A study on the influence of the dissolution test factors on in vitro release of ibuprofen from sustained release tablets

Alexandra Pali1, Georgiana Cristina Ordean1, Greta Maria Pomian1, Luca Liviu Rus2, Rares Iuliu Iovanov1 1 Department of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania 2 Preclinical Department, Faculty of Medicine, “Lucian Blaga” University, Sibiu, Romania Ref: Ro J Pharm Pract. 2020;13(2) DOI: 10.37897/RJPhP.2020.2.6 CLINICAL STUDIES


INTRODUCTION
Release rate of APIs from solid pharmaceutical dosage forms and also absorption rate is determined by dissolution so in vitro release plays an important role in predicting biopharmaceutical profile of a drug [1].
According to the Biopharmaceutical Classification System (BCS), ibuprofen is included in class II (due to its high permeability and low solubility). Bioavailability of pharmaceutical dosage forms containing APIs included in BCS II is limited by dissolution rate [2].
Modified-release dosage forms are used in therapy for more than 50 years and are an important field for pharmaceutical companies (R&D) and also for academics. An ideal MR dosage form can improve therapy and can offer the patient the following benefits: reduced administration frequency, adequate plasmatic concentrations, enhanced bioavailability and compliance [3]. Formulation of ibuprofen and the strategies applied to modulate its delivery, to acquire specific therapeutic benefits, are still under research [4,5].
Oral bioavailability of a drug is dictated by physicochemical properties but also by physiological conditions [6].
In the manufacturing of sustained release matrix tablets, Kollidon® SR is often used due to its excellent pharmaceutical properties (flowability, compressibility etc.) [7].
There are a few studies describing the determination of critical parameters of drug substances that may influence the dissolution but also the comparison of different apparatuses and conditions (media, surfactants, stirring speed) [8,9].

AIM
The aim of this paper was to investigate the influence of in vitro release test parameters on the release of ibuprofen from sustained release inert matrix tablets.

Reagents
Monopotassium phosphate, sodium acetate and potassium chloride were supplied by Chemical Company, Romania. Sodium hydroxide, glacial acetic acid and concentrated hydrochloric acid were manufactured by Merck -Germany, Sigma Aldrich -Germany and Nordic Invest -Romania, respectively. All reagents were analytical grade. In all experiments distilled water was used.

Tablets preparation
All powders were weighed on a three decimal places balance (Sartorius, Germany), passed through an 800 µm sieve and mixed in Mixer Y5, Y-shaped mixing vessel (Erweka, Germany). Due to excellent properties of powder blends (flowability and compressibility -data not shown) tablets were prepared by means of direct compression method using an eccentric tablet press Korsch EK-0 (Korsch, Germany) equipped with a 9 mm die, with flat punch. Also crushing strength, friability and disintegration time were within the European Pharmacopoeia requirements (data not shown). Qualitative and quantitative composition of tablets is presented in Table 1.  Where: R t and T t are the percentage of reference and test profile, at time t and n is the number of sampling points.

According to European Medicines
Agency, values of f 2 between 50 and 100 indicate the sameness of two in vitro release profiles. Evaluation of the goodness of fit of a model includes the calculation of coefficient of determination (R 2 ) and of adjusted coefficient of determination (R 2 adj ) [11,12]. In vitro release profiles of ibuprofen in different dissolution condition are presented in Figure 2.

Influence of the dissolution media pH on in vitro release of ibuprofen
In both cases (rotative basket apparatus and rotative paddle apparatus) percentage drug release increases together with the increase of pH due to higher ibuprofen solubility in phosphate buffers in comparison with its solubility in acetate and hydrochloric buffers ( fig. 2).

Influence of dissolution apparatus type on in vitro release of ibuprofen
Dissolution apparatus type has a significative influence on in vitro release of ibuprofen. Hydrodynamic forces are much powerful in case of rotative paddle apparatus in comparison with rotative basket apparatus and consequently in vitro release is more rapid (fig. 3). Also, some excipients may remain on the sieve of the basket, somehow explaining why release on rotative basket apparatus is lower.
Similarity factors for release profiles (tested at the same pH and the same stirring speed but on different apparatus type) were calculated (Table 3).

Influence of stirring speed on in vitro release of ibuprofen
As presented in figure 4, a bigger stirring speed will determine a (1)

FIGURE 1. Ibuprofen solubility variation versus pH
faster in vitro release of ibuprofen from sustained release tablets. Again, hydrodynamics plays an important role on dissolution.
Similarity factors for release profiles (tested at the same pH and on the same apparatus type but using different stirring speed) were calculated (Table 4). In vitro release profiles modeling All dissolution profiles were fitted

CONCLUSIONS
Sustained release matrix tablets with ibuprofen were manufactured. Factors related to experimental design of in vitro release testing were dissolution media pH, apparatus type and stirring speed.
Solubility of ibuprofen and percentage drug release proved to increase together with the increase of pH.
Stirring speed can influence the release of ibuprofen from matrix tablets. At 100 rpm, because of much higher hydrodynamic forces, more active substance is released in comparison with 50 rpm. Also, a faster in vitro released was proved at 100 rpm. Release profiles generated in hydrochloric and acetic buffers are comparable (50 < f 2 < 100) but the sameness is not achieved in phosphate buffers (f 2 < 50).

FIGURE 4. Influence of stirring speed on in vitro release of ibuprofen (pH 7.2 a -rotative basket and b -rotative paddle; pH 6.8 c -rotative basket and d -rotative paddle; pH 5.4 e -rotative basket and f -rotative paddle; pH 1.2 g -rotative basket and h -rotative paddle)
Apparatus type is another factor that can influence the release of ibuprofen. In vitro release using paddle apparatus is faster in comparison with rotative basket apparatus. Sometimes excipients may get stuck on the sieve of the basket altering the release. Again, release profiles generated in hydrochloric and acetic buffers are comparable (50 < f 2 < 100) but the sameness is not achieved in phosphate buffers (f 2 < 50).
The modeling of release kinetics was performed by means of Weitbull, Korsmeyer-Peppas and Higuchi equations. Higuchi model resulted in a fair goodness of fit (sometimes poor especially at 100 rpm). On the other hand, good fitting was achived by using Weitbull and Korsmeyer-Peppas (except kinetic model 6.8 100 P). All kinetic model seemed to have a better goodness of fit in phosphate buffers and 50 rpm (both apparatuses) in comparison with hydrochloric and acetate (with the exceptions presented in Table 5).
In vitro release of ibuprofen from sustained release matrix tablets depends on dissolution media pH and release rate depends on judicious choice of dissolution test factors to made precise in vitro/in vivo correlations.