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Dissolution of the six model compounds studied in FaSSIF using (a) a dose of 100 mg and a particle size of 25 μm and (b) a dose of 100 mg and a particle size of 5 μm. The time needed for complete dissolution has been calculated using the IDR, a transit time of 3.32 h (~200 min) (19) and a volume of 250 mL. The compounds with values above the dotted line at 400 μg are completely dissolved during the transit time.
Source publication
Purpose:
To develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds.
Methods:
The IDR and apparent solubility (Sapp) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensi...
Citations
... For all solubility and precipitation measurements presented in this paper, online UV measurements can help to face these challenges as the experimental steps are kept to a minimum. By using UV probes with interchangeable pathlengths in the tip, small volumes with 10-100-µg material in a 1-20-ml medium can be analyzed since samples do not have to be withdrawn, thus maintaining the volume at a constant level (26,27). As an alternative, inline UV measurements using flow-through cuvettes can also be used to collect data over multiple time points during an experiment (28). ...
This manuscript represents the view of the Dissolution Working Group of the IQ Consortium on the challenges of and recommendations on solubility measurements and development of dissolution methods for immediate release (IR) solid oral dosage forms formulated with amorphous solid dispersions. Nowadays, numerous compounds populate the industrial pipeline as promising drug candidates yet suffer from low aqueous solubility. In the oral drug product development process, solubility along with permeability is a key determinant to assure sufficient drug absorption along the intestinal tract. Formulating the drug candidate as an amorphous solid dispersion (ASD) is one potential option to address this issue. These formulations demonstrate the rapid onset of drug dissolution and can achieve supersaturated concentrations, which poses significant challenges to appropriately characterize solubility and develop quality control dissolution methods. This review strives to categorize the different dissolution and solubility challenges for ASD associated with 3 different topics: (i) definition of solubility and sink conditions for ASD dissolution, (ii) applications and development of non-sink dissolution (according to conventional definition) for ASD formulation screening and QC method development, and (iii) the advantages and disadvantages of using dissolution in detecting crystallinity in ASD formulations. Related to these challenges, successful examples of dissolution experiments in the context of control strategies are shared and may lead as an example for scientific consensus concerning dissolution testing of ASD.
... In this study, we introduce the intrinsic lipolysis rate (ILR) to enable direct comparison of the digestibility of lipids and to support systematic design of LBFs. A methodology developed for the suspension-based intrinsic dissolution rate [36,37] was adapted here for lipid digestion. Nanoemulsions of controlled lipid droplet size were prepared with pure acylglycerols that differed in acyl chain length, esterification, and unsaturation. ...
... The intrinsic lipolysis rate (ILR; µmol min −1 cm −2 ) was calculated analogous to the methodology developed for the suspension-based dissolution rate [36]: ...
... In this study, we introduced the ILR as a simple but efficient mean to directly compare the digestibility of lipids. The surface area independent ILR was obtained from in vitro lipolysis of nanoemulsions stabilized with polysorbate 80 and was calculated by adapting the methodology developed for the suspension-based intrinsic dissolution rate [36,37]. The IRL methodology can be combined with the previously published tool to predict the drug loading in LBFs [46]. ...
Lipid-based formulations (LBFs) are used by the pharmaceutical industry in oral delivery systems for both poorly water-soluble drugs and biologics. Digestibility is key for the performance of LBFs and in vitro lipolysis is commonly used to compare the digestibility of LBFs. Results from in vitro lipolysis experiments depend highly on the experimental conditions and formulation characteristics, such as droplet size (which defines the surface area available for digestion) and interfacial structure. This study introduced the intrinsic lipolysis rate (ILR) as a surface area-independent approach to compare lipid digestibility. Pure acylglycerol nanoemulsions, stabilized with polysorbate 80 at low concentration, were formulated and digested according to a standardized pH–stat lipolysis protocol. A methodology originally developed to calculate the intrinsic dissolution rate of poorly water-soluble drugs was adapted for the rapid calculation of ILR from lipolysis data. The impact of surfactant concentration on the apparent lipolysis rate and lipid structure on ILR was systematically investigated. The surfactant polysorbate 80 inhibited lipolysis of tricaprylin nanoemulsions in a concentration-dependent manner. Coarse-grained molecular dynamics simulations supported these experimental observations. In the absence of bile and phospholipids, tricaprylin was shielded from lipase at 0.25% polysorbate 80. In contrast, the inclusion of bile salt and phospholipid increased the surfactant-free area and improved the colloidal presentation of the lipids to the enzyme, especially at 0.125% polysorbate 80. At a constant and low surfactant content, acylglycerol digestibility increased with decreasing acyl chain length, decreased esterification, and increasing unsaturation. The calculated ILR of pure acylglycerols was successfully used to accurately predict the IRL of binary lipid mixtures. The ILR measurements hold great promise as an efficient method supporting pharmaceutical formulation scientists in the design of LBFs with specific digestion profiles.
Graphical abstract
... The intrinsic dissolution rate (IDR) of compounds with different crystal structures was measured by the disc method based on the literature [27][28][29][30]. About 10 mg of powder was loaded into the Mini-IDR compression system (Pion Inc., Billerica, MA, USA) and compressed at 100 psi (rivaroxaban) and 200 psi (Drug-A) for 1 min to obtain the miniaturized discs with a surface area of 0.071 cm 2 . ...
Generally, some weakly basic insoluble drugs will undergo precipitate and redissolution after emptying from the stomach to the small intestinal, resulting in the limited ability to predict the absorption characteristics of compounds in advance. Absorption is determined by the solubility and permeability of compounds, which are related to physicochemical properties, while knowledge about the absorption of redissolved precipitate is poorly documented. Considering that biorelevant media have been widely used to simulate gastrointestinal fluids, sufficient precipitates can be obtained in biorelevant media in vitro. Herein, the purpose of this manuscript is to evaluate the physicochemical properties of precipitates obtained from biorelevant media and active pharmaceutical ingredients (API), and then to explore the potential absorption difference between API and precipitates. Precipitates can be formed by the interaction between compounds and intestinal fluid contents, leading to changes in the crystal structure, melting point, and melting process. However, the newly formed crystals have some advantageous properties compared with the API, such as the improved dissolved rate and the increased intrinsic dissolution rate. Additionally, the permeability of some precipitates obtained from biorelevant media was different from API. Meanwhile, the permeability of rivaroxaban and Drug-A was decreased by 1.92-fold and 3.53-fold, respectively, when the experiments were performed in a biorelevant medium instead of a traditional medium. Therefore, the absorption of precipitate may differ from that of API, and the permeability assay in traditional medium may be overestimated. Based on the research results, it is crucial to understand the physicochemical properties of precipitates and API, which can be used as the departure point to improve the prediction performance of absorption.
... This can be a challenge in suspensions. Optical fibre ultra violet (UV) probes have been successfully used (Andersson et al., 2017;Teleki et al., 2020). ...
An important goal of the European Cooperation in Science and Technology (COST) Action UNGAP (UNderstanding Gastrointestinal Absorption-related Processes, www.ungap.eu) is to improve standardization of methods relating to the study of oral drug absorption. Solubility is a general term that refers to the maximum achievable concentration of a compound dissolved in a liquid medium. For orally administered drugs, relevant information on drug properties is crucial during drug (product) development and at the regulatory level. Collection of reliable and reproducible solubility data requires careful application and understanding of the limitations of the selected experimental method. In addition, the purity of a compound and its solid state form, as well as experimental parameters such as temperature of experimentation, media related factors, and sample handling procedures can affect data quality. In this paper, an international consensus developed by the COST UNGAP network on recommendations for collecting high quality solubility data for the development of orally administered drugs is proposed.
... Tax-ET IDR was 56.4 µg cm −2 min −1 , a value much lower than the non-ionizable ranitidine (47.9 mg cm −2 min −1 , MW 314 g/mol) [53], but higher than non-ionizable carbamazepine (24 µg cm −2 min −1 , MW 236 g/mol), griseofulvin (1.9-10.1 µg cm −2 min −1 , MW 353 g/mol) [53,54], and cinnarizine (0.06-0.09 µg cm −2 min −1 , MW 369 g/mol) [55]. Despite Tax possessing an equilibrium solubility that is relatively low, it will solubilize faster than other APIs already on the market. ...
Taxifolin, also known as dihydroquercetin, possesses several interesting biological properties. The purpose of the study was to identify polymorphs of taxifolin prepared using crystallization in different solvents. Data from X-ray powder diffraction, differential scanning calorimetry, and thermogravimetry enabled us to detect six different crystalline phases for taxifolin. Besides the already known fully hydrated phase, one partially hydrated phase, one monohydrated phase, two anhydrous polymorphs, and one probably solvated phase were obtained. The unit cell parameters were defined for three of them, while one anhydrous polymorph was fully structurally characterized by X-ray powder diffraction data. Scanning electron microscopy and hot stage microscopy were also employed to characterize the crystallized taxifolin powders. The hydrate and anhydrous forms showed remarkable stability in drastic storage conditions, and their solubility was deeply evaluated. The anhydrous form converted into the hydrate form during the equilibrium solubility study and taxifolin equilibrium solubility was about 1.2 mg/mL. The hydrate taxifolin intrinsic dissolution rate was 56.4 μg cm⁻² min⁻¹. Using Wood’s apparatus, it was not possible to determine the intrinsic dissolution rate of anhydrous taxifolin that is expected to solubilize more rapidly than the hydrate form. In view of its high stability, its use can be hypothesized.
... A rotating disc method typically, and theoretically incorrectly, uses the original disc's surface area as a constant in the calculation of the IDR [8]. Since pharmaceutical solid preparations contain typically polydisperse powders, IDR methods based on multiparticulate dissolution have also been used, e.g., a powder method [9,10] and a suspension method [11]. When the dissolution process is studied by utilizing a large number of particles, the dissolution condition for each single particle is varying due to the variations in particle size and shape [6]. ...
... This could assist in a better understanding of in vivo dissolution and to define the most suitable dissolution test conditions. Further, this technique is especially promising for poorly watersoluble compounds as previous studies have pointed out the difficulties of measuring the IDR from standardized dissolution methods, i.e., a compressed disc, since the dissolved material can be below the detection limit [11,32]. ...
The objective of this study was to determine the intrinsic drug dissolution rate (IDR) and the solute effective transport rate of some drugs, using a single particle dissolution technique, satisfying qualified dissolution conditions. The IDR of three poorly water-soluble compounds was measured in milli-Q water using four different fluid velocities. The enveloped surface area of the particles was calculated from the projected area and the perimeter of the particle observed in the microscope. Furthermore, computational fluid dynamics (CFD) simulations were used to theoretically investigate the flow conditions and dissolution rate, comparing box shaped particles and spherical particles with similar dimensions and surface area as the particles used the experiments. In this study, the IDR measurement of the single particles was determined within 5–60 min using particles with an initial projected area diameter (Dp) between 37.5–104.6 µm. The micropipette-assisted microscopy technique showed a good reproducibility between individual measurements, and the CFD simulations indicated a laminar flow around the particles at all flow velocities, even though there were evident differences in local particle dissolution rates. In conclusion, the IDR and solute effective transport rate were determined under well-defined fluid flow conditions. This type of approach can be used as a complementary approach to traditional dissolution studies to gain in-depth insights into the dissolution process of drug particles.
... The small quantities of the QSIs restricted the development of controlled suspensions through ball milling or ultrasonication. 33,34 For such formulations, typically larger volumes need to be prepared than the ones prepared herein, and much material is lost during processing. The developed PK model was used to evaluate the potential impact of formulation properties on local and systemic PK of the drugs. ...
For respiratory conditions, targeted drug delivery to the lungs could produce higher local concentrations with reduced risk of adverse events compared to systemic administration. Despite the increasing interest in pulmonary delivery, the pharmacokinetics (PK) of drugs following pulmonary administration remains to be elucidated. In this context, the application of modeling and simulation methodologies to characterize PK properties of compounds following pulmonary administration remains a scarcity. Pseudomonas aeruginosa (PA) lung infections are resistant to many of the current antibiotic therapies. Targeted treatments for pulmonary delivery could be particularly beneficial for these local conditions. In this study, we report the application of biopharmaceutical pharmacometrics (BPMX) for the analysis of PK data from three investigational antimicrobial agents following pulmonary administration of a suspension formulation. The observed drug concentration-time profiles in lungs and plasma of the compound series were combined for simultaneous analysis and modeling. The developed model describes the PK data, taking into account formulation properties, and provides a mechanism to predict dissolved drug concentrations in the lungs available for activity. The model was then used to evaluate formulation effects and the impact of variability on total and dissolved drug concentrations in lungs and plasma. The predictions suggest that these therapies for lung delivery should ideally be delivered in a sustained release formulation with high solubility for maximum local exposure in lungs for efficacy, with rapid systemic clearance in plasma for reduced risk of unwanted systemic adverse effects. This work shows the potential benefits of BPMX and the role it can play to support drug discovery and development in pulmonary delivery.
... In the powder-based assay, coarse powder is added directly to the vials used for the dissolution experiment, and the apparent total surface area of the compound can then be back-calculated after dissolution rate has been determined [10,15]. In contrast, in suspension-based assays, the particle surface area is determined prior to the dissolution experiment, for example by dynamic light scattering (DLS), and the suspension method provides a more accurate measure of total surface area than the powder method [7,16]. Furthermore, suspensions can be (and typically are) stabilized by polymers or surfactants to hinder sedimentation, which is a phenomenon often observed in powder-based assays [10]. ...
... Furthermore, suspensions can be (and typically are) stabilized by polymers or surfactants to hinder sedimentation, which is a phenomenon often observed in powder-based assays [10]. Several studies have demonstrated good agreement of IDR values determined by disc-(DIDR), powder-(PIDR) or suspension-based (SIDR) assays [7,13,17], so the choice of method is primarily governed by the solubility of the studied API. It has been recommended to use discs for S app (apparent solubility) > 1 mg/mL, whereas powder or suspension are used for S app < 100 µg/mL. ...
... Such data sets are suitable to be established with small-scale dissolution studies using in situ UV probes, ideally from suspension-based assays to increase throughput and reduce material needed. However, previous such studies have only explored a small data set with a maximum of six compounds in FaSSIF and phosphate buffer [7,17]. ...
The intrinsic dissolution rate (IDR) of active pharmaceutical ingredients (API) is a key property that aids in early drug development, especially selecting formulation strategies to improve dissolution and thereby drug absorption in the intestine. Here, we developed a robust method for rapid, medium throughput screening of IDR and established the largest IDR dataset in open literature to date that can be used for pharmaceutical computational modeling. Eighteen compounds with diverse physicochemical properties were studied in both fasted and fed state simulated intestinal fluids. Dissolution profiles were measured in small-scale experimental assays using compound suspensions or discs. IDR measurements were not solely linked to API solubility in either dissolution media. Multivariate data analysis revealed that IDR strongly depends on compound partitioning into bile salt and phospholipid micelles in the simulated intestinal fluids, a process that in turn is governed by API lipophilicity, hydrophobicity, and ionization.
... Miniaturised methods have therefore been developed which need only minimal drug, and utilise small volume vials (rotating and stationary disc systems), 96-well plates, flow through cells, and optical microscopy [17][18][19][20][21][22]. An example of a system utilising small volume vials (up to 20 mL) is the Pion µDISS Profiler™, which can measure disc, powder and controlled suspensions [23][24][25]. Standardised procedures for IDR determination using the μDISS Profiler™ were proposed based on an interlaboratory study [26] as part of the IMI OrBiTo collaboration [27,28]. The ability of the μDISS Profiler™ to use minimal amounts of API and the ease of use makes it an attractive option for IDR determination in early preformulation work. ...
The purpose of this study was to conduct an interlaboratory ring-study, with six partners (academic and industrial), investigating the measurement of intrinsic dissolution rate (IDR) using surface dissolution imaging (SDI) equipment. Measurement of IDR is important in pharmaceutical research as it provides characterising information on drugs and their formulations. This work allowed us to assess the SDI's interlaboratory performance for measuring IDR using a defined standard operating procedure (see supporting information) and six drugs assigned as low (tadalafil, bromocriptine mesylate), medium (carvedilol, indomethacin) and high (ibuprofen, valsartan) solubility compounds. Fasted State Simulated Intestinal Fluid (FaSSIF) and blank FaSSIF (without sodium taurocholate and lecithin) (pH 6.5) were used as media. Using the standardised protocol an IDR value was obtained for all compounds and the results show that the overall IDR rank order matched the solubility rank order. Interlaboratory variability was also examined and it was observed that the variability for lower solubility compounds was higher, coefficient of variation >50%, than for intermediate and high solubility compounds, with the exception of indomethacin in FaSSIF medium. Inter laboratory variability is a useful descriptor for understanding the robustness of the protocol and the system variability. On comparison to another published small-scale IDR study the rank ordering with respect to dissolution rate is identical except for the high solubility compounds. This results indicates that the SDI robustly measures IDR however, no recommendation on the use of one small scale method over the other is made.
... The path lengths (2-20 mm) of the in situ UV-probes and the range of the standard curves were selected on the basis of the expected concentrations in the compartments (see Section 2.6). Standard curves were established for each probe and each experimental condition with aliquots of a DMSO stock in: (i) modified lipolysis buffer containing relevant excipients (donor compartment), and (ii) HBSS containing 0.2% TPGS (pH 7.4, receiver compartment) to maintain sink conditions, as described previously [29,33]. Caco-2 monolayers (see Section 2.3) were used as absorptive membranes (1.54 cm 2 surface area) [13]. ...
Advanced drug delivery systems (ADDS) are widely explored to overcome poor aqueous solubility of orally administered drugs. However, the prediction of their in vivo performance is challenging, as in vitro models typically do not capture the interplay between processes occurring in the gut. In additions, different models are used to evaluate the different systems. We therefore present a method that allows monitoring of luminal processing (dissolution, digestion) and its interplay with permeation to better inform on the absorption of felodipine formulated as ADDS. Experiments were performed in a µFLUX-apparatus, consisting of two chambers, representing the intestinal and serosal compartment, separated by Caco-2 monolayers. During dissolution–digestion–permeation experiments, ADDS were added to the donor compartment containing simulated intestinal fluid and immobilized lipase. Dissolution and permeation in both compartments were monitored using in situ UV-probes or, when turbidity interfered the measurements, with HPLC analysis.
The method showed that all ADDS increased donor and receiver concentrations compared to the condition using crystalline felodipine. A poor correlation between the compartments indicated the need for an serosal compartment to evaluate drug absorption from ADDS. The method enables medium-throughput assessment of: (i) dynamic processes occurring in the small intestine, and (ii) drug concentrations in real-time.
