Application of Thermal Analysis to Study the Compatibility of Sodium Diclofenac with Different Pharmaceutical Excipients

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1 Application of Thermal Analysis to Study the Compatibility of Sodium Diclofenac with Different Pharmaceutical Excipients BOGDAN TITA, 1* ADRIANA FULIAS, 1 GEZA BANDUR, 2 IONUT LEDETI, 1 DUMITRU TITA 1 1 University of Medicine and Pharmacy Victor Babeº, Faculty of Pharmacy, Eftimie Murgu Square 2, Timiºoara, , Timisoara, Romania 2 Politehnica University of Timiºoara, Industrial Chemistry and Environmental Engineering Faculty, 2 Victoriei Square, , Timiºoara, Romania Thermal analysis is a routine method for analysis of drugs and substances of pharmaceutical interest. Thermogravimetry / derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC) are thermoanalytical methods which offer important information about the physical properties of drugs (stability, compatibility, phase transitions, polymorphism, kinetic analysis etc). In the present work, TG/DTG and DSC were used as screening techniques for assessing the compatibility between sodium diclofenac (DC) and its physical association as binary mixtures with some common excipients. Based on their frequent use in pharmacy, several different excipients as: starch, microcrystalline cellulose (PH101 and PH102), colloidal silicon dioxide, lactose (monohydrate and anhydre), polyvinylpyrrolidone (povidone K30 or PVP), magnesium stearate and talc were blended with DC. Samples were prepared by mixing the analyte and excipients in a proportion of 1:1 (w:w). In order to investigate the possible interactions between the components, the TG/ DTG and DSC curves of DC and each selected excipient were compared with those of binary mixtures, in order to evaluate any possible solid state modification. The Fourier transformed infrared spectroscopy (FT- IR) and X-ray powder diffractometry (XRPD) were used as complementary techniques to adequately implement and assist in interpretation of the thermal results. On the basis of DSC results, confirmed by FT IR and X-ray analyses, sodium diclofenac was found to be incompatible with lactose monohydrate, respectively anhydre, povidone K30 and magnesium stearate. Keywords: sodium diclofenac, thermal analysis, compatibility, excipient-drug interaction Diclofenac sodium {2-[(2,6-dichlorophenyl)aminophenyl]acetate} is a potent non-steroidal antiinflammatory drug (NSAID), therapeutically used in inflammatory and painful diseases of rheumatic and nonrheumatic origin. The anti-inflammatory activity of diclofenac and most of its other pharmacological effects are related to the inhibition of the conversion of arachidonic acid to prostaglandins, which are mediators of the inflammatory process. Diclofenac is a potent inhibitor of cyclo-oxygenase in vitro and in vivo, thereby decreasing the synthesis of prostaglandins, prostacyclin, and thromboxane products [1,2]. The structural formula for sodium diclofenac is shown in figure 1. Fig.1. The chemical structure of the sodium diclofenac The structure of diclofenac consists of a phenylacetic acid group, a secondary amino group, and a phenyl ring, both ortho positions of which are occupied by chlorine atoms. Moser et al. [3] studied 36 congeners of diclofenac as inhibitors of cyclooxygenase and the in vivo inhibition of rat adjuvant arthritis and found that both activities can be explained by lipophilicity and twisting of the two aromatic rings. These findings allowed the rationalization of the high activity of diclofenac [4 6]. Incompatibility between drugs and excipients can alter stability of drugs, thereby, affecting its safety and/or efficacy. Drug-excipient compatibility testing at an early stage helps in the selection of excipients that increase the probability of developing a stable dosage-form. In particular, the low availability of drug and the time constraints associated with the early stages of formulation development have made such predictability particularly desirable [7 11]. Despite the importance of drug-excipient compatibility testing, there is no universally accepted protocol for this purpose. The term thermal analysis refers to a group of techniques in which a physical property of a substance and/or a reaction product is measured as a function of temperature whilst the substance is subjected to a controlled temperature program [12 15]. In our previous papers we provided the importance of the thermal analysis in estimation on the thermal behaviour of different pharmaceuticals, respectively their possible interaction with excipients [16 24]. Differential scanning calorimeter (DSC) technique involves the application of a heating or a cooling signal to a sample and a reference, can evaluate the energy associated with various thermal events (e.g., melting, glass transition temperature, crystallization, etc). This method has been extensively reported in the literature for testing compatibility of excipients with number of drugs [13 15,25]. The use of DSC has been proposed as a rapid method for evaluating the physico-chemical interaction between two components. However, the caution needs to be exercised in the interpretation of DSC results. This is * bogdantita@yahoo.com REV. CHIM. (Bucharest) 62 No

2 because of temperature conditions required, superior to ambient temperature, respectively the lack of moisture. Therefore, the use of other analytical techniques, such as FT-IR spectroscopy, X-ray powder difractometry and scanning electron microscopy (SEM) as complementary tools to assist in the interpretation of DSC findings is necessary [26 28]. Though DSC cannot replace chemical methods for quantitative determination of drug concentration in longterm stability test, it gives fast and adequate data to classify acceptable and unacceptable excipients through the appearance, shift, or disappearance of endothermic or exothermic peaks, as well as variations in the relevant enthalpy values, in DSC profiles of drug-excipient combinations. In two previous works, it was studied the thermal stability and kinetic analysis of sodium diclofenac under non-isothermal [17], respectively isothermal conditions [24]. In this work, the sodium diclofenac characterization and compatibility studies have been investigated using a variety of techniques including thermal analysis (TG/DTG and DSC), Fourier transform infrared spectroscopy (FT IR) and X-ray powder diffraction (XRPD). Experimental part Materials and samples The sodium diclofenac (DC) and the excipients: starch; microcrystalline cellulose PH 101 (MC 101) and PH 102 (MC 102); colloidal silicon dioxide (CSD); lactose monohydrate (α lactose); lactose anhydre (β lactose); polyvinylpyrrolidone K30 (PVP K30 or PVP); magnesium stearate (MS) and talc were obtained from Terapia S.A./ Ranbaxy, Cluj-Napoca, Romania as pure compounds, able to be used for medical purpose. Physical mixtures of diclofenac with each selected excipient were prepared in the 1:1 (w:w) ratio by simple mixture of the components in an agate mortar with pestle for approximately 5 min. Methods Thermal analysis The TG/DTG/DTA curves were recorded using a Netzsch-STA 449 TG/DTA instrument in the temperature range of C, under a dynamic atmosphere of nitrogen (20 ml min 1 ) and at a heating rate (β) of 10 C. min 1, using platinum crucibles and weighed 20 mg of samples. DSC experiments were carried out with a Netzsch differential scanning calorimeter, model DSC 204, using aluminium crucibles with approximately 3 mg of samples, under dynamic nitrogen atmosphere (50 ml min 1 ) and a heating rate of 10 C min 1, up to a temperature of 500 C. Fourier transformed infrared spectroscopy (FT IR) and X- ray diffraction FT IR spectra of drug, excipients and drug-excipients blends were recorded on a Perkin Elmer Model 1600 apparatus using KBr discs in the range of cm 1. X ray diffraction patterns (XRPD), for the same category of substances, were obtained with a Bruker D8 Advance X-ray diffractometer using MoKα radiation (Zr filter on the diffracted beam, 50 kv and 40 ma) in a Bragg Brentano θ:2θ configuration, with Soller and fixed slits and a NaI (Tl) scintillation detector. The measurements of 2θ ranged between 0 and 30. Data analysis and acquisition were performed using DIFFRACT plus software from Bruker AXS. Results and discussions The TG/DTG and DTA curves obtained for sodium diclofenac are presented in figure 2. The first process corresponds to the dehydration and take place between 42.2 and 87.5 C with T peak DTG =78.5 C and a mass loss of 8%. The decomposition of sodium diclofenac occurs in C range with T peak DTG =300 C and this process has an exothermal nature. Over 400 C, the TG/DTG curves indicate a slow and continuous mass loss caused by elementary carbon formation from decomposition step, as consequence of the rupture of the aromatic ring. Fig.2. TG/DTG/DTA curves of pure sodium diclofenac REV. CHIM. (Bucharest) 62 No

3 Fig.3. TG curves of all substances used in compatibility study The DTA curve of diclofenac (for β=10 C min 1 ) presents a sharp endothermic event at 84.4 C which corresponds to the dehydration (ΔH fus =491.1 J. g -1 ). Further, it occurs the melting process (T peak DTA =285.9 C), which is an endothermic process and this process is followed immediately by an exothermic process corresponding to the decomposition process. Compatibility study with excipients Thermal behaviour of the mentioned excipients is more or less known that in this paper it was studied the thermal behaviour of the correspondent mixtures. For this purpose, the thermal curves of DC and excipients were compared with the curves obtained for 1:1 (w:w) physical mixtures. Figures 3 5 show the TG, DTG and DSC curves of the substances used in the compatibility study. Each curve shows a specific behaviour depending on the characteristics of each excipient. The TG/DTG curves of starch show a dehydration between C (Δm=7.2%; DTG peak =65 C), followed by the process of decomposition between C (DTG peak =325 C; Δm=79.7%). Initially the DSC curve exhibits a wide endothermic peak representing dehydration (T peak =94 C) [9,12,29]. The thermal behaviour of microcrystalline cellulose PH- 101 and respectively PH-102 is the same. Absorbed water (about 5%) is lost below 110 C, between 35 and 110 C, apparently in a single, endothermic and spread-out process Fig.4. DTG curves of all substances used in compatibility study Fig.5. DSC curves of all substances used in compatibility study REV. CHIM. (Bucharest) 62 No

4 (DSC peak =72 C). No other thermal phenomena are observed before the beginning of decomposition, between 307 and 385 C (DTG peak =355 C and Δm=88%), respectively DSC peak =320 C [9,11,30]. In the case of the colloidal silicon dioxide, on the thermoanalytical curves, no peak was observed in the range of C [9,11,31]. The amorphous form of lactose was identified by the presence of an exothermic peak at 167 C, which represented the transformation of amorphous to crystalline form. It is followed by two endothermic peaks, one at 210 and the other at 216 C. These melting peaks belong to alpha and beta-lactose respectively. It confirmed the transformation of the amorphous form of lactose to the two types of crystalline form by heating [31 33]. The 100% crystalline lactose, according to XRPD, contains α and β forms. According to the thermogram, the water-content (Δm=4.5%) of α-lactose monohydrate is evolved between 100 and 170 C (DTG peak =161 C). The water-free compound is stable up to about 265 C, then it decomposes up to 365 C and DTG peak =315 C. The DSC curve shows a first sharp endothermic peak (T peak =145 C) corresponding to the dehydration reaction, followed by two endothermic peaks, from the first sharp endothermic peak (DSC peak =215 C), which corresponds to the melting of α- lactose, the second weak peak (DSC peak =224 C) represents the melting of β-lactose [9, 11,32,33]. On the DSC curve, the β-lactose presents a small endothermic peak (T peak =145 C) with an insignificant mass loss on the TG curve, followed by two peaks, the first light corresponds to the melting of α-lactose (T peak =215 C), respectively the second represent the melting of the β- lactose (T peak =224 C). The decomposition process takes place in the temperature range of 275 and 365 C (DTG peak =312 C), accompanied by an endothermic event on the DSC curve (T peak =318 C) [9,11,33,34]. The TG/DSC curves of PVP, below 150 C display on initial mass loss of 9%. This mass loss is accompanied by a broad endothermic phenomena (DSC peak =82 C) over an ill-defined baseline which makes evaluation of the dehydration enthalpy quite uncertain. The sample readily dehydrates and its initial mass depends upon the moisture content of the atmosphere. Apparently, dehydration is completed at 110 C (DTG peak =164 C) in N 2. However, a second loss stage ( 2%) begins past 150 C and completes around 250 C. Thermal analysis, SEM and XRPD all show that the compound is in a vitreous phase with glass transition near 200 C. Decomposition begins around 384 C (DTG peak =442 C, Δm=86%) up to 485 C [30,35 37]. Simultaneous TG/DSC curves of magnesium stearate show several dehydration stages below 110 C. The first endothermic effect is due to the release of a small amount of surface water. Around 50 C begins the first dehydration stage of structural water, which partially overlaps with a second stage at higher temperature. The overall mass loss due to surface water and to the first stage is 3%, while the amplitude of the second stage is 1.5% of the initial mass. DSC curve of magnesium stearate initially show wide endothermic effect (T peak =75 C), representing dehydration. Melting begin at 110 C and produce an endothermic peak with a shoulder in the high temperature side which is caused by melting of magnesium palmitate or high-melting polymorphs. The decomposition of the sample begin around 311 C (DTG peak =362 C) and to 480 C, 92.5% of sample mass is lost. Corresponding to the decomposition process, the DSC curve presents a sharp endothermic with T max =372 C [9,30,33,34,37]. The TG/DTG and DSC curves of talc present any significant events under the conditions in the present work [9,11,33,34,37]. The experimental data obtained for each excipient correspond to those from the speciality literature [9,11,12,29 37], which confirms the purity of substances and the correctness of the used methods. TG, DTG and DSC curves of the pure diclofenac and the 1:1 drug:excipient physical mixture are shown in figures 6 8. In the 1:1 physical mixtures when there is no any interaction between drug and excipient the T peak value of melting event (DSC curve) and the first stage of the decomposition (T onset and T peak of TG/DTG curves) should remain practically unchanged, similarly when the drug is alone. In this case the thermal profiles of the mixture can be considered as a superposition of the curves of the diclofenac and excipients. Thus, in the DSC curve of DC and mixtures, the T peak value of melting, a reference constant, is the same. According to the thermal curves (fig.6 8), especially DSC curves that provide the most complete information, it is found some smaller or larger differences (the case of the mixtures with α-lactose, β-lactose, PVP and MS) regards to the melting temperature values and those of the dehydration, respectively of the thermal decomposition ranges. Basically, all the other excipients present some differences, however small, on the melting temperature, dehydration temperature, respectively the value of the dehydration enthalpies (table 1). These differences may be due to the small interactions that have not been confirmed by FTIR spectroscopy and X-ray diffraction patterns. Fig.6. TG curves of diclofenac and its 1:1 physical mixtures REV. CHIM. (Bucharest) 62 No

5 Fig.7. DTG curves of diclofenac and its 1:1 physical mixtures Fig.8. DSC curves of diclofenac and its 1:1 physical mixtures In the case of mixtures with lactose monohydrate (αlactose), respectively anhydre (β-lactose), povidone (PVP) and magnesium stearate (MS), the DSC curves demonstrated differences in the thermal profile of the DC, such as absence of drug s melting event. The TG curves demonstrated that excipients influence the decomposition process of the DC by displacing the T onset, respectively DTG peak of the first mass loss event at a lower temperature than the isolated drug. Frequently, this displacing is due to structural change and indicates interaction, incompatibilities between the compounds [31 33,36]. The DSC curve of the physical mixture of DC with α- lactose and β-lactose demonstrated the disappearance of the characteristic DC fusion peak. Initially, the curve presents a broad and strong peak which corresponds to the elimination of the adsorbed water, between C with DSC peak =76.5 C, respectively 84.5 C. This event is followed by a broad and strong peak for the α-lactose which corresponds to the elimination of the crystallisation water between C (DSC peak =150 C), respectively a broad and weak peak for the β-lactose which corresponds to the elimination of the crystallinity water (from α-lactose) between C (DSC peak =137.5 C) (fig.8). For the DC mixtures with PVP and MS, the DSC curves show the disappearance of the melting peak of DC (285.9 C). Also, the peaks which correspond to the dehydration are shifted to higher temperatures (97 C, respectively 89.4 C) and the decomposition intervals are wider. The differences are attributed to the interaction between the components as happens in the case of PVP and MS interaction with other drugs [9,11,12,29,30,37 39]. The results taken from the TG/DTG and DSC curves for the binary mixtures are collected in table 1. Increasing values of ΔH dehydration is due to the addition of the dehydration effect (in most of the cases), as well as to of the phenomena of co-crystallization of DC, which is confirmed by the IR and RX spectra. The FT IR spectroscopy was used as a supplementary technique in order to investigate the possible chemical interaction between drug-excipient and to confirm the results obtained by the thermal analysis. It is the most suitable technique of the non-destructive spectroscopic methods and has become an attractive method in the analysis of pharmaceutical solids, since the materials are not subject to thermal or mechanical energy during sample preparation, therefore preventing solid-state transformations. The appearance of new absorption band(s), broadening of band(s), and alteration in intensity are the main characteristics to evidence interactions between drug and excipients [7,9,11,33,40,41]. FT-IR spectra were drawn for diclofenac, excipients, respectively for the corresponding mixtures. Further, it will be presented only the spectra for the cases where the thermal analysis indicates a possible interaction, namely: sodium diclofenac, lactose monohydrate and anhydre, povidone, magnesium stearate and the corresponding mixtures (Fig.9 12). The DC spectrum was in accordance with the literature, which in the region of 3500 cm -1 describes a large band attributed to OH group from the absorbed water as well as to the N H stretching vibration. In the region of cm -1, there are four bands which correspond to: - a strong asymmetrical stretching band of carboxylate anion (COO ); - N H bending (scissoring) vibration; REV. CHIM. (Bucharest) 62 No

6 Table 1 THERMOANALYTICAL DATA OF SODIUM DICLOFENAC AND DRUG:EXCIPIENT PHYSICAL MIXTURES Fig.9. IR spectra of lactose monohydrate, DC and 1:1 blend as simple mixture of DC and lactose monohydrate Fig.10. IR spectra of lactose anhydre, DC and 1:1 blend as simple mixture of DC and lactose anhydre - a strong C=O stretching vibrations. The bands from 1453 and 1393 cm 1 correspond to the scissoring vibration of the CH 2 group adjacent to the carbonyl. The doublet from 1305 and 1284 cm -1 corresponds to C O stretching band, as well as to C N stretching absorption, together with C H bend (in plane) from aromatic ring. The strong bands from 769, respectively 747 cm -1 correspond to the out-of-plane C H bend. The spectra of lactose monohydrate, respectively lactose anhydre, are virtually identical with the observation that the lactose monohydrate shows a sharp medium band at 3528 cm -1 due to the vibration of O H bond of crystallization water. The main bands appear at: and 3343 cm -1, as strong and large band ( cm -1 ) attributed to O H stretch: intermolecular hydrogen bonded; - a triplet at 2977, 2933 and 2900 cm -1 that corresponds to the C H stretch: methylene; - the range of cm -1 corresponding to the O H bending vibrations (in plane) REV. CHIM. (Bucharest) 62 No

7 Fig.11. IR spectra of PVP, DC and 1:1 blend as simple mixture of DC and PVP Fig.12. IR spectra of MS, DC and 1:1 blend as simple mixture of DC and MS - the range of cm -1 which characterises the stretching vibrations C O (in fact C O C) and 876 cm -1 that corresponds to out-of-plane C H bend. In respect of the povidone, it presents the following bands, at: cm 1 a large band attributed to the OH group from the crystallization water; cm 1 that corresponds to the C=O bending; cm 1 that corresponds to the carbonyl amidic group; ; 1465; 1422 cm 1 these correspond to asymmetrical vibration (δ as CH 3 ); cm 1 that corresponds to the in-plane C H bending. Magnesium stearate presents a weak and large band in the region cm -1 (the maximum at 3421 cm -1 ). At 2918 and 2850 cm -1, there were observed two sharp bands with maximum absorption due to the CH 2 CH 3 vibrations. In the cm -1 region, it showed an asymmetric stretch corresponding to the carboxyl anion. Other bands that must be maintained have their peaks at 2956 cm -1 corresponding to the asymmetrical vibration of C H bond in methyl group, respectively those at 721 cm -1 which correspond to rocking deformation (H C H) n ; n>3. For the binary mixture with α-lactose, there were showed the following differences: - the disappearance of the bands from 3528, 2978, 2933 and 2900 cm -1, for the α-lactose spectrum. - the bands at 3464 cm -1 (DC), respectively cm -1 (α-lactose) are greatly enlarged, corresponding to the cm -1 range. - the bands from cm -1 corresponding to DC, respectively those from cm -1 corresponding to α-lactose, are grouped into three areas: cm -1 ; cm -1 and cm -1, from which the last two in particular are in the form of two wide bands with a low number for so-called maximum and a lot of shoulders. For most of the maximums, the intensity is not significantly reduced. In the case of the mixture with β-lactose, were found similar differences as for α-lactose s mixture. Thus: - the broad bands for DC (3464 cm -1 ) and for β-lactose ( cm -1 ) are greatly enlarged, corresponding to the range of cm the triplet bands at 2977; 2901 and 2878 cm -1 from the spectrum of β-lactose disappears. - the bands from the range: cm -1 (DC) and cm -1 (β-lactose) are grouped into three areas: cm -1 ; cm -1 and cm -1. In this case, the first area is in the form of broad bands too, with less of so-called maximum than the summation of the two spectra (DC and β-lactose). For the mixture of DC with PVP, it is found that: - the broad bands at 3464 cm -1 (DC) and 3447 cm -1 (PVP) are more wider than those corresponding to the range of cm the relatively large band corresponding to the maximum cm -1 from the spectrum of PVP disappears. - the intense band at 1662 cm -1 from the PVP s spectrum disappears. - the bands from the range: cm -1 (DC) and cm -1 (PVP) are reduced in number and they are in the form of a wide band with multiple maximums. - also the bands from cm -1 range (DC) and cm -1 (PVP) do not return to baseline in the case of the mixture, forming a band almost as wide at the top as the base. REV. CHIM. (Bucharest) 62 No

8 Fig.13. X-ray diffractogram of lactose monohydrate, DC and 1:1 blend as simple mixture of DC and lactose monohydrate. Fig.15. X-ray diffractogram of PVP, DC and 1:1 blend as simple mixture of DC and PVP Fig.14. X-ray diffractogram of lactose anhydre, DC and 1:1 blend as simple mixture of DC and lactose anhydre. In the case of DC-MS mixture, the main change is the fact that the doublet at 2918 and 2850 cm -1 of MS spectra with maximum absorption disappears. At the same time, the two broad bands of 3464 cm -1 (DC), respectively 3421 cm -1 (MS) are greatly enlarged ( cm -1 ) and they include the doublet which was mentioned above, but their intensity is reduced only with 10-15%. Also, the absorption bands at 1571 and 1468 cm -1 in the MS spectrum (absorption significantly as approx. 75%) together with the cm -1 (MS) are found as a broad band with a small number of maximums. In the same way, the bands at cm -1 are of the form of a band with the base wide as the top. The FT IR spectra from the figures 9 12 indicate some chemical interactions between DC and mentioned excipients. To investigate the possible interaction of diclofenac with α-lactose, β-lactose, povidone and magnesium stearate, besides the FT-IR spectroscopy which is a qualitative analysis technique, the X-ray powder diffraction has been Fig.16. X-ray diffractogram of MS, DC and 1:1 blend as simple mixture of DC and MS used for qualitative and quantitative identification of crystallinity [31,32,35,36,39,41]. The X-ray diffraction patterns of sodium diclofenac, α-lactose, β lactose, povidone, magnesium stearate and of the binary mixtures are shown in figures The additional prominent DSC peaks in the mixtures of the drugs and excipients are a positive indication of chemical interaction of the drugs with excipients. Such interaction should result in the partial or complete disappearance of the reactant phases and appearance of new phases, which can be inferred from X-ray diffraction patterns. X-ray diffraction patterns of the mixture, prepared at room temperature, when compared with those of its individual components showed appearance of new lines and disappearance of some of the lines present in the individual components. The X-ray patterns of diclofenac α-lactose mixture prepared at room temperature shows the lines in addition to those present in patterns of the individual components REV. CHIM. (Bucharest) 62 No

9 Table 2 X-RAY DIFFRACTION DATA FOR DICLOFENAC, LACTOSE MONOHYDRATE AND DICLOFENAC LACTOSE MONOHYDRATE (1:1) MIXTURE Table 3 X-RAY DIFFRACTION DATA FOR DICLOFENAC, LACTOSE ANHYDRE AND DICLOFENAC LACTOSE ANHYDRE (1:1) MIXTURE REV. CHIM. (Bucharest) 62 No

10 Table 4 X-RAY DIFFRACTION DATA FOR DICLOFENAC, MAGNESIUM STEARATE AND DICLOFENAC MS (1:1) MIXTURE (table 2). However, the number of lines present in the XRD patterns of the individual components was found missing in the similar pattern recorded for the mixture. The significant difference in the X-ray patterns of the drugexcipient mixtures compared to those of individual drugs and excipient indicates possible incompatibility of the drugs with the excipient, even at room temperature. The presence of majority of the lines of the parent substances in the thoroughly ground mixture prepared at room temperature, however, suggests the interaction of the drug with the excipient at room temperature, which could increase with the increased temperature. Also, for the binary mixture: DC β-lactose, the diffractogram (fig.14) and the X-ray diffraction data (table 3) show the interaction of these two substances. The number of new lines appeared in DC PVP, respectively DC MS mixtures are shown in tables 4 and 5. The same tables indicate disappearance of some of the diffraction lines of higher, moderate and lower intensities in the mixture which are originally present in the X-ray diffraction patterns of the individual components which indicates the interaction of DC with PVP and MS REV. CHIM. (Bucharest) 62 No

11 Table 5 X-RAY DIFFRACTION DATA FOR DICLOFENAC, PVP AND DICLOFENAC PVP (1:1) MIXTURE Conclusions This paper presents an issue of great importance, met more and more often in the speciality literature: the compatibility of the drugs with different excipients. The study refers to the compatibility of the DC with a range of excipients mentioned in the paper. As methods of study, there were used: the thermal methods of analysis, the FT IR spectroscopy and X-ray diffraction patterns. According to the thermal curves, especially DSC curves, one can say that all excipients present lower or higher interactions, with IB. This fact is supported by the differences between the values of T dehydration and T fusion, respectively of the enthalpies of dehydration. The disappearance of the characteristic DC fusion peak for the mixtures with α-lactose, β-lactose, PVP and MS certainly shows an interaction with DC. In the same context, the starch interaction occurs in a certain extent, while other excipients interaction is unlikely. Considering that the enthalpies of dehydration are quantitative data since they may be expressed as a fractional change, it could be said that all excipients interact with DC. Taking into account these differences correlated with the water content of the excipients as well as with the differences between the values of T dehydration, it can sustain the level of interaction which was mentioned above. The interaction of α-lactose, β-lactose, PVP and MS with DC was confirmed by FT IR spectroscopy and by X-ray diffraction patterns. In terms of starch interaction with DC, this wasn t confirmed by the two techniques mentioned, probably because of limited modifications. This study shows the incompatibility of DC with α- lactose, β-lactose, PVP and MS. References 1. FINI, A., FAZIO, G., BENETTI L., CHEDINI, V., Thermochim. Acta, 464, 2007, p KOVALA-DEMERTZI, D., J. Organomet. Chem., 691, 2006, p MOSER, P., SALLMANN, A.,WISENBERG, I., J. Med. Chem., 33, 1990, p BOGDAN, D., MORARI, C., Physics Letters A, 366, 2007, p KENAWI, I.M., BARSOUM, B.N., YOUSSEF, M.A., Eur. J. Pharm. Sci., 26, 2005, p KENAWI, I.M., J. Mol. Struc., 754, 2005, p NETO, H.S., NOVÁK, CS., MATOS, J.R., J. Therm. Anal. Cal., 97, 2009, p OLIVEIRA, P.R., STULZER, H.K., BERNARDI, L.S., BORGMANN, S.H.M., CARDOSO, S.G., SILVA, M.A.S., J. Therm. Anal. Cal., 100, 2010, p BERTOL, C.D., CRUZ, A.P., STULZER, H.K., MURAKANI, F.S., SILVA, M.A.S., J. Therm. Anal. Cal., 102, 2010, p LIRA, A.M., ARAÚJO, A.A.S., BASÍLIO, I.D.J., SANTOS, B.L.L., SANTANA, D.P., MACEDO, R.O., Thermochim Acta, 457, 2007, p BARBOZA, F., VECCHIA, D.D., TAGLIARI, M.P., SILVA, M.A.S., STULZER, H.K, Pharm. Chem. J., 43, 2009; p MORA CORVI, P., CIRRI, M., MURA, P., J. Pharm. Biomed. Anal., 42, 2006, p NETO, H.S., BARROS, F.A.P., DE SOUSA CARVALHO, F.M., MATOS, J.R., J. Therm. Anal. Cal. 2010;doi: /s REV. CHIM. (Bucharest) 62 No

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