Furosemide:Triethanolamine Salt as a Strategy To Improve the

Subscriber access provided by WEBSTER UNIV

Article

FUROSEMIDE:TRIETHANOLAMINE SALT AS A STRATEGY TO IMPROVE THE BIOPHARMACEUTICAL PROPERTIES AND PHOTOSTABILITY OF THE DRUG Julieta Abraham Miranda, Claudia Garnero, Ana K. Chattah, Yara Santiago de Oliveira, Alejandro P. Ayala, and Marcela R. Longhi Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01556 • Publication Date (Web): 22 Feb 2019 Downloaded from http://pubs.acs.org on February 23, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

1

FUROSEMIDE:TRIETHANOLAMINE SALT AS A STRATEGY TO IMPROVE THE

2

BIOPHARMACEUTICAL PROPERTIES AND PHOTOSTABILITY OF THE DRUG

3

Julieta Abraham Mirandaa, Claudia Garneroa*, Ana K. Chattahb, Yara Santiago de

4

Oliveirac, Alejandro P. Ayalad, Marcela R. Longhia*.

5

a)

Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA), CONICET and

6

Departamento de Ciencias Farmacéuticas, Facultad de Ciencias Químicas, Universidad

7

Nacional de Córdoba. Ciudad Universitaria, 5000-Córdoba, Argentina.

8

b) Facultad de Matemática, Astronomía y Física and IFEG (CONICET), Universidad Nacional de

9

Córdoba, Ciudad Universitaria, X5000HUA Córdoba, Argentina.

10

c)

11

d) Department of Physics, Federal University of Ceará, Fortaleza, Ceará, Brazil.

12 13

Department of Pharmacy, Federal University of Ceará, Fortaleza, Ceará, Brazil.

*Corresponding authors. E-mail addresses: [email protected] (M. Longhi) and [email protected] (C. Garnero)

14 15 16

Abstract

17

With the purpose of enhancing the biopharmaceutical properties of the furosemide, a

18

pharmaceutical salt was obtained and characterized by combining the drug and

19

triethanolamine. The solid system was prepared using different techniques such as

20

kneading, grinding and slow evaporation. It was characterizated by X-ray powder

21

diffraction, solid state Nuclear Magnetic Resonance, Infrared and Raman spectroscopy,

22

Thermal Analysis and Scanning Electron Microscopy. The results showed that the same

23

pharmaceutical compound in solid state was obtained through the different preparation

24

techniques. The crystalline structure was fully elucidated by Single Crystal X-ray

25

Diffraction. The salt formation was confirmed by Two-dimensional Nuclear Magnetic

26

Resonance experiments, which revealed the transference of the OH proton of the drug

27

to triethanolamine. Besides, the solubility studies demonstrated an increase in the drug

1

ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 32

28

solubility attributed not only to a pH change but also to a soluble salt formation in solution.

29

In addition, the combination of the drug with triethanolamine produces an enhancement

30

of the chemical photo-stability, whereas the physical photo-stability and the

31

hygroscopicity status were not modified. Finally, this new solid form of furosemide

32

constitutes an interesting strategy to improve the biopharmaceutical properties and

33

stability of furosemide, with potential application in pharmaceutical formulations.

34 35

Keywords: Furosemide, triethanolamine, characterization, solubility, stability.

36 37 38 39 40 41 42 43 44 45 46 47 48 49

2


Page 3 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


50

1. Introduction

51

An active pharmaceutical ingredient (API) can be given to the patient using several

52

administration routes such as intravenous, intramuscular, subcutaneous, oral, ocular and

53

dermal, among others. However, the oral route is the most commonly used due to its

54

numerous advantages like the easy administration of the medicine by the patient or the

55

versatility in the amount of pharmaceutical forms that it can be used.1 Unfortunately, most

56

API have limited aqueous solubility which can lead to slow dissolution in biological fluids

57

and consequent sub-optimal efficacy in patients, particularly when delivered via the oral

58

route of administration.2

59

Furosemide (FUR, Scheme 1) is a loop diuretic widely used in the treatment of

60

hypertension and edema associated with heart, kidney and liver failure.3,4 However, its

61

oral bioavailability is variable when it is administered orally, since it has low aqueous

62

solubility and low intestinal permeability (Class IV drug according the Biopharmaceutics

63

Classification System).5 Moreover, FUR has a tendency to be absorbed mainly in the

64

stomach and upper small intestine. Even though FUR presents seven polymorphic

65

forms,6,7 the form I is commercially available since it is the most stable. This API contains

66

a secondary amino group and, therefore, it is susceptible to acid catalyzed hydrolysis. In

67

addition, several authors demonstrated that FUR is susceptible to light exhibiting photo-

68

oxidation, photo-hydrolysis and photo-dechlorination.8,9 So as to increase its solubility

69

and dissolution rate, several techniques were investigated as prodrugs,10 ground mixture

70

and co-precipitate with polymeric material,11 dendrimer complexes,12 microcapsules with

71

self-microemulsifying core,13 cocrystals,14 solid dispersions15–17 and nanoparticles.18

72

However, some problems with these techniques include the use of large amounts of

73

solvent, solvent residues, broad particle size distributions, and incomplete reconversion

74

of these compounds in vivo, which limits the availability of the drug. Moreover, when

75

combining FUR with other substances, it has been shown that the system or complex

76

formed depends on the preparation technique, the solvent used and the time of reaction, 3



Page 4 of 32

77

among others. Because of this, it is difficult to assure the repeatable production of the

78

obtained system.

79

At present, more than 50% of the drugs are marketed as salts. Thereby, the

80

pharmaceutical design of salts emerged as a common strategy to improve poor solubility

81

and dissolution rate problems and, consequently, the absorption of the API. In addition,

82

the salt formation confers relevant attributes when modifying solubility, physicochemical

83

stability, manufacturability and toxicity.19,20 In recent years, the alkanolamines have been

84

used to optimize the unfavorable biopharmaceutical properties of APIs, such as their

85

solubility or permeability. The alkanolamines are compounds that have two functional

86

groups: an amine and an alcohol whereby they can undergo characteristic reactions of

87

amines and alcohols. The alcohol group is always primary, while the amine can be

88

primary (monoethanolamine, MEA), secondary (diethanolamine, DEA) or tertiary

89

(triethanolamine, TEA, Scheme 1). In this regard, salts of meloxicam (MX) with MEA and

90

DEA increased the solubility of the API, although the solubility with TEA was lower than

91

the API intrinsic solubility. However, the permeation rates were higher in all the salts than

92

in the free API.21 In addition, the dissolution rates were low at pH 1.2 but improved

93

significantly at pH 6.8, where the MX-DEA salt exhibited the highest dissolution rate. In

94

turn, the pharmacokinetic profiles revealed that the salts facilitated the rapid absorption

95

of MX while maintaining the prolonged exposure of the API in the organism.22

96

The objective of this study was the design and obtaining of a salt between FUR and TEA

97

using different preparation methods. Single Crystal X-ray Diffraction (SCXRD) was

98

performed to solve the crystalline structure of the new binary compound. In addition, its

99

physicochemical and biopharmaceutical properties were characterized using different

100

techniques including solid state Nuclear Magnetic Resonance (ssNMR), Fourier

101

transform infrared (FT-IR) and Raman spectroscopy, scanning electron microscopy

102

(SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and

4


Page 5 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


103

solubility measurements.

104

conditions.

Stability of the solid was also evaluated in accelerated

105 106

Scheme 1. Chemical structure of (a) FUR and (b) TEA showing the carbon numbering.

107 108

2. Experimental Section

109

2.1. Chemicals and reagents

110

Furosemide was provided by Parafarm (Argentina) and triethanolamine by Sigma Aldrich

111

(USA). All other chemicals were of analytical grade and the solvents were of HPLC

112

grade. A Millipore Milli Q Water Purification System (Millipore, Bedford, MA, USA)

113

generated the water used in these studies.

114 115

2.2. Salt preparation

116

The FUR:TEA salt was obtained using different preparation methods as described

117

below. All samples were prepared using FUR in equimolar ratio with TEA. Different

118

solvents, grinding time as well as the method of drying were evaluated.

119 120

2.2.1. Kneading method with water as solvent

121

The FUR:TEA60 sample was prepared by accurately weighing appropriate amounts of

122

FUR and TEA and then transferring them to a mortar. Water was added to the powder

123

mix in a relation 0.25 µl per gr of solid and the resultant slurry was kneaded for about 60

5



Page 6 of 32

124

min. The resultant powder was vacuum-dried, protected from light, at room temperature

125

for 48 h.

126 127

2.2.2. Grinding method

128

The FUR:TEA5 sample was prepared by grinding the corresponding components in a

129

mortar for about 5 min. The obtained solid was vacuum-dried at room temperature and

130

protected from light for 48 h.

131 132

2.2.3. Slow evaporation method

133

Appropriate amounts of FUR and TEA were weighed and dissolved in acetone

134

(FUR:TEAA) and methanol (FUR:TEAM). The amount of solvent used was sufficient to

135

completely solubilize both components. These solutions were transferred to crystallizers

136

at room temperature and protected from light, until the evaporation was completed.

137 138

2.3. Single Crystal X-ray Diffraction

139

Single-crystal X–ray diffraction data collection (ϕ scans and ω scans with κ and θ offsets)

140

were performed on a Bruker-AXS SMART-APEXIII-CCD diffractometer using graphite–

141

monochromated MoKαradiation (0.71073 Å) at 300 K. The software Saint v8.36A23 was

142

applied for acquisition, indexing, integration and scaling of Bragg reflections. The final

143

cell parameters were obtained using all reflections. The absorption correction was

144

applied. The structure was solved using Olex2,24 with the ShelXT25 structure solution

145

program using Direct Methods and refined with the ShelXL26 refinement package using

146

Least Squares minimization. Olex 2 was also used to prepare the crystallographic

147

information file (CIF). Program MERCURY (version 3.10)27 was used to prepare the

148

artwork representations for publication. The CIF of the structure FURTEA was deposited

149

at the Cambridge Structural Data Base under code 1864364.

150 151 6


Page 7 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


152

2.4. X-ray powder diffraction

153

X-ray powder diffraction (XRPD) was used to investigate the FUR:TEA salt. The

154

materials were ground and mounted on a glass sample holder. The XRPD patterns were

155

recorded using a D8 Advanced system (Bruker AXS) equipped with a theta/theta

156

goniometer configured in the Bragg Brentano geometry with a fixed specimen holder

157

using a Cu Kα (0.15419 nm) radiation source and a LynxEye detector. The voltage and

158

electric current applied were 40 kV and 40 mA, respectively. The slit used for the beam

159

incident on the sample was 0.6 mm wide. The samples were scanned between (2θ) 5-

160

40° in a step-scan mode (0.01 step size and 5 s).

161 162

2.5. Solid state NMR

163

High-resolution solid-state

164

the ramp cross polarization/magic angle spinning (CPMAS) sequence with proton

165

decoupling during acquisition.28 The ssNMR experiments were performed at room

166

temperature in a Bruker Avance II spectrometer equipped with a 4 mm MAS probe,

167

operating at 300.13 MHz for protons. The operating frequency for carbons was 75.46

168

MHz, using Glycine as external reference. A number of scans in the range 1200-2000

169

were used to obtain a good signal-to-noise ratio. Due to the long longitudinal relaxation

170

time (T1) of FUR, different recycling times between 5 s and 50 s were tested to obtain

171

the best signal-to-noise ratio within the shortest experimental time. Finally, a recycling

172

time of 5 s was set for all the experiments . The contact time during CP was 1.5 ms. The

173

non-quaternary suppression (NQS) spectra have been also performed, which results in

174

quaternary carbons and methyl groups spectra. The spinning rate for these experiments

175

was 10 kHz.

176

1H

177

inversion-recovery pulse sequence (π-t-π/2), by using recovery times t, between 10 µs

178

and 150 s. The recycling delay in these experiments was 50 s.

13C

spectra of FUR and FUR:TEA were performed by using

spin-lattice relaxation times in the laboratory frame (1H T1) were measured with an

7



Page 8 of 32

179

2D 1H-13C heteronuclear correlation (HETCOR) spectra for FUR and FUR:TEA were

180

recorded following the sequence presented by van Rossum et al.29 The pulse sequence

181

makes use of a train of off-resonance frequency-switched Lee−Goldburg (FSLG) pulses

182

to cancel the first two terms of the 1H−1H dipolar coupling Hamiltonian in the tilted rotating

183

frame. FSLG irradiation was applied during the t1 evolution period in successive times τ.

184

A ramped-amplitude CP sequence was used to enhance 13C signals, and the SPINAL64

185

pulse sequence was used for proton decoupling during 13C signal acquisition. The period

186

τ was set to 7.68 μs. The CP contact time was set to 200 μs to avoid any homonuclear

187

spin-diffusion processes, and the recycle delay was 5 s. Sixty-four t1 increments were

188

used corresponding to a total acquisition time of 1.14 ms. The spinning rate was 10 kHz.

189 190

2.6. FT-IR spectroscopy

191

FT-IR spectra of free FUR, TEA and FUR:TEA were measured on a Nicolet Avatar 360

192

FT-IR spectrometer, with the potassium bromide disks being prepared by compressing

193

the powders. The spectra of the samples were obtained and processed using the EZ 153

194

OMNIC E.S.P v.5.1 software.

195 196

2.7. Raman spectroscopy

197

Raman spectra of free FUR, TEA, and FUR:TEA were obtained on a LabRAM HR

198

(Horiba) spectrometer equipped with a liquid N2-cooled CCD detector which uses a near

199

infrared laser (785nm) for excitation.

200 201

2.8. Thermal analysis (DSC and TGA)

202

Thermogravimetric analysis (TGA) and Differential Scanning Calorimetric (DSC) curves

203

were obtained simultaneously using a STA 449 Jupiter system (Netzsch, Germany).

204

Measurements were taken at room temperature up to 450 °C using a heating rate of 10

205

K.min-1 and a sealed aluminum crucible with pierced lids containing 5 mg of sample. The

8


Page 9 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


206

sensors and the crucibles were under a constant flow of nitrogen (70 mL/min) during the

207

experiment.

208 209

2.9. Scanning electron microscopy studies (SEM)

210

The microscopic morphological structures of free FUR and FUR:TEA were investigated

211

and photographed using a Carl Zeiss Σigma scanning electron microscope at the

212

Laboratorio de Microscopía y Análisis por Rayos X (LAMARX) of the National University

213

of Córdoba. The samples were fixed on a brass stub using double-sided aluminium tape.

214

To improve their conductivity, they were gold-coated under vacuum employing a sputter

215

coater Quorum 150. The magnification selected was sufficient to appreciate in detail the

216

general morphology of the samples under study.

217 218

2.10. Solubility studies

219

The effect of TEA on the solubility of FUR was studied in water, simulated gastric fluid

220

(SGF) and buffer solution of pH 6.8 (PBS). Experiments were carried out in stoppered

221

glass tubes containing an excess of FUR (50 mg) and different amounts of TEA (3 mM

222

to 15 mM) according to the method reported by Higuchi & Connors.30 The tubes were

223

placed in a thermostatized orbital shaker at 37.0 (±0.1) ºC and 180 rpm for 72 h protected

224

from light. After equilibrium was reached, the suspensions were filtered through a 0.45

225

mm membrane filter (Millipore), and the filtrate was appropriately diluted for quantitative

226

analysis

227

spectrophotometer) at 274 nm. Each experiment was repeated at least three times and

228

the results reported were the mean values. The stability of the drug was determined in

229

water, SGF and PBS at 37 °C and no drug degradation was found after 72 h of

230

incubation.

of

FUR

by

UV–Vis

spectrophotometry

(Agilent

Cary

60

UV-160

231 232

2.11. Content determination

9



Page 10 of 32

233

For the determination of FUR content in FUR:TEA, 10 mg of powder was dissolved in a

234

methanol-water (50:50, v/v) mixture. After appropriate dilution, the samples were

235

analyzed with an HPLC-UV procedure previously reported.31 Each content determination

236

was performed in triplicate and the average and standard deviations were calculated.

237 238

2.12. Stability design

239

In order to investigate the effect of TEA on the photodegradation processes of FUR under

240

accelerated storage conditions, the tests were executed following the requirements of

241

the International Conference on Harmonization guidelines.32 Samples of FUR and

242

FUR:TEA were stored in triplicate in glass vials at 40 ºC and 75% relative humidity (RH),

243

and exposed to daylight into a stability chamber for 6 months.

244 245

2.12.1. Chemical stability study

246

To determine the chemical stability of the samples, the content of FUR was measured at

247

established times of storage (every 30 days) by an HPLC-UV method. The HPLC system

248

was an Agilent 1100 (Agilent, Waldbronn, Germany). The HPLC experiments were

249

performed under isocratic conditions using the method previously reported.31

250 251

2.12.2. Physical stability study

252

In order to evaluate possible solid phase transformations, the physical stability was

253

analyzed by using: ssNMR, XRPD and SEM. The samples were monitored at

254

predetermined times, initial time (t=0), one month (t=1), three months (t=3) and six

255

months (t=6).

256 257

2.13. Hygroscopicity study

258

The solid samples of FUR and FUR:TEA were accurately weighed before storage. The

259

samples were withdrawn at predetermined intervals (every 30 days) to monitor their

260

weight changes. All these experiments were carried out in triplicate. 10


Page 11 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


261 262

3. Results and discussion

263

3.1. Characterization studies

264

3.1.1. Crystalline structure of FUR:TEA salt

265

Single crystals of FUR:TEA with a prismatic habit were the samples produced by slow

266

evaporation. This compound crystallizes in the monoclinic P21/c space group, with the

267

following lattice parameters: a = 5.3311(3) Å, b = 23.0892(15) Å, c = 18.8492(13) Å, β =

268

93.868°. The crystallographic data is presented in Table S1 (Supporting information).

269

Besides FUR and TEA molecules (Z’=1), the asymmetric unit contains one molecule of

270

water, showing that this compound crystallizes as a monohydrate (Figure S1).

271

As shown in Figure 1, there is a charge transference in the structure, once the hydrogen

272

(H1’a) of the carbonyl group of the drug is transferred to the nitrogen (N1’) of TEA, leaving

273

it positively charged, characterizing a salt. In the case of carboxylic groups, the distinction

274

between salts and cocrystals may be based on the C-O distances, since both distances

275

should be similar when a salt is formed. Thus, the salt character of FUR:TEA is also

276

verified considering this rule, as the C-O distances of the carboxylate moiety of the drug

277

are very close (C12-O2=1.258 Å and C12-O3=1.252 Å).33

11



Page 12 of 32

278 279

Figure 1. Crystal structure of FUR:TEA salt.

280 281

The sulphonamide and carboxylic groups of FUR actively participate in hydrogen

282

bonding interactions capable of stabilizing the structure (Table S2 - Supporting

283

information). The O3’–H3’⋯O3 (2.637(3) Å) and O1’–H1’⋯O2 (2.649(3) Å)

284

intermolecular hydrogen bonds define FUR-TEA dimers, which form four member rings

285

composed by two dimers connected through the sulphonamide group by O2’–H2’⋯O5

286

(2.874(3) Å) bonds. Two water molecules are placed within this ring kept in place bridging

287

opposite FUR and TEA molecules by O1W–H1Wa⋯O3 (2.816(3) Å) and O1W–

288

H1Wb⋯O3’ (2.804(3) Å) interactions. The FUR-TEA tetramers are packed along the a

289

axis by hydrogen bonds between the nitrogen of sulphonamide group of FUR with one

290

of the water molecules in the upper/lower tetramer (N2-H2b⋯O1W=2.827(3) Å), as

291

shown in Figure S2.

292

Several authors have reported salts and cocrystals of FUR.34–42 As a rule, the carboxylic

293

synthon plays a key role in the interaction with the conformer/counter ion. Other

294

synthons, like the sulphonamide group, are mostly involved in the long-range crystal

295

packing. Regarding the salt/cocrystal relation among the FUR multicomponent solids, 12


Page 13 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


296

salts are frequent when the conformer is a nitro compound, as in the case of FUR:TEA.

297

This compound also fulfills the pKa rule, since this difference is bigger than 4 and a salt

298

is expected.43

299 300

3.1.2. XRPD

301

The XRPD patterns corresponding to FUR, FUR:TEA60, FUR:TEA5, FUR:TEAA,

302

FUR:TEAM are shown in Figure 2. The crystalline structure of the FUR was consistent

303

with the data previously reported.44,45

304

On the other hand, a distinctive powder diffraction pattern was observed in the four

305

obtained systems of the API with TEA, showing no residues of FUR. This pattern can be

306

compared with the one calculated from the determined crystalline structure (FUR:TEAC)

307

showing a good agreement and confirming that the observed patterns are characteristic

308

of the same solid form. These results revealed that the FUR:TEA monohydrated salt is

309

extremely easy to prepare using the different preparation methods, since the same

310

compound is always produced.

311 312

Figure 2. XRPD patterns of FUR and FUR:TEA salts.

313 13



Page 14 of 32

314

Consequently, we decided to continue the characterization and the study of the solid

315

sample obtained by the kneading method with water as solvent (FUR:TEA60), which will

316

be called hereinafter FUR:TEA. This decision was based on the macroscopic properties

317

of the solid obtained, since it is the one that presented more homogeneity in its

318

morphology and is the most easily manipulated.

319 320

3.1.3. Solid state NMR (ssNMR)

321 322

Figure 3: 13C CPMAS spectra of FUR and FUR:TEA. Carbon numbering belonging to

323

TEA are in red.

324 325

Figure 3 displays the

326

spectra are clearly distinguishable, showing some new resonances due to TEA signals,

327

and the shift of other signals in the case of the binary system. In particular, it must be

328

noted that FUR:TEA spectrum displays sharp resonances indicating that the binary

329

system is crystalline as it was confirmed by XRPD diffraction patterns. Assignments of

330

both spectra have been performed taking into account the NQS spectra of FUR and

13C

CPMAS spectra of FUR and FUR:TEA. In particular, both

13C

14


Page 15 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


331

FUR:TEA (Figure S3 - Supporting information) and the HETCOR correlations. In the FUR

332

spectrum, we could observe the widening and splitting of signals corresponding to C5

333

and C6, due to the dipolar interaction to quadrupolar nitrogen, and also the widening of

334

C7, due to dipolar coupling with the quadrupolar Cl. In addition, there are noticeable

335

splittings, for example note C9 and C10, due to the presence of two molecules in the unit

336

cell in the pure compound.46 Considering the binary system, except for C12 and C5 that

337

maintain their positions, the carbon signals are shifted, confirming that the new FUR:TEA

338

is a totally new solid phase.

339

Considering the T1 measurements, the binary system displays a single value of (14.6 ±

340

0.1) s being characteristic of a crystalline system and different to the T1 of FUR, which

341

is around 45 s.

342

The 2D 1H-13C HETCOR spectra for FUR and FUR:TEA are shown in Figure 4. As a

343

short contact time of 200 μs was used during the CP period, only short-range

344

heteronuclear correlations were developed. The carbon spectrum is shown in the

345

horizontal axis (direct projection, F1) while the proton spectrum is shown in the vertical

346

dimension (indirect projection, F2). The 2D spectrum reveals well-resolved carbon-

347

proton correlations, being useful for completing carbon spectra assignments and,

348

additionaly, to extract proton chemical shifts.

349

Comparing both 2D spectra, the most remarkable observation is that C12 in FUR

350

spectrum, displays a clear correlation with a proton at 12.51 ppm (in F2 dimension)

351

corresponding to the OH proton, which is absent in the FUR:TEA case, also showing a

352

diminishing in the C12 signal. This fact is indicative of transference of the OH proton in

353

FUR:TEA, confirming the fact of the salt formation.

354

With respect to the FUR 2D spectrum, natural correlations of protonated carbons appear

355

for C5, C2, C3 and C7. In addition, remarkable correlations are those corresponding to

356

the C10 with the H10 protons, allowing the assignment of this carbon. Visible correlations

15



Page 16 of 32

357

of C12 are also with H10. The quaternary C6 displays correlation with H5 and H7 protons.

358

Quaternary carbon C4 shows correlations with H(2,3,5) protons. A small signal

359

corresponding to carbon 11 arises from H10 proton correlation. Instead, C9 is not visible

360

in the HETCOR spectrum of FUR. Finally, a small level of correlation can be observed

361

between C5 and a proton at 10.45 ppm probably corresponding to the NH proton.

362

With respect to the FUR:TEA 2D spectrum, the protonated carbons C(1,2,3,5,7,10) of

363

FUR and C(1,2) of TEA display good noticeable correlations with their neighboring

364

protons, allowing the confirmation of the assignment of these carbons. In addition, C1

365

also displays a correlation with H(2,3). A small resonance assigned to the quaternary

366

carbon C12 displays a correlation with H10, and protons in the chemical shift of H1 (of

367

TEA), confirming the proximity of both molecules. Carbon 6 displays again a noticeable

368

correlation with H7, C1 also displays a correlation with H(2,3). Small signals

369

corresponding to the quaternary carbons C(9,11) display correlations with H10. In this

370

case, there are no visible correlations between carbons and NH protons, neither in FUR

371

nor in TEA molecules.

16


Page 17 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


372 373

Figure 4. 2D HETCOR spectra of FUR and FUR:TEA.

374 375

3.1.4. FT-IR and Raman spectroscopy

376

The FT-IR and Raman spectra of FUR, TEA and FUR:TEA are exibited in Figure 5. The

377

observed spectrum of FUR agreed with what was reported previously,44 while the

378

spectrum of FUR:TEA presented the appearance of a new band corresponding to COO-

379

group at 1612 cm-1. In addition, in these spectra, the band corresponding to secondary

17



Page 18 of 32

380

amine NH stretch disappeared and one of the bands corresponding to sulphonamide NH

381

stretch was shifted from 3285 cm-1 to 3237 cm-1.

382

On the other hand, the Raman spectrum of FUR showed the same signs as we reported

383

previously.47 Meanwhile, the FUR:TEA spectrum showed a new band at 1618 cm-1 which

384

could correspond to COO- group and the two bands corresponding to S=O stretch shifted

385

from 1338 cm-1 to 1361 cm-1 and from 1147 cm-1 to 1159 cm-1. These outcomes are

386

consequent with those explained for the FT-IR spectra, since they are confirming that

387

the sulphonamide and the carboxylic acid groups of FUR participate in the interactions

388

with the coformer.

389 390

Figure 5. FT-IR (a) and Raman (b) spectra of FUR, TEA and FUR:TEA.

391

18


Page 19 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


392

3.1.5. DSC and TGA

393

Figure 6 showed the DSC and TGA profiles of FUR, TEA and FUR:TEA. The DSC and

394

TGA curves of FUR and TEA exhibited the features informed on previous papers.47,48

395

The DCS curve of FUR:TEA showed the entire disappearance of the FUR thermal

396

features proving the molecular relationship of the drug with the coformer. On the other

397

hand, the TGA curves exposed a dehydration event with a mass loss of 2.5% for the

398

FUR:TEA salt and 1% for TEA. The molecules of water in the salt are being released at

399

a temperature lower than 100 ºC, which may be due to the fact that they can be easily

400

removed by being located in the internal channels of the FUR:TEA salt.

401 402

Figure 6. DSC profiles and TGA curves of FUR, TEA and FUR:TEA.

403 404

3.1.6. SEM

405

Through SEM images was possible to evaluate the morphology of the interaction

406

between FUR and TEA. In Figure 7, the structural differences between FUR and

407

FUR:TEA can be observed. As it was previously reported, the images of FUR showed

408

hexagonal tubular crystals, while the images of FUR:TEA exhibited changes in the size

409

and morphology of particles compared with the free drug. It presented a compact

410

structure with rugged appearance having an irregular size and shape, as well as

19



Page 20 of 32

411

attachment of particles with varied sizes. These differences in the appearance of the

412

particles could be ascribed to the interactions present in this solid system.

413 414

Figure 7. Microphotographs of FUR and FUR:TEA.

415 416 417

3.2. Phase solubility analysis

418

The solubility profiles of FUR are shown in Figure S4. The interaction of FUR with TEA

419

displayed typical AL-type solubility curves (Higuchi and Connors).30 A summary of these

420

results displayed in Table 1 showed that the intrinsic solubility of FUR in FGS (0.0158 ±

421

0.0005 mg/mL) was lower than its solubility in water (0.047 ± 0.003 mg/mL). In addition,

422

the solubility of FUR in PBS was 2.122 ± 0.003 mg/mL. These behaviors can be justified

423

by the ionization state of the API (pKa 3.8) in the different solutions.

20


Page 21 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


424

Additionally, as long as the concentration of TEA was increased, the profile obtained in

425

SGF showed a constant drug solubility where the conformer did not interact with FUR

426

since it was completely neutral. Moreover, it was observed that FUR solubility in water

427

increased with the increase of TEA concentration. FUR solubility in water was 0.047

428

mg/ml, while in TEA solution its solubility was from 0.54 mg/ml (2 mM TEA solution, pH

429

5.5) to 4.3 mg/ml (15 mM TEA solution, pH 6.3). As the pH of the solutions was

430

increased, the percentage of the ionized drug such as FUR- was also increased

431

confirming the ionized form of the drug, which was the one that can interact with the

432

conformer (TEA+) in ionic form. Besides, in PBS the solubility of the drug was from 2.86

433

mg/ml in a 2 mM TEA solution to 7.26 mg/ml in a 15 mM solution of TEA. From these

434

results, we can say that when combining TEA and PBS the effect is slightly synergistic

435

on the solubility of FUR.

436 437

Table 1. Results of solubility studies at 37.0 (±0.1) °C

FUR

FUR:TEA

438

Water

SGF

PBS

S0 (mg/mL)

0.047 ± 0.003

0.0158 ± 0.0005

2.122 ± 0.003

Smáx (mg/mL)

4.3 ± 0.1

0.017 ± 0.001

7.26 ± 0.05

Smáx/S0

91

1

3.4

Isotherm

BI

AL

AL

Kc (M-1)

77525 ± 72

-

11004 ± 89

S0: Solubility of free FUR, Smáx: maximum solubility of the salt

439 440

The interaction constant (KC) values (Table 1) were calculated using the following

441

equation:

442

𝐬𝐥𝐨𝐩𝐞

𝐊𝐜 = 𝐒𝐨 (𝟏 ― 𝐬𝐥𝐨𝐩𝐞)

equation (1)

443

Analyzing the Kc values and the effects of pH, it can be concluded that ionization

444

influences the association of FUR with TEA. The data derived from the phase solubility

21



Page 22 of 32

445

studies indicated that ionized FUR (in aqueous and PBS solutions) showed a greater

446

affinity for TEA, while the unionized FUR (in SGF), a more lipophilic form, does not

447

interact with the alkanolamine. This behavior confirms the ionic interaction between FUR

448

and TEA in solution.

449 450

3.3. Chemical stability

451

The photo-degradation of free FUR was compared to their photochemical degradation in

452

the FUR:TEA under identical experimental conditions. The drug content was measured

453

using an HPLC-UV method with the aim of getting data on the kinetics of the

454

decomposition development of the samples stored under accelerated conditions. The

455

measurements were collected once a month for a period of six months and the results

456

showed that the recovery percentage of free FUR decreased approximately 30% after 6

457

months stored at 40 ºC and 75% RH, while the recovery percentage of FUR in the

458

FUR:TEA salt only decreases 12% after the same time and the same stored conditions.

459

The FUR degradation plots, exhibited in Figure S5, were linear indicating that the photo-

460

degradation in solid state of FUR and its salt with TEA, followed first-order reactions.

461

Besides, the lower decrease in the amount of FUR as a function of time was determined

462

for FUR:TEA, which indicated that the drug in the salt is more stable than the free drug

463

upon storage under the applied conditions.

464

The degradation rate constant values were calculated by linear regression of ln C and t,

465

where C is the concentration of FUR at different reaction times and t is time, allowing to

466

determine the kinetic parameters shown in Table 2, such as the intrinsic rate constant of

467

photo-degradation of the free FUR (k0), the observed rate constant of photo-degradation

468

of FUR in the presence of TEA (kobs), the half-life (t50) and the shelf-life (t90) times.

469

The kinetic results evidence that TEA decreases the chemical reactivity of FUR.

470

Therefore, FUR:TEA salt had a stabilizing effect on FUR photodegradation. 22


Page 23 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


471 472

Table 2. Stability parameters of FUR in solid state in the presence of TEA. % FUR t90 t50 Sample K0 (day-1) KObs (day-1) recovered (day) (day) 53 352 FUR 69 ± 1 (2.0 ± 0.1) 10-3 FUR:TEA

88 ± 4

-

(0.6 ± 0.1) 10-3

175

1155

K0/KObs 3.3

473 474

3.4. Physical stability

475

Polymorphic transformations can be activated by different factors under storage, as for

476

example temperature and humidity, then leading to a physical instability of the drug.

477

Then, samples of FUR and FUR:TEA were examined spectroscopically by XRPD and

478

ssNMR at determined intervals (t = 0, t = 1, t =3 and t = 6 months) to evaluate possible

479

polymorphic transformations observed. Besides, the samples were analysed by SEM at

480

determined intervals (t = 0, t= 3 and t = 6 months) to assess changes in the morphology

481

of the particles.

482

At the end of 6 months of storage, FUR and FUR:TEA exhibit the same XRPD patterns

483

as the initial sample indicating the absence of phase transformation with respect to t =

484

0. (Figure S6a). The 13C CP-MAS for FUR and FUR:TEA, at t = 0, t = 1, t = 3, and t = 6,

485

displayed almost the same spectrum. These facts indicate that the samples maintained

486

the same microscopic structure under storage conditions, revealing their physical

487

stability and absence of polymorphic transformations (Figure S6b). Also, it was possible

488

to observe through SEM (Figure S6c) that FUR kept its characteristic hexagonal

489

morphology and the FUR:TEA also maintained its morphology. From all these results,

490

we can confirm that FUR:TEA salt is physically stable.

491 492

3.5. Hygroscopicity study

23



Page 24 of 32

493

The increase of weight of FUR and the FUR:TEA stored at 40 ºC and 75% RH is

494

expressed as g of adsorbed moisture per 100 g of dry solids. The results demonstrated

495

a slight weight gain for both cases corresponding to a change lower than 3%. In the case

496

of the drug, the increase was 2.6 (± 0.08) % while it was 2.8 (± 0.07) % for FUR:TEA

497

after six months. The increase in weight was less than 15% but higher than 2% indicating

498

that these samples can be classified as moderated hygroscopic according to the

499

European pharmacopoeia.49

500 501

4. Conclusions

502

Our studies demonstrated that the interaction of FUR with TEA resulted in the formation

503

of a pharmaceutical salt. Solid-state characterization by employing XRPD evidenced that

504

the same crystal structure was obtained using different methodologies for their

505

preparation. By performing exhaustive experiments as XRD, ssNMR, FT-IR and Raman

506

spectroscopy, the formation of the salt as a new solid form of FUR was proved. In

507

particular, 2D 1H-13C HETCOR spectra showed that the OH proton bound to the C12 was

508

involved in the salt formation. Furthermore, it was shown that TEA acts as an enhancer

509

on the solubility of FUR, increasing the aqueous drug solubility 91-fold. Finally, our

510

studies demonstrated that FUR:TEA improved the photo-chemical stability of FUR after

511

6 months of storage at 40 °C and 75% RH and, at the same time, the salt maintains the

512

physical stability and the higroscopicity of the drug. Therefore, the new FUR:TEA salt

513

constitutes an interesting pharmaceutical choice to improve the biopharmaceutical

514

attributes of the drug with potential application in the development of FUR formulations

515

with improved properties.

516 517

Supporting Information. This material showed the asymmetric unit of the FUR:TEA salt

518

(Figure S1), the packing motif along the a-axis (Figure S2), the NQS spectra of FUR and 24


Page 25 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


519

FUR:TEA (Figure S3), the solubility diagrams (Figure S4), the degradation curves

520

(Figure S5), the analysis of the physical stability of the samples (Figure S6), the crystal

521

data, structure determination parameters and refinement statistics for FUR:TEA (Table

522

S1) and the hydrogen-bonds of FUR:TEA (Table S2).

523 524

References

525

(1)

526 527

Adeoye, O.; Cabral-Marques, H. Cyclodextrin Nanosystems in Oral Drug Delivery: A Mini Review. Int. J. Pharm. 2017, 531 (2), 521–531.

(2)

Blagden, N.; de Matas, M.; Gavan, P. T.; York, P. Crystal Engineering of Active

528

Pharmaceutical Ingredients to Improve Solubility and Dissolution Rates. Adv.

529

Drug Deliv. Rev. 2007, 59 (7), 617–630.

530

(3)

De Zordi, N.; Moneghini, M.; Kikic, I.; Grassi, M.; Del Rio Castillo, A. E.; Solinas,

531

D.; Bolger, M. B. Applications of Supercritical Fluids to Enhance the Dissolution

532

Behaviors of Furosemide by Generation of Microparticles and Solid Dispersions.

533

Eur. J. Pharm. Biopharm. 2012, 81 (1), 131–141.

534

(4)

Harriss, B. I.; Vella-Zarb, L.; Wilson, C.; Evans, I. R. Furosemide Cocrystals:

535

Structures, Hydrogen Bonding, and Implications for Properties. Cryst. Growth

536

Des. 2014, 14 (2), 783–791.

537

(5)

FDA. US Food and Drug Administration, Center for Drug Evaluation and

538

Research (CDER). The Biopharmaceutics Classification Systems (BCS)

539

Guidance. 2001.

540

(6)

541 542 543

Doherty, C.; York, P. Frusemide Crystal Forms - Solid-State and Physicochemical Analyses. Int. J. Pharm. 1988, 47 (1–3), 141–155.

(7)

Matsuda, Y.; Tatsumi, E. Physicochemical Characterization of Furosemide Modifications. Int. J. Pharm. 1990, 60 (1), 11–26. 25



544

(8)

Page 26 of 32

Bundgaard, H.; Nørgaard, T.; Nielsen, N. M. Photodegradation and Hydrolysis of

545

Furosemide and Furosemide Esters in Aqueous Solutions. Int. J. Pharm. 1988,

546

42 (1–3), 217–224.

547

(9)

Vargas, F.; Volkmar, I. M.; Sequera, J.; Mendez, H.; Rojas, J.; Fraile, G.;

548

Velasquez, M.; Medina, R. Photodegradation and Phototoxicity Studies of

549

Furosemide. Involvement of Singlet Oxygen in the Photoinduced Hemolysis and

550

Lipid Peroxidation. J. Photochem. Photobiol. B Biol. 1998, 42 (3), 219–225.

551

(10)

Mørk, N.; Bundgaard, H.; Shalmi, M.; Christensen, S. Furosemide Prodrugs:

552

Synthesis, Enzymatic Hydrolysis and Solubility of Various Furosemide Esters.

553

Int. J. Pharm. 1990, 60 (2), 163–169.

554

(11)

Shin, S. C.; Oh, I. J.; Lee, Y. B.; Choi, H. K.; Choi, J. S. Enhanced Dissolution of

555

Furosemide by Coprecipitating or Cogrinding with Crospovidone. Int. J. Pharm.

556

1998, 175 (1), 17–24.

557

(12)

Devarakonda, B.; Otto, D. P.; Judefeind, A.; Hill, R. A.; de Villiers, M. M. Effect of

558

PH on the Solubility and Release of Furosemide from Polyamidoamine

559

(PAMAM) Dendrimer Complexes. Int. J. Pharm. 2007, 345 (1–2), 142–153.

560

(13)

Zvonar, A.; Berginc, K.; Kristl, A.; Gašperlin, M. Microencapsulation of Self-

561

Microemulsifying System: Improving Solubility and Permeability of Furosemide.

562

Int. J. Pharm. 2010, 388 (1–2), 151–158.

563

(14)

Goud, N. R.; Gangavaram, S.; Suresh, K.; Pal, S.; Manjunatha, S. G.; Nambiar,

564

S.; Nangia, A. Novel Furosemide Cocrystals and Selection of High Solubility

565

Drug Forms. J. Pharm. Sci. 2012, 101 (2), 664–680.

566

(15)

Akbuga, J.; Gürsoy, A.; Yetimoglu, F. Preparation and Properties of Tablets

567

Prepared from Furosemide-PVP Solid Dispersion Systems. Drug Dev. Ind.

568

Pharm. 1988, 14 (15–17), 2091–2108.

26


Page 27 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

569


(16)

570 571

Shin, S. C.; Kim, J. Physicochemical Characterization of Solid Dispersion of Furosemide with TPGS. Int. J. Pharm. 2003, 251, 79–84.

(17)

Rakesh, P. .; Dhaval, J. P.; Dipen, B. B.; Jayvadan, K. P. Physicochemical

572

Characterization and Dissolution Study of Solid Dispersions of Furosemide with

573

Polyethylene Glycol 6000 and Polyvinylpyrrolidone K30. Dissolution Technol.

574

2008, No. August, 17–25.

575

(18)

Radwan, S. E. S.; Sokar, M. S.; Abdelmonsif, D. A.; El-Kamel, A. H.

576

Mucopenetrating Nanoparticles for Enhancement of Oral Bioavailability of

577

Furosemide: In Vitro and in Vivo Evaluation/Sub-Acute Toxicity Study. Int. J.

578

Pharm. 2017, 526 (1–2), 366–379.

579

(19)

Cerreia Vioglio, P.; Chierotti, M. R.; Gobetto, R. Pharmaceutical Aspects of Salt

580

and Cocrystal Forms of APIs and Characterization Challenges. Adv. Drug Deliv.

581

Rev. 2017, 117, 86–110.

582

(20)

Elder, D. P.; Holm, R.; De Diego, H. L. Use of Pharmaceutical Salts and

583

Cocrystals to Address the Issue of Poor Solubility. Int. J. Pharm. 2013, 453 (1),

584

88–100.

585

(21)

Ki, H.-M.; Choi, H.-K. The Effect of Meloxicam/Ethanolamine Salt Formation on

586

Percutaneous Absorption of Meloxicam. Arch. Pharm. Res. 2007, 30 (2), 215–

587

221.

588

(22)

589

Han, H. K.; Choi, H. K. Improved Absorption of Meloxicam via Salt Formation with Ethanolamines. Eur. J. Pharm. Biopharm. 2007, 65 (1), 99–103.

590

(23)

Bruker, SAINT, Version 8.34A. Bruker AXS Inc. 2012, Madison, Wiscosin, USA.

591

(24)

Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H.

592

OLEX2: A Complete Structure Solution, Refinement and Analysis Program. J.

593

Appl. Crystallogr. 2009, 42 (2), 339–341.

27



594

(25)

595 596

Sheldrick, G. M. Crystal Structure Refinement with SHELXL. Acta Crystallogr. Sect. C Struct. Chem. 2015, 71 (Md), 3–8.

(26)

597 598

Page 28 of 32

Sheldrick, G. M. A Short History of SHELX. Acta Crystallogr. Sect. A Found. Crystallogr. 2008, 64 (1), 112–122.

(27)

Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor,

599

R.; Towler, M.; Van De Streek, J. Mercury: Visualization and Analysis of Crystal

600

Structures. J. Appl. Crystallogr. 2006, 39 (3), 453–457.

601

(28)

602 603

Harris, R. K. Nuclear Magnetic Resonance Spectroscopy. London: Logman Scientific and Technical. 1994.

(29)

Van Rossum, B. J.; Förster, H.; De Groot, H. J. M. High-Field and High-Speed

604

CP-MAS13C NMR Heteronuclear Dipolar-Correlation Spectroscopy of Solids

605

with Frequency-Switched Lee-Goldburg Homonuclear Decoupling. J. Magn.

606

Reson. 1997, 124 (2), 516–519.

607

(30)

Higuchi, T.; Connors, K. A. Phase-Solubility Techniques in Advances in

608

Analytical Chemistry and Instrumentation. Interscience: New York. 1965, p Vol.

609

4, pp 117-212.

610

(31)

Garnero, C.; Chattah, A. K.; Longhi, M. Stability of Furosemide Polymorphs and

611

the Effects of Complex Formation with β-Cyclodextrin and Maltodextrin.

612

Carbohydr. Polym. 2016, 152, 598–604.

613

(32)

ICH Q1A(R2), Stability Testing of New Drug Substances and Products, 2003.

614

(33)

Da Silva, C. C. P.; De Oliveira, R.; Tenorio, J. C.; Honorato, S. B.; Ayala, A. P.;

615

Ellena, J. The Continuum in 5-Fluorocytosine. toward Salt Formation. Cryst.

616

Growth Des. 2013, 13 (10), 4315–4322.

617 618

(34)

Thorat, S. H.; Sahu, S. K.; Patwadkar, M. V.; Badiger, M. V.; Gonnade, R. G. Drug-Drug Molecular Salt Hydrate of an Anticancer Drug Gefitinib and a Loop 28


Page 29 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


619

Diuretic Drug Furosemide: An Alternative for Multidrug Treatment. J. Pharm. Sci.

620

2015, 104 (12), 4207–4216.

621

(35)

Stepanovs, D.; Mishnev, A. Multicomponent Pharmaceutical Cocrystals:

622

Furosemide and Pentoxifylline. Acta Crystallogr. Sect. C Cryst. Struct. Commun.

623

2012, 68 (12).

624

(36)

Sangtani, E.; Sahu, S. K.; Thorat, S. H.; Gawade, R. L.; Jha, K. K.; Munshi, P.;

625

Gonnade, R. G. Furosemide Cocrystals with Pyridines: An Interesting Case of

626

Color Cocrystal Polymorphism. Cryst. Growth Des. 2015, 15 (12), 5858–5872.

627

(37)

Srirambhatla, V. K.; Kraft, A.; Watt, S.; Powell, A. V. A Robust Two-Dimensional

628

Hydrogen-Bonded Network for the Predictable Assembly of Ternary Co-Crystals

629

of Furosemide. CrystEngComm 2014, 16 (43), 9979–9982.

630

(38)

Banik, M.; Gopi, S. P.; Ganguly, S.; Desiraju, G. R. Cocrystal and Salt Forms of

631

Furosemide: Solubility and Diffusion Variations. Cryst. Growth Des. 2016, 16 (9),

632

5418–5428.

633

(39)

Ueto, T.; Takata, N.; Muroyama, N.; Nedu, A.; Sasaki, A.; Tanida, S.; Terada, K.

634

Polymorphs and a Hydrate of Furosemide − Nicotinamide 1 : 1 Cocrystal. Cryst.

635

Growth Des. 2012, 12 (1), 485–494.

636

(40)

Beloborodova, A. A.; Minkov, V. S.; Rychkov, D. A.; Rybalova, T. V.; Boldyreva,

637

E. V. First Evidence of Polymorphism in Furosemide Solvates. Cryst. Growth

638

Des. 2017, 17 (5), 2333–2341.

639

(41)

Minkov, V. S.; Beloborodova, A. A.; Drebushchak, V. A.; Boldyreva, E. V.

640

Furosemide Solvates: Can They Serve as Precursors to Different Polymorphs of

641

Furosemide? Cryst. Growth Des. 2014, 14 (2), 513–522.

642 643

(42)

Kerr, H. E.; Softley, L. K.; Suresh, K.; Nangia, A.; Hodgkinson, P.; Evans, I. R. A Furosemide-Isonicotinamide Cocrystal: An Investigation of Properties and

29



644 645

Extensive Structural Disorder. CrystEngComm 2015, 17 (35), 6707–6715. (43)

646 647

Cruz-Cabeza, A. J. Acid-Base Crystalline Complexes and the PKa Rule. CrystEngComm 2012, 14 (20), 6362–6365.

(44)

Garnero, C.; Chattah, A. K.; Longhi, M. Supramolecular Complexes of

648

Maltodextrin and Furosemide Polymorphs: A New Approach for Delivery

649

Systems. Carbohydr. Polym. 2013, 94 (1), 292–300.

650

(45)

Garnero, C.; Chattah, A. K.; Longhi, M. Improving Furosemide Polymorphs

651

Properties through Supramolecular Complexes of β-Cyclodextrin. J. Pharm.

652

Biomed. Anal. 2014, 95, 139–145.

653

Page 30 of 32

(46)

Babu, N. J.; Cherukuvada, S.; Thakuria, R.; Nangia, A. Conformational and

654

Synthon Polymorphism in Furosemide (Lasix). Cryst. Growth Des. 2010, 10 (4),

655

1979–1989.

656

(47)

Abraham Miranda, J.; Garnero, C.; Zoppi, A.; Sterren, V.; Ayala, A. P.; Longhi,

657

M. R. Characterization of Systems with Amino-Acids and Oligosaccharides as

658

Modifiers of Biopharmaceutical Properties of Furosemide. J. Pharm. Biomed.

659

Anal. 2018, 149, 143–150.

660

(48)

Maitre, M. M.; Longhi, M. R.; Granero, G. G. Ternary Complexes of Flurbiprofen

661

with HP-β-CD and Ethanolamines Characterization and Transdermal Delivery.

662

Drug Dev. Ind. Pharm. 2007, 33 (3), 311–326.

663

(49)

Newman, A. W.; Reutzel-Edens, S. M.; Zografi, G. Characterization of the

664

“Hygroscopic” Properties of Active Pharmaceutical Ingredients. J. Pharm. Sci.

665

2008, 97 (3), 1047–1059.

666 667 668 30


Page 31 of 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


669

"For Table of Contents Use Only"

670 671

MANUSCRIPT TITLE: FUROSEMIDE:TRIETHANOLAMINE SALT AS A STRATEGY

672

TO IMPROVE THE BIOPHARMACEUTICAL PROPERTIES AND PHOTOSTABILITY

673

OF THE DRUG

674

AUTHOR LIST: Abraham Miranda, Julieta; Garnero, Claudia; Chattah, Ana; Santiago

675

de Oliveira, Yara; Ayala, Alejandro; Longhi, Marcela.

676

TOC GRAPHIC:

677 678

SYNOPSIS:

679

A pharmaceutical salt combining furosemide and triethanolamine was obtained and

680

characterized. The solid sample was prepared using different techniques. The salt

681

formation produces an enhancement of the drug solubility and of its chemical photo-

682

stability, whereas the physical photo-stability and the hygroscopicity status were not

683

modified. This salt constitutes an interesting strategy with potential application for the

684

preparation of pharmaceutical furosemide formulations.

31



Furosemide (-) : Triethanolamine (+) salt 179x70mm (96 x 96 DPI)


Page 32 of 32

Furosemide:Triethanolamine Salt as a Strategy To Improve the

Recommend Documents