Phase separation in coamorphous systems: in silico prediction and the experimental challenge of detection.

Combinatorial chemistry has enabled the production of very potent drugs that might otherwise suffer from poor solubility and low oral bioavailability. One approach to increase solubility is to make the drug amorphous, which leads to problems associated with drug stability. To improve stability, one option is to molecularly disperse the drug in a matrix. However, the primary reason for the failed stabilization with this approach is phase separation, which has been carefully studied in polymeric systems. Nevertheless, the amorphous-amorphous phase separation in coamorphous small molecule mixtures has not yet been reported. The goal of the present study was to experimentally detect the amorphous-amorphous phase separation between two small molecules. A modified in silico method for predicting miscibility by the Flory-Huggins interaction parameter is presented, where conformational variations of the studied molecules were taken into account. A series of drug-drug mixtures, with different mixture ratios, were analyzed by conventional differential scanning calorimetry (DSC(conv)) to detect possible amorphous-amorphous phase separations. The phase separation of coamorphous drug-drug mixtures was also monitored by temperature modulated DSC (MDSC) and Fourier transform infrared (FT-IR) imaging at temperatures above Tg for prolonged time periods. Amorphous-amorphous phase separation was not detected with DSC(conv), probably due to the slow kinetics of phase separation. However, the melting of the separated and subsequently crystallized phases was detected by MDSC. Furthermore, FT-IR imaging was able to detect the separation of the two amorphous phases, which demonstrates the ability of this method to detect small molecule phase separations.

Continuous direct compression of a commercially batch-manufactured tablet formulation with two different processing lines.

The transfer from batch-based to continuous tablet manufacturing increases the quality and efficiency of processes. Nonetheless, as in the development of a batch process, the continuous process design requires optimization studies to ensure a robust process. In this study, processing of a commercially batch-manufactured tablet product was tested with two continuous direct compression lines while keeping the original formulation composition and tablet quality requirements. Tableting runs were conducted with different values of process parameters. Changes in parameter settings were found to cause differences in tablet properties. Most of these quality properties could be controlled and maintained within the set limits effortlessly already at this stage of studies. However, the API content and content uniformity seemed to require more investigation. The observed content uniformity challenges were traced to individual tablets with a high amount of API. This was suspected to be caused by API micro-agglomerates since tablet weight variability did not explain the issue. This could be solved by adding a mill between two blenders in the process line. Overall, this case study produced promising results with both tested manufacturing lines since many tablet properties complied with the test result limits without optimization of process parameter settings.

Microscale freeze-drying with Raman spectroscopy as a tool for process development.

Until recently, the freeze-drying process and formulation development have suffered from a lack of microscale analytical tools. Using such an analytical tool should decrease the required sample volume and also shorten the duration of the experiment compared to a laboratory scale setup. This study evaluated the applicability of Raman spectroscopy for in-line monitoring of a microscale freeze-drying process. The effect of cooling rate and annealing step on the solid-state formation of mannitol was studied. Raman spectra were subjected to principal component analysis to gain a qualitative understanding of the process behavior. In addition, mannitol solid-state form ratios were semiquantitatively analyzed during the process with a classical least-squares regression. A standard cooling rate of 1 °C/min with or without an annealing step at -10 °C resulted in a mixture of α, ß, δ, and amorphous forms of mannitol. However, a standard cooling rate induced the formation of mannitol hemihydrate, and a secondary drying temperature of +60 °C was required to transform the hemihydrate form to the more stable anhydrous polymorphs. A fast cooling rate of 10 °C/min mainly produced δ and amorphous forms of mannitol, regardless of annealing. These results are consistent with those from larger scale equipment. In-line monitoring the solid-state form of a sample is feasible with a Raman spectrometer coupled microscale freeze-drying stage. These results demonstrate the utility of a rapid, in-line, low sample volume method for the semiquantitative analysis of the process and formulation development of freeze-dried products on the microscale.

In-line multipoint near-infrared spectroscopy for moisture content quantification during freeze-drying.

During the past decade, near-infrared (NIR) spectroscopy has been applied for in-line moisture content quantification during a freeze-drying process. However, NIR has been used as a single-vial technique and thus is not representative of the entire batch. This has been considered as one of the main barriers for NIR spectroscopy becoming widely used in process analytical technology (PAT) for freeze-drying. Clearly it would be essential to monitor samples that reliably represent the whole batch. The present study evaluated multipoint NIR spectroscopy for in-line moisture content quantification during a freeze-drying process. Aqueous sucrose solutions were used as model formulations. NIR data was calibrated to predict the moisture content using partial least-squares (PLS) regression with Karl Fischer titration being used as a reference method. PLS calibrations resulted in root-mean-square error of prediction (RMSEP) values lower than 0.13%. Three noncontact, diffuse reflectance NIR probe heads were positioned on the freeze-dryer shelf to measure the moisture content in a noninvasive manner, through the side of the glass vials. The results showed that the detection of unequal sublimation rates within a freeze-dryer shelf was possible with the multipoint NIR system in use. Furthermore, in-line moisture content quantification was reliable especially toward the end of the process. These findings indicate that the use of multipoint NIR spectroscopy can achieve representative quantification of moisture content and hence a drying end point determination to a desired residual moisture level.

Effect of cocrystallization techniques on compressional properties of caffeine/oxalic acid 2:1 cocrystal.

CONTEXT: Caffeine/oxalic acid 2:1 cocrystal exhibited superior stability to humidity over caffeine, but compressional behavior is not studied yet. OBJECTIVE: To compare compressional properties of caffeine/oxalic acid 2:1 cocrystal obtained by different cocrystallization techniques. MATERIALS AND METHODS: Cocrystal was obtained by solvent precipitation and ultrasound assisted solution cocrystallization (USSC) and characterized by X-ray powder diffraction and scanning electron microscopy. Compaction study was carried out at different compaction forces. Compact crushing strength, thickness and elastic recovery were determined. RESULTS AND DISCUSSION: Compaction was in order, caffeine > solvent precipitation cocrystal > USSC cocrystal. Caffeine exhibited sticking and lamination, where solvent precipitation compacts showed advantage. Caffeine and solvent precipitation compacts showed sudden drop in compactability, higher elastic recovery with severe lamination at 20,000 N. This was due to overcompaction. Crystal habit of two cocrystal products was same, but USSC cocrystals were difficult to compact. Uniform needle shaped USSC cocrystals must be difficult to orient in different direction and fracture during compression. Elastic recovery of USSC cocrystals was also more compared to other powders indicating less fracture and poor bonding between particles resulting in poor compaction. CONCLUSION: Cocrystal formation did not improve compressional property of caffeine. Cocrystals exposed to different crystallization environments in two techniques may have resulted in generation of different surface properties presenting different compressional properties.

Flowsheet modelling of a powder continuous feeder-mixer system.

In this study, an integrated flowsheet model of the continuous feeder-mixer system was calibrated, simulated and compared against experimental data. The feeding process was first investigated using two major components (ibuprofen and microcrystalline cellulose (MCC)), in a formulation comprised of: 30 wt% of ibuprofen, 67.5 wt% MCC, 2 wt% of sodium starch glycolate and 0.5 wt% of magnesium stearate. The impact of a refill on feeder performance was experimentally evaluated for different operating conditions. Results showed that it had no influence on feeder performance. While simulations with the feeder model fairly reproduced the material behaviour observed in the feeder, unintended disturbances were underpredicted due to the model's low complexity. Experimentally, mixer's efficiency was assessed based on ibuprofen residence time distribution. Mean residence time pointed to a higher mixer's efficiency at lower flow rates. Blend homogeneity results showed that for the entire set of experiments, ibuprofen RSD < 5%, irrespective of process variables. A feeder-mixer flowsheet model was calibrated, after regressing the axial model coefficients. The regression curves exhibited a R2 above 0.96, whereas the RMSE varied from 1.58x10-4 to 1.06x10-3 s-1 across all fitted curves. Simulations confirmed that flowsheet model captured the powder dynamics inside the mixer and qualitatively predicted the mixer's filtering ability against feeding composition fluctuations, as well as ibuprofen RSD in blend, in line with real experiments.

Challenges encountered in the transfer of atorvastatin tablet manufacturing - commercial batch-based production as a basis for small-scale continuous tablet manufacturing tests.

As is the case with batch-based tableting processes, continuous tablet manufacturing can be conducted by direct compression or with a granulation step such as dry or wet granulation included in the production procedure. In this work, continuous manufacturing tests were performed with a commercial tablet formulation, while maintaining its original material composition. Challenges were encountered with the feeding performance of the API during initial tests which required designing different powder pre-blend compositions. After the pre-blend optimization phase, granules were prepared with a roller compactor. Tableting was conducted with the granules and an additional brief continuous direct compression run was completed with some ungranulated mixture. The tablets were assessed with off-line tests, applying the quality requirements demanded for the batch-manufactured product. Chemical maps were obtained by Raman mapping and elemental maps by scanning electron microscopy with energy-dispersive X-ray spectroscopy. Large variations in both tablet weights and breaking forces were observed in all tested samples, resulting in significant quality complications. It was suspected that the API tended to adhere to the process equipment, accounting for the low API content in the powder mixture and tablets. These results suggest that this API or the tablet composition was unsuitable for manufacturing in a continuous line; further testing could be continued with different materials and changes in the process.

Computational approach for fast screening of small molecular candidates to inhibit crystallization in amorphous drugs.

The applicability of the computational docking approach was investigated to create a novel method for quick additive screening to inhibit the crystallization taking place in amorphous drugs. Surface energy and attachment energy were utilized to recognize the morphologically most important crystal faces. The surfaces (100), (001), and (010) were identified as target faces, and the estimated free energies of binding of additives on these surfaces were computationally determined. The molecule of the crystallizing compound was included in the group of the modeled additives as the reference and for the validation of the approach. Additives having a lower estimated free energy of binding than the reference molecule itself were considered as potential crystallization inhibitors. Salicylamide, salicylic acid, and sulfanilamide with computationally prescreened additives were melt-quenched, and the nucleation and crystal growth rates were subsequently monitored by polarized light microscopy. As a result, computationally screened additives decelerated the nucleation and crystal growth rates of the studied drugs while the pure drugs crystallized too fast to be measured. The use of a computational approach enabled fast and cost-effective additive selection to retard nucleation and crystal growth, thus facilitating the production of amorphous binary small molecular compounds with stabilized disordered structures.

Parameter optimization in a continuous direct compression process of commercially batch-produced bisoprolol tablets.

Continuous tablet manufacturing is a competitive option to replace the traditional batch manufacturing approach. The aim of this study was to evaluate technology transfer from batch-based direct compression of a commercial tablet formulation to continuous direct compression without changes to the composition of the formulation. Some powder studies were conducted with the raw materials and multi-tip punches were utilized in the tableting studies. To lower the high level of tablet weight variability that was evident during preliminary tests, a process parameter optimization was performed using an experimental design with different rpm values of force feeder and mixer impeller. By selecting the most appropriate settings of these parameters for the studied product, the weights of the tablets could be controlled adequately to meet the specification criteria. The functionality of the best-performing parameter settings was investigated with a three-hour-long tableting run. The tablets were evaluated with the same quality criteria as the commercial batch-produced tablets, and they passed all the tests performed in this study. Despite the challenging material properties according to the flowability tests, production of tablets with the desired quality was achieved using the original composition with continuous direct compression.

Detecting different amorphous - Amorphous phase separation patterns in co-amorphous mixtures with high resolution imaging FTIR spectroscopy.

Many active pharmaceutical ingredients (API) in development suffer from low aqueous solubilities. Instead of the crystal form, the amorphous state can be used to improve the API's apparent solubility. However, the amorphous state has a higher Gibb's free energy and is inherently unstable and tends to transform back to the more stable crystal form. In co-amorphous mixtures, phase separation needs to occur before there can be crystallization. The aim of this study was to devise a method to study amorphous-amorphous phase separation with high resolution imaging Fourier transform infrared (FTIR) spectroscopy with seven 1:1 M ratio API-API binary mixtures being examined. The binary mixtures were amorphized by melt-quenching and stored above their glass transition temperature (Tg) to monitor their phase separation. Thermodynamic properties (crystallization tendency, melting point (Tm) and Tg) of these mixtures were measured with differential scanning calorimetry (DSC) to verify the amorphization method and to assess the optimal storage temperature. The phase separation was examined with FTIR imaging in the transmission mode. Furthermore, measurements with two pure APIs were performed to ensure that the alterations occurring in the spectra were caused by phase separation not storage stress. In addition, the reproducibility of the imaging FTIR spectrometer was verified. The spectra were analyzed with principal component analysis (PCA) and a characteristic peak comparison method. Scatter-plots were produced from the amount of phase separated pixels in the measurement area as a way of visualizing the progress of phase separation. The results indicated that imaging with FTIR spectroscopy can produce reproducible results and the progress of phase separation can be detected as either a sigmoidal or as a start-to-finish linear pattern depending on the substances.

Faster to First-time-in-Human: Prediction of the liquid solid ratio for continuous wet granulation.

In early development, when active pharmaceutical ingredient (API) is in short supply, it would be beneficial to reduce the number of experiments by predicting a suitable L/S ratio before starting the product development. The aim of the study was to decrease development time and the amount of API needed for the process development of high drug load formulations for continuous twin-screw wet granulation (TSWG). Mixer torque rheometry was used as a pre-formulation tool to predict the suitable L/S ratios for granulation experiments. Three different values that were based on the MTR curves, were determined and assessed for their ability to predict the suitable L/S ratio for TSWG. Three APIs (allopurinol, paracetamol and metformin HCl) were used as model substances in high drug load formulations containing 60% drug substance. The MCC-mannitol ratio was varied to assess the optimal composition for the high-dose formulations. The API solubility affected the mixer torque rheometer (MTR) curves and the optimum L/S ratio for TSWG. The highly soluble metformin needed a much lower L/S ratio compared with allopurinol and paracetamol. A design space was determined for each API based on granule flowability and tablet tensile strength. The flowability of the granules and tensile strength of the tablets improved with an increasing L/S ratio. The MCC-mannitol filler ratio had a significant effect on tabletability for paracetamol and metformin, and these APIs having poor compaction properties needed higher MCC ratios to achieve the 2 MPa limit. The MCC-mannitol ratio had no effect on the granule flow properties. Instead, API properties had the largest influence on both granule flow properties and tensile strength. Based on this study, both the L/S ratio and MCC-mannitol ratio are crucial in controlling the critical quality attributes in high drug load formulations processed by TSWG. The optimum flow and tablet mechanical properties were achieved when using 75:25 MCC-mannitol ratio. Both start of the slope and 2/3 of the L/S ratio at the maximum torque in MTR provided a solid guideline to aim for in a TSWG experiment.

Effect of shape on the physical properties of pharmaceutical tablets.

Despite a well-established process understanding, quality issues for compressed oral solid dosage forms are frequently encountered during various drug product development and production stages. In the current work, a non-destructive contact ultrasonic experimental rig integrated with a collaborative robot arm and an advanced vision system is presented and employed to quantify the effect of the shape of a compressed tablet on its mechanical properties. It is observed that these properties are affected by the tablet geometric shapes and found to be linearly sensitive to the compaction pressures. It is demonstrated that the presented approach significantly improves the repeatability of the experimental waveform acquisition. In addition, with the increased confidence levels in waveform acquisition accuracy and corresponding pressure and shear wave speeds due to improved measurement repeatability, we conclude that pharmaceutical compact materials can indeed have a negative Poisson's ratio, therefore can be auxetic. The presented technique and instrument could find critical applications in continuous tablet manufacturing, and its real-time quality monitoring as measurement repeatability has been significantly improved, minimizing product quality variations.

Kramers-Kronig analysis on the real refractive index of porous media in the terahertz spectral range.

We present a terahertz time-domain experimental technique for the detection of scattering from porous media. The method for detection of the scattering enables one to make a decision when Fresnel or Kramers-Kronig (K-K) analysis can be applied for a porous medium. In this study the real refractive index of a tablet is calculated using the conventional K-K dispersion relation and also using a singly subtractive K-K relation, which are applied to the extinction coefficient obtained from the Beer-Lambert law. The advantage of the K-K analysis is that one gets estimates both for absolute refractive index and also dispersion of the porous tablet, whereas Fresnel analysis provides only the absolute value of the index.

Preparation and characterization of hot-melt extruded polycaprolactone-based filaments intended for 3D-printing of tablets.

Hot-melt extruded (HME) filaments are an essential intermediate product for the three- dimensional (3D) printing of drug delivery systems (DDSs) by the fused deposition modelling (FDM) process. The aim of this study was to design novel polymeric 3D-printable HME filaments loaded with active pharmaceutical ingredients (APIs). The physical solid-state properties, mechanical properties, drug release and short-term storage stability of the filaments and 3D-printed DDSs were studied. Physical powder mixtures of polycaprolactone (PCL), plasticizer and API were manually blended, extruded by a single-screw extruder, and printed by a table-top FDM 3D-printing system. The composition of PCL and arabic gum (ARA) enabled the incorporation of 20%, 30% and 40% (w/w) of indomethacin (IND) and theophylline (THEO) into the HME filaments. The uneven distribution of API throughout the filaments impaired 3D printing. The HME filaments loaded with 20% IND or THEO were selected for the further analysis and printing tests (the ratio of PCL, ARA and IND or THEO was 7:1:2, respectively). The IND filaments were yellowish, mechanically strong and flexible, and they had a uniform filament diameter and smooth outer surface. The filaments containing THEO were smooth and off-white. The 3D-printed tablets fabricated from IND or THEO-loaded filaments showed sustained drug release in vitro. The drug release rate, however, significantly increased by changing the geometry of 3D-printed tablets from a conventional tablet structure to an unorthodox lattice ("honeycomb") structure. Overall, the combination of PCL and ARA provides an interesting novel polymeric carrier system for 3D-printable HME filaments and tablets.

Fast noncontact measurements of tablet dye concentration.

A non-contact, non-destructive technique for estimating the dye concentration of a tablet is presented. These measurements are performed by an optoelectronic system capable for fast acquisition of two-dimensional distribution of reflection spectra with high spatial resolution by using a subspace vector model of surface reflection. Vector components representing compressed spectral data are used directly (without reconstruction of the reflection spectra) for discrimination of tablets with small dye-concentration difference. Analysis of the data obtained after tablet illumination by 7 mutually orthogonal spectral functions allows us to find a single optimal spectral function which is enough for estimating the dye concentration. Using the optimal spectral function, either the mean concentration of riboflavin or distribution of the concentration over the tablet surface can be evaluated with high rate which ensures application of the technique for online quality control of each tablet.

Predicting the formation and stability of amorphous small molecule binary mixtures from computationally determined Flory-Huggins interaction parameter and phase diagram.

The Flory-Huggins interaction parameter has been shown to be useful in predicting the thermodynamic miscibility of a polymer and a small molecule in a binary mixture. In the present paper, this concept was extended and evaluated to determine whether or not the Flory-Huggins interaction parameter can be applied to small molecule binary mixtures and if this parameter can predict the phase stability of such amorphous binary mixtures. This study was based on the assumption that a thermodynamically miscible binary system is stable and cannot crystallize, and that phase separation is essential before the individual components can crystallize. The stabilization of a binary system is thought to derive from molecular interactions between components in a solid dispersion, which are characterized by the Flory-Huggins interaction parameter. Based on DSC experiments, drug molecules (39) in the present study were classified into three different categories according to their crystallization tendency; i.e., highly crystallizing, moderately crystallizing and noncrystallizing compounds. The Flory-Huggins interaction parameter was systematically calculated for each drug pair. The validity of this approach was empirically verified by hot-stage polarized light microscopy. If both compounds in the pair belonged to the category of highly crystallizing compound, the Flory-Huggins interaction predicted an amorphous or crystalline phase with approximately 88% (23 out of 26) confidence. If one or both compounds of the pair were either moderately crystallizing or noncrystallizing compounds, the binary mixture remained in the amorphous phase during the cooling phase regardless of the interaction parameter. The Flory-Huggins interaction parameter was found to be a reasonably good indicator for predicting the phase stability of small molecule binary mixtures. The method described can enable fast screening of the potential stabilizers needed to produce a stable amorphous binary mixture.

Perphenazine solid dispersions for orally fast-disintegrating tablets: physical stability and formulation.

AIM: The aim of this study was to prepare an orally fast-disintegrating tablet (FDT) by direct compression, containing a poorly soluble drug (perphenazine, PPZ) formulated as a stable solid dispersion. METHODS: The stability studies of the fast dissolving 5/1, 1/5, 1/20 (w/w), PPZ/polyvinylpyrrolidone K30 (PVP) or polyethylene glycol 8000 (PEG)) solid dispersions, and amorphous PPZ were conducted with differential scanning calorimetry, X-ray powder diffraction, Fourier-transform infrared spectroscopy, small-angle X-ray scattering, and dissolution rate studies. RESULTS AND DISCUSSION: It was found that 1/5 PPZ/PEG was the most stable dispersion under elevated temperature and/or humidity. FDTs containing 60% of mannitol, 15% of calcium silicate, 15% of crospovidone, and 10% of 1/5 PPZ/PEG solid dispersion exhibited fast disintegration times (37 +/- 3), sufficient hardness (1.28 +/- 0.06 MPa), and fast onset of drug dissolution (34% of PPZ dissolved in 4 minutes), and these properties were found to be retained with storage. Thus, by optimizing the drug/excipient ratio of the solid dispersion and tablet composition, it was possible to produce FDTs that possessed fast disintegration and satisfactory drug dissolution in addition to adequate tensile strength, so that they can be handled and packed normally.

Converting a batch based high-shear granulation process to a continuous dry granulation process; a demonstration with ketoprofen tablets.

When one wishes to convert a batch based manufacturing process of an existing tablet product to a continuous process, there are several available strategies which can be adopted. Theoretically, the most straightforward way would be to proceed with the corresponding processing principles, for example to change a wet granulation (WG) batch process into its continuous WG counterpart. However, in some cases, the choice of roller compaction (RC) could be very attractive due to the notably simpler and inherently continuous nature of the RC manufacturing principle. The aim of this study was to examine a process conversion from batch based high-shear wet granulation (HSWG) to continuous RC manufacturing, without any significant formulation changes. An optimization of the formulation is often needed during the process conversion. However, our primary goal was to demonstrate the possibilities to perform this kind of process adaptation with minimal formulation changes. Furthermore, the effect of three different locations of lubrication feeding with two production rate levels was studied. An additional target was to identify possible over-lubrication with these manufacturing configurations, and to clarify which of these three possibilities steps produced a final product that conformed to the same quality requirements as HSWG tablets. Previously, the effects of lubrication only on compacted ribbons (Miguelez-Moran A.M, 2008) and final product with CDC (continuous direct compression) (Taipale-Kovalainen, et al., 2017; 2019) have been investigated. Here, the effect of lubrication on both ribbon and on final product was examined. No signs of over-lubrication were observed, but there was a clear effect of the feeding location of lubricant on the final product. On the basis of these results, it is concluded that in the future, if a good product/process understanding of the alternative manufacturing process with different techniques can be obtained, it will be possible to devise more flexible and effective ways to allow the pharmaceutical industry to switch from batch manufacturing towards CM.

The Comparison of Two Challenging Low Dose APIs in a Continuous Direct Compression Process.

Segregation is a common problem in batch-based direct compression (BDC) processes, especially with low-dose tablet products, as is the preparation of a homogenous mixture. The scope of the current work was to explore if a continuous direct compression (CDC) process could serve as a solution for these challenges. Furthermore, the principle of a platform formulation was demonstrated for low dose tablets. The combination of filler excipients and the API in the formulation used was suitable for direct compression, but also prone to induce segregation in BDC process. The CDC process was found to be very promising; it was shown that tablets with the desired quality parameters could be manufactured successfully with both of the APIs studied. Powder analysis indicated that the APIs display some fundamental differences in their physical properties, which was also reflected in powder mixture properties and, hence, eventually in processing. However, process parameters, especially mixer impeller speed, were not found to have any significant influence on end product quality. The study suggests that a CDC process can be a viable solution to resolve the challenges described. Moreover, manufacturing by using a universal platform formulation seems to be a feasible way for producing low-dose tablets.

Simultaneous investigation of the liquid transport and swelling performance during tablet disintegration.

Fast disintegrating tablets have commonly been used for fast oral drug delivery to patients with swallowing difficulties. The different characteristics of the pore structure of such formulations influence the liquid transport through the tablet and hence affect the disintegration time and the release of the drug in the body. In this work, terahertz time-domain spectroscopy and terahertz pulsed imaging were used as promising analytical techniques to quantitatively analyse the impact of the structural properties on the liquid uptake and swelling rates upon contact with the dissolution medium. Both the impact of porosity and formulation were investigated for theophylline and paracetamol based tablets. The drug substances were either formulated with functionalised calcium carbonate (FCC) with porosities of 45% and 60% or with microcrystalline cellulose (MCC) with porosities of 10% and 25%. The terahertz results reveal that the rate of liquid uptake is clearly influenced by the porosity of the tablets with a faster liquid transport observed for tablets with higher porosity, indicating that the samples exhibit structural similarity in respect to pore connectivity and pore size distribution characteristics in respect to permeability. The swelling of the FCC based tablets is fully controlled by the amount of disintegrant, whereas the liquid uptake is driven by the FCC material and the interparticle pores created during compaction. The MCC based formulations are more complex as the MCC significantly contributes to the overall tablet swelling. An increase in swelling with increasing porosity is observed in these tablets, which indicates that such formulations are performance-limited by their ability to take up liquid. Investigating the effect of the microstructure characteristics on the liquid transport and swelling kinetics is of great importance for reaching the next level of understanding of the drug delivery, and, depending on the surface nature of the pore carrier function, in turn controlling the performance of the drug mainly in respect to dissolution in the body.