Abstract
One of the most effective, rapid, and simple methods reversed-phase high-performance liquid chromatography (RP-HPLC) was used for simultaneous development and validation of Eletriptan hydrobromide (ELE HBR) and Itopride hydrochloride (ITP HCL) in combination. The method was validated based on the regulations of United States Pharmacopeia (USP) and International Conference on Harmonization (ICH) guidelines. Separation of both drugs was achieved within approximately 5 min by using a mobile phase made up of a 70:30 ratio of phosphate buffer and acetonitrile having a flow rate of 1 mL min−1. Furthermore, a comprehensive study was conducted on precision, accuracy, linearity, inter-day, intra-day studies, an assay of formulated films, and stability studies of combined prepared film. Co-efficient of correlation ranged between 0.9993, and 0.9965 for ELE HBR and ITP HCL respectively. The accuracy of the developed method was accurate as drug recoveries in both cases of ITP HCL, and ELE HBR falls between (99.87, 99.96, and 99.84%) to (99.81, 99.12, and 98.44%) respectively having a concentration range of solutions between 10, 30 and 50 μg mL−1 dilution. Films developed by using both drugs in combination were then validated for assay studies, and it was found that substantial results of 99.05%, and 99.87% were found in the case of ITP HCL and ELE HBR respectively. The stability of the solution and mobile phase showed the method's accuracy as the results were 97% for ITP HCL and 99% for ELE HBR. The proposed method developed for simultaneous determination of ITP HCL and ELE HBR was developed and validation and no interaction of any excipient were found.
Introduction
Since oral solid dosage form was considered the oldest and most convenient oral solid dosage form. By the 1970s, a new dosage form based on the development of patches was formulated and later on was termed as fast dissolving films (FDF). These films were developed as an alternative dosage form which includes syrups, capsules, tablets, and other forms of oral solid dosage form that produce convenience during their administration. FDFs were defined as oral dosage forms that disintegrate rapidly within the buccal cavity without the aid of water followed by oral administration [1].
These films were formulated by using hydrophilic polymers that disintegrate rapidly within the buccal cavity. These films were considered a novel approach to quickly eradicate the symptoms, with rapid onset of action. The oral bioavailability of drugs could be increased up to 4–1000 times due to increased permeability and high blood flow of oral mucosa [2].
The term “Migraine” originates from a Greek word that means “Half-headed” [3]. Migraine due to their degree of causing handicap ranked 19th among the general population and 12th rank among the women population. According to World Health Organization (WHO) migraine was considered to be in the top 20 diseases worldwide, which affects about 15% [4] of the population out of which 6% are males and 17% are females [5]. In a study conducted by the Global Burden of Disease Study, Headache was ranked as second most commonly present neurological disorder worldwide [6]. Most migraineurs develop migraine between the age group of 25–55 [4].
Strategies for migraine treatment include preventive as well as abortive or acute treatment. The basic purpose of abortive or acute treatment was to withdraw the disease progression and to relieve from attack. While, precautionary treatment was used to lessen the duration, occurrence, and harshness of the next attack [7].
The drug achieves 50% bioavailability after oral administration [8–11]. Its peak plasma concentrations (Tmax) are achieved within 1 h [12–14]. ELE HBR was approximately 85% protein-bound [15]. By oral administration, its half-life varies from 4.8 to 7.0 h in healthy volunteers [16, 17]. These parameters remain unaffected by age, race, menstrual cycle, and gender [17].
Gastric stasis was also termed gastroparesis [18]. Gastroparesis is referred to as a delay in the emptying of stomach contents without any mechanical obstruction. That delay in emptying has some circumstances like loss in weight, nausea, bloating, vomiting, and other symptoms [18, 19]. There appears a strong relationship between migraine and gastric motility alternation [20].
Some general symptoms of gastroparesis include vomiting in 84% of patients, early satiety in 60% of patients, and nausea in more than 92% of patients [21]. Additional symptoms comprise post-postprandial fullness, bloating, abdominal pain, and postprandial abdominal distension, which are habitually meal stimulated [22]. This symptom can be constant or can appear in episodes of high to low intensity [21]. Clinicians have frequently seen gastrointestinal distress in patients with migraine [23].
It is being suggested that both gastroparesis and migraine arise because of the dysfunction of the Autonomic nervous system (ANS). During migraine, gastroparesis arises due to a rise in the sympathetic nervous system or decline in parasympathetic nervous system events, or due to both. During gastroparesis, vomiting is induced by migraine and which causes a delayed or inefficient absorption of the medication. ANS has some symptoms which include vasodilation, diarrhea, vomiting, nausea, vasoconstriction, diaphoresis, and piloerection which occurs commonly in migraine [18]. An extended delay in gastric emptying will lead to gastroparesis which causes the stomach failure to store and evacuate contents normally. If the condition of gastroparesis persists for a long duration it may result in malnutrition, esophagitis, electrolyte disturbance, and acute renal failure due to less volume [18]. The condition of gastroparesis was treated by giving medications that have prokinetic activity like 5-HT4 and dopaminergic agonists. Studies proved that usage of anti-migraine with the addition of prokinetic drugs could be beneficial for treating migraine and its associated disorders [20].
Itopride hydrochloride (ITPHCL) is a novel benzamide gastro prokinetic derivative [24–26] (Fig. 1). ITPHCL having chemical formula (N-[4-[2-(dimethylamino) ethoxy] benzyl] 3,4 dimethoxybenzamide HCl) (Fig. 2) [27–29]
The drug has cooperation effects on both dopamine D2 receptor antagonistic and anticholinesterase (AnchE) activity [26]. It is a member of the Biopharmaceutics Class System (BCS) class I drug [30, 31]. The drug improves gastric motility disorders [32], promotes emptying of gastric contents, comforts the acid reflux, and dyspepsia symptoms [33], and has an anti-emetic effect [34]. Clinically the recommended dose of ITP HCL is 50 mg [35], the method of ITP HCL was also determined on RP-HPLC [36].
In the Pharmaceutical industry, RP-HPLC has become the most preferable technique used for the analysis, separation, and quantification of samples due to its high nature of sensitivity, specificity, and versatility. It can further be used to identify structurally similar compounds.
During method development, a few parameters (flow rate, pH, and mobile phase) must be considered for ideal separation conditions. A single stationary phase was used during the process of method development [37]. In the current work, a simultaneous method for quantification of ELE HBR and ITP HCL was determined.
Material and method
ELE HBR (having a purity level of 101.0%) was received as a gift from Wilshire, Laboratories (Lahore, Pakistan), and ITP HCL (having a purity level of 99.66%) was generously gifted by CCL laboratories (Lahore, Pakistan). All of the solvents used in the study were purchased from Sigma Aldrich (Germany), and all of them are of analytical grade.
Instrumentation
HPLC (OpenLab CDS version 2.4 software was used, 1260 Infinity II LC System, Agilent Technologies, USA) was used having HPLC column C 18 of Agela technologies (USA) (250 × 4.6 mm; and particle size of 5 μm) was used for analysis purposes. Analytical Balance (ION Series Model BM-300, China) was used.
HPLC analysis
To analyze the simultaneous quantification of ELE HBR and ITP HCL drugs, the HPLC method was developed.
Method development and validation in the mobile phase
Preparation of mobile phase and stock solution
Phosphate buffer was prepared by weighing Accurately 1.36 g of Potassium dihydrogen phosphate and the final volume was made up to 1000 mL by using HPLC grade water.
Preparation of standard
Accurately weigh 30 mg of ITP HCL and ELE HBR using a digital weighing balance. Drugs were transferred to a 100 mL volumetric flask, making up the volume to 100 mL with the mobile phase (used as diluent). Accurately transfer 1 mL solution of drugs with the help of pipette and transfer it to 100 mL volumetric flask and make up the volume up to 100 mL that will make 30 μg mL−1 solution of both drugs.
Preparation of mobile phase
The mobile phase was prepared by using a 70:30 ratio of phosphate buffer and acetonitrile. 700 mL of buffer and 300 mL of acetonitrile were mixed thoroughly [38]. While the dilutions of stock solutions were made ranging from 10 to 50 μg mL−1 by using the mobile phase.
Preparation of sample solution
Films of ITP HCL (40 mg each) and ELE HBR (20 mg each) were dissolved in mobile phase up to 100 mL equivalent to and make up the concentration of 30 μg mlL−1 these prepared solutions were then filtered by using a 0.22 µm nylon syringe filter (Sterlitech, USA) before injecting.
Validation of the developed method
The method was validated for linearity, precision, system suitability, robustness, the limit of detection (LOD), the limit of quantification (LOQ), and accuracy as per the ICH guideline [39].
Linearity (Calibration curve)
Serial dilutions of both drugs ranging from 10 to 50 μg mL−1 were made and linearity was determined [40, 41]. The graph was plotted by taking the area under the curve on the y-axis and concentration on the x-axis. Meanwhile, the coefficient of correlation (R2) also concluded [42–44].
System suitability test
By using the mobile phase initially, a total number of 6 replicas were injected at the same concentrations. Injections were repeatedly injected to assess the suitability of the system each day. It includes the tailing factor, theoretical plate, and %RSD determined [44].
Intra-day and inter-day precision
Repetition of the test was done to ensure its precision. 30 μg mL−1 of standard from both ELE HBR and ITP HCL. Randomly three different concentrations were selected to calculate the precision of inter-day. Meanwhile, the precision of intra-day was evaluated by assessing standard solutions in a triplicate manner, beginning from starting, middle, and end of the day within the range of linearity [45–47].
Accuracy
System accuracy was assessed by doing recovery studies. It was assessed by analyzing standard solution and solution of buccal films analyzed earlier for both drugs ITP HCL and ELE HBR at 80, 100, and 120% solutions [48].
Robustness
The robustness of the method was determined by varying the conditions of the instrument which included the organic content and flow rate in the mobile phase [49]. ITP HCL and ELE HBR samples were infused their assay was performed and %RSD, mean, and SD were computed [50].
Specificity
Specificity was evaluated to determine any influence of solvent, and excipients used in the formulation on the method's efficacy. A total number of six injections each from standard drug and placebo was used and the resultant chromatograms were matched to determine the specificity of the method [44].
LOQ and LOD
Stability of mobile phase and solution
The mobile phase and solution of both drugs were assessed for stability by placing them at variable temperature conditions. Initially, they were placed at ambient temperature for 12 h in a measuring flask. Afterward, they were placed from −20 °C to −15 °C for 7 days. %RSD of ITP HCL and ELE HBR were estimated for the duration of stability studies [57].
Results
Development of mobile phase
The control of pH is an important factor to obtain peaks that are non-symmetrical, non-split, and non-broadened. So, the selection of pH in RP-HPLC is important because it controls the ratio of un-protonated, protonated species and the distribution between the mobile phase, and stationary phase, and their impact on retention time. pH ranges between 2–8 were considered the most favorable operational pH. Due to ease of availability, low cost, and high compatibility phosphate buffers were used for chromatography [37].
Flow rate is another parameter that showed, how fast a mobile phase travels in a column. It is also useful for the estimation of mobile phase consumption within a specified period. Retention time could be defined as the time taken by a sample to elute after its injection. Retention time is used to estimate the length of the chromatographic run from the last observed peak. Retention time depends on some factors which include mobile phase flow rate, nature of mobile phase, and chromatographic column used [58].
Various combinations of organic solvents like methanol, acetonitrile with buffer, and water in different concentrations were injected at 0.5–1.5 mL min−1 flow rate as represented in Table 1. As the flow rate increases the retention time decreases [59]. It is evident from table no 1 that, as flow rate varied from 0.5, 1, and 1.5 mL min−1 a significant decrease in retention time for both drugs ITP HCL and ELE HBR was observed. pH was varied from 2 to 7 and different chromatograms were assessed. Regarding better elution properties of ITP HCL and ELE HBR as illustrated in Fig. 3, the wavelength was adjusted to 220 nm [60]. Finally, the mobile phase was constructed by using buffer and acetonitrile in 70:30 ratios, pH was adjusted to 4.6 and column flow was 1 mL min−1. Injection volume was 10 µL, C 18 column having dimensions of 250 × 4.6 mm, and particle size of 5 μm was used for HPLC analysis at 25 °C.
Selection of optimized flow rate and pH
| Parameter | Used | ELE HBR (Retention time) | ITP HCL (Retention time) |
| Flow rate | 0.5 mL min−1 | 2.5 | 4.72 |
| 1 mL min−1 | 1.933 | 4.299 | |
| 1.5 mL min−1 | 1.5 | 3.855 | |
| pH | 2 | 1.233 | 3.312 |
| 3 | 1.438 | 3.631 | |
| 4 | 1.701 | 3.986 | |
| 4.6 | 1.933 | 4.299 | |
| 5 | 2.312 | 4.425 | |
| 6 | 2.525 | 4.786 | |
| 7 | 2.793 | 5.022 |
HPLC chromatogram represents the retention time of ITP HCL and ELE HBR
Citation: Acta Chromatographica 35, 4; 10.1556/1326.2022.01072
Validation of method developed
Linearity
Both of the drugs were identified separately quite successfully with satisfactory retention time and great resolution. ITP HCL and ELE HBR showed retention time at 4.229 and 1.933 min respectively. Both of the drugs were evaluated for linearity between 10 and 50 μg mL−1 concentration. ELE HBR and ITP HCL both drugs showed significant linearity values of R2 0.9993 and 0.9965 respectively represented in the figure.
System suitability test
Data obtained from suitability studies verified all of the parameters showed satisfactory peaks. The low %RSD of both drugs demonstrated good resolution represented in Table 2.
System suitability studies for developed method and values of calculated theoretical plate, tailing factor, resolution, and retention times
| Drugs | Mean | %RSD | Theoretical Plates | Tailing Factor | Resolution | Retention Time |
| ITP HCL | 10,945 | 0.615 | 3,132 | 0.97 | 2.65 | 4.229 |
| ELE HBR | 9,587 | 0.584 | 3,415 | 1.01 | 4.12 | 1.9 |
| USP recommendation | <2 | >2,000 | 0.8 to 1.5 | >2 | ||
Values were represented as their mean n = 6.
Inter and intra-day precision and accuracy
Inter-day and intra-day precision were done on both drugs. For the evaluation purpose of intra-day studies, a fixed concentration of a standard solution was injected after different intervals of time. During inter-day studies %RSD for ITP HCL was found to be 0.98, 1.09 and 1.1%, intra-day values ranges from 1.029, 0.845 and 0.111%. While for ELE HBR observed %RSD of inter-day studies was found to be 0.83, 0.89 and 0.41%, for intra-day studies values range between 0.637, 1.197 and 0.444% as the values fall within the limit (limit RSD <2.0%) [61] Table 3.
Inter and Intra-day precision and accuracy
| Drugs | Concentration found | |||
| Intra-day (Mean ± SD) | %RSD | Inter-day (Mean ± SD) | %RSD | |
| ITPHCL | 2.102 ± 0.25 | 1.029 | 1.989 ± 0.14 | 0.98 |
| 6.102 ± 0.12 | 0.845 | 5.961 ± 0.45 | 1.09 | |
| 9.876 ± 0.11 | 0.111 | 9.843 ± 0.21 | 1.1 | |
| ELEHBR | 1.947 ± 0.50 | 0.637 | 1.925 ± 0.11 | 0.83 |
| 4.798 ± 0.21 | 1.197 | 4.754 ± 0.23 | 0.89 | |
| 9.622 ± 0.15 | 0.444 | 9.617 ± 0.13 | 0.41 | |
Robustness
Further, the system was tested for robustness by making small variations in pH, flow rate, organic content, and temperature of the column. A total number of five replicates were injected and %RSD was calculated. Small changes in all these parameters would not affect the method, which proves that the method was robust [36, 62]. The flow rate was dropped to 0.9 mL min−1 from 1 mL min−1 and acetonitrile contents were varied at ± 2%. It was found that the variability has no ineffectual effects on the developed method and the calculated %RSD were 0.098%, and 0.152% for ITP HCL and ELE HBR respectively.
Accuracy
If the accuracy of the developed method falls between 98 and 102% it was considered acceptable [63] (Table 4). The developed method was accurate as drug recoveries of both ITP HCL (99.87, 99.96, and 99.84%) and ELE HBR (99.81, 99.12, and 98.44%) having concentrations of 10, 30, and 50 μg mL−1 solutions fall within prescribed criteria (Table 5).
Precision studies of ITPHCL and ELEHBR films regarding the developed method (n = 6)
| Injections | ITPHCL Average Standard AUC | ELEHBR Average Standard AUC | ITPHCL Average Sample AUC | ELEHBR Average Sample AUC |
| 1 | 2,972,336 | 1,526,157 | 2,981,006 | 1,521,886 |
| 2 | 2,974,567 | 1,525,789 | 2,990,017 | 1,525,961 |
| 3 | 2,979,876 | 1,525,258 | 2,997,614 | 1,528,667 |
| 4 | 2,980,122 | 1,527,521 | 2,986,125 | 1,544,091 |
| 5 | 2,979,910 | 1,528,847 | 2,985,641 | 1,528,821 |
| 6 | 2,979,859 | 1,527,891 | 2,996,541 | 1,529,948 |
| Mean | 2,977,778 | 1,526,910 | 2,989,490 | 1,529,895 |
| %RSD | 0.080798 | 0.098014 | 0.098451 | 0.152036 |
Recovery studies of ITP HCL and ELE HBR after replicated injection (n = 6) for known drugs concentration
| Drugs | % Solution | Amount Recovered | % Recovery | %RSD |
| ITPHCL | 80 | 10.48 ± 0.01 | 99.87 ± 0.04 | 1.14 |
| 100 | 27.85 ± 0.09 | 99.96 ± 0.10 | 1.78 | |
| 120 | 39.83 ± 0.10 | 99.84 ± 0.09 | 0.09 | |
| ELEHBR | 80 | 10.28 ± 0.05 | 99.81 ± 0.02 | 0.43 |
| 100 | 28.35 ± 0.03 | 99.12 ± 0.01 | 1.02 | |
| 120 | 47.62 ± 0.06 | 98.44 ± 0.06 | 0.34 |
Specificity
Furthermore, the developed method was analyzed for specificity (Fig. 3). It was observed that no interface was analyzed even by injecting separate injections of placebo, mobile phase, and active drugs. None of the interactive peaks were observed and the peaks of ITP HCL, and ELE HBR which were observed previously at 1.933, 4.229 remained there and no change in retention time has appeared as illustrated in Fig. 3.
LOD and LOQ
As LOD represents analyte concentration while LOQ yields noise to signal ratio [64]. In the case of ELE HBR LOD and LOQ were 3.56 and 10.79 µg/mL while for ITP HCL 1.5 and 4.6 µg/mL were observed as LOD and LOQ respectively.
Assay of formulated films
Formulated films of both ITP HCL and ELE HBR were determined for their assay studies. It was found that the assay result of films was 99.05% for ITP HCL and 99.87% for ELE HBR respectively. Results from Fig. 3 were indicative of the suitability of the developed method.
Stability of solution and mobile phase
Solution of both drugs and mobile phase showed good stability under provided conditions. Freshly prepared solutions of drugs and mobile phase were analyzed and their results were compared. The method accuracy was found in the range of 97%–99% for ITP HCL and ELE HBR respectively.
Discussion
While observing the obtained chromatograms, it was noted that ITP HCL results in high peaks as compared to ELE HBR. Solution of the same concentration (30 μg mL−1) was constituted for both drugs. The possible reason for high peaks could be the high level of absorption of ITP HCL, as compared to ELE HBR at the selected wavelength which was designated for the detection of both drugs simultaneously.
Whenever a high pH was used that could damage the silica support present in HPLC, reduces the life duration of the column. So, it is recommended not to use alkaline pH. A shorter retention time could be observed as the percentage of acetonitrile increases. The resolution between two neighboring peaks decreases as the concentration of acetonitrile increases [37].
Meanwhile, retention time was also observed to be an important factor of the analyte that depends on the composition of the mobile phase, pH of the buffer, flow rate, and polarity. In HPLC flow rate and retention time have an inverse relation, as the flow rate increases, it will cause a decrease in retention time and vice versa. So, retention time and flow rate were also important factors to be adjusted, because sometimes they affect the tail factor, theoretical plate number, and symmetry of the peaks.
So, it was observed from the results that the simultaneous method of ITP HCL and ELE HBR can further be used in animals for drug detection. The developed method was accurate as the accuracy of both drugs fall within limits. Specificity indicates that there appeared no extra peaks and our method was more specific. Meanwhile, the assay of formulated films was also indicative of system suitability.
The method appeared to be beneficial for both qualitative and quantitative analysis. The following method appeared to be reproducible. It appeared to be the most suitable method for the simultaneous determination of both drugs. The current method is simple, highly precise, and stable. So, all these parameters would suggest that the developed and validated method can be further used for the identification of both drugs in a dosage form as well as in bulk form.
Conclusion
One of the most promising factors which affect the retention time of analyte in RP-HPLC is pH. The chemical structure of an analyte consists of basic or acidic functional groups. A basic compound preferably gains a proton and pH decreases while an acid loses a proton and a rise in pH would be observed. So, the difference between pKa (it is the negative logarithm of the acid dissociation constant (Ka)) and pH, determines the complete suppression or complete dissociation of the analyte within a solution. Subsequently charged and uncharged species were entitled as different chemical substances, any variation in pH can cause deviations in retention time, absorbance, and physicochemical properties of the analyte. In the case of chromatographic retention, the hydrophobicity of the analyte decreases due to the presence of dissociated groups, which ultimately leads to a decrease in the retention time of the dissociated analyte as compared to the non-dissociated form [65]. For elution of desired purposes, acetonitrile was commonly used as a solvent in RP-HPLC. Acetonitrile possibly is used as a washing solution for injection ports or needle washing purposes. Different mobile phases on the basic principle of like dissolves like were constituted for elution purposes. Acetonitrile was used as the non-polar part and water was used as the polar solvent.
A very precise, quick, cost-effective HPLC method, for co-determination of ITP HCL and ELE HBR was established. Depending upon the short retention time (ITP HCL and ELE HBR showed retention time at 4.229 and 1.933 min) and flow rate (1 mL min−1), it saves time and cost. The composition of the mobile phase was selected based on the best and most optimized chromatograms. The proposed method was validated thoroughly as the method was demonstrated to be linear, accurate, precise, and robust. Finally, the proposed method is possibly used for the determination of both drugs simultaneously.
Acknowledgment
The authors would like to thank you CCL and Wilshire Laboratories for providing research facilities and raw materials.
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