Changes In Dissolution Rate Research Articles

Formulation-dependent stability mechanisms affecting dissolution performance of directly compressed griseofulvin tablets

During drug product development, stability studies are used to ensure that the safety and efficacy of a product are not affected during storage. Any change in the dissolution performance of a product must be investigated, as this may indicate a change in the bioavailability. In this study, three different griseofulvin formulations were prepared containing microcrystalline cellulose (MCC) with either mannitol, lactose monohydrate, or dibasic calcium phosphate anhydrous (DCPA). The tensile strength, porosity, contact angle, disintegration time, and dissolution rate were measured after storage under five different accelerated temperature and humidity conditions for 1, 2, and 4 weeks. The dissolution rate was found to decrease after storage for all three batches, with the change in dissolution rate strongly correlating with the storage humidity. The changes in physical properties of each formulation were found to relate to either the premature swelling (MCC/DCPA, MCC/lactose) or dissolution (MCC/mannitol) of particles during storage. These results are also discussed with consideration of the performance- and stability-controlling mechanisms of placebo tablets of the same formulations (Maclean et al., 2021; Maclean et al., 2022).

Formulation and Evaluation of Orodispersible Tablets Containing Co-Crystals of Modafinil

Background: Modafinil is a CNS stimulant used to treat Narcolepsy, sleepiness and other disorders related to sleep. It is a BCS class II drug having poor aqueous solubility.
 Objective: This study was aimed to formulate and evaluate orodispersible tablets of containing co-crystals of Modafinil for the improvisation of critical attributes of the product such as dissolution rates, solubility and oral bioavailability.
 Methods: Co-crystals were prepared by dry grinding method using Sodium acetate, Nicotinic acid, Benzoic acid, Urea and Succinic acetate as co-formers. Tablets were compressed by using direct compression method using SSG, Crospovidone, and Croscarmellose sodium as super disintegrants in different concentration.
 Results: Pre-formulation studies were performed and evaluation of prepared co-crystals revealed that Co-crystals formulated with sodium acetate showed best results. The manufactured orodispersible tablets were evaluated for different parameters including weight variation, hardness, thickness, friability, drug content, In-vitro disintegration and In-vitro dissolution studies. Formulation F2 shows significant change in dissolution rate and also helped to increase the solubility of poorly water soluble drugs and both of them i.e. solubility and percentage of drug release are the key factors to exhibit the efficiency of the drug. Formulation of co-crystal with sodium acetate in 1:1 ratio showed highest drug content (97.97%), while Benzoic acid in ratio 1:2 showed least drug content (56.48%).
 Conclusion: According to the result obtained, an orodispersible tablet containing co-crystals of modafinil enhances the dissolution rate, solubility and hence increases the therapeutic efficacy and could be considered convenient oral delivery systems to enhance the drug bioavailability.
 Keywords: Co-crystal, Oro-dispersible, Sodium acetate, Narcolepsy, Sleepiness

Comparison study of physicochemical and biopharmaceutics properties of hydrophobic drugs ground by two dry milling processes

This study focuses on the dry milling of biopharmaceutical classification system (BCS) class II molecules. These molecules have a limited bioavailability because of their low aqueous solubility, poor water wettability and low dissolution rate. In order to improve these properties, indomethacin (IND) and niflumic acid (NIF) were milled using two different types of equipment: Pulverisette 0® and CryoMill®. Milled samples were characterized and compared to commercial molecules. IND shows a modified solid state, like surface crystallinity reduction and an increase in water vapor adsorption from to 2- up to 5-fold due to milling processes. The obtained solubility data resulted in an improvement in solubility up to 1.2-fold and an increase in initial dissolution kinetics: 2% of dissolved drug for original crystals against 25% for milled samples. For NIF no crystallinity reduction, no change of surface properties and no solubility improvement after milling were noticed. In addition, milled particles seemed more agglomerated resulting in no changes in dissolution rate compared to the original drug. IND solubility and dissolution enhancement can be attributed to the modification of surface area, drug crystallinity reduction, and water sorption increase due to specific behavior related to the drug crystal disorder induced by milling process.

Physiologically based pharmacokinetic modeling and simulations to inform dissolution specifications and clinical relevance of release rates on elagolix exposure

The aim of this analysis was to use a physiologically based pharmacokinetic (PBPK) model to predict the impact of changes in dissolution rates on elagolix exposures and define clinically relevant acceptance criteria for dissolution. Varying in vitro dissolution profiles were utilized in a PBPK model to describe the absorption profiles of elagolix formulations used in Phase 3 clinical trials and for the to be marketed commercial formulations. Single dose studies of 200 mg elagolix formulations were used for model verification under fasted conditions. Additional dissolution scenarios were evaluated to assess the impact of dissolution rates on elagolix exposures. Compared to the Phase 3 clinical trial formulation, sensitivity analysis on dissolution rates suggested that a hypothetical scenario of ∼75% slower dissolution rate would result in 14% lower predicted elagolix plasma exposures, however, the predicted exposures are still within the bioequivalence boundaries of 0.8–1.25 for both Cmax and AUC. A clinically verified PBPK model of elagolix was utilized to evaluate the impact of wider dissolution specifications on elagolix plasma exposures. The simulation results indicated that a slower in vitro dissolution profile, would not have a clinically significant impact on elagolix exposures. These model results informed the setting of wider dissolution specifications without requiring in vivo studies.

The Chitosan-Based System with Scutellariae baicalensis radix Extract for the Local Treatment of Vaginal Infections.

Scutellarie baicalensis radix, as a flavone-rich source, exhibits antibacterial, antifungal, antioxidant, and anti-inflammatory activity. It may be used as a therapeutic agent to treat various diseases, including vaginal infections. In this study, six binary mixtures of chitosan with stable S. baicalensis radix lyophilized extract were obtained and identified by spectral (ATR-FTIR, XRPD) and thermal (TG and DSC) methods. The changes in dissolution rates of active compounds and the significant increase in the biological properties towards metal chelating activity were observed, as well as the inhibition of hyaluronic acid degradation after mixing plant extract with chitosan. Moreover, the combination of S. baicalensis radix lyophilized extract with a carrier allowed us to obtain the binary systems with a higher antifungal activity than the pure extract, which may be effective in developing new strategies in the vaginal infections treatment, particularly vulvovaginal candidiasis.

A Physiologically Based Pharmacokinetic Model for Studying the Biowaiver Risk of Biopharmaceutics Classification System Class I Drugs With Rapid Elimination: Dexketoprofen Trometamol Case Study.

Biowaiver based on the biopharmaceutics classification system (BCS) has been widely used in the global market for the approval of new generic drug products to avoid unnecessary in vivo bioequivalence (BE) studies. However, it is reported that three out of four formulations of dexketoprofen trometamol (DEX) tablets (BCS class I drug) failed the first BE study. The aim of this study was to determine whether the current biowaiver standard is reasonable for DEX. Thus, we successfully established a physiologically based pharmacokinetic (PBPK) model for DEX and examined the effects of dissolution, permeability, and gastric emptying time on DEX absorption under BCS-based biowaiver conditions using sensitivity analyses. Parameter sensitivity analysis showed that the dissolution rate in pH 1.2 media, permeability, and liquid gastric emptying time were sensitive parameters of Cmax. Therefore, gastric emptying variation was introduced into the PBPK model, and virtual BE studys were conducted on original research formulation and the formulation of the boundary dissolution rate (f2 = 50) prescribed by the biowaiver guideline. The virtual BE results showed dissolution rate changes within the biowaiver range will not cause high non-BE ratio, indicate waive of DEX generic drugs would not lead the risk of Cmax when generic products satisfy the requirements of biowaiver guideline. However, the effect of excipients on gastric emptying as a sensitive factor needs to be further studied when the rapid elimination of BCS class I drug is biowaived.

Study on the Dissolution and Diffusion of Supercritical Carbon Dioxide in Polystyrene Melts Based on Adsorption and Diffusion Mechanism.

In order to reveal the dissolution process, the adsorption kinetics and diffusion theory are combined and used to describe the adsorption-diffusion mechanism. This can not only predict the solubility of supercritical CO2 in polymer melts but also describe two important parameters of supercritical CO2 in the dissolution process: dissolution amount and dissolution rate, which can provide a good theoretical basis for microcellular foaming. To verify the feasibility and accuracy of the theoretical calculation method, an experimental device for the volume-changing method under static condition was established. The results showed that the theoretical calculation value was in good agreement with the experimental value. In addition, the dissolution amount and dissolution rate of supercritical CO2 in three polystyrene melts with different molecular weights under different temperature and pressure conditions were measured. The results showed that the difference of polystyrene molecular weight can cause the change of dissolution rate during the dissolution process, that is, the larger the molecular weight, the slower the dissolution rate.

The impact of ventilation patterns on calcite dissolution rates within karst conduits

Erosion rates in streams vary dramatically over time, as differences in streamflow and sediment load enhance or inhibit erosion processes. Within cave streams, and other bedrock channels incising soluble rocks, changes in water chemistry are an important factor in determining how erosion rates will vary in both time and space. Prior studies in surface streams, springs, and caves suggest that variation in dissolved CO2 is the strongest control on variation in calcite dissolution rates. However, the controls on CO2 variation remain poorly quantified. Limited data suggest that ventilation of karst systems can substantially influence dissolved CO2 within karst conduits. However, the interactions among cave ventilation, air–water CO2 exchange, and dissolution dynamics have not been studied in detail. In this study, three years of time series measurements of dissolved and gaseous CO2, cave airflow velocity, and specific conductance from Blowing Springs Cave, Arkansas, were analyzed and used to estimate continuous calcite dissolution rates and quantify the correlations between those rates and potential physical and chemical drivers. We find that chimney effect airflow creates temperature-driven switches in airflow direction, and that the resulting seasonal changes in airflow regulate both gaseous and dissolved CO2 within the cave. As in previous studies, partial pressure of CO2 (pCO2) is the strongest chemical control of dissolution rate variability. However, we also show that cave airflow direction, rather than streamflow, is the strongest physical driver of changes in dissolution rate, contrary to the typical situation in surface channel erosion where floods largely determine the timing and extent of geomorphic work. At the study site, chemical erosion is typically active in the summer, during periods of cave downdraft (airflow from upper to lower entrances), and inactive in the winter, during updraft (airflow from lower to upper entrances). Storms provide only minor perturbations to this overall pattern. We also find that airflow direction modulates dissolution rate variation during storms, with higher storm variability during updraft than during downdraft. Finally, we compare our results with the limited set of other studies that have examined dissolution rate variation within cave streams and draw an initial hypothesis that evolution of cave ventilation patterns strongly impacts how dissolution rate dynamics evolve over the lifetime of karst conduits.

Different Photostability of BiVO4 in Near-pH-Neutral Electrolytes.

Photoelectrochemical water splitting is a promising route to produce hydrogen from solar energy. However, corrosion of photoelectrodes remains a fundamental challenge for their implementation. Here, we reveal different dissolution behaviors of BiVO4 photoanode in pH-buffered borate, phosphate, and citrate (hole-scavenger) electrolytes, studied in operando employing an illuminated scanning flow cell. We demonstrate that decrease in photocurrents alone does not reflect the degradation of photoelectrodes. Changes in dissolution rates correlate to the evolution of surface chemistry and morphology. The correlative measurements on both sides of the liquid–semiconductor junction provide quantitative comparison and mechanistic insights into the degradation processes.

Influences of ZnO on the chemical durability and thermal stability of calcium iron phosphate glasses

This study aims to investigate influences form zinc oxide on glasses in xZnO-(100-x) (54P2O5-36Fe2O3-10CaO) (x = 3,6,9,12,15,18 mol%). Structure analyses were carried by FTIR, and chemical durability tests were introduced to study changes in dissolution rate and weight losses. Thermal stability properties were measured and discussed through DSC. Results from structure changes indicate that glass network turns less compact with more ZnO, the building units gradually evolving into Q0 groups from Q1 tetrahedra, even the whole glass system locates in orthophosphate glasses. Higher melting temperature results in more Fe2+ that would lead to octahedral and disordered octahedral in the prepared glasses also contributing to open glass network in glass structure. The resistance in both alkali and acid solution were deteriorated for the sake of the open network, accompanied with the less strong P-O-Zn bonds when compared with the P-O-P bonds. Reasons accounting for the weak resistance also refer to the transition from [ZnO6] to [ZnO4], larger volume of [ZnO4] than that of [PO4], small particle size in ternary phosphate glasses. Drops in weight loss for each test span with corrosion time might be owing to the formation of alter layer on the surface of glass samples during corrosion. The phenomenon in water also follow the similar trend as those in the other two solutions for the same reasons. The glass transition and crystalline temperatures of all glasses drop as the degree of polymerization in glass becomes small, with four glass stability parameters falling as the amount of ZnO rises.

Alloyed Fluxes of Aluminum–Stainless Steel Arc Brazing

Alloyed fluxes consisting of the non-corrosive flux KAlF4 and alloyed elements Cu, Mn, Ni, and Zr were investigated, respectively, for aluminum–stainless steel TIG brazing. All the alloyed fluxes could both increase the spreading area and decrease the IMC thickness notably. Utilizing the unalloyed flux in the standard braze alloy as a control for comparison, the area increased from 55.3 to 98.5 mm2 with 30% Mn alloyed flux and the thickness was reduced from 15.1 to 4.1 μm with 10% Ni alloyed flux, in maximum. The variation tendencies of spreading area and IMC thickness with element content were obviously different. The change of wetting and spreading behavior was attributed to the combination effect of flux and alloyed elements. The IMC decreased with the alloyed elements was related to the change of dissolution rate of the stainless steel into the liquid aluminum.

Assessment of Bioequivalence of Weak Base Formulations Under Various Dosing Conditions Using Physiologically Based Pharmacokinetic Simulations in Virtual Populations. Case Examples: Ketoconazole and Posaconazole

Postabsorptive factors which can affect systemic drug exposure are assumed to be dependent on the active pharmaceutical ingredient (API), and thus independent of formulation. In contrast, preabsorptive factors, for example, hypochlorhydria, might affect systemic exposure in both an API and a formulation-dependent way. The aim of this study was to evaluate whether the oral absorption of 2 poorly soluble, weakly basic APIs, ketoconazole (KETO) and posaconazole (POSA), would be equally sensitive to changes in dissolution rate under the following dosing conditions—coadministration with water, with food, with carbonated drinks, and in drug-induced hypochlorhydria. The systems-components of validated absorption and PBPK models for KETO and POSA were modified to simulate the above-mentioned clinical scenarios. Virtual bioequivalence studies were then carried out to investigate whether formulation effects on the plasma profile vary with the dosing conditions. The slow precipitation of KETO upon reaching the upper part of the small intestine renders its absorption more sensitive to the completeness of gastric dissolution and thus to the gastric environment than POSA, which is subject to extensive precipitation in response to a pH shift. The virtual bioequivalence studies showed that hypothetical test and reference formulations containing KETO would be bioequivalent only if the microenvironment in the stomach enables complete gastric dissolution. We conclude that physiologically based pharmacokinetic modeling and simulation has excellent potential to address issues close to bedside such as optimizing dosing conditions. By studying virtual populations adapted to various clinical situations, clinical strategies to reduce therapeutic failures can be identified.

Solubility and dissolution enhancement of efavirenz hot melt extruded amorphous solid dispersions using combination of polymeric blends: A QbD approach

Efavirenz is a non-nucleoside reverse transcriptase inhibitor and categorized in to BCS class II drug. The aim of the present investigation was to apply quality by design approach to enhance the solubility, dissolution and stability of amorphous solid dispersions (ASDs) of efavirenz using a combination of Soluplus® and HPMCAS-HF polymers. In design of experiments, the user defined quadratic model was used to study the effect of variable concentrations of Soluplus® and HPMCAS-HF for the formation of ASDs of efavirenz. Similarly, a prototype ASD was made using Soluplus® as a carrier with efavirenz loading of 30%. The efavirenz ASDs granular extrudates were evaluated for saturation solubility as well as dissolution rate studies. X-ray powder diffraction, Differential scanning calorimetry, Fourier transform infrared, Atomic force microscopy and FTIR imaging to determine the solid state of efavirenz in the ASDs. DSC and XRD data confirmed that bulk crystalline efavirenz transformed to the amorphous form during the hot melt extrusion processing. Prototype ASD batch showed instability upon storage as per ICH guidelines over a period of 6months, observations inferred from DSC, XRD and in vitro dissolution studies. The maximum dissolution rate was observed when Soluplus® and HPMCAS-HF was in ratio of (60:20) as optimized by design of experiments study. Moreover, the optimized ASDs batch were stable at 40°C, 75% RH for a period of 6months without any dissolution rate changes, and remained into amorphous state.

Direct Experimental Evidence for Differing Reactivity Alterations of Minerals following Irradiation: The Case of Calcite and Quartz.

Concrete, used in the construction of nuclear power plants (NPPs), may be exposed to radiation emanating from the reactor core. Until recently, concrete has been assumed immune to radiation exposure. Direct evidence acquired on Ar+-ion irradiated calcite and quartz indicates, on the contrary, that, such minerals, which constitute aggregates in concrete, may be significantly altered by irradiation. More specifically, while quartz undergoes disordering of its atomic structure resulting in a near complete lack of periodicity, calcite only experiences random rotations, and distortions of its carbonate groups. As a result, irradiated quartz shows a reduction in density of around 15%, and an increase in chemical reactivity, described by its dissolution rate, similar to a glassy silica. Calcite however, shows little change in dissolution rate - although its density noted to reduce by ≈9%. These differences are correlated with the nature of bonds in these minerals, i.e., being dominantly ionic or covalent, and the rigidity of the mineral’s atomic network that is characterized by the number of topological constraints (nc) that are imposed on the atoms in the network. The outcomes have major implications on the durability of concrete structural elements formed with calcite or quartz bearing aggregates in nuclear power plants.

Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm.

Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

Stability-enhanced Hot-melt Extruded Amorphous Solid Dispersions via Combinations of Soluplus® and HPMCAS-HF

The aim of this study was to evaluate a novel combination of Soluplus® and hypromellose acetate succinate (HPMCAS-HF) polymers for solubility enhancement as well as enhanced physicochemical stability of the produced amorphous solid dispersions. This was accomplished by converting the poorly water-soluble crystalline form of carbamazepine into a more soluble amorphous form within the polymeric blends. Carbamazepine (CBZ), a Biopharmaceutics Classification System class II active pharmaceutical ingredient (API) with multiple polymorphs, was utilized as a model drug. Hot-melt extrusion (HME) processing was used to prepare solid dispersions utilizing blends of polymers. Drug loading showed a significant effect on the dissolution rate of CBZ in all of the tested ratios of Soluplus® and HPMCAS-HF. CBZ was completely miscible in the polymeric blends of Soluplus® and HPMCAS-HF up to 40% drug loading. The extrudates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and dissolution studies. DSC and XRD data confirmed the formation of amorphous solid dispersions of CBZ in the polymeric blends of Soluplus® and HPMCAS-HF. Drug loading and release of CBZ was increased with Soluplus® (when used as the primary matrix polymer) when formulations contained Soluplus® with 7-21% (w/w) HPMCAS-HF. In addition, this blend of polymers was found to be physically and chemically stable at 40°C, 75% RH over 12 months without any dissolution rate changes.

Tablet Scoring and its Regulatory Perspective

The objective of this paper is to provide insight and better understanding of the regulations for the scored tablet in regulated markets and World Health Organization. Splitting of tablets is done for various reasons; but is associated with certain problems such as inaccurate split resulting in change of dose, enhanced drug degradation due to atmospheric exposure, change in dissolution rate and extent. The accuracy of split is not uniform even with the use of commercial tablet cutters. Often patients with impaired vision, and lack of skilled experience have difficulty during splitting tablets. Accurate dosing may not be possible with splitting of tablets, especially with potent drugs. Tablet splitting may reduce the cost of therapy and may accommodate dose changes as required, but impact on the overall quality of medication used in therapy. Keywords: Dissolution, score, splitting, tablet.

Coherent anti-Stokes Raman scattering (CARS) microscopy visualizes pharmaceutical tablets during dissolution.

Traditional pharmaceutical dissolution tests determine the amount of drug dissolved over time by measuring drug content in the dissolution medium. This method provides little direct information about what is happening on the surface of the dissolving tablet. As the tablet surface composition and structure can change during dissolution, it is essential to monitor it during dissolution testing. In this work coherent anti-Stokes Raman scattering microscopy is used to image the surface of tablets during dissolution while UV absorption spectroscopy is simultaneously providing inline analysis of dissolved drug concentration for tablets containing a 50% mixture of theophylline anhydrate and ethyl cellulose. The measurements showed that in situ CARS microscopy is capable of imaging selectively theophylline in the presence of ethyl cellulose. Additionally, the theophylline anhydrate converted to theophylline monohydrate during dissolution, with needle-shaped crystals growing on the tablet surface during dissolution. The conversion of theophylline anhydrate to monohydrate, combined with reduced exposure of the drug to the flowing dissolution medium resulted in decreased dissolution rates. Our results show that in situ CARS microscopy combined with inline UV absorption spectroscopy is capable of monitoring pharmaceutical tablet dissolution and correlating surface changes with changes in dissolution rate.

Coherent anti-Stokes Raman Scattering (CARS) Microscopy Visualizes Pharmaceutical Tablets During Dissolution

Traditional pharmaceutical dissolution tests determine the amount of drug dissolved over time by measuring drug content in the dissolution medium. This method provides little direct information about what is happening on the surface of the dissolving tablet. As the tablet surface composition and structure can change during dissolution, it is essential to monitor it during dissolution testing. In this work coherent anti-Stokes Raman scattering microscopy is used to image the surface of tablets during dissolution while UV absorption spectroscopy is simultaneously providing inline analysis of dissolved drug concentration for tablets containing a 50% mixture of theophylline anhydrate and ethyl cellulose. The measurements showed that in situ CARS microscopy is capable of imaging selectively theophylline in the presence of ethyl cellulose. Additionally, the theophylline anhydrate converted to theophylline monohydrate during dissolution, with needle-shaped crystals growing on the tablet surface during dissolution. The conversion of theophylline anhydrate to monohydrate, combined with reduced exposure of the drug to the flowing dissolution medium resulted in decreased dissolution rates. Our results show that in situ CARS microscopy combined with inline UV absorption spectroscopy is capable of monitoring pharmaceutical tablet dissolution and correlating surface changes with changes in dissolution rate.

In situ dissolution analysis using coherent anti-Stokes Raman scattering (CARS) and hyperspectral CARS microscopy

The solid-state form of an active pharmaceutical ingredient (API) in an oral dosage form plays an important role in determining the dissolution rate of the API. As the solid-state form can change during dissolution, there is a need to monitor the oral dosage form during dissolution testing. Coherent anti-Stokes Raman scattering (CARS) microscopy provides rapid, spectrally selective imaging to monitor the oral dosage form during dissolution. In this study, in situ CARS microscopy was combined with inline UV absorption spectroscopy to monitor the solid-state change in oral dosage forms containing theophylline anhydrate undergoing dissolution and to correlate the solid-state change with a change in dissolution rate. The results from in situ CARS microscopy showed that theophylline anhydrate converted to theophylline monohydrate during dissolution resulting in a reduction in the dissolution rate. The addition of methyl cellulose to the dissolution medium was found to delay the theophylline monohydrate growth and changed the morphology of the monohydrate. The net effect was an increased dissolution rate for theophylline anhydrate. Our results show that in situ CARS microscopy combined with inline UV absorption spectroscopy is capable of monitoring oral dosage forms undergoing dissolution and correlating changes in solid-state form with changes in dissolution rate.