Influence of immediate release tablet formulation on dissolution profile of paracetamol

Introduction: Paracetamol is analgesic and antipyretic, which is usually in the form of an immediate release tablet formulations. Therapeutic effects in terms of the speed and intensity of the analgesic effect is dependent on speed of liberation from formulation. Aim: The aim of this work was to determine and compare dissolution profiles of 4 paracetamol immediate release tablet formulations and to determine influence of excipients on kinetic of paracetamol dissolution. Materials and Methods: Dissolution profiles of paracetamol tablets were determined using method with paddles and phosphate buffer pH 6.8 as a medium. Release of paracetamol was followed 60 minutes (using 6 time points). Concentration of paracetamol was measured using UV/Vis spectrophotometric method (243 nm). Dissolution profiles were compared using model-independent method (difference factor and similarity factor), statistic method (ANOVA-based method and pair Student's T-test, p<0.05) and model dependent methods (to determinate the release kinetics of paracetamol). Results: All formulations in the first 45 minutes liberated more than 85 % of the labled content. Formulation D, which contained superdesintegrator, released 90% of the content in the first 5 minutes. Though based on values of difference and similarity factors formulations are, not significantly different, ANOVA-based method showed that formulation A and B, B and C, as well as formulation B and D do statistically differ in all 6 time points, meaning they have parallel profiles. The release of paracetamol from formulations A and D is best described by the first order kinetic model, while the release of formulations B and C by the logistic model. Conclusions: The release kinetic of paracetamol is mostly influenced by the type of superdisintegrants and lubricants. Formulation with superdisintegrant technology OptiZorb® demonstrated fastes release rate and thus it is expected to produce the fastest pharmacodynamic effect.

Drugs with the highest drug expenditure in the Republic of Serbia

Introduction: The policy concerning drugs represents a concentrated effort to achieve better health outcomes for all, with a particular focus on people's access to and rational use of medications. On the basis of pharmacoeconomic analyses, it is possible to modify established prescribing habits, it is possible to influence the creation of guidelines, development strategy and long-term health care planning. Aim: The aim of the work was to determine drugs with the highest expenditure in the Republic of Serbia, and to compare the results obtained in three consecutive years 2016, 2017 and 2018. Also, to analyze which are the most expensive medications listed in the National Register of Medications and what is the trend of changing them. Material and methods: The drug expenditure was monitored using the ATC/DDD methodology. It implies the classification of medications according to the internationally accepted ATC classification of drugs, while DDD, i.e. defined daily dose, is used as a statistical unit for consumption monitoring. The number of DDD/1,000 inhabitants per day provides an insight into how many inhabitants (out of 1,000 of them) used the observed medication and were exposed to its effects during one day. Results: The trend of expenditure of these medications was growing exponentially from 2016 to 2018. The most expensive medications per box are from group J - anti-infective drugs for systemic use and L - antineoplastics and immunomodulators, but their expenditure in the Republic of Serbia is very low. The drugs with the highest price per 1 DDD are: enzymes imiglucerase, laronidase and the biological medication basiliximab in all three years, but considering the indications and rare prescribing, the total cost for these drugs is not high. The largest funds in the Republic of Serbia for the mentioned period were spent on drugs such as: acetylsalicylic acid, paracetamol in combinations, trastuzumab, pantoprazole, amlodipine and rosuvastatin. Comparing the spending on L group of drugs in 2017 compared to 2016, there was a significant increase. Conclusion: The medications with the highest expenditure in the Republic of Serbia are used very little compared to countries with good pharmacotherapy practice. The most expensive drugs are those that are used for special and rare indications, and large amounts of money are not allocated for them as for some cheaper, but more frequently prescribed drugs

The Effect of Humidity on the Dissolution Kinetics and Tablet Properties of Immediate-Release Tablet Formulation Containing Lamotrigine

This study aims to find the effects of high (75%) and low (30%) humidity conditions and its correlation with formulation composition on dissolution kinetics of lamotrigine (LMT) from prepared immediate-release tablets during one- and four-week periods. Two types of fillers microcrystalline cellulose (MCC) or anhydrous lactose (LAC), disintegrant sodium starch glycolate (NaSG, 0.5% or 4%), and lubricant magnesium stearate (MgST, 0.25% or 5%) were used. A three-factor two-stage complete factorial design (23) was used to assess the influence of the composition of the tested formulations. The tablets were produced by direct compression and characterized using a disintegration test, a resistance to crushing test, and dissolution tests (pH 1.2 and pH 6.8). Using Design Expert software, it was concluded that in addition to the effect of fillers on pH 6.8, NaSG has a significant impact after exposure to high and low humidity, as well as its interaction with LAC and MCC. In the dissolution medium pH 1.2, under conditions of high humidity, the content of MgST and NaSG and their interaction show a significant influence. The release rate of LMT was affected by humidity as well as type of excipients and their interactions

In silico–in vitro estimation of lipophilicity and permeability association for succinimide derivatives using chromatographic anisotropic systems and parallel artificial membrane permeability assay

Passive permeability is one of the key features that determine absorbability and one of the most studied properties in the early phases of drug development. Newly synthesized succinimide derivatives from two different series (1-aryl-3-methylsuccinimides and 1-aryl-3-ethyl-3-methylsuccinimides) with high biological potential have been subjected to estimation of their passive permeability and their association with (a) experimentally obtained anisotropic lipophilicity, (b) in silico–calculated lipophilicity and (c) in silico–predicted permeability and absorbability. Non-cellular-based parallel artificial membrane permeability assay was applied for quantifying their passive permeation, expressed as logPapp. Passive permeation was governed by the lipophilicity of the analysed compounds, and anisotropic lipophilicity was related with statistically significant passive transcellular diffusion (r2 = 0.614, P < 0.001). Moreover, experimentally determined passive permeability, logPapp, was statistically significantly associated with both in silico–predicted absorption constant, ka (r2 = 0.7886, P < 0.001), and human intestinal absorption (HIA) in percentage (r2 = 0.484, P < 0.001), respectively. However, there was no statistically significant relationship between experimentally obtained permeability on non-cellular-based model and in silico–predicted Caco-2 permeability based on the predictions conducted on two different software. Based on the obtained results, anisotropic systems are promising surrogates for determining lipophilicity, except for compounds with acidic functional groups that are completely ionized under (pH = 7.4)

In silico–in vitro estimation of lipophilicity and permeability association for succinimide derivatives using chromatographic anisotropic systems and parallel artificial membrane permeability assay

Passive permeability is one of the key features that determine absorbability and one of the most studied properties in the early phases of drug development. Newly synthesized succinimide derivatives from two different series (1-aryl-3-methylsuccinimides and 1-aryl-3-ethyl-3-methylsuccinimides) with high biological potential have been subjected to estimation of their passive permeability and their association with (a) experimentally obtained anisotropic lipophilicity, (b) in silico–calculated lipophilicity and (c) in silico–predicted permeability and absorbability. Non-cellular-based parallel artificial membrane permeability assay was applied for quantifying their passive permeation, expressed as logPapp. Passive permeation was governed by the lipophilicity of the analysed compounds, and anisotropic lipophilicity was related with statistically significant passive transcellular diffusion (r2 = 0.614, P < 0.001). Moreover, experimentally determined passive permeability, logPapp, was statistically significantly associated with both in silico–predicted absorption constant, ka (r2 = 0.7886, P < 0.001), and human intestinal absorption (HIA) in percentage (r2 = 0.484, P < 0.001), respectively. However, there was no statistically significant relationship between experimentally obtained permeability on non-cellular-based model and in silico–predicted Caco-2 permeability based on the predictions conducted on two different software. Based on the obtained results, anisotropic systems are promising surrogates for determining lipophilicity, except for compounds with acidic functional groups that are completely ionized under (pH = 7.4)

Predicting percutaneous permeation for new succinimide derivatives by in vitro and in silico models

Percutaneous permeation of twenty-four newly synthesized succinimide derivatives was evaluated using parallel artificial membrane permeability assay (PAMPA) with 70% silicone oil and 30% isopropyl myristate. Different online tools were applied for in silico predicting of their skin permeability. According to the in silico estimation of the transdermal permeation, all compounds are expected to have relatively good ability to permeate the skin, at pH=6. However, for two compounds containing carboxylic groups, the concentration in the acceptor compartment was undetectable indicating limited permeation at pH=7.4. Statistically significant association was found between in silico predicted logKp values by the PreADMET and SwissADME online tools and the percutaneous permeability estimated from the experimental results using the artificial membranes (adj. r2 = 0.371, p = 0.00158 and adj. r2=0.232, p = 0.0135, respectively). The association between permeation through artificial membranes and the calculated logP data was also statistically significant. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) took into account in silico logKp and calculated logP data. The ranking of the lipophilicity and skin permeability parameters was conducted with sum of ranking differences (SRD) analysis which was validated. Based on the obtained results, it is predicted that lipophilicity is a pivotal physico-chemical parameter of the passive permeation of succinimide derivatives through hydrophobic barriers such as the skin. © 2022 Elsevier B.V