Quality by design-based evaluation and optimization of ceftibuten flexible dispersible tablet design with high drug loading using Design-Expert software

Abstract

There are challenges in developing dispersible tablets with a high drug loading of a water- insoluble drug having flexibility, either as dispersible in water or as dispersible in the oral cavity before swallowing with overall acceptability. Overall acceptability is determined by the characteristics of the drug product and user acceptance. This study aimed to design and optimise the flexible dispersible tablets design using a model drug, namely ceftibuten with the drug loading of about 72%w/w of targeted tablet weight, in a statistically significant manner using design-expert software. The significant effects of screened input parameters on target responses were characterised based on the half-normal plot for the magnitude of effects, pareto chart for standardised effects, and variance analysis for the statistically significant model. The characterised design was optimised using the response surface method (RSM). The optimised target response was statistically confirmed based on the extent of statistical significance (very significant <0.01, significant <0.05 but >0.01). Among the input factors studied, crospovidone concentration shows a statistically very significant effect (<0.0001) on target response namely in vitro disintegration time, in vivo disintegration time, and overall acceptability of intended flexible dispersible tablet design. The outcome of designed and evaluated flexible dispersible tablets (FDT) using design-expert software demonstrated its ability to predict the design space with a statistical significance, which maximises the robust product characteristics and overall user acceptance.

Keywords

• Quality by design
• design of experiments
• ceftibuten
• flexible dispersible tablet
• high drug loading
• user acceptance testing
• design-expert software.

References

1. [1] Sharrif Z, Kirby D, Missaghi S, Rajabi-Siahboomi A, Maidment I. Patient-Centric Medicine Design: KeyCharacteristics of Oral Solid Dosage Forms that improve Adherence and Acceptance in Older People. Pharmaceutics. 2020; 12(10): 1-15. [CrossRef]
2. [2] Govindan S P, Senthamarai R, Anbarasu K. Design of Flexible Dispersible Tablet with high drug loading using quality by Design: Proof of Concept study using third generation Cephalosporins Model Drug. Research J Pharm Tech. 2021; 14(2): 705-714.
3. [3] Walsh J, Ranmal S R, Ernest T B, Liu F. Patient acceptability, safety and access: A balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations. Int J Pharm. 2018; 536(2): 547-562. [CrossRef]
4. [4] Logrippo S, Ricci G, Sestili M, Cespi M, Ferrara L, Palmieri G F, Ganzetti R, Bonacucina G, Blasi P. Oral drug therapy in elderly with dysphagia: between a rock and a hard place. Clin Interv Aging. 2017; 12: 241-251.
5. [5] Orubu E SF, Tuleu C. Medicines for children: flexible solid oral formulations. Bull World Health Organ. 2017; 95: 238-240. [CrossRef]
6. [6] Hoppu, K. Time to change the paradigm of children's medicines from liquid formulations to flexible solid oraldosage forms. Ceylon Med J. 2016; 61(3): 93-95. [CrossRef]
7. [7] Liu F, Ranmal S, Batchelor H K, Gul M O, Ernest T B, Thomas I W, Flanagan T, Tuleu C. Patient-CentredPharmaceutical Design to Improve Acceptability of Medicine: Similarities and Differences in Pediatric and GeriatricPopulations. Drugs. 2014; 74(16):1871-1889. [CrossRef]
8. [8] Govindan S P, Senthamarai R, Anbarasu K. Refrigeration and the Shelf Life of Oral Cephalosporin Powder forSuspension Dosage Form: Review and Proposal. Int. J Emerg Technol. 2019; 10(2).376–383.

9. [9] International Conference on Harmonisation (ICH), 2009. ICH Harmonised Tripartite Guideline: PharmaceuticalDevelopment Q8 (R2). https://database. ich.org/sites/default/files/Q8_R2_Guideline.pdf (accessed June 30, 2020).
10. [10] Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms. https://www.fda.gov/media/83664/download (accessed June 30, 2020). [11] Dhoot A S, Fernandes G J, Naha A, Rathnanand M, Kumar L. Design of Experiments in Pharmaceutical Development. Pharm Chem J. 2019; 53(8): 730-735.
11. [12] Sangshetti J N, Deshpande M, Arote R, Zaheer Z, Shinde D B. Quality by design approach: Regulatory need. Arabian J Chem. 2017; 10(2): S3412-S3425. [CrossRef]
12. [13] Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation. https://www.fda.gov/media /81626/download(accessed June 30, 2020).
13. [14] Guidance for Industry Orally Disintegrating Tablets. https://www. fda.gov/media/70877/download (accessedJune 30, 2020).
14. [15] Guidance for Industry Size, Shape, and other Physical Attributes of Generic Tablets and Capsules.https://www.fda.gov/media/87344/download (accessed June 30, 2020).
15. [16] Bircan Y, Çomoğlu T. Formulation technologies of orally fast disintegrating tablets. Marmara Pharm J. 2012; 16: 77-81.
16. [17] Handbook for Experimenters Version 11.01. https://cdnm.statease.com/pubs/handbk_for_exp_sv.pdf (accessedJune 7, 2019).
17. [18] Ceftibuten. https://www.accessdata.fda.gov/scripts /cder/dissolution/dsp_SearchResults.cfm (accessed June 7, 2019).
18. [19] Ali T, Ediz Y, Gülcin T. Ceftibuten Capsule Formulations. European Patent 3 031 450 A1; 2016 (accessed June 7, 2019).
19. [20] Cedax® (ceftibuten capsule) and (ceftibuten for oral suspension).https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050685s011,050686s014IbI.pdf (accessed on June7, 2019).
20. [21] Belissa E, Vallet T, Caget S L, Chevallier A, Chedhomme F X, Abdallah F, et al. Acceptability of oral liquidpharmaeutical products in older adults: palatability and swallowability issues. BMC Geriatrics. 2019; 19(344): 2-9.[CrossRef]
21. [22] European Medicines Agency (EMEA), 2012. Presentation-acceptability and palatability- methods available forassessment. https://www.ema.europa.eu/en/documents/presentation/presentation-acceptability-palatability-Methods-available-assessment_en.pdf (accessed May 3, 2020).
22. [23] Brniak W, Jachowicz R, Pelka P. The practical approach to the evaluation of methods used to determine thedisintegration time of orally disintegrating tablets (ODTs). Saudi Pharm J. 2015; 23: 437-443. [CrossRef]
23. [24] Yoshita T, Uchida S, Namiki N. Clinical Disintegration Time of Orally Disintegrating Tablets Clinically AvailableJapan in Healthy Volunteers. Biol. Pharm. Bull. 2013; 36(9): 1488-1493.
24. [25] Kim J-II, Cho S-Min, Cui J-H, Cao Q-Ri, Oh E, Lee B-J. In Vitro and in Vivo Correlation of disintegration and bitterTaste masking using orally disintegrating tablet containing ion exchange resin-drug complex. Int J Pharm. 2013; 455: 31-39. [CrossRef]
25. [26] Callejo M J, Kostiuk-V Eugenia-M, Quijano-M R. Selection, training and validation of a sensory panel for breadanalysis: Influence of cultivar on the quality of breads made from common wheat and spelt wheat. J Cereal Sci. 2015; 61: 55-62. [CrossRef]
26. [27] Ranmal S R, O’Brien F, Lopez F, Ruiz F, Orlu M, Tuleu C, et al. Methodologies for assessing the acceptability of oralformulations among children and older adults : a systematic review. Drug Discov Today. 2018; 23(4): 830-847.[CrossRef]