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A STELLA simulation model for in vitro dissolution testing of respirable size particles.

ABSTRACT: In vitro dissolution testing is a useful quality control tool to discriminate the formulations and to approximate the in vivo drug release profiles. A dissolution apparatus has been custom-made for dissolution testing of dry powder formulations in a small volume of stationary medium (25??L spread over 4.91?cm² area i.e. ~50 ?m thick). To understand the system and predict the key parameters which influence the dissolution of respirable size particles, a simulation model was constructed using STELLA modeling software. Using this model, the permeation (dissolution followed by diffusion through the membrane) of two anti-tubercular drugs of differing solubilities, moxifloxacin (17.68?±?0.85?mg?mL^-1) and ethionamide (0.46?±?0.02?mg?mL^-1), from the respirable size particles and their diffusion from a solution were simulated. The simulated permeation profiles of moxifloxacin from solution and respirable size particles were similar, indicating fast dissolution of the particles. However, the simulated permeation profile of ethionamide from respirable size particles showed slower permeation compared to the solution indicating the slow dissolution of the respirable size particles of ethionamide. The sensitivity analysis suggested that increased mucus volume and membrane thickness decreased the permeation of drug. While this model was useful in predicting and distinguishing the dissolution behaviours of respirable size moxifloxacin and ethionamide, further improvement could be made using appropriate initial parameter values obtained by experiments.

SUBMITTER: Eedara BB

PROVIDER: S-EPMC6898627 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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A STELLA simulation model for in vitro dissolution testing of respirable size particles.

Eedara Basanth Babu BB Tucker Ian G IG Das Shyamal C SC

Scientific reports 20191206 1

In vitro dissolution testing is a useful quality control tool to discriminate the formulations and to approximate the in vivo drug release profiles. A dissolution apparatus has been custom-made for dissolution testing of dry powder formulations in a small volume of stationary medium (25 μL spread over 4.91 cm<sup>2</sup> area i.e. ~50 μm thick). To understand the system and predict the key parameters which influence the dissolution of respirable size particles, a simulation model was constructed ...[more]

PMID: 31811249

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Project description:BackgroundMan-made vitreous fibres (MMVF) are produced on a large scale for thermal insulation purposes. After extensive studies of fibre effects in the 1980ies and 1990ies, the composition of MMVF was modified to reduce the fibrotic and cancerogenic potential via reduced biopersistence. However, occupational risks by handling, applying, disposing modern MMVF may be underestimated as the conventional regulatory classification -combining composition, in-vivo clearance and effects- seems to be based entirely on MMVF after removal of the binder.ResultsHere we report the oxide composition of 23 modern MMVF from Germany, Finland, UK, Denmark, Russia, China (five different producers) and one pre-1995 MMVF. We find that most of the investigated modern MMVF can be classified as "High-alumina, low-silica wool", but several were on or beyond the borderline to "pre-1995 Rock (Stone) wool". We then used well-established flow-through dissolution testing at pH 4.5 and pH 7.4, with and without binder, at various flow rates, to screen the biosolubility of 14 MMVF over 32 days. At the flow rate and acidic pH of reports that found 47 ng/cm2/h dissolution rate for reference biopersistent MMVF21 (without binder), we find rates from 17 to 90 ng/cm2/h for modern MMVF as customary in trade (with binder). Removing the binder accelerates the dissolution significantly, but not to the level of reference biosoluble MMVF34. We finally simulated handling or disposing of MMVF and measured size fractions in the aerosol. The respirable fraction of modern MMVF is low, but not less than pre-1995 MMVF.ConclusionsThe average composition of modern stone wool MMVF is different from historic biopersistent MMVF, but to a lesser extent than expected. The dissolution rates measured by abiotic methods indicate that the binder has a significant influence on dissolution via gel formation. Considering the content of respirable fibres, these findings imply that the risk assessment of modern stone wool may need to be revisited based on in-vivo studies of MMFV as marketed (with binder).

Project description:IntroductionDissolution is the amount of substance that goes into solution per unit time under standardised conditions of liquid/solid interface, solvent composition and temperature. Dissolution is one of the most important tools to predict the in-vivo bioavailability and in some cases to determine bioequivalence and assure interchangeability.AimTo compare the differences in dissolution behaviour of solid dosage forms between innovators (reference products) and their generic counterparts (tested products).MethodsFour replicates for each batch of 37 tested medicines was carried out using A PT-DT70 dissolution tester from Pharma Test. A total of 13 branded medicines and 24 generic counterparts were obtained locally and internationally to detect any differences in their dissolution behaviour. They were tested according to the British Pharmacopeia, European Pharmacopeia and the US Pharmacopeia with the rate of dissolution determined by ultra-violet Spectrophotometery.ResultsMost tested medicines complied with the pharmacopoeial specifications and achieved 85% dissolution in 60 min. However, some generic medicines showed significant differences in dissolution rate at 60 and 120 min. Many generic medicines showed a slower dissolution rate than their branded counterparts such as the generic forms of omeprazole 20 mg. Some showed an incomplete dissolution such as the generic form of nifedipine 10 mg. Other generics showed faster dissolution rate than their branded counterpart such as the generic forms of meloxicam 15 mg. Moreover, some generics from different batches of the same manufacturer showed significant differences in their dissolution rate such as the generic forms of meloxicam 7.5 mg. Nevertheless, some generic medicines violated the EMA and the FDA guidelines for industry when they failed to achieve 85% dissolution at 60 min, such as the generic form of diclofenac sodium 50 mg.ConclusionMost medicines in this study complied with the pharmacopeial limits. However, some generics dissolved differently than their branded counterparts. This can clearly question the interchangeability between the branded and its generic counterpart or even among generics.

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A STELLA simulation model for in vitro dissolution testing of respirable size particles.

Publications

A STELLA simulation model for in vitro dissolution testing of respirable size particles.

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