– Catharina Wähling et al. November 2011

The percentage of poorly soluble compounds in drug discovery and development increases steadily. A variety of possibilities exists for increasing solubility and bioavailability; among them is the formation of salts. For the characterization of poorly soluble active pharmaceutical ingredients (API), it is necessary to develop appropriate 
analytical methods to determine relevant physicochemical properties. One important physicochemical parameter is the dissolution rate. As the flow-through cell (FTC) offers various advantages, such as operating with pH gradients and in sink conditions or applying unlimited amount of media, the FTC is particularly suitable for poorly soluble compounds. When developing an FTC method it is important to consider the physiological circumstances. By choosing the appropriate conditions for media, volume, flow rate, and so forth, it is possible to predict in vivo behavior. The focus of this work was to develop a small-scale FTC method for poorly soluble compounds designed for determining dissolution kinetics in the early development phase, where only limited amount of drug is available. The predictive power of the presented system could be demonstrated by an in vitro–in vivo relationship (IVIVR) study.

– Marina Navas-Bachiller et al. April 2022

The definition of the local dissolution environment is central to accurate particle dissolution simulation, and is determined by the apparatus and conditions used. In the flow-through apparatus dissolution occurs in the cell, often in a low velocity environment, with the reservoir considered the relevant volume for dissolution kinetics. Dissolution simulations were conducted using a reduced-order model based on the Ranz-Marshall correlation for mass transfer from spherical particles. Using ibuprofen as a model drug, the effect of defining a local volume to simulate dynamic bulk concentration conditions in the flow-through and paddle apparatus was assessed by comparing use of a near particle volume (NPV), extending a distance of one radius from the particle surface, with a flow-through apparatus cell volume or paddle apparatus vessel volume as the relevant instantaneous volume for dissolution. The instantaneous inlet concentration to NPV or cell volume is the reservoir/vessel concentration at that simulation time point, reflecting the continuous input to the cell of more dilute solution from the reservoir (closed system). Additionally, inputting particle size distribution (PSD) instead of a median particle size (MPS) and enabling or disabling particle motion were investigated, in two media (resulting in low and high solubility) and with two fluid velocity conditions in each apparatus.

– Dolores R. Serrano et al. April 2016

The aim of this work was to evaluate the influence of crystal habit on the dissolution and in vitro antibacterial and anitiprotozoal activity of sulfadimidine: 4-aminosalicylic acid cocrystals. Methods: Cocrystals were produced via milling or solvent mediated processes. In vitro dissolution was carried out in the flow-through apparatus, with shadowgraph imaging and mechanistic mathematical models used to observe and simulate particle dissolution. In vitro activity was tested using agar diffusion assays. Results: Cocrystallisation via milling produced small polyhedral crystals with antimicrobial activity significantly higher than sulfadimidine alone, consistent with a fast 
dissolution rate which was matched only by cocrystals which were milled following solvent evaporation. Cocrystallisation by solvent evaporation (ethanol, acetone) or spray drying produced flattened, plate-like or quasispherical cocrystals, respectively, with more hydrophobic surfaces and greater tendency to form aggregates in aqueous media, limiting both the dissolution rate and in vitro activity. Deviation from predicted dissolution profiles was attributable to aggregation behaviour, supported by observations from shadowgraph imaging. Conclusions: Aggregation behaviour during dissolution of cocrystals with different habits affected the dissolution rate, consistent with in vitro activity. Combining mechanistic models with shadowgraph imaging is a valuable approach for dissolution process analysis.

– Jana Brokesova et al. November 2021

To enhance dissolution rate of meloxicam (MX), a poorly soluble model drug, a natural polysaccharide excipient chitosan (CH) is employed in this work as a carrier to prepare binary interactive mixtures by either mixing or comilling techniques. The MX-CH mixtures of three different drug loads were characterized for morphological, granulometric, and thermal properties as well as drug crystallinity. The relative dissolution rate of MX was determined in phosphate buffer of pH 6.8 using the USP-4 apparatus; a significant increase in MX dissolution rate was observed for both mixed and co-milled mixtures comparing to the raw drug. Higher dissolution rate of MX was evidently connected to surface activation by mixing or milling, which was pronounced by the higher specific surface energy as detected by inverse gas chromatography. In addition to the particle size reduction, the carrier effect of the CH was confirmed for co-milling by linear regression between the MX maximum relative dissolution rate and the total surface area of the mixture (R2 = 0.863). No MX amorphization or crystalline structure change were detected. The work of adhesion/cohesion ratio of 0.9 supports the existence of preferential adherence of MX to the coarse particles of CH to form stable interactive mixtures.

– J. Patera et al. September 2022

Meloxicam (MLX) is a poorly soluble drug exhibiting strong hydrophobicity. This combination of properties makes dissolution enhancement by particle size reduction ineffective; therefore, combined formulation approaches are required. Various approaches were investigated in this study, including milling, solid dispersions, and self-emulsified lipid formulations. Whereas milling studies of MLX and its co-milling with various polymers have been reported in recent literature, this study is focused on investigating the dissolution kinetics of particulate formulations obtained by co-milling MLX with sodium lauryl sulfate (SLS) in a planetary ball mill with 5–25 wt.% SLS content. The effects of milling time and milling ball size were also investigated. No significant reduction in drug crystallinity was observed under the investigated milling conditions according to XRD data. For the dissolution study, we used an open-loop USP4 dissolution apparatus, and recorded dissolution profiles were fitted according to the Weibull model. The Weibull parameters and a novel criterion — surface utilization factor — were used to evaluate and discuss the drug release from the perspective of drug particle surface changes throughout the dissolution process. The most effective co-milling results were achieved using smaller balls (2 mm), with a co-milling time of up to 15 min SLS content of up to 15 wt.% to increase the dissolution rate by approximately 100 times relative to the physical mixture reference. The results suggest that for hydrophobic drugs, particle performance during dissolution is very sensitive to surface properties and not only to particle size. Co-milling with SLS prepares the surface for faster drug release than that achieved with direct mixing.

– Maziar Kakhi April 2009

The fluid dynamics in the flow-through cell (USP apparatus 4) has been predicted using the mathematical modeling approach of computational fluid dynamics (CFD). The degree to which flow structures in this apparatus can be qualified as ‘ideal’ both spatially and temporally has been assessed. The simulations predict the development of the velocity field in this apparatus for configurations with and without beads during the discharge stroke of the pump. When the cell is operated only with the red ruby bead (‘open column’ mode), highly nonuniform flow is predicted just downstream of the bead in the latter stages of the pump’s pulse. In contrast, a strong degree of profile uniformity and symmetry is predicted throughout the entire pulse in the region of the tablet holder for both standard configurations involving beads. However, noticeable differences in the tablet shear stress distribution are predicted at times when the same instantaneous inlet flow rates are being pumped through the apparatus. This effect is caused by flow separation in the velocity boundary layer formed around the tablet under the influence of an adverse pressure gradient, an effect not predicted with constant (non-pulsating) flow. While the degree of tablet erosion correlates with the average flow rate, during a particular pulse both the free-stream velocity and the boundary layer thickness are also influential.

– Deirdre D'Arcy et al. November 2009

Purpose. To simulate the hydrodynamics in the flow-through (USP 4) dissolution apparatus and investigate the effects of hydrodynamics on mass transfer in a low velocity pulsing flow. Methods. Computational fluid dynamics (CFD) was used to simulate the hydrodynamics and mass transfer in pulsing flow. Experimental flow visualisation was used to qualitatively confirm simulated hydrodynamic and mass transfer features. The experimental dissolution rate at 8 ml min−1 (22.6 mm flow-through cell) was compared to the experimental dissolution rate in a free convection system. Results. Simulations revealed periods of low velocity at all flow rates, evidence of boundary layer separation, and, at higher flow rates, residual fluid motion during zero inlet velocity periods. Thesimulated diffusion boundary layer thickness varied in certain regions over the course of the pulse. The experimental dissolution rate in the free convection system was faster than that at 8 ml min−1 in the flow-through apparatus. Conclusions. A low velocity pulsing flow running counter to gravity inhibited the experimental dissolution rate compared to that in a free convection system. From the CFD simulations generated, simulation of both hydrodynamics and species transfer is recommended to characterise the influence of hydrodynamics on dissolution in a low velocity pulsing flow.

– Deirdre D'Arcy et al. July 2011

The aim of this investigation was to evaluate the effect of solubility and related solution density gradients, on hydrodynamics and dissolution rate in a low velocity pulsing flow, in the USP 4 flow-through dissolution apparatus. The paddle apparatus, flow-through apparatus and a free convection system were used in dissolution testing, using benzoic acid (BA) and lactose monohydrate (LM), representing slightly and freely soluble model compounds, respectively. A flow rate of 8 ml min−1 (22.6 mm diameter cell) was used in the flow-through apparatus. Computational fluid dynamics (CFD) simulations were used to analyze the effect of the dissolved compounds on local hydrodynamics. A higher dissolution rate of both BA and LM was obtained in the free convection system compared to the flow-through apparatus, with highest dissolution rate from both compounds in the paddle apparatus. The effect of downward flow arising from natural convection had a significant effect for the more soluble compound, LM, on local fluid velocities, whereas flow reversal induced by the forced convection environment was a significant feature impacting on the hydrodynamics in the BA species transfer simulation. The effect of solution density on local hydrodynamics needs to be considered when selecting dissolution conditions in the USP 4 dissolution apparatus.

– Deirdre D'Arcy et al. July 2010

Accurate mechanistic modelling of a complex system requires insight into the process being simulated, in addition to a theoretical ‘first-principles’ approach. The current work uses a numerical mechanistic model to simulate dissolution of a particulate system in the flow-through dissolution apparatus. A shadowgraph imaging method is also used to monitor the dissolution process, providing real-time estimates of particle motion, number and total dissolution time. Experimental dissolution studies of ibuprofen particles are used to assess the accuracy of the model. The numerical model adequately predicts the ibuprofen particle dissolution rate at 16 mL min−1. Parameter sensitivity analysis identified dissolution test circumstances requiring more, or less, accuracy in the particle size and density calculations. The shadowgraph imaging method successfully determined the total dissolution time and decreasing particle numbers over time. The images confirmed the pulsing particle motion of the numerical model but revealed some more complex velocity patterns, assisting numerical model development. Further optimisation of the sampling window is required to capture all relevant particle motion and changing particle size distribution. A mechanistic model can successfully simulate particulate dissolution in the flow-through apparatus, and when used along with shadowgraph imaging, can give valuable insight into the dissolution process mechanisms and environment.

– Jin Xu et al. November 2020

Adopting a “prediction-then-validation” strategy for the development of oral ER formulations. Instead of the traditional approach using multiple ER formulations for IVIVC development, an enteric-coated fast release formulation was successfully utilized for the development of a biopredictive tool to estimate the drug release from enteric coated polymeric ER formulations in the intestine. A TS1 (time scale factor between Tvitro and Tvivo equals to 1) system was designed and developed, based on which the in vivo pharmacokinetic (PK) performance of ER formulations in dog and in human were well predicted prior to in vivo evaluations. The model further passed a posteriori validation using the criteria for level A IVIVC and, as designed, provided a Tscale value of 1 for the IVIVC model.

– Mel Merciadez et al. November 2011

A sensitive and robust method for the determination of the elution of an active drug substance, sirolimus, from drug-eluting coronary stents was developed using a USP Apparatus 4 elution system. The closed-loop configuration of the elution apparatus and the small volume of eluent allow the low drug levels that elute from a single stent to be reproducibly monitored. The in vitro elution profile obtained from USP Apparatus 4 over 24 h mirrors the 30-day in vivo porcine profile, providing an in vitro release method that captures the entire in vivo release profile of the stent in a shorter time. This method discriminates between common manufacturing and formulation product defects that were intentionally made. The method employs a novel elution medium containing an organic solvent, which allowed the in vitro elution curve to be fit to the in vivo porcine profile. The method has been accepted by the FDA as a release method for the elution of sirolimus or rapamycin in cardiovascular stents.

– Upkar Bhardwaj et al. January 2010

A novel dialysis adapter has been developed for USP apparatus 4 for in vitro release testing of dispersed system dosage forms. This USP apparatus 4 method was optimized and compared with currently used dialysis and reverse dialysis sac methods. Optimization studies for the USP apparatus 4 method showed that release from solution, suspension and liposome formulations was not flow rate limited and was not affected by change in the dialysis adapter sample volume from 250l to 500l. The USP apparatus 4 method could discriminate between solution, suspension and liposome formulations of dexamethasone. On comparing the different methods, only the USP apparatus 4 method provided discrimination between dexamethasone release from extruded and nonextruded liposomes, as well as among non-extruded DMPC, DPPC and DSPC liposomes. The dialysis sac method could not discriminate between the release profiles of non-extruded DMPC and DPPC liposomes. The reverse dialysis sac could not discriminate between the release profiles of extruded and non-extruded DMPC liposomes. In addition, the USP apparatus 4 method provided the highest release and the smallest variation in the data. This novel adapter might address the problem of the lack of a compendial apparatus for in vitro release testing of dispersed system dosage forms.

– Yulia Maslii et al. October 2020

The physicochemical properties, especially pH value of dental medicines, have significant influence on the health of oral cavity tissues. The pH of formulations should correspond to the value of saliva pH (5.5–8.0). For carbomer-based gels, the required pH value is obtained by neutralizing them with alkaline components, which leads to their structuring (thickening). This affects the physical properties of the gel, its residence time at the application site and the rate of release of active pharmaceutical ingredient. Therefore, the main purpose of this study is to evaluate the rheological, textural, and biopharmaceutical properties of Carbomer Polacril® 40Pbased dental gel depending on the pH value. Evaluation of the rheological properties of gel preparations were performed by measuring the structural viscosity of the samples as a function of pH and temperature. The textural properties of the gel were evaluated by performing tests regarding back extrusion and spreadability. Carbomer Polacril® 40P-based gels haven’t shown noticeable thixotropic behavior and were characterized by plastic flow in the whole studied pH range. The structural viscosity at the selected average pH value hasn’t differed at storage (25 C) and application (37 C) temperature. Texture studies of dental gels have shown a strong correlation with rheoparameters. Their rheological behavior and textural properties haven’t changed significantly between the pH range of 5.5–6.6. The relatively narrow range of working pH values does not affect the change in the viscosity of the preparation significantly and, consequently, does not affect the release of APIs from the developed Carbomer Polacril® 40P-based dental gel.

– Debora Faria Silva et al. July 2021

Standards of care for human visceral leishmaniasis (VL) are based on drugs used parenterally, and oral treatment options are urgently needed. In the present study, a repurposing strategy was used associating tamoxifen (TMX) with polyethylene glycol-block-polylactide nanocapsules (NC) and its anti-leishmanial efficacy was reported in vivo. Stable surface modified-NC (5 mg/mL of TMX) exhibited 200 nm in size, +42 mV of zeta potential, and 98% encapsulation efficiency. Atomic force microscopy evidenced core-shell-NC. Treatment with TMX-NC reduced parasite-DNA quantified in liver and spleen compared to free-TMX; and provided a similar reduction of parasite burden compared with meglumine antimoniate in mice and hamster models. Image-guided biodistribution showed accumulation of NC in liver and spleen after 30 min post administration. TMX-NC reduced the number of liver granulomas and restored the aspect of capsules and trabeculae in the spleen of infected animals. TMX-NC was tested for the first time against VL models, indicating a promising formulation for oral treatment.

– Cherng-Yih Perng et al. September 2002

SB-247083 is a potent, nonpeptidic, orally active, ETA-selective, endothelin receptor antagonist. The diacid form and three salts (monoarginine, diarginine and disodium) of SB-247083 were evaluated during the pre-clinical phase of development. The developability attributes (i.e., hygroscopicity, thermal behavior, aqueous solubility, 
and drug excipient compatibility) of these compounds were evaluated. In addition to these attributes, the flowthrough cell (FTC) dissolution testing (using USP Apparatus 4) was used as a screening technique to evaluate several SB-247083 formulations of the diacid and its salts. FTC dissolution testing offers two distinct advantages over the more traditional static-condition dissolution testing: (1) maintenance of sink conditions; and (2) the ability to change the dissolution medium during a dissolution run. The former advantage is especially important for poorly aqueous soluble drugs having associated dissolution-rate-limitations, and the latter advantage allows one to more closely simulate the pH gradient associated with transit through the GI tract. Based on the comparative dissolution data, three formulations were chosen for oral dosing in dogs. The reasonable correlation found between the FTC dissolution results and the oral bioavailability data demonstrate that FTC dissolution testing can be a valuable tool for aiding in salt (solid-state form) and formulation selection in the early stages of development of drug candidates.

– Aude Pestieau et al. April 2016

Fenofibrate, a BCS class II compound, has a low bioavailability especially when taken orally on an empty stomach. The challenge to find a new formulation for providing bioavailability, independent of food, is still ongoing. If the development of a suitable oral delivery formulation of BCS class II compounds is a frequent and great 
challenge to formulation scientists, the in vitro evaluation of these new formulations is also a great challenge. The purpose of this study was therefore to select an in vitro dissolution test that would be useful and as biorelevant as possible for the development of fenofibrate self-emulsifying lipid-based formulations. In this context, three different fenofibrate formulations, for which in vivo data are available in the literature, were tested using different dissolution tests until we found the one that was the most suitable. As part of this approach, we started with the simplest in vitro dissolution tests and progressed to tests that were increasingly more complex. The first tests were different single phase dissolution tests: a test under sink conditions based on the USP monograph, and different tests under non-sink conditions in non-biorelevant and biorelevant media. Given the inconclusive results obtained with these tests, biphasic dissolution systems were then tested: one with USP apparatus type II alone and another which combined USP apparatus types II and IV. This last combined test seemed the most suitable in vitro dissolution test for the development of the future fenofibrate lipid-based formulations we intend to develop in our own laboratory.

– Vibeke Hougaard Sunesen et al. November 2004

The purpose of the study was to design dissolution tests that were able to distinguish between the behaviour of danazol under fasted and fed conditions, by using biorelevant media. In vitro dissolution of 100 mg danazol capsules was performed using the flow-through dissolution method. Flow rates were 8, 16 or 32 ml/min, corresponding to total volumes dissolution medium of 960, 1920 and 3840 ml, respectively. The media used contained bile salt and phospholipid levels relevant for either fasted or fed conditions in vivo. Crude and inexpensive bile components, Porcine Bile Extract and soybean phospholipids, were used as the bile source. The effect of adding different concentrations and molar ratios of monoglycerides and fatty acids to the fed state media was investigated. In vivo release profiles under fasted and fed conditions were obtained from a previous study by deconvolution [Sunesen, V.H., Vedelsdal, R., Kristensen, H.G., Christrup, L., Müllertz, A. 2005.Effect of liquid volume and food intake on the absolute bioavailability of danazol, a poorly soluble drug, Eur. J. Pharm. Sci. 24, 297–303].In the fasted state, the physiologically most relevant correlation with in vivo results was achieved with a medium containing 6.3mM bile salts and 1.25mM phospholipids (8 ml/min). A medium containing 18.8mM bile salts, 3.75mM phospholipids, 4.0mM monoglycerides and 30 mM fatty acids (8 ml/min) gave the closest correlation with fed state in vivo results. By using the flow-through dissolution method it was possible to obtain correlations with in vivo release of danazol under fasted and fed conditions. Both hydrodynamics and medium composition were important for the dissolution of danazol. In the fed state an IVIVC could only be obtained by including monoglycerides and fatty acids in the medium.

– Angela Effinger et al. October 2020

Objectives: Drug product performance might be affected in Crohn’s disease (CD) patients compared to healthy subjects due to pathophysiological changes. Since a low number of clinical studies is performed in this patient population, physiologically-based pharmacokinetic (PBPK) models with integrated results from biorelevant in vitro dissolution studies could be used to assess differences in the bioavailability of drugs. Using this approach, budesonide was used as model drug and its performance in healthy subjects and CD patients was predicted and compared against observed pharmacokinetic data. The in vitro release tests, under healthy versus CD conditions, revealed a similar extent of drug release from a controlled-release budesonide formulation in the fasted state, whereas in the fed state a lower extent was observed with CD. Differences in the physiology of CD patients were identified in literature and their impact on budesonide performance was investigated with a PBPK model, revealing the highest impact on the simulated bioavailability for the reduced hepatic CYP3A4 enzyme abundance and lower human serum albumin concentration. For CD patients, a higher budesonide exposure compared to healthy subjects was predicted with a PBPK population adapted to CD physiology and in agreement with observed pharmacokinetic data. Budesonide performance in the fasted and fed state was successfully predicted in healthy subjects and CD patients using PBPK modeling and in vitro release testing. Following this approach, predictions of the direction and magnitude of changes in bioavailability due to CD could be made for other drugs and guide prescribers to adjust dosage regimens for CD patients accordingly.

– Agathe Thouvenin et al. September 2022

(S)-ketamine presents potential for the management of acute pain and, more specifically, for the prevention of pain associated with care. However, the administration route can be a source of pain and distress. In this context, a smart formulation of (S)-ketamine was designed for buccal administration. The combination of poloxamer 407 and sodium alginate enables increased contact with mucosa components (mucins) to improve the absorption of (S)-ketamine. In this study, rheological studies allowed us to define the concentration of P407 to obtain a gelling temperature around 32 C. Mucoadhesion tests by the synergism method were carried out to determine the most suitable alginate among three grades and its quantity to optimize its mucoadhesive properties. Protanal LF 10/60 was found to be the most effective in achieving interaction with mucins in simulated saliva fluid. P407 and alginate concentrations were set to 16% and 0.1%. Then, the impact of P407 batches was also studied and significant batch-to-batch variability in rheological properties was observed. However, in vitro drug release studies demonstrated that this variability has no significant impact on the drug release profile. This optimized formulation has fast release, which provides potential clinical interest, particularly in emergencies.

– Jing Li et al. December 2019

Human immunodeficiency virus (HIV) infection and unintended pregnancy, which can lead to life-threatening complications, are two major burdens for female reproductive health. To address these pressing health issues, multipurpose prevention technologies (MPTs) are proposed to deliver two or more drugs simultaneously. MPTs could over several benefits for users such as improved convenience, increased effectiveness, reduced cost, and decreased environmental burden. Here, we report the development, and in vitro and in vivo assessment of a bioadhesive vaginal film as a coitally-independent MPT dosage form for delivering dapivirine (DPV) and levonorgestrel (LNG) to prevent HIV infection and unintended pregnancy, respectively. After confirming the feasibility of bioadhesive film use for weekly drug delivery in vivo through colpophotography and MRI evaluation, the pharmacokinetics (PK) of DPV/LNG single entity and combination bioadhesive films was investigated in pigtailed macaques (n = 5). Both drugs from single entity or combination films were able to provide sustained drug release in vivo. The combination film showed lower local tissue clearance for DPV and exhibited significantly increased plasma concentration for LNG as compared to the single entity film. This proof-of-concept study demonstrates the ability of this novel bioadhesive film platform to deliver LNG and DPV simultaneously as an MPT product for the prevention of HIV infection and unintended pregnancy.

– Vladyslav Vivcharenko et al. May 2020

The treatment of chronic wounds is still a meaningful challenge to physicians. The aim of this work was to produce vitamin C-enriched chitosan/agarose (CHN/A) film that could serve as potential artificial skin substitute for chronic wound treatment. The biomaterial was fabricated by a newly developed and simplified method via mixing acidic chitosan solution with alkaline agarose solution that allowed to obtain slightly acidic pH (5.97) of the resultant material, which is known to support skin regeneration. Vitamin C was immobilized within the matrix of the film by entrapment method during production process. Produced films (CHN/A and CHN/A + vit C) were subjected to comprehensive evaluation of cellular response with the use of human skin fibroblasts, epidermal keratinocytes, and macrophages. It was demonstrated that novel biomaterials support adhesion and growth of human skin fibroblasts and keratinocytes, have ability to slightly reduce transforming growth factor-beta 1 (TGF1) (known to be present at augmented levels in the epidermis of chronic wounds), and increase platelet-derived growth factor-BB (PDGF-BB) secretion by the cells. Nevertheless, addition of vitamin C to the biomaterial formulation does not significantly improve its biological properties due to burst vitamin release profile. Obtained results clearly demonstrated that produced CHN/A film has great potential to be used as cellular dermal, epidermal, or dermo-epidermal graft pre-seeded with human skin cells for chronic wound treatment

– Eric Beyssac et al. May 2005

The flow through system has been employed for many years in the testing of different dosage forms such as tablets and capsules. The flow through cell is the method of choice for extended release and poorly soluble products. Thanks to the specific powder cell it is possible to characterize a drug substance with respect to its rate of dissolution. The aim of this work was to compare the biopharmaceutical properties of different batches of a drug substance using the dissolution rate determined using the flow-through apparatus. The apparatus consists of a reservoir of dissolution medium, a pump that forces the dissolution medium upwards through the flow-through cell and a cell specifically designed for powders, mounted vertically with a filter system preventing escape of undissolved particles. In the flow-through method the test sample is located in a small-volume cell through which solvent passes at a temperature of 37 °C. Five batches of theophylline with a mean diameter of 128 μm to 673 μm and two batches of acetylsalicylic acid, either fine particles or needles, were studied. The experiment was conducted using six cells in an open system. Through the results obtained, the relationship between particle size distribution and dissolution rate has been verified. The rate of dissolution is faster for drug with low particle size and a higher surface area. The experimental parameters such as flow rate have been studied and optimized. The overall results demonstrate that it is possible to characterize the biopharmaceutical qualities of active pharmaceutical ingredients using the flow-through cell. The method is reliable, reproducible and discriminating. It can easily be used to compare drugs with different particle size distributions.

– Dolores R. Serrano et al. July 2015

Objectives Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4-aminosalicylic acid (4-ASA), combined with changes in the crystal habit can favourably alter its physicochemical properties. The aim of this work was to engineer SDM : 4-ASA cocrystals with different habits to investigate the effect on dissolution, and the derived powder properties of flow and compaction. Methods Cocrystals were prepared in a 1 : 1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray drying (habit IV). Key findings Powder X-ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large plate-like crystals (habit II), small cube like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr’s compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties. Conclusions Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behaviour.

– Namita P. Tipnis et al. February 2020

The main objective of the current research was to develop a compendial flow-through cell apparatus based in vitro release testing method for sustained-release triamcinolone acetonide–loaded poly (lactic-co-glycolic) acid (PLGA) microspheres. Media-based and instrument-based parameters, such as surfactant type, concentration, media volume, flow rate, and testing temperature, were investigated. In addition, a detailed exploration was performed to reveal polymer degradation encompassing pore formation, channeling, and triamcinolone acetonide release from microspheres using freeze-fracture scanning electron microscopy. The developed USP apparatus 4 method demonstrated more than 85% drug release from the microspheres in 12 days and showcased reproducibility between different microsphere batches. Large medium volume (15 times saturation solubility) at low surfactant concentration was identified as a critical media-based parameter, with potential application in testing of other sensitive poorly soluble drugs. At 35 °C, drug release via pore channeling to the surface was evident, whereas at 39 °C, drug release slowed due to polymer plasticization. It was demonstrated here for the first time that elevated temperature-accelerated testing does not work for all PLGA-based microsphere products.

– Ivana Tomic et al. March 2016

The objective of this study was development of accelerated in vitro release method for peptide loaded PLGA microspheres using flow-through apparatus and assessment of the effect of dissolution parameters (pH, temperature, medium composition) on drug release rate and mechanism. Accelerated release conditions were set as pH 2 and 45 °C, in phosphate buffer saline (PBS) 0.02 M. When the pH was changed from 2 to 4, diffusion controlled phases (burst and lag) were not affected, while release rate during erosion phase decreased two-fold due to slower ester bonds hydrolyses. Decreasing temperature from 45 °C to 40 °C, release rate showed threefold deceleration without significant change in release mechanism. Effect of medium composition on drug release was tested in PBS 0.01 M (200 mOsm/kg) and PBS 0.01 M with glucose (380 mOsm/kg). Buffer concentration significantly affected drug release rate and mechanism due to the change in osmotic pressure, while ionic strength did not have any effect on peptide release. Furthermore, dialysis sac and sample-and-separate techniques were used, in order to evaluate significance of dissolution technique choice on the release process. After fitting obtained data to different mathematical models, flow-through method was confirmed as the most appropriate for accelerated in vitro dissolution testing for a given formulation.

– Archana Rawat et al. August 2011

The current manuscript addresses the need for a validated in vitro release testing method for controlled release parenteral microspheres. A USP apparatus 4 method was validated with the objective of possible compendial adaptation for microsphere in vitro release testing. Commercial microspheres (Risperdal® Consta®) were used for method validation. Accelerated and real-time release tests were conducted. The accelerated method had significantly reduced test duration and showed a good correlation with the real-time release profile (with limited number of sample analysis). Accelerated conditions were used for method validation (robustness and reproducibility). The robustness testing results revealed that release from the microspheres was not flow rate dependent and was not affected by minor variations in the method (such as cell preparation technique, amount of microspheres, flow-through cell size and size of glass beads). The significant difference in the release profile with small variations (±0.5 °C) in temperature was shown to be due to a change in risperidone catalyzed PLGA degradation in response to temperature. The accelerated method was reproducible as changing the system/equipment or the analyst did not affect the release profile. This work establishes the suitability of the modified USP apparatus 4 for possible compendial adaptation for drug release testing of microspheres.

– Jie Shen et al. September 2015

The objective of the present study was to determine whether an in vitro-in vivo correlation (IVIVC) can be established for polymeric microspheres that are equivalent in formulation composition but prepared with different manufacturing processes. Risperidone was chosen as a model therapeutic and poly(lactic-co-glycolic acid) (PLGA) with similar molecular weight as that used in the commercial product Risperdal® Consta® was used to prepare risperidone microspheres. Various manufacturing processes were investigated to produce the risperidone microspheres with similar drug loading (approx. 37%) but distinctly different physicochemical properties (e.g. porosity, particle size and particle size distribution). In vitro release of the risperidone microspheres was investigated using different release testing methods (such as sample-and-separate and USP apparatus 4). In vivo pharmacokinetic profiles of the risperidone microsphere formulations following intramuscular administration were determined using a rabbit model. Furthermore, the obtained pharmacokinetic profiles were deconvoluted using the Loo–Riegelman method and the calculated in vivo release was compared with the in vitro release of these microspheres. Level A IVIVCs were established and validated for the compositionally equivalent risperidone microspheres based on the in vitro release data obtained using USP apparatus 4. The developed IVIVCs demonstrated good predictability and were robust. These results showed that the developed USP apparatus 4 method was capable of discriminating PLGA microspheres that are equivalent in formulation composition but with manufacturing differences and predicting their in vivo performance in the investigated animal model.

– Jie Shen et al. December 2015

The objective of the present study was to develop a discriminatory and reproducible accelerated in vitro release method for long-acting PLGA microspheres with inner structure/porosity differences. Risperidone was chosen as a model drug. Qualitatively and quantitatively equivalent PLGA microspheres with different inner structure/porosity were obtained using different manufacturing processes. Physicochemical properties as well as degradation profiles of the prepared microspheres were investigated. Furthermore, in vitro release testing of the prepared risperidone microspheres was performed using the most common in vitro release methods (i.e., sampleand-separate and flow-through for this type of product. The obtained compositionally equivalent risperidone microspheres had similar drug loading but different inner structure/porosity. When microsphere particle size appeared similar, porous risperidone microspheres showed faster microsphere degradation and drug release compared with less porous microspheres. Both in vitro release methods investigated were able to differentiate risperidone microsphere formulations with differences in porosity under real-time (37 °C) and accelerated (45 °C) testing conditions. Notably, only the accelerated USP apparatus 4 method showed good reproducibility for highly porous risperidone microspheres. These results indicated that the accelerated USP apparatus 4 method is an appropriate fast quality control tool for long-acting PLGA microspheres (even with porous structures).

– Archana Rawat et al. February 2011

The objective was to develop an in vitro release method for protein loaded poly(lactide-co-glycolide) (PLGA) microspheres. A modified USP apparatus 4 and sample and separate methods were compared using a microsphere formulation encapsulating a model protein, bovine serum albumin (BSA). Microsphere characteristics such as porosity, drug loading, particle size and burst release were significantly affected by the formulation parameters (i.e., phase ratio, internal aqueous phase composition and theoretical drug loading). Incomplete release of BSA was observed using the sample and separate method and this was attributed to microsphere loss during sampling. This problem was overcome using the modified USP apparatus 4 method. However, an unusual decrease in cumulative percent release was observed which was considered to be due to BSA adsorption onto the hydrophobic surfaces of the modified USP apparatus 4. Addition of SDS to the release media prevented BSA adsorption and a zero order release profile was observed. The presence of SDS did not change the microsphere degradation kinetics. The results indicate the importance of understanding protein adsorption and aggregation behavior during in vitro release testing. The USP apparatus 4 method appears to be useful for investigation of in vitro release of protein loaded microspheres.

– Janki Andhariya et al. March 2017

Establishment of in vitro-in vivo correlations (IVIVCs) for parenteral polymeric microspheres has been very challenging, due to their complex multiphase release characteristics (which is affected by the nature of the drug) as well as the lack of compendial in vitro release testing methods. Previously, a Level A correlation has been established and validated for polymeric microspheres containing risperidone (a practically water insoluble small molecule drug). The objectives of the present study were: 1) to investigate whether a Level A IVIVC can be established for polymeric microspheres containing another small molecule drug with different solubility profiles compared to risperidone; and 2) to determine whether release characteristic differences (bi-phasic vs tri-phasic) between microspheres can affect the development and predictability of IVIVCs. Naltrexone was chosen as the model drug. Three compositionally equivalent formulations of naltrexone microspheres with different release characteristics were prepared using different manufacturing processes. The critical physicochemical properties (such as drug loading, particle size, porosity, and morphology) as well as the in vitro release characteristics of the prepared naltrexone microspheres and the reference-listed drug (Vivitrol®) were determined. The pharmacokinetics of the naltrexone microspheres were investigated using a rabbit model. The obtained pharmacokinetic profiles were deconvoluted using the Loo-Riegelman method, and compared with the in vitro release profiles of the naltrexone microspheres obtained using USP apparatus 4. Level A IVIVCs were established and validated for predictability. The results demonstrated that the developed USP 4 method was capable of detecting manufacturing process related performance changes, and most importantly, predicting the in vivo performance of naltrexone microspheres in the investigated animal model. A critical difference between naltrexone and risperidone loaded microspheres is their respective bi phasic and tri-phasic release profiles with varying burst release and lag phase. These variations in release profiles affect the development of IVIVCs. Nevertheless, IVIVCs have been established and validated for polymeric microspheres with different release characteristics.

– Banu Zolnik et al. May 2005

The objective of this study was to determine the applicability of USP Apparatus 4 and in situ fiber optic UV analysis to in vitro release testing of poly (lactic-co-glycolic acid) (PLGA) microspheres. The release of dexamethasone from microspheres prepared with both high and low Mw PLGA was evaluated. Dexamethasone release profiles obtained using USP apparatus 4 were compared with those obtained using a sample-and-separate method. Cumulative release obtained using USP Apparatus 4 was approximately 16% higher over a 30-day period when compared to that obtained using the sample-and-separate method. This difference was attributed to loss of microspheres during separation as well as to microsphere aggregation in the sample-andseparate method. The versatility of USP Apparatus 4 with respect to alteration of flow rate allowed demonstration of diffusion-controlled release from low Mw PLGA microspheres. Fiber optic UV probes used in conjunction with USP Apparatus 4 enabled complete characterization of the initial burst release of drug from the microsphere systems.

– Banu Zolnik et al. February 2006

Drug release from four different poly(lactic-co-glycolic) acid (PLGA) microsphere formulations was evaluated under “real-time” (37 °C) and accelerated release testing conditions of elevated temperature (45, 53, 60 and 70 °C) and increase in flow rate (4–35 ml/min) using United States Pharmacopeia (USP) apparatus 4. Formulation 5 K (composed of low Mw PLGA) exhibited diffusion-controlled kinetics in “real-time”. Whereas, formulations 25 K, 28 K and 70 K (composed of medium and high Mw PLGA) followed erosion-controlled kinetics at 37 °C. Temperature induced degradation of the microspheres was studied by monitoring drug release rates, change in molecular weight and morphological changes. Drug release rates at elevated temperature were used to predict “real-time” release applying the Arrhenius equation. The energy of activation for dexamethasone release from PLGA microspheres was calculated as 19.14 kcal/mol. Molecular weight change measured by gel permeation chromatography followed first order kinetics for both “real-time” and accelerated release. All four formulations exhibited morphological changes (such as surface pore closing and geometry change) at elevated temperature with consequent reduction in burst release.

– Banu Zolnik et al. May 2007

Polymer degradation and drug release kinetics from PLGA microspheres were investigated under neutral and acidic pH conditions. Two different Mw formulations (Mw: 25,000 and 70,000) were investigated and both exhibited a triphasic release profile at pH 7.4 as well as at pH 2.4. The initial burst and lag phases were similar for both pH values, while the secondary apparent-zero-order phase was substantially accelerated atpH 2.4. The polymer molecular weight change with time for the microspheres followed first order degradation kinetics for both pH values. A linear relationship was established between % drug release (post burst release) and Ln (Mw) for both pH conditions. Most significantly, morphological studies showed that the mechanism of polymer degradation changed from “inside-out” degradation at pH 7.4 to “outside-in” at pH 2.4. At pH 7.4, the microspheres followed the usual morphological changes such as surface pitting and pore formation. Whereas, at pH 2.4 the microspheres maintained smooth surfaces throughout the degradation process and were susceptible to fracturing. The fracturing of the microspheres was attributed to crystallization of oligomeric degradation products as a consequence of their low solubility at this pH. It also appeared that degradation occurred in a more homogeneous pattern at pH 2.4 than is typical of PLGA microspheres at pH 7.4. This may be a result of the entire microspheres experiencing a close-to-uniform pH at 2.4. However, at pH 7.4, the local micro-environmental pH within the microspheres has been reported to vary considerably due to a build up of acid oligomers. This heterogeneous degradation results in the random formation of channels within microspheres degraded at pH 7.4 which was not observed in those degraded at pH 2.4. This is the first time that morphological changes during PLGA microsphere degradation have been compared for low and neutral pH and the data shows a change in the mechanism of degradation at the low pH.

– Sravan Kumar Patel et al. January 2021

Currently, there is no compendial-level method to assess dissolution of particulate systems administered in the periodontal pocket. This work seeks to develop dissolution methods for extended release poly(lactic-co-glycolic acid) (PLGA) microspheres applied in the periodontal pocket. Arestin®, PLGA microspheres containing minocycline hydrochloride (MIN), is indicated for reduction of pocket depth in adult periodontitis. Utilizing Arestin® as a model product, two dissolution methods were developed: a dialysis set-up using USP apparatus 4 and a novel apparatus fabricated to simulate in vivo environment of the periodontal pocket. In the biorelevant method, the microspheres were dispersed in 250 μL of simulated gingival crevicular fluid (sGCF) which was enclosed in a custom-made dialysis enclosure. sGCF was continuously delivered to the device at a biorelevant flow rate and was collected daily for drug content analysis using UPLC. Both methods could discriminate release characteristics of a panel of MIN-loaded PLGA microspheres that differed in composition and process conditions. A mechanistic model was developed, which satisfactorily explained the release profiles observed using both dissolution methods. The developed methods may have the potential to be used as routine quality control tools to ensure batch-to-batch consistency and to support evaluation of bioequivalence for periodontal microspheres.

– Ritu Gupta et al. November 2022

In vitro drug release testing is an important quality control tool for formulation development. However, the literature has evidence that poly-lactide-co-glycolide (PLGA)-based formulations show a slower in vitro drug release than a real in vivo drug release. Much longer in vitro drug release profiles may not be reflective of real in vivo performances and may significantly affect the timeline for a formulation development. The objective of this study was to develop a surfactant mediated accelerated in vitro drug release method for the PLGA nanoparticles (NPs) of a novel chemotherapeutic agent AC1LPSZG, a model drug with a poor solubility. The Sotax USP apparatus 4 was used to test in vitro drug release in a phosphate buffer with a pH value of 6.8. The sink conditions were improved using surfactants in the order of sodium lauryl sulfate (SLS) < Tween 80 < cetyltrimethylammonium bromide (CTAB). The dissolution efficiency (DE) and area under the dissolution curve (AUC) were increased three-fold when increasing the CTAB concentration in the phosphate buffer (pH 6.8). Similar Weibull release kinetics and good linear correlations (R2~0.99) indicated a good correlation between the realtime in vitro release profile in the phosphate buffer (pH 6.8) and accelerated release profiles in the optimized medium. This newly developed accelerated and discriminatory in vitro test can be used as a quality control tool to identify critical formulation and process parameters to ensure a batch-to-batch uniformity. It may also serve as a surrogate for bioequivalence studies if a predictive in vitro in vivo correlation (IVIVC) is obtained. The results of this study are limited to AC1LPSZG NPs, but a similar consideration can be extended to other PLGA-based NPs of drugs with similar properties and solubility profiles.

– Lalinthip Sutthapitaksakul et al. July 2021

The objective of this research was to optimize the tasted-masked microparticles for orally disintegrating tablets containing donepezil hydrochloride using quality risk assessment and design of experiment approaches. The double emulsion solvent evaporation technique using amino alkyl methacrylate copolymer (AMC) was used to prepare taste-masked microparticles. Factors affecting the quality of the taste-masked microparticles were analyzed using an Ishikawa diagram. A risk ranking approach was used to rank the formulation and process risks. Furthermore, the effect of AMC quantity, stirring time, and volume of outer water phase on various responses, such as particle size, the amount of drug dissolved at 5 min (Q5) in simulated saliva fluid, and mean dissolution time (MDT) in simulated gastric fluid, was investigated using the Box-Behnken design. The optimized microparticles were then used to prepare orally disintegrating tablets (ODTs) and evaluated by in vitro and in vivo testing. The results demonstrated that particle size was influenced by the AMC amount and stirring time. Q5 was significantly affected by the amount of AMC and the volume of the outer water phase. On the other hand, these two factors had a positive effect on MDT. The optimized microparticles had a particle size of 174.45 18.19 m, Q5 of 5.04%, and MDT of 5.97 min. The ODTs with taste-masked microparticles showed acceptable in vitro dissolution with an MDT of 5 min. According to the results of a panel of six human volunteers, they greatly improved palatability.

– C.J. Andreas et al. July 2018

The EU research initiative OrBiTo (oral biopharmaceutics tools) involving partners from academia, pharmaceutical industry, small medium enterprises and a regulatory agency was launched with the goal of improving tools to predict the absorption of drugs in humans and thereby accelerating the formulation development process. The OrBiTo project was divided into four work packages (WP), with WP2 focusing on characterization of drug formulations. The present work introduces the OrBiTo WP2 Decision Tree, which is designed to assist the investigator in choosing the most appropriate in vitro methods for optimizing the oral formulation design and development process. The WP2 Decision Tree consists of four stages to guide the investigator. At the first stage, the investigator is asked to choose the formulation type of interest. At the second stage, the investigator is asked to identify which type of equipment (compendial/modified/noncompendial) is preferred/available. At the third stage, characteristics of the active pharmaceutical ingredient (API) are evaluated and in the fourth stage of the decision tree, suitable experimental protocols are recommended. A link to the living Decision Tree document is provided, and we now invite the pharmaceutical sciences community to apply it to current research and development projects and offer suggestions for improvement and expansion.

– Willian C. Smith et al. May 2021

Injectable suspensions occasionally exhibit variations in dissolution and bioavailability, which may impact the clinical outcome of the drug product. Here, variation in the injection method (i.e., applied shear) for triamcinolone acetonide (TA) injectable suspension (40 mg/mL) altered the flocculation state of the particles and subsequently their dissolution. Notably, TA suspensions contained primary particles of approximately 2 μm and secondary flocculates of tens of microns. The conversion between flocculated and deflocculated particles was rapid, reversible and highly shear dependent. As such, changing shear rates during laser diffraction (LD) measurement like stirring rate, sonication, and sample introduction method (micropipette vs 25-gauge needle) may result in variability in particle size distributions (PSD) that have the potential to alter drug dissolution. Furthermore, a nonsink, discriminatory in vitro release testing (IVRT) method was developed, which combined in-situ fiber optic UV with LD to simultaneously monitor the dissolution and changing PSD of the suspension. The simultaneously measured dissolution and PSD data showed that flocculated and deflocculated particles followed different dissolution pathways. Importantly, deflocculated particles dissolved up to six times faster than the flocculated particles. Similar shear-induced changes during injection could occur in a clinical setting and have implications for drug bioavailability.

– Quanying Bao et al. May 2022

Long-acting injectable (LAI) suspensions are complex parenterals intended to control drug release over a duration of weeks to months. Any unpredictive drug release behavior may cause serious side effects. Therefore, it is important to understand the in vitro and in vivo performance, as well as the in vitro-in vivo correlation (IVIVC) of these products. There are some US FDA recommended in vitro release testing methods for LAI suspensions. However, the release duration of all the recommended methods is less than two days which may not be appropriate for the establishment of IVIVCs for LAIs considering that their in vivo efficacies range from weeks to months. To develop in vitro release testing methods that may better correlate with in vivo release with longer durations, three compositionally equivalent medroxyprogesterone acetate suspensions were prepared with different particle size, using Depo-SubQ Provera 104® as the reference listed drug (RLD). Four different methods based on USP apparatus 2 (with dialysis sacs, enhancer cells or in-house designed devices) and USP apparatus 4 (with semisolid adapters) were utilized. USP apparatus 2 with enhancer cells and USP apparatus 4 with semisolid adapters showed the best discriminatory ability and reproducibility for the LAI suspensions investigated.

– Wenmin Yuan et al. July 2016

Doxil® is a complex parenteral doxorubicin (DOX) liposome formulation approved by the FDA. For generic doxorubicin liposomes, analyzing the release profile of DOX is important for quality control and comparability studies. However, there is no robust standard drug release assay available for doxorubicin liposomes. In this study, we describe a USP-4 apparatus assay capable of discriminating DOX liposomal formulations based on release profile. Establishment of the assay was hindered by limited DOX release from liposomes in physiological conditions at 37°C. The addition of NH4HCO3 to the release media facilitated DOX release proportionally to the salt concentration added but caused precipitation of released drug in USP-4 apparatus. Precipitation of DOX was avoided by adding hydroxypropyl-cyclodextrin (HP-CD) to the release medium. We optimized conditions for DOX release by varying a number of parameters such as: concentration of HP-CD, testing temperature, and concentration of tested samples. The optimized release medium contained: 100 mM NH4HCO3, 75 mM 2-(Nmorpholino) ethane sulfonic acid (MES) and 5% w/v HP-CD, 5% w/v sucrose, 0.02% w/v NaN3 (pH 6). The drug release assay was performed at 45°C. The optimized release assay can discriminate between DOX liposomal formulations of different compositions, physicochemical properties, and prepared by different manufacturing methods. This indicates that the assay could be used to compare DOX release from generic DOX formulations to the innovator product Doxil®.

– R. Diaz de Leon-Ortega et al. Mars 2018

Guidance on dissolution testing for parenteral formulations is limited and not often related in vivo performance. Critically ill patients represent a target cohort, frequently hypoalbuminaemic, to whom certain parenteral formulations are administered. Amphotericin B (AmB) is a poorly soluble, highly protein-bound drug, available aslipidbased formulations and used in critical illness. The aim of this study was to develop media representing hypoalbuminaemic and healthy plasma, and to understand and simulate the dissolution profile of AmB in biorelevant media. Dissolution media were prepared with bovine serum albumin (BSA) in Krebs-Ringer buffer and tested in a flow-through cell apparatus and a bottle/stirrer setup. Drug activity was tested against Candida albicans. BSA concentration was positively associated with solubility, degradation rate and maximum amount dissolved and negatively associated with dissolution rate constant and antifungal activity. In the bottle/stirrer setup, a biexponential model successfully described simultaneous dissolution and degradation and increased in agitation reduced the discriminatory ability of the test. The hydrodynamics provided by the flow-through cell apparatus was not adequate to dissolve the drug. Establishing discriminating test methods with albumin present in the dissolution media, representing the target population, supports future development of biorelevant and clinically relevant tests for parenteral formulations.

– Yuri Svirkin et al. Mars 2022

Liposomal drug product have shed light on the AmB aggregation status in the bilayer, which heat treatment (curing) modifies. Although toxicity was found related to aggregation status - loose aggregates significantly more toxic than tight aggregates - the precise mechanism linking aggregation and toxicity was not well understood. This study directly measured drug release rate from various AmB liposomal preparations made with modified curing protocols to evaluate correlations among drug aggregation state, drug release, and in vitro toxicity. UVVis spectroscopy of these products detected unique curing-induced changes in the UV spectral features: a ~25 nm blue-shift of the main absorption peak (λmax) in aqueous buffer and a decrease in the OD346/OD322 ratio upon thermal curing, reflecting tighter aggregation. In vitro release testing (IVRT) data showed, by applying and fitting first-order release kinetic models for one or two pools, that curing impacts two significant changes: a 3–5-fold drop in the overall drug release rate and a ten-fold decrease in the ratio between the loosely aggregated and the tightly aggregated, more thermodynamically stable drug pool. The kinetic data thus corroborated the trend independently deduced from the UV-Vis spectral data. The in vitro toxicity assay indicated a decreased toxicity with curing, as shown by the significantly increased concentration, causing half maximal potassium release (TC50). The data suggest that the release of AmB requires dissociation of the tight complexes within the bilayer and that the reduced toxicity relates to this slower rate of dissociation. This study demonstrates the relationship between AmB aggregation status within the lipid bilayer and drug release (directly measured rate constants), providing a mechanistic link between aggregation status and in vitro toxicity in the liposomal formulations.

– R. Diaz de Leon-Ortega et al. March 2020

In vitro release testing is a useful tool for the quality control of controlled release parenteral formulations, but in vitro release test conditions that reflect or are able to predict the in vivo performance are advantageous. Therefore, it is important to investigate the factors that could affect drug release from formulations and relate them to in vivo performance. In this study the effect of media composition including albumin presence, type of buffer and hydrodynamics on drug release were evaluated on a liposomal Amphotericin B formulation (Ambisome®). A physiologically based pharmacokinetic (PBPK) model was developed using plasma concentration profiles from healthy subjects, in order to investigate the impact of each variable from the in vitro release tests on the prediction of the in vivo performance. It was found that albumin presence was the most important factor for the release of Amphotericin B from Ambisome®; both hydrodynamics setups, coupled with the PBPK model, had comparable predictive ability for simulating in vivo plasma concentration profiles. The PBPK model was extrapolated to a hypothetical hypoalbuminaemic population and the Amphotericin B plasma concentration and its activity against fungal cells were simulated. Selected in vitro release tests for these controlled release parenteral formulations were able to predict the in vivo AmB exposure,and this PBPK driven approach to release test development could benefit development of such formulations.

– Jie Tang et al. November 2018

AmBisome® is a liposomal formulation of amphotericin B (Amp B), a complex parenteral antifungal product with no US FDA approved generic version available to date. For generic Amp B liposomal product development, examination of the drug release profile is important for product quality control and analytical comparability evaluation with the reference listed drug. Yet, there is no standardized in vitro drug release (IVR) assay currently available for Amp B liposomes. In this study, we describe the development of a USP-4 apparatus-based IVR assay capable of discriminating liposomal Amp B formulations based on the drug release profile. The goal of the IVR assay development was to identify release media compositions and assay temperatures capable of facilitating 70–100% of drug release from AmBisome® in 24 h without Amp B precipitation or disruption of liposome structure. We found that an addition of 5% w/v of γ-cyclodextrin to the release media of 5% sucrose, 10mM HEPES, and 0.01% NaN3 (pH=7.4) prevented Amp B precipitation and facilitated drug release. Increased IVR assay temperature led to increased drug release rate, and 55 °C was selected as the highest temperature that induced drug release close to our target without causing product precipitation. The developed IVR assay was used to discriminate between drug release rates from AmBisome® and micellar Amp B products like Fungizone® and Fungcosome. The IVR assay was also capable of discriminating between Amp B liposomes with the same composition as AmBisome® but prepared by either extrusion or homogenization processes, both of which resulted in measurable liposomal particle size heterogeneity and Amp B concentration differences. Finally, the USP-4 IVR assay was used to compare Amp B release profiles between AmBisome® and two generic products approved in India, Amphonex® (Bharat Serums and Vaccines Ltd.) (f2=66.3) and Phosome® (Cipla Ltd.)(f2=55.4). Taken together, the developed USP-4 IVR assay can be a useful tool for drug release profile characterization in generic liposomal Amp B formulation development.

– Aleksandra V. Bukhovets et al. June 2020

Interpolymer complexes (IPC) based on Eudragit® EPO and Eudragit® S100were investigated as potential carriers for oral controlled drug delivery to the colon. IPC samples were prepared by mixing copolymer solutions in organic solvents (ethanol, isopropanol:acetone mixture (60:40, % v/v) and tetrahydrofuran). According to the data of elemental analysis, FTIR-spectroscopy, X-ray photoelectron spectroscopy and thermal analysis these IPCs have excess of anionic copolymer (Eudragit® S100) in their structure; they are stabilized by hydrogen and ionic intermacromolecular bonds and do not include free copolymer domains. IPC have pH-independent swelling properties in the media mimicking gastrointestinal tract (GIT) conditions and provide colon-specific delivery of indomethacin in buffer solutions (pH 1.2; 5.8; 6.8; 7.4) and in biorelevant media (fasted state simulated gastric fluid, fasted state simulated intestinal fluid—version 2 and fasted stated simulated colonic fluid).

– Xiaoyi Wang et al. April 2022

In situ forming implants are injectable liquid formulations which form solid or semisolid depots following injection. This allows for minimally invasive administration, localized drug delivery, and extended drug release. Unfortunately, this drug delivery strategy lacks standardized in vitro dissolution methods due to the difficulties in recreating implant formation in vitro that is biomimicry and with reproducible and controllable shape and dimensions. In the present study, an innovative, adapter-based in vitro release testing method was developed to solve this problem. Two distinctively different in situ forming implants (a risperidone formulation (suspension) consisting of PLGA dissolved in N-methyl pyrrolidone (NMP), where risperidone powder was suspended to form a drug suspension, and a naproxen formulation (solution) consisting of PLGA dissolved in NMP, where naproxen was completely dissolved to form a solution), were used as model in situ-forming implants. The results revealed that the implants formed in the custom-designed adapter with a water-dissolvable polyvinyl alcohol (PVA) film were bio-mimicking and reproducible in both shape and burst release of drug according to rabbit data. For both the suspension and solution formulations, this adapter-based in vitro release testing method resulted in consistent release data. Compared with a direct injection in vitro release testing method, the release profiles generated using the adapter-based method were capable of distinguishing the different release phases (initial release within 24 h, diffusion-facilitated release, and degradation-controlled release). In addition, the adapter-based method could discriminate formulation and dissolution apparatus changes and could be utilized to develop accelerated release testing methods. This adapter-based method has the promise of wide use in release testing of in situ forming implant formulations and has the potential to be used in the development of in vivo-predictive in vitro release methods.

– Pierre-Louis Destruel et al. April 2020

Mydriasis is required prior to many eye examinations and ophthalmic surgeries. Nowadays, phenylephrine hydrochloride (PHE) and tropicamide (TPC) are extensively used to induce mydriasis. Several pharmaceutic dosage forms of these two active ingredients have been described. However, no optimal therapeutic strategy has reached the market. The present work focuses on the formulation and evaluation of a mucoadhesive ion-activated in situ gelling delivery system based on gellan gum and hydroxyethyl cellulose (HEC) for the delivery of phenylephrine and tropicamide. First, in vitro drug release was studied to assess appropriate sustained drug delivery on the ocular surface region. Drug release mechanisms were explored and explained using mathematical modeling. Then, in situ gelling delivery systems were visualized using scanning electron microscopy illustrating the drug release phenomena involved. Afterward, cytotoxicity of the developed formulations was studied and compared with those of commercially available eye drops. Human epithelial corneal cells were used. Finally, mydriasis intensity and kinetic was investigated in vivo. Mydriasis pharmacodynamics was studied by non-invasive optical imaging on vigilant rabbits, allowing eye blinking and nasolacrimal drainage to occur physiologically. In situ gelling delivery systems mydriasis profiles exhibited a significant increase of intensity and duration compared with those of conventional eye drops. Efficient mydriasis was achieved following the administration of a 
single drop of in situ gel reducing the required amount of administered active ingredients by four- to eight-fold compared with classic eye drop regimen.

– Krzysztof Marycz et al. January 2019

In response to the demand for new multifunctional materials characterized by high biocompatibility, hydrogel (HG) nanocomposites as a platform for bioactive compound delivery have been developed and fabricated. A specific crosslinking/copolymerization chemistry was used to construct hydrogels with a controlled network organization. The hydrogels were prepared using 3,6-anhydro-α-L-galacto-β-D-galactan (galactose hydrogel) together with resveratrol(trans-3,5,40-trihydroxystilbene) and calcium hydroxyapatite nanoparticles. The resveratrol was introduced in three different concentrations of 0.1, 0.5, and 1 mM. Nanosized calcium hydroxyapatite was synthesized by a microwave-assisted hydrothermal technique, annealed at 500 C for 3 h, and introduced at a concentration 10% (m/v). The morphology and structural properties of Ca10(PO4)6(OH)2 and its composite were determined by using XRPD (X-ray powder diffraction) techniques, as well as the absorption and IR (infrared) spectroscopy. The average nanoparticle size was 35 nm. The water affinity, morphology, organic compound release profile, and cytocompatibility of the obtained materials were studied in detail. The designed hydrogels were shown to be materials of biological relevance and of great pharmacological potential as carriers for bioactive compound delivery. Their cytocompatibility was tested using a model of human multipotent stromal cells isolated from adipose tissue (hASCs). The biomaterials increased the proliferative activity and viability of hASCs, as well as reduced markers of oxidative stress. In light of the obtained results, it has been thought that the designed materials meet the requirements of the tissue engineering triad, and may find application in regenerative medicine, especially for personalized therapies.
 

– J.W Hoffman et al. September 2023

We report the successful evaluation of a US Pharmacopeia Apparatus 4 (USP-4) system in measuring the dissolution profiles of man-made vitreous fibers (MMVF) 1. Glass and stone wool fibers with different (high- and low-) solubility profiles were tested in closed-loop configuration using a sodium/potassium phosphate buffer solution or an acetate buffer, respectively. Results confirm a need to operate in diluted conditions to avoid silicon saturation in the simulant solution and suppression of fiber dissolution. A clear fiber-to-fiber differentiation with good cell-to-cell reproducibility was achieved. These findings support the continued development of a USP-4 protocol for MMVF in vitro acellular testing.

– Marius Tidau et al. March 2022

On demand production of totally customizable combinative preparations is a central goal of a patient-centricpharmaceutical supply chain. Additive manufacturing techniques like fused deposition modelling (FDM) couldbe key technologies towards such individualized dosage forms. As so far only a limited number of studies on 3D printed combinative preparations applying FDM have been reported, a core-shell dosage form was the focus of the present study. Dosage forms with an initial and a sustained release part with theophylline as model API were successfully produced applying a dual nozzle FDM 3D printer. Investigations identified microstructural defects at the interface between the two formulations by means of μCT analysis. Dissolution testing proved the achievement of the intended release profile. In combination with additionally characterized release profile of single material prints of different shapes, the combinative release profiles could be predicted by developing model equations and taking into account the geometric composition. As these model approaches can accordingly facilitate the pre- diction of API release from 3D printed combinative preparations with only data from single material release. This is a first step towards a truly individualized and reliable patient-centric pharmaceutical supply via 3D printing.

– Justyna Skowyra et al. November 2014

Rapid and reliable tailoring of the dose of controlled release tablets to suit an individual patient is a major challenge for personalized medicine. The aim of this work was to investigate the feasibility of using a fused deposition modelling (FDM) based 3D printer to fabricate extended-release tablet using prednisolone loaded poly (vinyl alcohol) (PVA) filaments and to control its dose. Prednisolone was loaded into a 32 PVA-based (1.75 mm) filament at approximately 1.9% w/w via incubation in a saturated methanolic solution of prednisolone. The physical form of the drug was assessed using differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Dose accuracy and in vitro drug release patterns were assessed using HPLC and pH change flowthrough dissolution test. Prednisolone loaded PVA filament demonstrated an ability to be fabricated into regular ellipse-shaped solid tablets using the FDM-based 3D printer. It was possible to control the mass of printed tablet through manipulating the volume of the design (R2 = 0.9983). On printing tablets with target drug contents of 2, 3, 3, 4, 5, 7.5 and 10 mg, a good correlation between target and achieved dose was obtained (R2 = 0.9904) with a dose accuracy range of 88.7–107%. Thermal analysis and XRPD indicated that the majority of prednisolone existed in amorphous form within the tablets. In vitro drug release from 3D printed tablets was extended up to 24 h.FDM based 3D printing is a promising method to produce and control the dose of extended-release tablets, providing a highly adjustable, affordable, minimally sized, digitally controlled platform for producing patient-tailored medicines

– Mirjana Krkobabic et al. August 2020

Three-dimensional (3D) printing technologies are based on successive material printing layer-by-layer and are considered suitable for the production of dosage forms customized for a patient’s needs. In this study, tablets of atomoxetine hydrochloride (ATH) have been successfully fabricated by a digital light processing (DLP) 3D printing technology. Initial materials were photoreactive suspensions, composed of poly (ethylene glycol) diacrylate 700 (PEGDA 700), poly (ethylene glycol) 400 (PEG 400), photoinitiator and suspended ATH. The amount of ATH was varied from 10.00 to 25.00% (w/w), and a range of doses from 12.21 to 40.07 mg has been achieved, 
indicating the possibility of personalized therapy. The rheological characteristics of all photoreactive suspensions were appropriate for the printing process, while the amount of the suspended particles in the photoreactive suspensions had an impact on the 3D printing process, as well as on mechanical and biopharmaceutical characteristics of tablets. Only the formulation with the highest content of ATH had significantly different tensile strength compared to other formulations. All tablets showed sustained drug release during at least the 8h. ATH crystals were observed with polarized light microscopy of photoreactive suspensions and the cross-sections of the tablets, while no interactions between ATH and polymers were detected by FT-IR spectroscopy.

– Agne Mazurkeviciute et al. July 2022

Emulsions are thermodynamically unstable systems and it is difficult to produce biphasic formulations with large amounts of oil. The aim of our study was to prepare biphasic formulations containing 1% ciclopirox olamine and to determine the influence of the method of oil incorporation (without and with emulsifier and gelifier) on the physical (pH, particle size, rheological properties), mechanical, and biopharmaceutical properties of the formulations. It was found that the use of a poloxamer 407 gel as the hydrophase could result in a stable formulation when an oil with (EPG) or without an emulsifier (APG) or oleo gel (OPG) was used as the oily phase. The results of the studies showed that the addition of an emulsifier (polysorbate 80) led to a decrease in the sol-gel temperature, a slower release of ciclopirox olamine, and a higher stability in the freeze–thaw test. However, regardless of the way the oil is incorporated, the particles are distributed in the same range and the antifungal activity against T. rubrum is the same. It is possible to create a biphasic formulation with a large amount of oil and poloxamer gel, but for greater stability, it is recommended to include an emulsifier in the composition.

– Reka Szoleczky et al. March 2022

The aim of our study was to adapt the analytical quality by design (AQbD) approach to design an effective in vitro release test method using USP apparatus IV with a semi-solid adapter (SSA) for diclofenac sodium hydrogel. The analytical target profile (ATP) of the in vitro release test and ultra-high-performance liquid chromatography were defined; the critical method attributes (CMAs) (min. 70% of the drug should be released during the test, six time points should be obtained in the linear portion of the drug release profile, and the relative standard deviation of the released drug should not be over 10%) were selected. An initial risk assessment was carried out, in which the CMAs (ionic strength, the pH of the media, membrane type, the rate of flow, the volume of the SSA (sample amount), the individual flow rate of cells, drug concentration %, and the composition of the product) were identified. With the results, it was possible to determine the high-risk parameters of the in vitro drug release studies performed with the USP apparatus IV with SSA, which were the pH of the medium and the sample weight of the product. Focusing on these parameters, we developed a test protocol for our hydrogel system.

– Jian B.Fang et al. August 2010

Dissolution testing is frequently used to determine the rate and extent at which a drug is released from a dosage form, and it plays many important roles throughout drug product development. However, the traditional dissolution approach often emphasizes its application in quality control testing and usually strives to obtain 100% drug release. As a result, dissolution methods are not necessarily biorelevant and meaningful application of traditional dissolution methods in the early phases of drug product development can be very limited. This article will describe the development of a biorelevant in vitro dissolution method using USP apparatus 4, biorelevant media, and real-time online UV analysis. Several case studies in the areas of formulation selection, lot-to-lot variability, and food effect will be presented to demonstrate the application of this method in early phase formulation development. This biorelevant dissolution method using USP apparatus 4 provides a valuable tool to predict certain aspects of the in vivo drug release. It can be used to facilitate the formulation development/selection for pharmacokinetic (PK) and clinical studies. It may also potentially be used to minimize the number of PK studies, and to aid in the design of more efficient PK and clinical studies.

– Stephen R. Cammarn et al. March 2000

A model was established for the dissolution of non-disintegrating salicylic acid tablets as a function of hydrodynamic conditions in the Flow-Through Cell system (USP Apparatus 4). The approach was to model the dissolution rate of the material as a function of the Reynold’s number, the dimensionless engineering term that describes the degree of turbulence. The dissolution rate of USP calibrator salicylic acid tablets was measured as a function of tablet size, orientation within the cell, dissolution media flow rate, and cell size. All of these variables were found to have an effect on dissolution rate, consistent with theory.

– Bo Wennergren et al. December 1988

A collaborative in vitro dissolution study has been performed in 5 laboratories using the flow-through method with different cell types and at various hydrodynamic conditions. The USP disintegrating prednisone calibrator tablets have been used as a test formulation The results obtained by the flow-through method were compared with data generated using the USP XXI paddle method. The flow-through method was found to produce reproducible and corresponding dissolution data both within and between the different laboratories. It was found that the linear flow rate in the flow-through cells is a fundamental parameter for the dissolution rate of the formulation. There was a conformity in dissolution rate between cells with different diameters when applying the same linear flow rate of the dissolution medium using the flow-through method. At low flow rates the flow-through method was found to be a sensible instrument to establish differences in the disintegration properties between the various prednisone tablets examined.

– Bartlomiej Minlanowski et al. December 2013

Niacin (nicotinic acid, NA) is administered orally as an antihyperlipidemic agent in extended-release (ER) tablets in high doses. Due to rapid absorption and extensive metabolism (non-linear pharmacokinetics), the drug plasma levels are highly variable, which may correlate with side effects. Interestingly, this erratic drug delivery behavior of niacin ER products cannot be clarified by compendial in vitro release testing. The standard dissolution tests do not allow to mimic the selected GI tract characteristics in order to estimate the robustness of formulation under the variability of the physiological conditions. These are characterized by the pH value, impact of motility forces and composition, as well as volume of GI liquids. Our paper demonstrates a comparison of a newly developed ER HPMC niacin formulation with an originator product. The research aimed to design a robust matrix tablet of comparable biopharmaceutical behavior, safety and efficacy. The extensive in vitro investigation, including dynamic studies in flow-through cell apparatus and stress test device, forms the basis for the evaluation of nicotinic acid plasma concentrations in vivo. The occurrence of erratic, multiple NA plasma peaks after the administration of both extended-release products is a result of its local input excess over the metabolic threshold (at the level corresponding to maximum 2% of the administered dose, i.e., 20 mg of drug) due to the mechanical stresses of physiological intensity. We demonstrate how this behavior is similar for both marketed and test products. In this context, we describe how a robust ER matrix and well-designed formulation does not guarantee the test product’s bioequivalence to the comparator one out of reasons unrelated to technology and biopharmaceutical properties, but because of the active compound’s intrinsic pharmacokinetic characteristics, i.e., highly variable, extensive metabolism of nicotinic acid.

– Mercedes Prieto-Escolar et al. May 2021

Montelukast is a weak acid drug characterized by its low solubility in the range of pH 1.2 to 4.5, which may lead to dissolution-limited absorption. The aim of this paper is to develop an in vivo predictive dissolution method for montelukast and to check its performance by establishing a level-A in vitro-in vivo correlation (IVIVC). During the development of a generic film-coated tablet formulation, two clinical trials were done with three different experimental formulations to achieve a similar formulation to the reference one. A dissolution test procedure with a flow-through cell (USP IV) was used to predict the in vivo absorption behavior. The method proposed is based on a flow rate of 5 mL/min and changes of pH mediums from 1.2 to 4.5 and then to 6.8 with standard pharmacopoeia buffers. In order to improve the dissolution of montelukast, sodium dodecyl sulfate was added to the 4.5 and 6.8 pH mediums. Dissolution profiles in from the new method were used to develop a level-A IVIVC. One-step level-A IVIVC was developed from dissolution profiles and fractions absorbed obtained by the Loo–Riegelman method. Time scaling with Levy’s plot was necessary to achieve a linear IVIVC. One-step differential equation-based IVIVC was also developed with a time-scaling function. The developed method showed similar results to a previously proposed biopredictive method for montelukast, and the added value showed the ability to discriminate among different release rates in vitro, matching the in vivo clinical bioequivalence results.

– Paloma Frutos et al. July 2021

There has been growing interest in the subject of drug delivery and the design and evaluation of controlled release systems. The simplest way to control the release of an active agent is to disperse it in an inert polymeric matrix. Controlled-release systems are of interest because they are technologically simple, relatively cheap, and practically unaffected by physiological changes. In this study, a new matrix system was formed by an active principle, metoclopramide hydrochloride, scattered into a biocompatible hydrophobic polymerical mesh, polyamide 12, to achieve sustained and controlled delivery of metoclopramide hydrochloride. This research was conducted to investigate the in vitro drug release behavior from these new inert polymeric matrix tablets. The drug release process was investigated both experimentally and by means of mathematical models. Different models were applied for the evaluation of drug release data. On the basis of our results, a biexponential equation was proposed, in an attempt to explain the mechanism responsible for the release process. Additionally, the influence of the experimental conditions of the dissolution devices, such as rate of flow and pH of dissolution medium, on the parameters that characterize the release mechanism was studied, and it was found that the main factor was the hydrodynamic condition of rate of flow.

– Shotaro Ikuta et al. November 2022

The purpose of this study was to develop a bicarbonate buffer flow-through cell (FTC) dissolution test. Mesalazine colon targeting tablets of a generic development product (test formulation, TF; Mesalazine 400 mg tablet) and the original product (reference formulation, RF; Asacol® 400 mg tablet) were used as model formulations. A clinical bioequivalence (BE) study was conducted on 48 healthy male subjects under fasting conditions. The oral absorption time profiles were calculated by point-area deconvolution. The compendial paddle and FTC apparatus were used for dissolution tests. Bicarbonate or phosphate-citrate buffer solutions (McIlvaine buffer) were used as the dissolution media. A floating lid was used to maintain the pH value of the bicarbonate buffer solution in the vessel (paddle) or the reservoir (FTC). In the development of bicarbonate FTC method, the pH changes of bi-carbonate buffer solution (pH 5.5–7.5; 5–50 mM bicarbonate) were evaluated. For the evaluation of colon targeting tablets, the dissolution profiles of TF and RF were measured at a pH of 7.5. The TF and RF formulations were exposed to 0.01 HCl (pH 2.0) for 2 h before pH 7.5. In the clinical BE study, drug dissolution started 4–8 h after oral administration and continued slowly more than 10 h. Both the area under the curve (AUC) and maximum plasma concentration (Cmax) of TF were approximately twice as high as those of RF. In the development of the bicarbonate FTC method, the pH change of the bicarbonate buffer solution was suppressed by the floating lid within ΔpH < 0.1 over 10 h. In the dissolution test of McIlvaine buffer solutions, TF and RF showed faster disintegration and higher dissolution than those observed in the clinical BE study. When using the paddle apparatus the dissolution profiles of TF and RF in both buffer solutions were not consistent with those of the clinical result. In bicarbonate FTC, the disintegration time, dissolution rate, and dissolution inequivalence between TF and RF were consistent with the results of the clinical BE study. In conclusion, the bicarbonate FTC method was constructed for the first time in this study. This method is simple and practically useful for predicting in vivo performance of colon targeting tablets during drug development.

– José Raul Medina-Lopez et al. May 2019

Objective: To study the in vitro dissolution performance of four generic formulations of the poorly soluble drug meloxicam and the reference under hydrodynamic environments generated by flow-through cell method and USP paddle apparatus (pharmacopeial test). Methods: Dissolution method was validated according to ICH guidelines. Dissolution profiles were carried out with an automated flow-through cell apparatus (laminar flow at 16 ml/min with 22.6 mm cells) and USP paddle apparatus at 75 rpm. Phosphate buffer pH 7.5 at 37.0±0.5 °C was used as dissolution medium. Spectrophotometric determination of drug at 362 nm was carried out during 30 min. Dissolution profiles were compared with model-dependent and-independent methods. Results: Practically, all generic formulations showed significant differences with the percentage of drug dissolved at 30 min, mean dissolution time and dissolution efficiency, when USP paddle apparatus was used (*P<0.05), while only two generic formulations were different to reference using flow-through cell method. After adjustment to different mathematical equations, Weibull function was the best model to describe meloxicam dissolution performance and significant differences were found with all drug products when USP paddle apparatus was used, while only one formulation was different with flow-through cell method. Conclusion: The study reveals the need to look for better dissolution schemes for meloxicam tablets since USP paddle apparatus may not reflect properly the in vitro dissolution performance of meloxicam generic formulations and reference.

– Alice Paprskarova et al. October 2015

Supersaturation and precipitation are common limitations encountered especially with poorly soluble basic drugs. The aims of this work were to explore the pattern of dissolution and precipitation of poorly soluble basic drugs using a United States Pharmacopoeia (USP) IV dissolution apparatus and to compare it to the widely used USP II dissolution apparatus. In order to investigate the influence of gastric emptying time on bioavailability, tables of two model drugs (dipyridamole 100 mg and cinnarizine 15 mg) were investigated and pH change from 1.2 to 6.8 were achieved after 10, 20 or 30 min using USP II or USP IV dissolution apparatuses. Using USP II, dipyridamole and cinnarizine concentrations dropped instantly as a result of drug precipitation with drug crystals evident in the dissolution vessel. At pH change times of 10, 20 and 30 min, the total amount of dissolved drug was dependent on pH change time. Using USP IV, at a flow rate of 8 ml/min, it was possible to have comparable release to agitation at 50 rpm using USP II suggesting that comparable hydrodynamic forces are possible. No drop in drug percentage occurs as the dissolved fraction was readily emptied from the flow cell, preventing drug accumulation in the dissolution medium. However, a negligible percentage of drug release took place following pH change. In conclusion, the use of the flow-through cell dissolution provided laminar flow, use of realistic fluid volumes and avoided precipitation of dissolved drug fraction in the gastric phase as it is discharged before pH change.

– Nesrin F.Taha et al. July 2022

The present study evaluated the effect of different configuration setups of the Flow-Through Cell (USP IV) dissolution tester in developing in vitro–in vivo correlation (IVIVC). A Biopharmaceutics Classification System (BCS) Class I Diltiazem (DTZ), formulated in extended-release (ER) gel-matrix system, was employed for this purpose. The study also assessed the validity and predictability of IVIVC employing both deconvolution- and convolution-based approaches. In vitro release was conducted in USP IV as open- or closed-loop setups, while the pharmacokinetic (PK) data were obtained from a previous fasted-state cross-over study conducted on 8 healthy male volunteers, after oral administration of ER matrix tablets against market product (Tildiem Retard® 90 mg). PK parameters (Cmax, AUC 0-t and AUC 0-∞) were predicted, and compared with actual data to establish the strength of correlation models. Results showed that DTZ release from ER products was influenced by operating the FTC in different configuration-setups, where ≥ 75% of labeled DTZ was released after 6 h and 12 h using the open- and closed-loop settings, respectively. Correlation between fraction-dissolved versus fraction absorbed for both ER products displayed linear relation upon employing FTC open-loop setup. Convolutionbased approach was more discriminative in predicting DTZ in vivo PK parameters with a minimal prediction error, compared to deconvolution-based approach. A successful trial to predict DTZ PKs from individual in vitro data performed in USP IV dissolution model was established, employing convolution technique. Basic principle of the convolution approach provides a simple and practical method for developing IVIVC, hence could be utilized for other BCS Class I extended-release drug products.

– Maja Kincl et al. September 2003

In the present work different parameters, which influence the release of diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzene acetic acid mono sodium salt) from lipophilic matrix prolonged release tablets, were investigated. Solubility characteristics of diclofenac sodium in aqueous media with various ionic strengths, ionic compositions and pH in the range of 1 to 10 were determined. According to the obtained results different experimental conditions of the dissolution test on the drug release profiles were studied, i.e. different dissolution apparatus, various rotation speeds of the stirring elements, different buffer media with a pH in the range of 5.8 to 10.0 and various ionic strengths. The amount of released diclofenac sodium was determined by ultraviolet spectrophotometry at the wavelength of maximum absorbance at 276 ± 2 nm. From the obtained results it can be concluded, that solubility of diclofenac sodium depends mainly on composition and pH of the dissolution medium and also on ionic strengths of the dissolution medium. Besides these parameters, on the release of diclofenac sodium from lipophilic matrix tablets influence also type of dissolution apparatus and particularly rotation speeds of the stirring elements.

– Laila H. Emara et al. May 2009

This study was proposed to evaluate the effect of different cell designs and hydrodynamic conditions of the flowthrough cell (FTC), USP dissolution Apparatus 4, on the release rate of a sustained-release product. Sustained release (SR) diclofenac sodium (DS), 100 mg/tablet, was selected for this study. Different cell sizes and types, the flow rate of dissolution medium, and the tablet position within the FTC were considered. Results revealed that some of these variables affect the release rate of DS. It was obvious that the turbulent flow of the dissolution medium resulted in a higher DS release rate compared with the laminar flow. In addition, the results show that the drug release rate decreased when the tablet was buried in the glass beads compared with the unburied tablet. On the other hand, variables such as cell size (12-mm and 22.6-mm diameter), flow rates (8 and 16 mL/min), and presence of a tablet holder had a negligible role in drug release rate.

– Laila H. Emara et al. February 2013

Floating amoxicillin trihydrate (AmoxT) tablets, used for eradication of Helicobacter pylori (H. pylori), were prepared according to a gas-generating technique to extend the drug residence time in the stomach. The drug release rate from the floating tablets in acidic dissolution medium, in which AmoxT is known to be unstable, was studied using two dissolution techniques: open loop system of the flow-through cell (FTC) and the beaker method. Analysis of AmoxT in the dissolution medium was carried out by UV spectrophotometric and HPLC methods. The comparison indicates that the open-loop system of the FTC, which is based on non-cumulative (fresh) dissolution samples, is the preferred dissolution technique, and in this case, the drug could be analyzed by UV spectrophotometric and HPLC methods. However, in the case of a large number of QC samples, UV spectrophotometry is preferred to the HPLC method, which requires relatively longer time for analysis thereby increasing drug degradation. On the other hand, in the case of the beaker method, which is based on cumulative dissolution samples, the drug must be analyzed by HPLC. Generally, the beaker method is not recommended due to the problems associated with the accumulation of AmoxT degradation product in the dissolution medium. This study describes a simple dissolution method capable of discriminating between different AmoxT gastroretentive formulations without any additional experimental or calculational steps.

– Jean-Marie Aiache et al. May 1987

The ‘in vitro’ dissolution kinetics of two suppository formulations containing indomethacin were compared and a correlation with the ‘in vitro’ kinetics was established. The device used ‘in vitro’ was a special through flow cell. A mean dissolution curve was obtained for each dosage form, one containing a hydrophilic excipient (PEG), the other, a fatty base. A relative bioavailability study was then carried out on 12 healthy volunteers. Thus, from the pharmacokinetic parameters obtained, the simulation of plasma concentration values was made possible from the amounts of drug released and dissolved during the dissolution test. With the simulation programme used it was possible to predict the plasma level values and the results showed a good superimposition of the experimental plasma concentration curve validating the "in vitro" study method of drug release from suppositories.

– D.V. Okhrimenko et al. October 2021

The biopersistence of fiber materials is one of the cornerstones in estimating potential risk to human health upon inhalation. To connect epidemiological and in vivo investigations with in vitro studies, reliable and robust methods of fiber biopersistence determination and understanding of fiber dissolution mechanism are required. We investigated dissolution properties of oil treated stone wool fibers with and without sugar-based binder (SBB) at 37 ◦C in the liquids representing macrophages intracellular conditions (pH 4.5). Conditions varied from batch to flow of different rates. Fiber morphology and surface chemistry changes caused by dissolution were monitored with scanning electron microscopy and time-of-flight secondary ion mass spectrometry mapping. Stone wool fiber dissolution rate depends on liquid composition (presence of ligands, such as citrate), pH, reaction products transport and fibers wetting properties. The dissolution rate decreases when: 1) citrate is consumed by the reaction with the released Al cations; 2) the pH increases during a reaction in poorly buffered solutions; 3) the dissolution products are accumulated; 4) fibers are not fully wetted with the fluid. Presence of SBB has no influence on dissolution rate if fiber material was wetted prior to dissolution experiment to avoid poorly wetted fiber agglomerates formation in the synthetic lung fluids.

– Festo Damian et al. January 2021

Recently, the development of soft gelatin capsules (SGCs) dosage forms has attracted a great deal of interest in the oral delivery of poorly water-soluble drugs. This is attributed to the increased number of poorly soluble drugs in the pipeline, and hence the challenges of finding innovative ways of developing bioavailable and stable dosage forms. Encapsulation of these drugs into SGCs is one of the approaches that is utilized to deliver the active ingredients to the systemic circulation to overcome certain formulation hurdles. Once formulated, encapsulated drugs in the form of SGCs require suitable in vitro dissolution test methods to ensure drug product quality and performance. This review focuses on challenges facing dissolution test method development for SGCs. A brief discussion of the physicochemical and formulation factors that affect the dissolution properties of SGCs will be highlighted. Likewise, the influence of cross-linking of gelatin on the dissolution properties of SGCs will also be discussed.

– Jack Hu et al. May 2005

The USP Apparatus 2 and Apparatus 4 were compared for dissolution of soft gelatin capsule formulations of a poorly water-soluble amine drug. Data is presented for the solubility of the drug in acidic media – with and without added surfactant. A 0.01N HCl/0.25% Polysorbate 80 medium was selected for further development. When the soft gelatin capsule ruptures during dissolution, the oil phase is released into the aqueous medium. Both dissolution methods were adapted to handle the problems caused by the oil phase passing into the filters and sample collection system. Using this acidic medium with added surfactant, both apparatuses gave similar dissolution profiles. Apparatus 2 tended to give a faster rate of dissolution, but Apparatus 4 was better able to distinguish between different formulations.

– John H.Miller et al. January 2020

Developing dissolution testing methods to measure the nicotine release profiles from smokeless tobacco products is valuable for product assessment and product-to-product comparisons. In this work, we developed a robust dissolution method to study the in vitro release of nicotine from smokeless tobacco products using the U.S. Pharmacopeia flow-through cell dissolution apparatus 4 (USP-4). We further developed and validated a sensitive Ultra Performance Liquid Chromatography coupled to Photodiode Array detector (UPLC-PDA) method for the accurate quantitation of the released nicotine into artificial saliva, which is our selected dissolution medium. We have successfully shown the applicability of the validated method by investigating the release profiles of nicotine from various commercial and CORESTA reference smokeless tobacco products [CRP 1.1 (Swedishstyle snus pouch), CRP 2.1 (American-style loose moist snuff), CRP 4 (looseleaf chewing tobacco) and CRP 4.1 (chopped loose-leaf chewing tobacco)]. Nicotine release profiles were analyzed by calculating the difference factor (f1) and similarity factor (f2) by adopting a methodology referenced in the Guidance for Industry from FDA’s Center for Drug Evaluation and Research (CDER) and by fitting the release profile curves using a first order kinetic model. Nicotine release was found to be dependent on the form and cut of the smokeless tobacco products, with a slower release observed for snus and loose-leaf, compared to chopped and loose moist snuff smokeless tobacco. This dissolution methodology can be extended to measure and compare release of other constituents from smokeless tobacco products and has the potential for method standardization.

– Fadi Aldeek et al. January 2021

In recent years, oral tobacco-derived nicotine (OTDN) pouches have emerged as a new oral tobacco product category. They are available in a variety of flavors and do not contain cut or ground tobacco leaf. The on!® nicotine pouches fall within this category of OTDN products and are currently marketed in seven (7) flavors with five (5) different nicotine levels. Evaluation of the nicotine release from these products is valuable for product assessment and product-to-product comparisons. In this work, we characterized the in vitro release profiles of nicotine from the 35 varieties of on!® nicotine pouches using a fit-for-purpose dissolution method, employing the U.S. Pharmacopeia flow-through cell dissolution apparatus 4 (USP-4). The nicotine release profiles were compared using the FDA’s Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms. The cumulative release profiles of nicotine show a dose dependent response for all nicotine levels. The on!® nicotine pouches exhibit equivalent percent nicotine release rates for each flavor variant across all nicotine levels. Furthermore, the nicotine release profiles from on!® nicotine pouches were compared to a variety of other commercially available OTDN pouches and traditional pouched smokeless tobacco products. The percent nicotine release rates were found to be dependent on the product characteristics, showing similarities and differences in the nicotine release profiles between the on!® nicotine pouches and other compared products.

– Vladislav Vivcharenko et al. May 2020

The treatment of chronic wounds is still a meaningful challenge to physicians. The aim of this work was to produce vitamin C-enriched chitosan/agarose (CHN/A) film that could serve as potential artificial skin substitute for chronic wound treatment. The biomaterial was fabricated by a newly developed and simplified method via mixing acidic chitosan solution with alkaline agarose solution that allowed to obtain slightly acidic pH (5.97) of the resultant material, which is known to support skin regeneration. Vitamin C was immobilized within the matrix of the film by entrapment method during production process. Produced films (CHN/A and CHN/A + vit C) were subjected to comprehensive evaluation of cellular response with the use of human skin fibroblasts, epidermal keratinocytes, and macrophages. It was demonstrated that novel biomaterials support adhesion and growth of human skin fibroblasts and keratinocytes, have ability to slightly reduce transforming growth factor-beta 1 (TGFβ1) (known to be present at augmented levels in the epidermis of chronic wounds), and increase platelet-derived growth factor-BB (PDGF-BB) secretion by the cells. Nevertheless, addition of vitamin C to the biomaterial formulation does not significantly improve its biological properties due to burst vitamin release profile. Obtained results clearly demonstrated that produced CHN/A film has great potential to be used as cellular dermal, epidermal, or dermo-epidermal graft pre-seeded with human skin cells for chronic wound treatment.

– Deirde M. D'Arcy et al. November 2018

Viscosity, influenced by medium composition, will affect the hydrodynamics of a dissolution system. Dissolution simulation methods are valuable tools to explore mechanistic dissolution effects, with an understanding of limitations of any simulation method essential to its appropriate use. The aims of this paper were a) to explore, using dissolution simulation, the effects of slightly viscous media on particulate dissolution and b) to illustrate approaches to, and limitations of, the dissolution simulations. A lumped parameter fluid dynamics dissolution simulation model (SIMDISSO™) was used to simulate particulate (20 and 200 μm diameter) dissolution in media with viscosity at 37 °C of water (0.7 mPa.s), milk (1.4 mPa.s) and a nutrient drink (12.3 mPa.s). Effects of flow rate, modality (constant vs pulsing), viscosity and gravitational and particle motion/sedimentation effects on simulated dissolution were explored, in the flow-through and paddle apparatuses as appropriate. Shadowgraph imaging (SGI) was used to visualise particle suspension behaviour. Flow rate, hydrodynamic viscous effects and disabling particle motion and gravitational effects affected simulated dissolution of larger particles. SGI imaging revealed retention of particles in suspension in 1.4 mPa.s medium, which sedimented in water. The effect of diffusion adjusted for viscosity was significant for both particle sizes. The limitations of this 1D simulation approach would be greater for larger particles in low velocity regions of the paddle apparatus. Even slightly viscous media can affect dissolution of larger particles with dissolution simulation affording insight into the mechanisms involved, provided the assumptions and limitations of the simulation approach are clarified and understood.

– Trevor Riley et al. July 2012

The purpose of this article is to review the suitability of the analytical and statistical techniques that have thus far been developed to assess the dissolution behavior of particles in the respirable aerodynamic size range, as generated by orally inhaled products (OIPs) such as metered-dose inhalers and dry powder inhalers. The review encompasses all analytical techniques publicized to date, namely, those using paddle-over-disk USP 2 dissolution apparatus, flow-through cell dissolution apparatus, and diffusion cell apparatus. The available techniques may have research value for both industry and academia, especially when developing modified-release formulations. The choice of a method should be guided by the question(s) that the research strives to answer, as well as by the strengths and weaknesses of the available techniques. There is still insufficient knowledge, however, for translating the dissolution data into statements about quality, performance, safety, or efficacy of OIPs in general. Any attempts to standardize a dissolution method for compendial inclusion or compendial use would therefore be premature. This review reinforces and expands on the 2008 stimulus article of the USP Inhalation Ad Hoc Advisory Panel, which “could not find compelling evidence suggesting that such dissolution testing is kinetically and/or clinically crucial for currently approved inhalation drug products.”

– Yosuke Yamamoto et al. October 2019

The main objective of this study was to investigate the mechanism of solifenacin release from a pH-responsive ion-complex oral resinate suspension under conditions simulating the environment in the upper gastrointestinal lumen. A secondary objective was to propose an appropriate in vitro methodology for evaluating the quality of orally administered solifenacin suspensions. The mechanism of solifenacin release from polacrilin potassium resin (Amberlite® IRP88) was investigated using biorelevant media and compendial setups (USP Apparatus 2 and USP Apparatus 4) and using newer, recently validated in vitro methodologies [biorelevant gastrointestinal transfer (BioGIT) system]. We evaluated the impact of particle size and concentration of the resin; thickener concentration (carbomer homopolymer, type B); and the impact of pH, cationic strength, agitation intensity and level of simulation of contents in the upper gastrointestinal lumen. Data suggested that solifenacin release from the resinate was determined by the resin particle size, the medium pH, cationic strength (when the conditions in the upper small intestine are simulated) and the level of simulation of contents in the upper small intestine. The interaction of solifenacin with taurocholic acid/lecithin aggregates was significant, but unlikely to affect the degree of solifenacin absorption, as a BCS Class I compound. Under acidic conditions, solifenacin was dissociated and released from the pH-responsive resin rapidly. Under conditions simulating the contents of the upper small intestine, solifenacin was replaced by cations from the testing media and diffused through the resin matrix. All three in vitro systems with or without a pH gradient are useful in distinguishing solifenacin release characteristics from resinate suspensions with different particle sizes. Because of this drug release mechanism, USP Apparatus 2 with fixed pH media demonstrated equivalent or slightly higher discriminative sensitivity than the other setups and appears to be appropriate for product quality control.

– Raul Diaz-Salmeron et al. January 2021

Oral lichen planus (OLP) is an ongoing and chronic inflammatory disease affecting the mucous membrane of the oral cavity. Currently, the treatment of choice consists in the direct application into the buccal cavity of semisolid formulations containing a corticosteroid molecule to decrease inflammatory signs and symptoms. However, this administration route has shown various disadvantages limiting its clinical use and efficacy. Indeed, the frequency of application and the incorrect use of the preparation may lead to a poor efficacy and limit the treatment compliance. Furthermore, the saliva clearance and the mechanical stress present in the buccal cavity also involve a decrease in the mucosal exposure to the drug. In this context, the design of a new pharmaceutical formulation, containing a steroidal anti-inflammatory, mucoadhesive, sprayable and exhibiting a sustained and controlled release seems to be suitable to overcome the main limitations of the existing pharmaceutical dosage forms. The present work reports the formulation, optimization and evaluation of the mucoadhesive and release properties of a poloxamer 407 thermosensitive hydrogel containing a poorly water-soluble corticosteroid, dexamethasone acetate (DMA), threaded into hydroxypropyl-beta- cyclodextrin (HP-β-CD) molecules. Firstly, physicochemical properties were assessed to ensure suitable complexation of DMA into HP-β-CD cavities. Then, rheological properties, in the presence and absence of various mucoadhesive agents, were determined and optimized. The hydration ratio (0.218–0.191), the poloxamer 407 (15–17 wt%) percentage and liquid-cyclodextrin state were optimized as a function of the gelation transition temperature, viscoelastic behavior and dynamic flow viscosity. Deformation and resistance properties were evaluated in the presence of various mucoadhesive compounds, being the sodium alginate and xanthan gum the most suitable to improve adhesion and mucoadhesion properties. Xanthan gum was shown as the best agent prolonging the hydrogel retention time up to 45 min. Furthermore, xanthan gum has been found as a relevant polymer matrix controlling drug release by diffusion and swelling processes in order to achieve therapeutic concentration for prolonged periods of time.

– Shilpa Pater et al. September 2020

The current investigation was carried out to identify appropriate parameters for measuring the in vitro release of tobramycin (TOB) ophthalmic ointments and to evaluate the feasibility of in vitro release testing methods to assess the product performance. Drug release was assessed using USP dissolution apparatus IV and a modified USP dissolution apparatus I with simulated tear solution (STS) as the dissolution medium. The study variables included temperature, membrane material, source and pore size. The results demonstrated a significant influence of the membrane source and pore size on the release of TOB from the ointments. A dissolution medium temperature of 40 ◦C was found to be appropriate for the release studies. Both of the apparatuses were able to discriminate between the release profiles of ointments with different physicochemical/rheological properties. Maximum release rate of TOB was observed in the first hour which followed a logarithmic time dependent release. The correlation between the release rates/amounts and yield stress of the ointments was observed in both the dissolution apparatuses. These results support a rational approach to guide the in vitro release testing of TOB ophthalmic ointments.

– Quanying Bao et al. April 2017

It is essential as well as challenging to develop a reliable in vitro release testing method for determining whether differences in release profiles exist between qualitatively and quantitatively equivalent ophthalmic ointment formulations. There is a lack of regulatory guidance on in vitro release testing methods for ophthalmic formulations. Three different in vitro release testing methods 1) USP apparatus 4 with semisolid adapters; 2) USP apparatus 2 with enhancer cells; and 3) Franz diffusion cells were investigated. Qualitatively and quantitatively equivalent ointments were prepared via hot melting and simple mixing methods using four different sources of excipients (i.e. white petrolatum). The ointment formulations were characterized for content uniformity, particle size, and rheological parameters. All the formulations showed adequate content uniformity and similar particle size. The ointments prepared via the hot melting processes showed higher rheological parameters, as did the ointments prepared using ‘white’ petrolatum that exhibited a yellowish color. The three in vitro release testing methods were compared and evaluated for reproducibility, discriminatory capability, and correlation with the rheological parameters. Compared with the compendial methods, the non-compendial method (Franz diffusion cells) showed poorer reproducibility. All three methods possessed the ability to discriminate between the ophthalmic ointments with manufacturing differences. However, the USP apparatus 4 method displayed the largest margin 
of discrimination between the release profiles of the different ophthalmic ointments. In addition, the in vitro release rate obtained using the USP apparatus 4 method showed the strongest logarithmic linear correlation with the rheological parameters (Power law consistency index (K value) and crossover modulus) compared to the other two methods.

– Quanying Bao et al. April 2018

In vitro drug release testing and ex vivo transcorneal drug permeation can provide valuable information on the performance of the Q1/Q2 equivalent ointments prior to any animal studies. Good correlation between in vitro and ex vivo drug release may be indicative of good in vitro and in vivo correlation. Accordingly, it is important to investigate in vitro as well as ex vivo drug release from Q1/Q2 equivalent ophthalmic ointments and evaluate whether a correlation between these release profiles can be established. Four Q1/Q2 equivalent loteprednol etabonate ointments were prepared using different processing methods and excipient sources. The rheological parameters (crossover modulus and K value) of the four formulations were determined. The in vitro drug release testing of the four ointment formulations were performed using three different apparati (Franz diffusion cells, USP apparatus 2 with enhancer cells and USP apparatus 4 with semisolid adapters). Three models (zero order, logarithmic and the Higuchi model) were used to study the release kinetics of the ointment formulations. The transcorneal (rabbit corneas) permeation studies were performed using spherical joint Franz diffusion cells. The USP apparatus 4 method demonstrated better discriminatory ability compared to the USP apparatus 2 and the Franz diffusion cell methods. The in vitro release profiles of the four Q1/Q2 equivalent ointments with manufacturing differences showed a better fit using the Higuchi model (R2 > 0.98) for all three release testing methods, compared to the other two models. Ex vivo drug release through the rabbit corneas displayed zero order release kinetics. A logarithmic correlation between rheological parameters (crossover and K value) and transcorneal flux were established. In addition, a plot of the in vitro release rate against the ex vivo release flux of the four ointment formulations, yielded a straight line (R2 > 0.98) for all three release methods. Accordingly, the rheological parameters may be useful in predicting in vitro as well as ex vivo release properties.

– Jie Shen et al. January 2013

Nanoparticulate systems have emerged as prevalent drug delivery systems over the past few decades. These delivery systems (such as liposomes, emulsions, nanocrystals, and polymeric nanocarriers) have been extensively used to improve bioavailability, prolong pharmacological effects, achieve targeted drug delivery, as well as reduce side effects. Considering that any unanticipated change in product performance of such systems may result in toxicity and/or change in vivo efficacy, it is essential to develop suitable in vitro dissolution/release testing methods to ensure product quality and performance, and to assist in product development. The present review provides an overview of the current in vitro dissolution/release testing methods such as dialysis, sample and separate, as well as continuous flow methods. Challenges and future directions in the development of standardized and biorelevant in vitro dissolution/ release testing methods for novel nanoparticulate systems are discussed.

– Jacqueline Morais et al. August 2014

This study reports the release properties of the poorly water-soluble active vitamin E acetate from oil/water nanoemulsions containing canola oil, CremophorRH401 and Span801 prepared using a low energy emulsification method (EPI process). Drug release was measured via dialysis sac and reverse dialysis sac methods as well as USP apparatus 4 fitted with dialysis sac adapters. Macro- and microscopic stability were evaluated and no instabilities were observed during the test period. In vitro release testing was adequately performed using the reverse dialysis sac and USP apparatus 4 methods. However, the dialysis method produced a slower release rate compared to the other methods and this was considered a result of violation of sink conditions within the dialysis sacs as well as inadequate mixing. Micellar solubilization was able to increase vitamin E transport from canola oil to buffer solution, but no model active concentration increase in the nanoemulsion external aqueous phase was observed despite the presence of micelles. Accordingly, it appeared that diffusion across the interfacial film was the rate-limiting step for in vitro release from these nanoemulsions. Sustained/prolonged release of vitamin E was observed and could be explained based on the high partition coefficient and on the nanoemulsion interfacial film proprieties.

– Rita Gupta et al. May 2021

Nano drug delivery systems (NDDS) offer promising solution for the translation of future nanomedicines. As bioavailability and therapeutic outcomes can be improved by altering the drug release from these NDDS, it becomes essential to thoroughly understand their drug release kinetics. Moreover, U.S. Food and Drug Administration requires critical evaluation of potential safety, efficacy, and public health impacts of nanomaterials. Spiraling up market share of NDDS has also stimulated the pharmaceutical industry to develop their cost-effective generic versions after the expiry of patent and associated exclusivity. However, unlike the conventional dosage forms, the in vivo disposition of NDDS is highly intricate and different from their in vitro behavior. Significant challenges exist in the establishment of in vitro–in vivo correlation (IVIVC) due to incomplete understanding of nanoparticles' in vivo biofate and its impact on in vitro experimental protocols. A rational design of dissolution may serve as quality and quantity control tool and help develop a meaningful IVIVC for favorable economic implications. Clinically relevant drug product specifications (critical quality attributes) can be identified by establishing a link between in vitro performance and in vivo exposure. In vitro dissolution may also play a pivotal role to understand the dissolution-mediated clearance and safety of NDDS. Prevalent in vitro dissolution methods for NDDS and their limitations are discussed in this review, among which USP 4 is gaining more interest recently.  Researchers are working diligently to develop biorelevant in vitro release assays to ensure optimal therapeutic performance of generic versions of these NDDS. This article focuses on these studies and presents important considerations for the future development of clinically relevant in vitro release methods.