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1 23 Journal of Thermal Analysis and Calorimetry An International Forum for Thermal Studies ISSN 1388-6150 Volume 115 Number 3 J Therm Anal Calorim (2014) 115:2407-2414 DOI 10.1007/s10973-013-3271-4 Characterization and compatibility study of desloratadine Isabela P. Veronez, Josiane S. P. Daniel, Jerusa S. Garcia & Marcello G. Trevisan 1 23 Your article is protected by copyright and all rights are held exclusively by Akadémiai Kiadó, Budapest, Hungary. This e-offprint is for personal use only and shall not be self- archived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”. Characterization and compatibility study of desloratadine Isabela P. Veronez • Josiane S. P. Daniel • Jerusa S. Garcia • Marcello G. Trevisan Received: 27 March 2013 / Accepted: 24 May 2013 / Published online: 22 June 2013 � Akadémiai Kiadó, Budapest, Hungary 2013 Abstract Desloratadine (DL) is a selective antagonist of the histamine H1 receptor, which has been widely used to treat allergic symptoms, and stands out from other drugs in this therapeutic class because it does not cause sedative effects. In the present study, the physico-chemical prop- erties of DL were fully characterized using six analytical techniques such as Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TG/DTG), Fourier transform infrared spectroscopy (FT-IR), Raman spectros- copy, Powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The DSC curve shows a sharp endothermic event at 158.4 �C, and the TG/DTG curve presents two decomposition events between 178.4 and 451.9 �C. A compatibility study involving DL and nine pharmaceutical excipients generally used in pharmaceuti- cal formulations was performed. Physical binary mixtures of DL with each excipient were prepared in a 1:1 (w/w) ratio. After preparation, the samples were analyzed immediately and the results reveal solid-state interaction with anhydrous lactose, microcrystalline cellulose, mag- nesium stearate, and stearic acid. Keywords Desloratadine � Compatibility � Thermal analysis � Solid-state characterization Introduction Histamine H1 receptor antagonists inhibit the binding of histamine to the histamine H1 receptor, prevent many of histamine’s adverse effects, and are considered to be a first- line therapy for the treatment of allergies. Most of the older histamine H1 receptor antagonists have the potential for adverse central nervous system effects and are character- ized by poor receptor specificity [1]. Desloratadine (DL) is a potent and selective antagonist of the histamine H1 receptor, which has been widely used to treat allergic symptoms. DL does not cross the blood– brain barrier and does not cause drowsiness or sedation. In addition, DL effectively improves nasal and non-nasal symptoms of allergic rhinitis and is not associated with adverse cardiovascular or central nervous system effects [1]. Chemically identified as 8-chloro-6,11-dihydro-11-(4- piperdinylidene)-5H-benzo[5, 6]cyclohepta[1,2-b]pyridine, DL is slightly soluble in water, but it is very soluble in ethanol and propylene glycol [2]. Preformulation testing encompasses all studies on a new drug and is an essential pre-requisite in the development of new products, or for the reformulation of an existing one, to produce useful information for the formulation of a stable and biopharmaceutically suitable drug dosage form. This stage includes the physico-chemical characterization of the new drug, as well as stability and compatibility tests with pharmaceutical excipients [3]. Presented orally at the 3rd Pan-American Congress of Thermal Analysis and Calorimetry (CBRATEC 2012), Campos do Jordão, SP, Brazil, 01–04 April 2012. Electronic supplementary material The online version of this article (doi:10.1007/s10973-013-3271-4) contains supplementary material, which is available to authorized users. I. P. Veronez � J. S. P. Daniel � J. S. Garcia � M. G. Trevisan (&) LACFar, Institute of Chemistry, Federal University of Alfenas (UNIFAL-MG), Alfenas, Minas Gerais 37130-000, Brazil e-mail: trevisan@unifal-mg.edu.br M. G. Trevisan National Institute of Science and Technology of Bioanalytical (INCTBio), State University of Campinas, Campinas, São Paulo 13084-653, Brazil 123 J Therm Anal Calorim (2014) 115:2407–2414 DOI 10.1007/s10973-013-3271-4 Author's personal copy http://dx.doi.org/10.1007/s10973-013-3271-4 The characterization of solid-state properties at an early stage by using appropriate analytical techniques is an important step during the development of solid dosage formulations, both from scientific and regulatory points of view [4]. Furthermore, characterization tests provide important information about the API particle shape, size, polymorphism, and crystallinity to maintain pharmaceuti- cal quality [4, 5]. Variations in the physico-chemical properties of the pharmaceutical active ingredient (API) may have an impact on therapeutic efficacy and on the manufacturing, commercial, and legal aspects of drug formulation [3, 4]. Most of the solid drugs that are intended for oral administration require formulations with different excipi- ents to allow appropriate administration, facilitate manu- facturing, increase the stability of the formulations, promote release and bioavailability of the drug, improve patient compliance, and control the drug’s release in the body [5, 6]. Although excipients have traditionally been considered to be inert, several current studies have shown that they can interact with the API included in the formu- lation [4–6]. The successful formulation of a stable and effective solid dosage form depends on careful selection of excipients [7]. The study of drug–excipient compatibility, which is recommended by the International Conference on Harmo- nization (ICH), represents an important phase in the pre- formulation stage for the development of all dosage forms. The drug stability guidelines (Q1A) require that stability tests of formulations should be conducted under acceler- ated temperature and humidity conditions, with testing occurring every 3 months [8]. In fact, potential physical and chemical interactions between drugs and excipients can affect the chemical nature, stability, and bioavailability of drugs and, consequently, their therapeutic efficiency and safety [9]. Thermal analyses such as differential scanning calo- rimetry (DSC) have been widely used in preformulation studies and routine pharmaceutical analyses, as it is a versatile, fast, low-cost, and sensitive technique [9–12]. Solid-state interactions can be evaluated by thermal anal- ysis, allowing the extraction of information about potential physical or chemical incompatibilities between the API and excipients, and contributing to the development of more stable pharmaceutical formulations [9]. In this study, DL was fully characterized using six analytical techniques, and its compatibility with nine dif- ferent pharmaceutical excipients, commonly used in the development of solid dosage forms, was evaluated. Accordingly, DSC measurements were performed on each of the components, both in their pure forms and the cor- responding 1:1 (w/w) physical mixtures. Experimental Materials and samples DL was provided by Dr. Reddys, India. Nine pharmaceu- tical excipients generally used in pharmaceutical formula- tions, and purchased from qualified pharmaceuticalsuppliers, were evaluated: dibasic calcium phosphate, microcrystalline cellulose, corn starch, talc, mannitol, magnesium stearate, polyvinylpyrrolidone K25 (PVP K25), stearic acid, and anhydrous lactose. Physical mixtures of DL with each excipient were pre- pared in a 1:1 (w/w) ratio by simple mixture of the com- ponents in a polyethylene container (3 cm 9 2 cm diameter). The samples were homogenized using a vortex and two stainless steel balls for 1 min. The 1:1 (w/w) ratio was chosen to maximize the probability of observing any interaction [9]. After preparation, the samples were ana- lyzed immediately. Methods Thermogravimetric analysis (TG/DTG) The TG/DTG curves were recorded on a thermogravimet- ric analyzer Q600 (TA Instruments) employing the fol- lowing parameters: a temperature range of 25–600 �C; a dynamic nitrogen atmosphere (50 mL min-1); a heating rate of 10 �C min-1; Al2O3 crucibles; and samples weighing approximately 10 mg. Powder X-ray diffraction (PXRD) X-ray diffraction patterns of DL were obtained with an Ultima IV diffractometer (Rigaku), operating at 40 kV and 30 mA, using Cu Ka source. The measurements of 2h ranged between 5� and 55� (±0.02). Fourier transform infrared spectroscopy (FT-IR) Infrared spectra (FT-IR) of the drug, excipients, and binary mixtures were obtained using an IRPrestige – Shimadzu spectrometer and employing potassium bromide disks in the range of 2,000–400 cm-1. Each spectrum was the average of more than 20 consecutive scans on the same sample using a spectral resolution of 8 cm-1. Raman spectroscopy Raman spectra were recorded at room temperature using a RamanStation 400F (PerkinElmer) equipped with a 785 nm excitation laser and an attachment for solids. Each 2408 I. P. Veronez et al. 123 Author's personal copy spectrum was the average of four scans from 2,000 to 200 cm-1, using 1 cm-1 of spectral resolution. Scanning electron microscopy (SEM) SEM micrographs were obtained with a JSM-6340F Field Emission–JEOL microscope. The samples were vacuum coated with gold and analyzed directly by SEM (5009/ 10,0009). Differential scanning calorimetry (DSC) Studies of the compatibility between API and excipients were achieved by analysis of the DSC curves of the drug, the excipients, and mixtures of the two components in 1:1 ratios (w/w). DSC experiments were conducted using a high-sensitivity differential scanning calorimeter, model DSC-7020 EXSTAR (SII NanoTechnology Inc.). Samples (approx. 3.3 mg) were placed in open aluminum crucibles and heated from an initial temperature of 25 �C to a final temperature of 180 �C at 10 �C min-1, under a dynamic nitrogen atmosphere (50 mL min-1). The DSC cell was previously calibrated with indium (purity greater than 99.99 %, Tonset = 156.6 ± 0.3 �C, and heat of fusion of 28.6 ± 0.5 J g-1). Results and discussion Characterization of DL In the first phase of this study, DL was fully characterized by six analytical techniques. The TG/DTG and DSC curves obtained for DL are shown in Fig. 1a. Thermal decompo- sition of DL in a nitrogen atmosphere occurs in two steps and begins at 178.4 �C. The temperature range of decom- position is from 178.4 to 451.9 �C, with the total mass loss of 97.1 % and DTG peak at 340.8 �C. The DSC curve of DL shows a well-defined endothermic event, indicating melting at 158.4 �C (Tonset = 156.4 �C and DHfus = 105 J g -1). In this temperature range, the TG/ DTG curves did not show mass loss. To evaluate the stability of polymorphic forms, a cyclic DSC (CDSC) experiment was performed. Approximately 3 mg of DL was maintained in the isotherm for 3 min at 180 �C, after the end of the fusion event. The crucible was then cooled at a rate of 10 �C min-1 to a final temperature of 25 �C. No exothermic peak of DL recrystallization was observed. After cooling, the same sample was reheated at a rate of 10 �C min-1 up to a final temperature of 300 �C, and the curve did not show any thermal events, as shown in Fig. 1b. This sample was analyzed by X-ray diffraction to investigate its nature. Powder X-ray diffractometry is a powerful technique for the identification of crystalline solid phases and determination of the degree of crystallinity [13, 14]. Prior to the thermal analysis, the sample showed strong peaks at 12.14, 13.14, 18.68, 20.08, 21.16, 26.3, and 29.24�2h, which is characteristic of Form 1 crystallinity [15] (Fig. 2a). However, after subjecting the DL to CDSC, it did not show peaks (Fig. 2a) and was characterized as amorphous. Thus, the heating process applied to the sample was efficient in achieving amorphization of the API. The SEM micrographs of the samples, both before and after CDSC, obtained at magnification 5009 and 10,0009, are presented in Fig. 2b. The morphological analysis of the API before and after CDSC confirmed that the heating was efficient at achieving amorphization of the API. Irregularly shaped particles, including aggregates of flakes, were visualized in the sample before CDSC [16]. In contrast, a fused mass with agglomerated particles was observed in the sample after CDSC. In addition to the diffractogram data, the FT-IR spectra of the samples, both before and after CDSC, were obtained to evaluate the thermal stability of the API. The spectra of DL before CDSC (Fig. 3a-I) show prominent bands at 1,479 and 1,435 cm-1, which is attributed to the C–C stretching of aromatic rings, while the bands at 1,177 and 779 cm-1 correspond to C–N amines and C–Cl stretching, respectively. These results are in agreement with other published data [17]. The spectra of DL obtained after CDSC (Fig. 3a-II) show the same absorption bands, indi- cating that the DL did not decompose in the range of applied temperatures. Therefore, DL is sufficiently ther- mally stable to allow analysis by the DSC method. Raman spectroscopy was used to complement the data obtained by FT-IR. The Raman spectra of DL, both before and after CDSC, were recorded at ambient conditions (Fig. 3b). The spectra show strong bands at 1,635 and 1,585 cm-1, corresponding to C=N stretching and C=C stretching of aromatic rings, respectively, and a band at 689 cm-1 which is attributed to C–Cl stretching. Compatibility studies with excipients DSC has been proposed to be a rapid method for evaluating the physico-chemical interactions between components of formulations and, therefore, to aid in the selection of ex- cipients with suitable compatibility [9–11]. The DSC curves obtained for DL and the tested excip- ients are shown in Fig 4a. Each curve shows unique behavior, depending on the characteristics of each excipi- ent. None of the excipients showed any thermal event near the melting peak of DL; thus, it was possible to investigate the interactions between the components of binary Characterization and compatibility study of desloratadine 2409 123 Author's personal copy mixtures of drug and excipient by comparing the temper- ature profiles obtained for the mixtures with those of their individual components [4, 5, 10, 11]. The possible interactions between components are deduced from DSC curves by examining the appearance, shift, or disappearance of DSC peaks, especially the melting peak, and/or variations in the expected enthalpy (DH) values. An interaction was assumed to result in a decrease or, in the case of overlapping, an increase in the enthalpy, which is a more complex process [9]. The thermo-analytical data regarding isolated DL and the physical mixtures, obtained from the thermal curves, are presented in Table 1. The data show that the thermal profile of DL, particularly the parameters of fusion (Tonset and DHfus), remained almost constant in the binary mix- tures for the majority of the tested excipients. In a practical sense, the thermal curves of binary mixtures can be con- sidered as superpositions of the individual curves of DL and the excipients. However, for mixtures containing microcrystallinecellulose, magnesium stearate, stearic acid, and anhydrous lactose, there were some changes with the API melting temperature and enthalpy, as shown in Fig. 4b. For mixtures containing anhydrous lactose, there was a small decrease in the value of the melting peak, which is a sign of possible solid–solid interactions but not necessarily an indication of chemical incompatibility between the drug and excipient. Anhydrous lactose is a reducing sugar with the potential to interact with primary and secondary amines when stored under conditions of high humidity for exten- ded periods [18]. Anhydrous lactose is employed as a dil- uent for tablets and capsules, and several incompatibilities [18–20] and compatibilities [21] with other APIs are reported in the literature. The values obtained from the heat of fusion were compared statistically by using an analysis of variance. The 1 % significance test showed that the composition of the mixture influences the value of the enthalpy (p \ 0.0001). The Scott–Knott test was performed to compare the mean values (data not shown). After analyzing the data, a sta- tistically significant change in the heat of fusion was observed for the blends containing excipients, such as 0 100 a b 50 0 –500 –1000 H ea t f lo w /W g –1 M as s lo ss /% –1500 E nd o 100 0 –400 –800 –1200 –1400 30 60 90 120 150 180 210 240 270 300 200 300 Temperature/°C 400 500 600 D er iv at iv e m as s/ % ° C –1 DSC DTG TG 0.5 0.0 –0.5 –1.0 –1.5 –2.0 H ea t f lo w /W g –1 Temperature/°C E nd o Tp = 158.4 °C 1st Heating Cooling 2nd Heating Fig. 1 TG/DTG and DSC curves of DL (a) and CDSC curves of DL (b) 2410 I. P. Veronez et al. 123 Author's personal copy microcrystalline cellulose, anhydrous lactose, magnesium stearate, and stearic acid, which may indicate interactions between these components and the API. The differences in enthalpy between the binary mixtures containing microcrystalline cellulose and those containing anhydrous lactose suggest physical interactions, but not chemical incompatibilities (degradation products). The microcrystalline cellulose is used as a tablet and capsule diluent and as a tablet disintegrant [18], and some inter- actions between this excipient and drugs, such as the production of enalapril maleate, are detailed in the litera- ture [22]. The most obvious changes were observed in the mixture containing stearic acid, in which the endothermic peak relating to the melting point of DL disappeared and the signals of stearic acid were altered, indicating the occur- rence of a strong interaction between the components as the temperature changed. The appearance of a new peak at 99.1 �C shows a clear chemical interaction between the components of the binary mixture (Fig. 5a). 100a b 80 60 40 R el at iv e in te ns ity /% 20 0 5 10 15 (I) (II) 20 25 30 2θ/° 35 40 45 50 55 Before CDSC After CDSC Fig. 2 PXRD of DL before and after CDSC (a) and SEM photomicrographs of DL at 5009 and 10,0009 magnification (b): (I) before CDSC; (II) after CDSC. (Color figure online) Characterization and compatibility study of desloratadine 2411 123 Author's personal copy Stearic acid and magnesium stearate are used as lubri- cants to improve the flow properties of the mixtures and reduce the loss during compression [5, 18]. Several inter- actions in pharmaceutical formulations between magne- sium stearate and drugs, such as ketoprofen, captopril, ibuproxan, and ibuprofen, are detailed in the literature [5, 7, 9, 20]. Magnesium stearate cannot be included in products containing aspirin, those containing certain vita- mins or most alkaloidal salts [18]. Commercially available magnesium stearate is a mix- ture of long-chain aliphatic acids with variable water content [23]. The DSC curves of the DL/magnesium stea- rate mixture showed three endothermic events, with the first occurring at approximately 80–110 �C, a second occurring at 110–130 �C, and a third occurring at 155–160 �C. The first event is attributable to a loss of water from the hydrated state of the magnesium stearate, the second event indicates that the material melted at this point [4, 23], and the third event corresponds to the melting point of DL (Fig. 5b). In the mixture containing magne- sium stearate, a slight reduction in the melting enthalpy of the DL was observed, an alteration that can be explained by the partial solubility of the DL in the excipient as mag- nesium stearate melts around 130 �C, which is below the melting point of the API. FT-IR spectroscopy was used as a supplementary tech- nique to investigate the possible chemical interactions between the drug and excipients. The appearance of new absorption bands, broadening of the absorption bands, and alterations in their intensity are the main signals of inter- actions between the drug and excipients [9, 24]. 2000 I a II Tr an sm ita nc e/ % R el at iv e in te ns ity /% 1600 1200 Wavenumber/cm–1 800 400 200 400 600 800 1000 Raman shift/cm–1 1200 1400 I II 1600 1800 2000 b Fig. 3 FT-IR spectra (a) and Raman spectra (b) of DL: before (I) and after (II) CDSC E nd o DL a Dibasic calcium phosphate Microcrystalline cellulose Corn starch Talc Mannitol Magnesium stearate PVP Stearic acid Anhydrous lactose 30 60 90 120 Temperature/°C 150 180 DL DL + Dibasic calcium phosphate DL + Microcrystalline cellulose DL + Corn starch DL + Talc DL + Mannitol DL + Magnesium stearate DL + PVP DL + Stearic acid DL + Anhydrous lactose E nd o 30 60 90 120 Temperature/°C 150 180 b Fig. 4 DSC curves of DL and excipients (a) and DSC curves of DL and binary mixtures (b) 2412 I. P. Veronez et al. 123 Author's personal copy The spectra of the drug and all tested excipients were obtained for the pure compounds, as well as for binary mixtures of the two components in 1:1 ratios (w/w), to identify possible chemical interactions between the two species. The FT-IR spectra show that the characteristic bands of DL and each excipient individually were not altered in binary mixtures, which indicates no interactions between DL and the selected excipients when immediate contact is established at room temperature (supplementary material). X-ray diffraction is another approach used for qualita- tive and quantitative determination of crystallinity to investigate the possible interactions between DL and ex- cipients. Such interactions between the drugs and excipi- ents, observed in the DSC curves, should result in the partial or complete disappearance of the reactant phases and appearance of new phases. These changes can be inferred from X-ray diffraction patterns. X-ray diffraction patterns of the mixture, as prepared at room temperature, when compared to the patterns produced by the individual components, show the appearance of new lines and the disappearance of some of the lines characteristic to the individual components [9, 24]. The diffractograms of two of the binary mixtures—DL/stearic acid and DL/magne- sium stearate—do not show the appearance of new lines in the XRD patterns (supplementary material). These results indicate that there are no interactions between DL and these excipients when immediate contact is established at room temperature. However, the interactions could increase if the temperature was increased. Conclusions The solid-state characterization of crystalline forms of drug candidates is important to the pharmaceutical development process. In this study, DL was fully characterized using thermal analyses (DSC, TG), FT-IR, Raman, PXRD, and SEM, demonstrating the drug’s physico-chemical proper- ties. The CDSC reaction confirmed that the heating process applied to the sample was efficient at achieving amorph- ization of the API. FT-IR spectra confirmed the thermal stability of the API within the working temperature range, which indicates that analysisby DSC is appropriate. Table 1 Thermo analytical fusion event data for DL in different physical mixtures (n = 3) Sample Tonset/�C Tf/�C Tpeak/�C DHf/J g-1 Desloratadine (DL) 156.4 ± 0.2 161.3 ± 0.1 158.4 ± 0.1 105.0 ± 0.2 DL ? dibasic calcium phosphate 155.6 ± 0.1 160.3 ± 0.4 158.5 ± 0.5 51 ± 3 DL ? microcrystalline cellulose 155.4 ± 0.1 162.0 ± 0.5 158.2 ± 0.1 44 ± 5 DL ? corn starch 155.5 ± 0.1 162.6 ± 0.3 158.5 ± 0.4 50 ± 2 DL ? talc 155.7 ± 0.1 161.1 ± 0.6 158.2 ± 0.1 47.5 ± 0.7 DL ? mannitol 151.9 ± 0.2 157.2 ± 0.3 154.6 ± 0.2 56 ± 4 DL ? magnesium stearate 155.10 ± 0.01 161.0 ± 0.7 157.8 ± 0.1 37 ± 3 DL ? PVP 151.2 ± 0.3 159.8 ± 0.5 156.3 ± 0.1 56 ± 7 DL ? stearic acid 94.6 ± 0.4 101.3 ± 0.2 99.1 ± 0.2 39 ± 2 DL ? lactose anhydrous 150.1 ± 0.1 158.1 ± 0.5 155.10 ± 0.01 42 ± 1 0 a –500 –1000 H ea t f lo w /W g –1 –1500 30 60 90 Temperature/°C 120 DL Stearic acid DL + Stearic acid 150 180 0 –500 –1000 H ea t f lo w /W g –1 –1500 DL Magnesium stearate DL + Mg stearate 30 60 90 Temperature/°C 120 150 180 b Fig. 5 DSC curves of DL, excipient, and 1:1 binary mixtures (w/w): DL/Stearic acid (a); DL/magnesium stearate (b) Characterization and compatibility study of desloratadine 2413 123 Author's personal copy In the compatibility studies with excipients, the DSC results indicated that the dibasic calcium phosphate, corn starch, and talc present in the binary mixtures were stable and that there was no incompatibility between the DL and these excipients. However, preliminary interactions may be presumed in the case of mixtures containing microcrys- talline cellulose, anhydrous lactose, magnesium stearate, and stearic acid. These results confirm the utility of DSC in preformulation studies, as it is a fast and appropriate technique for determining the most suitable excipients. Additionally, FT-IR and X-ray analyses were per- formed, and no evidence of solid-state interaction or incompatibility was observed when immediate contact between the components was established at room temperature. Acknowledgements This study was supported by FAPEMIG (Process APQ-04835-10) and CAPES (Fellowship). The authors would like to thank the Laboratory of Crystallography/UNIFAL-MG for PXRD analysis and the Institute of Chemistry/UNICAMP for SEM microscopies. References 1. Anthes JC, Gilchrest H, Richard C, Eckel S, Hesk D, West RE Jr, Williams SM, Greenfeder S, Billah M, Kreutner W, Egan RW. 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Compatibility studies between nebicapone, a novel COMT inhibitor, and excipients using stepwise isothermal high sensitivity DSC method. J Therm Anal Calorim. 2010;102:317–21. 24. Tita B, Fulias A, Bandur G, Ledeti I, Tita D. Application of thermal analysis to study the compatibility of sodium diclofenac with dif- ferent pharmaceutical excipients. Rev Chim. 2011;62:443–54. 2414 I. P. Veronez et al. 123 Author's personal copy http://dx.doi.org/10.1007/s10973-012-2476-2 Characterization and compatibility study of desloratadine Abstract Introduction Experimental Materials and samples Methods Thermogravimetric analysis (TG/DTG) Powder X-ray diffraction (PXRD) Fourier transform infrared spectroscopy (FT-IR) Raman spectroscopy Scanning electron microscopy (SEM) Differential scanning calorimetry (DSC) Results and discussion Characterization of DL Compatibility studies with excipients Conclusions Acknowledgements References
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