Dissolution Kinetics of a BCS Class II Active Pharmaceutical Ingredient: Diffusion-Based Model Validation and Prediction.
Ontology highlight
ABSTRACT:
SUBMITTER: Gao Y
PROVIDER: S-EPMC8014923 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Controlling the physical properties of solid forms for active pharmaceutical ingredients (APIs) through cocrystallization is an important part of drug product development. However, it is difficult to know a priori which coformers will form cocrystals with a given API, and the current state-of-the-art for cocrystal discovery involves an expensive, time-consuming, and, at the early stages of pharmaceutical development, API material-limited experimental screen. We propose a systematic, high-throughput computational approach primarily aimed at identifying API/coformer pairs that are unlikely to lead to experimentally observable cocrystals and can therefore be eliminated with only a brief experimental check, from any experimental investigation. On the basis of a well-established crystal structure prediction (CSP) methodology, the proposed approach derives its efficiency by not requiring any expensive quantum mechanical calculations beyond those already performed for the CSP investigation of the neat API itself. The approach and assumptions are tested through a computational investigation on 30 potential 1:1 multicomponent systems (cocrystals and solvate) involving 3 active pharmaceutical ingredients and 9 coformers and one solvent. This is complemented with a detailed experimental investigation of all 30 pairs, which led to the discovery of five new cocrystals (three API-coformer combinations, a polymorphic cocrystal example, and one with different stoichiometries) and a cis-aconitic acid polymorph. The computational approach indicates that, for some APIs, a significant proportion of all potential API/coformer pairs could be investigated with only a brief experimental check, thereby saving considerable experimental effort.
| S-EPMC9337750 | biostudies-literature
Project description:Washing is a key step in pharmaceutical isolation to remove unwanted crystallization solvents and dissolved impurities (mother liquor) from the active pharmaceutical ingredient (API) filter cake to ensure the purity of the product whilst maximizing yield. It is therefore essential to avoid both product dissolution and impurity precipitation during washing, especially precipitation of impurities caused by the wash solvent acting as an antisolvent, affecting purity and causing agglomerate formation. This work investigates the wash solvent flow through a saturated filter cake to optimize washing by displacement, taking account of diffusional mechanisms and manipulating the wash contact time. Constant rate filtration/washing is employed in this study using readily available laboratory equipment. One advantage of using constant rate filtration in this work is that it allows for the collection of separate aliquots during all stages of filtration, washing, and deliquoring of the API cake. This enables a wash profile to be obtained, as well as providing an overall picture on the mass of API lost during isolation and so can assist in optimizing the washing strategy. Particle size analysis of damp cake obtained straight after washing is also performed using laser diffraction. This allowed for agglomerate formation caused during washing to be distinguished from agglomeration that would be caused by subsequent drying of the wet filter cake. This work aims at improving pharmaceutical product quality, increasing sustainability, and reducing manufacturing cost.
| S-EPMC8787817 | biostudies-literature
Project description:The continuous flow, enantioselective, organophotoredox catalytic asymmetric alkylation of aldehydes was studied, by using a homemade, custom-designed photoreactor for reactions under cryogenic conditions. Going from microfluidic conditions up to a 10 mL mesofluidic reactor, an increase of productivity by almost 18000 % compared to the batch reaction was demonstrated. Finally, for the first time, a stereoselective photoredox organocatalytic continuous flow reaction in a fully telescoped process for an active pharmaceutical ingredient (API)synthesis was successfully achieved. The final process consists of four units of operation: visible light-driven asymmetric catalytic benzylation under continuous flow, inline continuous work-up, neutralisation and a final oxidative amidation step afforded the pharmaceutically active molecule in 95 % e.e.
| S-EPMC9325444 | biostudies-literature
Project description: Not available
| S-EPMC11203897 | biostudies-literature
Project description:An environmental risk assessment is presented for mycophenolic acid (MPA), an immunosuppressive pharmaceutical used for prevention of organ rejection, and its prodrug mycophenolate mofetil (MPM). Mycophenolic acid will not significantly adsorb to activated sludge. In activated sludge, 14 C-MPA attained >80% degradation, supporting an older environmental fate test with the same compound. Based on n-octanol/water distribution coefficient (log DOW ) values of 2.28, 0.48, and ≤-1.54 at pH 5, 7, and 9, respectively, MPA is not expected to bioaccumulate. Sales amounts of MPA+MPM in Europe were used to derive predicted environmental concentrations (PECs) in surface waters; PECs were refined by including expected biodegradation in sewage treatment, average drinking water use, and average dilution of the effluents in the receiving waters per country. In addition, the exposure to pharmaceuticals in the environment (ePiE) model was run for 4 European catchments. The PECs were complemented with 110 measured environmental concentrations (MECs), ranging from below the limit of quantitation (<0.001 µg/L) to 0.656 µg/L. Predicted no-effect concentrations (PNECs) were derived from chronic tests with cyanobacteria, green algae, daphnids, and fish. The comparison of PECs and MECs with the PNECs resulted in a differentiated environmental risk assessment in which the risk ratio of PEC/PNEC or MEC/PNEC was <1 in most cases (mostly >90%), meaning no significant risk, but a potential risk to aquatic organisms in generally <10% of instances. Because this assessment reveals a partial risk, the following questions must be asked: How much risk is acceptable? and Through which measures can this risk be reduced? These questions are all the more important in view of limited alternatives for MPM and MPA and the serious consequences of not using them. Environ Toxicol Chem 2019;38:2259-2278. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
| S-EPMC6856805 | biostudies-literature
Project description:Washing is a key step in pharmaceutical isolation to remove the unwanted crystallization solvent (mother liquor) from the active pharmaceutical ingredient (API) filter cake. This study looks at strategies for optimal wash solvent selection, which minimizes the dissolution of API product crystals while preventing the precipitation of product or impurities. Selection of wash solvents to avoid both these phenomena can be challenging but is essential to maintain the yield, purity, and particle characteristics throughout the isolation process. An anti-solvent screening methodology has been developed to quantitatively evaluate the propensity for precipitation of APIs and their impurities of synthesis during washing. This is illustrated using paracetamol (PCM) and two typical impurities of synthesis during the washing process. The solubility of PCM in different binary wash solutions was measured to provide a basis for wash solvent selection. A map of wash solution composition boundaries for precipitation for the systems investigated was developed to depict where anti-solvent phenomena will take place. For some crystallization and wash solvent combinations investigated, as much as 90% of the dissolved PCM and over 10% of impurities present in the PCM saturated mother liquor were found to precipitate out. Such levels of uncontrolled crystallization during washing in a pharmaceutical isolation process can have a drastic effect on the final product purity. Precipitation of both the product and impurities from the mother liquor can be avoided by using a solvent in which the API has a solubility similar to that in the mother liquor; for example, the use of acetonitrile as a wash solvent does not result in precipitation of either the PCM API or its impurities. However, the high solubility of PCM in acetonitrile would result in noticeable dissolution of API during washing and would lead to agglomeration during the subsequent drying step. Contrarily, the use of n-heptane as a wash solvent for a PCM crystal slurry resulted in the highest amount of precipitation among the solvent pairs evaluated. This can be mitigated by designing a multi-stage washing strategy where wash solutions of differing wash solvent concentrations are used to minimize step changes in solubility when the mother liquor and the wash solvent come into contact.
| S-EPMC8057229 | biostudies-literature
Project description:The enhancement of the properties (i.e., poor solubility and low bioavailability) of currently available active pharmaceutical ingredients (APIs) is one of the major goals of modern pharmaceutical sciences. Among different strategies, a novel and innovative route to reach this milestone seems to be the application of nanotechnology, especially the incorporation of APIs into porous membranes composed of pores of nanometric size and made of nontoxic materials. Therefore, in this work, taking the antipsychotic API aripiprazole (APZ) infiltrated into various types of mesoporous matrices (anodic aluminum oxide, native, and silanized silica) characterized by similar pore diameters (d = 8-10 nm) as an example, we showed the advantage of incorporated systems in comparison to the bulk substance considering the crystallization kinetics, molecular dynamics, and physical stability. Calorimetric investigations supported by the temperature-dependent X-ray diffraction measurements revealed that in the bulk system the recrystallization of polymorph III, which next is converted to the mixture of forms IV and I, is visible, while in the case of confined samples polymorphic forms I and III of APZ are produced upon heating of the molten API with different rates. Importantly, the two-step crystallization observed in thermograms obtained for the API infiltrated into native silica templates may suggest crystal formation by the interfacial and core molecules. Furthermore, dielectric studies enabled us to conclude that there is no trace of crystallization of spatially restricted API during one month of storage at T = 298 K. Finally, we found that in contrast to the crystalline and amorphous bulk samples, all examined confined systems show a logarithmic increase in API dissolution over time (very close to a prolonged release effect) without any sign of precipitation. Our data demonstrated that mesoporous matrices appear to be interesting candidates as carriers for unstable amorphous APIs, like APZ. In addition to protecting them against crystallization, they can provide the desired prolonged release effect, which may increase the drug concentration in the blood (resulting in higher bioavailability). We believe that the "nanostructirization" in terms of the application of porous membranes as a novel generation of drug carriers might open unique perspectives in the further development of drugs characterized by prolonged release.
| S-EPMC10630940 | biostudies-literature
Project description:The purpose of this study was to predict in vivo performance of three oral products of Etoricoxib (Arcoxia® as reference and two generic formulations in development) by conducting in vivo predictive dissolution with GIS (Gastro Intestinal Simulator) and computational analysis. Those predictions were compared with the results from previous bioequivalence (BE) human studies. Product dissolution studies were performed using a computer-controlled multicompartmental dissolution device (GIS) equipped with three dissolution chambers, representing stomach, duodenum, and jejunum, with integrated transit times and secretion rates. The measured dissolved amounts were modelled in each compartment with a set of differential equations representing transit, dissolution, and precipitation processes. The observed drug concentration by in vitro dissolution studies were directly convoluted with permeability and disposition parameters from literature to generate the predicted plasma concentrations. The GIS was able to detect the dissolution differences among reference and generic formulations in the gastric chamber where the drug solubility is high (pH 2) while the USP 2 standard dissolution test at pH 2 did not show any difference. Therefore, the current study confirms the importance of multicompartmental dissolution testing for weak bases as observed for other case examples but also the impact of excipients on duodenal and jejunal in vivo behavior.
| S-EPMC8067797 | biostudies-literature
Project description:N-nitrosamines, which are well-known pro-mutagens, are found in drugs, pickled food and tobacco. Therefore, controlling their concentrations is very important. When an HPLC, GC or NMR analysis is conducted to investigate certain asymmetrical N-nitrosamines, two sets of signals attributed to the asymmetric N-nitrosamine isomers are usually observed. However, few reports on the NMR assignment of asymmetrical N-nitrosamine isomers have been published. In this study, we investigated the NMR assignments of the Z/E isomers of six asymmetrical N-nitrosamines by means of density functional theory (DFT) calculations. The configuration of the major isomer of asymmetrical N-nitrosamine 3 was the Z-configuration. The configuration of the major isomers of asymmetrical N-nitrosamines 4-7 was the E-configuration. Then, we determined the Z/E ratios of these asymmetrical N-nitrosamines by means of variable temperature (VT) and room temperature (RT) 1H-NMR experiments. The ratios of the Z/E isomer 3 quickly increased beyond 100% in the VT 1H NMR experiments. The ratios of Z/E isomers 4-7 were increased in the range of 10-60% in the VT 1H NMR experiments. The results of this study indicate that identifying the isomers of asymmetrical N-nitrosamine is necessary to control the quality of N-nitrosamines for active pharmaceutical ingredients (APIs).
| S-EPMC9331877 | biostudies-literature
Project description:Integrated API and drug product processing enable molecules with high clinical efficacy but poor physicochemical characteristics to be commercialized by direct co-processing with excipients to produce advanced multicomponent intermediates. Furthermore, developing isolation-free frameworks would enable end-to-end continuous processing of drugs. The aim of this work was to purify a model API (sodium ibuprofen) and impurity (ibuprofen ethyl ester) system and then directly process it into a solid-state formulation without isolating a solid API phase. Confined agitated bed crystallization is proposed to purify a liquid stream of impure API from 4% to 0.2% w/w impurity content through periodic or parallelized operations. This stream is combined with a polymer solution in an intermediary tank, enabling the API to be spray coated directly onto microcrystalline cellulose beads. The spray coating process was developed using a Design of Experiments approach, allowing control over the drug loading efficiency and the crystallinity of the API on the beads by altering the process parameters. The DoE study indicated that the solvent volume was the dominant factor controlling the drug loading efficiency, while a combination of factors influenced the crystallinity. The products from the fluidized bed are ideal for processing into final drug products and can subsequently be coated to control drug release.
| S-EPMC9145956 | biostudies-literature