Moisture-Activated Dry Granulation Part II: The Effects of Formulation Ingredients and Manufacturing-Process Variables on Granulation Quality Attributes - Pharmaceutical Technology

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Moisture-Activated Dry Granulation Part II: The Effects of Formulation Ingredients and Manufacturing-Process Variables on Granulation Quality Attributes
In this article, the authors evaluated the effects of the granulating binder level, binder type, water amount, and water-droplet size on the MADG process.


Pharmaceutical Technology
Volume 33, Issue 12, pp. 42-51


Figure 9
Effect of different binders. Formulation G was used to prepare granulation batches with different types of granulating binder. The effect of different binders was studied by using the same amounts of different binders to prepare the granulation of Formulation G at 400-g batch size. As shown in Table IV, PVP K-12, HPC EXF, copovidone, and Maltrin 180 were used in Formulations G, GH, and GC, and GM, respectively. During the preliminary studies, each binder required a slightly different amount of water to hydrate. Therefore, the amount of water used for each binder in each formulation was adjusted to provide approximately similar hydration effects. Figure 9 shows the granule images at the end of the agglomeration stage for each batch. Among the binders, PVP K-12 appears to be better for this process, and HPC EXF does not appear to be as efficient (see Figures 9a and 9b). Figure 10 shows the final blend particle-size distribution with the different binders. The particle-size distribution results are consistent with the images of the wet agglomerates, indicating that the final blend made with HPC EXF has more fines than others (see Figures 9 and 10). However, the final blend using HPC EXF as a granulating binder was still a free-flowing granulation. These results suggest that different granulating binders can be used successfully in the MADG process to develop granulations with satisfactory properties.


Figure 10
Process applicability. The MADG process is suitable for making solid dosage forms in which various APIs with a wide range of physicochemical properties and drug-loading requirements can be accommodated. Table V shows three formulations in which the main ingredient was lactose monohydrate, mannitol, or acetaminophen. The particle-size distribution of the three final blends is also shown in Figure 11. These results demonstrate that, with proper adjustment of the binder and water levels, all three formulations produced granulations of essentially similar product characteristics such as final-blend moisture content, apparent bulk density, and flowability. The pellets of these three formulations have similar properties such as pellet ejection force, crushing strength, and disintegration time as well.


Figure 11
Table VI shows the formulation compositions of various compounds that differ with respect to solubility, particle size, and drug-loading requirements. As shown in Table VI, compounds A, B, C, and D were developed into Formulations CA, CB, CC, and CD, respectively. All of these formulations achieved satisfactory final blend and tablet-quality attributes using the MADG process. For compound B, copovidone was used as the granulating binder for reasons of product chemical stability. For compound D, which was a micronized, less wettable, and fluffy material, 70.5% of the API (45.8% of the entire formula) was included in the agglomeration stage, and the remaining 29.5% (19.2% of the entire formula) was added in the moisture absorption and redistribution stage. Because this compound appeared more difficult to moisten and granulate during agglomeration, larger amounts of PVP K-12 (11.5%) and water (4.2%) were used in the formulation. As a result, more Aeroperl 300 (5.2%) and less Avicel PH102 (5.2%) were used, compared with the other formulations. Formulation CD demonstrated that although Avicel PH200 LM can make it easier to develop an MADG formulation, it is not required.


Table VII: Active-ingredient content uniformity in tablets of Compound C.
An acceptable granulation process must provide satisfactory content uniformity of dose. In general, the lower the drug loading in the formulation, the greater the challenges of the drug-content uniformity in the final granulation. Taking Compound C as an example, the API-content uniformity in the tablets was analyzed using a validated high-performance liquid chromatography method. Table VII shows that the drug loadings of Formulation CC were 2.5% and 25.0%, and the relative standard deviation values of the API content uniformity of the Compound C tablets were 1.9% and 1.1%, respectivley. According to the acceptance criteria in the "Uniformity of Dosage Units" in the General Chapter <905> of the US Pharmacopeia 31, the results were satisfactory.

Advantages of the MADG process


Table VIII: Physical properties of Formulation G.
The MADG process makes it possible to do only that which is necessary to produce solid dosage forms with desirable quality attributes. In a sense, it is a minimalist process. The MADG process has many advantages. For example, it creates relatively small granules of narrow particle-size distribution with good flowability. The MADG-based granulations also tend to have good compactibility and weight control during tablet compression. The potential for segregation is eliminated for two main reasons. First, the agglomeration stage constitutes 70–90% of the entire formulation in most cases. Second, the excipients added in the moisture-absorption stage often have a particle size similar to that of the agglomerates. The MADG process is also amenable to scale-up with few or no risks. For example, a large-scale batch typically results in a uniform water distribution, which is desirable and beneficial. The minimalist aspect of the process is manifest in the fact that the process involves few pieces of equipment and manufacturing steps. The net processing time of the MADG process is also short, and no additional requirements for drying, extra material transfer, milling, and separate blending exist. These advantages make the MADG process a good candidate for the application of the US Food and Drug Administration's quality by design (QbD) philosophy. Because the process does not need granulation drying or milling steps, it is a green process that has a great potential to be developed into a continuous process.

The MADG process has been employed successfully at Bristol-Myers Squibb (New York) to develop tablet formulations for at least 20 new investigational drug compounds. In addition, several existing wet-granulation and roller-compaction tablet formulations have been converted to the MADG process successfully with or without formula changes. The finished products made with the MADG process have had similar or better pro duct-quality attributes than those of the original formulations.

The main drawbacks of the MADG process for solid dosage-form development arise from the use of drug compounds that are water labile and when a large amount of water (i.e., more than 5–10%) is needed for special reasons (e.g., phase transformation) during the granulation process. Product instability results from the use of water-labile drug compounds, and the excessive use of water defeats the fundamental purpose of the MADG process. For these reasons, the authors do not recommend the MADG process if these two situations exist.


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