(T1030-07-40) New Direct Compressible Mannitol for Minitablets Industrial Scale Manufacturing

Purpose: Minitablets are a downsized version of conventional round tablets with diameter of less than 3.0 mm. They enable treatment flexibility by varying the administrated number as per dosage requirements. Moreover, minitablets are a convenient drug delivery system for patients with swallowing difficulties who are undergoing polypharmacy treatments and pediatrics/geriatrics. The aim of the study was to create minitablets containing melatonin (used as a model drug) by direct compression, with the goal of replacing conventional tablets of the same strength.

Methods: Formulation for 3 mg melatonin strength (in each minitablets) consists of 20 % melatonin (BOC Science), 78.53 % of mannitol (PEARLITOL^® 200 GT, Roquette) with no disintegrant (to minimize the number of components) and 1.47 % of magnesium stearate (Roquette). Screened blend of melatonin and PEARLITOL^® 200 GT (sieve no 30) was mixed in TURBULA^® mixer (WAB T2F) at 49 rpm for 5 min. The lubricant, magnesium stearate, was added to the blend and mixed at 49 rpm for 2 min. Approximately, 10 mg of sample blend was taken from three different spots for content uniformity evaluation. The powder mix was compressed using 2.5 mm standard concave punch (Natoli Engineering) multitips (4 tip) using Korsch XL 100 tablet press at 3.0 kN compression force (on 4 tips) with a target minitablet weight of 15 mg, compression speed 20 RPM with a force feeder speed of 10 RPM. Minitablets breaking force was checked using hardness tester, and content uniformity was performed on 10 individuals minitablets with acceptance value of content uniformity calculated as per USP < 905 >. Melatonin content uniformity in powder blend and minitablets was evaluated by high performance liquid chromatography (HPLC) at 277 nm. Conventional marketed regular size melatonin tablets (same strength 3 mg/tablet) were used as reference for dissolution comparison. To reach within linearity range of HPLC method, three tablets were required in each vessel. Dissolution of 9 mg melatonin (three tablets) in each of three vessels of 500 mL distilled water at 37 °C with a paddle speed of 100 rpm was performed. For melatonin quantification by HPLC, 3.0 mL samples were taken at 5 min, 10 min, 15 min, 30 min, and 60 min time points from each vessel and filtered using 0.20 µm nylon filter.

Results: Flowability of blend was excellent with a Hausner ratio of 1.11. Advantage of having excellent flow can be seen in weight variation of 10 minitablets average weight was 15.32 ± 0.17 mg (Figure 1). 2. API uniformity in powder blend was 98.34 ± 1.44 %. 3. Minitablets (15 mg weight) content uniformity was 98.18 ± 5.12 % (measured on 10 minitablets). 4. For commercial tablets, despite the higher weight (900 mg), higher weight variation was observed (302.4 ± 12 mg) but still in the range. 5. Dissolution profile (Figure 2) shows minitablets (formulated with no disintegrant) released more than 80% API within 15 min. While commercial product (formulated with super disintegrant croscarmellose sodium) released 92 % API within 5 min.

Conclusion: Scaling up the direct compression production of melatonin minitablets, PEARLITOL^® 200 GT proved to be an excellent filler using a rotary press with multi-tip punch. In the case of minitablets, formulation content uniformity is the most critical parameter and difficult to achieve by direct compression, and using a new grade of direct compressible mannitol content uniformity was reached (98.18 ± 5.12 %). Decreasing 20 times the conventional tablet size (8 mm) and weight (300 mg), minitablets are a patient-friendly dosage form which offers flexibility in dose adjustment for any age group at 15 mg weight with 2.5 mm diameter. Size reduction was possible due to good powder flowability and compactibility of PEARLITOL® 200 GT and elimination of a disintegrant in the composition. With this formulation, we achieved 80.0 % of drug release within 15 min with a smaller number of components (highly recommended by FDA) for a pediatric formulation


Figure 1: Comparison of minitablet (15 mg/2.5 mm) and regular size tablet (300 mg/9.0 mm) at the same dose strength of 3 mg of melatonin.


Figure 2: Dissolution profile of minitablets (Tablet wt.: 15 mg) and marketed product (Tablet wt.: 300 mg) both having 3 mg melatonin potency. Dissolution of three minitablets and marketed tablets were performed in 500 mL of distilled water in each vessel to get the needed melatonin concentration for HPLC method linearity range.