Decoding the small size challenges of mini-tablets for enhanced dose flexibility and micro-dosing

Mitra, Biplob; Thool, Prajwal; Meruva, Saikishore; Aycinena, J. Alex; Li, Jianmin; Patel, Jhalak; Patel, Kuldip R.; Agarwal, Anjali; Karki, Shyam; Bowen, William E.

doi:10.1016/j.ijpharm.2019.118905

Cited by 24 publications

(19 citation statements)

References 27 publications

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“…The QTPP shown in Table II was established by the authors after a thorough review of the published papers on minitablets and ODMTs. Minitablets or ODMTs were feasible at diameters between 1 mm and 3 mm, although Tissen et al reported processability issues for the 1 mm tablets as tablet bisection by the scraper affecting 25% of the batch [15,26]. Acceptable mechanical properties of the tablets were reported at crushing strengths above 7 N or tensile strengths over 2 MPa [15,24].…”

Section: Risk Managementmentioning

confidence: 99%

“…Minitablets or ODMTs were feasible at diameters between 1 mm and 3 mm, although Tissen et al reported processability issues for the 1 mm tablets as tablet bisection by the scraper affecting 25% of the batch [15,26]. Acceptable mechanical properties of the tablets were reported at crushing strengths above 7 N or tensile strengths over 2 MPa [15,24]. The development and manufacturing of ODTs are often challenging tasks because of the need to establish a balance between the good disintegration properties in small volumes of liquid and sufficient mechanical resistance to withstand packaging, transport and administration.…”

Section: Risk Managementmentioning

confidence: 99%

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The Evaluation of Dynamic Compaction Analysis as a QBD Tool for Paediatric Orodispersible Minitablet Formulation

Iurian¹

2020

FARMACIA

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The formulation of orodispersible minitablets (ODMTs) usually targets the disintegration time and mechanical strength, but should also consider a series of technological issues related to powder flow and compression behaviour. In this regard, the present study aimed to evaluate the contribution of dynamic compaction analysis as Quality by Design (QbD) tool in ODMTs' formulation. Placebo tablets were prepared by direct compression following a design of experiments (DoE). Each powder blend was subjected to dynamic compaction analysis; the work of compression, the elastic recovery, the detachment stress, the ejection stress as well as the disintegration time and crushing strength were determined. The effects of input variables on the responses were quantified as regression models and two sets of constraints were applied for Design Space (DS) development: one regarding tablet characteristics and the second one including compression performance parameters. The DS was validated and the robust point and negative control were used to prepare ODMTs. Their characteristics confirmed the benefits of including the compression parameters into the early formulation stages of ODMTs. Rezumat Formularea minicomprimatelor orodispersabile (ODMT) vizează de obicei optimizarea timpului de dezagregare și a rezistenței mecanice, dar ar trebui să ia în considerare și o serie de probleme tehnologice legate de curgerea amestecului de pulbere și de performanță a comprimării. În această privință, studiul de față a urmărit să evalueze contribuția analizei dinamice a comprimării ca instrument al conceptului de Calitate prin Design (QbD) în formularea ODMT. S-au preparat comprimate placebo prin comprimare directă după un plan experimental (DoE). Fiecare amestec de pulbere a fost supus unei analize dinamice de compactare; s-au determinat lucrul mecanic al comprimării, revenirea elastică, tensiunea de detașare, tensiunea de ejecție, precum și timpul de dezagregare și rezistența mecanică. Efectele variabilelor de intrare asupra răspunsurilor au fost cuantificate ca modele de regresie și s-au aplicat două seturi de constrângeri pentru dezvoltarea Domeniului Optim (DS): unul cu privire la caracteristicile tabletei, iar al doilea adăugând parametrii de performanță ai comprimării. DS a fost validat, iar punctul robust și controlul negativ au fost utilizate pentru prepararea ODMT. Caracteristicile lor au confirmat avantajele includerii parametrilor de performanță a comprimării în etapele de formulare a ODMT.

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Section: Risk Managementmentioning

confidence: 99%

Section: Risk Managementmentioning

confidence: 99%

The Evaluation of Dynamic Compaction Analysis as a QBD Tool for Paediatric Orodispersible Minitablet Formulation

Iurian¹

2020

FARMACIA

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“…Content uniformity risk at low doses is well-known in the pharmaceutical industry, 3,5 and this risk further aggravates as the tablet size decreases from a conventional tablet to a mini-tablet (2−3 mm) or a micro-tablet (1.2 and 1.5 mm). [6][7][8] Micro-/mini-tablets offer many advantages, such as enhanced patient compliance, reduced excipient burden, and enhanced dose titration flexibility (especially low dose micro-/mini-tablets) in the clinic to establish the dose range [6][7][8][9] concurrently retaining the specific benefits associated with conventional tablets, such as downstream process flexibility, cost of manufacturing, and product stability. 6 To alleviate the CU related challenges associated with low dose solid oral drug products, investigators have focused their research on achieving uniform distribution of API amongst the formulation components by various approaches like reduction in API particle size via dry and wet-milling methods, efficient mixing of API with other formulation components, and use of dry granulation/fluid-bed granulation/high shear wet granulation technology, etc.. 3,[10][11][12][13][14][15][16] Though the approaches mentioned above offer reasonable solutions to overcome the CU issues, sometimes there might be practical issues that limit their application.…”

Section: Introductionmentioning

confidence: 99%

“…The lowest reported API loading with acceptable individual micro-tablet CU variability by direct compression was 14% w/w (i.e., 0.16 mg dose). 6 Further reduction in API loading will enhance the dose titration flexibility achieved by micro-tablets and reduce the excipient burden in the pediatric population. 6,8 In our previous study, we demonstrated that high shear wet granulation of micronized API with proper selection of process parameters helps in achieving acceptable CU variability at even low API loadings (0.67% w/w and 3.33% w/w).…”

Section: Introductionmentioning

confidence: 99%

A Novel Use of Nanocrystalline Suspensions to Develop Sub-Microgram Dose Micro-Tablets

Meruva

Thool

Gong

et al. 2021

Journal of Pharmaceutical Sciences

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“…For the purpose of this article, these distinctions are denoted, in order of decreasing size, as product (dosage form) > module > component. Modular pharmaceutical product archetypes already exist both on the market and in academic research [ 17 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ], including, for example, granules, pellets, mini tablets, layered dosage forms, and compartmentalized structures, as well as the more recently demonstrated combined API and flexible dose product architectures [ 22 , 52 , 58 ]. However, these are currently designed to either promote process flexibility within the currently dominant mass production paradigm or potentially product variety within a full customization context.…”

Section: Introductionmentioning

confidence: 99%

Independent Tailoring of Dose and Drug Release via a Modularized Product Design Concept for Mass Customization

et al. 2020

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Independent individualization of multiple product attributes, such as dose and drug release, is a crucial overarching requirement of pharmaceutical products for individualized therapy as is the unified integration of individualized product design with the processes and production that drive patient access to such therapy. Individualization intrinsically demands a marked increase in the number of product variants to suit smaller, more stratified patient populations. One established design strategy to provide enhanced product variety is product modularization. Despite existing customized and/or modular product design concepts, multifunctional individualization in an integrated manner is still strikingly absent in pharma. Consequently, this study aims to demonstrate multifunctional individualization through a modular product design capable of providing an increased variety of release profiles independent of dose and dosage form size. To further exhibit that increased product variety is attainable even with a low degree of product modularity, the modular design was based upon a fixed target dosage form size of approximately 200 mm3 comprising two modules, approximately 100 mm3 each. Each module contained a melt-extruded and molded formulation of 40% w/w metoprolol succinate in a PEG1500 and Kollidon® VA64 erodible hydrophilic matrix surrounded by polylactic acid and/or polyvinyl acetate as additional release rate-controlling polymers. Drug release testing confirmed the generation of predictable, combined drug release kinetics for dosage forms, independent of dose, based on a product’s constituent modules and enhanced product variety through a minimum of six dosage form release profiles from only three module variants. Based on these initial results, the potential of the reconfigurable modular product design concept is discussed for unified integration into a pharmaceutical mass customization/mass personalization context.

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Decoding the small size challenges of mini-tablets for enhanced dose flexibility and micro-dosing

Cited by 24 publications

References 27 publications

The Evaluation of Dynamic Compaction Analysis as a QBD Tool for Paediatric Orodispersible Minitablet Formulation

The Evaluation of Dynamic Compaction Analysis as a QBD Tool for Paediatric Orodispersible Minitablet Formulation

A Novel Use of Nanocrystalline Suspensions to Develop Sub-Microgram Dose Micro-Tablets

Independent Tailoring of Dose and Drug Release via a Modularized Product Design Concept for Mass Customization

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