• Prior to encapsulation the capsule filling process was Figure 3. Flow Behavior of SAIB at RT Figure 7. Rheological Pro le: 40% ibuprofen in SAIB MATERIALS 60 developed and optimized based on the rheological Drug substance G' • Ibuprofen profiles of the fill materials 50 Viscosity 2-(4-isobutylphenyl)-propionic acid • ‘Hot filling’ encapsulation trials were conducted using 40 Figure 1. Structure of Ibuprofen

1) conventional gelatin-based encapsulating films Pa and 2) novel, polysaccharide-based encapsulating 30 0 10 20 30 films. Softgels were produced using the rotary-die minutes 20 encapsulation process Gelatin-free Softgel Studies: Ingredients used in the ll formulation studies Figure 2. Softgel Manufacture using the Rotary-die Encapsulation Process Encapsulation trials 10 Development of Novel Shell • Polyethylene glycols • Gelatin-free softgels were produced using elevated Compositions and Processes • Lecithin 0 temperature, filling and sealing techniques 40 45 50 55 60 Suitable for the ‘Hot Filling’ of • Sucrose acetate isobutyrate (SAIB) Temperature, °C High Viscosity and Semi-solid Fill RESULTS Ingredients used in the shell formulation Capsule Shell Development Materials. Figure 8. SAIB softgel Figure 9. Softgel with solid-like core studies • The most suitable gelatin-free gel/shell compositions Norman Stroud, Keith Tanner, Elizabeth Youngblood, Didier Kiyali, were found to comprise T=0 and Shawn McKee • Gelatin NF • Polyol plasticizers (Glycerol, Sorbitol, Anhydrized - iota-carrageenan:hydroxypropylated starch in the Catalent Pharma Solutions Liquid Sorbitol) ratio, 1.0 : 2.5-3.5 • Hydroxypropylated starch - Sorbitol-based plasticizers

INTRODUCTION • Iota-carrageenan ° Plasticizer : shell polymer in the ratio, 0.8 : 1.0 Purpose • Di-sodium phosphate T=8 HOURS • To develop polysaccharide-based shell formulations • Purified water EXPERIMENTAL STUDIES Rheological Pro les of Fill Formulations and elevated temperature filling processes suitable Capsule Shell Development Figure 4. Rheological Pro le: High molecular weight PEG’s for the encapsulation of high viscosity and METHODS Composition of Capsule Shell Formulations 10000 semi-solid, pharmaceutical fill formulations. Table 1. Composition of Polysaccharide-based Shell Formulations 10000 • The polysaccharides, iota-carrageenan and 6000 Solid region 3000 hydroxypropylated starch, were formulated, in Ingredient Functional role in shell % w/w of dry shell 1000 1500 Background combination with polyol plasticizers and water, to Hydroxypropylated starch Shell polymer 33 - 37 • Pharmaceutical fill formulations that exist as give thermo-reversible film-forming gels. The iota-carrageenan Shell polymer 7 - 12 mPa s • Rheological profiling and filling studies showed that Polyol plasticizer Plasticizer 36 - 42 100 the optimum filling temperature for the fill materials solid-like or semi-solid systems at room temperature formulations were prepared in accordance with the Di-sodium phosphate Buffer 1 Water associated with was in the range 60°-70°C. At these temperatures and melt at temperatures greater than 40°C pose a compositions and processes described in US patents: Water 10 - 12 plasticizer & polymers challenge for the softgel formulator. These types of - 6,582,727 10 the material is sufficiently mobile; viscosities range formulations typically do not lend themselves - 6,340,473 • Shell formulations were developed containing blends between 2,000 and 5,000 mPa s

readily to encapsulation using traditional of the two polysaccharides in the ratio 0.75 - 1.5: 2.0 - 1 45 50 55 60 65 70 75 80 85 90 • The polysaccharide-based shell compositions were gelatin-based encapsulation films, since during • Gelatin-based gel mass/capsule shell formulations 4.0, iota-carrageenan : hydroxypropylated starch. The Temperature, °C capsule formation the films have a sealing limit of were prepared using conventional compositions and effect of plasticizer on film performance was found to retain their film-like characteristics at the approximately 38°- 42°C. In recent years the processes investigated over the range 0.5-1.0 : 0.9-1.6, shell Figure 5. Rheological Pro le: 40% ibuprofen in PEG 6000 elevated temperatures (55° - 75°C) required for filling and sealing the capsules. At these potential of polysaccharide-based encapsulating polymers: plasticizer 4 G ' temperatures the gelatin-based films deformed films for ‘hot filling’ high melting point fill 3.5 • The suitability of the gel/shell formulations for the V is c o s ity formulations has been investigated. This poster and/or melted. encapsulation of a range of high melting point, high Fill Formulation Development 3 summarizes the results obtained from studies that viscosity fill materials was investigated using a Characteristics and Composition of Fill Formulations 2.5 • Soft capsules were successfully produced using the have been conducted using ‘high melting point’ rotary-die encapsulation machine equipped with a Pa Solid region Table 2. Characteristics of Fill Formulations 2 encapsulating films containing iota-carrageenan high temperature fill/injection system polysaccharide-based shell compositions and using Vehicle Formula Physical state of formulation 1.5 ‘hot filling’ techniques and hydroxypropylated starch, as the shell-forming Base characteristic at type vehicle polymers. • The high viscosity and semi-solid fill materials were room temperature 20°C 40°C 60°C 1 High m.w. Hydrophilic Solid Solid Solid Mobile fluid A PEG’s 0.5 formulated using 1) hydrophilic and 2) lipophilic Hydrophilic and lipophilic Extremely Very viscous vehicles. The fill formulations were prepared using B Lecithin characteristics Mobile fluid 0 Scope Very viscous fluid viscous fluid fluid 50 55 60 65 70 75 80 Temperature, °C conventional, elevated temperature processing Sucrose Lipophilic Extremely Extremely • Investigate the melting point and temperature Acetate Viscous fluid C Extremely viscous fluid techniques Isobutyrate viscous fluid viscous fluid dependency of the viscosity and viscoelasticity of fill Figure 6. Rheological Pro le: 50% ibuprofen in Lecithin CONCLUSION

formulations that exist as solid-like or semi-solid • Type A formulations were prepared using 40 • The viscosity and viscoelasticity of the fill materials Novel, polysaccharide-based softgel shell materials at room temperature. compositions (35% - 43% w/w drug) and processes G' was measured using a Haake RS 150 rheometer 35 compositions have been developed that, in described in US patent 5,360,615 Viscosity • Establish the filling and sealing temperatures for equipped with a cone and plate measuring system. 30 conjunction with ‘hot filling’ processing satisfactory capsule formation using A gap setting of 1.00 mm was used for both tests. 25 techniques, are suitable for the encapsulation • Type B formulations were prepared using drug Pa The samples were examined over the range 40°C - 20 1) conventional gelatin-based encapsulating films, loadings in the range 45% - 50% w/w of fill formulations that are highly viscous or 80°C. Temperature control was achieved using a and 15 semi-solid at room temperature peltier plate. Viscosity was determined using a test 2) polysaccharide-based encapsulating films, • Type C formulations were prepared using drug 10 containing iota-carrageenan and frequency of 1.0 Hz. Viscoelasticity was determined loadings in the range 40% - 50% w/w 5 hydroxypropylated starch using oscillatory shear, over the frequency range 0 1.0 – 10 Hz. 40 45 50 55 60 Temperature, °C

Size: 17” x 11”