A New Way of Stabilization of Furosemide upon Cryogenic Grinding

Article pubs.acs.org/molecularpharmaceutics

A New Way of Stabilization of Furosemide upon Cryogenic Grinding by Using Acylated Saccharides Matrices. The Role of Hydrogen Bonds in Decomposition Mechanism E. Kaminska,*,† K. Adrjanowicz,‡,§ K. Kaminski,§,∥ P. Wlodarczyk,⊥ L. Hawelek,§,⊥ K. Kolodziejczyk,§ M. Tarnacka,§ D. Zakowiecki,# I. Kaczmarczyk-Sedlak,† J. Pilch,∇ and M. Paluch§ †

Department of Pharmacognosy and Phytochemistry, Medical University of Silesia, ul. Jagiellonska 4, 41-200 Sosnowiec, Poland NanoBioMedical Centre, Adam Mickiewicz University, Umultowska 85, 61-614 Poznan, Poland § Institute of Physics, Silesian University, ul. Uniwersytecka 4, 40-007 Katowice, Poland ∥ Institute of Experimental Physics, University of Leipzig, Linnestr. 5, 04103 Leipzig, Germany ⊥ Institute of Non-Ferrous Metals, ul. Sowinskiego 5, 44-100 Gliwice, Poland # R&D Department, Pharmaceutical Works, Polpharma SA, ul. Pelplinska 19, 83-200 Starogard Gdanski, Poland ∇ Department of Biological Sciences, Academy of Physical Education, ul. Raciborska 1, 40-074 Katowice, Poland ‡

ABSTRACT: Recently it was reported that upon mechanical milling of pure furosemide significant chemical degradation occurs (Adrjanowicz et al. Pharm. Res. 2011, 28, 3220−3236). In this paper, we present a novel way of chemical stabilization amorphous furosemide against decomposing that occur during mechanical treatment by preparing binary mixtures with acylated saccharides. To get some insight into the mechanism of chemical degradation of furosemide induced by cryomilling, experimental investigations supported by density functional theory (DFT) computations were carried out. This included detailed studies on molecular dynamics and physical properties of cryoground samples. The main thrust of our paper is that we have shown that furosemide cryomilled with acylated saccharides forms chemically and physically stable homogeneous mixtures with only one glass transition temperature, Tg. Finally, solubility measurements have demonstrated that furosemide cryomilled with acylated saccharides (glucose, maltose and sucrose) is much more soluble with respect to the crystalline form of this active pharmaceutical ingredient (API). KEYWORDS: cryogenic grinding, amorphous pharmaceuticals, furosemide, acylated sugars, chemical stabilization

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INTRODUCTION Most of biologically active drugs that can be found in the market are formulated in the crystalline form, even though crystalline state is in some cases the most important factor limiting solubility and bioavailability of given active pharmaceutical ingredients (APIs). This is probably because crystalline forms of APIs are thermodynamically stable and relatively easy to characterize with the use of standard methods such as X-ray diffraction, differential scanning calorimetry, raman and infrared spectroscopy, and so forth. There are many different ways to enhance bioavailability of poorly water-soluble drugs that are classified in group II (low soluble and highly permeable) and IV (weakly soluble and permeable) accordingly to the Biopharmaceutical Classification System (BCS).1,2 For this purpose the following physical as well chemical methods were introduced and developed: (i) the particle size reduction by micronization,3,4 (ii) application of cyclodextrins,5,6 (iii) polymeric matrixes,7−9 (iv) molecular dispersion,10,11 v) incorporation of surfactants,12 or (vi) changing drugs into salts (e.g., hydrochloric, citric, etc.),13−15 © 2013 American Chemical Society

and so forth. However, poorly water-soluble active substances can also be prepared in the amorphous form, as this particular form is more preeminent than the crystalline phase. For example, amorphous APIs usually dissolve in water much better than their crystalline equivalents16−23 and have a greater ability to form tablets.13 Moreover, their chemical reactivity is also significantly enhanced.13,24−26 Despite these obvious advantages, preparation of the amorphous APIs for commercial use is not well-established because of their thermodynamic instability.18,27 As a result, amorphous substances tend to revert to the crystalline state during storage. It was also suggested that enhanced chemical reactivity of amorphous pharmaceuticals, related to the molecular mobility, might cause their chemical degradation28 as well as unwanted isomeric transformations during manufacturing and storage.29 Received: Revised: Accepted: Published: 1824

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decreases chemical stability of this API.58 To understand this process, we have performed experimental studies supported by DFT calculations. In this paper we have demonstrated that acylated saccharides can be used to avoid chemical degradation of furosemide upon cryomilling. This finding enables us to make some conclusions about the mechanism of the degradation process of investigated API under mechanical milling.

To obtain the amorphous form of a drug, various techniques can be applied. Amorphous solids can be produced via melting followed by quench-cooling,13,21,30,31 (amorphous form obtained in such way is usually termed glass), from a solution (by spray-drying,32,33 freeze-drying,34 or precipitation), from a solid state (by milling,35,36 pressurization of crystals37), through vapor condensation,38 or by a combination of the aforementioned techniques (e.g., hot-melt extrusion). Such a large variety of amorphization methods enable us to produce amorphous materials with completely different thermodynamical as well as chemical properties that, for sure, differ in stability and reactivity. The most conventional way of amorphization is certainly rapid cooling of a molten crystal. However, in some cases this method cannot be employed, due to thermal degradation of many drugs at melting temperatures. A less well-known, but very efficient way of amorphization is high-energy milling (i.e., ball-milling or grinding). This technique is applicable in many fields of industry to reduce particle size. However, the large amount of mechanical perturbations generated during milling may result in significant changes in the structure of the grinded material, including crystal defects, polymorphic transformations, and partial or complete amorphization.39,40 In recent years a lot of effort has been put into getting deep insight into crystal-glass transformation induced by milling both in inorganic41 as well as organic materials (both in food and pharmaceutical science36,42,43). Solid state amorphization via milling is an alternative for the materials undergoing thermal degradation at the melting point33,43,44 and methods which based on solvent evaporation, sublimation, precipitation, and so forth. However, one should note that amorphous drugs prepared by grinding of crystalline solids are typically less stable than that obtained by quenching of liquid, for example, indomethacin (IMC).44 There are many theories that try to explain the mechanism of solid state amorphization induced by milling.45−47 However, none of them is commonly accepted. To obtain the amorphous form of a given material, the following basic parameters must be taken into account. First, grinding must take place at temperatures lower than the glass transition temperature (Tg); otherwise transformation between different polymorphic forms might occur48−50 Second, the crucial technical parameter is the intensity of milling. Typically, the higher grinding intensity, the better effectiveness of the amorphization process. In recent years a new milling technique, so-called cryomilling (alternatively called cryogenic grinding or cryogrinding), was developed.15,31,44,51,52 Cryomilling is a high-impact process which takes place at liquid nitrogen temperature and makes the amorphization process faster and more effective (cryogenic temperature minimizes the energy expenditure and produce amorphous system without thermal degradation). It is also considered to be the more efficient in preparing the disordered drugs than conventional grinding at ambient conditions.44,53 As amorphous APIs obtained by cryogrinding frequently show physical and chemical instability, they are typically comilled with some additives like polyvinylpyrrolidyne (PVP),51,52,54 crospovidone (CPVP),55,56 silicates,57 polysaccharides like inulin,58 or cyclodextrins.59 Due to relatively high values of Tg, polymers and polysaccharides improve the physical and chemical stability of binary mixture, resulting in lowering mobility in the amorphous state. What is even more, the solubility of molecularly dispersed drugs can be enhanced as well.55 In contradiction to what is stated above, our recent experimental studies pointed out that comilling binary mixtures of diuretic agent furosemide with inulin or PVP significantly

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EXPERIMENTAL METHODS Materials. Furosemide (4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbenzoic acid, C12H11ClN2O5S) having a purity greater than 99%, and acylated sugars (pentaacetyl glucose, octaacetyl sucrose, octaacetyl maltose, acetyl α-cyclodextrin), having purities greater than 98%, were supplied by the Pharmaceutical Works Polpharma SA (Starogard Gdanski, Poland) and used without further purification. The chemical structure of furosemide is shown in Scheme 1. Scheme 1. Chemical Structure and 3D Representation of Furosemide Moleculea

a

In the 3D model, oxygens are red, sulphur is yellow, chlorine is dark red, and nitrogen is blue. In the scheme, the probable decay pattern is drawn. Dissociation occurs by the breaking of the N−C bond.

Methods. Preparation of Amorphous Systems of Furosemide with Acylated Sugars by Cryogenic Grinding. The grinding was performed using a cryogenic impact mill (6750 freezer/mill SPEX CertiPrep, Inc., USA) consisting of a stainless steel vessel immersed in liquid nitrogen, within which a stainless steel rod was vibrated by means of magnetic coil. Before grinding, a 10 min precooling time was programmed. Then, the mill was set at an impact frequency of 15 Hz for 6 min grinding periods separated by 3 min cool-down periods. The powdered mixtures of furosemide−acylated sugars were prepared at 1:1 mass ratios and cryomilled for 90 min. The mass of each sample was 1 g. To avoid or minimize effect of moisture on the chemical stability of the cryoground mixtures, samples were dried under the vacuum before cryomilling was started. Then, samples were loaded into the stainless steel vessel in the glovebox flushed by nitrogen. After cryomilling was finished, the vial was transferred to the oven and stored under vacuum until it warmed up. The content of water was evaluated to be lower than 0.5%. Differential Scanning Calorimetry (DSC). Thermodynamic properties of amorphous binary mixtures of furosemide− acylated glucose, furosemide−acylated sucrose, and furosemide−acylated maltose obtained by cryogrinding, have been investigated by differential scanning calorimetry. Calorimetric measurements were performed with Mettler-Toledo DSC apparatus equipped with a liquid nitrogen cooling accessory and a HSS8 ceramic sensor (heat flux sensor with 120 1825

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thermocouples). Temperature and enthalpy calibrations were carried out by using indium and zinc standards. Measurements on cryoground samples were carried out starting from 273 to 473 K. Thermograms of pure acylated saccharides were obtained in the following way. First, the crystalline sample was melted in the crucible, and next the melt was immediately cooled to vitrify the sample. Crystalline and amorphous samples were scanned at a rate of 10 K/min over a temperature range of 298 K to well above the respective melting points. X-ray Diffraction (XRD). The X-ray diffraction experiment was performed at ambient temperature using a Rigaku-Denki D/ MAX RAPID II-R diffractometer with a rotating anode Ag Kα tube (λ = 0.5608 Å), an incident beam (002) graphite monochromator, and an image plate in the Debye−Scherrer geometry. The pixel size was 100 × 100 μm. All samples were placed inside Lindemann glass capillaries (2 mm in diameter). Measurements were run with the sample filled and empty capillaries, and the intensity of the empty capillary was then subtracted. The beam width at the sample was 0.1 mm. The twodimensional diffraction patterns were converted into the onedimensional intensity data using a suitable software. Broadband Dielectric Spectroscopy. Isobaric measurements of the dielectric permittivity ε*(ω) = ε′(ω) − iε″(ω) were carried out using the Novo-Control Alpha dielectric spectrometer over the frequency range from 10−2 to 107 Hz in combination with an Agilent network analyzer (107−109 Hz). The temperature was controlled by the Quatro system, employing a nitrogen gas cryostat, and the temperature stability of the sample achieved was better than 0.1 K. Test of the Purity of Cryomilled Furosemide and Chemical Stability in Solid State and Solutions (Ultra-Performance Liquid Chromatography (UPLC)). For the analysis of pure furosemide, its mixtures with acylated sugars and degradation products (impurities), a simple and sensitive chromatographic method has been developed. The analyses were performed using the Waters Acquity UPLC system (Millford, MA, USA), equipped with a binary solvent manager, sample manager, column manager, and photodiode array eλ detector. Chromatographic data were acquired and calculated using the Empower Pro 2 software (Waters, Millford, MA, USA). A summary of the chromatographic conditions is given in Table 1. The LC separation was achieved within a run time of 10 min. The employed UPLC method was specificno interference was determined between the peaks due to the sample solvent,

used excipients (sugars), drug substance, and its impurities. LOD was determined at the level of 0.00004 mg/mL, while LOQ was determined at 0.00013 mg/mL. LOQ was at the same time chosen as the reporting threshold. The method was linear for concentration range of 0.00013 mg/mL (LOQ) to 0.25 mg/mL; the regression coefficient stood at 0.9996. This method was also used to determine the solubility of the active pharmaceutical ingredient cryomilled with different ingredients. Solubility Study. The solubility of all samples was determined in different medias such as purified water (pH∼6.9), hydrochloric acid (0.1 M), and phosphate buffer (pH 4.5)Table 2. Solubility measurements were performed at specific pH values using a shake flask method at 37 °C ± 0.5 °C. DFT Calculations. Geometry optimizations of furosemide− acylated glucose, as well as furosemide−inulin were performed on the X3LYP/6-31g(d,p) level. Initial structures were modeled by hand. All calculations were performed in the orca quantum program.60 The binding energy was calculated as rgw difference between total energy and the energy of nonbonded molecules. The furan−methyl acetate model was optimized on the X3LYP/ 6-311+G(d,p) level of theory.

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RESULTS AND DISCUSSION Furosemide is a potent diuretic (antihypertensive compound) that is used to eliminate water and salt from the body and as a control for evaluation of the therapeutic effect of drugs on renal insufficiency. This API belongs to the Class IV-type drugs according to the BCS. It has a very poor water solubility (0.006 mg/Ml61) as well as bioavailability (20−60%).62 Furosemide has been known to be unstable during adverse storage conditions. It undergoes acid-catalyzed hydrolysis in water solutions, photochemical degradation in the solid state, and thermal decomposition at melting point.63,64 In all three cases, the same degradation product is formed, namely, 4-chloro-5-sulfamoylanthranilic acid (CSA), which might undergo further photodechlorination to N-furfuryl-5-sulfamoylanthranilic acid (FSA).65 For this reason, it seems that the furosemide itself is strongly sensitive to degradation when exposed to inappropriate storage or manufacturing conditions. In fact in our previous paper we have shown that furosemide undergoes chemical decomposition during cryogrinding.58 This time CSA was identified also as the main product of furosemide decomposition. We have also shown that cryogrinding of furosemide with standard excipients such as inulin and PVP (very often used to enhance solubility of the poorly soluble drugs) shifts the reaction equilibrium toward formation of CSA. The fact that addition of inulin and PVP does not inhibit but rather increases the rate of chemical decomposition of furosemide is quite intriguing. In our previous paper we have mentioned that probably hydrogen bonds are responsible for the observed effects. Herein, we present more sophisticated data which should confirm our supposition. This time we have decided to cryomill furosemide with materials having no ability to form hydrogen bonds. For this purpose, acylated sugars: glucose, maltose, sucrose, and cyclodextrin have been chosen. In these carbohydrates hydrogen atoms were substituted by acetyl moieties. This procedure eliminates the possibility of hydrogen bonding formation between the given acetyl saccharide and furosemide molecules. It is worth to mention here that the first application of carbohydrate derivatives with acylated groups (i.e., acylated maltose) to enhance physical stability of amorphous drugs has been recently described by Grzybowska et al.66 In this work the

Table 1. Chromatographic Conditions (UPLC) column mobile phase A mobile phase B gradient program

flow rate column temp injection volume injection mode detection wavelength data collection rate

ACQUITY UPLC BEH C18 1.7 μm 2.1 × 150 mm (Waters, Wexford, Ireland) 0.1% formic acid in water, pH adjusted to 5.6 with triethylamine acetonitrile start with 10% of mobile phase B at 9.0 min 50% of mobile phase B at 10.0 min 70% of mobile phase B 0.3 mL/min 30 °C 1.0 μL partial loop with needle overfill 270 nm 40 points/s

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Table 2. Solubility of Different Forms of Furosemide Determined in Different Media such as Hydrochloric Acid (0.1 M), Phosphate Buffer (pH 4.5), and Purified Water with pH about 6.9 saturation solubility of furosemide ± SD [mg/100 mL] media 0.1 M HCl phosphate buffer, pH 4.5 purified water, pH ∼ 6.9

temperature

crystalline

amorphous

with inulin

with PVP

with acyl. cyclodextrin

with acyl. glucose

with acyl. maltose

with acyl. sucrose

37 °C

1.39 ± 0.16 13.97 ± 1.51

1.73 ± 0.18 15.09 ± 0.91

0.98 ± 0.08 10.46 ± 1.19

19.57 ± 1.59 55.74 ± 4.37

10.63 ± 0.94 25.09 ± 1.97

1.17 ± 0.11 11.32 ± 1.04

3.30 ± 0.38 18.86 ± 1.64

2.42 ± 0.19 17.14 ± 1.66

3.57 ± 0.45

8.63 ± 0.69

4.28 ± 0.36

34.44 ± 2.74

26.93 ± 2.02

4.52 ± 0.43

8.61 ± 0.70

7.36 ± 0.65

Figure 1. Overlaid example chromatograms of crystalline (black) and amorphous (blue) furosemide as well as furosemide cryomilled with: inulin (pink), acyl. maltose (navy blue), and acyl. sucrose (green).

authors indicated that hydrogen bonds formed between celecoxib and octaacetylmaltose can be responsible for enhancing a physical stability of the amorphous drug. In this paper, we have utilized the same protocol, but to stabilize a chemically cryoground sample. To verify whether modified carbohydrates stabilize furosemide upon cryomilling (i.e., prevents its chemical decomposition), UPLC measurements were performed, as chromatographic analysis is a well-established and reliable means of checking whether any decomposition of chemical entities occur (see ref 67). In Figure 1, a comparison of chromatograms obtained for furosemide prepared in different ways as well as the crystalline substance (used herein as a reference) are presented. The chromatogram of crystalline furosemide revealed that the initial material has a very high purity, equal to 99.95%, owing to the formation of only one peak of impurity (0.05%) with a relative retention time of 0.26. Other chromatograms registered for furosemide cryomilled alone for 90 min. (blue), with inulin (pink), acylated maltose (navy blue), and acylated sucrose (green) are shown in Figure 1. In each case additional peaks indicating chemical decomposition of furosemide can be observed. In Table 3 we have listed the purity of furosemide cryomilled with acylated glucose, maltose, sucrose, and cyclodextrin (values equal to 99.38%, 99.63%, 99.48%, and 98.97%,

respectively). For comparison, impurity profiles of crystalline furosemide, cryomilled alone for 60 min and with PVP or inulin are also shown (see ref 58). It is clearly visible that in the case of furosemide cryomilled with PVP the amount of total impurities was the highest (6.08%). Slightly smaller, but comparable values were obtained for amorphous furosemide cryomilled for 90 min (3.48%) and cryomilled with inulin (4.31%). Thus, modified saccharides have inhibited chemical decomposition of furosemide to a very significant extent. This result confirms our supposition that hydrogen bonds can be indeed responsible for the chemical stability of furosemide upon mechanical treatment. Grzybowska et al.66 reported that the binary mixture of API with acetyl derivative might significantly enhance its solubility. As furosemide is poorly soluble in water (see Table 2), we have decided to perform solubility studies of our croyoground amorphous solid solutions. In Table 2 the solubility of furosemide cryoground with different ingredients measured in media of different pH (chosen from physiological pH range) has been depicted. As illustrated, the solubility of amorphous furosemide cryomilled with PVP is the highest in all considered media. These results were quite predictable since Doherty and York found out earlier that molecules of furosemide and PVP form hydrogen bonds which significantly improves solubility of this API.68,69 It is also worth to note that furosemide cryomilled with acylated sugars (cyclodextrin, maltose, sucrose) is 1827


0.10 ± 0.007 0.37 ± 0.004 0.62 ± 0.031 1.03 ± 0.037 0.20 ± 0.011 6.08 ± 0.085

Figure 2. Powder X-ray diffraction patterns (XRDP) for furosemide cryomilled with inulin, PVP, and acylated saccharides (sucrose, maltose, and glucose). In the inset X-ray diffraction patterns of crystalline furosemide and acylated maltose were presented.

patterns measured for these binary mixtures are shown. It can be seen that in each case (with only one exception that will be discussed later on) there is no Bragg peaks and broad amorphous halo pattern, characteristic feature of disordered materials, was obtained. Thus, we could be sure that applied cryomilling procedure yields completely amorphous materials. More evidence of the amorphous character of cryoground samples came from DSC measurements. In Figure 3 thermograms obtained for furosemide cryomilled with acylated maltose (panel a), acylated sucrose (panel b), and acylated glucose (panel c), are presented. A few thermal events have been recorded. Starting from lower temperatures, the glass transition which occurs at T = 308 K (furosemide−acylated glucose), T = 314 K (furosemide−acylated sucrose), and T = 321 K (furosemide− acylated maltose) can be detected. Above the glass transition temperature Tg we also observed cold crystallization. The highest onset of cold crystallization was determined for furosemide cryoground with acylated maltose indicating the highest physical stability of this system. Besides the above-mentioned thermal events, one can also observe two additional endothermic peaks in furosemide cryomilled with acylated glucose (T = 379 K) and maltose (T = 428 K). To explain these effects, DSC measurements on pure acylated saccharides were necessary. These thermograms are presented in Figure 4. Basing on calorimetric data, glass transition and melting temperatures of

0.09 ± 0.004 2.18 ± 0.015 0.17 ± 0.007 3.48 ± 0.086 0.05 ± 0.008

0.06 ± 0.003 0.23 ± 0.012 0.12 ± 0.005 0.11 ± 0.002 0.51 ± 0.012

0.15 ± 0.007 4.31 ± 0.102

0.08 ± 0.005

0.20 ± 0.009

99.38 ± 0.031 95.69 ± 0.102 0.12 ± 0.006 0.05 ± 0.005 0.05 ± 0.002 0.25 ± 0.010 97.82 ± 0.015 0.06 ± 0.002 99.95 ± 0.008

0.06 ± 0.005 96.59 ± 0.086

2.29 ± 0.053 0.15 ± 0.007

characterized by significantly improved solubility in comparison with the crystalline API. This confirms that modified saccharides increase not only chemical stability of furosemide, but also its solubility. To better understand the mechanism of chemical stabilization of furosemide by acylated saccharides as well as describe physicochemical properties of obtained binary systems we have performed additional measurements. First, we carried out X-ray diffraction measurements on furosemide cryoground with modified saccharides, PVP, and inulin. In Figure 2 diffraction

0.11 ± 0.005 0.52 ± 0.035

99.48 ± 0.035 99.63 ± 0.004

0.33 ± 0.024 0.08 ± 0.006 0.20 ± 0.012 0.07 ± 0.004 3.44 ± 0.090 0.19 ± 0.008 0.06 ± 0.004

Amount of Analyte ± SD [%] 5.17 ± 0.098 0.86 ± 0.033 0.26 ± 0.013 0.06 ± 0.004 0.16 ± 0.007 0.05 ± 0.005 93.92 ± 0.085 98.97 ± 0.037 0.07 ± 0.005 0.12 ± 0.008 0.08 ± 0.006

0.42 ± 0.021

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imp. 1 imp. 2 imp. 3 imp. 4 furosemide imp. 5 imp. 6 imp. 7 imp. 8 imp. 9 imp. 10 total impur.

0.05 ± 0.008

1.68 ± 0.019 0.06 ± 0.004

fur. (cryom. with PVP 1:1 ratio) fur. (cryom.with inulin 1:1 ratio) fur. cryom. for 60 min) fur. amorphous fur. crystall. analyte denotation

Table 3. Comparison of Impurity Profiles of Furosemide Prepared in Different Ways

fur. (cryom.with acyl. cyclodext. 1:1 ratio)

fur. (cryom.with acyl. glucose 1:1 ratio)

fur. (cryom. with acyl. maltose 1:1 ratio)

fur. (cryom.with acyl. sucrose 1:1 ratio)


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Figure 3. Thermograms measured for the furosemide cryomilled with acylated maltose 1:1 ratio (a), acylated sucrose 1:1 ratio (b), and acylated glucose 1:1 ratio (c).

acylated: glucose (Tg = 288 K, Tm = 386 K), sucrose (Tg = 299 K, Tm = 357 K), and maltose (Tg = 332, Tm = 434 K) have been evaluated (see Table 4). It can be seen that melting temperatures of acylated glucose and modified maltose are comparable to the temperatures at which additional endothermic events occurred in cryoground binary mixtures. The slight shift in the melting temperature can be explained in view of interaction between furosemide and modified saccharides. The DSC thermogram of pure furosemide milled for 3 h can be found in ref 58. The glass transition of furosemide as well as the temperature of cold crystallization of furosemide are Tg = 326 K and Tc = 347 K, respectively. However, one should note that furosemide used for DSC measurements was highly contaminated by decomposition products (≈7%). Hence, the evaluated Tg of this API should not be regarded as credible. On the other hand, DSC thermograms obtained for cryoground furosemide58 revealed that cold crystallization begins at 347 K. It is almost the same temperature at which cold crystallization starts for binary cryomilled systems. This is a clear sign that furosemide is the main agent recrystallizing from our mixtures. To check this premise additional X-ray measurements were carried out on crystallized binary cryomilled mixture, furosemide−acylated maltose (see Figure 2, first diffractogram on the top). Additionally, in the inset we have included diffractograms obtained for crystalline acylated maltose and crystalline furosemide. By comparing the X-ray diffraction pattern obtained for the crystalline API and recrystallized cryomilled furosemide− acylated maltose mixture one can conclude that furosemide it the dominant recrystallizing compound. We did not observe any additional Bragg peaks which should indicate recrystallization of modified saccharide. An analogical situation was observed for furosemide cryoground with acylated sucrose. On the other hand, a completely different scenario has been reported for furosemide cryoground with acylated glucose, where both systems recrystallized (data not shown). Finally, one should note that our calorimetric data presented in Figure 3 revealed very important feature of investigated cryomilled binary mixtures (furosemide−modified saccharide). In each thermograms there is only one glass transition event detected. We can interpret this finding as a direct prove that complete homogenization of

cryomilled systems occurred. One can mention that if upon cryogrinding heterogeneous systems were obtained two glass transition temperatures originating from furosemide and modified saccharide should be visible. In the next step dielectric measurements were carried out to describe molecular dynamics of such complex systems. In Figure 5 dielectric loss spectra measured for furosemide cryomilled with modified saccharides above respective glass transition temperatures are presented. In each case we can observe structural relaxation process shifting toward higher frequencies with increasing temperature. This mode is sensitive to viscosity changes and originates from cooperative motions of molecules. Thus, it is responsible for glass transition phenomenon. Further heating above the glass transition temperature effects in dramatic drop in amplitude of primary relaxation due to cold crystallization of furosemide from the mixtures. Our dielectric data revealed that again the least stable system is furosemide cryoground with acylated glucose. This corroborates the conclusion derived from calorimetric measurements. In Figure 6 dielectric loss spectra measured below the glass transition of the cryomilled mixtures are presented. A wellresolved secondary relaxation process (γ-relaxation) shifts to lower frequencies with decreasing temperature. The loss spectra of both structural (α) and γ-relaxations were analyzed using Havriliak−Negami function to obtain their relaxation times. The relaxation times plotted as a function of inverse temperature are shown in Figure 7. In this figure the structural relaxation times of pure modified saccharides have been also included. The temperature dependences of the αrelaxation times are well described by the VFT equation (the dotted lines)

⎛ D T ⎞ τ = τ0 exp⎜ T 0 ⎟ ⎝ T − T0 ⎠

(1)

where DT is a measure of the fragility of the analyzed relaxation process, T is a temperature, τ0 is a pre-exponential factor, and T0 is a Vogel−Fulcher−Tamman temperature. In the case of the γ-relaxation process, the Arrhenius equation was used (the solid lines) 1829



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Figure 4. Thermograms measured for crystalline and glassy acylated maltose (a), acylated glucose (b), and acylated sucrose (c). Thermograms for pure amorphous furosemide is not shown (because of chemical degradation upon melting). The samples have been heated at 10 K/min from room temperature (298 K) to above melting temperature and immediately cooled down to 273 K with steps of 10 K/min.

⎛ E ⎞ τ = τ0 exp⎜ a ⎟ ⎝ kBT ⎠

ments coincide (within experimental accuracy) with the Tg’s evaluated from the calorimetric data. From the Arrhenius fits to the temperature dependences of γrelaxation times activation barriers were evaluated. It is interesting that for each cryoground mixture (furosemidemodified saccharide), the activation energy of γ-process was found to be Ea = 47 kJ/mol. Moreover, we found that relaxation times of this mode are the same independently on the sample. For comparison, in Figure 7 we also included relaxation times obtained for γ-relaxation process in the pure acylated saccharides.

(2)

where Ea is an activation energy barrier and kB is a Boltzmann constant. From the VFT fits, the glass transition temperatures for the pure modified saccharides as well as cryoground mixtures have been evaluated (see Table 4). Here Tg was defined as temperature at which τα = 100 s. We can see that the glass transition temperatures determined from dielectric measure1830



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HB molecules, the acylated compound may create one-way very strong hydrogen bonds. To study these problems more carefully, theoretical computations with the use of DFT method have been carried out. In Figure 8 two studied systems, that is, furosemide connected with acylated glucose and furosemide connected with the small fragment of inulin (five rings) are presented. Geometry optimizations of two models have been carried out on the X3LYP/6-31G(d,p) level of theory and thereafter, hydrogen bond analysis have been performed. The hydrogen bond energy was calculated as EHB = Ec − (Ef + Em), where EHB is the binding energy between two molecules which is in good approximation equaled to the total energy of intermolecular hydrogen bonds, Ec is the total energy of system, Ef is the energy of single furosemide molecule, and Em is the energy of the single second molecule (inulin or acylated glucose). Both systems have a very high energy of hydrogen bonds. In case of acylated glucose complex, the energy is equaled to 122 kJ/mol, while in case of inulin with furosemide, the energy is equaled to 131 kJ/mol. In both molecules, typical hydrogen bonds N−H−O and O−H−O can be found, in which oxygen from supporting molecule, that is, acylated glucose or inulin acts as a Π acceptor. Energy of such bonds is usually about 10 kJ/mol in case of N−H−O and about 20 kJ/mol in case of O−H−O. The parameters (bond angles and distances) of hydrogen bonds have been placed in Figure 8. Despite the fact that on the first sight both systems are very similar (similar binding energy and hydrogen bonds), in the system with acylated glucose, a very subtle and strange interaction occurs. The furan part of furosemide molecule (aromatic ring) acts as a proton donor and forms a hydrogen bond. Normally, furan molecules can form hydrogen bonds; however such bonds are created via the oxygen from the aromatic ring, which acts as Π acceptor. To study this extraordinary interaction, the bimolecular system furan−methyl acetate has been modeled. The hydrogen bond in this system is clearly visible in the inset of Figure 8. The bond has an energy equal to 9.3 kJ/mol, bond distance equal to 2.4 Å, and angle C−H−O equal to 175°. Molecules in the inset have been colored adequately to atomic charges of atoms. Mulliken gross atomic charges on the atoms involved in the formation of hydrogen

Table 4. Glass Temperatures (Tg) and Activation Energies (Eγ) of Secondary Relaxation Processes for Acylated Sugars and Their Binary Mixtures with Furosemide binary mixtures acylated glucose acylated maltose acylated sucrose furosemide− acylated glucose furosemide− acylated maltose furosemide− acylated sucrose

Tg (K) (from DSC measurements)

Tg ± SD (K) (from dielectric spectroscopy)

Eγ ± SD (kJ/mol)

288 332 299 308

289 ± 2 325 ± 2 296 ± 2 309 ± 2

41 ± 1 41 ± 1 51 ± 1 47 ± 1

322

325 ± 2

47 ± 1

314

319 ± 2

47 ± 1

It is well seen that relaxation times as well as activation barrier of this mode are slightly different from the same parameters derived for the γ-relaxation in cryoground mixtures. Thus, we can suppose that the presence of furosemide affects dynamics of γrelaxation process in acylated maltose and other modified saccharides. After physical properties of cryoground samples have been described in detail, we decided to explain the role of acylated saccharides in chemical stabilization of furosemide upon milling. Our experimental studies indicate that the tendency of furosemide to degrade into simpler molecules might be connected to the hydrogen bond pattern in the sample. In the system consisting of furosemide and the polysaccharide (inulin) or PVP, the furosemide molecule has a higher tendency to degradation. Contrary to this situation, mixing furosemide with acylated glucose stabilizes the API. There is a significant difference between acylated compounds like acylated glucose and other hydrogen-bonding (HB) agents. Acylated compounds are rich in the oxygens from the carboxyl group, which are good acceptors for hydrogen bonds. However they do not have any proton donors. In consequence, pure acylated system is a van der Waals liquid (this nomenclature was used for the systems having no ability to form hydrogen bonds), while in a mixture with other

Figure 5. Dielectric loss spectra of binary mixtures of furosemide−acylated sucrose 1:1 (a), furosemide−acylated maltose 1:1 (b), and furosemide− acylated glucose 1:1 (c), measured at ambient pressure (P = 0.1 MPa) and different temperatures above Tg in steps of 2 or 3 K. 1831



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Figure 6. Dielectric loss spectra for binary mixtures of furosemide−acylated glucose 1:1 (left panel) and furosemide−acylated maltose 1:1 (right panel) measured at ambient pressure (P = 0.1 MPa) and temperatures below Tg in steps of 20 K.

substituent is linked via three very strong hydrogen bonds, while the part with furan is being repulsed from the inulin due to the positive charge of hydroxyl groups. In the acylated glucose complex the situation is different. The first part of furosemide is connected by slightly weaker hydrogen bonds, while the second part with furan is attracted by the negatively charged oxygens from acetyl groups. Therefore, the furan part in furosemide connected with inulin may be exposed to the reactants inducing dissociation of furosemide. It should be stressed that in carbohydrates (such as inulin) or PVP the strong so-called proton hopping phenomenon occurs through the hydrogen bond patterns. As the decay of furosemide may be connected with the proton migrations in the system, pure sugars should increase the rate of decomposition of furosemide during the cryomilling.

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CONCLUSIONS In this paper, cryomilling was applied to obtain amorphous binary mixtures of furosemide with acylated sugars. Complete amorphization and homogenization of studied samples was confirmed by X-ray diffraction and DSC measurements. However, upon heating of investigated systems, furosemide is the main recrystallizing compound. We have also shown that it is possible to inhibit chemical decomposition of furosemide, after cogrinding with acylated saccharides such as acylated glucose, acylated sucrose, or acylated maltose. Unlike standard pharmaceutical excipients such as inulin or PVP which increase the rate of chemical decomposition of furosemide during mechanical treatment, acetyl derivatives stabilize investigated API. Our theoretical computations have indicated that hydrogen bonds play a key role in destabilization mechanism of furosemide upon milling. We suppose that ingredients with hydrogen bonding abilities, like inulin or PVP, catalyze decomposition of the examined drug as one part of furosemide molecules is strongly connected to the matrix molecule, while the second one is repulsed. In the case of binary mixture containing acylated glucose, both parts of furosemide are strongly attracted due to the creation of unusual hydrogen bond C−H−O by the furan

Figure 7. Relaxation map for mixtures of furosemide with acylated sugars (glucose, maltose, and sucrose). The relaxation times obtained for pure acylated sucrose and maltose are also included. The solid lines are fits to the secondary relaxations using the Arrhenius law (for τγ). The dotted lines are fits to α-relaxation using the VFT equation.

bond are equal to: QC = −0.41 on the carbon in the furan ring, QH = 0.25 on the hydrogen, and QO = −0.34 on the oxygen in methyl acetate. These values along with the bond parameters indicate that the described interaction can be treated as a hydrogen bond of the medium strength. In both models furosemide is strongly attracted by the matrix molecule (inulin or acylated glucose); thus it is hard to explain why inulin catalyzes dissociation of furosemide, while acylated sugar stabilizes the system. The key to answer this question might be interaction of the furan part of furosemide molecule. From the NMR studies we have some evidence that the decay is initialized in the −N(H)− site of furosemide,58,70 and it probably decays into two simpler molecules presented in Scheme 1; therefore a good stabilizer should be strongly connected with both parts of furosemide molecule. In the model with inulin, the first part with the sulfonyl 1832



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Figure 8. Complexes formed between furosemide−inulin and furosemide−acylated glucose as obtained from DFT calculations on the X3LYP/631G(d,p) level of theory. In the complex with acylated glucose, whole furosemide molecule is connected to the acylated glucose by strong hydrogen bonds. In the complex with inulin part (five rings), part of furosemide with the furan ring is being repulsed away from the inulin due to the positive charge of hydrogens from hydroxyl groups. In the inset, an unusual hydrogen bond between furan and methyl acetate is presented. Molecules are colored adequately to Mulliken gross atomic charges. This furan−methyl acetate model has been calculated on the X3LYP/6-311+G(d,p) level of theory, and it is an analogue of similar interaction in the furosemide−acylated glucose complex. the Interaction in Solution and in Solid State. J. Pharm. Sci. 2005, 94, 676. (7) Shin, S. C. Dissolution characteristics of furosemide− polymer coprecipitates. Arch. Pharm. Res. 1979, 2, 35−48; Physicochemical characteristics of furosemide−PVP coprecipitates. Arch. Pharm. Res. 1979, 2, 49−64. (8) Iwata, M.; Ueda, H. Dissolution properties of glibenclamide in combinations with polyvinylpyrrolidone. Drug Dev. Ind. Pharm. 1996, 22, 1161−1165. (9) Okimoto, K.; Miyake, M.; Ibiki, R.; Yasumura, M.; Ohnishi, N.; Nakai, T. Dissolution mechanism and rate of solid dispersion particles of nilvadipine with hydroxypropylmethylcellulose. Int. J. Pharm. 1997, 159, 85−93. (10) Saito, M.; Ugajin, T.; Nozawa, Y.; Sadzuka, Y.; Miyagishima, A.; Sonobe, T. Preparation and dissolution characteristics of griseofulvin solid dispersions with saccharides. Int. J. Pharmaceutics 2002, 249, 71− 79. (11) Vervaet, C.; Remon, J. P. Bioavailability of hydrochlorothiazide from pellets, made by extrusion spheronisation, containing polyethylene glycol 400 as a dissolution enhancer. Pharm. Res. 1997, 14, 1644−1646. (12) Pinnamaneni, S.; Das, N. G.; Das, S. K. Formulation approaches for orally administered poorly soluble drugs. Pharmazie 2002, 57, 291− 300. (13) Kaminski, K.; Kaminska, E.; Adrjanowicz, K.; Grzybowska, K.; Wlodarczyk, P.; Paluch, M.; Burian, A.; Ziolo, J.; Lepek, P.; Mazgalski, J.; Sawick,i, W. Dielectric relaxation studies on Tramadol monohydrate and its hydrochloride salt. J. Pharm. Sci. 2010, 99, 94−106. (14) Hancock, B. C.; Carlson, G. T.; Ladipo, D. D.; Langdon, B. A.; Mullarney, M. P. Comparison of the mechanical properties of the crystalline and amorphous forms of a drug substance. Int. J. Pharmaceutics 2002, 241, 73−85. (15) Kaminski, K.; Adrjanowicz, K.; Wojnarowska, Z.; Grzybowska, K.; Hawelek, L.; Paluch, M.; Zakowiecki, D.; Mazgalski, J. Molecular Dynamics of the Cryomilled Base and Hydrochloride Ziprasidones by Means of Dielectric Spectroscopy. J. Pharm. Sci. 2010, 7, 2642. (16) Sato, T.; Okada, A.; Sdekiguchi, K.; Tsuda, Y. Differences in physicopharmaceutical properties between crystalline and noncrystalline 9,3′-diacetylmidecamycin. Chem. Pharm. Bull. 1981, 29, 2675− 2682.

group in furosemide and one of numerous acetyl substituents in acylated glucose. From the results given in this paper one can conclude that pure carbohydrates used as a matrix for amorphous furosemide may have a significant impact on the degradation mechanism. Therefore acylated sugars seem to be appropriate stabilizers for chemically unstable drugs like furosemide.

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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 M. Paluch and K. Adrjanowicz are deeply grateful for the financial support by the National Science Centre within the framework of the Opus3 project (Grant No. DEC-2012/05/B/NZ3/03233).

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A New Way of Stabilization of Furosemide upon Cryogenic Grinding

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