Comparison Of Dissolution Profiles Research Articles

Model Independent and Dependent Methods for Dissolution Profiles Comparison: Can we take the Road Less Travelled?

Dissolution testing plays an important role in pharmaceutical development due to its ability to provide critical insight into in vivo performance. Dissolution testing during routine pharmaceutical development can ensure batch-to-batch consistency and helps to ensure that the commercial batches are of representative quality to that of studied in the pivotal clinical studies. For comparing the dissolution profiles, there are multitude of approaches suggested by various regulatory agencies that consist of model independent and dependent approaches. The present review aims to summarize the current understanding of dissolution profile similarity approaches. Dissolution profile comparison approaches suggested by various regulatory agencies were compared and contrasted. Further, detailed procedural aspects were provided for the determination of similarity using model independent and dependent approaches. Model independent approaches such as f2 bootstrap, and Multivariate Statistical Distance (MSD) were portrayed from a practical perspective. Advanced tools such as Bias-Corrected and accelerated (BCa) for f2 bootstrap were discussed in depth. Further, model dependent approaches such as zero order, and Weibull models were discussed from realistic scenarios. Finally, the utility of modeling and simulation approaches such as physiologically based pharmacokinetics model (PBPK) and physiologically based biopharmaceutics model (PBBM) were discussed in the context of their ability and potential to supersede traditional dissolution dissimilarity. Overall, this article acts as a ready-to-use guide for pharmaceutics and biopharmaceutics scientists for effective methodologies for dissolution profile comparison for internal decision-making and regulatory justifications.

Simulated acetaminophen plasma profiles from fixed-dose combination formulations: studies using the flow-through cell dissolution method

The aim of this work was to simulate acetaminophen plasma profiles from two fixed-dose combination formulations (acetylsalicylic acid, acetaminophen, and caffeine of generic vs. reference formulation) and in vitro dissolution data generated by the flow-through cell apparatus (laminar flow of 16 ml/min, 22.6 mm cells and 0.1 M phosphate buffer pH 7.4). Results were compared with in vitro release information of USP apparatus type II (paddle at 100 rpm and 900 ml of same dissolution medium). Dissolved drugs until 60 min were determined with a ratio-derivative spectrophotometric method. To compare dissolution profiles of each drug, dissolution efficiency and mean dissolution time were calculated. To predict in vivo behavior a convolution approach as well as acetaminophen published information were used. Peak plasma concentrations and area under the curve (zero time to infinity) were considered and values of predicted error for these pharmacokinetic parameters were established. When comparing dissolution profiles with Student’s t-tests significant differences were found (p < 0.05). All values of predicted error showed satisfactory results since only data generated by the flow-through cell dissolution method achieved < 10% for each pharmacokinetic parameter. It is important to carried out in vivo studies with used formulations to corroborate the obtained results.

HME-assisted formulation of taste-masked dispersible tablets of cefpodoxime proxetil and roxithromycin

ObjectivesAntibiotics are the most commonly administered medications among pediatric patients. However most of the time, accurate dose administration to children becomes a problem due to the extremely bitter taste. Cefpodoxime proxetil (CP) and roxithromycin (ROX) are antibiotics often prescribed to the pediatric population and have a bitter taste. Marketed formulations of these drugs are dry suspension and/or tablets. The lyophilization method involves various steps and thus is time consuming and expensive. The objective of this study was to mask the bitter taste of CP and ROX without compromising the solubility and drug release profile compared to marketed formulations, as well as to overcome the disadvantages associated with the currently used lyophilization technique. MethodsHot melt extrusion (HME) technology was used to process CP and ROX individually with Eudragit E PO polymer. The extrudates obtained were characterized by Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The powdered extrudates were formulated as dispersible tablets and evaluated for in vitro and in vivo taste-masking efficiency. ResultsThe tablets prepared in this study showed comparable dissolution profiles but the taste-masking efficiency was significantly enhanced compared to the marketed tablets of CP and ROX. The results of in vivo human taste-masking evaluation were also in agreement with the in vitro taste-masking studies. ConclusionThe current work presents solvent-free, scalable, and continuous HME technology for addressing the bitter taste issues of CP and ROX. The disadvantages associated with the currently used lyophilization technique were overcome by developing the formulations using HME technology.

In vitro dissolution equivalence of Jordanian sildenafil generics via validated, stability-indicating HPLC method.

This study was conducted to compare dissolution profiles of four Jordanian registered sildenafil (SDF) products to the originator. Dissolution samples were analyzed utilizing a validated and stability-indicating HPLC method in human plasma. Validation was performed forspecificity, linearity, limit of detection, lower limit of quantification, precision, trueness and stability. SDF was extracted from plasma samples using liquid-liquid extraction. The analysis wasperformed utilizing isocratic elution on C18 column with 1.0ml/min flow rate. The regression value was ∼0.999 over 3days with drug recovery between86.6 to 89.8%with 10ng/ml lower limit of quantitation. This method displayed a good selectivity of SDF with improved stability under various conditions. The method was used for SDF quantification in dissolution medium. Similarity factors for local products varied according to the used mediums, but all SDF local products passed the dissolution in vitro test since all of them showed a released of >85% after 60min at the dissolution mediums.

Application of bootstrap f2 to dissolution data from biorelevant media and evidence of the conservative nature of bootstrap f2

f2 with or without bootstrapping is the most common method to compare in vitro dissolution profiles, but methods to compare dissolution profiles have become less harmonized. The objective was to compare outcomes from bootstrap f2 and f2 (i.e. not-bootstrapped f2) using a large set of in vitro dissolution data. Non-parametric bootstrapping was performed on the 104 profile comparisons that did not meet the percent coefficient of variation (CV%) criteria to use average dissolution data. Bootstrap f2 was taken as the lower 90 % confidence interval of bootstrapped samples. There was concordance between bootstrap f2 and f2 in 92 of the 104 comparisons (88 %). There were no false positives. However, 12 % were false negative. Inspection of these discordance pairs suggests that bootstrap f2 serves as a conservative approach to assess profile similarity, particularly when a value of 50 is being used as decision criteria.

FORMULATION AND EVALUATION OF ORODISPERSIBLE TABLET OF PROCHLORPERAZINE MALEATE

In the present work, fast disintegrating tablets of prochlorperazine maleate were designed with a view to enhance patient compliance by effervescent method. Prochlorperazine Maleate, a potent antipsychotic medication with antiemetic properties, holds significance in treating various conditions such as nausea, vomiting, and vertigo. The decision to formulate it into orodispersible tablets aimed to address issues related to patient compliance and convenience, particularly for individuals who experience difficulty swallowing conventional tablets. Formulation F10, enriched with 10% Croscarmellose sodium as a superdisintegrant and an effervescent mixture for taste masking, exhibited remarkable characteristics. Croscarmellose sodium, chosen for its exceptional disintegration properties, ensures rapid breakdown upon contact with saliva, facilitating swift drug release and subsequent onset of action. Moreover, the incorporation of an effervescent mixture not only aids in masking the potentially unpleasant taste of Prochlorperazine Maleate but also holds the potential to enhance palatability and overall patient acceptance. Physicochemical characterization of Prochlorperazine Maleate unveiled favorable attributes, including a loss on drying of 0.413±0.002%, a melting point range of 234-236°C, and a moisture content of 0.0354%, affirming its suitability for formulation into orodispersible tablets. Through dissolution profile comparisons, formulation F10 demonstrated superior drug release kinetics compared to the commercial formulation, underscoring its potential therapeutic advantages.

Biowaiver as a Bioequivalence Study Option

SCIENTIFIC RELEVANCE. Biowaiver is a procedure for establishing the bioequivalence of generic and reference products without in vivo studies. Regulatory requirements for this procedure, as described in a variety of documents, differ in certain features and aspects. These differences need to be analysed.AIM. The aim was to compare international and Russian regulatory approaches to the Biopharmaceutics Classification System-based biowaivers, provide recommendations on comparative dissolution testing, and outline opportunities for streamlining the regulatory framework of the Eurasian Economic Union (EAEU).DISCUSSION. In this article, the authors analyse biowaiver requirements and describe procedures for assessing the permeability and pH-dependent solubility of medicines, comparing dissolution profiles in various media that simulate the gastrointestinal environment, and interpreting test results. This paper shows the role of excipients in the solubility and permeability of an active substance.CONCLUSIONS. The authors recommend a methodological approach to the biowaiver procedure for replacing in vivo bioequivalence studies with in vitro tests under the current EAEU regulatory framework and list the characteristics of medicines that limit the applicability of the procedure. In conclusion, this article provides a rationale for harmonising the existing guidelines and requirements.

Comparison of In vitro Dissolution Tests of five brands of Diclofenac Sodium delayed release tablets in Moroccan market

This study aims to evaluate the similarity of in-vitro dissolution profiles, of commercially available generics of diclofenac sodium delayed-release tablets, of 25mg strength, with the innovator brand in Moroccan Market. Dissolution profiles for five brands were determined using the paddle method from the United States Pharmacopoeia. For the aptitude verification of the method, in our experimental conditions, linearity and accuracy tests were performed. The rate of dissolution was determined by Ultra-Violet Spectroscopy at 276nm. The assessment between the generics and the brand medicine was carried out under the similarity factor approach. We also presented an overview of the dissolution principles of tablet dosage form, and the pharmacopoeia dissolution test recommendations in our case. To compliance with US pharmacopoeia specifications, the rate of dissolution should be not more than 10% after 2hours in the acid stage, and not less than 75% at 45 minutes in the buffer stage. Furthermore, two dissolution profiles are considered similar when the f2 value is ≥50. According to routine quality control, evaluating the rate dissolution at the final point, all the generic medicines marketed in Morocco, meet the specification of the dissolution testing. However, using the comparison of dissolution profiles, only generic-2 is interchangeable with the innovator brand.

<i>In-vitro</i> dissolution profiles comparison for various drugs with active ingredient Febuxostat commercially available on the Russian market

Introduction. Gout treatment drugs are widely represented on the pharmaceutical market of the Russian Federation, including those with INN febuxostat. These drugs differ in excipients composition, in the dosage form (tablets and capsules) and production technology. The Dissolution Kinetics Test was chosen to assess the rate and extent of active ingredient release for drugs with INN febuxostat for different manufacturers as in vitro test dissolution allows to suggest the release from the dosage form in vivo. The rate and percent of active substance release are factors that have a direct impact on the bioavailability of drugs. Drug release was studied in a phosphate buffer solution pH 6.8, sampling was carried out at time points 0 min, 5 min, 10 min, 15 min, 20 min, 30 and 45 min. The analysis of the obtained solutions was carried out using the UV spectrophotometry method at a wavelength of 317 nm. The comparison of dissolution profiles was carried out in accordance with the requirements of Decision of the Council of the Eurasian Economic Commission dated November 3, 2016 N 85 "On approval of the Rules for conducting bioequivalence studies of medicinal products within the framework of the Eurasian Economic Union". The purpose of the study. The purpose of this study was to compare the kinetics of the release of the active substance febuxostat from drugs registered in the territory of the Russian Federation in the form of tablets and capsules. Materials and methods. Drug release studies were performed using the Sotax dissolution tester AT Xtend, Switzerland. Each drug was analyzed in 12 repetitions in a pH 6.8 phosphate buffer dissolution medium, on a "Paddle apparatus", special sinkers were used for capsule dosage forms. The selected samples were analyzed on a Shimadzu UV 1800 UV spectrophotometer, Japan, at a wavelength of 317 nm. Results. Dissolution profile studies for three drugs with the active substance febuxostat were conducted in a phosphate buffer solution pH 6,8. For the studied drugs, the release of febuxostat was observed to be more than 85 % at 15 minutes. The release profiles can be recognized as equivalent without further mathematical processing. Conclusion. Based on the results of dissolution profile studies, no differences were found in dissolution profiles of febuxostat from drugs with different dosage forms (tablets and capsules).

Kinetic Modeling to Explain the Release of Medicine from Drug Delivery Systems

AbstractProper medication dissolution must be ensured when developing or manufacturing a new solid dosage form. Quantitative analyses performed in dissolution or release tests become simpler when applying mathematical formulae which represent dissolution outcomes as a function of several dosage form properties. Methodologies utilized to examine the kinetics of drug release from controlled‐release formulations are reviewed. The analysis of variance was conducted using statistical, model‐independent, and ‐dependent techniques for the dissolution profile comparison and fitting, respectively. Model equations, including zero‐ and first‐order, Hixson‐Crowell, Weibull, Higuchi, Korsmeyer‐Peppas, Baker‐Lonsdale, Hopfenberg, etc., were employed to match the experimental data. Additional release parameters were taken to illustrate the drug release patterns. Using correlation factors and the Akaike information criterion (AIC), the best‐fitting model was discovered, as were the transport phenomena affecting the behavior of the recognized formulations.

Discriminative Dissolution Method Using the Open-Loop Configuration of the USP IV Apparatus to Compare Dissolution Profiles of Metoprolol Tartrate Immediate-Release Tablets: Use of Kinetic Parameters.

The use of the USP IV apparatus (flow-through cell) has gained acceptance in recent years due to its versatility and ability to discriminate due to its hydrodynamic conditions. Therefore, the objective of the present study was to develop a discriminative dissolution method in the USP IV apparatus using the open-loop configuration, as well as to propose a method to compare non-cumulative dissolution profiles obtained in the open-loop configuration considering kinetic parameters and validate its predictive power through its comparison with independent and dependent methods using five commercial immediate-release tablet drugs (one reference drug and four generic drugs) of metoprolol tartrate as a model drug. The comparison of the non-accumulated dissolution profiles consisted of determining the geometric ratio of Cmax, AUC0∞, AUC0Cmax, and Tmax (kinetic parameters) of the generic/reference drugs, whereby generic drugs "C" and "D" presented the highest probability of similarity since their 90% confidence intervals were included, or they were very close to the acceptance interval (80.00-125.00%). These results were consistent with the f2, bootstrap f2, and dissolution efficiency approaches (independent models). In conclusion, the proposed comparison method can be an important tool to establish similarity in dissolution profiles and to facilitate the development/selection of new formulations and positively ensure bioequivalence in clinical studies.

Dissolution Profile Similarity Assessment—Best Practices, Decision Trees and Global Harmonization

During the write-up of the meeting summary reports from the 2019 dissolution similarity workshop held at the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI), several coauthors continued their discussions to develop a "best-practice" document defining the steps required to assess dissolution profiles in support of certain biowaivers and postapproval changes. In previous reports, current challenges related to dissolution profile studies were discussed such that the steps outlined in the two flow charts ("decision trees") presented here can be applied. These decision trees include both recommendations for the use of equivalence procedures between reference and test products as well as application of the dissolution safe space concept. Common approaches towards establishing dissolution safe spaces are described. This paper encourages the preparation of protocols clearly describing why and how testing is performed along with the expected pass/fail criteria prior to generating data on the materials to be evaluated. The target audience of this manuscript includes CMC regulatory scientists, laboratory analysts, as well as statisticians from industry and regulatory health agencies involved in the assessment of product quality via in vitro dissolution testing. Building upon previous publications, this manuscript provides a solution to the current ambiguity related to dissolution profile comparison. The principles outlined in this and previous manuscripts provide a basis for global regulatory alignment in the application of dissolution profile assessment to support manufacturing changes and biowaiver requests.

A pharmaceutical monitoring system to assess the quality of antituberculosis drug products used in Mauritania.

The quality of drug products may be affected from manufacture to dispensing, particularly at high temperature and humidity as in Mauritania. This country is not included in the World Health Organization reports on poor quality products due to the lack of a qualified laboratory and monitoring system. Ensuring the quality of medicine is even more relevant in the case of diseases such as Tuberculosis, due to its high prevalence, complex treatment and continuous bacterial resistance. The aim was to develop a monitoring system to assess the quality of antituberculosis drugs products, by the substandard detection based on European and United States Pharmacopeial recommendations regarding quality control. In addition to studying the influence of accelerated storage conditions (40 ± 2°C/75 ± 5% relative humidity) on their qualities and comparing the dissolution profiles to contrast the quality. 18 antituberculosis drug products were taken from Europe and Mauritania, and quality was studied through visual inspection and according to the compliance of the mass uniformity, uniformity of dosage units, dissolution, disintegration and friability pharmacopeial tests. Furthermore, a dissolution profile comparison was carried out to examine quality. A stability study was conducted to assess the influence of climatic conditions on the content and the dissolved amount of the active pharmaceutical ingredients, which were determined by an ultra-performance liquid chromatography system. As result, 69.3% of 13 Mauritanian formulations had a substandard quality mainly due to non-compliance with the test for friability or content uniformity of these medicines. All European drug products complied with pharmacopeia specifications. In addition, storage conditions affected the dissolution rate of ethambutol and the uniformity of the 4 antituberculosis combination drug products.

In vitro dissolution profile comparison using bootstrap bias corrected similarity factor, f 2

ABSTRACT In vitro dissolution profile has been shown to be correlated with the drug absorption and has often been considered as a metric for assessing in vitro bioequivalence between a test product and corresponding reference one. Various methods have been developed to assess the similarity between two dissolution profiles. In particular, similarity factor has been reviewed and discussed extensively in many statistical articles. Although the lacks inferential statistical properties, the estimation of and its various modified versions were the most widely used metric for comparing dissolution profiles. In this paper, we investigated performances of the naive estimate method, bootstrap confidence interval method and bias corrected-accelerated (BCa) bootstrap confidence interval method for comparing dissolution profiles. Our studies show that naive estimate method and BCa bootstrap confidence interval method are unable to control the type I error rate. The bootstrap confidence interval method can control the type I error rate under a specific level. However, it will cause great conservatism on the power of the test. To solve the potential issues of the previous methods, we recommended a bootstrap bias corrected (BC) confidence interval method in this paper. The type I error rate, power and sensitivity among different methods were compared based on simulations. The recommended bootstrap BC confidence interval method shows better control of type I error than the naive estimate method and BCa bootstrap confidence interval method. It also provides better power than the bootstrap confidence interval method.

Physicochemical and In-Vitro Equivalence of 15 Generic Amlodipine Besylate Tablets Marketed in Davao City, Philippines

This study investigated the physicochemical and in-vitro equivalence of the innovator and fifteen generic brands of amlodipine besylate tablets marketed in selected community drugstores in Davao City, Philippines. The samples were coded from A to P and assayed for weight uniformity, hardness, friability, disintegration, potency, content uniformity, and dissolution using the methods described in the USP. The percentage of drug content was determined using the spectrophotometric method. The results showed that all brands conformed to the USP standard for weight uniformity, friability, and disintegration test. In addition, nine generic brands did not conform to the USP standard for the hardness test. All brands meet the USP requirement for potency with a mean content of not less than 90% and not greater than 110% of the labeled claim. Six generic brands did not conform to the USP standard for content uniformity, with acceptance values higher than the specification of 15.0%. All brands conformed to the USP standard for dissolution or percentage drug release. Further, the dissolution profile comparisons showed that 14 out of 15(93.33%) generic brands of amlodipine besylate tablets could be used interchangeably with the innovator drug. In conclusion, this study confirmed the importance of continuous monitoring of generic drugs' safety, quality, and efficacy to ensure equivalence and compliance with pharmacopeia standards and aid the prescribers’ decision-making in generic dispensing.

Statistical modeling approaches for the comparison of dissolution profiles.

Dissolution studies are a fundamental component of pharmaceutical drug development, yet many studies rely upon the and model-independent approach that is not capable of accounting for uncertainty in parameter estimation when comparing dissolution profiles. In this paper, we deal with the issue of uncertainty quantification by proposing several model-dependent approaches for assessing the similarity of two dissolution profiles. We take a statistical modeling approach and allow the dissolution data to be modeled using either a Dirichlet distribution, gamma process model, or Wiener process model. These parametric forms are shown to be reasonable assumptions that are capable of modeling dissolution data well. Furthermore, based on a given statistical model, we are able to use the difference factor and similarity factor to test the equivalency of two dissolution profiles via bootstrap confidence intervals. Illustrations highlighting the success of our methods are provided for both Monte Carlo simulation studies, and real dissolution data sets.

Comment on: Comparative dissolution profiles of two anti-emetic delayed-release dosage forms of doxylamine and pyridoxine: Xonvea® tablets vs. Cariban® capsules.

Comment on: Comparative dissolution profiles of two anti-emetic delayed-release dosage forms of doxylamine and pyridoxine: Xonvea® tablets vs. Cariban® capsules.

Comparison of Dissolution profile for Immediate-Release Dosage form for US and Europe

Any oral medication product control strategy must include the creation of a dissolve method with appropriate specifications. In the creation of drug, dissolution testing is critical IV approach. In some cases, an IV dissolution test can be used instead of an in vivo dissolution test. As a result, regulatory agencies have formally acknowledged in vitro methods to determine the dissolution frequency of API from the solid oral form as a significant factor when manufacturing solid-oral-dosage forms. Dissolution tests have long been acknowledged as critical quality-control tools for ensuring batch-to-batch consistency. Following post-approval changes to pharmaceutical products, dissolution testing is also important in providing quality information of the product.

Comparative dissolution profiles of two anti-emetic delayed release dosage forms of doxylamine and pyridoxine: Xonvea® tablets vs. Cariban® capsules.

Nausea and vomiting of pregnancy is a common disease that affects many women suffering from mild to severe symptoms. Amongst the different treatments, a fixed dose combination of doxylamine and pyridoxine has been proven safe and effective although the mechanism of action is not well established. There are different pharmaceutical dosage forms in the European market. The objective of this study was to compare the characteristics of a capsule formulation, Cariban® and a tablet formulation, Xonvea® to evaluate the potential impact of their release profiles on their onset of action. 10 mg/10 mg of doxylamine succinate/pyridoxine hydrochloride capsules (Cariban®) and tablets (Xonvea®) were used as reference materials. Appearance, mass, composition, and in vitro dissolution profiles were compared. Bibliographic data from 4 pharmacokinetic studies of Xonvea® and 1 pharmacokinetic study of Cariban® was reviewed. In vitro dissolution studies showed significant differences in dissolution profiles of tablets and capsules. The later exhibiting some release of both drug substances in acid conditions followed by a non-complete release after a total of 3 hours while the tablets demonstrated gastro-resistant properties and rapid API release in about 20-30 minutes after the acid stage. Comparison of PK data showed greater Cmax for pyridoxine. At pH 6.8, complete and faster release of the fixed dose combination for Xonvea® gastro-resistant tablets compared to Cariban® capsules could possibly explain the greater Cmax observed in vivo for the tablet's formulation. This could translate into faster onset of action and relief of nausea for pregnant women taking the tablets vs. the capsules.

Maraviroc Oral Disintegration Tablet: Analytical Design of Experiments (DoE) for Assessment and Comparison of In vitro Dissolution Profiles

Background: The bioavailability of a drug in a solid oral dose depends on its release from the drug product and its balance in dissolution. Compared with a reference drug, the newly developed formulation needs to establish bioequivalence by comparing the dissolution profile. Objective: To compare dissolution profiles of a newly developed maraviroc oral disintegration tablet and the reference Axentri® tablet. The current research was designed to establish and validate an integral analytical consistency by Quality by Design (QbD) approach to quantify maraviroc from dissolution samples using the RP-HPLC method. Methods: Maraviroc was formulated into an orally disintegrating tablet using a direct compression technique at different concentrations of sodium starch glycolate as super disintegrants and talc and magnesium stearate as glidants. The dissolution test in 0.1N HCl was performed according to standard procedures to predict bioequivalence. The results of dissolution tests were analyzed using the QbD Box Behnken Design multivariate RP-HPLC method. Results: The optimized formulation (F2) was selected as it showed 90% drug release in 5 min and a disintegration time of 22 sec with dissolution profiles to the marketed reference to meet the FDA requirements of f2 similarity factor statistics. The integrated analytical QbD method was statistically analyzed by ANOVA, counter-plot, and 3D response surface plots, which demonstrated that the model is statistically significant. The developed method was validated as per ICH guidelines Q2 (R1). Conclusion : In conclusion, maraviroc oral disintegrating tablets have been well prepared, and superior statement consistency is established by the implementation of the QbD analytical method for orally disintegrating tablet excellence and adoption.