DEVELOPMENT AND FORMULATION OPTIMISATION OF MODIFIED RELEASE DOSAGE FORM USING QUALITY BY DESIGN – QbD APPROACH

Abstract

The aim of this work was to apply quality by Design approach for development of modified release tablets containing morphine sulfate. As a holistic approach, quality by design assembles predermined goals, product/formulation and process/process parameters understanding. Quality by design is science and risk assessment based. Variability is reduced by product and process understanding which translates into quality improvement, risk reduction and productivity enhancement. After the referent product evaluation, the primary goal was quality target product profile to be defined for modified release tablet containing morphine sulfate. The product is pharmaceutically equivalent to the referent product. The quality target product profile was used to guide the development of the product. Critical quality attributes of the product were defined based on prior knowledge and literature evaluation considering the type of products. The active substance – morphine sulfate pentahydrate was evaluated considering the physical characteristics: appearance, solubility, melting point, morphology of the particles, particle size distribution and the flowability. The crystals of morphine sulfate pentahydrate have prismatic to rhomboid form with affinity towards creating agglomerates. High SPAN values indicate wide size distribution and high degree of polydispersity of the particles. Considering the flowability, the active supstance has poor flowability. The characterization of the active supstance structure performed using Fourier-transform infrared spectroscopy, Differential scanning calorimetry, Termogravimetric analysis. Differential scanning calorimetry and termogravimetric analysis curve confirms the presence of crystal water in the molecule structure. The experimental results of the Fourier-transform infrared spectrum were in correlation with the theoretical results calculation using molecular modelling approach. In order to identify critical material attributes and critical process parameters, Failure Mode Effects Analysis was used as a risk assessment tool. Formulation and process development were in the direction to mitigate the level of risk of critical material attributes and critical process parameters. Formulation development was performed in two phases: design, formulation development and manufacturing process selections and formulation and manufacturing process optimisation. In the first phase, the selected manufacturing process was wet granulation with alcohol; and controlled release polymers were: hydroxypropyl methylcellulose K100 as intragranular polymer and hydroxypropyl methylcellulose K15 and hydroxypropyl methylcellulose K4 as extragranular excipients. The experimental design was performed using the software Design-Expert ® V7 (Stat-Ease, Inc., Minneapolis, USA). The formulation ‖design space” was obtained, and the few optimal formulations were characterized in aspect of flowability, assay of AS, release dissolution profile and the similarity with the RF was calculated. Manufacturing process development resulted in setting the Proven acceptable range (PAR) for the critical process parameters of the selected operation. The chopper speed was set in a range of 500 to 1500 rpm, granulation wet massing time to 1 to 5 min, mixing time with rate controlling polimer to 1 to 20 min., and mixing time with lubricant to 1 to 20 min. With QbD approach, the methodology and the tolls in the development of the product (formulation and process) a good founding was set for the next step in the development – the scale up of the process. After that stage, a control strategy (excipient and process) should be established in order for the product to meet its predetermined quality.