(M1530-08-53) Facilitating Robust Manufacturing of Low-Dose Oral Solid Drug Products using Directly Compressible Mannitol

Purpose: With the advent of combinatorial chemistry and high throughput screening, more and more active pharmaceutical ingredients (API) are becoming potent. As a result, many oral solid drug products (tablets and capsules) face blend uniformity (BU) and content uniformity (CU) challenges due to low drug loads. Uniform distribution of API in blend is essential to ensure robustness of the drug product manufacturing process. Additionally, the pharmaceutical industry is moving more towards direct compression (DC) as the preferred method for oral solid dosage form manufacturing as it is a cost-effective, simple process, suitable for thermal and moisture sensitive drugs and is amenable to continuous manufacturing. This study investigates a new directly compressible mannitol for its ability to facilitate robust drug product manufacturing (BU and CU) as a function of varying drug loads.

Methods: Micronized Omeprazole Mg (BOC Science) was selected as a model API for study with particle size of D_10: 0.68 µm, D₅₀: 1.67 µm, and D₉₀: 4.52 µm. Formulation 1 and 2 consist of 10% w/w and 2.0% w/w omeprazole with 83.5% w/w and 91.5% w/w of mannitol (PEARLITOL^® 200 GT), respectively. Other components of both formulations were the same with 5.0% w/w of croscarmellose sodium (SOLUTAB^®) and 1.5% w/w of magnesium stearate . Both formulations were blended using the steps mentioned in Figure 1 at 4 kg batch size using V-blender (8 qt). Geometric mixing and milling (Quadro Comil^®, Burlington, USA) steps were included as part of the manufacturing process. For BU, an adequate amount (600 mg) of powder sample in triplicate was withdrawn using sample thief from 10 different locations in V-blender[1]. The blend was compressed using 5.5 mm flat face bevel edge punches (Natoli Engineering) using Korsch XL 100 tablet press at 5.9 – 6.1 kN compression force with a target tablet weight of 130 mg, compression speed 25 RPM, with a force feeder speed of 10 RPM. Content uniformity samples (10 tablets) were withdrawn every 6 mins from 10 equidistant times (locations) for a total run of 60 mins. Physical properties of tablets (thickness, diameter, and hardness) were measured using a ST50 hardness tester (Sotax Corp, MA, USA). Blend uniformity and content uniformity samples were analyzed using high performance liquid chromatography (Vanquish Core, Thermo Scientific™, MA, USA). Acceptance criteria were determined based on process flow diagram for assessment of blend and content uniformity[2].

Results: PEARLITOL® 200 GT mannitol exhibits good flow (Hausner ratio:1.19) and particle size (d50:150 µm). Flowability of formulation 1 and 2 was with a Hausner ratio of 1.1 and 1.06, respectively. Both formulation 1 and formulation 2 passed blend uniformity with SD < 3.0% (Table 1). Content uniformity of 10% w/w and 2% w/w omeprazole tablets passed with acceptance value of AV < 15.0 (Table 2) [3]. Both formulations exhibited good tablet mechanical strengths (1.7 ± 0.2 MPa) and absence of any tablet defects (capping or sticking). The disintegration times of both formulations ranged between 3.0 to 3.2 min.

Conclusion: PEARLITOL^® 200 GT, a new directly compressible grade mannitol, successfully demonstrated good BU and CU at low drug loads of 2-10% w/w using omeprazole mg as a model API. The formulations containing granulated mannitol can be used for robust drug product manufacturing of highly potent drug products in oral solid dosage form.

References: 1. Pharmacia Lettre D, Singhai SK, Chopra VS, Nagar M, Jain N, Trivedi P. Scholars Research Library Scale Up factor determination of V Blender: An overview [Internet]. 2010. Available from: www.scholarsresearchlibrary.com
2. Garcia T, Bergum J, Prescott J, Tejwani R, Parks T, Clark J, et al. Recommendations for the Assessment of Blend and Content Uniformity: Modifications to Withdrawn FDA Draft Stratified Sampling Guidance. J Pharm Innov. 2015;10:76–83.
3. United State of Pharmacopeia. USP . 2011 [cited 2024 Feb 8]; Available from: https://www.usp.org/sites/default/files/usp/document/harmonization/gen-method/q0304_stage_6_monograph_25_feb_2011.pdf

Figure 1: Manufacturing process flow for omeprazole low dose (10 % w/w and 2% w/w) blend formulations.

Table 1: Blend uniformity of formulation 1 and 2.

Table 2: Content uniformity of formulation 1 and 2.