(T1230-01-02) Effect of Mixing Time and Mixing Process on Lubricant Sensitivity of Excipients with Different Deformation Characteristics

Purpose: Lubricants are commonly used in tablet formulations to reduce die wall friction during tablet compression and ejection. Three lubricants predominantly used in pharmaceutical applications are magnesium stearate, stearic acid, and sodium stearyl fumarate. Some of commonly used excipients for tablet formulations are modified starch (Starch 1500), microcrystalline cellulose (MCC), and lactose monohydrate. Starch 1500 is partially pregelatinized maize starch, commonly used in tablet and capsule formulations for various functional benefits. Starch 1500 can be considered as plastically deforming material with less strain rate sensitivity and high elastic energy in comparison to MCC [1]. MCC is widely utilized as tableting excipient with excellent dry binding properties due to its plasticity [2]. Our previous study demonstrated that combination of starch and MCC is beneficial for direct compression (DC) of tablets [1]. Along with that, lactose is utilized in DC due to its high-flow and less lubricant sensitivity owing to its brittle fracture characteristics. Plasticly deforming excipients (i.e., MCC and Starch 1500) exhibit a greater reduction in tablet tensile strength at increased mixing times in comparison to brittle fracturing excipients [3]. The purpose of this study was: To determine impact of different mixing times and shear on tabletability and ejection forces of a combination of microcrystalline cellulose, lactose, and modified starch (Starch 1500), and To determine most suitable lubricant for a blend containing MCC and Starch 1500.

Methods: Blend Preparation: Formulation composition is shown in Table 1. Lubricant concentration was standardized at 1% for all three lubricants. MCC and colloidal silicon dioxide were mixed and passed through #18 mesh (1000 micron) sieve, and lubricant was passed through #30 mesh (600 micron) sieve prior to blending. All excipients were blended using twin shell V-blender (Patterson Kelley, USA) with and without shear using intensifier bar for 2, 5, 10, and 15 minutes. Tablet Preparation: Tablets were prepared using rotary tablet press (Piccola, Riva, Argentina) at 100 to 250 MPa compaction pressures using 10 mm round standard concave tooling at tablet weight of Turret speed was 25 rpm; feeder speed was kept at minimum ( < 10 rpm) to prevent over blending of lubricant. Tablet properties (mass, thickness, hardness, diameter) were collected using automated tablet tester (MultiCheck, Erweka, Germany); ejection force data was collected from tablet press instrumentation. Impact of mixing with and without shear: Blends containing MCC-Starch 1500 with different lubricants were prepared without shear, then compressed and evaluated for tensile strength and ejection force. Similar studies conducted for the same blends prepared with shear to evaluate impact on tabletability using selected lubricants. Based on results, stearic acid was selected as a choice of lubricant for blending time study with lactose and MCC as diluents.

Results: Figure 1 illustrates impact of mixing time on tensile strength and ejection force for formulations prepared using three different lubricants. Ejection force was low ( < 100 N) for all formulations. As mixing time increased, tensile strength was reduced significantly from tablets prepared using 2 minutes in comparison to 15 minutes blending time. Tablets prepared with magnesium stearate showed even greater reductions in tensile strength as mixing time increased, with values lower than tablets prepared with other lubricants. Hence, magnesium stearate was excluded from further studies. Similarly, tablets were produced using similar compositions but prepared at different mixing times with shear/intensifier bar was used during blending. Results demonstrated that ejection forces increased when shear was used (Figure 2). Tablets prepared using stearic acid and sodium stearyl fumarate showed that both lubricants are less susceptible to blend time and shear. Results of tabletability as shown in Figure 2, indicates that stearic acid and sodium stearyl fumarate have minimum impact of over blending on tensile strength of tablets, and can be choice of lubricant for powder blend containing MCC and Starch 1500. Similar studies were carried out with use of stearic acid as lubricant with lactose and MCC as diluents. Formulation composition is given in Table 1 where lactose to MCC was selected at 2:1 ratio. Results indicated that inclusion of brittle abrasive material in powder blend lead to increase in ejection forces (data not shown here), which was related to abrasive nature of lactose. Identical tabletability profiles were observed for tablets prepared at different mixing time blends (with and without shear), which may be due to lower lubricant sensitivity of brittle material, as they generate new surfaces for binding during tablet compression. Hence, inclusion of brittle material along with selected lubricant in tablet blend helps minimize lubricant sensitivity.

Conclusion: The presence of stearic acid or sodium stearyl fumarate as lubricant in tablet formulations containing either Starch 1500 or MCC reduced lubricant sensitivity and maintained tablet tensile strength with different lubricant mixing time. Over lubrication may be minimized with use of selected lubricants and inclusion of brittle materials in tablet formulations.

References: 1. Levina M, Roberts M, Vass S, Farrell TP, Rajabi-siahboomi AR. The Investigation of Synergistic Behavior of Excipients in Direct Compression Using a Rotary Press Simulator. Colorcon. 2012.
2. Thoorens G, Krier F, Leclercq B, Carlin B, Evrard B. Microcrystalline cellulose, a direct compression binder in a quality by design environment - A review. Int J Pharm. 2014.
3. Paul S, Sun CC. Systematic evaluation of common lubricants for optimal use in tablet formulation. European Journal of Pharmaceutical Sciences. 2018;117.


Figure 1: Impact of mixing time (without shear) with different lubricant using MCC-Starch-1500 as diluents. Data represents n=70 for ejection force profile and n=20 for tensile strength profile.


Figure 2: Impact of mixing time (with shear) with different lubricant using MCC-Starch-1500 as diluents. Data represents n=70 for ejection force profile and n=20 for tensile strength profile.


Table 1: Formulation composition using different lubricants (Batch size: 2.0 kg)