(T1130-09-58) Investigation of Formulation of Mini-tablets with Direct Compressible Excipients

Purpose: Mini-tablets, syrup and dry syrup are the main oral formulation used in pediatric medicine. In particular, mini-tablet is a small tablet with φ1-4 mm, which is attracting attention. In recent years, efforts related to pediatric formulations are becoming active. It has been reported that children (including infants) are more likely to accept mini-tablets than glucose syrup for administration [1]. However, there is the issue of drug content uniformity in the production of mini-tablets, and some studies are being conducted for improvement. Therefore, in this study, we investigated the effects of direct compressible excipients with different manufacturing methods and particle sizes on the drug content uniformity of mini-tablets.

Methods: In this study, the raw materials for mini-tablets were prepared by mixing API (Propranolol Hydrochloride), select one of the fillers (Lactose Monohydrate for direct compression: Dilactose-F, Dilactose-S, Dilactose-R (Fluidized-bed granulated type) and Spray-dried lactose monohydrate), a binder (Microcrystalline Cellulose, CEOLUS PH-101), and a fluidizing agent (Silicon Dioxide, Adsolider-101). Magnesium stearate was added as a lubricant. Mini-tablets were tableted by using a rotary tableting machine (VIRGO) equipped with 8-tip tools (φ2-R3, 9 mg / tablet) at 30 rpm rotary table speed. Tablet hardness was measured by tablet testing system SmartTest 50. Tensile Strength (T.S.) was calculated according to following equation.
T.S. = 2H / πDT
H: Tablet Hardness (N), D: Tablet Diameter (mm), T: Tablet Thickness
Drug content was measured by spectrophotometer V-630. Furthermore, the flow properties of mixing powder were measured by Powder Rheometer FT4.

Results: In this experiment, the content of Propranolol Hydrochloride was 10% in the tablet formulations. As a result, for the tensile strength about 2 MPa, a compression force of 3 kN was required for the Dilactose-F formulation and 4 kN for the other formulations (Dilactose-F formulation: 1.64 MPa, Dilactose-S formulation: 1.95 MPa, Dilactose-R formulation: 1.75 MPa, Spray-dried lactose formulation: 1.75 MPa). Furthermore, at all formulations and compression forces (2-6 kN), the weight RSD was approximately 3%, and the flowability of the mixed powder and the filling into the die were good. Next, continuous tableting was performed for 45 minutes at the compression force to achieve tensile strength of approx. 2 MPa. Then, there was no change over time in weight RSD, tensile strength, disintegration time, and friability in all formulations. Regarding the drug content uniformity, the acceptance value of lower than 15 was obtained regardless of the type of fillers (Dilactose-F formulation: 7.05-9.46, Dilactose-S formulation: 5.08-9.03, Dilactose-R formulation: 9.70-13.10, Spray-dried lactose formulation: 10.39-13.22). In particular, the Dilactose-S formulation had the lowest drug content RSD (Dilactose-F formulation: 2.58-3.73%, Dilactose-S formulation: 2.14-3.76%, Dilactose-R formulation: 3.20-4.13%, Spray-dried lactose formulation: 3.50-4.30%). To evaluate adequacy of fillers, we defined as segregation RSD (The drug content was calculated for each tablet, and the RSD for 10 mini-tablets was obtained). This was used as an indicator of segregation, the Dilactose-S formulation had the lowest segregation RSD (Dilactose-F formulation: 2.72-3.35%, Dilactose-S formulation: 1.46-3.04%, Dilactose-R formulation: 3.68-4.80%, Spray-dried lactose formulation: 3.34-3.84%). The powder rheometer FT4 was used to measure the flow properties of the mixed powder. As a result, it was found that the adhesive force of the mixed powder tended to vary depending on the particle size and particle surface state of the filler. Dilactose-S had fine pores on the particle surface, but Spray-dried lactose was smooth. Therefore, it was inferred that Dilactose-S has more contacts with propranolol hydrochloride than Spray-dried lactose, and has a stronger retention of propranolol. It was thought that this difference affected the segregation RSD.

Conclusion: We investigated the formulation of mini-tablets. As a result, it was possible to prepare mini-tablets with a diameter of φ2 mm by using a lactose as an direct compressible excipients. In addition, stable tableting was possible in continuous tableting for 45 minutes. Especially in the case of the Dilactose-S formulation, the segregation RSD of mini-tablets was low because the mixed powder was less likely to cause segregation, and it was easy to ensure drug content uniformity. We believe that the findings of this study provide important insights to support systematic improvements in the manufacture of mini-tablets.

References: [1]: Klingmann V., et al. “Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children” J. Pediatr. 2013; 163: 1728-1732.