The construction and performance characteristics of a novel (diphenhydramine) DPH CC-sensor based on DZCE were reported in this work. The CC-membrane was prepared by incorporating of (diazacrown ether) DZCE and/or (tetraflorophenyl borate) TFPB into a plasticized poly(vinyl chloride) membrane. The CC-sensor revealed a Nernstian behavior over a DPH-concentration range (9.1 × 10 -3 - 6.3 × 10 -7 mol ·L -1), and relatively low detection limit (1 × 10 -7 mol ·L -1). The potentiometric response was independent on the pH of the solution in the range of 7 - 10. The DPH-CC showed a very short response time (<5 s). It showed good selectivity towards different cations and pharmaceutical compounds. The relative selectivity coefficient was applied for evaluation of the selectivity properties of the DPH-CC. The DPH-CC was used successfully for determination of DPH in its samples. The found recovery range was 95% - 98.5%, and the standard deviation value ranged between 0.13 - 0.42. The DPH-CC facilitates the analysis of DPH directly without pretreatment and it can be built-in as a detector in chromatographic apparatus. It can be used as a tool for on-line monitoring of the drug levels.
Diphenhydramine (C17H21NO) is 2-(diphenylmethoxy)-N,N-dimethylethanamine. It has an antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties that is mainly used to treat allergies. It is also used in the management of drug-induced Parkinsonism and other extrapyramidal symptoms. The drug has a strong hypnotic effect and is FDA-approved as a nonprescription sleep aid, especially in the form of diphenhydramine citrate. The drug was first synthesized by George Rieveschl and first made publicly available through prescription in 1946 [
Several methods were used for analysis of diphenhydramine. Eman et al. [
In this work, original compact cell for diphenhydramine “DPH-CC” was applied successfully for determination of the drug. There was no need to use separate reference and sensor electrode for analysis like old electrode methods [
Diphenhydramine hydrochloride (C17H21NOHCl) 291.855 g/mol was purchased from (Sigma). Diaza-18-crown- 6 ether (DZCE) (previously prepared) [
The potentiometric/pH-measurements were carried out at 25˚C ± 1˚C on a digital research pH-meter (model 5986) Cole-Parmar (sensitivity ± 0.1 mV) coupled with a channel selector of the same make. pH-meter (Jenway, UK), hotplate & stirrer (LabTech Co. Ltd, Indonesia).
The measurement was carried using a compact-cell [
Three membrane compositions (I-III) were tried 1% w/w ionophore (either DZCE or TFPB); 33% w/w PVC and 66% w/w solvent mediators (NOPE) or (DDP).
Fifty milliliter aliquots of DPH solution (10−7 - 10− 2 M ) were transferred to 100 mL beakers. The DPH -compact cell was dipped into the solution. The cell potential was recorded corresponding to each DPH concentration. A calibration graph was constructed for the cell potential versus log( DPH ). The following cell assembly was applied:
Ag-AgCl/Inner filling soln./membrane//sample solution//reference inner filling soln./Ag-AgCl
The pH-measurements were carried out by immersing the proposed DPH-CC plus glass electrode into 50 ml DPH-solutions of concentrations 10−2 - 10−4 M DPH. The potential values of the proposed cell were recorded
against pH values. The potentiometric selectivity coefficient
Composition, w/w % | PVC, mg | DZCE, mg | TFPB, mg | DDP, mg | NPOE, mg |
---|---|---|---|---|---|
I-membrane | 33.8 | 0 | 1.2 | 0 | 60 |
II-membrane | 31.5 | 2 | 1.6 | 67 | 0 |
III-membrane | 30.5 | 1.15 | 0 | 67 | 0 |
Different DPH-containing samples were prepared. Either the direct potentiometry or the standard addition method was used for analyzing these samples by using the proposed DPH-CC. In direct potentiometric method, 50 ml aliquots of the chosen samples: Exylin Pediatris (syrup), Amydramine Expectorant (syrup), Koffex (sytrup) or Ezipect (syrup), were transferred to the potentiometric cell. Then, the DPH-CC was immersed into the syrup. The potential values were recorded and compared to a previously prepared calibration graph.
For the standard addition method, 50 ml aliquouts were transferred to the potentiometric cell. Then, 5 ml of each drug sample was added. Finally, the potential values were recoded and compared to the previously prepared calibration graphs. The concentration of each sample was calculated after deduction of the standard concentration.
Three DPH -CC compositions were tried. The first type was based on TFPB as a charged ionophore (type-I). Other types (II and III) were based on neutral ionphore DZCE (2 and 1.15 mg) in presence of TFPB (2 mg). The slope of the calibration graphs for the three types of cells was (56.86 mV/decade), which is close to Nernstian value (59.8 mV/decade). The linear range of the three types of DPH-CC was (9.1 × 10−3 - 6.3 × 10−7 M). The detection limit for all types was 10−7 M.
The mechanistic equation that represents the exchange reaction at the membrane-solution interface for DPH- CC type-I (contains only DZCE) is written as below:
In case of DPH-CC types-II and III (contains DZCE/K-TFPB), the following equilibrium is expected:
The dynamic response of the three cells was tested by measuring the potential value against time. The measurements were carried for different concentrations in the range of 10−2 to 10−7 M.
The potential changes versus different pH-values for the three kinds of the membranes were studied. It was tested for 9.1 × 10−3 - 7 × 10−5 M DPH solutions for the three types (I,II,III) of DPH-CC. The measurement aimed to find the optimum working pH-range for each type. The optimum pH-range is defined as the pH-range where the potential value of the cell does not change whatever the pH is changed. Wide pH range was found for three types. The pH range was 3.57 - 8.4. The break in acidic part was due to the interference from H+. After pH 8.4 the sudden change in potential was due to the formation of free base of DPH.
The selectivity coefficient (
It can be recorded that the
the studied electrodes are ready for the DPH-measurement in presence of these cations. The
towards the tested pharmaceutical compounds showed higher
and III. It was found that the
and III, they are of order of 10−3. This shows better selectivity for DPH-CC types II and III with respect to the
tested pharmaceutical compounds than for type-I. Only quinine showed the highest value of the
values, which reflects the lower selectivity towards this compound.
The relative selectivity coefficient Krel was defined by Zareh [
where (n) is the number of interferents under study.
Interferent | |||
---|---|---|---|
I | II | III | |
Glycine | 6.8 × 10−3 | 1.5 × 10−3 | 2.2 × 10−3 |
Arginin | 5.8 × 10−3 | 1.0 × 10−3 | 1.9 × 10−3 |
Sodium glutmate | 1.4 × 10−2 | 5.2 × 10−3 | 6.3 × 10−3 |
Ephedrine | 1.4 × 10−2 | 5.2 × 10−3 | 6.3 × 10−3 |
Pilocarpine | 2.4 × 10−2 | 2.9 × 10−3 | 3.5 × 10−3 |
Atropine | 2.6 × 10−2 | 1.0 × 10−2 | 1.2 × 10−2 |
Quinine | 2.8 × 10−1 | 2.2 × 10−1 | 2.3 × 10−1 |
Caffeine | 2.0 × 10−3 | 4.3 × 10−4 | 5.9 × 10−4 |
KCL | 1.37 × 10−4 | 1.68 × 10−4 | 1.62 × 10−4 |
NaNO3 | 4.99 × 10−5 | 6.23 × 10−5 | 6.33 × 10−5 |
LiNO3 | 3.23× 10−5 | 4.21 × 10−5 | 4.67 × 10−5 |
CaCl2 | 2.96 × 10−5 | 3.7 × 10−5 | 2.51 × 10−5 |
Mg(NO3)2 | 2.02 × 10−5 | 2.66 × 10−5 | 2.15 × 10−5 |
NH4NO3 | 3.13 × 10−5 | 4.64 × 10−5 | 4.65 × 10−5 |
Ba(NO3)2 | 1.83 × 10−5 | 2.15 × 10−5 | 1.59 × 10−5 |
Finally, the Ktot(x=I, II, and III) was calculated for overall evaluation.
where X, is the electrode under study; (1, 2, 3, 4, ×××, m), refers to the number of electrodes to be compared with.
It can be predicted that the smaller the K-value, the better the selectivity properties of an electrode. The Ktot (x=II) (0.86) is the least among the three tested electrodes. This indicates that the electrode type-II was the best among the tested electrode types.
By using DPH-CC the DPH assessment becomes easier without sample pretreatment. Since DPH-CC based on membrane type-II exhibited the best electrode performance, so it was applied for an actual analysis of DPH samples. Diphenhydramine formulations Exylin (7 mg/ml), Amydramine Expectorant (15 mg/ml), Koffex Syrup (10 mg/ml), and Ezipect Syrup (2.5 mg/ml) were assayed using the mentioned DPH-CC. The procedure was applied using both the direct potentiometric and the known addition techniques. The obtained results (
Ø It can be concluded that diphenhydramine can be determined by using new generation of sensors based on using Compact Cell (CC).
Interferent | Krel-I | Krel-II | Krel-III | |||
---|---|---|---|---|---|---|
K-(I-II) | K-(I-III) | K-(II-I) | K-(II-III) | K-(III-I) | K-(III-II) | |
Glycine | 0.81 | 0.84 | 1.23 | 1.04 | 1.19 | 0.96 |
Arginin | 0.80 | 0.79 | 1.25 | 0.98 | 1.27 | 1.02 |
Sodium glutmate | 0.77 | 0.69 | 1.30 | 0.90 | 1.45 | 1.11 |
Ephedrine | 0.80 | 1.18 | 1.25 | 1.47 | 0.85 | 0.68 |
Pilocarpine | 0.76 | 0.94 | 1.32 | 1.24 | 1.06 | 0.81 |
Atropine | 0.68 | 0.67 | 1.48 | 1.00 | 1.49 | 1.00 |
Quinine | 0.85 | 1.15 | 1.18 | 1.35 | 0.87 | 0.74 |
Caffeine | 4.35 | 3.09 | 0.23 | 0.71 | 0.32 | 1.41 |
KCL | 5.82 | 3.07 | 0.17 | 0.53 | 0.33 | 1.90 |
NaNO3 | 2.74 | 2.27 | 0.36 | 0.83 | 0.44 | 1.21 |
LiNO3 | 2.74 | 2.27 | 0.36 | 0.83 | 0.44 | 1.21 |
CaCl2 | 8.49 | 6.99 | 0.12 | 0.82 | 0.14 | 1.21 |
Mg(NO3)2 | 2.50 | 2.14 | 0.40 | 0.86 | 0.47 | 1.17 |
NH4NO3 | 1.29 | 1.21 | 0.77 | 0.94 | 0.83 | 1.07 |
Ba(NO3)2 | 4.74 | 3.43 | 0.21 | 0.72 | 0.29 | 1.38 |
K(av-x)* | 2.54 | 2.05 | 0.78 | 0.95 | 0.76 | 1.13 |
K(tot-x)* | 2.30 | 0.86 | 0.94 |
No. | Diphenhydramine sample | Taken amount, mg/ml | Direct potentiometry | Known addition method | ||
---|---|---|---|---|---|---|
Percentage found, % | STD* | Percentage found, % | STD* | |||
1 | Exylin Pediatric Syrup (Diphenhydramine Hydrochloride, Menthol), Spimaco Saudi Arabia | 7 | 98.2 | 0.17 | 95.71 | 0.29 |
2 | Amydramine Expectorant Syrup Sugar Free, (Diphenhydramine Hydrochloride, Ammonium, Sodium Citrate, Menthol), Gulf Pharm. Ind. (Julphar, United Arab Emirates | 15 | 98.5 | 0.25 | 98.5 | 0.22 |
3 | Koffex Syrup For Adult, (Diphenhydramine Hydrochloride, Ammonium, Sodium Citrate) Xellia Pharm. Aps, Denmark | 10 | 97.8 | 0.25 | 98 | 0.42 |
4 | Ezipect Syrup, (Diphenhydramine Hydrochloride), Tabuk Pharmaceutical Manufacturing Co., Saudi Arabia | 2.5 | 98 | 0.13 | 95 | 0.17 |
*Standard deviation (4-determinations).
*Corresponding author.
Ø This type of cells can be elaborated for use to determine other drugs.
Ø The benefits of using such cell can be expanded as built-in detector for HPLC-devices.
Ø The proposed cell is perfect for the on-line monitoring of drug levels.
The authors would like to acknowledge financial support for this work, from the Deanship of Scientific Research (DSR), University of Tabuk, Tabuk, Saudi Arabia, under grant no. S-080-1436.
Mohsen M. Zareh,1 1,Mohammed I. ALahmdi,Ali A. Keshk, (2016) Diphenhydramine Compact-Cell Sensor. Journal of Sensor Technology,06,1-10. doi: 10.4236/jst.2016.61001