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Investigation of adsorption and release of diclofenac sodium by modifiedzeolites composites
Danina Krajišnik a,⁎, Aleksandra Daković b, Anđelija Malenović c, Maja Milojević-Rakić d, Vera Dondur d,Željka Radulović e, Jela Milić a
a Department of Pharmaceutical Technology and Cosmetology, University of Belgrade-Faculty of Pharmacy Vojvode Stepe 450, 11000 Belgrade, Serbiab Institute for Technology of Nuclear and Other Mineral Raw Materials, Franche d' Epere 86, 11000 Belgrade, Serbiac Department of Drug Analysis, University of Belgrade-Faculty of Pharmacy Vojvode Stepe 450, 11000 Belgrade, Serbiad Faculty of Physical Chemistry, University of Belgrade, Studentski Trg 12-16, 11000 Belgrade, Serbiae R & D Institute, Galenika a.d., Batajnički drum, b.b., 11000 Belgrade, Serbia
Results on adsorption of diclofenac sodium (DS) by modified natural zeolite composites at three levels (10, 20and 30 mmol/100 g) of cationic surfactant-hexadecyltrimethylammonium bromide (HB), in a buffer solution,were compared. Characterization of composites before and after drug adsorption was performed by determina-tion of electrokinetic mobility, FTIR and thermal analysis. The results indicated interactions between drug andcarriers. The pharmaceutical performance of cationic surfactant-modified zeolites as drug formulation excipientswas evaluated by in vitro dissolution experiments. The results were compared with the drug release from corre-sponding physical mixtures. Prolonged drug release over a period of 8 h (up to 30%) was achieved with bothgroups of samples. Furthermore, DS release reached up to 85% from physical mixtures containing drug amountcloser to a therapeutic dose.
Almost all therapeutic products, including therapeutic products forhuman and veterinary use include excipients. As with drug, excipientsare derived from natural sources or are synthesized either chemicallyor by othermeans (Bhattacharyya et al., 2006).Minerals are traditional-ly employed in pharmaceutical products (Carretero and Pozo, 2009,2010; Rowe et al., 2006) and they generally act as a carrier, binder, lubri-cant, diluent, etc., but sometimes they are also involved in the therapeu-tic processes. For example, natural zeolite (clinoptilolite) has been usedsuccessfully as a carrier–releaser of zinc and erythromycin for topicalapplication against acne (Bonferoni et al., 2007; Cerri et al., 2004).Chemicalmodification of zeoliteswith long chain organic cations resultsin an increased hydrophobicity of the mineral surface, thus providinghigh affinity for organic i.e. drug molecules. The study of Li et al.(1998) demonstrated the long-term and biological stability of zeolitemodified with hexadecyltrimethylammonium bromide (HB) over awide range of pH values, with a minimum of surfactant desorptionand lack of microbial toxicity making them a potential candidate as adrug formulation excipient.
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vestigation of adsorption and6/j.clay.2013.08.011
Diclofenac sodium (DS) is a potent non-steroidal anti-inflammatorydrugwith pronounced analgesic and antipyretic properties. Nevertheless,it produces a relatively high incidence of gastrointestinal side effects dueto the physicochemical action on the gastric mucous (Oddsson et al.,1990) and inflammatory action on both the small bowel and the colon(Carson et al., 1990; Witham, 1991). Due to these adverse effects and itsshort biological half life (Todd and Sorkin, 1988), DS is an ideal candidatefor prolonged release preparations with the aim to maintain therapeuticactivity, reduce toxic effects and improve patient compliance. Adsorptionof DS by the zeolite composites with three different levels (10, 20 and30 mmol/100 g) of cetylpyridinium chloride — CPC (ZCPC-10, ZCPC-20and ZCPC-30) was previously reported. It was pointed that drug adsorp-tion increased with increasing the amount of CP in composites. Thehighest percentage of DS released was obtained with the compositewith the lowest level of CPC (Krajišnik et al., 2013). Diclofenac sodiumup-take by composites obtained by modification of the initial zeolitic tuff(ZVB) with 10 and 20 mmol/100 g of HB (ZHB-10 and ZHB-20) andbenzalkonium chloride — BC (ZBC-10 and ZBC-20) was also followed(Krajišnik et al., 2010). As in the case of ZCPCs, adsorption of DS byZHBs and ZBCs increased with increasing amounts of HB or BC at the ze-olite surface. The similar maximumDS adsorption capacity was achievedwith composites ZHB-10 and ZBC-10 (~24 mg/g), while with increasingthe amount of surfactants much higher adsorption of DS was observedfor ZHB-20 (45 mg/g) than for ZBC-20 (31 mg/g). These results indicated
release of diclofenac sodiumbymodified zeolites composites, Applied
DHB-10 C Adsorption DS ZHB-10 1.2DHB-20 C DS ZHB-20 1.3DHB-30 C DS ZHB-30 1.3DHB-10 P Physical mixture DS ZHB-10 1.2DHB-20 P DS ZHB-20 1.4DHB-30 P DS ZHB-30 1.4DHB-20 Pa Physical mixture DS ZHB-20 1.0DHB-20 Pb DS ZHB-20 0.7DHB-20 Pc DS ZHB-20 0.4
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that drug adsorption by surfactant modified zeolites may be dependenton the type of surfactant at the zeolite surface. Additionally, dissolutionof DS from ZHB-20 and ZBC-20 was permanent over 8 h (max 30% forZHB-20 and max 43% for ZBC-20). Because the higher adsorption of DSwas achievedwith ZHB-20 thatwith ZBC-20 and since the DS therapeuticdose bymouth is 75 to 150 mg daily in divided doses (Sweetman, 2009),it was important to investigate if higher levels of HB at the zeolitic surfacewill additionally increase DS adsorption and consequently prolong thedrug release. Therefore a composite with 30 mmol HB/100 g (ZHB-30)was prepared and adsorption/desorption of the drugwas studied. The re-sults were discussed together with DS adsorption/desorption by ZHB-10and ZHB-20.
Characterization of ZHB-10, ZHB-20 and ZHB-30 composites be-fore and after adsorption of DS was done by determination of theirelectrokinetic mobility and by differential thermal analysis (DTA),differential thermogravimetry (DTG) and Fourier transform infraredspectroscopy (FTIR) using attenuated total reflection (ATR) tech-nique. Furthermore, the drug release from the composites after ad-sorption was compared with DS release from each composite anddrug physical mixtures.
2. Materials and methods
Raw material used for the preparation of the composite wasclinoptilolite rich tuff from Zlatokop deposit (Vranje, Serbia). Based onqualitative X-ray powder diffraction analysis (XRPD), the clinoptilolitecontent was ~80% with trace amounts of quartz, pyrite and feldspar.The complete chemical characterization of the starting zeolitic tuffwas given previously (Daković et al, 2007a, 2007b; Krajišnik et al.,2010). Cationic surfactant hexadecyltrimethylammonium bromide(HB) (Sigma-Aldrich, St. Louis, MO, USA) was used for the preparationof ZHB-30. For that purpose, 10% aqueous (w/w) suspension of ZVBwas treated with HB equivalent to 300% of its external cation exchangecapacity — ECEC (33.3 mmol/l). The cation exchange capacity (CEC) ofthe startingmaterialwas 146 mmol M+/100 gmeasured by the ammo-nium chloride method, while its ECEC was 10 mmol M+/100 g(Daković et al., 2007a). The conditions for preparation of ZHB-30 andthe subsequent adsorption of DS were the same as for ZHB-10 andZHB-20 and are given elsewhere (Krajišnik et al., 2010). The stabilityof ZHBs was studied by placing 35 mg of either ZHB-10, ZHB-20 orZHB-30 in 50 ml of a buffer (pH 6.8)(USP 30) followed byultrasonication for 15 min. The supernatants were analyzed by HPLCanalysis.
The electrokinetic mobility of each composite before and after DSadsorption in aqueous suspension (0.1 mg/ml) was measured using aZetasizer Nano ZS90 (Malvern Instuments, UK). Thermal analysis wasperformed on a Netzsch STA 409 EP (Selb, Germany). Samples wereheated (20–700 °C) in an air atmosphere at a rate of 10 °C min−1. TheFourier transform infrared (FTIR) spectra, using attenuated total reflec-tion (ATR) technique were recorded on Nicolet 6700 FTIR spectrometerwith a diamond ATR smart accessory. Spectra over the 4000–400 cm−1
rangewere obtained by the co-addition of 256 scanswith the resolutionof 2 cm−1 and the mirror velocity of 0.6329 cm/s.
The pharmaceutical performance of modified zeolites-drug com-posites and modified zeolite-drug physical mixtures was evaluatedby in vitro dissolution experiments. The flat-faced punches with adiameter of 9 mm were used to compress the tested powders into200 mg comprimates using an eccentric compressing machine(EKO Korsch, Berlin, Germany). First group of comprimates was pre-pared from the ZHB-10, ZHB-20 or ZHB-30 and DS composites thatwere collected at the end of DS adsorption experiments from thestock solutions with the highest initial drug concentration (samplesdenoted as DHB-10 C, DHB-20 C and DHB-30 C). Second group ofcomprimates contained physical mixtures prepared by mixing ofDS and each composite to attain the similar (mmol HB/mmolDS ~ 1.4) molar ratio. These samples were denoted as DHB-10 P,
Please cite this article as: Krajišnik, D., et al., Investigation of adsorption andClay Science (2013), http://dx.doi.org/10.1016/j.clay.2013.08.011
DHB-20 P and DHB-30 P. Third group of samples were physicalmixtures prepared at lower molar ratios of ZHB-20 and DS (mmolHB/mmol DS = 1.0, 0.7 or 0.4) — DHB-20 Pa, DHB-20 Pb and DHB-20 Pc. Components in each comprimate, appropriate molar ratioand method of preparation are presented in Table 1. Details on de-termination of DS, HB and conditions for dissolution study were de-scribed in previous papers (Krajišnik et al., 2010, 2011).
3. Results and discussion
3.1. Characterization of modified zeolites
It was mentioned that DS adsorption by composites ZHB-10 andZHB-20 was previously studied (Krajišnik et al., 2010) and maximumadsorbed amount of DS was 74 mmol/kg for ZHB-10 and 142 mmol/kgfor ZHB-20. Also, compared to the adsorption of DS by ZCPCs where ad-sorption by ZCPC-20was almost twice higher than by ZCPC-10 and thenslightly increased for ZCPC-30, further proportional increase of DS ad-sorption with increasing amounts of HB at the surface was observedfor ZHB-30–212 mmol/kg (67.4 mg/g). Slight differences in adsorptionof DS by ZCPCs and ZHBs confirmed that drug adsorption is dependenton the type of surfactant used for modification. Since HB at the zeoliticsurface are the active sites onto which DS was adsorbed, we calculatedthe molar ratios by dividing the amount of HB in each composite(mmol/g) by the maximum amount of DS adsorbed at its surface(mmol/g) which gave the number of HB at the surface of specific com-posite available for adsorption of one molecule of DS. Similar molar ra-tios obtained for all ZHBs (1.2 for ZHB-10 and 1.3 for ZHB-20 and ZHB-30) confirmed that HB were relevant for DS adsorption.
Electrokinetic mobility is a reflection of surface potential and it ischanged with respect to different surfactant loadings, leading to a tran-sition betweenmonolayer and bilayer coverage. The results of determi-nation of electrokinetic mobility of ZHBs before and after DS adsorptionare presented in Fig. 1. Compared to ZVB which surface acquired a neg-ative charge (−27.4 mV) (Krajišnik et al., 2011), for ZHB-10 with theconcentration of HB equal to 100% of ECEC, electrokinetic mobilityapproached zero (−1.0 mV) confirming a monolayer formation andcomplete hydrophobicity of the zeolitic surface. For HB loadings of200% and 300% of ECEC, the electrokinetic mobility became positive(+20.3 mV for ZHB-20 and +34.5 mV for ZHB-30) indicating chargereversal and bilayer or extensive admicelles formation at the zeoliticsurface, similar to findings of Li and Bowman (1998). After adsorptionof DS, electrokinetic mobility of resulted complexes was: −20.0 mVfor ZHB-10,+13.4 mV for ZHB-20 and+20.1 mV for ZHB-30. These re-sults showed that DS induced changes in the surface charge of the ZHBsconfirming presence of the drug molecules at the surface of thecomposites.
Compared to the differential thermal analysis (DTA) curve of ZVBat which an endothermic dehydration peak at 113 °C with a shoulderat 213 °C and the exothermic peak at 476 °C were present (Krajišnik
release of diclofenac sodiumbymodified zeolites composites, Applied
Sample label---hexadecyltrimethylammonium ion ---diclofenac sodium (anion)
Fig. 1. Electrokinetic mobility of ZHB 10–30 composites and DHB-10 C, DHB-20 C andDHB-30 C samples.
Fig. 2. Thermal: DTA (a) and DTG (b) curves of the starting zeolitic tuff (ZVB) and ZHB10–30 composites. The insets show the DTA and DTG curves of HB alone.
et al., 2011), DTA curves of all ZHBs showed two broad low intensityendothermic peaks around 120 °C and 229 °C and three exothermicpeaks at higher temperatures (Fig. 2a). The endothermic peak at229 °C may suggest elimination of weakly bound HB, while the exo-thermic peaks were related to the decomposition of sorbed HB. Theintensities of the exothermic peaks increases with increasingamounts of HB at the surface, and first peak shifts toward highertemperatures with increasing amounts of HB (from 312 °C for ZHB-10 to 346 °C for ZHB-30). For all ZHBs, the position of the second(426 °C) and third (556 °C) exothermic peak was identical. TheDTA curve of pure HB had three exothermic peaks visible at 200 °C,346 °C and 493 °C, followed by one sharp intensive DTG peak withthe centre at 297 °C indicating that oxidation of most of the pureHB occurs in the temperature region between 200 °C and 400 °C.At lower temperatures, differential thermogravimetric (DTG) curves(Fig. 2b) of ZHBs showed one DTG peak related to dehydration, whileat higher temperatures there was a significant increase in intensityof the second DTG peak (around 230 °C) with increasing amountsof HB was observed. ZHB-30 containing the highest amount of HBhad an additional intensive DTG peak at 330 °C. This may be addi-tional evidence that in the temperature region between 180 °C and400 °C elimination of weakly bound HB from the bilayer and/oradmicelles (ZHB-20 and ZHB-30) together with oxidation of tightlybound HB had occurred. Haggerty and Bowman (1994) reportedthat loosely bound HB is easily desorbed from the zeolitic surface,however to support the obtained results desorption of HB from com-posites was followed in phosphate buffer at pH 6.8 (dissolution me-dium). It was determined that for all ZHBs, less than 5% of HB wasdesorbed from the zeolitic surface.
After adsorption of DS, DTA curves of all ZHBs (Fig. 3a), had fourexothermic peaks (around 350 °C, 420 °C, 520 °C and 610 °C)assigned to the thermal decomposition of HB and the oxidation ofDS. It was observed that intensities of the higher temperature exo-thermic peaks (above 500 °C) increased with increasing theamount of DS in composites confirming DS interacting with HB atthe zeolite surface. Also, at DTA curves of ZHB-20 and ZHB-30after adsorption of DS, instead of endothermic peak originatingfrom loosely bound HB, at 229 °C, low intensity endothermic peakat 278 °C was visible. The position of this peak was close to themelting temperature of pure DS (Krajišnik et al., 2013) thus thispeak may originate from loosely bound DS. Additionally, the inten-sities of DTG peaks of ZHBs around 230 °C and 330 °C decreased
Please cite this article as: Krajišnik, D., et al., Investigation of adsorption andClay Science (2013), http://dx.doi.org/10.1016/j.clay.2013.08.011
after adsorption of DS, while higher temperature DTG peaks weremore pronounced.
Infrared spectra of pure DS and ZHB-20 and ZHB-30 before andafter the drug adsorption are presented in Fig. 4. Compared to theIR spectra of the natural zeolite (Daković et al., 2007a), in thespectra of ZHBs, three new bands appear around 2950 cm−1,2850 cm−1, and 1465 cm−1, which evidences the presence of HBat the zeolite surface. The first two bands were attributed to asym-metric and symmetric stretching vibrations of C\C in the alkyl chainand the third one corresponds to the carbon–hydrogen bending inthe methyl groups. Although DS showed intensive vibration bandsin the same region in which characteristic bands of ZHBs appeared(between 1660 and 1260 cm−1), the evidence of presence of DS inboth modified zeolites–drug composites was clearly visible. Also,no relevant changes were observed in the structural vibration regionof zeolite after adsorption of HB and DS confirming structural stabil-ity of these composites.
release of diclofenac sodiumbymodified zeolites composites, Applied
Fig. 3. Thermal: DTA (a) and DTG (b) curves of DHB-10 C, DHB-20 C and DHB-30 Csamples.
Fig. 4. FT-IR spectra of DS, ZHB 20–30 composites and DHB-20 C and DHB-30 C samples.
4 D. Krajišnik et al. / Applied Clay Science xxx (2013) xxx–xxx
Please cite this article as: Krajišnik, D., et al., Investigation of adsorption andClay Science (2013), http://dx.doi.org/10.1016/j.clay.2013.08.011
3.2. In vitro drug release studies
Interactions during solid-state powder mixing process between drugand hydrophobic excipient affecting the drug dissolution rate have beenpreviously reported (Li-Hua and Chowhan, 1990). Javadzadeh et al.(2012) compared DS release rates from drug and magnesium stearate(MS), a highly hydrophobic excipient, physical mixtures with cogroundsamples, at different mass ratios of DS and MS (1:0.5, 1:1, 1:2, 1:3 and1:5). They found that in the ratio 1:5, 100% release was obtained after180 min and 360 min in physical and coground mixtures, respectively,while pure drug formulation (without adding MS) released about 95%of its drug content within 10 min.
In our study, the physical mixtures of ZHB-10, ZHB-20 or ZHB-30containing the same amount of DS as appropriate modified zeolites-drug composite (DHB-10 C, DHB-20 C and DHB-30 C) were preparedand release of the drug from both groups of samples was studied. Thedrug dissolution from both composites and physical mixtures (DHB-10 P, DHB-20 P and DHB-30 P) (Table 1) was permanent over a peri-od of 8 h (Fig. 5a). The maximum amounts of DS released from thecomposites were 27% for DHB-10 C, 30% for DHB-20 C and 20% forDHB-30 C.
Results of DS release from drug/ZCPCs composites (ZCPC-10, ZCPC-20 and ZCPC-30) during 8 h showed that 55% of the drug was releasedfromZCPC-10, and 30% from ZCPC-20 and ZCPC-30. The results of DS re-lease from ZCPC-10 were compared with the DS release from a corre-sponding physical mixture. It was found that slightly lower DS releasewas achieved with the physical mixture (38%) suggesting that becauseof high affinity of ZCPCs for DS, during dissolution of the drug fromthe physicalmixture, interactions between ZCPC-10 andDS in buffer so-lution occurred prior to the dissolution process (Krajišnik et al., 2013).Hexadecyltrimethylammonium showed also high affinity for DS, thus
Fig. 5. In vitro dissolution profiles of DS from (a) drug-modified zeolite composites (closedsymbols) and drug-modified zeolite physical mixtures (open symbols) (b) physical mix-tures with different (mmol HB/mmol DS) molar ratio.
release of diclofenac sodiumbymodified zeolites composites, Applied
prolonged similar drug release from corresponding physical mixtures(DHB-10 P, DHB-20 P and DHB-30 P) was observed indicating similarrelease mechanism. Since the most similar release profile was achievedwith DHB-20 P with the maximum DS release of 28%, it was chosen forfurther investigations. To investigate if an increase of DS amount inphysical mixtures (closer to the therapeutic dose) could also enableprolonged DS release, dissolution of DS from additional physical mix-tures at lower (mmol HB/mmol DS) ratios (Table 1) was followed. Forall physical mixtures, the amount of DS released increased over time(Fig. 5b). It was noticed that dissolution of DS increasedwith decreasingmolar ratio in physical mixture (28% for DHB-20 P, 44% for DHB-20 Pa,53% for DHB-20 Pb and 85% DHB-20 Pc) indicating that, the highestamount of DS was released from the physical mixture with the highestDS amount (150 mg/g). Also, from the slopes of the curves presented inFig. 5b, it can be seen that the dissolution was faster with increasing theamount of DS in the physical mixture. Because of the reported strong af-finity of HB for DS, to define optimal amount of the drug in the physicalmixture necessary for prolong drug release, determination of drug ad-sorption capacity is essential. Additionally, the detailed characterizationof composites before and after adsorption of the drug is helpful in defi-nition of interactions between composite and drug.
4. Conclusions
Results on adsorption of diclofenac sodium (DS) bymodified naturalzeolite composites at three levels (10, 20 and 30 mmol/100 g) of cation-ic surfactant-hexadecyltrimethylammonium bromide (HB) showedproportional increase of drug adsorption by increasing the amount ofsurfactant used for modification. Characterization of drug-modifiedcomposites revealed interactions between DS andHB at the zeolitic sur-face. In vitro release data of the drug-modified zeolite composites andcorresponding physical mixtures showed that the prolonged DS releasefor both group of samples over a period of 8 h was achieved. Thepresented results showed that the investigated materials could be suc-cessfully used as a functional drug formulation excipient.
Acknowledgments
Thisworkwasdoneunder the projects TR34031 andOI 172018 sup-ported by the Ministry of Education, Science and Technological Devel-opment, Republic of Serbia. The authors express special thanks to Prof.George E. Rottinghaus for his helpful comments and suggestions onthe manuscript.
The company ˝Nemetali˝ from Vranjska Banja, Serbia kindly provid-ed the natural zeolitic sample for this research. The authors would likealso to thank Jugoslav Krstić, MSc., Institute for Chemistry, Technology& Metallurgy, University of Belgrade for performing FTIR analysis.
Please cite this article as: Krajišnik, D., et al., Investigation of adsorption andClay Science (2013), http://dx.doi.org/10.1016/j.clay.2013.08.011
References
Bhattacharyya, L., Shuber, S., Sheehan, S., William, R., 2006. Excipients: background/introduction. In: Katdare, A., Chaubal, M.V. (Eds.), Excipient Development forPharmaceutical, Biotechnology, and Drug Delivery Systems. Informa HealthcareUSA, Inc., New York, pp. 1–2.
Bonferoni, M.C., Cerri, G., de' Gennaro, M., Juliano, C., Caramella, C., 2007. Zn2+-exchangedclinoptilolite-rich rock as active carrier for antibiotics in anti-acne topical therapy: in-vitro characterization and preliminary formulation studies. Appl. Clay Sci. 36,95–102.
Carretero, M.I., Pozo, M., 2009. Clay and non-clayminerals in the pharmaceutical industry.Part I. Excipients and medical applications. Appl. Clay Sci. 46, 73–80.
Carretero, M.I., Pozo, M., 2010. Clay and non-clay minerals in the pharmaceutical and cos-metic industries. Part II. Active ingredients. Appl. Clay Sci. 47, 171–181.
Carson, J., Notis, W.M., Orris, E.S., 1990. Colonic ulceration and bleeding during diclofenactherapy (I). N. Engl. J. Med. 323, 135.
Cerri, G., De Gennaro, M., Bonferoni, M.C., Caramella, C., 2004. Zeolites in biomedicalapplication: Zn-exchanged clinoptilolite-rich rock as active carrier for antibioticsin anti-acne topical therapy. Appl. Clay Sci. 27, 141–150.
Daković, A., Tomašević-Čanović, M., Rottinghaus, G.E., Matijašević, S., Sekulić, Ž., 2007a.Fumonisin B1 adsorption to octadecyldimethylbenzyl ammonium-modified clinoptilolite-rich zeolitic tuff. Microporous Mesoporous Mater. 105, 285–290.
Daković, A., Matijašević, S., Rottinghaus, G.E., Dondur, V., Pietrass, T., Clewett, F.M., 2007b.Adsorption of zearalenone by organomodified natural zeolitic tuff. J. Colloid InterfaceSci. 311, 8–13.
Haggerty, G.M., Bowman, R.S., 1994. Sorption of chromate and other inorganic anions byorgano-zeolite. Environ. Sci. Technol. 28, 452–458.
Javadzadeh, Y., Adibkia, K., Bozorgmehr, Z., Dastmalchi, S., 2012. Evaluating retardationand physicochemical properties of co-ground mixture of Na-diclofenac with magne-sium stearate. Powder Technol. 218, 51–56.
Krajišnik, D., Milojević, M., Malenović, A., Daković, A., Ibrić, S., Savić, S., Dondur, V.,Matijašević, S., Radulović, A., Daniels, R., Milić, J., 2010. Cationic surfactants-modified natural zeolites: improvement of the excipient functionality. Drug Dev.Ind. Pharm. 36 (10), 1215–1224.
Krajišnik, D., Daković, A., Milojević, M., Malenović, A., Kragović, M., Bajuk-Bogdanović, D., Dondur, V., Milić, J., 2011. Properties of diclofenac sodium sorp-tion onto natural zeolite modified with cetylpyridinium chloride. Colloids Surf.,B 83, 165–172.
Krajišnik, D., Daković, A., Malenović, A., Djekić, Lj, Kragović, M., Dobričić, V., Milić, J., 2013.An investigation of diclofenac sodium release from cetylpyridinium chloride-modified natural zeolite as a pharmaceutical excipient. Microporous MesoporousMater. 167, 94–101.
Li, Z., Bowman, R., 1998. Sorption of perchloroethylene by surfactant-modified zeolite ascontrolled by surfactant loading. Environ. Sci. Technol. 32, 2278–2282.
Li, Z., Roy, S., Zou, Y., Bowman, R., 1998. Long-term chemical and biological stability ofsurfactant-modified zeolite. Environ. Sci. Technol. 32, 2628–2632.
Li-Hua, W., Chowhan, Z., 1990. Drug-excipient interactions resulting from powdermixing. V. Role of sodium lauryl sulfate. Int. J. Pharm. 60, 61–78.
Oddsson, E., Gudjonsson, H., Thjodleifsson, B., 1990. Endoscopic findings in the stomachand duodenum after treatment with enteric-coated and plain naproxen tablets inhealthy subjects. Scand. J. Gastroenterol. 25, 231–234.
Rowe, R.C., Sheskey, P.J., Owen, S.C. (Eds.), 2006. Handbook of Pharmaceutical Excipients,fifth ed. Pharmaceutical Press and American Pharmacists Association, London &Washington.
Sweetman, S.C. (Ed.), 2009. Martindale. The Complete Drug Reference, Thirty-sixth edi-tion. Pharmaceutical Press, London, p. 46.
Todd, P.A., Sorkin, E.M., 1988. Diclofenac sodium. A reappraisal of its pharmacody-namic and pharmacokinetic properties, and therapeutic efficacy. Drugs 35,244–285.
United States Pharmacopeia 30 (USP 30), 2007. United States Pharmacopoeial Conven-tion, Rockville, MD.
Witham, R., 1991. Voltaren (diclofenac sodium)-induced ileocolitis. Am. J. Gastroenterol.86, 246–247.
release of diclofenac sodiumbymodified zeolites composites, Applied
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