Dissolution Test Research Articles

Development and Characterization of Olaparib-Loaded Solid Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) for Pharmaceutical Applications.

This study aims to enhance the solubility of Olaparib, classified as biopharmaceutical classification system (BCS) class IV due to its low solubility and bioavailability using a solid self-nanoemulsifying drug delivery system (S-SNEDDS). For this purpose, SNEDDS formulations were created using Capmul MCM as the oil, Tween 80 as the surfactant, and PEG 400 as the co-surfactant. The SNEDDS formulation containing olaparib (OLS-352), selected as the optimal formulation, showed a mean droplet size of 87.0 ± 0.4 nm and drug content of 5.53 ± 0.09%. OLS-352 also demonstrated anticancer activity against commonly studied ovarian (SK-OV-3) and breast (MCF-7) cancer cell lines. Aerosil® 200 and polyvinylpyrrolidone (PVP) K30 were selected as solid carriers, and S-SNEDDS formulations were prepared using the spray drying method. The drug concentration in S-SNEDDS showed no significant changes (98.4 ± 0.30%, 25℃) with temperature fluctuations during the 4-week period, demonstrating improved storage stability compared to liquid SNEDDS (L-SNEDDS). Dissolution tests under simulated gastric and intestinal conditions revealed enhanced drug release profiles compared to those of the raw drug. Additionally, the S-SNEDDS formulation showed a fourfold greater absorption in the Caco-2 assay than the raw drug, suggesting that S-SNEDDS could improve the oral bioavailability of poorly soluble drugs like olaparib, thus enhancing therapeutic outcomes. Furthermore, this study holds significance in crafting a potent and cost-effective pharmaceutical formulation tailored for the oral delivery of poorly soluble drugs.

Monitoring the Dissolution Behavior of Novel Pharmaceutical Cocrystals Consisting of Antimalarial Drug Artemisinin with Probe-Type Low-Frequency Raman Spectrometer.

Artemisinin (ART) is a most promising antimalarial agent. However, its low aqueous solubility limits its oral absorption, resulting in low bioavailability. In this study, we have successfully discovered a novel cocrystal with 2-methyl resorcinol (ART-2MRE) providing improved solubility compared with a previously reported cocrystal with resorcinol (ART-RES). Single crystal X-ray structure analysis revealed that the ART-2MRE cocrystal was composed of ART and 2MRE in a molar ratio of 2 : 1. Though the ART-2MRE and ART-RES cocrystals were found to have similarities in their crystal structures, with one layer of a cocrystal former and two layers of ART arranged in alternating rows, the ART-2MRE cocrystal showed higher dissolution rate than ART-RES cocrystal. In situ real-time low-frequency (LF) Raman monitoring and powder X-ray diffraction (PXRD) measurements of the crystals during the dissolution test proved useful to investigate the dissolution behavior of the cocrystals. Low-frequency Raman monitoring revealed that as dissolution progressed, there was a continuous shift from the peak unique to the ART-2MRE cocrystal to the peak unique to the ART stable form. Similar observations were obtained in PXRD measurements as well. Furthermore, experiments were conducted by adding a polymer to the dissolution test solution to investigate the dissolution behavior under supersaturation, indicating the possibility of differences in the dissolution behavior between the ART-2MRE cocrystal and ART-RES cocrystal. Understanding the dissolution behavior from cocrystals is essential in developing cocrystals.

A Novel and Sensitive Spectrophotometric Approach for Quantifying Vardenafil Hydrochloride Trihydrate in Tablets: Application to Dissolution Testing

A Novel and Sensitive Spectrophotometric Approach for Quantifying Vardenafil Hydrochloride Trihydrate in Tablets: Application to Dissolution Testing

Design and in vitro Evaluation of Cocoa Butter-based Amlodipine Besylate Fast Melt Tablets

Background: Oral fast-melting tablets (FMTs) have been gaining popularity due to their advantages in resolving swallowing issues of conventional oral tablets. Cocoa butter is an excipient of choice to develop FMT with an acceptable taste and faster onset of action of the drug. Purpose: The present study aimed to prepare and characterize the amlodipine besylate-loaded cocoa butter FMTs. objective: To prepare and characterise the formulation of cocoa butter tablet as fast melt buccal delivery system of amlodipine besylate. Method: Amlodipine besylate FMTs were prepared using a simple freezing (refrigeration) method. Cocoa butter (Form V) was used as the base to achieve a final tablet weight of 500 mg with drug and other functional excipients. The designed prototype tablet formulations were subjected to disintegration tests to determine the robust selected batch. The formulation F4, containing 7% high-molecular-weight chitosan, exhibited the quickest disintegration time of 1.45 ± 0.10 min. Afterwards, the selected formulation, F4, was subjected to quality evaluation parameters. Results: Fourier transform infrared spectroscopy (FTIR) studies revealed that there was no incompatibility between amlodipine besylate, cocoa butter, and other excipients. The average hardness of the F4 formulation tablet batch was found to be 2.69 ± 0.21 kg/cm2 and a friability of less than 1%. The drug content in F4 tablets was found to be 102.38 ± 5.29% and showed an in-vitro drug release of 94.30 ± 2.63% within 30 min. Over a six-month stability testing period, the chosen F4 formulation did not significantly change in terms of tablet average weight, disintegration time, drug content, and in-vitro dissolution rate. Conclusions: Selected formulation F4 with 7% of high molecular weight chitosan exhibited good physical properties, indicating the suitability of cocoa butter as a base to produce FMTs with the aid of a natural super-disintegrant.

Development of a new method for analyzing the behavior of rapidly dissolving films in contact with liquids

Oral Thin Film (OTF) is a promising dosage form, easy to use and patient-friendly drug delivery systems suitable for every consumer profile. This dosage form ensures safety, stability, and acceptability of the drug, that's why it can be a good alternative for tablets and capsules for children and elderly therapies. As no detailed monography of OTFs including characterization methods and uniform requirements has been presented in any of the pharmacopoeias to date, this study focuses on the development of an innovative analyzing method to characterize the OTF behavior and particularly to determine its disintegration time by goniometry. These parameters are key for the development of OTFs and for studying, at an early stage, the impact of formulation and process variables on product quality and impacting Critical Quality Attributes (CQA) by a Quality by Design approach.Different model OTF preparations were investigated as models to determine the suitability of the disintegration test systems. These placebos OTF were used to compare the disintegration times obtained by the tablets pharmacopeial method (conducted in 800 mL of distilled water) and the novel proposed method. As expected, the disintegration times determined by the proposed method were similar than those obtained by the conventional disintegration test. Moreover, they seem more reliable to the in vivo behavior because of the small amount of solvent used. The experiments showed acceptable reproducibility (low variation within sample replicates due to a well-defined determination of the measurement endpoint). This method provides clear endpoint detection and is applicable for different types of OTFs based on different polymers. Moreover, a better understanding of the physical-chemical properties of oral thin films towards water could be obtained. This new method of analysis could provide a valuable approach to the development of new OTF formulas, thanks to the different information that can be obtained, such as critical energy, free energy and polar and dispersive components.

Optimizing Construction Spoil Reactivity for Cementitious Applications: Effects of Thermal Treatment and Alkaline Activation

Construction spoil (CS), a prevalent type of construction and demolition waste, is characterized by high production volumes and substantial stockpiles. It contaminates water, soil, and air, and it can also trigger natural disasters such as landslides and debris flows. With the advent of alkali activation technology, utilizing CS as a precursor for alkali-activated materials (AAMs) or supplementary cementitious materials (SCMs) presents a novel approach for managing this waste. Currently, the low reactivity of CS remains a significant constraint to its high-value-added resource utilization in the field of construction materials. Researchers have attempted various methods to enhance its reactivity, including grinding, calcination, and the addition of fluxing agents. However, there is no consensus on the optimal calcination temperature and alkali concentration, which significantly limits the large-scale application of CS. This study investigates the effects of the calcination temperature and alkali concentration on the mechanical properties of CS–cement mortar specimens and the ion dissolution performance of CS in alkali solutions. Mortar strength tests and ICP ion dissolution tests are conducted to quantitatively assess the reactivity of CS. The results indicate that, compared to uncalcined CS, the ion dissolution performance of calcined CS is significantly enhanced. The dissolution amounts of active aluminum, silicon, and calcium are increased by up to 420.06%, 195.81%, and 256.00%, respectively. The optimal calcination temperature for CS is determined to be 750 °C, and the most suitable alkali concentration is found to be 6 M. Furthermore, since the Al O bond is weaker and more easily broken than the Si O bond, the dissolution amount and release rate of active aluminum components in calcined CS are substantially higher than those of active silicon components. This finding indicates significant limitations in using CS solely as a precursor, emphasizing that an adequate supply of silicon and calcium sources is essential when preparing CS-dominated AAMs.

A novel sodium caseinate lipid-based auto-emulsifying delivery system to increase resveratrol intestinal permeation: Characterization and in vitro assessment

In recent years, nutraceuticals have emerged as a promising strategy for maintaining health and represent a high-growth market in Italy and across Europe. However, the lack of strict regulations regarding formulation requirements and proof of efficacy raises serious concerns about their poor bioavailability and, consequently, their uncertain health benefits. An emblematic example is t-resveratrol (RES), a cardioprotective stilbene polyphenol that undergoes extensive metabolism in the intestine and liver, resulting in a bioavailability of <1 %.This manuscript describes a novel technological matrix developed with the primary goal of improving RES oral bioavailability. This technology can be classified as a lipid-based autoemulsifying drug delivery system (LIBADDS), in which RES is thoroughly solubilized in a hot liquid phase composed of lipids and surfactants, and the mixture is further adsorbed onto a powder composed of polysaccharides and sodium caseinate (NaC), along with inert excipients, and then compressed.In this study, NaC was used for the first time to trigger pancreatin-mediated hydrolysis of an enteric-coated tablet, allowing micellar delivery of RES to the small intestine. The RES-containing tablets were characterized via differential scanning calorimetry (DSC) and X-ray diffraction (PXRD). The digested formulation, with simulated gastric and enteric fluids, was dimensionally assessed via dynamic light scattering (DLS). Finally, calculations of the bioaccessible fraction, dissolution tests, and in vitro permeability experiments using Caco-2 cell monolayers were carried out to preliminarily define the overall efficiency and applicability of this new technology in improving RES intestinal permeability.

Circulation of COVID-19-Related Medicines on Japanese Websites during the COVID-19 Pandemic and Their Quality and Authenticity.

Substandard and falsified medical products for treating COVID-19 have spread worldwide. These medicines have entered Japan through personal importation of products purchased via the Internet. In this study, we investigated the circulation of 19 COVID-19-related medicines on the Internet in Japan and evaluated the pharmaceutical quality and authenticity of 2 medicines (dexamethasone tablets and ivermectin tablets) obtained online. We purchased 23 samples of 0.5-mg dexamethasone tablets and 13 samples of 3-mg ivermectin tablets from the Internet in December 2020 and July 2022. We investigated the quality and authenticity of the obtained samples through visual observation and tested their authenticity. We conducted pharmacopoeia compliance testing (quantitative assay, content uniformity tests, and dissolution tests) using the high-performance liquid chromatography-photodiode array detector method. No prescription was ever required at the time of purchase. Visual observation revealed that most samples lacked a package insert and some samples had packaging deficiencies. In terms of authenticity, eight ivermectin samples were genuine; the authenticity of the other samples remained uncertain. Four dexamethasone samples and three ivermectin samples failed quality testing based on pharmacopeia validation standards. Our findings illustrate that dexamethasone and ivermectin tablets of poor quality are available online. It is important to increase consumer awareness and provide information about these medicines to prevent the purchase of substandard medicines via the Internet.

Assessment of Quality Control parameters under Accelerated Stability Conditions for Manasamitra Vatakam; A Herbo Mineral Formulation

Accelerated Stability Studies predicts the stability data and significantly explains the drug decision process. In the present study, Manasamitra Vatakam, a Herbo mineral formulation was subjected to stability conditions at 40°C ± 2°C /75%± 5% RH for 06 months. Control and stability samples were determined for parameters like Weight variation, Moisture content, Marker content determination, and Disintegration test, Dissolution study with different mediums, Friability and Hardness test. The phytomarker analysis showed decrease assay value for β-sitosterol, Vitexin, Kampferol and Withaferin. The dissolution studies were performed for the major biomarker Berberine in 0.1N HCl, pH 4.5 acetate and pH 6.8 phosphate buffer in which pH 6.8 buffer showed maximum release of 66.82% at 04 hours. The other Quality control parameters showed minimal difference under acceptance criteria. The study explains the need of stability analysis in polyherbal formulations and developed method can be used for routine analytical studies in various formulation containing berberine. Keywords: Berberine, HPLC, Manasamitra Vatakam, Quality Control, Stability.

Synergistic Effects of Radical Distributions of Soluble and Insoluble Polymers within Electrospun Nanofibers for an Extending Release of Ferulic Acid.

Polymeric composites for manipulating the sustained release of an encapsulated active ingredient are highly sought after for many practical applications; particularly, water-insoluble polymers and core-shell structures are frequently explored to manipulate the release behaviors of drug molecules over an extended time period. In this study, electrospun core-shell nanostructures were utilized to develop a brand-new strategy to tailor the spatial distributions of both an insoluble polymer (ethylcellulose, EC) and soluble polymer (polyvinylpyrrolidone, PVP) within the nanofibers, thereby manipulating the extended-release behaviors of the loaded active ingredient, ferulic acid (FA). Scanning electron microscopy and transmission electron microscopy assessments revealed that all the prepared nanofibers had a linear morphology without beads or spindles, and those from the coaxial processes had an obvious core-shell structure. X-ray diffraction and attenuated total reflectance Fourier transform infrared spectroscopic tests confirmed that FA had fine compatibility with EC and PVP, and presented in all the nanofibers in an amorphous state. In vitro dissolution tests indicated that the radical distributions of EC (decreasing from shell to core) and PVP (increasing from shell to core) were able to play their important role in manipulating the release behaviors of FA elaborately. On one hand, the core-shell nanofibers F3 had the advantages of homogeneous composite nanofibers F1 with a higher content of EC prepared from the shell solutions to inhibit the initial burst release and provide a longer time period of sustained release. On the other hand, F3 had the advantages of nanofibers F2 with a higher content of PVP prepared from the core solutions to inhibit the negative tailing-off release. The key element was the water permeation rates, controlled by the ratios of soluble and insoluble polymers. The new strategy based on core-shell structure paves a way for developing a wide variety of polymeric composites with heterogeneous distributions for realizing the desired functional performances.

Comparative in-Vitro dissolution study of some sitagliptin generic tablets under biowaiver conditions by UV-Spectroscopy

The objective of this study is to evaluate the bioequivalence of generic sitagliptin tablets from different manufacturers using in-vitro dissolution study under biowaiver conditions through UV Spectroscopy, and compare them with the innovator brand. The dissolution media consisted of three different buffers with varying pH levels, including HCl Buffer pH 2.0, Phosphate Buffer pH 4.0, and Phosphate Buffer pH 7.2. The dissolution process was conducted using a USP type-2 dissolution apparatus with a 900 ml basket. The rotational speed of the paddle was set at 50 RPM, while maintaining a temperature of 37.5°C +/- 2°C. Samples were collected at four different intervals as recommended by the USFDA, which were 15, 30, 45, and 60 minutes. Validation parameters such as Accuracy, Precision, Linearity, LOD, and LOQ were assessed. The dissolution profiles exhibited no significant variability between different brands and within the same brand. Furthermore, the dissolution results of all tablet formulations, including the innovator brand, were analysed using the difference factor (f1) and similarity factor (f2). The findings from this study indicate that both generic brands of sitagliptin tablets meet the USFDA dissolution specifications and can be considered interchangeable.

Quality assessment of common anti-malarial medicines marketed in Gambella, National Regional State, South Western-Ethiopia

BackgroundOver the past years, there has been a growing concern that a considerable amount of anti-malarial supply in the underdeveloped world particularly in the private sector, is of poor quality. The World Health Organization (WHO) has received about 1500 reports that mentions instances of substandard and falsified products since 2013. The majority of the reports concerned antibiotics and anti-malarials. The majority of reports (42%) originate from the WHO African region.ObjectiveThis study intends to assess the quality of the most widely used anti-malarial medications [artemether-lumefantrine tablets, chloroquine phosphate tablets, primaquine phosphate tablets, artesunate, and artemether injections] in Gambella, South-West, Ethiopia.MethodsA total of 52 samples were collected on June 2022 from Gambella National Regional State, Ethiopia. Half of the districts (six) located in the four zones of the region were chosen using simple random sampling technique. All drug retail outlets available in the selected districts (locally known as woredas) were included. The samples were subjected to visual inspection with a tool adopted from the joint WHO/FIP/ USP checklist. The pharmacopeial tests for identification, uniformity of dosage forms, assay, thickness, diameter, hardness, friability, disintegration test, dissolution, and sterility tests were carried out according to the USP 44-NF 39 and International Pharmacopoeia 11th edition, 2022 monographs.Results and DiscussionOnly 25% of the samples were registered on the Ethiopian Food and Drug Authority (EFDA’s) electronic regulatory/ registration system (ERIS). Besides, 88.8% of artemether injection products were presented in clear glass ampoules. This might expose the products to photochemical degradation that leads to in loss of anti-plasmodial activity. In addition, 50% of the artemether products assessed were not bioequivalent with the comparator product in the in vitro dissolution comparison tests. Overall, the study findings reveal a high prevalence (58.3%) of substandard anti-malarial drugs in the region. The stated percent of the samples had failed in one or more of the quality test parameters assessed in this study.ConclusionThe study findings reveal a high prevalence (58.3%) of substandard anti-malarial drugs in the region. Only a quarter were registered and 38% of the unregistered products failed the quality tests. Hence, the national, regional medicine regulatory bodies and other stake holders should perform the required roles to circumvent presence of Substandard and Falsified (SF) anti-malarial drugs in the study sites.

A sustainable HPLC method coupled with diode array detection for versatile quantification of telmisartan, chlorthalidone and amlodipine in a fixed-dose antihypertensive formulation and dissolution studies

Cardiovascular diseases, especially hypertension, stand as prominent contributors to global mortality. Hypertension, often referred to as a silent killer syndrome, necessitates the use of multiple medications for effective control and management. A new environmentally friendly HPLC–DAD method is introduced in this study for the concurrent analysis of telmisartan (TEL), chlorthalidone (CHT) and amlodipine besylate (AML), in both pure forms and combined pharmaceutical dosage form. An isocratic elution mode was employed to achieve chromatographic separation, utilizing an Inertsil C18 column (250 × 4.6 mm, 5.0 µm) and a mobile phase mixture of acetonitrile and phosphate buffer (pH 3.0 ± 0.1) with ratio of 35:65, v/v. The separation was achieved within 10 min at a flow rate of 1.0 mL/min. The proposed method's validation was carried out following the guidelines outlined by the International Council for Harmonisation (ICH). The achieved linearity range was 1.0–140.0 μg/mL for TEL and 1.0–100.0 μg/mL for CHT and AML with quantification limits of 0.061, 0.177, and 0.313 μg/mL for TEL, CHT, and AML, respectively. The fixed combination tablet dosage form demonstrated acceptable release profile, as indicated by the in-vitro dissolution studies. The studied dissolution media were phosphate buffer pH 7.5, 0.01 N HCl, and water, utilizing a USP type II apparatus at 37 ± 0.5 °C with a stirring rate of 75 rpm. The proposed method was applied successfully for the quality assessment of Telma-ACT® Tablets with good precision and accuracy. Various tools were used for evaluating the level of greenness, including Green Analytical Procedure Index (GAPI), Analytical Greenness Metric for Sample Preparation (AGREEprep), Analytical Eco-Scale (AES), and Analytical Method Greenness Score (AMGS). These tools had confirmed the eco-friendliness of the proposed method. Additionally, the newly introduced White Analytical Chemistry (WAC), and the Blue Applicability Grade Index (BAGI) have been specifically developed to evaluate the sustainability and the applicability of the method.

Fabrication of PLA-Based Nanoneedle Patches Loaded with Transcutol-Modified Chitosan Nanoparticles for the Transdermal Delivery of Levofloxacin.

Current transdermal drug delivery technologies, like patches and ointments, effectively deliver low molecular weight drugs through the skin. However, delivering larger, hydrophilic drugs and macromolecules remains a challenge. In the present study, we developed novel transdermal nanoneedle patches containing levofloxacin-loaded modified chitosan nanoparticles. Chitosan was chemically modified with transcutol in three ratios (1/1, 1/2, 1/3, w/w), and the optimum ratio was used for nanoparticle fabrication via the ionic gelation method. The successful modification was confirmed using ATR-FTIR spectroscopy, while DLS results revealed that only the 1/3 ratio afforded suitably sized particles of 220 nm. After drug encapsulation, the particle size increased to 435 nm, and the final formulations were examined via XRD and an in vitro dissolution test, which suggested that the nanoparticles reach 60% release in a monophasic pattern at 380 h. We then prepared transdermal patches with pyramidal geometry nanoneedles using different poly(lactic acid)/poly(ethylene adipate) (PLA/PEAd) polymer blends of varying ratios, which were characterized in terms of morphology and mechanical compressive strength. The 90/10 blend exhibited the best mechanical properties and was selected for further testing. Ex vivo permeation studies proved that the nanoneedle patches containing drug-loaded nanoparticles achieved the highest levofloxacin permeation (88.1%).

The Use of Systemically Absorbed Drugs to Explore An In Vitro Bioequivalence Approach For Comparing Non-Systemically Absorbed Active Pharmaceutical Ingredients in Drug Products For Use in Dogs.

Currently, for veterinary oral formulations containing one or more active pharmaceutical ingredient (API) that are not systemically absorbed and act locally within the gastrointestinal (GI) tract, the use of terminal clinical endpoint bioequivalence (BE) studies is the only option for evaluating product BE. This investigation explored the use of a totality of evidence approach as an alternative to these terminal studies. Three formulations of tablets containing ivermectin plus praziquantel were manufactured to exhibit distinctly different in vitro release characteristics. Because these APIs are highly permeable, plasma drug concentrations served as a biomarker of in vivo dissolution. Tablets were administered to 27 healthy Beagle dogs (3-way crossover) and the rate and extent of exposure of each API for each formulation was compared in a pairwise manner. These results were compared to product relative in vitro dissolution profiles in 3 media. In vivo and in vitro BE predictions were compared. In vivo/in vitro inconsistencies in product relative performance were observed with both compounds when considering product performance across the 3 dissolution media. Formulation comparisons flagged major differences that could explain this outcome. The finding of an inconsistent in vivo/in vitro relationship confirmed that in vitro dissolution alone cannot assure product BE for veterinary locally acting GI products. However, when combined with a comparison of product composition and manufacturing method, this totality of evidence approach can successfully alert scientists to potential therapeutic inequivalence, thereby supporting FDA's efforts to Replace, Reduce, and/or Refine terminal animal studies.

Amphiphilic disodium glycyrrhizin as a co-former for ketoconazole co-amorphous systems: Biopharmaceutical properties and underlying molecular mechanisms

Co-amorphous systems (CAMs) have been extensively investigated to improve the dissolution of hydrophobic drugs. However, drug precipitation during the storage or dissolution of CAMs has still been a major challenge. Here, disodium glycyrrhizin (Na2GA) was first used as a co-former in CAMs based on its multiple hydroxyl groups and amphiphilic structure. Ketoconazole (KTZ), a BCS class II drug, was selected as a model drug. KTZ-Na2GA CAMs at mass ratios of 1:1, 1:2.5, 1:5 and 1:10 were prepared by the spray drying method and further characterised by PXRD and DSC. The 1:2.5, 1:5 and 1:10 groups exhibited significantly enhanced Cmax (all approximately 26.67-fold) and stable maintenance of supersaturation compared to the crystalline KTZ and the corresponding physical mixtures in non-sink dissolution tests, while the 1:1 group exhibited an unstable medium Cmax (all approximately 14.67-fold). The permeability tests revealed that the permeation rate of KTZ in KTZ-Na2GA CAMs under the concentration of Na2GA in solution above the critical micelle concentration (CMC) showed a significant downwards trend compared to that below CMC. The underlying molecular mechanisms were involved in molecular miscibility, hydrogen bond interactions, solubilisation and crystallisation inhibition by Na2GA. Pharmacokinetic studies demonstrated that the AUC0-∞ of KTZ in 1:1, 1:2.5, 1:5 and 1:10 groups were significantly higher than those of the crystalline KTZ group with 2.13-, 2.30-, 2.16- and 1.86-fold, respectively (p < 0.01). In conclusion, Na2GA has proven to be a promising co-former in CAMs to enhance hydrophobic drug dissolution and bioavailability. Its effect on intestinal permeation rate of drugs also deserves attention.

Physiologically based in vitro – in vivo correlation of modified release oral formulations with non-linear intestinal absorption: A case study using mirabegron

Establishing an in vitro – in vivo correlation (IVIVC) for oral modified release (MR) formulations would make it possible to substitute an in vitro dissolution test for human bioequivalence (BE) studies when changing the formulation or manufacturing methods. However, the number of IVIVC applications and approvals are reportedly low. One of the main reasons for failure to obtain IVIVCs using conventional methodologies may be the lack of consideration of the dissolution and absorption mechanisms of drugs in the physiological environment. In particular, it is difficult to obtain IVIVC using conventional methodologies for drugs with non-linear absorption processes. Therefore, the aim of the present study was to develop a physiologically based biopharmaceutics model (PBBM) that enables Level A IVIVCs for mirabegron MR formulations with non-linear absorption characteristics.Using human pharmacokinetic (PK) data for immediate-release formulations of mirabegron, the luminal drug concentration-dependent membrane permeation coefficient was calculated through curve fitting. The membrane permeation coefficient data were then applied to the human PK data of the MR formulations to estimate the in vivo dissolution rate by curve fitting. It was assumed that in vivo dissolution could be described using a zero-order rate equation. Furthermore, a Levy plot was generated using the estimated in vivo dissolution rate and the in vitro dissolution rate obtained from the literature. Finally, the dissolution rate of the MR formulations from the Levy plot was applied to the PBBM to predict the oral PK of the mirabegron MR formulations.This PB-IVIVC approach successfully generated linear Levy plots with slopes of almost 1.0 for MR formulations with different dose strengths and dissolution rates. The Cmax values of the MR formulations were accurately predicted using this approach, whereas the prediction errors for AUC exceeded the Level A IVIVC criteria. This can be attributed to the incomplete description of colonic absorption in the current PBBM.

A Rapid, Sensitive, and High-throughput Method for the Simultaneous Determination of Antihypertensive Drug Combinations in Dog Plasma by UHPLC-MS/MS: The Assessment of Predicable Bioequivalence of In-vitro Dissolution Condition.

Essential hypertension is a common clinical disease and a risk factor for cardiovascular and cerebrovascular diseases. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide are commonly used antihypertensive drugs. The aim of this study was to establish a robust UPLC-MS/MS method for the simultaneous determination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide in dog plasma. At the same time, the in vivo and in vitro release studies were conducted, and a preliminary in vitro-in vivo correlation (IVIVC) evaluation was performed. The bioequivalence experiment was conducted with a double-crossed design. Three major components were extracted and analyzed by UHPLC-MS/MS. With the MRM scan, olmesartan and amlodipine were quantified by fragment conversion (m/z 447.10→190.10) and (m/z 408.95→294.00) under positive ESI mode, while hydrochlorothiazide was quantified with fragment conversion (m/z 295.90→268.90) under negative ESI mode. The in vitro release studies were performed using a USP paddle, and the dissolution medium was chosen from pH 6.0 to pH 6.8 according to the BCS classification of compounds. The IVIVC was calculated using the Wagner-Nelson equation. The linear ranges of olmesartan, amlodipine, and hydrochlorothiazide in the plasma were 5.0-2500, 0.1-50, and 3.0-1500 ng/mL, respectively. All accuracies were within 3.8% of the target values, and the findings revealed that intra-day and inter-day accuracies were less than 12.1%. Moreover, the recoveries exceeded 88.3%, the matrix effect tests were positive, and the stability tests were positive. With the establishment of correlation, the distinguishable dissolution condition (pH 6.8) was selected as the predictable condition. The established method was suitable for the preclinical pharmacokinetic study of tripartite drugs with strong specificity and high sensitivity. Through the evaluation of IVIVC, the connection between in vivo and in vitro drug testing was initially established.

Structure based release kinetics analysis of doxazosin mesylate sustained-release tablets using micro-computed tomography

The structures of solid dosage forms determine their release behaviors and are critical attributes for the design and evaluation of the solid dosage forms. Here, the three-dimensional (3D) structures of doxazosin mesylate sustained-release tablets (DM SRT) as reference listed drug (RLD) and a generic preparation were parallelly assessed by micro-computed tomography (micro-CT). There were no significant differences observed in the release profiles between the RLD and the generic formulation in the conventional dissolution, but the generic preparation released slightly faster in media with ethanol for an alcohol-induced dose-dumping test. With their 3D structures obtained via micro-CT determination, the unique release behaviors of both RLD and the generic were investigated for samples from dissolution tests to reveal the effects of internal fine structure on the release kinetics. The structural parameters for both preparations were similar in conventional dissolution test, whilst the dissolutions in ethanol media of RLD were more or less distinguished from that of generic preparations, attributing to their static and dynamic structures. Furthermore, the findings revealed that the presence of ethanol accelerated the dissolution and induced changes in the internal structure of both the RLD and the generic preparations. Moreover, the structure parameters like volume and area of outer contour, remaining solid volume and cavity volume were not equivalent between the two formulations in 40 % ethanol. In conclusion, the structure data obtained from this study provided valuable insights into the diverse release behaviors observed in various modified-release formulations in drug development and quality control.

Formulation Variables Influencing the Development of Ketoconazole Gastroretentive Drug Delivery System

Background: Ketoconazole (KZ) is categorized as class II according to the Biopharmaceutics Classification System (BSC) classification, which shows a strong pH-dependent solubility where its solubility is enhanced under an acidic medium (pH below 3). This strong pH dependence results in unpredictable absorption and a wide range of bioavailabilities. Objective: To prolong the gastric residence time of KZ’s tablet to enhance KZ’s solubility and hence its bioavailability for better therapeutic activity. Methods: To prepare mucoadhesive tablets, we use both direct and wet granulation methods. We employed various evaluation tests to assess the prepared tablets. These tests encompass a range of assessments, including weight variation, hardness, thickness, friability, disintegration test, swelling study, mucoadhesive strength study, and in vitro drug release studies. Results: The study found that polymer viscosity, as well as polymer concentration, have a significant effect on mucoadhesive strength and drug release, whereas diluent type has a non-significant influence on drug release. We selected Formula 7, which employs xanthan gum as a mucoadhesive polymer in a 1:1 drug polymer ratio, as the optimum formula because it provides an accepted physico-mechanical property and releases 87% of the drug over 8 hours. Conclusions: Gastric mucoadhesive tablets may be an effective method of delivering active ingredients, as they provide a favorable environment that enhances their dissolution by extending their duration in the stomach, thereby increasing their bioavailability.