Dissolution testing of prolonged-release tablets using experimental design approach

Dissolution testing is an essential tool in the pharmaceutical industry and is used in formulation and process development, in monitoring of the manufacturing process, as a quality control test, to predict the in vivo performance. The purpose of this study is to evaluate the behaviour of the test and reference products using conventional dissolution apparatus basket and paddle, with tendency to evaluate the dependence of the in vitro dissolution of the dissolution test conditions (dissolution apparatus, medium, agitation, pH). Experimental design (ED) approach has been employed for assessment of the discriminatory properties of different dissolution conditions. The responses statistically evaluated were: f2 similarity factor and the difference in the dissolution rate between the test and reference product, expressed in percentage, at every time point. Furthermore, this study focusses on developing a statistically reliable mathematical model for predicting discriminatory experimental conditions. Research Article Dissolution testing of prolonged-release tablets using experimental design approach Blagica Manchevska*, Filip Smilcevski, Maja H Gigovska, Packa Antovska and Sonja Ugarkovic Research & Development, ALKALOID AD, Skopje, Republic of North Macedonia Received: 22 September, 2020 Accepted: 05 October, 2020 Published: 06 October, 2020 *Corresponding author: Blagica Manchevska, Research & Development, ALKALOID AD, Skopje, Republic of North Macedonia, Tel: +389-71-214-655; E-mail:


Introduction
A logical, systematic approach taking into consideration both scientifi c and regulatory principles, should be followed when developing a dissolution method. Properly designed dissolution tests will guide and accelerate drug development, assess batch to batch quality of a drug product, compare new or generic formulations with an existing product, assess the stability of the drug product, ensure the product quality in case of certain scale-up and post approval changes and provide a basis for achieving an in vitro/in vivo correlation. The method should also be challenged to discriminate between batches of material with different quality attributes.
Recently, Experimental Design (ED) have been widely used to understand the effects of multidimensional and interactions of input factors on the output responses of pharmaceutical products and analytical methods [1]. ED is a systematic approach to dissolution method development that begins with predefi ned objectives, emphasizes product and process understanding and sets up process control based on sound science. The knowledge obtained during development may be used to support the establishment of an operable design space with suitable process controls during the life cycle of the product. These principles are now being considered for application to analytical methods through what is being termed Analytical Quality by Design (AQbD) [2].
In this study, the experimental condition parameters for dissolution testing of the drug product have been evaluated.
In order to characterize the release from the dosage form adequately, it is recognized that a drug release profi le should be generated, in which release (dissolution) values are determined as a function of time [3]. The experimental test conditions should be discriminating enough ("mild" conditions) to detect formulation and manufacturing variables that may affect pharmaceutical product performance. The following independent variables have been considered: media volume, different pH media, use of apparatus (basket and paddle) and different rotation speed. The purpose of this dissolution study is to evaluate the behaviour of the test and reference products to determine the dependency of the in vitro dissolution of the dissolution test conditions [4]. The objective is to assess the discriminatory potential of the dissolution method dependent Citation: Manchevska B, Smilcevski F, Gigovska MH, Antovska P, Ugarkovic S (2020) Dissolution testing of prolonged-release tablets using experimental design approach. Open J Anal Bioanal Chem 4(1): 034-039. DOI: https://dx.doi.org/10.17352/ojabc.000022 from all the regulatory permitted parameters. The responses statistically evaluated are: f 2 similarity factor and the difference in the dissolution rate between the test and reference product, expressed in percentage, at every time point.

Materials and methods
Chemicals and reagents: Analytical grade acetonitrile, methanol, sodium heptansulfonate, phosphoric acid, sodium hydroxide, sodium chloride, hydrochloric acid, sodium acetate, acetic acid and potassium hydrogen phosphate were purchased from Merck (Darmstadt, Germany). Water was purifi ed by a Werner water purifi cation system, obtained in-house at Alkaloid AD Skopje, Skopje, Republic of North Macedonia.
Experimental design: Experimental runs were designed using software MODDE Go ver.12.0.1.3948 (Umetrics, Sweden). D-optimal quadratic design was applied for examining 4 independent variables (factors) at different levels within 24 runs. All the parameters from the dissolution method have been included: media volume, different pH media, use of apparatus (basket and paddle) and different rotation speed. The levels of the independent variables include the entire working spectrum from regulatory aspect. Summary of the design, the coded and actual experimental levels based on two-factorial three-level approach and the experimental matrix are given in Tables 1-3 respectably. The selection of the input factors was performed with intention for the design space to include all the regulatory permitted dissolution parameters. In order to gain more information, the design was enabled with "centre points" option to include mid values of each factor in the experimental design to check for lack of fi t and curvature. Thus, a total of 24 runs were arrived for experimentation including 3 centre points.
Chromatographic method: Quantifi cation was performed using HPLC method. HPLC studies were carried out on Agilent 1200 Series liquid chromatograph (Agilent Technologies Inc., Santa Carla, USA) equipped with a Photo diode array detector and UV detector. The mobile phase was comprised of 1.1 g/l sodium heptansulfonate solution adjusted to pH 2.0, acetonitrile and methanol in ratio 70:10:20 (v/v/v) at a fl ow rate of 0.8 ml/min. Kromasil C18 150 mm x 4.6 mm i.d; 5 μm column was used, maintained at 55°C. Detection was at 230 nm wavelength. Run time of 12 minutes is utilized with injection volume of 50 μl from the sample and the standard solution. Standard solution was prepared in fi nal concentration of 0.08 mg/ml. Dissolution sample solutions at predefi ned intervals were withdrawn and fi ltered through 0.45 μm regenerated cellulose membrane fi lter.

Results and discussion
In order to predict the variability of the results for response variables in relationship with the independent variables within proposed acceptance criteria, the results from the experiments were evaluated. Partial least squares technique (PLS) has been used as a nonlinear regression method for fi tting a model to the data. This type of analysis has two objectives: to approximate the response variables and independent variables     The apparatus is a qualitative factor, which means that the value of the coeffi cients origins from the infl uence of the volume, increasing the volume contributes to increasement of the similarity factor f 2 . Furthermore, the volume has different effect on different type of apparatus.   Response variables are given in Table 5. An f 2 value between 50 and 100 suggests that the two dissolution profi les are Citation: Manchevska B, Smilcevski F, Gigovska MH, Antovska P, Ugarkovic S (2020) Dissolution testing of prolonged-release tablets using experimental design approach. Open J Anal Bioanal Chem 4(1): 034-039. DOI: https://dx.doi.org/10.17352/ojabc.000022  The difference of the percent released in the time points up to 2 hours is less than 5%, which confi rms the similarity of the dissolution profi les of both products.

Conclusions
The goal of a well-characterized method development effort is to characterize and develop a reliable method that can be demonstrated with a high degree of assurance to consistently produce data meeting predefi ned criteria when operated within defi ned boundaries.
From the above data it can be concluded that all the variable conditions of the dissolution testing with conventional apparatus basket and paddle result in similar dissolution profi les of the test and reference product. According to the sweet spot plot, design space of the analytical method can be defi ned where the results are independent from the test conditions. In vitro dissolution of both drug products is independent of the dissolution test conditions. The proposed experimental design approach was able to identify critical factors and the gained information could aid in general decision making.