CONCOMITANT ORAL ADMINISTRATION OF IBUPROFEN AND SOME COMMONLY USED ANTIBIOTICS FOR CHILDREN: COMPATIBILITY STUDY USING DSC AND FTIR

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1 Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 74 No. 6 pp. 1627ñ1636, 2017 ISSN Polish Pharmaceutical Society ANALYSIS CONCOMITANT ORAL ADMINISTRATION OF IBUPROFEN AND SOME COMMONLY USED ANTIBIOTICS FOR CHILDREN: COMPATIBILITY STUDY USING DSC AND FTIR HAMZAH MASWADEH Department of Pharmaceutics, College of Pharmacy, Qassim University, P. O. Box 6800, Buraydah, 51452, Kingdom of Saudi Arabia Abstract: The main objective of this work was to use the Differential Scanning Calorimetry (DSC) and FTIR spectroscopy to study the possible drug-drug or drug-excipient(s) interaction in case of concomitant oral administration of ibuprofen with the most common used antibiotics for children. Amoxicillin, azithromycin, cefuroxime axetil and their commercially available suspensions, Amoxil Æ, Azithromax Æ and Zinnat Æ were used. DSC curves for ibuprofen, pure antibiotics, commercially available antibiotics and all binary mixtures used in this study showed drug-drug or drug-excipient(s) interaction and indicate a possible chemical interaction. To confirm chemical drug-drug or drug-excipient(s) interaction additional ATR-IR spectra for all samples used in this study were obtained. Chemical interaction in solid state (drug-drug interaction) was observed by FTIR between cefuroxime axetil and ibuprofen in the binary mixture cefuroxime axetil / ibuprofen (1 : 1, w/w). Also a chemical interaction in solid state (drug-excipients interaction) was observed in Zinnat Æ suspension (between cefuroxime and excipients), Azithromax Æ suspension (between azithromycin and excipients) and mixture of Azithromax Æ -ibuprofen (between ibuprofen and excipients). From this study it can be concluded that the concomitant oral administration of ibuprofen with commercially available antibiotics used in this study in not recommended and duration of two hours between the oral administrations of these drugs is strongly recommended to avoid drug-drug or drug-excipient(s) interaction. Keywords: ibuprofen, amoxicillin, azithromycin, cefuroxime axetil, compatibility, DSC, FTIR, drug-drug interaction Ibuprofen, a commonly used Non-Steroidal Anti-inflammatory (NSAID), shows slow dissolution and high permeability through stomach. According to the Biopharmaceutics Classification System, ibuprofen is classified as class II drug in which the dissolution is rate limiting step in the process of drug absorption (1-4). Compatibility studies are usually aimed at identifying the most common incompatibility, for example, an incompatibility in dosage form can be identified as any of the following changes: change in appearance, decrease in potency, loss in mechanical properties, changes in dissolution profile, loss through sublimation and increase in degradation products (5-8). Previous studies reported that ibuprofen was incompatible with Eudragit due to physical and chemical interaction with the carboxylic group of ibuprofen, because of electrostatic interactions and / or hydrogen bonding with the quaternary ammonium groups in Eudragit (9). Recent study showed that the decrease in the dissolution rate of ibuprofen in ternary interactive mixture was due to the incompatibility of ibuprofen with lactose and polyvinylpyrrolidone (10). Another study showed that ibuprofen was incompatible with polyethylene glycol (PEG) in tablets stored for three weeks at 70 O C resulting in the ibuprofen degradation (11). A solid-solid reaction of ibuprofen with magnesium oxide, calcium oxide, magnesium hydroxide, sodium bicarbonate and potassium carbonate were also observed (12). A number of experimental techniques (i.e., DSC, X-ray powder diffraction, optical and Electron Microscopy, FTIR spectroscopy, etc.) have been used to investigate the interaction between drug and excipients (13-16). Differential Scanning Calorimetry is a quick technique to investigate drug-drug or excipient-drug incompatibility derived from the * Corresponding author: msodh@qu.edu.sa; maswadehhamza@hotmail.com; phone: ; fax:

2 1628 HAMZAH MASWADEH appearance, disappearance or shifts of peaks and/ or variation in the corresponding H (enthalpy of transition) (17-19). Antibiotics are compounds that are used to treat infection caused by bacteria and fungi. They are very useful medications used to treat bacterial infections in children, including pneumonia, skin infection, septicemia, ear infection and meningitis. Infections almost associated with fever in children, fever might rise very quickly or it might come on slowly and rise over a few days (20-22). Doctors usually describe an antibiotic with an antipyretic drug for children and the common practice of oral administration is to administer both formulations at the same time. The antibiotics used for children present in the market in form of suspension, while the syrup form is the most common formulation for antipyretic present in the market, both formulations containing different excipients. It is possible that in case of concomitant oral administration of antibiotic formulation (suspension) with the antipyretic formulation (syrup), drug-drug or drug-excipient(s) present in the second formulation interaction may occur. In this study we investigate drug-drug or drug-excipient (present in the second formulation) compatibility in case of concomitant oral administration of ibuprofen with three most common used antibiotics for children (amoxicillin, azithromycin and cefuroxime axetil) by using DSC and FTIR. A Figure 1. DSC curves for amoxicillin, ibuprofen, mixture of amoxicillin / ibuprofen (1 : 1, w/w), Amoxil Æ and mixture of Amoxil Æ / ibuprofen (1 : 1, w/w)

3 Concomitant oral administration of ibuprofen and some commonly used Figure 2. DSC curves for azithromycin, ibuprofen, mixture of azithromycin / ibuprofen (1 : 1 w/w), Azithromax Æ and mixture of Azithromax Æ / ibuprofen (1 : 1, w/w) comparison study between the mixtures of pure antibiotics or/ commercially available antibiotic suspensions (Amoxil Æ, Azithromax Æ and Zinnat Æ ) with ibuprofen was also investigated. EXPERIMENTAL Materials Commercial antibiotic suspensions (Amoxil Æ, Azithromax Æ and Zinnat Æ ) were purchased from the local Saudi pharmacies. Pure amoxicillin, azithromycin and cefuroxime axetil as well as ibuprofen powders were donated by Deef (Deef, Qassim, Kingdom of Saudi Arabia). Differential scanning calorimetry (DSC) The thermal profiles of all materials and mixtures used in this study were measured by DSC-60 (Shimadzu, Japan) using 4-6 mg of sample in open aluminum pans, with empty pan as a reference. The

4 1630 HAMZAH MASWADEH temperature increased with a heating rate of 10 O C/min from 30 O C to 250 O C under a nitrogen gas flow. FTIR spectroscopy Diamond ATR-IR spectra for ibuprofen, amoxicillin, azithromycin, cefuroxime axetil, Amoxil Æ, Azithromax Æ, Zinnat Æ and their mixtures were obtained between 400 and 4000 cm -1 by using Bruker Tensor 27 FTIR to study any possible drugñdrug or drug-excipient(s) interaction. RESULTS AND DISCUSSION As shown in Figure 1, pure amoxicillin exhibits a first endothermic peak appeared at O C ( H = j g -1 ), which corresponds to the dehydration of amoxicillin. The second and third endothermic peaks appeared at O C and O C attributed to the amoxicillin fusion degradation event ( H = j g -1 and j g -1, respectively). Also, amoxicillin DSC curve displays an exothermic peak at O C represent the amox- Figure 3. DSC curves for cefuroxime axetil, ibuprofen, mixture of cefuroxime axetil / ibuprofen (1 : 1 w/w), Zinnat Æ and mixture of Zinnat Æ / ibuprofen (1 : 1 w/w)

5 Concomitant oral administration of ibuprofen and some commonly used Figure 4. ATR-IR spectra for (A) amoxicillin (B) ibuprofen (C) mixture of amoxicillin / ibuprofen (1 : 1 w/w) (D) Amoxil Æ and (E) mixture of Amoxil Æ / ibuprofen (1 : 1 w/w)

6 1632 HAMZAH MASWADEH Figure 5. ATR-IR spectra for (A) azithromycin (B) ibuprofen (C) mixture of azithromycin / ibuprofen (1 : 1 w/w) (D) Azithromax Æ and (E) mixture of Azithromax Æ / ibuprofen (1 : 1 w/w)

7 Concomitant oral administration of ibuprofen and some commonly used Figure 6. ATR-IR spectra for (A) cefuroxime axetil (B) ibuprofen (C) mixture of cefuroxime axetil / ibuprofen (1 : 1 w/w) (D) Zinnat Æ and (E) mixture of Zinnat Æ / ibuprofen (1 : 1 w/w)

8 1634 HAMZAH MASWADEH icillin transition into the crystal state ( H = j g -1 ). DSC curve for the mixture of amoxicillin / ibuprofen (1 : 1, w/w) showed interaction between ibuprofen (melting peak 77.4 O C) and amoxicillin indicated by the disappearance of the exothermic peak of amoxicillin as well as by a decrease of the endothermic peak of amoxicillin from O C to 98.7 O C. Also a new endothermic broad curve with a peak at O C was appeared instead of the two endothermic peaks of amoxicillin observed at O C and O C supporting the presence of interaction between ibuprofen and amoxicillin.dsc curves for Amoxil Æ (commercially available suspension of amoxicillin for children) and a mixture of Amoxil Æ / ibuprofen (1 : 1, w/w) were compared with DSC curves of pure amoxicillin with and without ibuprofen. DSC curve for Amoxil Æ suspension showed three endothermic peaks at O C, O C and O C, the exothermic peak of pure amoxicillin was disappeared and a small decrease of the three endothermic peaks was observed due to a possible interaction of amoxicillin with the excipient(s) present in Amoxil Æ suspension. Also, the addition of ibuprofen to Amoxil Æ suspension (1 : 1, w/w) showed an interaction of ibuprofen with Amoxil Æ suspension by complete disappearance of the endothermic peak of Amoxil Æ present at O C as well as the appearance of new small endothermic peak at O C (Fig. 1). Figure 2 shows the DSC curves for pure azithromycin, pure ibuprofen, mixture of azithromycin / ibuprofen (1 : 1 w/w), Azithromax Æ suspension for children and mixture of Azithromax Æ / ibuprofen (1 : 1 w/w). DSC curve for pure azithromycin showed one small exothermic peak at 87.5 O C ( H = 1.50 j g -1 ) and two endothermic peaks at 95.4 O C ( H = j g -1 ) and O C ( H = j g -1 ). The addition of ibuprofen to azithromycin produced disappearance of the exothermic peak at 87.5 O C as well as the two endothermic peaks at 95.4 O C and O C, associated with the appearance of new endothermic peaks at O C and O C which indicate drug-drug interaction. DSC curve for Azithromax Æ suspension (commercially available suspension of azithromycin for children) was completely different from pure azithromycin due to the presence of excipients. DSC curve for Azithromax Æ suspension showed that the second endothermic peak at O C was disappeared; also, new peaks at 69.5 O C, O C, O C and O C were appeared due to the presence of excipients in Azithromax Æ suspension. Figure 2 showed that the addition of ibuprofen to Azithromax Æ suspension (1 : 1 w/w) produced a decrease in the first endothermic peak from 69.5 O C to 58.6 O C and complete disappearance of endothermic peaks present at O C and O C. DSC curve for cefuroxime axetil showed three endothermic peaks at 85.8 O C, ( H = j g -1 ) O C ( H = j g -1 ) and O C ( H = j g -1 ) which indicates that the pure drug was polymorphs (Fig. 3). The binary mixture of ibuprofen and cefuroxime axetil (1 : 1, w/w) showed an increase in the third endothermic peak to O C, while the first and second endothermic peaks were disappeared, indicating an interaction between ibuprofen and cefuroxime axetil. The DSC for Zinnat Æ (commercially available suspension of cefuroxime for children) showed new additional endothermic peaks at 57.1 O C and O C due to the presence of excipients in the formulation. The addition of ibuprofen to Zinnat Æ (1 : 1. w/w) produced disappearance of the endothermic peaks present at 78.6 O C and O C and reduced the endothermic peak present at 57.1 O C to 54.5 O C; also the peak of ibuprofen was reduced to 69.3 O C indicating an interaction between ibuprofen and Zinnat Æ suspension. DSC curves for the binary mixtures (1 : 1, w/w) consist of ibuprofen and pure antibiotics (amoxicillin, azithromycin and cefuroxime axetil) or for ibuprofen and commercially available suspensions of antibiotics used for children (Amoxil Æ, Azithromax Æ and Zinnat Æ ) showed physical drugdrug or drug-excipient(s) interaction and indicate a possible chemical drug-drug or drug-excipient(s) interaction. To confirm a chemical drug-drug or drug-excipient(s) interaction an additional diamond ATR-IR spectra for ibuprofen, pure antibiotics, commercially available antibiotics and all binary mixtures used in this study were obtained between 400 and 4000 cm -1 by using Bruker Tensor 27 FTIR. The ATR-IR spectra for pure ibuprofen showed characteristic peaks at cm -1 (hydroxyl stretching), cm -1 (carbonyl stretching), cm -1 (aromatic disubstitution), cm -1 (-OH group bending vibrations), cm -1, cm -1 and cm -1 (aromatic structure bending vibration). The ATR-IR spectra for pure amoxicillin showed a band at cm -1 (O-H, N-H stretching vibration) and characteristic peaks at cm -1 (C=O stretching of β-lactamic), cm -1 (C=O stretching of amide), cm -1 (asymmetric stretching of carboxylate) and cm -1 (C=O stretching vibration ). The ATR- IR spectra for Amoxil Æ and mixture of Amoxil Æ / ibuprofen (1 : 1 w/w) as well as for amoxicillin and mixture of amoxicillin / ibuprofen (1 : 1 w/w)

9 Concomitant oral administration of ibuprofen and some commonly used showed no chemical drug-drug or drug-excipient interaction in solid state (Fig. 4). The ATR-IR spectra for azithromycin (Fig. 5) showed bands at cm -1 ñ cm -1 and cm -1 related to the axial stretching and bending of C-H of the methyl groups. The axial stretching of the C=O was observed at cm -1. Other bands in the spectrum in the range of cm -1 ñ cm -1 were appeared due to the absorption associated to the axial stretching of C-O. Also, ATR-IR spectra in Figure 5 for the mixture of azithromycin / ibuprofen (1 : 1 w/w) showed all characteristic peaks of both drugs without any significant shift indicating the absence of drug-drug interaction in solid state. The ATR-IR spectra for Azithromax Æ showed the appearance of new peaks at cm -1 and cm -1 as well as the disappearance of some azithromycin peaks at cm -1, cm -1, cm -1, cm -1 and cm -1 indicating that azithromycin was interacted with the excipients present in Azithromax Æ suspension (Fig. 5). The ATR-IR spectra for the mixture Azithromax Æ / ibuprofen (1 : 1 w/w) showed that the peak of pure ibuprofen at cm -1 was shifted to higher wave number ( cm -1 ) and that the peaks at cm -1 and cm -1 were disappeared indicating solid-solid interaction between ibuprofen and excipient(s) present in Azithromax Æ suspension. The ATR-IR spectra for cefuroxime axetil (Fig. 6) showed characteristic NH stretching, β-lactam C=O stretching, amide C=O stretching and carboxylate stretching O=C=O at cm -1, cm -1, cm -1 and cm -1, respectively. The ATR-IR spectra for the mixture of cefuroxime axetil / ibuprofen (1 : 1 w/w) showed that drug-drug interaction was occurred by disappearance of some peaks of cefuroxime axetil at cm -1, cm -1, cm -1 and cm -1. The ATR-IR spectra (Fig. 6) for Zinnat Æ showed that new peaks were appeared at cm -1, cm -1, cm -1, cm -1, cm -1, cm -1, cm -1 and cm -1 duo to the presence of some excipients in Zinnat Æ suspension. Also, the disappearance of some peaks ( cm -1, cm -1, cm -1, cm -1 and cm -1 ) of pure cefuroxime axetil from Zinnat Æ spectra indicates drug-excipient(s) interaction in solid state. The ATR-IR spectra obtained for the mixture of Zinnat Æ / ibuprofen (1 : 1 w/w) showed no interaction between ibuprofen and Zinnat Æ suspension in solid state. CONCLUSIONS The DSC curves for the binary mixtures of ibuprofen with most common used antibiotics for children (pure or commercially available suspensions) showed physical interaction. Chemical interaction in solid state (drug-drug interaction) was observed by ATR-IR between cefuroxime axetil and ibuprofen in the binary mixture cefuroxime axetil / ibuprofen (1 : 1 w/w). Also chemical interaction drug-excipients in solid state was observed in Zinnat Æ suspension (cefuroximeexcipients), Azithromax Æ (azithromycin-excipients) and mixture of Azithromax Æ / ibuprofen (ibuprofen-excipients). Physical or chemical interaction in case of concomitant oral administration of ibuprofen with most commonly used antibiotic for children may affect the physicochemical properties such as dissolution rate, solubility and absorption, which can reduce bioavailability for one or for both drugs. From this study it can be concluded that the concomitant oral administration of ibuprofen with antibiotics used in this study is not recommended and duration of two hours between the oral administrations of these drugs is strongly recommended to avoid drug-drug or drug-excipient(s) interaction. REFERENCES 1. Saharan V., Kataria M., Gera M., Choudhury P.: Int. J. Health Res. 2, 107 (2009). 2. Patel R., Nirav P., Patel N., Patel M.: Int. J. Res. Pharm. Sci. 1, 57 (2010). 3. Rasenack N., M ller B.: Int. J. Pharm. 245, 9 (2002). 4. Charoenchaitrakool M., Dehghani F., Foster NR., Chan H.K.: Ind. Eng. Chem. Res. 39, 4794 (2000). 5. Hotha K.K., Roychowdhury S., Subraqmanian V.: Am. J. Anal. Chem. 7, 107 (2016). 6. Maswadeh H.: Acta Pol. Pharm. 73, 739 (2016). 7. Ajit SN., Divyakant D., Sherif B.: Pharm. Res. 29, 2660 (2012). 8. Bruni G., Amici L., Berbenni V., Marini A., Orlandi A.: J. Therm. Anal. Calorim. 68, 561 (2002). 9. Tişa B1., Fulia A., Bandur G., Marian E., Tişa D.: J. Pharm. Biomed. Anal. 56, 221 (2011). 10. Maswadeh H.: J. Therm. Anal. Calorim. 123, 1963 (2016). 11. Sekizaki H., Danjo K., Eguchi H., Yonezawa Y., Sunada H., Otsuka A.: Chem. Pharm. Bull. 43, 988 (1995).

10 1636 HAMZAH MASWADEH 12. Bogdanova S., Pajeva I., Nikolova P., Tsakovska I., Muller B.: Pharm. Res. 22, 806 (2005). 13. Pignatello R., Spadaro D., Vandelli M.A., Forni F., Puglisi G.: Drug Dev. Ind. Pharm. 30, 277 (2004). 14. Cory W.C., Harris C., Martinez S.: Pharm. Dev. Technol. 15, 636 (2010). 15. Pani N., Nath L., Acharya S., Bhuniya B.: J. Therm. Anal. Calorim. 108, 219 (2012). 16. Mura P., Manderioli A., Bramanti G., Furlanetto S., Pinzauti S.: Int. J. Pharm. 119, 71 (1995). 17. Botha S.A., Lotter A.P.: Drug Dev. Ind. Pharm. 16, 331 (1990). 18. Marini A., Berbenni V., Pegoreti M., Bruni G., Cofrancesco P. et al.: J. Therm. Anal. Calorim. 73, 547 (2003). 19. Misra M., Misra A.K., Panpalia G.M.: J. Therm. Anal. Calorim. 89, 803 (2007) Majeed A., Moser K.: Br. J. Gen. Pract. 49, 735 (1999). 21. Vaccheri A., Castelvetri C., Esaka E.: Eur. J. Clin. Pharmacol. 56, 417 (2000). 22. Nyquist A.C., Gonzales R., Steiner J.F.: JAMA. 279, 875 (1998). Received:

International Journal of PharmTech Research CODEN (USA): IJPRIF, ISSN: Vol.7, No.1, pp 22-26,

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