Dissolution
Dotaz
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sv.
- MeSH
- chemický průmysl MeSH
- chemie MeSH
- farmaceutická technologie MeSH
- rozpouštědla MeSH
- Publikační typ
- periodika MeSH
- Konspekt
- Chemie. Mineralogické vědy
- NLK Obory
- chemie, klinická chemie
In vitro dissolution testing is commonly performed to ensure that oral solid dosage medicines are of high quality and will achieve their targeted in vivo performance. However, this testing is time and material consuming. Therefore, pharmaceutical companies have been developing predictive dissolution models (PDMs) for drug product release based on fast at- and/or on-line measurements, including real-time release testing of dissolution (RTRT-D). Recently, PDMs have seen acceptance by major regulatory bodies as release tests for the dissolution critical quality attribute. In this paper, several methodologies are described to develop and validate a fit-for-purpose model, then to implement it as a surrogate release test for dissolution. These approaches are further exemplified by real-life case studies, which demonstrate that PDMs for release are not only viable but more sustainable than in vitro dissolution testing and can significantly accelerate drug product release. The rise of continuous manufacturing within the pharmaceutical industry further favors the implementation of real-time release testing. Therefore, a steep uptake of PDMs for release is expected once this methodology is globally accepted. To that end, it is advantageous for global regulators and pharmaceutical innovators to coalesce around a harmonized set of expectations for development, validation, implementation, and lifecycle of PDMs as part of drug product release testing.
- MeSH
- aplikace orální MeSH
- farmaceutická chemie metody MeSH
- léčivé přípravky chemie aplikace a dávkování MeSH
- lidé MeSH
- příprava léků MeSH
- rozpustnost MeSH
- schvalování léčiv MeSH
- uvolňování léčiv * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Biorelevant dissolution instruments represent an important tool for pharmaceutical research and development. These instruments are designed to simulate the dissolution of drug formulations in conditions most closely mimicking the gastrointestinal tract. In this work, we focused on the optimization of dissolution compartments/vessels for an updated version of the biorelevant dissolution apparatus-Golem v2. We designed eight compartments of uniform size but different inner geometry. The dissolution performance of the compartments was tested using immediate release caffeine tablets and evaluated by standard statistical methods and principal component analysis. Based on two phases of dissolution testing (using 250 and 100 mL of dissolution medium), we selected two compartment types yielding the highest measurement reproducibility. We also confirmed a statistically ssignificant effect of agitation rate and dissolution volume on the extent of drug dissolved and measurement reproducibility.
Merala sa rozpustnost kalciového antagonistu nimodipínu vo vode a vo vodných roztokoch β-cyklodextrínu (β-CD, až 0,014 mol/l) a rozpustnejšieho hydroxypropyl-β-cyklodextrínu (HP-β-CD, až 0,05 mol/l) s priememým stupňom substitúcie 0,8. Zvýšenie rozpustnosti bolo priamoúmerné koncentrácii cyklodextrínu, pričom v roztoku β-CD bola rozpustnost nimodipínu až 2,2 mg/100 ml, v roztoku HP-β-CD až 6 mg/100 ml, za daných podmienok po 14 dňoch rozpúšťania. Riedením vodou sa takto solubilizovaný nimodipín nezráža. Zo smerníc lineárnych fázových diagramov rozpustnosti sa vypočítali príslušné asociačné konštanty tvorby inklúznych komplexov (1:1) v roztoku nimodipínu s β-CD (401 mol-1 1) a s HP-p-CD (268 mol-1 1). Kinetika rozpúšťania substancie nimodipínu v roztoku HP-β-CD sledovaná od 3 min. až po 14 dní sa vyznačovala oscilováním medzi presýteným roztokom a rozpúšťacou rovnováhou, pre prípravu stálych roztokov v rozpúšťacej rovnováhe sa preto odporúča merať disolučnú krivku v dlhšom časovom intervale. Rozotieracou metódou sa pripravili veľmi lahko rozpustné tuhé zmesi nimodipínu s HP-β-CD a termickou analýzou sa dokázala tvorba tuhého komplexu 1:1.
The solubility of the calcium antagonist nimodipine was measured in water and in aqueous solutions of both β-cyclodextrin (β-CD, up to 0.014 mol/l) and the more soluble hydroxypropyl-β-cyclodextrin (HP-β-CD, up to 0.05 mol/l) with an average substitution degree of 0.8. The solubility enhancement of nimodipine was proportional to the cyclodextrin concentration, it was up to 2.2 mg/100 ml and 6 mg/100 ml in the respective solutions of β-CD and HP-β-CD, under the studied conditions, after 14 days of nimodipine dissolution. The solubilized nimodipine does not precipitate on diluting the Solutions with water. The association constant of the inclusion complexes (1:1) were evaluated from the slopes of the linear phase solubility diagrams of nimodipine in the respective solutions of β-CD (401 mol-1 1) and HP-β-CD (268 mol-1 1). The kinetics of dissolution of the solid nimodipine in the solution of HP-β-CD was followed from 3 min till 14 days and oscillations between the supersaturation and the equilibrium solution were observed. Long term measurements of the dissolution curve are thus recommended if stable solutions, in terms of the solubility equilibrium, are to be prepared. Easily soluble solid mixtures of nimodipine with HP-β-CD were prepared by the kneading method and the formation of the solid complex 1:1 was demonstrated by the differential thermal analysis.
Dissolution studies bring important characteristics of the oral preparations. They are used for estimation of behavior of new dosage forms in vivo. Pharmacopoeias prescribe dissolution testing using buffers, which can contain enzymes and surfactants. However, current methods are not always mimicking the real conditions in vivo. The preparations administered orally pass through the gastrointestinal tract (GIT) at varying pH values. A dissolution method was developed intended for drug targeting into the colon using the time periods and pH of buffers corresponding to those in the GIT. The dissolution method in the presence or absence of ?-glucosidase was used to evaluate drug release from pellets coated with a polysaccharide or polyacrylic.
The vaginal rings research is almost exclusively focused on rings for human medicine, although the dosage form offers improvement of therapeutic effect in other mammals as well. This contribution studied an effect of varying dimension parameters (diameter 20, 30 or 40 mm; height 3, 4 or 5 mm; width of annulus 5, 7.5 or 10 mm) on mechanical properties and dissolution behaviour of silicone vaginal rings with constant drug amount, intended for use in dogs. Results showed that altering dimensions influenced mechanical properties (compressive force, tensile strength and resistance of removal thread), in vitro drug release and water uptake. The removal thread resistance was increasing with increasing height and width. Compression force was higher for the rings with smaller diameter. The total drug release was increasing with decreasing height and rising diameter, surface area and water uptake during dissolution test. The initial dissolution rate was slower for the rings with higher width. As the best candidate for use in model dog subjects, the ring with 30 mm diameter, 3 mm height and 7.5 mm width was found. These drug-free vaginal rings were further tested in in vivo safety study. The results did not show any major deviation from the physiological conditions. Graphical abstract.
- MeSH
- antikoncepční prostředky ženské * MeSH
- mechanické jevy MeSH
- pevnost v tahu MeSH
- psi MeSH
- rozpustnost MeSH
- testy toxicity MeSH
- uvolňování léčiv MeSH
- zvířata MeSH
- Check Tag
- psi MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Práce podává souborné výsledky studia rozpouštění kalciového antagonisty nimodipinu ve vodnýchroztocích devíti cyklodextrinů, nativního β-cyklodextrinu (β-CD) a jeho derivátů hydroxyethyl-β-CD(HE-β-CD), tří hydroxypropyl-β-CD (HP-β-CD) s navzájem různým stupněm substituce, methyl-β--CD (M-β-CD), nativního α-cyklodextrinu (α-CD), hydroxypropyl-α-CD (HP-α-CD) a hydroxypropyl--γ-CD (HP-γ-CD). Rozpouštění nimodipinu bylo sledováno v závislosti na čase (až 14 dní) a koncentracicyklodextrinu zhruba do 0,07 mol/l, s výjimkouméně rozpustného β-CD.Ve sledovanémrozmezíbyly pozorovány vesměs lineární fázové diagramy rozpustnosti nimodipinu v roztocích studovanýchcyklodextrinů, z nichž byly vyhodnoceny konstanty stability inkluzních komplexů nimodipin –cyklodextrin (1:1) a odvozeny lineární empirické rovnice pro výpočet koncentrace solubilizovanéhonimodipinu při dané koncentraci cyklodextrinu.Nejúčinnějším solubilizérem nimodipinu je M-β-CD,dobrou solubilizační účinnost mají též HE-β-CD a HP-β-CD s nízkým stupněm substituce, kterémohou být přijatelné i pro přípravu parenterálních roztoků nimodipinu.
The results of a comprehensive study of the dissolution of the calcium antagonist nimodipine inaqueous solutions of nine cyclodextrins are reported. The used cyclodextrins were native β-cyclodextrin(β-CD), its derivatives hydroxyethyl-β-CD (HE-β-CD), three hydroxypropyl-β-CD (HP-β-CD)with various degree of substitution and methyl-β-CD (M-β-CD), native α-cyclodextrin (α-CD),hydroxypropyl-α-CD (HP-α-CD) and hydroxypropyl-γ-CD (HP-γ-CD). The nimodipine dissolutionwas studied as a function of time (up to 14 days) and cyclodextrin concentration up to 0.07 mol/l,excepting the less soluble β-CD. In this range of cyclodextrin concentration, linear phase diagramsof nimodipine solubility in the cyclodextrin solutions were observed. From them we derived thestability constants of the inclusions complexes nimodipine – cyclodextrin (1:1) as well as theempirical linear equations for the calculation of the saturated nimodipine concentration at a givencyclodextrin concentration. The most efficient solubiliser of nimodipine was M-β-CD, a good solubilizingefficiency was also shown by HE-β-CD and HP-β-CDs (with a low degree of substitution),which may be acceptable for the preparation of parenteral nimodipine solutions.
Different batches of atorvastatin, represented by two immediate release formulation designs, were studied using a novel dynamic dissolution apparatus, simulating stomach and small intestine. A universal dissolution method was employed which simulated the physiology of human gastrointestinal tract, including the precise chyme transit behavior and biorelevant conditions. The multicompartmental dissolution data allowed direct observation and qualitative discrimination of the differences resulting from highly pH dependent dissolution behavior of the tested batches. Further evaluation of results was performed using IVIVC/IVIVR development. While satisfactory correlation could not be achieved using a conventional deconvolution based-model, promising results were obtained through the use of a nonconventional approach exploiting the complex compartmental dissolution data.
- MeSH
- atorvastatin chemie terapeutické užití MeSH
- farmaceutická chemie MeSH
- gastrointestinální trakt účinky léků fyziologie MeSH
- lidé MeSH
- tenké střevo účinky léků MeSH
- uvolňování léčiv * MeSH
- zdravotnické prostředky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
