Study on the conversion from batch to continuous manufacturing processes for amiodarone hydrochloride tablets = 아미오다론 염산염 정제의 배치공정에서 연속공정으로의 전환 연구

다국어 초록 (Multilingual Abstract)

This study aimed to effectively design and optimize the manufacturing process for
amiodarone hydrochloride tablets by applying continuous wet granulation. The properties of
the resulting granules and tablets were evaluated to compare the differences between a
conventional batch process using a high-shear mixer (HSM) and a continuous process
using a twin-screw granulator (TSG). Furthermore, twin-screw rpm was identified as a
Critical Process Parameter (CPP) affecting granule and tablet properties. A Design of
Experiments (DoE), specifically a central composite design, was conducted to establish
optimal process conditions. The independent variables (X) investigated were twin-screwrpm and milling size, while the dependent variables (Y) included dissolution, flowability,
assay, disintegration, and friability. The results from the comparative study indicated no
significant differences in the in-process controls (IPCs) for tablets manufactured by either
process. Moreover, the dissolution profiles demonstrated equivalence to the reference drug,
with a similarity factor (f2) greater than 50. Furthermore, measurement of the actual
duration for each process revealed that the continuous process achieved a time reduction of
over 80% relative to the batch process. In conclusion, this study confirms the feasibility of converting the manufacturing of a drug product from a traditional batch-based process to a
continuous one.

국문 초록 (Abstract)

본 연구는 연속 습식 과립화 공정을 적용하여 아미오다론 염산염 정제 제조를 효과적으로설계하고 최적화하는 것이다. 배치공정에서 High shear mixer(HSM)와 연속공정에서 Twin
screw granulator(TSG) 사용에 따른 차이점을 비교하기 위해 과립물 및 정제의 특성을평가하였다. 또한, 과립화 공정 중 과립 및 정제 특성에 영향을 미치는 Critical Process
Parameters(CPP)로 Twin screw rpm를 선정하여 Design of Experiment(DoE) 중 중심 합성설계법으로 실험을 수행하였다. X값으로 Twin screw rpm, milling size를 선정하였고, Y값으로dissolution, flowability, assay, disintegration, friability를 선정하여 최적의 연속공정 조건을도출하고, 이를 배치공정과 비교하였다. 배치공정과의 비교 연구 결과 제조된 정제들의 공정중시험(IPC)에서 유의한 차이가 없었고, 용출 프로파일 또한 유사성 인자(F2)가 50 이상으로대조약과의 동등성을 확보하였다. 또한, 각 공정의 실제 소요시간을 측정한 결과 배치공정 대비연속공정의 소요시간이 85% 이상 단축되는 것을 확인하였다. 결론적으로 본 연구를 통해배치공정 기반 약물을 연속공정 기반으로의 전환 가능성을 확인하였다.

다국어 초록 (Multilingual Abstract)

This study evaluates the formulation possibilities of amiodarone hydrochloride, an
antiarrhythmic agent used for the treatment and prevention of arrhythmia, for development
into a continuous manufacturing process dosage form. Amiodarone hydrochloride is a calciumchannel blocker and an antiarrhythmic agent listed on the national essential medicines list.
We predicted and tested the physicochemical properties and essential preformulation results
of amiodarone hydrochloride using our proprietary AI formulation design software. In this
study, apparent and equilibrium solubility tests were conducted in various solvents, and
degradation was examined to confirm the compatibility between amiodarone hydrochloride
and various excipients. Additionally, flowability was assessed to predict the physical
properties of the active pharmaceutical ingredient (API). The solubility test results showed
that amiodarone hydrochloride was practically insoluble in aqueous solutions but was
'soluble' in methanol. Furthermore, it was confirmed to be more soluble in Polysorbate 80
(Tween 80) than in Sodium Lauryl Sulfate among the tested surfactants. In the compatibility
study, the interaction between amiodarone hydrochloride and 21 different excipients was
observed for up to 4 weeks under long-term (25°C/60%RH) and accelerated (40°C/75%RH)
storage conditions. The flowability study of the API resulted in a Carr's index of 30. Through this research, we confirmed the potential for developing amiodarone hydrochloride
into an oral tablet dosage form with improved flow properties by using a glidant.

다국어 초록 (Multilingual Abstract)

The purpose of this study was to develop an oral formulation of amiodarone hydrochloride
optimized for manufacturing via a continuous wet granulation process. A significant
challenge arose when a formulation, previously established as pharmaceutically equivalent in
a batch process, was converted to continuous production. Specifically, the initial dissolution
rates were diminished by 20% under simulated gastric pH conditions and by 30% under
simulated intestinal pH conditions. To address this issue and enhance the initial dissolution
rates amiodarone hydrochloride tablets were manufactured by optimizing the proportions of
the binder and the binding solution. The formulation's critical quality attributes (CQA) were
assessed using in-process controls (IPC) and dissolution profiling. In a supplementary
investigation the effects of varying the type and ratio of lactose on IPC results and
dissolution profiles were also compared. The in vitro studies revealed no statistically
significant impact of lactose type or ratio on dissolution rate. However the newly
manufactured amiodarone hydrochloride tablets with an adjusted binder and binding solution
ratio showed a 33% increase in the initial dissolution rate in the gastric pH environment and
a 24% increase in the intestinal pH environment compared to the tablets that had established pharmaceutical equivalence in the batch process. In conclusion the novel tablet formulation
developed in this study is anticipated to be highly suitable for efficient application in a
continuous wet granulation process.

목차 (Table of Contents)

• Part 1. Studies on preformulation of amiodarone hydrochloride tablets through AI formulation software 1
• 1. Abstract 2
• 2. Introduction 4
• 3. Materials and Methods 8
• 3.1. Materials 8
• 3.2. Physicochemical property prediction of amiodarone hydrochloride 9
• 3.3. Differential scanning calorimetry (DSC) analysis 10
• 3.4. Dynamic light scattering (DLS) analysis 11
• 3.5. Solubility 12
• 3.6. Compatibility 14
• 3.7. Flowability study 15
• 3.8. RP-HPLC analysis 16
• 3.8.1. Method for quantitative analysis 16
• 3.8.2. Analytical method for impurities in amiodarone hydrochloride 16
• 4. Results and Discussion 18
• 4.1. Physicochemical property of amiodarone hydrochloride 18
• 4.2. Solubility 22
• 4.3. Compatibility 25
• 4.4. Flowability study 28
• 4.5. Comparison between AI predictions and experimental results 29
• 5. Conclusion 32
• 6. References 34
• Part 2. A formulation study of amiodarone hydrochloride tablets based on a batch process with consideration for conversion to continuous manufacturing 37
• 1. Abstract 38
• 2. Introduction 40
• 3. Materials and Methods 43
• 3.1. Materials 43
• 3.2. Formulation study of amiodarone hydrochloride 44
• 3.2.1. Binder ratio study 44
• 3.2.2. Binding solution ratio study 45
• 3.2.3. Filler type study 45
• 3.2.4. Filler ratio study 47
• 3.3. In process control (IPC) 48
• 3.4. Dissolution conditions 50
• 3.5. RP-HPLC conditions 51
• 4. Results and Discussion 52
• 4.1. Formulation study of amiodarone hydrochloride 52
• 4.1.1. Binder ratio study 52
• 4.1.2. Binding solution ratio study 54
• 4.1.3. Filler type study 56
• 4.1.4. Filler ratio study 58
• 5. Conclusion 60
• 6. References 62
• Part 3. Comparative conversion study of batch and continuous wet granulation processes for amiodarone tablets 65
• 1. Abstract 66
• 2. Introduction 68
• 3. Materials and Methods 71
• 3.1. Materials 71
• 3.2. Formulation study 72
• 3.3. Manufacturing process study 74
• 3.3.1. Batch wet granulation process 74
• 3.3.2. Continuous wet granulation process 74
• 3.4. Comparative flowability evaluation 76
• 3.5. Tablet manufacturing process study 77
• 3.6. Comparative evaluation study of batch and continuous processes 78
• 3.6.1. Hardness 78
• 3.6.2. Friability 78
• 3.6.3. Disintegration 79
• 3.6.4. In vitro comparative dissolution study 79
• 3.6.5. Design of Experiment 80
• 4. Results and Discussion 82
• 4.1. Comparative evaluation of batch and continuous wet granulation 82
• 4.2. Comparative evaluation of tablets manufactured by batch and continuous processes 85
• 4.2.1. Hardness 85
• 4.2.2. Friability 85
• 4.2.3. Disintegration 86
• 4.2.4. In vitro comparative dissolution study 87
• 4.2.5. Design of Experiment 90
• 4.3. Comparison of processing time for HSM and TSG 95
• 5. Conclusion 96
• 6. References 98