Study of direct compression coverage in view of design space – Ceolus UF grades

1. What is the design space?

The design space (DS) is a multidimensional combination and interaction of input variables (e.g., properties of raw materials) and process parameters that have been proven to ensure the quality of drug products. Operation within the DS is not considered a change, therefore the DS is proposed by the applicant, and evaluated and approved by the regulatory authority. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) recommends the DS as a prerequisite for the production of drug products to improve product quality.

1st to 3rd Study Forum for Standardized Formulation

2. Purpose of this study

Our previous research was carried out on a laboratory scale (small rotary press), the range of experimental conditions was limited, and could not sufficiently evaluate the reproducibility of results and the robustness of formulations at actual production scale.

Thus, we thought it was necessary to confirm the robustness of applications across a wide range of experimental conditions in terms of method, scale, and speed of mixing and tableting that closely mimicked actual production conditions.

Ceolus^TM UF grades were used in this study. Since Ceolus^TM UF are MCC grades that have a superior balance of flowability and compactibility with respect to Ceolus^TM PH and KG grades, it is anticipated that Ceolus^TM UF grades will be more robust to variations in manufacturing process parameters.

The aims of this study are to clarify the DS for the use of PH and UF grades of Ceolus^TM and confirm whether UF grades are superior to PH grades.

As a step toward DS construction, we chose high API dosage and direct compression for the formulation, both of which are possible using UF grades. In the formulations of UF-711/ascorbic acid and UF-702/acetaminophen, we focused on tablet hardness and tablet weight relative standard deviation (RSD), and selected three important parameters: (1) API dosage, (2) lubricant content, and (3) tableting speed. We then compared the applicable range of the parameters satisfying tablet hardness and tablet weight RSD above a certain level between UF grade and PH grade (PH-102).

3. Experiments

Since UF grades enable the development of formulations with high API dosage and the miniaturization of tablets, the use of UF grades is expected to improve drug administration and cost efficiency. Accordingly, in the present study, we selected formulation examples using UF grades and implemented design spacing. Two formulations of UF grades are described below.^２)

3-1. Direct compression of high-dose ascorbic acid (VC), a low compactible API, using UF-711

1) Experimental procedures

The process for direct compression of high-dose VC, a low compactible API, is shown below.

Conditions of variation (PP) are shown below.

*1         The MCC addition rate was selected based on our previous studies and the results of a preliminary test.

*2         With an upper VC limit of 60% for the UF formulation and 40% for the PH formulation, the SD-Lactose (S-tab) amount was varied in accordance with the VC content.

*3         Three different conditions for VC content, Magnesium stearate (Mg-St) content, and tableting speed (3 × 3 × 3) were selected for each UF and PH formulation, for a total of 54 conditions.

*4       The target tablet hardness was ≥110 N (approx. 50 N equivalent of φ8 mm 180 mg tablet).

4. Summary

The results of direct tableting of UF-702/APAP, a low compactible and low flowable API, are summarized below.

Comparisons of UF-702 and PH-102 with regard to the applicable range of the API content, Mg-St content, and tableting speed for a target tablet hardness ≥110 N and tablet weight RSD ≤1% revealed the following:

• The UF-702 formulation showed a wide applicable range of hardness, API content, tablet weight RSD, Mg-St content, and tableting speed compared to the PH-102 formulation.
• The bulk density and angle of repose of the UF-702 formulation was less affected by variations in the Mg-St content.
• It was possible to increase the API content, because the decrease in tablet hardness was not caused by low Mg-St content compared to the PH-102 formulation.
• When the API content is maintained, the variations in hardness and tablet weight RSD of the UF-702 formulation due to the increase in tableting speed and Mg-St content are small compared to those of the PH-102 formulation. Therefore, use of the UF-702 formulation mitigates tableting issues and enables increases in tableting speed. Thus, various benefits can be expected from the UF-702 formulation, such as shortening the formulation development time, reducing production costs, ensuring robustness in terms of compactibility or flowability of the API and also against variations in other factors.

See the full PDF on “Ceolus™ UF grades” here

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Source: Asahi Kasei PDF “Ceolus™ UF grades”

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