Tablet Compression Optimization of Ivabradine Sustained-Release Tablet Using Full Factorial Design

Aim: This study aimed to qualitatively identify the ranges of the factors involved in the tablet compression process for ivabradine Sustained Release (SR) tablets. Materials and Methods: A full factorial design of experiments study was used to identify three factors (pre-and main-compression force and paddle rotation time) involved in the compression process of ivabradine SR tablets. For robust tableting, three responses (content uniformity, friability, and dissolution) were evaluated as critical quality attributes via analysis of variance using Design Expert software. Results: The main compression force significantly influenced dissolution (1 hr, p <0.0001; 3 hr, p <0.0001; and 8 hr, p =0.0002). Precompression and paddle rotation time slightly influenced friability ( p =0.0510) and content uniformity ( p =0.0968). These results showed that paddle rotation time (0.27-1.37 sec), pre-compression (1.5 kN), and main compression (7.7-9.2 kN) influenced the tablet compression process of the optimal ivabradine SR tablet. Conclusion: In summary, robust ranges of three factors for tableting were successfully evaluated. It can be concluded that the ranges of tablet compression leading to high quality (low friability and content uniformity, and optimal dissolution) for tableting were successfully observed by the DoE approach.


INTRODUCTION
Chronic angina is defined as chest pain or discomfort caused by exercise or emotional stress caused by an imbalance between myocardial oxygen supply and consumption. 1,2The American College of Cardiology and American Heart Association (ACC/AHA) guidelines recommend single or complex prescriptions, such as calcium channel blockers, short-and long-acting nitrates, beta-blockers, and potassium channel activators, for chronic angina. 3Ivabradine hydrochloride (Procoralan ® ) reduces heart rate by selectively inhibiting the I f channel of the sinoatrial node, which is activated by hyperpolarization and regulated by the autonomic nervous system. 4,5According to the recommendations of the European Medicines Agency (EMA), ivabradine is approved for the treatment of chronic stable angina with a heart rate of over 70 beats per minute in adults who cannot use beta-blockers with normal sinus rhythm. 4,6 drug delivery systems, oral administration is the preferred option for various administration forms, such as immediate release, controlled release, and Sustained Release (SR).SR is widely used in drug development to reduce side effects by reducing drug administration frequency and preventing changes in the concentration. 7,8Currently, ivabradine is developed as an immediate-release tablet, and it is necessary to develop an SR tablet for patient convenience and compliance.Drug development should be developed to meet patient needs and achieve the target quality.Quality control of the drugs is necessary to ensure their efficacy and safety. 9Quality by Design (QbD) is a scientific, systematic, risk-based approach to each process parameter based on knowledge of drug development. 10In drug development, there is always uncertainty in the process; therefore, risk management is important for eliminating this uncertainty. 9The International Conference on Harmonization (ICH) Q8 guidelines represent process design based on quality control and scientific application. 11valuated by measuring content uniformity, dissolution (1, 3, and 8 hr), and friability.

Risk assessments and DoE study
For the initial risk assessment of the tablet compression process before the DoE study, three responses (content uniformity, friability, and dissolution, such as critical quality attributes (CQAs)) were determined as risks (high) of responses in the tableting process of the ivabradine SR tablet (Table 1).The selected risk assessment of the tableting (pre-and main-compression force, and paddle rotation time) process that may affect quality attributes, such as pre-and main-compression force and paddle rotation time, is shown in Table 2. 12 A three-factor (pre-and main-compression force and paddle rotation time), three-level, full factorial design was also used to optimize the process, as shown in Table 2. Eleven formulations (200 g per formulation) were prepared by the tableting press for the DoE study and analyzed using Design Expert software version 13.0.5.0 (Stat-Ease Inc., Minneapolis, MN, USA) (Table 3).We identified whether pre-and main-compression force and paddle rotation time for the tableting process had an impact on content uniformity, friability, and dissolution affecting the drug product (Table 3).

Loss on Drying (LOD)
Moisture content was measured using a halogen moisture analyzer (MB90, Ohaus, Seoul, Korea) exposed to 105ºC for 15 min.

Hardness
A tablet hardness tester (8M, Dr. Schleuniger, Switzerland) was used to test for tablet hardness.Five tablets per batch were randomly selected and identified.

Friability test
A friability test for assessing the friability of the tablet (n=20) was performed using a friability tester (FR-2000, Nottingham, United Kingdom) at 25 rpm for 4 min.

Content uniformity
Content uniformity test was performed by the modified method of Lodhi et al. 13

Dissolution testing
The dissolution tests of tablets at pH 6.8 (900 mL; time points: 1, 3, and 8 hr) were performed using the basket method (USP apparatus 1, 100 rpm).

Statistical analysis
All statistical analyses were evaluated with a full-factorial design using Design Expert software version 13.0.5.0 (Stat-Ease Inc., Minneapolis, MN, USA) for p-values<0.05,F test, coefficient of determination (R 2 ), and adjusted coefficient of determination (adjusted R 2 ) parameters.

Initial risk evaluation in the tableting process of ivabradine SR tablets
Table 1 shows the initial risk assessment of the tableting processes for ivabradine SR tablets.An initial risk assessment was conducted to determine which tableting process potentially affected CQAs.The initial risk assessment was evaluated based on the initial experimental data and prior formulation knowledge (Table 1). 12able 1 shows the process variables evaluated on a three-level scale (high, medium, and low).Paddle rotation time and preand main-compression force were individually identified as "high risk" of content uniformity and dissolution, friability, and dissolution and friability.4).Additionally, contour plots showed that all factors affected the response (Figure 1).

Design space, control strategy, and updated risk assessment
To identify the tablet compression process robustness, a design space (95% confidence interval) of the mean values of feeder paddle time and pre-and main-compression forces was drawn in Figure 2. The white parts indicate that the target goal values were not reached.The satisfied range for the targeted goal values was identified as black (Figure 1).The range of pre-and main-compression forces and paddle rotation time for the control strategy (CS) was well justified, with the following values:

DISCUSSION
The goal of the tablet compression process DoE for the critical material attributes (CMA) and critical process parameters (CPP) is to confirm the robustness of ivabradine SR tablets using three factors (pre-and main-compression forces and paddle rotation time).A QbD approach is applied to optimize the initially developed formulation and manufacturing process based on brainstorming of the team and past experience. 14,15The process of QbD is as follows: (1) defining Quality Target Product Profile (QTPP), (2) defining CQAs, (3) identifying the initial risk assessment, (4) setting up DoE based on high-risk factors in the initial RA, and (5) determining the DS, which is derived from the ranges of responses as CQAs.Finally, (6) determining a control strategy. 12 this study, the initial risk assessments of the tablet compression process were established as low, medium, or high risk, considering CQAs (Table 1).QTPP influenced by CQAs of ivabradine SR tablets was established based on a reference drug (Procoralan ® ). 12 Generally, feed speed, precompression force, main compression force, turret speed, press, and compression run time can be factors in the tablet compression process for the DoE study. 16In this study, the factors (pre-and main-compression force and paddle rotation time) for the tablet compression process constituted the DoE because these factors can affect the product CQAs of content uniformity, friability, and dissolution (Table 2).
The results for all responses are shown in Table 3, and the results were analyzed through ANOVA using Design Expert software version 13.0.5.0 (Table 4).The main compression force of the ivabradine SR tablet had a strong influence on dissolution, except for two factors (precompression and paddle rotation time) (Table 4).Additionally, the various effects of the factors are shown in Figure 1. Figure 1A shows that none of the factors had an important effect on the content uniformity of tablet compression.The results of the content uniformity between 1.31% and 4.09% were also found to be not significant (Table 3).However, a lower paddle rotation time may increase the content uniformity of the tablet (Figure 1A).The results of the friability between 0.20% and 0.40% were also found to be not significant (Table 3).However, the pre-compression force had a minimally significant effect (p=0.051) (Table 4).As shown in Figure 1B, a lower pre-compression force may increase the friability of the tablet.The main compression force had a significant effect (1 hr, p<0.0001; 3 hr, p<0.0001; and 8 hr, p=0.0002) on tablet dissolution (Table 4).Figure 1(C, D, and E) shows that the main compression force had a significant effect on the dissolution (1, 3, and 8 hr) of the tableting process.First, the main effect indicated that a decrease in the main compression force may have increased the dissolution rate at 1 and 3 hr.Batches 2, 7, and 9 resulted in unacceptable ranges (46.65, 44.16, and 48.58) of dissolution rate (1 hr) based on the acceptance criteria (20.0-40.0%)(Table 3).Batches 1, 2, 7, and 9 also resulted in unacceptable ranges (65.42, 69.58, 69.86, and 67.04) of dissolution rate (3 hr) based on the acceptance criteria (40.0-60.0%)(Table 3).Second, the main effect indicated that an increase in the main compression force may have decreased the dissolution rate at 8 hr.Batches 4, 5, 6, 8, and 10 also resulted in unacceptable dissolution rates (78.45,62.56, 79.94, 76.18, and 67.77) of dissolution rate (8 hr) based on the acceptance criteria (≥80.0)(Table 3).This result indicates that the main compression force can affect the dissolution, hardness, and friability. 16The main compression force strongly affected dissolution.Content uniformity can also be slightly affected by the paddle rotation time.
In general, if the regression coefficient (R 2 ) value is 0.7 or higher, the DS can be established. 17,18Our results showed that the values of R 2 for content uniformity, friability, and dissolution (1, 3, and 8 hr) were 0.7886, 0.6144, 0.7378, 0.7855, and 0.8487, respectively (Table 4).According to the results in Table 3, the DS was fitted to  the tableting process with respect to content uniformity, friability, and dissolution.To ensure the robustness of the tableting process, the DS (95% confidence interval) is shown in Figure 2. 19 The white area indicates that the goal of the response was not reached.The optimal range is indicated by the black area.If the paddle rotation time and pre-and main-compression forces are produced at approximately 0.27-1.37s, 1.5 kN, and 7.7-9.2kN, the desired content uniformity, friability, and dissolution rate of tablets will be obtained.The CS was established by the DS, and the values of three factors (paddle rotation time and pre-and main-compression forces) were identified as 0.7 s, 1.5 kN, and 8 kN, which are representative of good processes for all responses. 15,20This study aimed to optimize the drug product tablet compression process and reduce the risk of failure.The initial risks of the tablet compression process were updated according to the DoE results.

CONCLUSION
The robust ranges in the tableting process for ivabradine SR tablets were identified using a DS through responses.We identified that the dissolution was highly affected by the main compression force.Content uniformity and friability were slightly affected by paddle rotation time and pre-compression force, respectively.Based on the results of this tableting DoE, the paddle rotation time (0.7 s) and pre-and main-compression forces (1.5 and 8 kN) for the tablet compression process were identified with optimal ranges for the acceptance criteria of content uniformity, friability, and dissolution.

(
paddle rotation time and precompression force) nearly affected the responses of content uniformity (p=0.0968) and friability (p=0.0510)within the studied ranges.However, the main compression force of the independent factors strongly affected the dissolution (1 and 3 hr: p<0.0001; 8 hr: p=0.0002) of critical quality attributes.All models had values of p<0.05.The lack-of-fit had values of p>0.05.This means that these are the appropriate models for our adjustments (Table pre-compression force (approximately 1.5 kN), main compression force (approximately 7.2 kN), and paddle rotation time (approximately 1.0 s).The mean values of the three factors had the best range for all the responses.Acceptable ranges of parameters (pre-and main-compression forces and paddle rotation time) in the tableting satisfying all responses were pre-compression force (1.0-2.0 kN), main-compression force (6.5-10.0kN), and paddle rotation time (0.2-1.77 s).In this study, the manufacturing process (tablet compression) with established ranges of factors impacting hardness, disintegration time, dissolution, and content uniformity were updated from high to low risks.

Table 2 : 2 3 full factorial design for DoE of tablet compression process.
a degrees of freedom.