Obtaining Stable Homogenous Mixtures with Micronized APIs - Pharmaceutical Technology

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Obtaining Stable Homogenous Mixtures with Micronized APIs
The authors examine the use of various grades of direct-compression mannitol in direct-compression tableting process to evaluate the content uniformity of micronized APIs and excipients in a solid-dosage formulation.


Pharmaceutical Technology
Volume 36, Issue 10, pp. 66-72

Results of field testing in a R&D case study


Figure 8: Composition of the investigated pharmaceutical formulation used for the R&D case study.
The question whether low-dose pharmaceutical formulations with micronized APIs are suitable for a DC process was challenged using a water-sensitive R&D API at only 0.4% in the final dosage form (0.5 mg API in a 120-mg tablet). Wet granulation could not be applied because of the water-sensitivity of the API. The micronized API (Dv50 10 μm), therefore, was premixed for 30 min using a shaker-mixer (Turbula T2C) with 15% of the total amount of DC-grade mannitol DC-Mannitol M (Dv50 200 μm) and mixed with the rest of the formulation using a Turbula T20P (Bachofen AG) (see Figure 8). A test run of 2 h on a rotary press (Korsch Pharmapress PH230, Korsch AG) was performed at two different rotation speeds (40,000 and 80,000 tablets/h). The tablets were assessed for their weight, hardness, and disintegration time.


Table II: Comparison of tablets manufactured at different speeds of the rotary press.
This result was surprisingly good as constant values were detected for tablet weight (RSD 0.6–0.9%), tablet hardness (RSD 4.1%), and disintegration time (see Table II). Content uniformity was measured to be 1.8 %.

Conclusion

Although the concept of ordered mixtures has been extensively studied and reported, little was known about the mechanisms and reasons behind ordered mixtures (6–9). The results clearly show that the effect of ordered mixtures can be found with DC-mannitols as a function of surface area and structure. To a greater extent, this functionality can be found for spray-dried qualities with a porous surface structure. A large surface area is helpful for good binding capacity. Stable mixtures are not only achieved with components of similar particle sizes as the literature suggests. It is also possible to achieve a stable mixture of micronized API particles (< 15 μm) with a DC-mannitol with a mean particle size of 200 μm. The stability is caused by an adsorptive binding force strong enough to withstand the mechanical separation forces. This effect was successfully demonstrated for hydrophilic and hydrophobic APIs. This result confirms the feasibility of DC for low-dose applications with acceptable content uniformity as the example showed. It also helps to show that micronized APIs at higher concentrations can be applied in solid formulations to enhance their solubility. This approach can be applied for DC, sachet formulations, or in roller compaction.

H. Leonhard Ohrem* is a technical manager,
, Roberto Ognibene is head of the formulation laboratory, and Thorsten Wedel is a pharmaceutical engineer, all with Merck KGaA, Darmstadt, Germany 64271.

*To whom all correspondence should be addressed.

References

1. Y. Qiu et al, Eds., Developing Solid Oral Dosage Forms (Academic Press, Burlington, MA, 2009).

2. I. Nikolakakis and J.M. Newton, J. Pharm. Pharmacol. 41 (3), 145–148 (1989).

3. P.C. Schmidt and K. Benke, Pharm. Ind. 46 (2), 193–198 (1984).

4. J.A. Hersey, Powder Technol. 11 (1), 41–44 (1975).

5. EurPh, "General Monographs: Riboflavin" (7th edition, EDQM, Strasbourg, France), pp. 2852–2853.

6. L. Bryan, Y. Rungvejhavuttivittaya, and P.J. Stewart, Powder Technol. 22 (2), 147–151 (1979).

7. C.W. Yip and J.A. Hersey, Powder Technol. 16 (2), 189–192 (1977).

8. C.C Yeung, J.A. Hersey, Powder Technol. 22 (1), 127–131 (1979).

9. N. Harnby, Pharm. Sci. Technol. Today 3 (9), 303–309 (2000).


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