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Quantification of potential impurities by a stability indicating UV-HPLC method in niacinamide active pharmaceutical ingredient
Abstract
A sensitive, stability indicating reverse phase UV-HPLC method has been developed for the quantitative determination of potential impurities of niacinamide active pharmaceutical ingredient. Efficient chromatographic separation was achieved on C18 stationary phase in isocratic mode using simple mobile phase. Forced degradation study confirmed that the newly developed method was specific and selective to the degradation products. Major degradation of the drug substance was found to occur under oxidative stress conditions to form niacinamide N-oxide. The method was validated according to ICH guidelines with respect to specificity, precision, linearity and accuracy. Regression analysis showed correlation coefficient value greater than 0.999 for niacinamide and its six impurities. Detection limit of impurities was in the range of 0.003-0.005% indicating the high sensitivity of the newly developed method. Accuracy of the method was established based on the recovery obtained between 93.3% and 113.3% for all impurities.
... PT (Penta erythritol tetra acrylate) is a tetra-functional acrylate monomer widely used as crosslinker in polymerization. In previous studies, PT has been used as crosslinker for polyethylene oxide (PEO) via UV radiation [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] and for HA via exposure to high temperature (80 • C) in the oven [12]. Such crosslinked hydrogel films can be suitable for the delivery of drugs and cosmetic active ingredients by transdermal and topical (cosmetic) formulations, respectively, via application of the hydrogel film on the intact skin surface. ...
... The anti-ageing role of Vitamin B 3 is attributed to the fact that these two enzymes often decline in number with age; when these enzymes are sufficiently present in the skin, they can create an effective defense mechanism against ageing-induced external factors. Vitamin B 3 also assists the skin in remaining hydrated as it encourages the production of natural emollients [19][20][21]. Niacinamide is an active amide form of vitamin B 3 , and its chemical structure consists of 3-pyridine carboxamide. Due to vitamin B 3 's excretion from the body without in vivo storage, it should be taken from various food sources and supplements [19]. ...
Novel crosslinked hyaluronic acid (HA) hydrogel films were previously invented by reacting the HA polymer with the PT (Pentaerythritol Tetra-acrylate) crosslinker over basic pH conditions in the oven. HA is considered a natural polymer present in cosmetic as well as pharmaceutical formulations. This current study aimed to highlight the effect of loading method (post-loading and in situ) of selected actives (salicylic acid and niacinamide B3) in the hydrogel films and then study their release kinetics. Differential scanning colometry (DSC) and Fourier transform infrared spectroscopy (FTIR) analysis evidenced the loading of the actives and full release from the HA hydrogel films, while the scanning electron microscopy (SEM) demonstrated the morphological changes to the films during the study by comparing the average molecular weight between crosslinks (M¯c), gel fraction, crosslinking density (Ve) and mesh size (ξ) of the films. The loading percentage of the SA and B3 showed high percentage loading of actives via both loading methods. In conclusion, the (95–100%) release of the actives achieved from the HA hydrogel films within 10 min revealed that the films are an efficient immediate release system of actives.
... Linear range (μg/mL) LOD (μg/mL) Sample matrix Ref. [47]. This reliability was further supported by the coefficients from the Student's ttest and variation F-test, which did not exceed theoretical values, indicating no significant difference between the methods. ...
This study presents the development of two simple, sensitive, and selective microextraction and preconcentration procedures for determining nicotinamide (NAM) in pharmaceutical formulations and blood samples. The methods utilize the König reaction, where cyanogen chloride, formed by reacting potassium thiocyanate with sodium hypochlorite in acidic medium, interacts with NAM and couples with buffered barbituric acid at pH 3.5 to form a pink polymethine dye. This dye is extracted into an isobutanol layer using tetrabutylammonium bromide and exhibits maximum absorption at 560 nm for spectrophotometric quantification. In the smartphone paper‐based (SPB) method, the dye is applied to a paper strip, captured by a smartphone, and analyzed for red, green, and blue components. Both methods were thoroughly evaluated for key parameters, demonstrating adherence to Beer’s law over a NAM concentration range of 1.0–7.8 µg mL‒1, with limits of detection (LOD) of 0.76 µg mL‒1 for the spectrophotometric method and 0.91 µg mL‒1 for the SPB method. Our smartphone paper‐based combines paper‐based analysis, smartphone detection, and microextraction for the first time, offering a cost‐effective, portable, and sensitive solution for NAM assay in plasma. A comparison with the established HPLC method, using statistical tests, showed no significant differences, confirming the reliability of these novel methods.
... The exposure of drugs and excipients to environmental variations, such as temperature, light, and humidity, aids in identifying potential degradation products and the conditions favoring their formation [5]. These stress factors contribute to investigating drug-excipient compatibility [4]. ...
... Niacinamide (NIA), chemically known as pyridine-3-carboxamide, is an amide form of vitamin B3 and a water-soluble molecule with a wide range of mechanisms of action that have been described in the literature [6,7]. This vitamin is not naturally stored in the body, but it can be obtained by the dietary intake of vitamin B3 and tryptophan [8]. ...
Niacinamide (NIA) has been widely used in halting the features of ageing by acting as an antioxidant and preventing dehydration. NIA’s physicochemical properties suggest difficulties in surpassing the barrier imposed by the stratum corneum layer to reach the target in the skin. To improve cutaneous delivery of NIA, a hybrid nanogel was designed using carrageenan and polyvinylpyrrolidone polymers combined with jojoba oil as a permeation enhancer. Three different types of transethosomes were prepared by the thin-film hydration method, made distinct by the presence of either an edge activator or a permeation enhancer, to allow for a controlled delivery of NIA. Formulations were characterized by measurements of size, polydispersity index, zeta potential, encapsulation efficiency, and loading capacity, and by evaluating their chemical interactions and morphology. Skin permeation assays were performed using Franz diffusion cells. The hybrid hydrogels exhibited robust, porous, and highly aligned macrostructures, and when present, jojoba oil changed their morphology. Skin permeation studies with transethosomes-loaded hydrogels showed that nanogels per se exhibit a more controlled and enhanced permeation, in particular when jojoba oil was present in the transethosomes. These promising nanogels protected the human keratinocytes from UV radiation, and thus can be added to sunscreens or after-sun lotions to improve skin protection.
A simple, sensitive and accurate spectrophotometric method for determination of PYR.HCl and NTA in pure and pharmaceutical forms. The method based on group of known digital data used to separate the response signals for sample contains the two components without need to separating via first and second derivative of spectra. The method obtained obeying to the Beers law in the concentration range between )5-45 µg.ml-1( for two components in the presence of PYR. HCl )15µg.ml-1( and NTA (5µg.ml-1) with another components at wavelength (210 nm ) respectively . The Rec % range was between ) 98.5354 - 103.4335 % (and RSD% (0.0864 - 0.1487 %), LOD) 1.0822 µg.ml-1, ( LOQ ( 3.6075 µg.ml-1 (PYR.HCl in presence of NTA, The Rec% range was between )96.1418 - 102.9273 % (and RSD% (0.2165–0.4933 % ), LOD (0.7273µg.ml-1 ,(LOQ (2.4252 µg.ml-1( NTA in presence of PYR. HCl .
The compatibility of formulation components is crucial for safe and high-quality medicines. To detect the potential for incompatibility and to assess formulation stability it is beneficial to conduct compatibility study during the drug development phase. The therapy of tuberculosis normally consists of two or more medicines taken together. Consequently, different antituberculotic fixed-dose combination (FDC) formulations have been developed. Isoniazid is first-line medicine and present in several FDCs. Low bioavailability due to the active substances’ incompatibility in acidic medium was reported for some of these FDCs forms. Rifabutin, also a first-line antituberculotic, is available in the market as a single component formulation. This study presents compatibility testing of these two active substances for a new FDC and evaluates the impact of the most common solid dosage forms’ excipients on the stability of two active substances. The potential for interaction between the formulation components was analyzed by the UHPLC method. One degradation product and one interaction product were observed and further characterized by high-resolution mass spectrometry. Still, significant degradation of two active substances, such as reported in marketed FDC formulations was not detected for this combination. The stability and drug delivery of the proposed combination were confirmed by the dissolution test in acidic medium.
Ferulic acid (FEA) and nicotinamide (NIC) are molecules with antioxidant and anti-inflammatory properties employed in the pharmaceutical field, with highlights to their skin protection and recovery activities. In this study, new HPLC and UHPLC RP methods were developed and validated for quantification of FEA and NIC in the presence of their degradation products. The method developed in HPLC was initially transferred to UHPLC and six different stationary phases were tested, in which a core shell column was chosen. In both methods, diode-array detector and C18 columns were used. The mobile phase in both methods consisted of phosphate buffer 20 mM and methanol, being the solvent proportion of 70:30 and 75:25 for HPLC and UHPLC, respectively. The oven temperature was set at 40ºC, while flow rate were 0.4 mL/min and 1.0 mL/min for UHPLC and HPLC, respectively. The wavelength was 268 nm for HPLC and 262 nm for UHPLC. The FEA and NIC forced degradation studies resulted in photo and basic degradation products, being nicotinic acid the degradation product of NIC in basic condition and the cis isomer of FEA acid its photo degradation product. For both methodologies, good values of chromatographic parameters were obtained. The accuracy and precision values were close to 100% and 2%, respectively, while R²> 0.998, for both molecules in HPLC and UHPLC. The LOD, LOQ and robustness evaluation were satisfactory. In conclusion, both developed methodologies were validated and are available to be applied to the analyses of the FEA and NIC raw materials.
Introduction: Hydrolytic degradation is the most common cause of formation of impurities or degradation products in drugs during different stages of drug product development and/or shelf life of the drug/product. Degradation products formed by hydrolysis of ester, amide, urethane, sulfonamide, sulfonate and ether linkages, and of nitrile, hydroxyl and amino groups in drugs can be conveniently predicted and identified. Many drugs are known to degrade to such expected conventional hydrolytic degradation products, and the mechanisms of such degradations are also well known and reported. However, many drugs are reported to degrade under hydrolytic conditions to products, which cannot be justified by the conventional hydrolytic reactions. Objectives: Though structures of such unconventional hydrolytic products can be characterized through different spectral techniques, but there is a need to understand the mechanisms of such unconventional hydrolytic reactions in order to help in establishing intrinsic stability characteristics of a drug. Methodology: In the present review, we have studied and critically analysed all possible reports on hydrolytic degradation of various dugs to provide a thorough insight into unconventional routes of hydrolytic degradations of drugs. The various unconventional hydrolytic reactions found responsible for degradation of drugs are classified as oxidation, dehydrogenation, coupling/condensation, N-alkylation, C-C bond cleavage, C-N bond cleavage, dehalogenation, cyclization, decarboxylation and hydroxylation. Discussion: Varied types of reactions under hydrolytic conditions are triggered/controlled by the nature of substituent (s) across or around the susceptible bonds/groups. The mechanisms for such unconventional hydrolytic reactions have been discussed or proposed with support from the standard literature. The contents are expected to enable an analyst and a drug formulator to predict various possible as well as seemingly improbable hydrolytic degradation products of a drug well ahead of systematic forced degradation studies. © Indian Journal of Pharmaceutical Education and Research. All rights reserved.
The objective of the study is to demonstrate the development and validation of a transmission Raman spectroscopic method using the ICH-Q2 Guidance as a template. Specifically, Raman spectroscopy was used to determine niacinamide content in tablet cores. A 3-level, 2-factor full factorial design was utilized to generate a partial least-squares model for active pharmaceutical ingredient quantification. Validation of the transmission Raman model was focused on figures of merit from three independent batches manufactured at pilot scale. The resultant model statistics were evaluated along with the linearity, accuracy, precision and robustness assessments. Method specificity was demonstrated by accurate determination of niacinamide in the presence of niacin (an expected related substance). The method was demonstrated as fit for purpose and had the desirable characteristics of very short analysis times (∼2.5s per tablet). The resulting method was used for routine content uniformity analysis of single dosage units in a stability study.
The development of the pharmaceuticals brought a revolution in human health. These pharmaceuticals would serve their intent only if they are free from impurities and are administered in an appropriate amount. To make drugs serve their purpose various chemical and instrumental methods were developed at regular intervals which are involved in the estimation of drugs. These pharmaceuticals may develop impurities at various stages of their development, transportation and storage which makes the pharmaceutical risky to be administered thus they must be detected and quantitated. For this analytical instrumentation and methods play an important role. This review highlights the role of the analytical instrumentation and the analytical methods in assessing the quality of the drugs. The review highlights a variety of analytical techniques such as titrimetric, chromatographic, spectroscopic, electrophoretic, and electrochemical and their corresponding methods that have been applied in the analysis of pharmaceuticals.
Abstract
Impurities are nothing but the unidentified, unintended substance present along with desired substance. The newer regulations of US FDA, MHRA intends for the requirements of impurities rather than purity of pharmaceuticals. The impurity profiling of pharmaceuticals can be done by using various analytical methods like UV, HPLC, LC-MS, GC-MS, SCFC etc. Mostly RP-HPLC method commonly adopted for the qualification as well as quantification of impurities. The present review is an attempt made in the respect of highlighting the some important methods, quality guidelines and applications of impurity profiling.
Keywords: Impurity, quality control, pharmaceuticals, impurity fate mapping, analytical techniques.
Supported silver nanoparticles on filter paper were synthesized using Tollens' reagent. Experimental designs were performed to obtain the highest SERS enhancement factor by study of the influence of the parameters: filter paper pretreatment, type of filter paper, reactants concentration, reaction time and temperature. To this end, fractional factorial and central composite designs were used in order to optimize the synthesis for quantification of nicotinamide in the presence of excipients in a commercial sample of cosmetic. The values achieved for the optimal condition were 150mM of ammonium hydroxide, 50mM of silver nitrate, 500mM of glucose, 8min for the reaction time, 45°C temperature, pretreatment with ammonium hydroxide and quantitative filter paper (1-2µm). Despite the variation of SERS intensity, it was possible to use an adapted method of internal standard to obtain a calibration curve with good precision. The coefficient of determination of the linear fit was 0.97. The method proposed in this work was capable of quantifying nicotinamide on a commercial cosmetic gel, at low concentration levels, with a relative error of 1.06% compared to the HPLC. SERS spectroscopy presents faster analyses than HPLC, also complex sample preparation and large amount of reactants are not necessary.
This review describes an epigrammatic impression of the recent trends in analytical perspectives of degradation and impurities profiling of pharmaceuticals including active pharmaceutical ingredient (API) as well as drug products during 2008-2012. These recent trends in forced degradation and impurity profiling were discussed on the head of year of publication; columns, matrix (API and dosage forms) and type of elution in chromatography (isocratic and gradient); therapeutic categories of the drug which were used for analysis. It focuses distinctly on comprehensive update of various analytical methods including hyphenated techniques for the identification and quantification of thresholds of impurities and degradants in different pharmaceutical matrices.
A simple, selective, precise and stability-indicating high-performance liquid chromatographic (HPLC) method for determination of vitamins B 1, B2, B3 and B6 in pharmaceutical liquid dosage form was developed and validated. The chromatographic conditions comprised a reversed-phase C18 column (250 × 4.6 mm), 5 μ with a mobile phase consisting of a mixture of solution (0.015 M l-hexane sulphonic acid sodium salt, pH 3.0 ± 0.05) and methanol in gradient elution. The flow rate was kept at 1.5 mL/min. and the detection was carried out at 280 nm. The retention times of vitamins B3, B2, B 6 and B1 were 6.3, 15.1, 19.9 and 42.7 min. respectively. The linear regression analysis data for the calibration plots showed good linear relationship with coefficient of correlation values, r = 0.999 for vitamins B1, B2, B3 and B6 in the concentration ranges of 23.08-42.85, 9.61-17.84, 116.36-216.09 and 7.01-13.02 μg/mL respectively. The method was validated for precision, recovery and robustness. The vitamins undergo degradation under acidic, basic, peroxide, photochemical and thermal conditions. Statistical analysis proves that the method is reproducible and selective for the estimation of vitamins under study. As the method could effectively estimate the vitamins in presence of their degradation products, it can be employed as a stability-indicating method.
A high-pressure liquid chromatographic procedure for the simultaneous determination of niacin, niacinamide, pyridoxine, thiamine, and riboflavin was developed and applied to the analysis of multivitamin blends for these water-soluble vitamins. Reversed-phase ion-pair chromatography, using sodium hexanesulfonate as the counterion, was employed. Analysis time is shortened considerably and precision is improved by the application of this analytical technique as compared to the current official methods of analysis. Involved sample pretreatment is not required.
Description d'un protocole de dosage de ces substances (vitamines du groupe B), qui presentent en outre une activite de fixation de la couleur de la viande mais dont l'ingestion a haute dose presente des inconvenients avec parfois des symptomes pathologiques
A high-pressure liquid chromatographic assay was developed for the determination of four water-soluble vitamins: niacinamide, pyridoxine, thiamine, and riboflavin. The four vitamins are assayed simultaneously in multivitamin products not containing minerals. Thiamine currently is not quantitated in formulations containing minerals because it is not stable under the extraction conditions. The method was applied to the analysis of at least 12 different multivitamin products, including various formulations of sterile products, fluids, compressed tablets, and coated, compressed tablets. The method is stability indicating and is applicable to single-tablet assays.
Isonicotinic acid impurity in bulk niacin was detected and identified by comparison with a reference material by liquid chromatography with a diode array detector. The niacin was dissolved in dilute hydrochloric acid and chromatographed on an amine column with a mobile phase of methanol and water acidified with formic acid. Isonicotinic acid has a relative retention time of 1.5 compared with niacin (nicotinic acid), and the wavelengths of maximum ultraviolet (UV) absorbance for isonicotinic acid and niacin are 270 and 260 nm, respectively. The amount of impurity found in the niacin sample was 0.3%. Twelve formulations, including sustained-release products, one bulk material, and the United States Pharmacopoeia (USP) reference standard were tested. The impurity was detected in only the bulk and USP reference material samples.
Treatment with high doses of nicotinamide (niacinamide, vitamin B3) prevents or delays insulin-deficient diabetes in several animal models of type 1 diabetes and protects islet cells against cytotoxic actions in vitro. In recent-onset type 1 diabetes, nicotinamide administration improves beta-cell function, without significantly decreased insulin requirements. This review discusses the possible mechanism of action of nicotinamide in vivo. It is proposed that the key target of nicotinamide is the poly(ADP-ribose)polymerase (PARP), and to a lesser extent (mono)ADP-ribosyl transferases (ADPRTs). Suppression of PARP activity by nicotinamide not only decreases consumption of NAD+, the substrate of PARP, but also has major regulatory effects on gene expression, as shown for the major histocompatibility complex class II gene. In addition, PARP activity controls early steps of apoptosis. The possible suppression of ADPRTs by nicotinamide would also affect CD38, a membrane-bound external ADP-ribosyl transferase with potent immunoregulatory properties. Taken together, it is proposed that high doses of nicotinamide primarily affect ADP-ribosylation reactions in beta-cells as well as in immune cells and the endothelium. As a consequence, cell death pathways and gene expression patterns are modified, leading to improved beta-cell survival and an altered immunoregulatory balance.