In vitro Interaction of Fexofenadine with H2 Receptor Antagonist
Hina Shahnaz1*, M. Saeed Arayne2, Najma Sultana2 and Amir Haider2
1Department of Chemistry, University of Karachi, Karachi.
2Research Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Karachi, Karachi.
*Corresponding Author E-mail: hinashehnaz@gmail.com
ABSTRACT:
Fexofenadine is a second generation H1-receptor antagonist, much widely used due to its non-sedative effects. The in vitro availability of fexofenadine in the presence of H2-receptor antagonist (cimetidine, ranitidine and famotidine) was studied on a BP 2005 dissolution test apparatus to observe the kinetics and energies of fexofenadine in the presence of H2-receptor antagonist (cimetidine, ranitidine and famotidine). These studies were carried out in buffers of pH 2, 4 (simulated gastric juice), 7.4 (blood pH) and 9 (simulated intestinal juice) at 37°C and at elevated temperatures. These studies showed that all H2-receptor antagonist (cimetidine, ranitidine and famotidine) interact to fexofenadine. Moreover, these interactions were not temperature dependent but pH dependent.
KEYWORDS: Fexofenadine, H1-receptor antagonist, in vitro, H2-receptor antagonist, interactions.
Fexofenadine (Fig. 1), a non-anticholinergic, non-sedative antihistamine [1] is prescribed for oral treatment of allergic rhinitis and chronic urticaria [2]. It is a recemate and exists as zwitter ions in aqueous media at physiological pH [3-5]. The non sedating fexofenadine actually is an active metabolite of terfenadine [6, 7]. In seasonal allergic rhinitis, a comparative trial showed that the effect of fexofenadine (120 mg/day in a single intake) is moderate and not different from that of cetirizine. The most common adverse events were headache, throat irritation, viral infection, nausea, dysmenorrhoea, drowsiness, dyspepsia and fatigue [8].
Fexofenadine has been identified as a substrate for the efflux transporter, P-glycoprotein (P-gp), as well as the influx transporter, organic anion transporting polypeptide (OATP). Findings suggest that in rats, fruit juices may also preferentially inhibit OATP rather than P-gp-mediated transport fexofenadine oral absorption, albeit to a lesser extent than observed in humans [9]. Juices also decreased the absorption of the non metabolized OATP substrate, fexofenadine. Taken together, the data support inhibition of intestinal uptake transporters by fruit juices to decrease drug bioavailability [9].
St John's Wort (Hypericum perforatum) is one of the most commonly used herbal antidepressant which decreased the blood concentrations of amitriptyline, cyclosporine, digoxin, fexofenadine, indinavir, methadone, midazolam, nevirapine, phenprocoumon, simvastatin, tacrolimus, theophylline and warfarin [10, 11]. The inhibitory action of fexofenadine may be partially responsible for the attenuating effect of the agent on allergic diseases [12-16]. The bioavailability of fexofenadine was increased after nasal administration of the microsphere formulation in rabbits [17] and the significant increase of area under curve of fexofenadine enantiomers in presence of itraconazole and/or verapamil [18]. Fexofenadine bioavailability also reduced by taking long term use panax ginseng [19].
The histamine H2 receptor antagonists are widely used in the management of peptic ulcer. They include cimetidine, famotidine, nizatidine, niperotidine, ranitidine and roxatidine [9]. H2-receptor antagonists fall into four main structural classes. Cimetidine is an imidazole derivative; ranitidine belongs to the basically substituted furans, famotidine a member of the guanidinothiazole group and roxatidine belongs to the amino alkyl phenoxy series. Famotidine is the most potent, selective H2-receptor antagonist yet available for ulcer therapy [20]. Famotidine and cimetidine were efficiently taken up by mkOAT3-expressing human embryonic kidney cells and their uptake was strongly inhibited by probenecid [21]. The imidazole ring of cimetidine and carboxylic acid moiety of naproxen interacted in 1:1 solid state proved by raman spectroscopy [22]. It is also reported that, captopril and fosinopril interaction with cimetidine, famotidine and ranitidine may alter the antihypertensive effect of both these compounds [23-28].
H1 and to a lesser extent H2 receptors are involved in the interaction between brain acetylcholine and histamine consummate by the study of central histaminergic and cholinergic systems interact with each other in the modulation of yawning [29]. During most of the allergic diseases concomitant administration of an H1 receptor and H2 receptor antagonist is more effective than the administration of these two antagonists alone. For most of the allergic diseases (wheal and flare urticaria and dermatographism), findings have shown that concomitant administration of an H1 receptor antagonist with an H2 receptor antagonist is more effective than the administration of an H1 antagonist or an H2 antagonist alone [30-33].
Present paper deals with the unfavorable clinical practice drug-drug interactions studies of fexofenadine with H2-receptor antagonists (cimetidine, famotidine and ranitidine). Stability constant and thermodynamic function had also been calculated in order to evaluate the reaction mechanism.
Figure 1
EXPERIMENTAL:
Materials
Fexofenadine was a gift from Getz Pharmaceuticals (Pvt.) Ltd. The Ulcerax® 200 mg, Ulcer® 200 mg and Panalba® 20 mg tablets were purchased from the market.
Reagents
Methanol, hydrochloric acid, potassium chloride, ammonia solution 33%, deionized water and all other reagents used were of analytical grade or purified in the laboratory according to standard procedures as given in Vogel [34]. Potassium chloride recrystallized before use in water and methanol. Deionized water was used through out the work.
Equipment
The dissolution equipment was manufactured to the B.P 2005 [35]. A double beam UV/visible spectrophotometer (Shimadzu) model UV1601A coupled with a Pentium IV PC was used for analysis of drug samples. All the glassware’s were of Pyrex A grade, washed with chromic acid followed by thorough washing with water and finally rinsed with double distilled or deionized water, which was freshly prepared in the laboratory.
RESULTS AND DISCUSSION:
Reference standards of fexofenadine and interacting drugs
The absorption maximum of fexofenadine hydrochloride has been tested measured individually in simulated gastric juice pH 2 and 4, buffer of pH 7.4 simulating blood pH and pH 9 simulating intestinal pH by scanning the unknown solution in the region of 200–360 nm against the reagent blank. During these studies maxima was recorded at 218 nm for fexofenadine. From these, ε values were calculated and calibration curve of concentration against absorbance was plotted which signifies that the drug follows Beers and Lamberts law Fig. (2).
Similarly, solutions of cimetidine, ranitidine and famotidine were prepared absorbance measured at their absorption maxima as well as at the wavelength complementary to the maxima of fexofenadine hydrochloride. These reference studies were carried out in simulated gastric juice pH 2, 4 buffer of pH 7.4 simulating blood pH and pH 9 simulating intestinal pH.
In vitro availability of fexofenadine
The in vitro availability of fexofenadine hydrochloride studied in simulated gastric juice (pH 2 and 4), 7.4 and 9 on a modified B.P 2005 dissolution apparatus (B.P 2005) as described earlier. 60 mg tablet was added in one liter dissolution medium already maintained at specified temperature (37ºC), aliquots of 5 mL withdrawn periodically at fifteen minutes time intervals (for 180 minutes) and assayed for drug contents after appropriate dilution. The volume of dissolution medium was maintained by adding an equivalent amount of dissolution fluid withdrawn, which was maintained at the same temperature in the same apparatus. The absorbances of all the aliquots were measured and drug contents were calculated. It was observed that availability of fexofenadine hydrochloride in simulated gastric juice (pH 2 and 4), 7.4 and 9 were 11.2, 45.46, 11.09 and 15.4%, respectively.
In case of H2 receptor antagonists, it was observed that the availability of cimetidine, ranitidine and famotidine was 100% available after 3 hours in simulated gastric juice (pH 2 and 4), 7.4 and 9 where in all the drugs was available at the end of the experiment i.e. cimetidine 100% in pH 2, 12.7% in pH 4, 99.54% in pH 7.4 and 67.16% in pH 9, famotidine 100% in pH 2, 99.7% in pH 4, 99.74% in pH 7.4 and 99.99% in pH 9 ranitidine 99.98% in pH 2, 31.27% in pH 4, 100%in pH 7.4 and 88% in pH 9, respectively. Most of these dissolution profiles were linear. The linear regression analysis for these in vitro availability studies are given in (table 1-5).
Table 1 Availability (%) of fexofenadine and interacting drugs in simulated gastric juice at 37°C
S. No Time Fexofenadine Cimetidine Famotidine Ranitidine
(mins) 218 nm 216 nm 266 nm 313 nm
1 0 11.21 0 0 0
2 15 10.50 97.07 86.75 89.86
3 30 10.55 97.69 87.56 92.91
4 45 9.950 97.83 88.37 93.46
5 60 9.670 98.17 90.8 94.02
6 75 10.77 98.31 92.42 94.43
7 90 9.835 98.65 96.48 95.27
8 105 9.725 99.06 96.48 95.27
9 120 10.06 99.34 98.1 95.68
10 135 9.945 99.54 98.91 96.10
11 150 10.22 99.75 99.72 98.87
12 165 10.44 99.95 100 99.01
13 180 10.44 100 100 99.98
Fexofenadine added = 0.06 g, Cimetidine added = 0.20 g, Famotidine added = 0.02 g, Ranitidine added = 0.15 g,
Table 2 Availability (%) of fexofenadine and interacting drugs in buffer pH 4 at 37°C
S.No Time Fexofenadine Cimetidine Famotidine Ranitidine
(mins) 218 nm 216 nm 266 nm 228 nm
1 0 10.5 0.58 0 0
2 15 21.64 3.64 54.1 15.44
3 30 13.74 8.6 56.0 21.05
4 45 11.85 9.12 61.6 21.82
5 60 10.74 10.56 68.5 21.08
6 75 10.91 11.21 72.2 23.89
7 90 10.36 11.07 76.5 22.02
8 105 10.22 10.92 81.5 31.27
9 120 10.29 11.23 85.5 21.63
10 135 10.35 10.99 92.0 24.55
11 150 10.29 10.19 94.0 23.21
12 165 10.39 11.02 98.0 9.54
13 180 10.2 12.7 99.7 10.22
Fexofenadine added = 0.06 g, Cimetidine added = 0.20 g, Famotidine added = 0.02 g, Ranitidine added = 0.15 g
Table 3 Availability (%) of fexofenadine and interacting drugs in buffer pH 7.4 at 37°C
S.No Time Fexofenadine Cimetidine Famotidine Ranitidine
(mins) 218 nm 216 nm 276 nm 228 nm
1 0 9.33 0 0 0
2 15 9.29 97.47 81.46 96.19
3 30 9.13 97.71 86.43 96.19
4 45 9.17 97.71 87.68 97.25
5 60 9.13 97.88 90.78 97.38
6 75 9.39 97.94 91.41 97.38
7 90 9.42 98.12 91.41 98.3
8 105 9.84 98.36 92.65 98.3
9 120 10.06 98.54 94.52 98.44
10 135 9.74 98.71 94.52 99.1
11 150 10.06 98.89 97.62 99.23
12 165 10.06 99.01 99.74 99.49
13 180 11.09 99.54 99.74 100
Fexofenadine added = 0.06 g, Cimetidine added = 0.20 g, Famotidine added = 0.02 g, Ranitidine added = 0.15 g
Table 4 Availability (%) of fexofenadine and interacting drugs in buffer pH 9 at 37°C
S.No Time Fexofenadine Cimetidine Famotidine Ranitidine
(mins) 218 nm 216 nm 209 nm 228 nm
1 0 9 0.00 0.00 0.00
2 15 13.4 1.95 78.02 54.64
3 30 13 5.04 75.52 76.12
4 45 12.75 11.84 78.93 81.45
5 60 13.5 17.17 77.26 79.67
6 75 13.05 38.22 83.78 81.56
7 90 12.75 56.21 84.24 87.14
8 105 12.5 66.06 87.72 87.40
9 120 12.95 66.15 90.23 87.28
10 135 12.05 67.04 90.23 87.64
11 150 12.45 67.09 89.47 87.89
12 165 13 67.03 90.99 87.76
13 180 15.4 67.16 90.99 88.01
Fexofenadine added = 0.06 g, Cimetidine added = 0.20 g, Famotidine added = 0.02 g, Ranitidine added = 0.15 g
Table 5 Linear regression functions and their statistical parameters
Drug pH Abs Regression equation r β S.E. S.E.E. LOD LOQ
Fexofenadine 2 218 A= 0.0278Cx + 0.1429 0.9900 0.9900 0.0004 0.0006 0.3056 0.9575
4 218 A = 0.0165Cx + 0.0608 0.9900 0.9900 0.0004 0.0006 0.3093 0.9695
7.4 218 A = 0.0272Cx + 0.1414 0.9900 0.9900 0.0004 0.0006 0.1213 0.3801
9 218 A = 0.0171Cx + 0.0902 0.9900 0.9900 0.0004 0.0004 0.1930 0.6047
Cimetidine 2 216 A = 1.9447Cx + 0.0016 0.9900 1.0000 0.0049 0.0071 0.0170 0.0532
4 216 A = 1.9507Cx + 0.0059 0.9900 1.0000 0.0028 0.0041 0.0169 0.0530
7.4 216 A = 2.2735Cx - 0.0017 0.9900 1.0000 0.0022 0.0031 0.0145 0.0464
9 216 A = 2.2582Cx + 0.0049 0.9900 1.0000 0.0048 0.0070 0.0146 0.0465
Famotidine 2 266 A = 1.453Cx - 0.0847 0.9957 1.0000 0.2144 0.2700 0.0133 0.0417
4 266 A = 0.946Cx - 0.0026 0.9980 0.9960 0.1090 0.0041 0.0227 0.0710
7.4 276 A = 0.9378Cx + 0.0277 0.9900 0.9900 0.3450 0.0040 0.0352 0.1103
9 209 A = 1.3782Cx + 0.0236 0.9960 0.9900 0.1850 0.0030 0.0239 0.0750
Ranitidine 2 313 A = 2.0125Cx - 0.0399 0.9960 0.9970 0.0220 0.3100 0.0105 0.0321
4 228 A = 1.6404Cx + 0.0047 0.9900 0.9960 0.0030 0.1640 0.0106 0.0334
7.4 228 A = 0.8878Cx + 0.0239 0.9900 1.0000 0.0044 0.4660 0.1095 0.3431
9 228 A = 1.6047Cx + 0.0033 0.9900 1.0000 0.0031 0.2700 0.0115 0.0359
Simultaneous determination of interacting drugs
This method has been developed in order to calculate the simultaneous determination of fexofenadine and H2-receptor antagonists in presence of each other. This procedure was formulated to measure the quantities of two drugs present in the same solution simultaneously, without separating them. The solution of fexofenadine and famotidine gave absorption maxima at 218 and 266 nm in buffer pH 2 but to different intensities, and both of these drugs interfered at each other's wavelength and also to different intensities. Taking this into consideration a mathematical relationship was developed which gave the concentration of the two drugs simultaneously, when measured at their wavelengths. This is very simple and least time consuming method and is used to determine the quantity of fexofenadine and H2-receptor antagonist. Standard solutions of fexofenadine, cimetidine, ranitidine and famotidine in simulating stomach pH, buffer of pH 4, pH 7.4 and pH 9 were prepared and absorbance of each drug was measured at respective wavelengths. Molar absorptivities were proved to be useful in calculating the quantities of the drugs in a solution of unknown concentration. According to Beer's law,
A = ε b C (1)
Where, A = absorbance at a certain wavelength, ε = Molar absorptivity, b= path length of the cell taken as 1 cm and C =concentration of the solution. Fexofenadine and famotidine absorb at 218 and 266 nm in buffer of pH 2, respectively. Let Ca be the concentration of fexofenadine and Cb the concentration of famotidine. Now equation 2 may be written as:
A218= a1 b Ca + b1 b Cb (2)
A266= a2 b Ca + b2 b Cb (3)
Where, a1 and a2 are the absorptivities of fexofenadine at 218 and 266 nm, while b1 and b2 are absorptivities of famotidine at 218 and 266 nm, respectively.
Fexofenadine interaction with H2 receptor antagonist
The in vitro interactions of fexofenadine hydrochloride in the presence of H2-receptor antagonist were also carried out in simulated gastric juice (pH 2 and 4), 7.4 and 9 at 37°C, 48°C and 60°C [35]. For each experiment (Fexet 60 mg) tablet of fexofenadine was taken in the dissolution medium, while after 5 minutes before collecting the sample, cimetidine (Ulcerax 200 mg) was added to the dissolution medium and aliquots were withdrawn after every 15 minutes till three hours and assayed. Interaction of ranitidine (Nulcer 200 mg tablet) and famotidine (panalba 20 mg tablet) was studied with fexofenadine in individual experiments.
The maximum % availability of fexofenadine observed, in presence of cimetidine was 96.2 (37°C), 99.8 (48°C) and 84.6% (60°C) and cimetidine was 19.23 (37°C), 18.35 (48°C) and 16.53% (60°C) at pH 2. The % availability of fexofenadine in presence of cimetidine was zero (37, 48 and 60°C) and % availability of cimetidine was 23.15 (37°C), 28.35(48°C) and 30.19% (60°C) at pH 4. At pH 7.4 % availability of fexofenadine in presence of cimetidine was 914 (37°C), 919 (48°C) and 1080% (60°C) and cimetidine was zero (37 and 48°C) and 130.17% (60°C) and at pH 9 maximum % availability of fexofenadine in presence of cimetidine was 183 (37°C), 193 (48°C) and 203% (60°C) and cimetidine was 19.97 (37°C), 21.81(48°C) and 22.07% (60°C) The results were compared in (Tables 6-8) (Fig. 3).
Table 6 Availability (%) of fexofenadine and cimetidine in presence of each other at 37°C
Time Absorbance (nm) % Availability
(min) <–Fexofenadine–> <––Cimetidine––----------> Ca Cb Ca Cb Ca Cb Ca Cb
<––––––––––––––––––––––––––––––––––––––– pH –––––––––––----–––––––––––––––––––––----------------------------------------------––––>
2 4 7.4 9 2 4 7.4 9 2 4 7.4 9
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
15 0.54 0.47 0.61 0.63 0.52 0.47 0.57 0.58 63.3 13.19 0 17.4 653 0 119 13
30 0.71 0.57 0.75 0.74 0.69 0.56 0.70 0.69 83.9 17.37 0 20.8 812 0 142 16
45 0.75 0.59 0.80 0.84 0.73 0.59 0.75 0.79 88.8 18.34 0 21.8 873 0 165 18
60 0.73 0.62 0.83 0.84 0.71 0.61 0.79 0.80 86.4 17.88 0 22.7 914 0 166 18
75 0.69 0.63 0.77 0.79 0.66 0.63 0.73 0.75 79.4 16.88 0 23.1 841 0 155 17
90 0.68 0.60 0.77 0.86 0.65 0.60 0.74 0.82 77.9 16.59 0 22.1 853 0 170 18
105 0.70 0.61 0.77 0.81 0.67 0.61 0.74 0.77 81.0 17.19 0 22.5 855 0 161 17
120 0.73 0.63 0.77 0.88 0.69 0.62 0.74 0.84 83.6 17.70 0 23.0 854 0 175 19
135 0.71 0.61 0.77 0.76 0.68 0.61 0.73 0.72 82.1 17.44 0 22.5 850 0 149 16
150 0.70 0.58 0.87 0.87 0.67 0.58 0.79 0.83 80.9 17.19 0 21.4 913 0 173 18
165 0.69 0.60 0.80 0.86 0.65 0.59 0.76 0.81 79.1 16.80 0 21.9 876 0 169 18
180 0.79 0.61 0.81 0.94 0.79 0.60 0.79 0.88 96.2 19.23 0 22.3 912 0 183 20
Ca= Concentration of fexofenadine; Cb= Concentration of cimetidine. Amount of drug added: fexofenadine 60 mg; cimetidine 200 mg
Table 7 Availability (%) of fexofenadine and cimetidine in presence of each other at 48°C
Time Absorbance (nm) % Availability
(min) <–Fexofenadine–> <––Cimetidine––> Ca Cb Ca Cb Ca Cb Ca Cb
<––––––––––––––––––––––––––––––––––––––– pH –––––––––––––––––––––––––––––---------------------------------------------––––––––––>
2 4 7.4 9 2 4 7.4 9 2 4 7.4 9
0 0 0 0 0 0 0 0.02 0 0 0 0 0.1 0 0 0 0
15 0.62 0.62 0.60 0.60 0.56 0.48 0.88 0.79 76.08 15.04 0 21.9 543 0 162 19.0
30 0.66 0.67 0.76 0.76 0.83 0.74 0.88 0.80 81.4 16.09 0 28.1 845 0 163 18.9
45 0.68 0.68 0.77 0.77 0.86 0.78 0.92 0.83 83.3 16.42 0 28.3 889 0 171 19.7
60 0.76 0.80 0.77 0.77 0.85 0.76 0.90 0.81 98.9 18.26 0 28.3 876 0 167 19.2
75 0.76 0.81 0.77 0.78 0.85 0.77 0.92 0.84 99.4 18.35 0 28.3 880 0 172 19.8
90 0.76 0.80 0.77 0.77 0.86 0.78 0.89 0.81 98.7 18.18 0 28.4 898 0 166 19.2
105 0.71 0.75 0.77 0.76 0.84 0.76 0.89 0.81 92.9 17.01 0 28.2 874 0 167 19.2
120 0.76 0.81 0.73 0.72 0.86 0.79 0.91 0.83 99.8 18.34 0 26.7 903 0 171 19.6
135 0.73 0.78 0.74 0.74 0.84 0.77 0.89 0.81 96.4 17.66 0 27.2 887 0 167 19.0
150 0.76 0.80 0.74 0.74 0.87 0.79 0.95 0.87 99.3 18.25 0 27.3 914 0 179 20.4
165 0.77 0.81 0.76 0.76 0.89 0.79 0.92 0.85 10 18.41 0 28.0 907 0 175 19.8
180 0.69 0.70 0.76 0.75 0.88 0.80 1.02 0.94 85.1 16.67 0 27.8 919 0 193 21.8
Ca= Concentration of fexofenadine; Cb= Concentration of cimetidine. Amount of drug added: fexofenadine 60 mg; cimetidine 200 mg
Table 8 Availability (%) of fexofenadine and cimetidine in presence of each other at 60°C
Time Absorbance (nm) % Availability
(min) <–Fexofenadine–> <––Cimetidine––> Ca Cb Ca Cb Ca Cb Ca Cb
<––––––––––––––––––––––––––––––––––––––– pH ––––––––––––––––––––––––––––––––––--------------------------------------------–––––>
2 4 7.4 9 2 4 7.4 9 2 4 7.4 9
0 0 0 0 0 0 0 0 0 0 0 0 6.74 0 0 0 0.24
15 0.66 0.72 1 0.78 0.67 0.72 0.80 0.71 81.4 16.11 0 26.37 910 107 147 16.81
30 0.67 0.77 1 0.86 0.68 0.77 0.85 0.79 82.6 16.26 0 28.29 976 117 163 18.45
45 0.68 0.80 1 0.86 0.69 0.80 0.79 0.79 84.6 16.53 0 29.54 908 109 163 18.43
60 0.67 0.76 1 0.92 0.69 0.76 0.82 0.85 84.0 16.34 0 28.07 936 112 175 19.69
75 0.67 0.79 1 0.85 0.68 0.79 0.83 0.77 83.9 16.25 0 29.09 953 114 160 18.12
90 0.64 0.75 1 0.88 0.66 0.75 0.81 0.81 80.5 15.53 0 27.70 933 111 167 18.75
105 0.66 0.80 1 0.89 0.68 0.80 0.84 0.83 83.1 15.95 0 29.48 962 115 171 19.08
120 0.64 0.80 1 0.94 0.66 0.79 0.87 0.87 81.4 15.55 0 29.20 998 119 181 20.05
135 0.66 0.82 1 0.90 0.69 0.82 0.89 0.84 84.5 16.02 0 30.1 1020 121 173 19.14
150 0.61 0.82 1 0.97 0.64 0.82 0.94 0.90 78.3 14.78 0 30.19 1070 130 187 20.76
165 0.64 0.81 1 1.03 0.66 0.81 0.92 0.98 81.8 15.35 0 29.69 1060 123 203 21.94
180 0.57 0.79 1 1.03 0.60 0.79 0.94 0.96 73.6 13.64 0 28.96 1080 129 198 22.07
Ca= Concentration of fexofenadine; Cb= Concentration of cimetidine. Amount of drug added: fexofenadine 60 mg; cimetidine 200 mg
The results of interaction of fexofenadine with famotidine was 2.3 (37°C), zero (48 and 60°C) and famotidine was 127.24 (37°C), 341.71 (48°C) and 385.91% (60°C) at pH 2. The % availability of fexofenadine in presence of famotidine was zero (37 and 48°C) and 1.13 % at (60°C) and the availability of famotidine was 152.05 (37°C), 136 (48°C) and 278.96% (60°C) at pH 4. At pH 7.4 % availability of fexofenadine in presence of famotidine was zero (37°C, 48 and 60°C) and famotidine was 800, 810.68 (37 and 48°C) and 937.84% (60°C) and at pH 9 maximum % availability of fexofenadine in presence of famotidine was 276 (37°C), 260.3 (48°C) and 273.7% (60°C) and famotidine was zero (37, 48 and 60°C). The results of % availability were discussed in (Tables 9-11), respectively.
Table 9 Availability (%) of fexofenadine and famotidine in presence of each other at 37°C
Time Absorbance (nm) % Availability
(min) <–Fexofenadine–> <––Famotidine––> Ca Cb Ca Cb Ca Cb Ca Cb
<––––––––––––––––––––––––––––––––––––––– pH –––––––––––––––––––––––––––––––---------------------------------------––––––––>
2 4 7.4 9 2 4 7.4 9 2 4 7.4 9
0 0.03 0 0.01 0.01 0.02 0 0 0.01 0 17 0 0 0 5 4.77 0
15 0.12 0.45 0.72 0.37 0.05 0.06 0.04 0.53 0 62 0 114 0 595 140 0
30 0.17 0.55 0.90 0.39 0.11 0.12 0.08 0.56 0 69 0 139 0 737 150 0
45 0.19 0.59 0.96 0.46 0.13 0.13 0.10 0.64 2 75 0 149 0 779 174 0
60 0.21 0.60 0.95 0.47 0.13 0.13 0.10 0.66 0 85 0 150 0 776 181 0
75 0.22 0.61 0.96 0.50 0.14 0.14 0.10 0.70 1 93 0 153 0 782 192 0
90 0.24 0.60 0.95 0.51 0.15 0.13 0.10 0.72 0 101 0 151 0 774 197 0
105 0.23 0.60 0.95 0.51 0.14 0.14 0.10 0.71 0 99 0 151 0 776 195 0
120 0.23 0.59 0.95 0.52 0.13 0.13 0.10 0.72 3 101 0 149 0 774 199 0
135 0.23 0.60 0.97 0.52 0.13 0.13 0.11 0.73 0 105 0 151 0 88 201 0
150 0.25 0.61 0.97 0.53 0.14 0.14 0.11 0.75 0 112 0 153 0 789 203 0
165 0.27 0.59 0.97 0.56 0.15 0.13 0.11 0.78 0 124 0 148 0 792 213 0
180 0.27 0.60 0.98 0.68 0.15 0.14 0.12 0.81 0 127 0 152 0 800 276 0
Ca= Concentration of fexofenadine; Cb= Concentration of famotidine. Amount of drug added: fexofenadine 60 mg; famotidine 20 mg
Table 10 Availability (%) of fexofenadine and famotidine in presence of each other at 48°C
Time Absorbance (nm) % Availability
(min) <–Fexofenadine–> <––Famotidine––> Ca Cb Ca Cb Ca Cb Ca Cb
<––––––––––––––––––––––––––––––––––––––– pH –––––––––––––––––––------------------------------------–––––––––––-----–––––––––>
2 4 7.4 9 2 4 7.4 9 2 4 7.4 9
0 0.01 0 0.01 0.02 0 0 0 0.03 0 10 0 0 0 7 0 0
15 0.27 0.26 0.79 0.57 0.10 0.06 0.05 0.81 0 146 0 65 0 651 215 0
30 0.36 0.42 0.91 0.66 0.13 0.13 0.09 0.93 0 194 0 105 0 743 250 0
45 0.39 0.45 0.93 0.66 0.13 0.13 0.10 0.93 0 218 0 113 0 761 252 0
60 0.43 0.47 0.91 0.67 0.14 0.13 0.10 0.95 0 243 0 117 0 740 257 0
75 0.46 0.48 0.94 0.66 0.14 0.13 0.10 0.93 0 259 0 120 0 770 252 0
90 0.49 0.49 0.94 0.68 0.15 0.13 0.10 0.95 0 278 0 122 0 766 258 0
105 0.46 0.50 0.94 0.67 0.17 0.13 0.11 0.94 0 290 0 125 0 768 256 0
120 0.53 0.48 0.93 0.68 0.16 0.12 0.10 0.96 0 303 0 121 0 762 260 0
135 0.57 0.50 0.94 0.68 0.17 0.13 0.10 0.95 0 329 0 126 0 762 258 0
150 0.58 0.52 0.94 0.69 0.17 0.13 0.10 0.96 0 335 0 130 0 767 260 0
165 0.57 0.54 0.93 0.66 0.18 0.13 0.10 0.93 0 318 0 136 0 754 205 0
180 0.61 0.53 0.99 0.67 0.20 0.13 0.10 0.95 0 342 0 133 0 811 206 0
Ca= Concentration of fexofenadine; Cb= Concentration of famotidine. Amount of drug added: fexofenadine 60 mg; famotidine 20 mg
Table 11 Availability (%) of fexofenadine and famotidine in presence of each other at 60°C
Time Absorbance (nm) % Availability
(min) <–Fexofenadine–> <––Famotidine––> Ca Cb Ca Cb Ca Cb Ca Cb
<––––––––––––––––––––––––––––––––––––––– pH –––––––––––––––––––––––––––––––––––------------------------------------------––––>
2 4 7.4 9 2 4 7.4 9 2 4 7.4 9
0 0.03 0.00 0.02 0.02 0.01 0.00 0.00 0.03 0 18 0 1 0 19 264 0
15 0.46 0.61 0.72 0.70 0.13 0.13 0.10 1.01 0 265 0 154 0 580 259 0
30 0.51 0.65 0.73 0.68 0.14 0.15 0.10 0.97 0 296 0 163 0 594 260 0
45 0.54 0.63 0.74 0.68 0.14 0.14 0.11 0.97 0 319 0 158 0 595 254 0
60 0.56 0.63 0.78 0.67 0.15 0.14 0.11 0.95 0 327 0 159 0 629 264 0
75 0.57 0.62 0.79 0.69 0.15 0.14 0.11 0.98 0 337 0 156 0 642 267 0
90 0.59 0.63 0.82 0.70 0.15 0.14 0.11 1.00 0 348 0 159 0 667 266 0
105 0.59 0.63 0.84 0.70 0.15 0.14 0.11 0.99 0 347 0 158 0 683 265 0
120 0.59 0.63 0.90 0.70 0.16 0.14 0.11 0.99 0 348 0 158 0 735 270 0
135 0.61 0.63 0.96 0.71 0.16 0.14 0.11 1.00 0 362 0 157 0 779 270 0
150 0.61 1.10 0.99 0.71 0.16 0.36 0.00 1.00 0 361 1 272 0 820 274 0
165 0.65 1.11 1.05 0.72 0.17 0.36 0.12 1.01 0 383 1 276 0 857 269 0
180 0.65 1.12 1.15 0.71 0.17 0.36 0.12 1.01 0 386 1 278 0 938 206 0
Ca= Concentration of fexofenadine; Cb= Concentration of famotidine. Amount of drug added: fexofenadine 60 mg; famotidine 20 mg
The % availability of fexofenadine at these temperatures (37, 48 and 60°C) in presence of ranitidine was zero and ranitidine was 16.9 (37°C), 18.17 (48°C) and 18.41% (60°C) at pH 2. The % availability of fexofenadine in presence of ranitidine was 96, 87.6 and 107% (37, 48 and 60°C) and % availability of ranitidine was 8.25 (37°C), 7.98 (48°C) and 10.63% (60°C) at pH 4. At pH 7.4 % availability of fexofenadine in presence of ranitidine was 79.1 (37°C), 77.9 (48°C) and 83.5% (60°C) and ranitidine was 12.2, 109.47 (37 and 48°C) and 14.36% (60°C) and at pH 9 maximum % availability of fexofenadine in presence of ranitidine was 133 (37°C), 78 (48°C) and 143% (60°C) and ranitidine was 14.36 (37°C), 11.77 (48°C) and 13% (60°C) The results of % availability are given in (Tables 12-14).
Table 12 Availability (%) of fexofenadine and ranitidine in presence of each other at 37°C
Time Absorbance (nm) % Availability
(min) <–Fexofenadine–> <––Ranitidine––> Ca Cb Ca Cb Ca Cb Ca Cb
<––––––––––––––––––––––––––––––––––––––– pH ––––––––––––––––––––––––––––––––––----------------------------------------------–––––>
2 4 7.4 9 2 4 7.4 9 2 4 7.4 9
0 0.02 0 0 0.02 0 0 0 0 0 0 0 0 0 0 1.0 0.3
15 0.20 0.34 0.51 0.51 0.01 0.39 0.53 0.25 0 2.5 34.2 3.1 32.9 6.9 89 8.6
30 0.59 0.84 0.81 0.82 0.02 0.99 1.04 0.82 0 7.7 87.7 7.5 67.1 9.74 128 11.3
45 1.18 0.90 0.90 1.01 0.05 1.05 1.18 1.15 0 15.3 93.2 8.0 76.6 10.5 132 12.9
60 1.25 0.77 0.92 1.05 0.05 0.90 1.20 1.20 0 16.3 89.0 6.8 77.7 10.8 132 13.3
75 1.26 0.93 0.95 1.07 0.05 1.09 1.21 1.22 0 16.4 96.0 8.3 78.3 11.3 133 13.6
90 1.28 0.92 0.94 1.07 0.05 1.06 1.20 1.22 0 16.7 93.9 8.2 77.4 11.2 133 13.6
105 1.28 0.91 0.96 1.10 0.05 1.06 1.21 1.25 0 16.6 93.4 8.1 77.9 11.5 131 14.0
120 1.30 0.88 0.97 1.08 0.06 1.01 1.21 1.23 0 16.9 89.6 7.8 78.2 11.7 131 13.8
135 1.30 0.92 0.96 1.09 0.05 1.06 1.20 1.25 0 16.9 93.7 8.2 77.4 11.6 131 13.9
150 1.29 0.88 0.95 1.16 0.06 1.01 1.18 1.32 0 16.8 89.0 7.8 76.0 11.6 130 14.8
165 1.28 0.90 0.94 1.10 0.05 1.04 1.18 1.25 0 16.7 91.5 8.1 75.8 11.4 130 14.1
180 1.28 0.91 1.0 1.13 0.05 1.05 1.23 1.29 0 16.7 92.8 8.1 79.1 12.2 132 14.4
Ca= Concentration of fexofenadine; Cb= Concentration of ranitidine. Amount of drug added: fexofenadine 60 mg; ranitidine 20 mg
Table 13 Availability (%) of fexofenadine and ranitidine in presence of each other at 48°C
Time Absorbance (nm) % Availability
(min) <–Fexofenadine–> <––Ranitidine––> Ca Cb Ca Cb Ca Cb Ca Cb
<––––––––––––––––––––––––––––––––––––––– pH ––––––––––––––––––––––---------------------------------------------–––––––––––––––––>
2 4 7.4 9 2 4 7.4 9 2 4 7.4 9
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.07
15 0.18 0.33 0.57 0.33 0.01 0.37 0.27 0.26 0 2.3 32.4 3.0 10.9 4 28 4.32
30 0.60 0.75 0.64 0.39 0.03 0.86 0.40 0.35 0 7.8 75.9 6.7 19.9 18 39 4.93
45 0.94 0.84 0.76 0.66 0.03 0.96 0.64 0.70 0 12.2 84.6 7.5 36.8 44 78 7.75
60 1.16 0.84 0.95 0.94 0.04 0.96 1.04 1.04 0 15.1 84.8 7.6 64.7 88 18 10.7
75 1.28 0.85 1.06 1.01 0.04 0.97 1.21 1.12 0 16.7 85.4 7.7 76.8 107 27 1.3
90 1.36 0.88 1.11 1.02 0.05 1.00 1.25 1.14 0 17.7 87.9 7.9 78.5 109 29 1.5
105 1.43 0.87 1.06 1.02 0.06 0.99 1.22 1.13 0 18.5 86.8 7.8 77.2 109 29 1.5
120 1.37 0.86 1.07 1.04 0.05 0.97 1.24 1.16 0 17.8 85.4 7.7 78.2 109 32 1.8
135 1.40 0.86 1.06 1.02 0.05 0.97 1.23 1.14 0 18.2 85 7.7 78.1 109 29 1.5
150 1.38 0.89 1.07 1.02 0.05 1.00 1.23 1.14 0 17.9 87.6 8.0 78.0 109 29 1.6
165 1.39 0.87 1.06 0.99 0.05 0.97 1.23 1.10 0 18.1 85.7 7.8 77.5 108 25 1.2
180 1.40 0.88 1.06 1.02 0.06 0.99 1.23 1.14 0 8.2 86.9 8.0 77.9 109 29 1.6
Ca= Concentration of fexofenadine; Cb= Concentration of ranitidine. Amount of drug added: fexofenadine 60 mg; ranitidine 20 mg
Table 14 Availability (%) of fexofenadine and ranitidine in presence of each other at 60°C
Time Absorbance (nm) % Availability
(min) <–Fexofenadine–> <––Ranitidine––> Ca Cb Ca Cb Ca Cb Ca Cb
<––––––––––––––––––––––––––––––––––––––– pH ––––––––––––––––––––––––––––––––––––––-------------------------------------------–>
2 4 7.4 9 2 4 7.4 9 2 4 7.4 9
0 0 0 0 0 0 0 0 0 0 0.5 0 0 0.3 0 0 0
15 0.49 0.93 0.51 0.55 0.02 0.98 0.25 0.52 0 6.3 858 8.6 11.1 8.6 57 6.9
30 1.17 1.10 0.82 0.99 0.03 1.18 0.82 1.08 0 15.2 103 10.2 49.8 11.3 122 11.3
45 1.37 1.14 1.01 1.08 0.03 1.21 1.15 1.19 0 17.8 106 10.5 72.5 12.9 135 12.2
60 1.38 1.14 1.05 1.07 0.04 1.22 1.20 1.19 0 17.9 106 10.5 75.8 13.3 134 12.2
75 1.41 1.11 1.07 1.10 0.03 1.18 1.22 1.22 0 18.4 103 10.2 77.4 13.6 138 12.5
90 1.41 1.13 1.07 1.09 0.04 1.20 1.22 1.21 0 18.3 105 10.4 77.4 13.6 137 12.4
105 1.40 1.14 1.10 1.13 0.03 1.21 1.25 1.25 0 18.3 106 10.5 79.1 14.0 141 12.8
120 1.41 1.15 1.08 1.13 0.03 1.22 1.23 1.24 0 18.4 107 10.6 77.9 13.8 141 12.9
135 1.33 1.15 1.09 1.14 0.03 1.22 1.25 1.26 0 17.4 107 10.6 78.7 13.9 143 13.0
150 1.36 1.10 1.16 1.11 0.03 1.17 1.32 1.23 0 17.8 102 10.1 83.5 14.8 139 12.7
165 1.36 1.11 1.10 1.14 0.03 1.18 1.25 1.26 0 17.7 103 10.3 78.7 14.1 143 13.0
180 1.34 1.12 1.13 1.14 0.03 1.19 1.29 1.26 0 17.5 103 10.4 81.8 14.4 142 13.0
Ca= Concentration of fexofenadine, Cb= Concentration of ranitidine. Amount of drug added: fexofenadine 60mg; ranitidine 20mg
Kinetic studies
Similarly to study the kinetics of the reaction the similar dissolution with similar conditions, the availability of fexofenadine and H2-receptor antagonists, were studied at 48 and 60 ˚C. The Gibbs free energy (∆G), Entropy (∆S) and Enthalpy values (∆H) were studied. The rate of formation of complex increased at elevated temperatures (48 and 60 ˚C). The free energy function (∆G) can be measured by the following equation and are representing in table 15-17.
∆G = -Rt ln Ka (4)
Using the calculated ∆G values, ∆S values can also be found out by the equation;
∆G = ∆H - T∆S (5)
CONCLUSION:
The in vitro interactions studies of fexofenadine with cimetidine at pH 2 and 9, with ranitidine at pH 4, 7.4 and 9 showed that % availability of fexofenadine was affected (increased or decreased) at all three temperatures which showed probable complex formation. In case of fexofenadine with cimetidine at pH 4 and 7.4, with famotidine at all four pH and with ranitidine at pH 2 interaction was observed. While the results of kinetic studies of fexofenadine with interacting drugs showed that all these reactions are non-spontaneous under all reaction conditions.
Table 15 Activation parameters for the interaction of fexofenadine with cimetidine
T (K) KC ∆G ∆H ∆S KC ∆G ∆H ∆S
(mol-1) (KJmol-1) (Jmol-1K-1) (mol-1) (KJmol-1) (Jmol-1K-1)
<-------------------------pH 2----------------------------------------> <------------------pH 4------------------------------------------------->
310 193.22 3232 -2197 3.3386 7485.03 5476.48 900.40 20.57
321 260 3535 2152.51 3.7186 7552.87 5676.55 931.36 19.96
333 617 4237 -3162 0.9286 4697 5575.52 899.81 19.15
<-------------------------pH 7.4---------------------------------------> <------------------------------ pH 9------------------------------------->
310 6485.1 5388.45 776.88 19.88 893.12 4171.41 13045.28 55.54
321 13382.92 6040.20 905.45 19.60 -1550.98 0.00 13828.05 56.07
333 4280.82 5514.32 774.45 18.50 -3315.76 0.00 13030.50 51.65
Table 16 Thermodynamic parameters for the interaction of fexofenadine with famotidine
T (K) KC ∆G ∆H ∆S KC ∆G ∆H ∆S
(mol-1) (KJmol-1) (Jmol-1K-1) (mol-1) (KJmol-1) (Jmol-1K-1)
<----------------------pH 2----------------------------------------------------> <-----------------------pH 4----------------------------------------------->
310 476027 8026 8845 54.42 2044 4680 14743 62.65
321 51923 6902 8850 52.57 1218 4516 15194 61.91
333 5090 5628 8845 50.66 -70.03 0.00 14735 58.30
<---------------------pH 7.4----------------------------------------------------> <--------------------------------pH 9--------------------------------------->
310 489.45 3802.16 11963 50.85 10886 5706.45 18283 77.38
321 502.98 3954.37 12391 50.45 8484.97 5908.95 17636 72.71
333 -285.88 0.00 11955 47.32 22531 6129.84 18295 70.09
Table 17 Thermodynamic parameters for the interaction of fexofenadine with ranitidine
T (K) KC ∆G ∆H ∆S KC ∆G ∆H ∆S
(mol-1) (KJmol-1) (Jmol-1K-1) (mol-1) (KJmol-1) (Jmol-1K-1)
<----------------------pH 2------------------------------------------------------> <-----------------------------pH 4--------------------------------------->
310 -4513.83 0.00 18283 58.97 418583 7946 1817.14 31.49
321 -38483 0.00 17636 54.94 347831 8111 1778.77 30.29
333 13188 0.00 18295 52.96 163953 7918 1736.50 29.07
<---------------------pH 7.4-----------------------------------------------------> <------------------------------------pH 9-------------------------------->
310 -1821.74 0.00 -327.1 -1.055 -997.72 0.00 327.10 -1.055
321 502.98 3954.37 957.129 2.98 -223.05 0.00 957.13 2.98
333 -285.88 0.00 351.37 -1.055 -242.08 0.00 351.37 -1.055
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Received on 06.11.2010 Modified on 12.10.2011
Accepted on 28.11.2011 © AJRC All right reserved
Asian J. Research Chem. 5(5): May 2012; Page 668-677