Introduction Methods & Objectives - PowerPoint Presentation

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Introduction Methods & Objectives

In order to optimize this process and maximize desirability for formulations comprising of certain spray-dried amorphous dispersions, we recommend using:

Mannitol

as a filler and a ratio of brittle: ductile components (Mannitol: MCC ratio 2:1) with a higher intragranular % loading and a lower % SDI loading would result in a preferable formulation. Targeting a SF of 0.6 would also be beneficial to the formulation.

A placebo formulation was chosen for this investigation comprising of a spray-dried hypromellose acetate succinate, a common spray drying polymer. A description of the granulation process is in Figure 2. The formulation consisted of intragranular and extragranular components. A dry granulation method using a Vector TFC-Micro roller compactor was utilized to improve blend flowability. A Quadro U5 Comil was used to mill down the granules. Milling parameters were held constant, whereas roller compaction was performed targeting a high and low solid fraction.An i-optimal, 19-run custom design was outlined with the independent variables being type & ratio of filler used (microcrystalline cellulose (MCC), mannitol vs lactose), % SDI loading, amount of intragranular vs extragranular addition & ribbon solid fraction (SF) (indicative of granule density) (Fig 1)The responses were outlined as bulk density 1 & 2 (before & after granulation), Hausner ratio 1 & 2 (before & after granulation) and % fines (after granulation). These responses are indicative of blend flow properties, with a high bulk density and a low Hausner ratio being beneficial for the blend.

Results

Conclusion

A higher SDI loading reduced blend bulk density, whereas a higher intragranular addition improved it. Having more SDI in the formulation also increased % fines.

Figure 4.A depicts that high SDI loading and low extragranular addition resulted in the highest Hausner Ratio 1 and a targeted SF of 0.6 and above with 85% intragranular addition led to high bulk density 2.

Systematic Analysis of Tableting: Effect of Formulation and Process Variables on Final Product Quality Attributes

P. Taskar, B. Greco, S. Zojwala, K. Brookhart, S. Konagurthu

Fig 2. Process flow diagram for dry granulation process using roller compactor

The model effects were constructed assessing the main effects and second degree interactions.

Data was evaluated using Standard Least Squares personality in the Fit Model function.

Fig 1. Independent/Dependent variable identification

Fig 3. Prediction Profiler evaluating trends provided by the responses at different levels of independent variables

A

B

Fig 4. Surface Profiler evaluating impact of (A) intragranular % and SDI loading on Hausner Ratio 1 and (B) target solid fraction and intragranular loading on bulk density 2

Results (Fig 3.) determined that presence of lactose provided the blend with a higher initial bulk density. However, post granulation, a higher % of fines were detected possibly lowering the blend bulk density post granulation. This could be attributed to the fact that lactose is more brittle in comparison to mannitol and the roller compaction resulted in higher fragmentation of the lactose granules.

Increasing SF from 0.5 to about 0.6 improved bulk density 2 and this effect plateaued at 0.6. The Hausner ratio 2 & % fines ratio decreased slightly at a higher SF.

References

1. Design Space Estimation of the Roller Compaction Process

Nabil

Souihi

, Mats

Josefson

,

Pirjo

Tajarobi, Bindhu Gururajan, and Johan TryggIndustrial & Engineering Chemistry Research 2013 52 (35), 12408-12419DOI: 10.1021/ie303580y

Pharmaceutical tableting is a process in which an active moiety (API) is blended with excipients to achieve a free-flowing blend. This blend is compressed into final dosage form, a tablet. Some API depict low bioavailability due to their crystalline nature. Techniques such as spray drying can be employed to convert API into a more soluble and bioavailable amorphous form fortified by a polymer. This tableting intermediate is called a spray-dried intermediate (SDI) and typically has poor flowability. Pharmaceutical process such as dry-granulation can help improve flow properties of SDI.Critical quality attributes of the tablet are impacted by the tablet composition (formulation) and the process parameters used for different tableting processes. This work focuses on using the JMP software to identify main effects and interactions between these variables.

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