Category: Manufacturing and Bioprocessing
Purpose: Twin-screw wet granulation (TSWG) has many advantages over conventional batch wet granulation. As a continuous process, TSWG offers a more versatile process design, better process control, more consistent product quality, less development time, and easier scale-up. In spite of the recent progress, there still lacks systematic understanding of process-induced chemical and physical changes of actives during processing. In this study, gabapentin (GABA) was used as the model drug and hydroxypropyl cellulose (Klucel™) was used as the binder. Water is used as the granulation medium. GABA is susceptible to intramolecular cyclization degradation to form gabapentin-lactam (GABA-L) during wet granulation. The effect of a number of processing variables such as feed rate, screw speed, and liquid to solid ratio on the chemical stability and physical properties of the GABA granules was investigated.
Methods: Twin screw wet granulation was performed on a Leistritz Micro 18 twin screw extruder with L/D ratio of 25:1. Initially, a screening study was conducted to identify the significant factors using a Box-Behnken design programmed with Minitab 18® software with three factors and three levels for a total of 15 runs. The three factors were feed rate, screw speed and liquid to solid ratio (L/S). The levels were 8, 15 and 22 g/min for feed rate, 80, 150 and 220 rpm for screw speed, and 5, 10 and 15% for L/S (liquid to solid) ratio. Formulation blend consisting of 93% gabapentin and 7% Klucel was prepared using a V-shaped blender at 25 rpm for 10 minutes. GABA-L content was measured using a reversed-phased HPLC method with UV detection. Wet granules were dried in a convection oven at 40 ⁰C to a final moisture content of 1-1.5%. GABA-L content of granules was measured following 4 weeks storage at 50 ⁰C/5% RH.
Dried granules were milled using a Quadro Comil at 1500 rpm with a feed rate of 20 g/min. Size of the milled granules was measured using a vibrating sieve shaker with a stack of sieves with the size classes of 1000, 600, 425, 250, 125, and 63 µm. Compaction properties of the milled granules were assessed using a Carver lab press at operated at 4000 psi compaction pressure.
Results: At any given feed rate and screw speed combination, GABA-L content was higher at higher L/S ratio. For example, when L/S ratio increased from 5% to 15%, GABA-L content increased from 0.2% to 1.76% at 8 g/min feed rate and 150 rpm screw speed. This is primarily attributed to the increase in the crystal defects and amorphous content in GABA granules at higher water level. GABA is freely soluble in water. At higher water level, a higher percentage of the gabapentin was solubilized. Recrystallization of the solubilized GABA was interfered by the solubilized Klucel during drying, resulting in development of crystal defects and amorphous GABA fraction.
At a given L/S ratio and feed rate, higher screw speed led to higher GABA-L level, except for at 5% L/S ratio (Fig 1(a)). At higher screw speed, the residence time decreases while the peak shear and specific mechanical energy increases. The correlation between screw speed and GABA-L level is postulated to be related to the effect of residence time (which is a rate controlling factor at lower L/S ratio) as opposed to the effect of shear on generation of crystal defects at higher L/S ratios.
Extruded GABA granules were larger at higher L/S ratio, higher feed rate, and lower screw speed (Figure 1b). The effects of feed rate and screw speed on the size of extruded granules were more significant at higher L/S ratio. Tabletability of GABA granules was found to be mainly affected by L/S ratio with higher L/S ratios producing more tabletable granules (Fig 1(c)).
Conclusion: The results demonstrate the role of processing parameters (e.g. screw speed, feed rate and L/S ratio) and their interrelationships on the quality attributes of GABA granules produced using TSWG process. Higher screw speed, low feed rate and higher L/S ratio resulted in granules with more GABA crystal defects and higher amorphous GABA content. As a result, granules prepared under these parameters degraded faster during the storage. The tabletability of GABA granules was mainly dependent on L/S ratio with more compressible granules at higher L/S ratio.