Development of low dose micro-tablets by high shear wet granulation process

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

“…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.…”

“…In addition to the discussed concerns of the respective approaches, the application of the approaches mentioned above to manufacture of low dose micro-/mini-tablets can be further challenging due to the additional requirements like superior powder flow and maintenance of adequate die-hole diameter to blend particle size ratio (typically high) to ensure consistent and reproducible die filling that are essential pre-requisites to ensure good micro-/mini-tablet quality. 8,20 For example, i) reduction in API particle size to improve CU may result in increased cohesion, segregation, and flow issues [21][22][23] impacting the process of die filling during the direct compression process, ii) granulation of micronized API to improve flow and CU may lead to oversized granules if process parameters were not adequately controlled, resulting in lower die-hole diameter to particle size ratio which subsequently leads to die-filling issues and thus the production of micro-/ mini-tablets of poor quality 20 iii) particle size differences between the drug particle or drug-carrier composite and excipients might lead to segregation.…”

“…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). 8 Though the HSWG process of micronized API resulted in acceptable CU variability, it was observed that the manufactured micro-tablets had a lower mean potency value likely due to pragmatic issues associated with granulation of micronized API.…”

“…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). 8 Though the HSWG process of micronized API resulted in acceptable CU variability, it was observed that the manufactured micro-tablets had a lower mean potency value likely due to pragmatic issues associated with granulation of micronized API. 8 Further enhancement in dose titration flexibility could particularly be beneficial for pediatric patients including neonates as the pediatric doses are significantly lower than the adult dose.…”

Tableting of mini-tablets in comparison with conventionally sized tablets: A comparison of tableting properties and tablet dimensions

“…The acceptability and swallowability of mini-tablets as a single or multiparticulate dosage form for children and paediatric patients was proven in several studies ( Klingmann et al, 2013 ; Klingmann et al, 2015 ; Klingmann et al, 2018 ). Furthermore, the ability of dose flexibility of different mini-tablet sizes and different drug loading was shown by producing mini-tablets by direct compression or an intermediate high shear granulation step ( Gupta et al, 2020 ; Mitra et al, 2020 ). Mini-tablets are therefore considered a promising dosage form for pharmaceutical companies for developing child-appropriate medicines.…”