A study on the influence of the formulation factors on in vitro release of ketoprofen from sustained release tablets

Objectives. The aim of this study was to investigate the influence of formulation factors on in vitro release of ketoprofen from sustained release inert matrix tablets. Materials and methods. Laboratory scale, Ketoprofen sustained release inert matrix tablets were manufactured using Kollidon® SR as matrix formator, by direct tableting of powder blends. The influence of the formulation factors (X1 – matrix formator excipient and X2 – diluent type) on in vitro release of ketoprofen from sustained release tablets was studied by using a full factorial 23 experimental plan. Outcomes. Pharmacotechnical characterization of manufactured laboratory scale batches was performed and all 12 batches fulfilled European Pharmacopeia requests. In vitro release showed a sustained release profile in all cases. Variance analysis (ANOVA) showed a good correlation between experimental conditions and answers. In vitro release testing was performed in phosphate buffer pH = 7.4. Percentage release was determined spectrophotometrically at 258 nm. A decrease in the rate of in vitro release was registered, up to 4 h and 6 h when lactose DC and mannitol DC were used as diluents, respectively. Isomalt DC has increased the rate of in vitro release up to 6 h. Conclusions. In vitro release data, corresponding to formulation N1 shoed a good fitting with Weitbull, KorshmeyerPeppas and Higuchi models while in vitro release data corresponding to formulation N8 presented a good fitting with Weitbull and Korsmeyer-Peppas. In case of formulations N1 and N8 a non-Fickian diffusion mechanism seems to be involved in drug release from the matrix tablets.

gastrointestinal tract, it has a short half-life, it is highly bound to plasma proteins. More, the bitter taste of ketoprofen must be masked and also the gastric mucosa must be protected from the irritation it may cause [4].
Modified-release dosage forms have gained much attention in the last half a century. Modified-release dosage forms, despite immediate release dosage forms can increase patient compliance and can offer some benefits: reducing the number of administrations, adequate plasmatic concentrations for a long period of time, enhanced bioavailability and compliance, low incidence of side effects [5].
Due to its excellent pharmaceutical properties (flowablity, compressibility etc), Kollidon® SR is often used in the manufacturing of sustained release inert matrix type tablets [6].
Several papers described different preparations of matrix type tablets with ketoprofen. The role of excipients in modulating drug released was discussed [7][8][9].
The aim of this paper was to investigate the influence of formulation factors (matrix formator percentage and diluent type) on the release of ketoprofen from sustained release tablets, inert matrix type.

Reagents
Monopotassium phosphate and sodium hydroxide were supplied by Cristal R Chim, Romania and POCH Basic, Poland, respectively. All reagents were analytical grade. All experiments were performed using distilled water.

Experimental design
Twelve formulations (laboratory batches) were manufactured according to a full-factorial experimental design with 2 factors and 3 levels. The experimental design, statistic parameters calculation and quality of fitting were performed by using Modde 12.0 (Sartorius Stedim Data Analytics AB, Sweden). Partial Least Squares (PLS) was chosen as a multivariate model. All formulation contained 100 mg ketoprofen/tablet and consisted of tablets with a total weight of 430 mg.
The independent factors, or formulation factors (Table  1), were matrix forming agent percent (X1) and the type of diluent (X2).  The dependent variables or responses are presented in Table 3. Release percentage after 4.0 h Y6 7 Release percentage after 5.0 h Y7 8 Release percentage after 6.0 h Y8 9 Release percentage after 8.0 h Y9 10 Release percentage after 10.0 h Y10 11 Release percentage after 12.0 h Y11

Tablets preparation
All powders were weighed on a three decimal places balance (Sartorius, Germany), passed through a 700 µm sieve and mixed in Mixer Y5, Y-shaped mixing vessel (Erweka, Germany). Tablets were prepared by means of direct compression method using an eccentric tablet press Korsch EK-0 (Korsch, Germany) equipped with an 8 mm die, with flat punch. Qualitative and quantitative composition of tablets (types 1-3) is presented in Table 4.

Pharmacotechnical characterization of tablets
For all tablet batches the determination of the following parameters was performed: uniformity of mass, friability and crushing strength.
Uniformity of mass was determined on 20 tablets, for each batch, according to European Pharmacopoeia -Uniformity of mass single-dose preparations, monograph.
Friability determination was performed on 20 tablets, for each batch, according to European Pharmacopoeia (Friability of uncoated tablets -monograph) using friability tester TA from Erweka GmbH, Germany.

In vitro release of ketoprofen from sustained release tablets
In vitro release was tested by means of a dissolution tester (PT-DT7 PharmaTest, Germany) equipped with rotative basket (

Release kinetics and statistical comparison of in vitro release profiles
Modeling of dissolution profiles was performed by means of DDSolver [10,11]. Tested kinetic models and corresponding equations are presented in Table 5.  Table 6 [12,13].
Evaluation of the goodness of fit of the kinetic model includes the calculation of several parameters: coefficient of determination (R2) and, meaningful, adjusted coefficient of determination (R2adj) [10,11].

Pharmacotechnical characteristics of tablets
For each tablet batch uniformity of mass, friability and crushing strength fulfilled requests of European Pharmacopoeia (data not shown).

In vitro release of ketoprofen
In vitro release profiles of ketoprofen are presented in Figure 1. In case of all formulations a sustained release is observed.

Experimental data fitting with the model
Variance analysis (ANOVA test) is used to test if results variability is due to formulation factors modification or it represents a natural variation related to phenomenon.
ANOVA test results showed good results for all dependent variables (p < 0.05 for the model and also p > 0.05 for error). According to data resulted from fitting with the model a good correlation between experimental conditions and experimentally obtained answers.
Results obtained by data fitting using PLS method are presented in figure 2.
As a conclusion, according to values of R2 and Q2, ANOVA results and residual curves, all answers are fitted satisfactory with chosen model.

Influence of formulation factors on in vitro release of ketoprofen
According to obtained data and analyzing coefficients of equation used for experimental data fitting ( Figure  4) the following conclusions can be presented: The matrix formator percentage (X1 -Kollidon® SR), as expected, has the role to slow the release of ketoprofen from tablets. By increasing percentage of matrix formator from 25 to 55%, the release rate is decreased at all release times (Y1-Y11). In case of tablets with increased matrix formator percentage, dissolution media can penetrates with difficulty, observed by a decreased release rate.
The diluent lactose DC (X2) has the role to decrease the release rate, between 0.5 h (Y1) and 4 h (Y6) due to its low solubility in dissolution media resulting in a prolonged release.
The diluent mannitol DC (X2) has the role to decrease the release rate, between 0.5 h (Y1) and 6 h (Y8) due to its low solubility in dissolution media resulting in a prolonged release. The solubility of mannitol DC in dissolution media is higher in comparison with the one of lactose DC.
The diluent isomalt DC (X2) increases the release rate due to its high solubility in dissolution media. Dissolution media can penetrate much easier into the matrix facilitating ketoprofen release. This observation

FIGURE 5. Matrix tablets before (left) and after (right) in vitro release test
is valid for dissolution times between 0.5 h (Y1) and 6 h (Y8).
The influence of the dissolution on matrix tablets is observed in figure 5.
By analyzing Figure 5 it can be observed that tablets are inert matrix type due to the fact that the matrix has was not eroded during in vitro release test. The matrix remained intact, just a light swelling process can be observed (mostly in diameter).

In vitro release profiles modeling
Two dissolution profiles were fitted by First order, Weitbull, Korsmeyer-Peppas and Higuchi models ( Table 7).
In case of N1 formulation, good fitting was achieved by using Weitbull, Korsmeyer-Peppas and Higuchi models while a fair fitting was achieved by using First order model. Release kinetics of formulation N8 was good fitted by Weitbull and Korsmeyer-Peppas models while using First order and Higuchi models a fair goodness of fit was obtained. A non-Fickian diffusion mechanism seems to be involved in drug release, considering formulations N1 and N8. Pharmacotechnical characterization of tablets showed a fulfill of pharmacopeial requests (uniformity of mass, friability and crushing strength).
The majority of the formulations presented a sustained release profile (for almost 12 h) while performing in vitro release test. Results (answers) were well fitted with chosen model meaning a good agreement between obtained results and predicted results was found.
By analyzing coefficients of equation used for experimental data fitting it can be concluded that matrix formator percentage has the most significant influence on ketoprofen release. Increasing this percentage of Kollidon® SR from 25% to 55% a decrease in release rate was observed resulting in a sustained release profile. While some diluents (lactose DC and mannitol DC) are able to decrease release rate (for the first 6 or 7 hours), isomalt DC increased release rate for the first 7 hours, due to its high solubility in dissolution media.
The release kinetics of two formulations (N1 and N8) presented a good fitting with Weitbull and Korsmeyer-Peppas models while a fair goodness of fit was observed by fitting data with First order and Higuchi models.
Inert matrix type sustained released tablets containing ketoprofen (a substance insoluble in water and with a short half-life) were manufactured using Kollidon® SR as matrix formator by means direct tableting. Formulations presented a sustained release profile for 12 h.