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 paracetamol with the most common used antibiotics for children. Amoxicillin, azithromycin, cefuroxime axetil and their commercially available suspensions, Amoxil ®, Azithromax ® and Zinnat ® were used. DSC curves for paracetamol, pure antibiotics, commercially available antibiotics and all binary mixtures used in this study showed drug-drug or drug-excipient (s) physical interaction and indicated 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. Results obtained from ATR-IR spectra showed drug-excipient (s) interaction in Zinnat ®, Azithromax ® and binary mixture Azithromax ®-paracetamol, while chemical drug-drug interaction was not observed. From this study it can be concluded that the concomitant oral administration of paracetamol with commercially available 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.
There are three classes of drug incompatibilities: therapeutic, physical and chemical. Therapeutic incompatibilities are the modification of the therapeutic effect of one drug by the prior concomitant administration of another. Physical incompatibilities are often called pharmaceutical incompatibilities and are evidenced by the failure of the drug to combine properly. Chemical incompatibilities occur when prescribed agents react chemically upon combination to alter the composition of one or more of the ingredients [
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 [
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, septicemia, ear infection, skin infection and meningitis. In general practice, antibiotic drug use is highest among children and approximately 70% of all antibiotics in children are prescribed for upper respiratory tract infections. Infections almost associated with fever in children, fever might rise very quickly or it might come on slowly and rise over a few days [
Commercial antibiotic suspensions (Amoxil®, Azithromax® and Zinnat®) were purchased from the local Saudi pharmacies. Pure amoxicillin, azithromycin and cefuroxime as well as Paracetamol powders were donated by Deef (Deef, Qassim, Kingdom of Saudi Arabia).
Preparation of Samples
The samples were prepared by weighing 10 mg from a mixture of paracetamol/ Pediatric suspension (1:1 w/w) and placing it in a glass vial. The glass vial was initially turned over several times to prevent the particles from sticking to the sides of the vial and then shaken vigorously for 3 min by hand.
Differential Scanning Calorimetry (DSC)
The thermal profiles of all materials and mixtures used in this study were measured by DSC-60 (Shimazo, Japan) using 4 - 6 mg of sample in open aluminum pans, with empty pan as a reference. The temperature increased with a heating rate of 10˚C /min from 30˚C to 250˚C under a nitrogen gas flow.
FT-IR Spectroscopy
Diamond ATR-IR spectra for paracetamol, amoxicillin, azithromycin, cefuroxime, Amoxil®, Azithromax®, Zinnat® and their mixtures were obtained over the range of 400 - 4000 cm−1 by using Bruker Tensor 27 FT-IR equipped with a horizontal Attenuated Total Reflectance (ATR) device with a diamond crystal. Spectra were recorded using OPUS software (Bruker Optik, Germany) by averaging 100 scans for each spectrum with resolutions of 2 cm−1. Background spectra were obtained and subtracted from each sample IR spectra.
As shown in
w/w) showed that the addition of pure paracetamol (melting peak 170.5˚C) to amoxicillin produced disappearance of the two endothermic peaks of amoxicillin observed at 195.0˚C and 222.3˚C and appearance of new endothermic curve with two peaks at 166.7˚C and 168.9˚C indicating a strong interaction between paracetamol and amoxicillin. This interaction was also associated with increase in the height of the exothermic peak that shifted to 153.9˚C. DSC curves for Amoxil® (commercially available suspension of amoxicillin for children) and a mixture of Amoxil®/paracetamol (1:1 w/w) were compared with DSC curves of pure amoxicillin with and without paracetamol. DSC curve for Amoxil® suspension showed three endothermic peaks at 102.8˚C, 191.4˚C and 219.1˚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® suspension. Also, addition of paracetamol to Amoxil® suspension (1:1 w/w) showed an interaction of paracetamol with Amoxil® suspension by decreasing the endothermic peak from 102.8˚C to 91.7˚C and margining of three curves (two for Amoxil® suspension and one for paracetamol) in to one broad curve with three peaks at 168.3˚C, 176.8˚C and 189.9˚C (
DSC curve for cefuroxime axetil showed three endothermic peaks at 85.8˚C, (∆H = −5.83 j g−1) 105.2˚C (∆H = −6.09 j g−1) and 181.7˚C (∆H = −3.08 j g−1) which indicates that the pure drug was polymorphs (
The addition of paracetamol to Zinnat® produced an appearance of new peaks at 97.0˚C and 149.8˚C as well as broadening and reducing the endothermic peak present at 181.8˚C to 176.1˚C, which indicate an interaction between paracetamol and Zinnat®.
DSC curves for the binary mixtures (1:1 w/w) consist of paracetamol and pure antibiotics (amoxicillin, azithromycin and cefuroxime axetil) or for paracetamol and commercially available suspensions of antibiotics used for children (Amoxil®, Azithromax® and Zinnat®) showed physical drug-drug 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 paracetamol, 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 FT-IR.
The Diamond ATR-IR spectra for pure paracetamol showed characteristic O-H, N-H, C=O (amide) stretching bands at 3322.38 cm−1, 3160.66 cm−1 and 1650.32 cm−1, respectively. Also, the amide II bands C-N-H group, para-disubstituted aromatic rings at 1561.34 cm−1, 1258.23 cm−1 and 836.25 cm−1, respectively, were observed.
The Diamond ATR-IR spectra for pure amoxicillin showed a band at 3447.5 cm−1 (O-H, N-H stretching vibration) and characteristic peaks at 1772.78 cm−1 (C=O stretching of β-lactamic), 1684.94 cm−1 (C=O stretching of amide), 1578.05 cm−1 (asymmetric stretching of carboxylate) and 1002 cm−1 (C=O stretching vibration). The Diamond ATR-IR spectra for Amoxil® were almost same with the spectra obtained for amoxicillin as shown in
The ATR-IR spectra for azithromycin (
The ATR-IR spectra for Azithromax® showed the appearance of new peaks at 3384.40 cm−1 and 3330.55 cm−1 as well as the disappearance of some azithromycin peaks at 3488.84 cm−1, 2913.17 cm−1, 1719.86 cm−1, 1653.29 cm−1 and 1558.47 cm−1 indicating that azithromycin was interacted with the excipients present in Azithromax® suspension (
The ATR-IR spectra for cefuroxime axetil (
The ATR-IR spectra (
Product | Excipients |
---|---|
Amoxil® | Maltodextrin (glucose), carboxymethylcellulose Sodium, lemon-Peach-Strawberry, dry flavor, crospovidone, aspartame (E951), sodium benzoate (E211), xanthan Gum (E415), silica hydrophobic colloidal, magnesium Stearate |
Zinnat® | Aspartame, xanthan gum, acesulfame potassium, povidone K30 stearic Acid, sucrose, tutti frutti flavor, purified water, sucrose |
Azithromax® | Hydroxypropylcellulose, sodium phosphate tribasic anhydrous, sucrose, xanthan gum, artificial banana, artificial cherry, artificial creme de vanilla |
It is important to note that the three commercial products Amoxil®, Azithromax® and Zinnat® containing deferent types of excipients as shown in
The DSC curves for the mixtures of paracetamol with most common used antibiotics for children (pure or commercially available suspensions) showed physical interaction. While chemical interaction in solid state (drug-excipients) was observed by FTIR for Zinnat® (cefuroxime-excipients), Azithromax® (azithromycin- excipients) and mixture of Azithromax®-paracetamol (paracetamol-excipients interaction). Results obtained from FTIR showed that drug-drug interaction was not occurring. However, physical or chemical interaction in case of concomitant oral administration of paracetamol with most common used antibiotic for children may affect the physicochemical properties, dissolution rate, solubility, absorption and bioavailability for one or for both drugs. From this study it can be concluded that the concomitant oral administration of paracetamol 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.
Maswadeh, H. (2017) Incompatibility of Paracetamol with Pediatric Suspensions Containing Amoxicillin, Azithromycin and Cefuroxime Axetil. Pharmacology & Pharmacy, 8, 355-368. https://doi.org/10.4236/pp.2017.811026