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Aman Patel, Prashant Kumar Vinode*
Sagar Institute of Pharmaceutical Science, Sagar M.P. 470228 India
*Address for Corresponding Author
Prashant Kumar Vinode
Sagar Institute of Pharmaceutical Science, Sagar M.P. 470228 India
Abstract
The study is focused at development and validation for estimation of aceclofenac in pharmaceutical dosage form. The High-performance liquid chromatography method applied for better understanding of the process and to generate, accuracy, efficacy, linearity, precision for target product quality attributes, the safe efficacious stable and patient compliant drug of aceclofenac. Various formulation studies were reported which helped in developing the accurate form of drug by High-performance liquid chromatography (HPLC). These studies deal with developed at validated methods of aceclofeanc to control and measure the active form of drug and to improve the systematic exposure for their analgesic properties. Aceclofenac is soluble in ethanol, dimethyl sulfoxide internal phase volume. In this review we summarize the parameters to measurement, for the quality and efficacy of aceclofenac by the using of various HPLC parameters.
Keywords: Aceclofenac, chromatography, validation, ICH guideline, quantitative
Introduction
Aceclofenac (ACE), 2-[(2, 6-dichlorophenyl) amino] phenyl] acetyl] oxyacetic acid is used as anti-inflammatory drug. It is official in B.P. and I.P. Aceclofenac is a non-steroidal anti-inflammatory drug (NSAID). It is a cytokine inhibitor. Aceclofenac works by blocking the action of a substance in the body called cyclooxygenase. Cyclooxygenase is involved in the production of prostaglandin (chemical in the body) which causes pain, swelling and inflammation. It is a NSAID, Aceclofenac has higher anti-inflammatory action than conventional NSAIDs. used in the management of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis (Choudhari et al., 2010). The favorable mainstay of pain relief due to its synergistic effects, multiple actions, quick relief, and patient acceptance (Shirke et al., 2015). Aceclofenac relieves pain by stimulating cartilage synthesis (Dudhe et al., 2013).
Figure 1. Chemical structure of Aceclofenac
A prodrug is defined as a biologically inactive derivative of a parent drug molecule that usually requires a chemical or enzymatic transformation within the body to release the active drug, and possess improved delivery properties over the parent molecule (Shirke et al., 2015; Kristina et al., 2011). Analytical method development and validation play important roles in the discovery, development, and manufacture of pharmaceuticals. Various analytical methodologies are employed for the determination of related components in pharmaceuticals (Hussian et al., 2014; Hussain et al., 2015; Bhardwaj et al., 2015).
Dosage and administration
The usual dosage of AC in adult patients with arthritic disorders or moderate to severe pain is 100 mg orally twice daily (Broden et al., 1996; Dooley et al., 2001). Due to short half life, it is necessary to be administered frequently in order to maintain the desired concentration12. Therefore, AC is an ideal candidate for sustained release formulation, resulting in more reproducible drug absorption compared to single dosage forms (Shivhare et al., 2009). AC should not be administered to patients with peptic ulcers or GI bleeding, moderate or severe renal impairment, sensitivity to aceclofenac or other NSAIDs. The drug is not recommended in pregnant or breast-feeding women.
Pharmacodynamic properties
AC is non-steroidal anti-inflammatory drug (NSAID) and Analgesic Properties. The mode of action of Aceclofenac is largely based on the inhibition to prostaglandin synthesis. Aceclofenac is a potent inhibitor of the enzyme cyclooxygenase, which is involved in the production of prostaglandins.
Pharmacokinetic properties
After oral administration, Aceclofenac is rapidly and completely absorbed as unchanged drug. Peak plasma concentrations are reached approximately 1.25 to 3.00 hours following ingestion. Aceclofenac penetrates into the synovial fluid, where the concentrations reach approximately 57% of those in plasma. The volume of distribution is approximate 25 L. The mean plasma elimination half-life is around 4 hours. Aceclofenac is highly proteinbound (>99%). Aceclofenac circulates mainly as unchanged drug. 4- hydroxyaceclofenac is the main metabolites detected in plasma. Approximately two- thirds of the administered dose is excreted via the urine, mainly as hydroxyl metabolites. No changes in the pharmacokinetics of Aceclofenac have been detected in the elderly.
Uses
Aceclofenac is used to relieve pain. It relieves pain and inflammation in conditions such as rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.
Rheumatoid arthritis- Aceclofenac is used to treat symptoms such as swelling, pain, and stiffness of the joints associated with rheumatoid arthritis.
Osteo-arthritis- Aceclofenac is used to treat symptoms such as tender and painful joints associated with osteoarthritis.
Ankylosing Spondylitis - Aceclofenac is used to treat symptoms such as stiffness and pain associated with Ankylosing Spondylitis.
Aceclofenac is mainly metabolized by the enzyme CYP2C9. All the drugs which are metabolized through the same enzyme system would exhibit drug interaction like phenytoin. The elimination half life of phenytoin is reduced in presence of aceclofenac (Medhi et al., 2012). The co-administration of rosiglitazone (antidiabetic) results in reduced anti-diabetic activity (sathish et al., 2012). When aceclofenac is given with sucralfate, the absorption of aceclofenac is affected and results in irregular and delayed absorpton (Naz et al., 2011).
Safety
New concerns on the safety profile of NSAIDs have been raised by the European Medicines Agency (EMEA) and other regulatory authorities. Aceclofenac is well tolerated and possesses higher safety profile over other NSAIDs like indomethacin (Kornasoff et al., 1996), diclofenac (Pareek et al., 2006) ketorolac (Lolorente et al., 2002). It can be safely use in the longterm treatment of osteoarthritis(batlle et al.,1996,Gijon et al.,1997), rheumatoid arthritis (Hunter et al., 1996), active ankylosing spondylitis (Martindale, 2009; Grav et al., 1991; Skaikh et al., 2006; Cho.,2007). Hence it is well-accepted therapy for both acute and chronic inflammatory and degenerative disease (Lemmel et al., 2002).
High Performance Liquid Chromatography method
Instrumentation
Quantitative HPLC is performed on a high pressure gradient high performance liquid chromatograph (SHIMADZU LC-20AT prominence liquid chromatograph) with two LC-20AT VP pumps, manual injector with loop volume of 20 µL (Rheodyne), programmable variable wavelength SHIMADZU SPD-20A prominence UV-Vis detector and WELCHROM C18 Column (4.6 X 250mm, 5µm). The HPLC system is equipped with “Spincotech” software. In addition an electronic balance (Shimadzu TX223L), digital pH meter (Systronics model 802), a sonicator (spectra lab, model UCB 40), UV- Visible Spectrophotometer (Systronics model- 2203) are used generally.
Accuracy
The accuracy of an analytical method is the closeness of the test results obtained by that method to the true value. This is sometimes termed trueness. It is recommended that accuracy should be determined using a minimum of nine determinations over a minimum of the three concentration levels, covering the specified range (3 concentrations/3 replicates each of total analytical procedures).
It is measured as the percent of analyte recovered by assay. The recovery can be determined by the equation:
Recovery = (Analytical result/True value)x100
The recovery should be in the range of Control limit.
This method can be applied for calculating the Upper Control Limit (UCL) and Lower Control Limit (LCL). The method involves the moving range, which is defined as the absolute difference between two consecutive measurements.
Precision
The precision of an analytical method is the degree of agreement among individual test results when the method is repeated to multiple samplings of a homogeneous sample.The precision of an analytical procedure is usually expressed as the standard deviation or relative standard deviation (coefficient of variation) of a series of measurements.
Repeatability
Repeatability refers to the use of the analytical procedure within a laboratory over a short period of time using the same analyst with the same equipment. Repeatability should be assessed using a minimum of nine determinations covering the specified range for the procedure (i.e., three concentrations and three replicates of each concentration or using a minimum of six determinations at 100% of the test concentration).
Reproducibility
Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology). Reproducibility is usually demonstrated by means of an inter-laboratory trial.
Intermediate
Intermediate precision is the results from within lab variations due to random events such as different days, different analysts, different equipment, etc. The standard deviation, relative standard deviation (coefficient of variation) and confidence interval should be reported for each type of precision investigated.
Limit of quantitation
The limit of quantitation is the minimum injected amount that produces quantitative measurements in the target matrix with acceptable precision in chromatography, typically requiring peak heights 10 to 20 times higher than the baseline noise. If the required precision
of the method at the limit of quantitation has been specified, the approach can be used. A number of samples with decreasing amounts of the analyte are injected six times.
The calculated RSD percent of the precision is plotted against the analyte amount. The amount that corresponds to the previously defined required precision is equal to the limit of quantitation. It is important to use not only pure standards for this test but also spiked matrices that closely represent the unknown samples. For the limit of quantitation, the ICH recommends, in addition to the procedures as described above, the visual inspection and the standard deviation of the response and the slope of the calibration curve. Any results of limits of detection and quantitation measurements must be verified by experimental tests with samples containing the analytes at levels across the two regions. It is equally important to assess other method validation parameters, such as precision, reproducibility and accuracy, close to the limits of detection and quantitation.
Specificity
Specificity is defined as the ability of an analytical method to measure the analyte clearly in the presence of other components.
Consider the example of a medical test for diagnosing a disease. Specificity relates to the test's ability to correctly reject healthy patients without a condition. Specificity of a test is the proportion of those who truly do not have the condition who test negative for the condition.
{\displaystyle {\begin{aligned}{\text{specificity}}&={\frac {\text{number of true negatives}}{{\text{number of true negatives}}+{\text{number of false positives}}}}\\[8pt]&={\frac {\text{number of true negatives}}{\text{total number of well individuals in population}}}\\[8pt]&={\text{probability of a negative test given that the patient is well}}\end{aligned}}}A positive result in a test with high specificity is useful for ruling in disease. The test rarely gives positive results in healthy patients. A positive result signifies a high probability of the presence of disease. A test with 100% specificity will recognize all patients without the disease by testing negative, so a positive test result would definitely rule in the presence of the disease. However, a negative result from a test with high specificity is not necessarily useful for ruling out disease. For example, a test that always returns a negative test result will have a specificity of 100% because specificity does not consider false negatives. A test like that would return negative for patients with the disease, making it useless for ruling out the disease.
Range
The range of the method is the interval between upper level and lower level of analyte that have been determined with acceptable accuracy, precision and linearity. It is determined on either a linear or nonlinear response curve and expressed in the same unit as the test results are expressed. The range is normally expressed in the same units as test results (e.g., percent) obtained by the analytical procedure.
The following minimum specified ranges should be considered:
(a) For assay of a drug substance (or a drug product) the range should be from 80% to 120% of the test concentration.
(b) For determination of an Impurity: from 50% to 120% of the acceptance criterion.
(c) For Content Uniformity: a minimum of 70% to 130% of the test concentration, unless a wider or more appropriate range based on the nature of the dosage form (e.g., metered-dose inhalers) is justified.
(d) For dissolution Testing: ±20% over the specified range
(e) (e.g., if the acceptance criteria for a controlled-release product cover a region from 20%, after 1 hour, and up to 90%, after 24 hours, the validated range would be 0% to 110% of the label claim).
Robustness
Ruggedness is normally evaluated during method development, typically by the originating laboratory, before collaborating with other laboratories and is a measure how well a method stands up to less than perfect implementation. In any method there will be certain stages, which, if not carried out sufficiently carefully, will have a severe effect on method performance, and may even result in the method not working at all. These stages should be identified, usually as part of method development, and if possible, their influence on method performance evaluated using ‘ruggedness tests’, sometimes also called ‘robustness tests.
Linearity
It may be demonstrated directly on the drug substance (by dilution of a standard stock solution) and/or separate weighing of synthetic mixtures of the drug product components, using the proposed procedure. The latter aspect can be studied during investigation of the range. Linearity should be evaluated by visual inspection of a plot of signals as a function of analyte concentration or content. The correlation coefficient, y-intercept, slope of the regression line, and residual sum of squares should be submitted. A plot of the data should be included. According to the Beers Lambert Law, absorbance is the ratio of logarithm of Intensity of incident light and Intensity of transmitted light, or A = εCT. Knowledge of the sensitivity of the color is important and the following terms are commonly employed for expressing sensitivity. The absorbance (A) is proportional to the concentration (C) of the absorbing species, if absorptivity (ε) and thickness of the medium (t) are constant. When concentration is in moles per liter, the constant is called molar absorptivity.
Conclusion
HPLC method is the most reliable accurate and precised validated and quantitative analytical method for estimation of drug in any sample. It is concluded that from the reported studies the analysis of validation parameters proved that the method is efficient for the estimation of aceclofenac.
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