Lubrication of Direct-Compressible Blends with Magnesium Stearate Monohydrate and Dihydrate - Pharmaceutical Technology

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Lubrication of Direct-Compressible Blends with Magnesium Stearate Monohydrate and Dihydrate
The influence of magnesium stearate (MgSt) on powder lubrication and finished solid-dose properties presents big challenges to drug manufacturers.

Pharmaceutical Technology

The prelubrication homogeneity of the blends was determined on the basis of real-time analysis conducted with Effusivity Sensor Package software (ESP, Mathis Instruments, Fredericton, Canada). The system synchronization enabled the sensors to dynamically obtain a real-time data stream from the rotating blender (see Figure 4). Effusivity sensors monitor the blending of powder particles on the basis of the heat-transfer properties of the composite powder mixture. An explanation for this sensitivity to material blending or mixing is related to the ability of these powder particles or ingredients to mix in various proportions as they attend homogeneity. This is analogous to a move from "divergence" toward "convergence" or uniformity. The selection of any empirical uniformity value may depend on several factors, including the nature of materials, type of process, and individual effusivity values of the ingredients. Several works have shown that low relative standard deviation (RSD) in a blending process signifies uniformity in mixing or blending (6, 12, 18, 19). End-point prediction with effusivity was based on the combination of stable average effusivity and a decaying RSD.

Blend samples were collected using a sample thief from each batch at the end of prelubrication and postlubrication blending. Blend samples of about two times the unit-dose (500 mg 2 = 1000 mg) were tested based on an internally validated HPLC method for APAP. The mobile phase was a mixture of methanol and water with a flow rate of 1.0 mL/min and detection at 280 nm.

Tablets' physical attributes and content uniformity. Compression of the batches was conducted using a 10-station instrumented press (Natoli Engineering). Compression parameters were monitored based on constant (target) tablet weight (500 mg) and hardness (8 kp). Based on the fact that MgSt type, percentage of MgSt, and lubrication time differed in the batches, the effects of these variables on precompression force, main compression force, ejection force, knock-off force, and tablet friability were monitored or measured to evaluate the level of such influence. Additional influence was also expected from the differing percentage of APAP and diluents. An attempt was made to statistically analyze such influence to understand the main effects and interactions.

Using a stratified sampling method, tablets were collected at intervals during the compression runs (20). Content uniformity was conducted using an internally validated HPLC method for APAP. Mean assay and %RSD for 10 tablets were determined.

In vitro dissolution. In vitro dissolution studies were performed using an USP Type 2 dissolution apparatus at 50 rpm. The dissolution media consisted of 900 mL degassed purified water, USP, maintained at 37 C 0.5 C. A 5-mL aliquot was withdrawn at intervals of 5, 10, 15, and 30 min. Drug content was determined by HPLC at 280 nm. All dissolution tests were conducted in triplicate. The similarity was determined by the model independent approach using a similarity factor (f2) as described in the FDA Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms (21). The similarity factor (f2) is defined as follows:

Figure 1
in which Rt and Tt are the average percentage of drug dissolved at each sampling time for reference (R) and the test (T) preparations, respectively, and n is the number of samples. An f2 value between 50 and 100 suggests that the two dissolution profiles are similar.


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