Julian Quodbach

Systematic classification of tablet disintegrants by water uptake and force development kinetics.

Water uptake and force development of disintegrating tablets provide a high degree of information about the disintegration mechanisms and process itself. An apparatus for the simultaneous measurement of water uptake and force development of tablets is presented, and the gathered data are analysed.

Assessment of disintegrant efficacy with fractal dimensions from real-time MRI.

An efficient disintegrant is capable of breaking up a tablet in the smallest possible particles in the shortest time. Until now, comparative data on the efficacy of different disintegrants is based on dissolution studies or the disintegration time. Extending these approaches, this study introduces a method, which defines the evolution of fractal dimensions of tablets as surrogate parameter for the available surface area. Fractal dimensions are a measure for the tortuosity of a line, in this case the upper surface of a disintegrating tablet. High-resolution real-time MRI was used to record videos of disintegrating tablets. The acquired video images were processed to depict the upper surface of the tablets and a box-counting algorithm was used to estimate the fractal dimensions. The influence of six different disintegrants, of different relative tablet density, and increasing disintegrant concentration was investigated to evaluate the performance of the novel method. Changing relative densities hardly affect the progression of fractal dimensions, whereas an increase in disintegrant concentration causes increasing fractal dimensions during disintegration, which are also reached quicker. Different disintegrants display only minor differences in the maximal fractal dimension, yet the kinetic in which the maximum is reached allows a differentiation and classification of disintegrants.

A New Apparatus for Real‐Time Assessment of the Particle Size Distribution of Disintegrating Tablets

The aim of this study is the introduction of a novel apparatus that is capable of continuously measuring the particle size reduction of disintegrating tablets and analysis of the obtained results. The apparatus is constructed such that no particles pass directly through the pumping system. Thereby, the overall energy input into the particle suspension is reduced, and continuous measurement is possible without rapid destruction of the generated particles. The detected particle sizes at the beginning and at the end of the measurement differ greatly, depending on the applied disintegrant. The median particle sizes at the end of the measurement vary between 621.5 and 178.0 μm for different disintegrants. It is demonstrated that the particle size reduction follows an exponential function and that the fit parameters can be used to describe the disintegration behavior. A strong correlation between the median particle size of crospovidone disintegrants and generated particle size of the tablets is observed. This could be due to a more homogeneous distribution of the disintegrant particles in the tablets. Similar trends are observed for sodium starch glycolate and croscarmellose sodium. The new apparatus provides an innovative method to describe disintegrant effectiveness and efficiency.

Performance of tablet disintegrants: impact of storage conditions and relative tablet density

Abstract Tablet disintegration can be influenced by several parameters, such as storage conditions, type and amount of disintegrant, and relative tablet density. Even though these parameters have been mentioned in the literature, the understanding of the disintegration process is limited. In this study, water uptake and force development of disintegrating tablets are analyzed, as they reveal underlying processes and interactions. Measurements were performed on dibasic calcium phosphate tablets containing seven different disintegrants stored at different relative humidities (5–97%), and on tablets containing disintegrants with different mechanisms of action (swelling and shape recovery), compressed to different relative densities. Disintegration times of tablets containing sodium starch glycolate are affected most by storage conditions, which is displayed in decreased water uptake and force development kinetics. Disintegration times of tablets with a swelling disintegrant are only marginally affected by relative tablet density, whereas the shape recovery disintegrant requires high relative densities for quick disintegration. The influence of relative tablet density on the kinetics of water uptake and force development greatly depends on the mechanism of action. Acquired data allows a detailed analysis of the influence of storage conditions and mechanisms of action on disintegration behavior.

Formulation development and process analysis of drug-loaded filaments manufactured via hot-melt extrusion for 3D-printing of medicines

Abstract Three dimensional(3D)-printing via fused deposition modeling (FDM) allows the production of individualized solid dosage forms. However, for bringing this benefit to the patient, active pharmaceutical ingredient (API)-loaded filaments of pharmaceutical grade excipients are necessary as feedstock and have to be produced industrially. As large-scale production of API-loaded filaments has not been described in literature, this study presents a development of 3D-printable filaments, which can continuously be produced via hot-melt extrusion. Further, a combination of testing methods for mechanical resilience of filaments was applied to improve the prediction of their printability. Eudragit RL was chosen as a sustained release polymer and theophylline (30%) as thermally stable model drug. Stearic acid (7%) and polyethylene glycol 4000 (10%), were evaluated as suitable plasticizers for producing 3D-printable filaments. The two formulations were printed into solid dosage forms and analyzed regarding their dissolution profiles. This revealed that stearic acid maintained sustained release properties of the matrix whereas polyethylene glycol 4000 did not. Analysis of the continuous extrusion process was done using a design of experiments. It showed that powder feed rate and speed of the stretching device used after extrusion predominantly determine the diameter of the filament and thereby the mechanical resilience of a filament.

Applicability of two automated disintegration apparatuses for rapidly disintegrating (mini)tablets

Abstract Objectives: Orally disintegrating (mini)tablets (OD(M)Ts) are of interest in the field of pharmaceutics. Their orodispersible character is defined by the disintegration time, which is measured with a basket apparatus according to the European Pharmacopoeia. This method, however, lacks applicability for ODTs and especially ODMTs. New disintegration apparatuses have been described in literature, but a qualification to assess the applicability has not been described. A qualification procedure for two automated disintegration apparatuses, OD-mate and Hermes apparatus, is introduced. Methods: Aspects of the operational qualification as well as precision and accuracy regarding a performance qualification were evaluated for both apparatuses analog to the ICH guideline Q2. While the OQ study is performed separately for each apparatus, accuracy and precision were performed following the same protocol for both testers. Key findings: Small RSDs (16.9% OD-mate; 15.2% Hermes compared to 32.3% for the pharmacopeial method) were found despite very fast disintegration times (1.5 s for both apparatuses). By comparing these RSDs to practical examples, the authors propose threshold values for repeatability depending on the mean disintegration time. Obtained results from the qualification were used to assess the applicability of both apparatuses.

Compaction Behavior of Isomalt after Roll Compaction

The suitability of the new isomalt grade galenIQ™ 801 for dry granulation and following tableting is evaluated in this study. Isomalt alone, as well as a blend of equal parts with dibasic calcium phosphate, is roll compacted and tableted. Particle size distribution and flowability of the granules and friability and disintegration time of the tablets are determined. Tensile strength of tablets is related to the specific compaction force during roll compaction and the tableting force. In all cases, the tensile strength increases with raising tableting forces. The specific compaction force has a different influence. For isomalt alone the tensile strength is highest for tablets made from granules prepared at 2 kN/cm and 6 kN/cm and decreases at higher values, i.e., >10 kN/cm. Tensile strength of the blend tablets is almost one third lower compared to the strongest tablets of pure isomalt. Friability of pure isomalt tablets is above the limit. Disintegration time is longest when the tensile strength is at its maximum and decreases with higher porosity and lower tensile strengths. Isomalt proves to be suitable for tableting after roll compaction. Even though the capacity as a binder might not be as high as of other excipients, it is a further alternative for the formulation scientist.

Application of a chromatic confocal measurement system as new approach for in-line wet film thickness determination in continuous oral film manufacturing processes

Graphical abstract Figure. No Caption available. ABSTRACT The key parameter of the oral film production process is the wet film thickness since it regulates the active pharmaceutical ingredient (API) content of the finished product. There is no general recommendation on how to adjust the gap height of the coating knife during the film manufacturing process to obtain the target content. Therefore, trial and error approaches are common to determine the surplus of drug for every newly developed formulation. This wastes resources, money and time and calls for an adequate in‐line tool for wet film thickness measurement during the film manufacturing process to ensure consistent quality. In this work, a chromatic confocal optical probe was implemented into a continuous oral film manufacturing process on a pilot‐scale coating bench. The optical probe allows a non‐destructive and contactless wet film thickness measurement. The validation of the method showed good results. Linearity was demonstrated over a wide range of film thicknesses (R2 = 0.999). A good precision between different films was revealed by a coefficient of variation smaller than 2%. The robustness investigations showed that the method is applicable for transparent and non‐transparent film forming masses. Furthermore, coloring agents, particles in the polymer mass and different viscosities do not influence the thickness measurement.

Competing for water: A new approach to understand disintegrant performance

ABSTRACT The understanding of tablet disintegration is still incomplete as not all involved factors and processes are known or accounted for. E.g., the negative influence of soluble fillers, on disintegration is usually attributed to increased viscosity due to dissolved filler. When the most common filler, lactose, dissolves, the viscosity increases only slightly. The impact of binders has hardly been studied systematically. In this study, water uptake and force development as well as water sorption experiments were performed of tablets containing either a soluble or an insoluble filler, one of four different binders, and one of four different disintegrants. For both fillers, one disintegrant performed distinctly worse than the others. For the insoluble filler, dibasic calcium phosphate (DCP), sodium starch glycolate resulted in the longest disintegration, for the soluble filler, lactose, croscarmellose sodium performed worst. Based on the experimental results, the authors introduce the competition‐for‐water hypothesis, which takes into consideration the amount of freely available water molecules and hydration kinetics of excipients. Soluble fillers bind a large number of water molecules in hydrate shells and prevent, therefore, proper disintegrant action. Previously inconsistent observations can be approached with this hypothesis and a better understanding of the underlying processes and explanations is possible.