Optimization of bilayer tablet manufacturing process for fixed dose combination of sustained release high-dose drug and immediate release low-dose drug based on quality by design (QbD)

Won, Dong Han; Park, Heejun; Ha, Eun‐Sol; Kim, Hwan-Ho; Jang, Sun Woo; Kim, Min‐Soo

doi:10.1016/j.ijpharm.2021.120838

Cited by 24 publications

(15 citation statements)

References 71 publications

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“…All batches were within the compendial limit of <1%. The harder the tablet, there will be fewer chances of chipping and breakage [11]. The drug content of the film-coated bi-layer tablets was found to be in the range of 93.56-96.97% for both metoprolol succinate and amlodipine besylate.…”

Section: Conflicts Of Interestmentioning

confidence: 98%

“…A cube mixer was used for dry-mixing, dry-mixing completion stages of amlodipine besylate powder mixture, and dry-mixing completion of metoprolol succinate granules. The process of powder blending is influenced by diffusional and convective forces [11,21]. Following an increase in blending duration, it is likely that the movement of powder bed through convection increases the distribution of drug particles between the excipients to result in the generation of a random blend.…”

Section: Determination Of the Mixing Time And The Drying Time Of Granulesmentioning

confidence: 99%

“…The Shewhart R and X chart results for tablet weight of the three batches are also summarized in Tables 8 and 9. Bi-layer tablet is suitable for sequential release of two drugs in a combination form of two incompatible substances, in which one layer was immediate-release as initial dose and the second layer was maintenance dose [11,18,25]. Compression force-controlled presses were clearly limited when a quality bi-layer tablet needed to be produced in conjunction with accurate weight control of both layers.…”

Section: Process Of Tablet Compressionmentioning

confidence: 99%

“…Low pre-compression forces were necessary to secure interlayer bonding. The use of a higher compression force in the second layer may rapidly result in separation and hardness problems when compressing bi-layer tablets [11]. Therefore, the produced tablets' quality fulfilled all product specifications [23].…”

Section: Process Of Tablet Compressionmentioning

confidence: 99%

“…Indeed, moisture content, friability, and granule size distribution can significantly affect the final tablet properties such as tablet hardness, the dissolution rate of the active ingredient, etc. [11]. In this study, for the first time, we report the formulation and detailed production process of film-coated bi-layer tablets containing sustained-release metoprolol succinate and immediate-release amlodipine besylate at a scale of 10,000 tablets.…”

Section: Introductionmentioning

confidence: 99%

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Development of a Scalable Process of Film-Coated bi-Layer Tablet Containing Sustained-Release Metoprolol Succinate and Immediate-Release Amlodipine Besylate

et al. 2021

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The development of new drugs that combine active ingredients for the treatment hypertension is critically essential owing to its offering advantages for both patients and manufacturers. In this study, for the first time, detailed development of a scalable process of film-coated bi-layer tablets containing sustained-release metoprolol succinate and immediate-release amlodipine besylate in a batch size of 10,000 tablets is reported. The processing parameters of the manufacturing process during dry mixing-, drying-, dry mixing- completion stages were systematically investigated, and the evaluation of the film-coated bi-layer tablet properties was well established. The optimal preparation conditions for metoprolol succinate layer were 6 min- dry mixing with a high-speed mixer (120 rpm and 1400 rpm), 30-min drying with a fluid bed dryer, and 5-min- mixing completion at 25 rpm. For the preparation of amlodipine besylate layer, the optimal dry-mixing time using a cube mixer (25 rpm) was found to be 5 min. The average weight of metoprolol succinate layers and bi-layer tablets were controlled at 240–260 mg and 384–416 mg, respectively. Shewhart R chart and X¯ charts of all three sampling lots were satisfactory, confirming that the present scalable process was stable and successful. This study confirms that the manufacturing process is reproducible, robust; and it yields a consistent product that meets specifications.

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Section: Conflicts Of Interestmentioning

confidence: 98%

Section: Determination Of the Mixing Time And The Drying Time Of Granulesmentioning

confidence: 99%

Section: Process Of Tablet Compressionmentioning

confidence: 99%

Section: Process Of Tablet Compressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of a Scalable Process of Film-Coated bi-Layer Tablet Containing Sustained-Release Metoprolol Succinate and Immediate-Release Amlodipine Besylate

et al. 2021

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Injectable sustained‐release poly(lactic‐co‐glycolic acid) (PLGA) microspheres of exenatide prepared by supercritical fluid extraction of emulsion process based on a design of experiment approach

Park

Kim

et al. 2023

Bioengineering & Transla Med

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This study aimed to develop an improved sustained‐release (SR) PLGA microsphere of exenatide using supercritical fluid extraction of emulsions (SFEE). As a translational research, we investigated the effect of various process parameters on the fabrication of exenatide‐loaded PLGA microspheres by SFEE (ELPM_SFEE) using the Box–Behnken design (BBD), a design of experiment approach. Further, ELPM obtained under optimized conditions and satisfying all the response criteria were compared with PLGA microspheres prepared using the conventional solvent evaporation (ELPM_SE) method through various solid‐state characterizations and in vitro and in vivo evaluations. The four process parameters selected as independent variables were pressure (X1), temperature (X2), stirring rate (X3), and flow ratio (X4). The effects of these independent variables on five responses, namely the particle size, its distribution (SPAN value), encapsulation efficiency (EE), initial drug burst release (IBR), and residual organic solvent, were evaluated using BBD. Based on the experimental results, a desirable range of combinations of various variables in the SFEE process was determined by graphical optimization. Solid‐state characterization and in vitro evaluation revealed that ELPM_SFEE improved properties, including a smaller particle size and SPAN value, higher EE, lower IBR, and lower residual solvent. Furthermore, the pharmacokinetic and pharmacodynamic study results indicated better in vivo efficacy with desirable SR properties, including a reduction in blood glucose levels, weight gain, and food intake, for ELPM_SFEE than those generated using SE. Therefore, the potential drawback of conventional technologies such as the SE for the preparation of injectable SR PLGA microspheres could be improved by optimizing the SFEE process.

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QbD Application for a Fixed-Dose Combination with Biowaiver Potential: Evaluations of In Vitro and In Vivo Applications

Sarisaltik-Yasin

Uslu²,

Uyar

et al. 2022

J Pharm Innov

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Optimization of bilayer tablet manufacturing process for fixed dose combination of sustained release high-dose drug and immediate release low-dose drug based on quality by design (QbD)

Cited by 24 publications

References 71 publications

Development of a Scalable Process of Film-Coated bi-Layer Tablet Containing Sustained-Release Metoprolol Succinate and Immediate-Release Amlodipine Besylate

Development of a Scalable Process of Film-Coated bi-Layer Tablet Containing Sustained-Release Metoprolol Succinate and Immediate-Release Amlodipine Besylate

Injectable sustained‐release poly(lactic‐co‐glycolic acid) (PLGA) microspheres of exenatide prepared by supercritical fluid extraction of emulsion process based on a design of experiment approach

QbD Application for a Fixed-Dose Combination with Biowaiver Potential: Evaluations of In Vitro and In Vivo Applications

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