Dissolution Test Conditions Research Articles

Application of shadowgraph imaging (SGI) particle characterisation data to interpret the impact of varying test conditions on powder dissolution and to develop an automated agglomeration identification method (AIM) in the USP flow-through apparatus

The aims of this work were 1) to explore the application of shadowgraph imaging (SGI) as a real time monitoring tool to characterize ibuprofen particle behaviour during dissolution testing under various conditions in the USP 4 flow-through apparatus and 2) to investigate the potential to develop an SGI-based automated agglomeration identification method (AIM) for real time agglomerate detection during dissolution testing. The effect of surfactant addition, changes in the drug mass and flow rate, the use of sieved and un-sieved powder fractions, and the use of different drug crystal habits were investigated. Videos at every sampling time point during dissolution were taken and analysed by SGI. The AIM was developed to characterize agglomerates based on two criteria – size and solidity. All detections were confirmed by manual video observation and a reference agglomerate data set. The method was validated under new dissolution conditions with un-sieved particles. Characterisation of particle dispersion behaviour by SGI enabled interpretation of the impact of dissolution test conditions. Higher numbers of early detections reflected greater dissolution rates with increased surfactant concentration, using sieved fraction or plate-shaped crystals, but was impacted by drug mass tested. An AIM was successfully developed and applied to detect agglomerates during dissolution, suggesting potential, with appropriate method development, for application in quality control.

Commentary on 'Combined experiments and atomistic simulations for understanding the effect of ZnO on the sodium silicate and sodium borosilicate glass network'

Recently, Sahu et al. [Combined experiments and atomistic simulations for understanding the effect of ZnO on the sodium silicate and sodium borosilicate glass network, J. of Non-Cryst. Solids 618 (2023) 122,550] published results from a combined experiment and simulation investigation that describes the effect of ZnO on sodium silicate and sodium borosilicate glass networks. Whilst the majority of the investigation remains sound, their conclusions relating to the chemical durability of silicate and borosilicate glasses containing ZnO are in need of clarification. This commentary addresses their conclusions and aligns them alongside the state-of-the-art understanding of the effect of Zn on the chemical durability, where the well-known positive effect of Zn on short-term glass dissolution becomes adverse over the long-term. This is caveated to consider the quantity of ZnO in the glass and on the specific dissolution test conditions.

Development of Biopredictive Dissolution Method for Extended-Release Desvenlafaxine Tablets.

This study aimed to develop a biopredictive dissolution method for desvenlafaxine ER tablets using design of experiments (DoE) and physiologically based biopharmaceutics modeling (PBBM) to address the challenge of developing generic drug products by reducing the risk of product failure in pivotal bioequivalence studies. For this purpose, a PBBM was developed in GastroPlus® and combined with a Taguchi L9 design, to evaluate the impact of different drug products (Reference, Generic #1 and Generic #2) and dissolution test conditions on desvenlafaxine release. The influence of the superficial area/volume ratio (SA/V) of the tablets was observed, mainly for Generic #1, which presented higher SA/V than the others, and a high amount of drug dissolved under similar test conditions. The dissolution test conditions of 900 mL of 0.9% NaCl and paddle at 50 rpm with sinker showed to be biopredictive, as it was possible to demonstrate virtual bioequivalence for all products, despite their release-pattern differences, including Generic #3 as an external validation. This approach led to a rational development of a biopredictive dissolution method for desvenlafaxine ER tablets, providing knowledge that may help the process of drug product and dissolution method development.

Dissolution Effectiveness of Moringa Leaf Pills (Moringa Oleifera L.) and Aloe Vera (Aloe Barbadensis Miller)

Oral preparations with level solubility tall so speed dissolution substance active from form preparations Becomes more fast, anyway with preparations with speed dissolution low so speed dissolution substance active from form preparations Becomes slow, so rate absorption drug more slow as well as produce bioavailability low. Materials potion drug traditional for example from ingredient plant natural around which not yet experience processing whatever. Ingredient nature used _ as drug traditional in study this is plant leaf moringa and tongue crocodile. Leaf Moringa (Moringa oleifera L.) has various type effect therapy like antimicrobial, anticancer, anti-inflammatory, effect antidiabetic as well as as antioxidants. Compound chemical in the leaves _ moringa that is there is polyphenols, acids phenolics, flavonoids, glucosinolates, alkaloids, vitamins, acids phenolics, isothiocyanates, tannins and saponins. Plant tongue crocodile (Aloe barbadensis Miller). kindly chemistry, tongue crocodile consists over 90% water and 4% carbohydrates, the rest consists of minerals, 17 kinds amino acids. Gel found on the tongue crocodile there is content substance antibacterial as well as possible antifungal _ stimulate tiroblast . Study this aim for knowing effectiveness dissolution pill from leaf moringa and tongue crocodile with use method study experimental. Result of study this yield extract leaf moringa and tongue crocodile obtained on the leaves moringa by 6.38% and tongue crocodile 6.268%. Assessment test preparations pill Fulfill condition uniformity weight and fulfill dissolution test conditions because time the required crush for 30 minutes.

Dissolution test for oral suspension: an overview about use and importance

This work aims to ascertain the comprehensiveness of dissolution tests for oral suspensions registered in Brazil and the USA. After consulting literature since 1994, a paucity of information about dissolution methods for suspensions was detected. It makes it difficult to establish the most appropriate test parameters. In January, 2019, there were 46 drugs registered in Anvisa (Brazil) as oral suspension, being 47 reference, 173 generic and 114 interchangeable similar (IS) medicines; while in the USA, 90 drugs were registered as oral suspension by FDA, 235 Abreviatted New Drug Application and 111 New Drug Application medicines. Out of 46 and 90, only six and 15 drugs as oral suspension had a pharmacopeial dissolution test, corresponding to 70 (20.9%) and 82 (23.7%) products in Brazil and the USA, respectively. Dissolution studies were found for 17 drugs as oral suspension in the non-compendial literature. Dissolution test conditions were established to few marketable oral suspension drugs, most of which are BCS class II or IV. Thus, investing in dissolution studies could subsidize the registration of these products by regulators, especially for generic and IS drugs, by comparing dissolution profiles, and predicting their in vivo behavior to avoid exposure of healthy individuals to clinical research.

Biphasic Dissolution as an Exploratory Method During Early Drug Product Development.

Dissolution testing is a major tool used to assess a drug product’s performance and as a quality control test for solid oral dosage forms. However, compendial equipment and methods may lack discriminatory power and the ability to simulate aspects of in vivo dissolution. Using low buffer capacity media combined with an absorptive phase (biphasic dissolution) increases the physiologic relevance of in vitro testing. The purpose of this study was to use non-compendial and compendial dissolution test conditions to evaluate the in vitro performance of different formulations. The United States Pharmacopeia (USP)-recommended dissolution method greatly lacked discriminatory power, whereas low buffer capacity media discriminated between manufacturing methods. The use of an absorptive phase in the biphasic dissolution test assisted in controlling the medium pH due to the drug removal from the aqueous medium. Hence, the applied non-compendial methods were more discriminative to drug formulation differences and manufacturing methods than conventional dissolution conditions. In this study, it was demonstrated how biphasic dissolution and a low buffer capacity can be used to assess in vitro drug product performance differences. This can be a valuable approach during the early stages of drug product development for investigating in vitro drug release with improved physiological relevance.

Optimization and statistical evaluation of discriminative dissolution method for bisoprolol immediate-release film coated tablets

This study presents optimization of a statistically based approach for setting up the dissolution test conditions for bisoprolol film-coated tablets using multivariate release models as predictive in vivo assessment tools for formulation behaviour. Additionally, the dissolution profiles of three different strengths of bisoprolol film-coated tablets were evaluated. According to the biopharmaceutics classification system, the tested medicinal product belongs to BCS Class I (high solubility, high permeability). Three dissolution media, including the dissolution medium of choice (pH 1.2) according to the USP monograph for bisoprolol tablets and two apparatus, paddle and basket were applied. The optimal conditions for performing the dissolution test were following: 900 mL of pH 1.2 as dissolution medium, apparatus 2 (paddle) with 75 r/min stirring speed. The quantity of the released active substance was determined using HPLC method. For a reliable statistical analysis, multivariate methods such as model-dependent approach coupled to multivariate statistics (Weibull), multivariate model-independent approach based on generalized statistical distance (Mahalanobis distance) have been applied for evaluation of dissolution profiles. All applied statistical approaches unequivocally support the underlying similarity of the pairs in different media between different strengths. Moreover, the optimized dissolution method has a discriminatory power to reflect the characteristics of the medicinal product in order to distinguish any changes related to quantitative composition of the formulation. Keywords: bisoprolol film-coated tablet, dissolution profiles, model-independent multivariate statistical distance, model-dependent multivariate statistical distance

Bilayer Tablet Dissolution Kinetics Based on a Degassing Cyclic Flow UV-Vis Spectroscopy with Chemometrics.

Dissolution kinetics of a bilayer direct compress tablet was evaluated by using degassing cyclic flow UV-visible (Vis) spectroscopy with chemometrics. The model bilayer nicotinamide (NA)-pyridoxine hydrochloride (PH) 100.0 mg tablets were prepared via the dual compress method. The fast diffusion layer of the bilayer tablet contained nicotinamide, microcrystal cellulose, beta-lactose, magnesium stearate, and croscarmellose sodium. The slow release layer contained pyridoxine hydrochloride and carnauba wax. The monolayer direct compress tablets were prepared as dual ingredient (API)s formulation tablets. The degassing cyclic flow UV-Vis spectroscopy dissolution test was carried out using the prepared tablets. The dissolution test conditions were as follows: time, 60 min; temperature, 37°C; paddle method, 50 rpm, and UV-Vis spectra measurement 1 time/min. The UV-Vis spectra of the flow solution were measured in the range of 240-380 nm. API concentration was predicted by partial least squares (PLS) regression models based on UV-Vis spectra. The dissolution kinetics of the bilayer and monolayer tablets were evaluated based on the UV-Vis spectra with the predicted API concentration profile. The degassing flow system could prevent air bubbles in the flow cell at 1800 min. Therefore, simultaneous determination of NA and PH concentration based on the PLS regression was suggested to have high accuracy. PLS regression has advantages over the conventional λmax absorbance method of simultaneous determination. We found that the kinetics of the separated bilayer tablet can be evaluated by the same kinetic analysis method used for the single layer model tablet.

Development of a Discriminative and Biorelevant Dissolution Test Method for Atorvastatin/Fenofibrate Combination with Appliance of Derivative Spectrophotometry.

Nowadays, the market is flooded with combinations of drugs in various dosage forms, but there is a lack of official methods to quantify them. A single dissolution test method for the analysis of combined dosage form is preferred for simplification of quality control testing. If the developed dissolution medium mimics the biorelevant and discriminating dissolution procedure for drug products with limited drug aqueous solubility it is a useful tool for qualitative forecasting of the in vivo behavior of formulations. Dissolution profiles were evaluated for atorvastatin and fenofibrate in capsules, using a paddle-type United States Pharmacopeia dissolution apparatus in 900 mL of medium at 50 rpm and 37±0.5°C. The best medium was 900 mL of 0.5% w/v sodium lauryl sulfate. The cumulative % dissolution was more than 85% within 45 min for marketed tablets. The proposed dissolution test conditions have discriminative power, dissimilarity factor (f1) values are low (12-16%), and similarity (f2) factor values are also low (45-48%). Hence the use of 0.5% w/v sodium lauryl sulfate solution is justified. The dissolution method was validated (% relative standard deviation <2). To quantify both drugs simultaneously, a second derivative spectrophotometric method was established (λmax 281 nm and 296 nm, respectively, for atorvastatin and fenofibrate) in acetate buffer, pH 2.8 solution.

Design of Experiments for the Establishment of the Dissolution Test Conditions of Rupatadine Fumarate 10 mg tablets

Design of Experiments (DoE) is a statistical model that aims to determine if the factors under study affect the response, and if so, it determines the conditions under which this variable of interest can be optimized. In terms of pharmaceutical technology, independent variables are usually factors of the formulation, while dependent variables are properties of the product or parameters that indicate the performance of the process. Precisely, the dissolution test is a tool of interest for the developers of medicines since it allows them to evaluate the performance of a formulation designed in a solid pharmaceutical form, such as tablets. The present investigation used the design of experiments to establish and optimize the conditions of the dissolution test of a 10 mg Rupatadine fumarate tablets formulation, resulting in the use of HCl 0,1 N (pH 1) dissolution medium and a rotation speed of 100 rpm for the apparatus II USP, which allow the analysis of the product in a reproducible and reliable way.&#x0D; Keywords: Analysis of variances, Design of experiments, Dissolution test, Factorial design, Rupatadine Fumarate, Tablets, Test conditions.

Effect of batch age on potency and dissolution of levothyroxine sodium tablets: impact of BP and USP monograph differences on dissolution results

Controversies surround levothyroxine sodium as a drug and product, and are reflected in compendia (USP vs BP) differences in levothyroxine sodium tablets specifications concerning potency limit and dissolution test conditions, and in lack of consensus on several issues such as whether the drug BCS class I or III. We have recently published a clinical study in patients comparing the efficacy of multisource 100 mcg levothyroxine sodium tablets (three sources, two brands, a total of five batches). Clinical efficacy and dissolution rate data varied among the tablet batches studied and indicated that brand/source interchangeability could not be claimed. The efficacy parameters showed good correlation with dissolution data generated under BP 2014, but not under USP 2014 dissolution test conditions. In the present study, we decided to expand the number of tablet batches studied in vitro to a total of 12, to report potency and content uniformity data missing in the clinical study, and to further examine the discrepancy in dissolution results based on the medium used. The wide range of batch age in the studied samples allowed investigating the effect of batch age on in-vitro tablet performance parameters. Generated potency values indicated the prevalence of super-potent tablet batches. The dissolution data reflected the effect of compendia monograph differences in dissolution medium. The results also indicated an inverse relationship between tablet potency and batch age and, between dissolution and batch age. The possible effect of potency results on the generated dissolution data was discussed. Statistical significance of correlations examined was assessed by linear and non-linear regression analysis. Statistical significance was evident for the relation between batch age and BP 2014 dissolution data, compared to USP 2014 dissolution results.

Development and Validation of a Discriminating Dissolution Method for Atorvastatin Delayed-Release Nanoparticles Using a Flow-Through Cell: A Comparative Study Using USP Apparatus 4 and 1

Atorvastatin, an HMG CoA reductase inhibitor, is widely used for the treatment of dyslipidemia and prevention of cardiovascular disease. It belongs to Class 2 of the Biopharmaceutics Classification System owing to its low solubility and high permeability. In vitro dissolution testing is an essential tool for the design of a dosage form. Appropriate selection of dissolution test conditions is essential since it will help establish an appropriate in vitro-in vivo correlation (IVIVC), which is imperative for a waiver of costly bioequivalence studies. Compounds belonging to BCS Class 2 are suitable for establishing a significant IVIVC. USP Apparatus 4 (flow-through cell) is an attractive alternative to conventional dissolution methods like Apparatus 1 and 2. The ability of the apparatus to maintain sink conditions over a longer period of time has proved useful in the development of dissolution methods for poorly soluble drugs, making the development of IVIVCs easier for such drugs. Nanoparticles of atorvastatin were formulated by an emulsion-solvent evaporation method to overcome its bioavailability problems. Development of a discriminatory dissolution method for the same was attempted using a flow-through cell (Apparatus 4) because dissolution performed using Apparatus 1 did not provide complete release of the drug within 60 min. Phosphate buffer pH 6.8 with 1.5% SLS was selected as the dissolution medium based on the results of the solubility studies. Various parameters such as flow rate and sample-loading method were optimized. The dissolution method was validated with respect to various parameters as per ICH guidelines.

Development and Validation of a RP-HPLC Method for Simvastatin Capsules

Simvastatin, a lipid-lowering agent of the statins class, is widely used in the treatment of hypercholesterolemia and in the prevention of cardiovascular diseases. Currently, simvastatin is available in the global market in both tablet and capsule forms. No official method has been reported for the assaying or dissolution testing of simvastatin capsules. Dissolution specifications were established to evaluate in vitro release studies for simvastatin capsules in this work. Adequate dissolution test conditions were obtained with 0.5% sodium dodecyl sulfate in 0.01 M monobasic sodium phosphate buffer at pH 7.0±0.05 (900 mL), and paddle agitation at 75 rpm for 45 min was used to investigate the immediate release (IR) of simvastatin capsules. Simvastatin quantified in the dissolution medium for capsules using the developed HPLC method, showed R2>0.98, selectivity (no placebo interference), precision (%RSD0.05) according to the United States Pharmacopeia (2011) criteria. This work highlights the need to develop suitable dissolution conditions to establish criteria for the analysis of IR solid oral dosage form. The developed HPLC simvastatin quantitation method does not require the previous treatment of aliquots with manganese oxide, as described in the US Pharmacopeia and in the British Pharmacopoeia for ultraviolet spectroscopic methods.

Development and Validation of Dissolution Test for Fluconazole Capsules by HPLC and Derivative UV Spectrophotometry

The purpose of this study is to develop and validate a dissolution test for fluconazole, an antifungal used for the treatment of superficial, cutaneous, and cutaneomucous infections caused by Candida species, in capsules dosage form. Techniques by HPLC and UV first derivative spectrophotometry (UV-FDS) were selected for quantitative evaluation. In the development of release profile, several conditions were evaluated. Dissolution test parameters were considered appropriate when a most discriminative release profile for fluconazole capsules was yielded. Dissolution test conditions for fluconazole capsules were 900 mL of HCl 0.1 M, 37 ± 0.5 °C using baskets with 50 rpm for 30 min of test. The developed HPLC and UV-FDS methods for the antifungal evaluation were selective and met requirements for an appropriate and validated method, according to ICH and USP requirements. Both methods can be useful in the registration process of new drugs or their renewal. For routine analysis application cost, simplicity, equipment, solvents, speed, and application to large or small workloads should be observed.

Estabelecimento de condições para ensaio de dissolução de cápsulas de cinarizina empregando planejamento fatorial

This work describes the establishment of dissolution test conditions for 75 mg cinnarizine capsules using a multivariate approach. A 23 full factorial design was carried out to achieve the best conditions and HCl 0.1 mol L-1 as dissolution medium, basket as apparatus at 100 rpm and collect time at 30 min were considered adequate. The quantification was carried out by spectrophotometry at 251 nm. Both dissolution procedure and analytical method were validated and all parameters were within the acceptable limits. Since there is no official monograph for this pharmaceutical product, this dissolution test could be applied for quality control routine.

Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products

Abstract Objectives The dissolution characteristics of immediate-release doxycycline hyclate products with certified in-vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver-based approval. Methods Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin-ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy-Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA). Key findings The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in-vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over-discriminating. Conclusions Bioequivalence of immediate-release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.

Application of Experimental Design for Screening Study of Dissolution Test Conditions: Levothyroxine Sodium Immediate-Release Tablets

The aim of the study was to present an example of experimental design application to set up the dissolution test conditions for the two immediaterelease products of levothyroxine sodium (L-Na) with proven bioequivalence: the generic product A and the reference product B [1, 2]. [...]

Optimization of an In Vitro Dissolution Test Method for Inhalation Formulations

The aim of this research project was to investigate a potential standardized test method to characterize the dissolution properties of numerous formulation types available for pulmonary delivery. A commercially available dissolution tester was adapted for use as a testing apparatus by the incorporation of a membrane-containing holder. The holder was designed to enclose previously air-classified formulations so that they could be uniformly tested in the dissolution apparatus. Dissolution procedures, the apparatus, dose collection, medium, and test conditions were developed relying on USP General Chapter . To collect an active pharmaceutical ingredient (API) fraction from the devices for subsequent dissolution studies, aerodynamic particle separation on the membrane holder was achieved using the Next Generation Impactor (NGI) for two commercially available products, Ventolin HFA and Pulmicort Flexhaler. The dissolution profiles of budesonide (BD) and albuterol sulfate (AS) were successfully estimated by analyzing the amount of drug released from the membrane holder. This dissolution method may be applied to quality control studies for various inhalation products. In particular, the in vitro dissolution profiles of the drugs may provide an estimate of their dispersion characteristics, which directly relate to the device or aerosol performances.

Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products

The dissolution characteristics of immediate-release doxycycline hyclate products with certified in-vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver-based approval. Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin-ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy-Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA). The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in-vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over-discriminating. Bioequivalence of immediate-release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.

Clinical Relevance of Dissolution Testing in Quality by Design

Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound.