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Binary mixtures of thermal binder and GABA were processed using a Leistritz Nano 16 extruder. Three different types of materials: polyethylene glycol (PEG 8000), Compritol 888ATO, and hydroxypropyl cellulose (HPC) were evaluated as thermal

binders. HPC particle sizes and processing condition were varied to study their effect on the gabapentin chemical stability and granule physical properties.

Granulation mechanisms and the effect of processing conditions on physicochemical properties of gabapentin granules prepared by continuous twin-screw extrusion N. Kittikunakorn1, David White2, Tony Listro2, Charlie Martin3, Xin Feng4, F. Zhang1 1University of Texas at Austin, 2Foster Delivery Science, 3American Leistritz Extruder Corporation, 4University of Mississippi

As a solvent-free, continuous manufacturing process, twin-screw melt granulation (TSMG) offers many advantages over high shear wet granulation, batch melt granulation, and roller compaction processes. TSMG provides efficient mixing and can

improves compressibility of the granules. TSMG is suitable for processing moisture-sensitive drugs and high-dose drugs. Our research will build scientific understanding of

TSMG for pharmaceutical tablet manufacturing. This study aims to investigate (1) the effect of processing parameters on the physicochemical properties of gabapentin granules, and (2) the granulation mechanisms.

• Processing temperature and reduction of GABA particle size during granulation are significant factors that can

affect the chemical stability of GABA. • Small particle size of HPC can cause higher degradation due to higher surface area in contact with GABA

particles. • Processing parameters (screw speed and feed rate) should be optimized to achieve the balance between

improving compaction properties but still maintaining chemical stability of GABA. This study demonstrated that TSMG is a viable continuous process to prepare GABA granules with improved compressibility. GABA granules with desired physicochemical properties can be achieved by optimizing the type of thermal binders, particle size of binders, and processing parameters.

CONTACT INFORMATION: nada.k@utexas.edu

Poster Number T2037

Binder type PEG8000, Compritol ATO888, HPC ELF

Binder particle size Klucel ELF, Klucel EXF, Spray dried HPC

Processing condition Screw speed, Feed rate

5 g/min

7.5 g/min

10 g/min

100 rpm 150 rpm 200 rpm 300 rpm

GRANULATION MECHANISM

Binder distribution :

Size reduction of GABA during melt granulation :

Granule morphology at different zone along the barrel :

RESULTS

METHODS

PURPOSE

Feeding zone Zone 1 Zone 2 Zone 3

20% Binder

80% GABA

1

2

3

Degradation of GABA GABA GABA-L

GABA • Tm: 175°C • pka: 3.7 (acid), 10.7 (base) • Water solubility: 100 mg/mL

BINDER • PEG 8000: Tm ~ 60°C • Compritol 888ATO: Tm ~ 70°C • HPC: Tg ~ 0°C (soften at 100-150°C)

• The lower the degree of fill, the lower the degradant level. • No correlation between specific energy and degradant level • The residence time ranged from 11 to 50 seconds.

HPC EXF was selected to evaluate the effect of extrusion parameters on the properties of GABA granules

Chemical properties test

• Significant improvement in the compressibility was achieved with TSMG for all three binders.

• HPC was more effective in improving the compressibility than PEG 8000 and Compritol 888 ATO.

• GABA-HPC granules contained higher level of GABA-L (0.10%) than GABA-PEG (0.01%) and GABA-Compritol (0.02%) granules, due to the higher processing temperature and reduction in GABA particle size.

• For GABA-HPC granules, GABA-L

content increased with the decrease in HPC particle size, especially at a high barrel temperature of 120 C

• The compressibility of GABA-HPC granules was not affected by HPC particle size.

Figure 2 : Microscope image of granules (A) GABA-PEG 8000 (B) GABA-Compritol 888ATO (C) GABA-HPC ELF

CONCLUSION

(A) (B) (C)

• GABA crystals were broken down by both conveying and kneading elements.

• During granulation, binder particles melted or softened at higher temperature, and coated the surface of GABA particles

• The higher the degree of fill, the greater GABA particle size reduction.

• However, the granules with the least amount of degradant exhibited the least improvement in compressibility.

𝐾𝑊 (𝑎𝑝𝑝𝑙𝑖𝑒𝑑) =𝐾𝑊 𝑚𝑜𝑡𝑜𝑟 𝑟𝑎𝑡𝑖𝑛𝑔 𝑥 %𝑡𝑜𝑟𝑞𝑢𝑒 𝑥 𝑟𝑝𝑚

0.97 (𝑔𝑒𝑎𝑟𝑏𝑜𝑥 𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑐𝑦) 𝑥 𝑀𝑎𝑥. 𝑟𝑝𝑚

𝑆𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑒𝑛𝑒𝑟𝑔𝑦 =𝐾𝑊 𝑎𝑝𝑝𝑙𝑖𝑒𝑑

𝐹𝑒𝑒𝑑 𝑟𝑎𝑡𝑒 (𝑘𝑔ℎ𝑟

)

ACKNOWLEDGEMENTS

%𝐹𝑖𝑙𝑙 = 𝐹𝑒𝑒𝑑 𝑟𝑎𝑡𝑒

(𝐶𝑟𝑜𝑠𝑠 𝑠𝑒𝑐𝑡𝑖𝑜𝑛 𝑎𝑟𝑒𝑎 𝑥 𝑃𝑖𝑡𝑐ℎ 𝑙𝑒𝑛𝑔𝑡ℎ 𝑥 𝑟𝑝𝑚 𝑥 𝑆𝐺)/2 x100

Instrument : • Polarized Light Microscope • Hydraulic Tablet Compression Machine • Laser Diffraction Particle Size Analyzer • HPLC (Reversed phase) • Time-of-Flight Secondary Ion Mass Spectrometry (TOF-SIMS)

Physical properties test

TGA and DSC of GABA show that GABA degrade upon melting.