Implementing the Design of Experiments (DoE) Concept into the Development Phase of Orodispersible Minitablets (ODMTs) Containing Melatonin.

Development of orodispersible minitablets (ODMTs) requires consideration of aspects related to small dimensions, while ensuring short disintegration time with sufficient mechanical stability. In order to meet these and other critical quality attributes (CQAs), quality by design is encouraged. According to this approach, formulation and compression process factors were systematically studied using design of experiments (Plackett-Burman for screening purposes, full and fractional factorial design for in-depth characterization) to understand their influence on CQAs of orodispersible minitablets containing melatonin. Mathematical models describing the relationships between processing variables and attributes such as resistance to crushing and disintegration time were successfully developed, characterized by high coefficients of determination (R2adj = 0.90-0.97) and prediction errors in the range (+2.4 to -10.8%). In conclusion, based on these models, the design space was created for melatonin ODMTs, ensuring the product's quality and process robustness. Moreover, the study demonstrated the suitability of texture analysis as an alternative to compendial measurement methods of resistance to crushing and disintegration time. Graphical abstract.

Implementation of quality by design approach in manufacturing process optimization of dry granulated, immediate release, coated tablets - a case study.

The aim of this study was to optimize the process of tablets compression and identification of film-coating critical process parameters (CPPs) affecting critical quality attributes (CQAs) using quality by design (QbD) approach. Design of experiment (DOE) and regression methods were employed to investigate hardness, disintegration time, and thickness of uncoated tablets depending on slugging and tableting compression force (CPPs). Plackett-Burman experimental design was applied to identify critical coating process parameters among selected ones that is: drying and preheating time, atomization air pressure, spray rate, air volume, inlet air temperature, and drum pressure that may influence the hardness and disintegration time of coated tablets. As a result of the research, design space was established to facilitate an in-depth understanding of existing relationship between CPPs and CQAs of intermediate product (uncoated tablets). Screening revealed that spray rate and inlet air temperature are two most important factors that affect the hardness of coated tablets. Simultaneously, none of the tested coating factors have influence on disintegration time. The observation was confirmed by conducting film coating of pilot size batches.

The influence of direct compression powder blend transfer method from the container to the tablet press on product critical quality attributes: a case study.

OBJECTIVE: The aim of this article is to compare the gravitational powder blend loading method to the tablet press and manual loading in terms of their influence on tablets' critical quality attributes (CQA). SIGNIFICANCE: The results of the study can be of practical relevance to the pharmaceutical industry in the area of direct compression of low-dose formulations, which could be prone to content uniformity (CU) issues. METHODS: In the preliminary study, particle size distribution (PSD) and surface energy of raw materials were determined using laser diffraction method and inverse gas chromatography, respectively. For trials purpose, a formulation containing two pharmaceutical ingredients (APIs) was used. Tablet samples were collected during the compression progress to analyze their CQAs, namely assay and CU. RESULTS: Results obtained during trials indicate that tested direct compression powder blend is sensitive to applied powder handling method. Mild increase in both APIs content was observed during manual scooping. Gravitational approach (based on discharge into the drum) resulted in a decrease in CU, which is connected to a more pronounced assay increase at the end of tableting than in the case of manual loading. CONCLUSIONS: The correct design of blend transfer over single unit processes is an important issue and should be investigated during the development phase since it may influence the final product CQAs. The manual scooping method, although simplistic, can be a temporary solution to improve the results of API's content and uniformity when compared to industrial gravitational transfer.

Evaluation of drug-carrier interactions in quaternary powder mixtures containing perindopril tert-butylamine and indapamide.

Interactions occurring between components in the quaternary powder mixtures consisting of perindopril tert-butylamine, indapamide (active pharmaceutical ingredients), carrier substance and hydrophobic colloidal silica were examined. Two grades of lactose monohydrate: Spherolac(®) 100 and Granulac(®) 200 and two types of microcrystalline cellulose: M101D+ and Vivapur(®) 102 were used as carriers. We determined the size distribution (laser diffraction method), morphology (scanning electron microscopy) and a specific surface area of the powder particles (by nitrogen adsorption-desorption). For the determination of the surface energy of powder mixtures the method of inverse gas chromatography was applied. Investigated mixtures were characterized by surface parameters (dispersive component of surface energy, specific interactions parameters, specific surface area), work of adhesion and cohesion as well as Flory-Huggins parameter χ23('). Results obtained for all quaternary powder mixtures indicate existence of interactions between components. The strongest interactions occur for both blends with different types of microcrystalline cellulose (PM-1 and PM-4) while much weaker ones for powder mixtures with various types of lactose (PM-2 and PM-3).

Recent progress in continuous and semi-continuous processing of solid oral dosage forms: a review.

CONTEXT: Continuous processing is an innovative production concept well known and successfully used in other industries for many years. The modern pharmaceutical industry is facing the challenge of transition from a traditional manufacturing approach based on batch-wise production to a continuous manufacturing model. OBJECTIVE: The aim of this article is to present technological progress in manufacturing based on continuous and semi-continuous processing of the solid oral dosage forms. METHODS: Single unit processes possessing an alternative processing pathway to batch-wise technology or, with some modification, an altered approach that may run continuously, and are thus able to seamlessly switch to continuous manufacturing are briefly presented. Furthermore, the concept of semi-continuous processing is discussed. Subsequently, more sophisticated production systems created by coupling single unit processes and comprising all the steps of production, from powder to final dosage form, were reviewed. Finally, attempts of end-to-end production approach, meaning the linking of continuous synthesis of API from intermediates with the production of final dosage form, are described. RESULTS: There are a growing number of scientific articles showing an increasing interest in changing the approach to the production of pharmaceuticals in recent years. Numerous scientific publications are a source of information on the progress of knowledge and achievements of continuous processing. These works often deal with issues of how to modify or replace the unit processes in order to enable seamlessly switching them into continuous processing. A growing number of research papers concentrate on integrated continuous manufacturing lines in which the production concept of "from powder to tablet" is realized. Four main domains are under investigation: influence of process parameters on intermediates or final dosage forms properties, implementation of process analytical tools, control-managing system responsible for keeping continuous materials flow through the whole manufacturing process and the development of new computational methods to assess or simulate these new manufacturing techniques. The attempt to connect the primary and secondary production steps proves that development of continuously operating lines is possible. CONCLUSION: A mind-set change is needed to be able to face, and fully assess, the advantages and disadvantages of switching from batch to continuous mode production.