Evaluation of dilution capacity and compaction behaviour of the excipients co-processed by in situ fluidized bed melt granulation

Abstract

1. INTRODUCTION Co-processing has emerged as a suitable approach to meet the increasing demands for excipients with improved tableting performance. Apart from the most commonly used energy-consuming co-processing methods (e.g. spray-drying and wet granulation), melt granulation as a solvent-free and more environmentally friendly technique has recently gained more attention [1]. The aim of the present study was to investigate the influence of meltable binder particle size and compaction parameters on dilution capacity and compaction behaviour of lactose-based coprocessed excipients. 2. MATERIALS AND METHODS 2.1. Materials Paracetamol (Acros Organics, Belgium) was used as the model drug. Lactose monohydrate (Carlo Erba Reagents, Italy) was used as filler and glyceryl palmitostearate (Precirol® ATO 5 Gattefossé S.A.S, France) as meltable binder. 2.2. Preparation of co-processed excipients Co-processed excipients were prepared by in situ melt granulation in Mycrolab fluid bed processor (OYSTAR Hüttlin, Germany). Precirol® particles (15%) from the 125–180 μm (≈ 150 μm) or 600–710 μm sieve fraction (≈ 655 μm) were used for granulation of lactose (85%). The inlet air flow rate was 30 m3/h, and product temperature during agglomeration was 65 °C. 2.3. Particle size and shape analysis Granule size distribution was evaluated by sieve analysis, and median particle diameter (d50) was calculated by linear interpolation of the cumulative percentage frequency curve. Granule shape was examined by 2D scanned image (4800 dpi resolution) analysis using ImageJ software. The aspect ratio (AR) and circularity (C) were calculated for granule shape evaluation. 2.3. Determination of the Carr index The bulk and tapped (1250 taps) densities of coprocessed excipients and their mixtures with 30, 40 or 50% paracetamol were determined using tap density tester STAV 2003 (J. Engelsmann AG, Germany), and Carr index was calculated. 2.4. Dynamic compaction analysis Co-processed excipients and their mixtures with paracetamol were compressed on a single punch instrumented tablet press (GTP D series, Gamlen Tableting Ltd, UK). Compacts (100 mg) were compressed under compression load of 200 kg (≈ 70 MPa) or 500 kg (≈ 173MPa), and compression speed of 60 or 120 mm/min. 6 mm flat faced punches were used. The obtained force-displacement curves were used to calculate: net work of compression (NW), detachment stress (DS), ejection stress (ES). Tablet crushing force was determined using tablet hardness tester Erweka TBH 125D (Erweka GmbH, Germany), and the values obtained were used to calculate tensile strength (TS). Elastic recovery (24 h after compression) was calculated, as well. 2.4. Experimental Design In order to investigate the influence of binder particle size, paracetamol content and compression speed on the abovementioned compaction properties, compacts were prepared, at compression load of 500 kg, according to 23 full factorial design. 3. RESULTS AND DISCUSSION 3.1. Particle size and shape Larger initial binder particle size led to formation of larger and more spherical granules (Table 1). 147 Table 1. The size and shape of the co-processed excipients’ particles. Binder PS (μm) d50 AR C 150 564.9 1.33 0.81 655 846.2 1.14 0.86 3.2. Flowability The Carr index values obtained indicated considerably better flowability of the coprocessed excipient prepared by using larger binder particles (P655) in comparison with the excipient prepared with smaller binder particles (P150). This might be ascribed to more spherical and larger particles of P655. However, the addition of paracetamol led to an increase in Carr index values and less pronounced differences between two excipients (Fig. 1). Figure 1. The influence of paracetamol loading on flowability of co-processed excipients. 3.3. Compaction behaviour The results obtained revealed better mechanical properties of P150 in comparison with P655 compacts, irrespective of the compression pressure applied. The addition of paracetamol, as the model API with poor compaction properties, led to decrease in tensile strength of the compacts prepared with both excipients, and paracetamol content showed statistically significant influence on TS (p < 0.0001). Acceptable tensile strength (> 1 MPa) could be achieved for compacts with 30% paracetamol compressed at higher compression pressure (≈ 173 MPa). Paracetamol content, compression speed and interaction between binder particle size and paracetamol content were found to significantly affect NW. The influence of binder particle size was more pronounced at higher paracetamol content, with lower NW observed in the case of P655. Higher compression speed led to higher NW. Relatively low values of detachment and ejection stress (< 3.5 MPa) indicate good antiadhesive and lubricating properties of the investigated excipients. Lower values of both parameters were observed in the case of P655 which could be related to different agglomeration mechanisms involved. Besides binder particle size, compression speed and paracetamol content were found to significantly influence these properties. Elastic recovery values of the investigated samples ranged between 12 and 28%. In the case of both excipients, higher elastic recovery values were obtained at higher compression pressure. ER values of the compacts prepared at higher compression pressure were significantly affected by compression speed and interactions of the investigated variables. 4. CONCLUSION The results obtained show that meltable binder particle size affects granule size and shape, and consequently may influence flowability and compaction behaviour of the co-processed excipients. Interactions between binder particle size and compaction variables were also found to affect compaction properties of the investigated excipients.