. (22) Ma, W. J.; Chen, J. M.; Jiang, L.; Yao, J.; Lu, T. B. Mol. Pharm. 2013, 10, 4698–4705. (23) Arias, M. J.; Ginés, J. M.; Moyano, J. R.; Pérez-Martinez, J. I.; Rabasco, A. M. Int. J. Pharm. 1995, 123, 25−31. (24) Frank, D.; Gray, J.; Weaver, R. Am. J. Pathol. 1976, 83, 367−382. (25) Serajuddin, A. T. J. Pharm. Sci. 1999, 88, 1058−1066. (26) Schwalbe, C. H.; Williams, G. J. B. Acta Cryst. 1987, C43, 1097−1100. (27) Tao, Q.; Chen, J. M.; Ma, L.; Lu, T. B. Cryst. Growth Des. 2012, 12, 3144–3152. (28) Putten, P. L. Anton. Leeuw. 1979, 45, 622−623. (29) Generally

Regarded

as

Safe

chemicals

by

the

US

FDA:

http://www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/ucm0910 48.htm. (30) CrysAlisPro, Version 1.171.36.20, 2012, Agilent Technologies Inc., Santa Clara, CA, USA. (31) Sheldrick, G. M. SHELXTL-97, Program for Crystal Structure Solution and Refinement; University of Gottingen: Gottingen, Germany, 1997. (32) United States Pharmacopoeia, 2012 edition. (33) Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharm. 2007, 4, 323–338. (34) Domańska, U.; Pobudkowska, A.; Pelczarska, A.; Żukowski, Ł. Int. J. Pharm. 2011, 403, 115−122. (35) Shevchenko, A.; Bimbo, L. M.; Miroshnyk, I.; Haarala, J.; Jelínková, K. N.;

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Syrjänen, K.; Veen, B.; Kiesvaara, J.; Santos, H. A.; Yliruusi, J. Int. J. Pharm. 2012, 436, 403−409.

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Table 1. Crystallographic Data and Refinement Parameters for 1 and 2 1

2

chemical formula

C20H19N7O3

C19H18N8O4S

formula wt

405.42

454.47

293(2)

293(2)

crystal size (mm )

0.15×0.05×0.04

0.30× 0.20× 0.10

crystal system

Monoclinic

Triclinic

space group

P21/c

P-1

a (Å)

13.0395(3)

6.7826(7)

b (Å)

17.6175(4)

8.4877(9)

c (Å)

8.4419(2)

17.628(2)

α (deg)

90

78.261(10)

β (deg)

104.560(2)

89.201(10)

90

86.388(9)

1877.02(8)

991.5(2)

4

2

1.435

1.522

temperature (K) 3

γ (deg) 3

volume (Å ) Z -3

density (g cm ) 2θ range

5.13-62.99

F (000)

848

472

index ranges

-13≤ h ≤15

-7≤ h ≤7

-20≤ h ≤13

-7≤ h ≤9

-9≤ h ≤8

-20≤ h ≤19

no. of reflns

3142

3104

no. of unique reflns

2512

2235

no. of params

303

325

Rall, Robsa

0.0551, 0.0409

0.0770, 0.0494

wR2,all, wR2,obsb

0.1013, 0.0932

0.1326, 0.1120

Goodness-of-fit on F2

1.044

1.062

a

R1 = Σ Fo - Fc/Σ Fo. wR2 = [Σ[w(Fo2 - Fc2)2]/Σw(Fo2)2]1/2, w = 1/[σ2 (Fo)2 + (aP)2 + bP ],where P = [(Fo 2) +2Fc2]/3

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Table 2. Hydrogen Bonding Distances and Angles of 1 and 2 H…A (Å)

D…A (Å)

∠D—H…A (deg)

N3+-H3A⋅⋅⋅O2-

1.89(3)

2.788(2)

174(2)

N6-H6B⋅⋅⋅O3

1.82(3)

2.774(2)

173(2)

N6-H6A⋅⋅⋅O3

1.95(3)

2.818(2)

163(2)

N7-H7B⋅⋅⋅O2-#1

1.86(2)

2.747(2)

163(2)

N7-H7B⋅⋅⋅N8-

2.07(4)

2.968(4)

175(3)

N4+-H4A⋅⋅⋅O1

1.89(4)

2.716(4)

171(4)

N7-H7A⋅⋅⋅O4

2.14(4)

2.933(4)

161(4)

N6-H6B⋅⋅⋅N3#1

2.15(5)

3.041(4)

174(3)

-x +3, -y, -z +1

N5-H5B⋅⋅⋅N2#2

2.25(5)

3.111(4)

172(4)

-x +1, -y +1, -z+1

O4-H3A⋅⋅⋅O3#3

2.36(6)

2.964(4)

135(5)

x +1, y, z

hydrogen bond

symmetry

1

x, -y +1/2, z +1/2

2

Table 3. Solubility and Iintrinsic Dissolution Rates of TA, 1 and 2 in HCl Solution (pH 1.20) Maximum solubility

IDR

(µg/mL)

(mg/min/cm2)

TA

228

0.053

1

260

0.070

2

411

0.111

sample

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(a)

(b)

(c)

(d)

Figure 1. (a) The asymmetric unit, (b) top view and (c) side view of 1D chain, and (d) packing of the chains in 1.

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(a)

(b)

(c)

(d)

Figure 2. (a) The asymmetric unit, (b) top view and (c) side view of 1D chain, and (d) packing of the chains in 2.

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(a)

(b)

Figure 3. DSC-TG curves for 1 (a) and 2 (b).

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(a)

(b)

Figure 4. Powder dissolution profiles of TA, 1 and 2 in HCl solution (pH 1.20) at 25 °C for (a) 1 h and (b) 8 h.

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Figure 5. Intrinsic dissolution profiles of TA, 1 and 2 in HCl solution (pH 1.20) at 37 °C.

Figure 6. Water vapour sorption/desorption isotherm plots of TA, 1 and 2 at 25 ºC.

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For Table of Contents Use Only

Solubility and Dissolution Rate Enhancement of Triamterene by a Cocrystallization Method Ai-Yan Li, Lin-Lin Xu, Jia-Mei Chen,* and Tong-Bu Lu*

Triamterene was successfully cocrystallized with DL-mandelic acid (1) and saccharin (2) to form one anhydrous and one monohydrate molecular salts, respectively, which were fully characterized by IR, XRD, DSC, TG and DVS analysis. The apparent solubility values and intrinsic dissolution rates of 1 and 2 in simulated gastric fluid (pH 1.20) are effectively enhanced after cocrystallization.

25


Solubility and Dissolution Rate Enhancement of Triamterene by a

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