Dissolution method
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Warfarín je stále rozsiahle diskutovaným liečivom s úzkym terapeutickým indexom. Jeho generické náhrady boli v minulosti príčinou krvácavosti. Ako príčina boli diskutované kvalita substancie a miera obsahovej rovnorodosti. Kvalitu substancie je možné posúdiť vhodnou disolučnou metódou. Doteraz existuje pre tablety s obsahom warfarínu oficiálna miešadlová disolučná metóda s vodným médiom, ktorá nemá rozlišujúci charakter. V priebehu prvých 15 minút u nej dochádza k takmer úplnému uvoľneniu účinnej látky z liekovej formy, čím je znemožnené vzájomné porovnanie tabliet od rôznych výrobcov alebo sledovanie prípadných zmien v priebehu stabilitných testov. Z literatúry je známa aj metóda s médiom s pH 6,8, ktorá sa odporúča ako vhodná alternatíva. Cieľom tejto práce bolo vyskúšať, či táto metóda pri dvoch rýchlostiach otáčok (50 a 25 rpm) bude vhodná k výpočtom faktorov podobnosti a rozdielnosti a prípadne bude mať rozlišujúci charakter vzhľadom k veľkosti častíc účinnej látky a pevnosti tabliet. Za týmto účelom boli vyrobené tablety s obsahom 10 mg sodnej soli warfarínu vo forme kryštalického klathrátu s izopropanolom. Pripravené tablety sa líšili veľkosťou častíc účinnej látky (d50 = 4,8, resp. 22,5 μm) a ich radiálnou pevnosťou (30, resp. 100 N). Obsahová rovnorodosť tabliet, bola overená pomocou indexu spôsobilosti procesu (Cpk) a Bergumovej metódy. Bolo potvrdené, že disolučné médium s pH 6,8 umožňuje vzájomné porovnanie disolučných profilov pomocou výpočtov faktorov podobnosti a rozdielnosti, no za daných podmienok nemá rozlišujúci charakter.
Warfarin is intensively discussed drug with narrow therapeutic index. In the past, its generic substitution was identified as a cause of bleeding. Altered quality of the active substance or varying drug content was discussed. The substance quality can be evaluated with adequate dissolution method. An official dissolution method with aqueous medium exists, however this method is non-discriminatory. In the first 15 minutes the whole amount of the active pharmaceutical ingredient is released from a tested dosage form, which does not allow comparison between tablets from different producers and it also makes difficult to track the changes throughout stability testing. In the literature, there is a well known method using pH 6.8 buffer, which seems to be a suitable alternative to water. The aim of this study was to prove, that this alternative medium, when two stirring speeds for dissolution (50 or 25 rpm) are used, will be suitable for calculation of similarity and difference factor and if it will be eventually discriminatory with regard to particle size and radial hardness. For this purpose we prepared tablets with 10 mg of warfarin sodium in form of crystalline clathrate with isopropanol. Tablets differed by particle size of active pharmaceutical ingredient (d50 = 4.8, or d50 = 22.5 μm respectively) and by radial hardness (30, or 100 N respectively). The content uniformity of the tablets was determined using process capability index (Cpk) and Bergum method. It was confirmed that the dissolution medium with pH of 6.8 allows comparison of dissolution profiles by similarity and difference factors but under given conditions it is not discriminatory.
- Klíčová slova
- disoluční metoda, disoluční metoda, faktor rozdílnosti, faktor podobnosti, radiální pevnost,
- MeSH
- koncentrace vodíkových iontů MeSH
- kontrola léčiv a omamných látek metody MeSH
- rozpouštědla chemie MeSH
- tablety analýza farmakokinetika MeSH
- terapeutická ekvivalence * MeSH
- terapeutický index léčiva MeSH
- uvolňování léčiv * MeSH
- velikost částic MeSH
- výzkum MeSH
- warfarin * chemie MeSH
Flow-through cell dissolution method was implemented in pharmacopoeias in 1990 and since that time its usage significantly increased. It is employed in oral dosage forms with controlled drug release to measure dissolved drug amount within particular time intervals and to characterize pure drug properties (apparent dissolution). Modified flow-through cell is used to determine the drug dissolution from lipophilic dosage forms such as suppositories and soft capsules. Recently, few modifications of this method were published in order to provide drug release studies from parenteral controlled release products and inhalation dosage forms. Review article is presenting last innovations in this area, i.e. new adjustment and arrangement of flow-through cell method, to assess drug release from implants, micro- and nanoparticulate systems, stents and inhalation medicaments in the way more corresponding to in-vivo conditions.
- Klíčová slova
- in vitro - in vivo,
- MeSH
- aplikace inhalační MeSH
- biologická dostupnost MeSH
- elektrochemické techniky * metody přístrojové vybavení využití MeSH
- farmaceutická technologie normy MeSH
- hodnocení léčiv * MeSH
- lékové formy normy MeSH
- lékové transportní systémy * MeSH
- lidé MeSH
- nanočástice MeSH
- protézy a implantáty MeSH
- referenční knihy normy MeSH
- rozpustnost * MeSH
- stenty MeSH
- Check Tag
- lidé 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.
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
A drug dissolution profile is one of the most critical dosage form characteristics with immediate and controlled drug release. Comparing the dissolution profiles of different pharmaceutical products plays a key role before starting the bioequivalence or stability studies. General recommendations for dissolution profile comparison are mentioned by the EMA and FDA guidelines. However, neither the EMA nor the FDA provides unambiguous instructions for comparing the dissolution curves, except for calculating the similarity factor f2. In agreement with the EMA and FDA strategy for comparing the dissolution profiles, this manuscript provides an overview of suitable statistical methods (CI derivation for f2 based on bootstrap, CI derivation for the difference between reference and test samples, Mahalanobis distance, model-dependent approach and maximum deviation method), their procedures and limitations. However, usage of statistical approaches for the above-described methods can be met with difficulties, especially when combined with the requirement of practice for robust and straightforward techniques for data evaluation. Therefore, the bootstrap to derive the CI for f2 or CI derivation for the difference between reference and test samples was selected as the method of choice.
- Publikační typ
- časopisecké články MeSH
The rising demands on discriminatory and prediction abilities of dissolution methods and the increasing complexity of new drug products are the main driving forces of the progress in this field. The research moves forward as imperfections and shortcomings of classical methods are being described, and where the capabilities of the contemporary methods are insufficient, new methods are being developed. The review discusses these advances with respect to the issues that currently draw the most attention, i.e. correct simulation of hydrodynamics and stress forces, maintenance of sink conditions, study of precipitation, use of biorelevant media and the employment of more physiologically relevant methods in general.
