CELLETS® are pellets or spheres made of microcrystalline cellulose. The size ranges from 100 µm to 1400 µm. Being neutral starter cores, they can be used as carrier system for low-dosed APIs and allow diverse functional coating. See pellet technologies for a detailed description.
Electron microscopy yield perfect imaging data of the MCC pellets’ surfaces. Magnification: 250x, working distance 8.0 mm, voltage: 10 keV.
Available size classes are (click for more information):
Methylphenidate Modified Release Formulations and Their Clinical Importance
Methylphenidate modified release formulations play a central role in modern ADHD treatment. These dosage forms control the rate and timing of drug release after administration. As a result, they maintain therapeutic drug levels over an extended period and reduce the need for multiple daily doses. Methylphenidate is a central nervous system stimulant that improves attention and reduces hyperactivity and impulsivity. Amphetamine-based active pharmaceutical ingredients (APIs), including amphetamine salts and related derivatives, belong to the same therapeutic class. However, they act through somewhat different pharmacological mechanisms by increasing catecholamine release and inhibiting neurotransmitter reuptake.
Both stimulant classes benefit from modified-release technologies because they provide longer symptom control and reduce fluctuations in plasma concentrations. In particular, pellet-based systems have become highly important in extended-release products. These systems contain numerous small drug-loaded pellets (CELLETS® 500) coated with functional polymer layers. Consequently, formulators can precisely control drug release kinetics. Furthermore, pellet coatings improve dose uniformity, support reproducible gastrointestinal transit, and lower the risk of dose dumping. Therefore, patients often experience more consistent therapeutic effects and improved treatment adherence.
Composition and Functional Differences in the Patent
The patent US20260076916A1 describes several methylphenidate modified release formulations based on coated pellet technology. The disclosed formulations share the same overall objective but differ in their composition and functional design. For example, the formulations vary in drug loading, pellet structure, coating composition, coating thickness, and the ratio of immediate-release and extended-release fractions. These differences directly influence dissolution behavior and pharmacokinetic performance. As a result, each formulation can generate a distinct release profile. Some compositions provide a rapid initial release followed by sustained drug delivery. In contrast, other formulations focus on maintaining a smoother and more prolonged release pattern throughout the day. Thus, the patent demonstrates how targeted formulation changes can tailor therapeutic performance to specific clinical needs.
The Role of Pellet Coatings in Extended-Release Performance
Pellet coatings represent the key functional element in these formulations. They regulate water penetration, drug diffusion, and ultimately drug release. Depending on the selected polymer, the coating may function as a diffusion barrier, a delayed-release layer, or a permeability-controlled membrane. Moreover, coating thickness strongly influences release kinetics. Thicker coatings generally slow drug release, whereas thinner or more permeable coatings accelerate release. In addition, manufacturers can combine pellets with different coating properties in a single capsule or tablet. This approach creates multiphasic release profiles that better match daily therapeutic requirements. Consequently, patients receive both rapid symptom relief and sustained efficacy from a single dose. Such multiparticulate systems also improve formulation flexibility during product development.
Importance of CELLETS® 500 in the Methylphenidate Modified Release Formulations Patent
In the patent US20260076916A1, CELLETS® 500 serve as the inert starter cores on which methylphenidate and the functional coating layers are applied. These spherical pellets, consisting of 100% microcrystalline cellulose and having a particle size range of approximately 500–710 µm, provide an ideal substrate for uniform drug layering and subsequent polymer coating. Their high sphericity, smooth surface, mechanical strength, and low friability support reproducible coating processes and consistent pellet quality. As a result, formulators can precisely control coating thickness and permeability, which are critical parameters for achieving the desired modified-release profile.
Moreover, the relatively large surface area of CELLETS® 500 enables efficient drug loading while maintaining excellent flowability and processing characteristics during fluid-bed coating operations. In multiparticulate methylphenidate formulations, these properties contribute directly to uniform drug release, reduced variability in pharmacokinetic performance, and reliable therapeutic outcomes. Therefore, CELLETS® 500 are not merely inactive excipients but a key enabling technology that supports the development of robust extended-release formulations with predictable dissolution behavior and improved patient adherence.
Conclusion and Outlook
Methylphenidate modified release formulations combine established stimulant therapy with advanced drug delivery technology. The patent clearly shows that differences in pellet composition and coating design create distinct release characteristics. Therefore, formulation scientists can fine-tune onset of action, duration of effect, and overall pharmacokinetic performance. Pellet coating technology offers significant advantages for both pharmaceutical manufacturers and patients. Furthermore, it supports consistent drug delivery, improved treatment adherence, and reliable symptom control. Looking ahead, continued advances in polymer science and multiparticulate formulation design will likely produce even more precise release profiles. As a result, future methylphenidate modified release formulations may further improve individualized ADHD therapy and long-term patient outcomes.
Patent Summary
Name of Patent: Methylphenidate modified release formulations
Multiparticulate formulations based on pellets, granules or beads, could be advantageous for paediatrics, geriatrics and patients with swallowing difficulties. However, these formulations may require suitable administration media to facilitate administration. The aim of this work was to investigate the effect of administration media properties on palatability and ease of swallowing of multiparticulates. A range of vehicles were developed using xanthan gum (XG) and carboxymethyl cellulose (CMC) as model hydrocolloids. Such vehicles were prepared at three consistency levels (Level 1 – ‘syrup’, Level 2 – ‘custard’ and Level 3 – ‘pudding’) to investigate the effect of viscosity on their performance as administration media. A randomised, single-blind sensory evaluation study was carried out in thirty healthy adult volunteers using microcrystalline cellulose pellets as model multiparticulates, dispersed in the hydrogels (and water as control) at a concentration of 250 mg in 5 ml. Samples were evaluated using 5-point scales. The use of hydrogels as administration media improved a range of sample attributes compared to water formulations, including appearance, taste, mouthfeel, ease of swallowing and residue in the mouth (all improved by ca. 0,5 points) and oral grittiness perception (improved by ca. 1 point). Polymeric hydrogels thickened to medium consistency (Level 2, XG 0.5% and CMC 1.0% w/v) demonstrated the best performance.
Reference
Article: “The effect of administration media on palatability and ease of swallowing of multiparticulate formulations”
Authors: Felipe L. Lopez, Terry B. Ernest, Mine Orlu, and Catherine Tuleu.
Multiparticulate formulations, in the form of pellets, granules or beads, offer a range of advantages over conventional tablets and capsules, such as ease of swallowing, flexible dose titration, and suitability for taste-masking and controlled-release (Lopez et al., 2015). They are considered a flexible solid dosage form for the delivery of drugs to a broad range of patients, including paediatrics, geriatrics and patients with swallowing difficulties. However, previous studies suggest that grittiness and rough mouthfeel perception might be a barrier to palatability and patient acceptability (Kimura et al., 2015, Lopez et al., 2018, Lopez et al., 2016). A potential solution to overcome palatability and acceptability issues could be co-administration with a suitable vehicle (i.e. sprinkle), which could help to conceal the presence of multiparticulates. Some drug products that contain multiparticulates within a capsule or sachet indicate in the labelling that the internal beads can be sprinkled on soft foods for their administration (FDA, 2012). Commercial examples include Depakote® sprinkle capsules (divalproex sodium), Creon® capsules (pancrelipase), Granupas® gastro-resistant granules in sachets (para-aminosalicylic acid) and Cipla’s lopinavir/ritonavir pellets in capsules (Hanning et al., 2016, Ternik et al., 2017). Typical vehicles recommended for products labelled for sprinkle include apple sauce and yogurt that provide both flavour and viscosity to facilitate administration and improve patient acceptability (Ternik et al., 2017).
Studies comparing sprinkle formulations to liquid dosage forms in children have commonly showed preference for the solid over the liquid form. A range of studies showed acceptance of iron supplement sprinkles and preference for these compared to oral drops in children with anaemia (Adu-Afarwuah et al., 2008, Geltman et al., 2009, Zlotkin et al., 2003). Likewise, studies involving children suffering from epilepsy consistently showed preference for sprinkle formulations over syrup (Cloyd et al., 1992, Motte et al., 2005, Verrotti et al., 2012). In a recent study, children showed preference for sprinkles over syrup after 12-week antiretroviral therapy; 72% of children below 12 months and 64% of children between 1 and 4 years preferred the multiparticulate dosage form. For those preferring syrups, key issues with sprinkles were problems masking the pellets with food and food refusal, and concerns about not giving the whole dose. However, multiparticulates overcome the storing and transporting issues of syrups (Kekitiinwa et al., 2016).
Medicines are known to be mixed with liquid and semi-solid foodstuff to allow administration in clinical practice (Akram and Mullen, 2015, Akram and Mullen, 2012). However, this is not without the risks that mixing medication with foodstuff could alter bioavailability and introduce poor control over dose intake (EMA, 2013). Therefore, when co-administration of medicines and foodstuff is recommended in the package leaflet, the potential impact on patient acceptability, dosing accuracy, compatibility and drug bioavailability of the proposed vehicle(s) must be investigated (EMA, 2013). This task becomes very impractical when medicines can be mixed with a range of foods with different composition and physical properties (e.g. rheology, pH, ionic strength) (Kersten et al., 2016). The development of a standard pharmaceutical vehicle, rationally designed and fit for purpose, could facilitate such investigations. This vehicle could be manufactured by industry and provided with the finished drug product (although this would increase the overall cost of the product) or it could be compounded in a pharmacy (Kluk and Sznitowska, 2014). Investigation into swallowing aids for the administration of oral solid formulations have been the focus of previous research, with some products already in the market in the form of sprays, pastes or jellies (Bunupuradah et al., 2006, Diamond and Lavallee, 2010, Yoshida et al., 2011).
The rheological properties of the administration media require special consideration. Thick fluids are known to exhibit prolonged oral transit times than thinner fluids, which can be used in the management of patient with dysphagia (Soares et al., 2015). Conversely, greater efforts are required to manipulate in the mouth and swallow thick fluids compared to thin ones (Ong et al., 2018, Steele et al., 2015). Consequently, overly thick liquids may increase the risk of post-swallow residue in the mouth and pharynx, especially for patients with reduced tongue or pharyngeal muscle strength (Steele et al., 2015). Newtonian fluids have also been reported to require greater effort in oral processing and swallowing than shear thinning fluids (Steele et al., 2015). In addition, the rheology of the vehicle also affects its palatability, with organoleptic attributes often reported to worsen as the consistency of the fluid increases (Garcia et al., 2005, Ong et al., 2018). Therefore, it is imperative that the rheological and sensory properties of the vehicle are adequately characterised.
The use of a suitable vehicle could facilitate administration of multiparticulates by preventing fast sedimentation, improving palatability and reducing the risk of aspiration or choking often associated with this dosage form design (Walsh et al., 2018). Development of media for the administration of multiparticulates and evaluation of its effect on palatability has been the focus of two recent studies (Kluk and Sznitowska, 2014, Lopez et al., 2016), both of which concluded that the use of polymeric hydrogels as administration media could help conceal the presence of particles, reducing oral grittiness perception. However, both studies focussed on a swirl and spit methodology, which overlooks other important sample attributes such as ease of swallowing. Moreover, neither of those studies investigated the palatability of the liquid vehicles alone, which limited their understanding on the effect of the palatability of the vehicle on the overall palatability and acceptability of the final formulations.
The aim of this work was to develop liquid vehicles for the administration of multiparticulates and to investigate the effect of the administration media properties on palatability and ease of swallowing of multiparticulate formulations. Administration media were developed using xanthan gum (XG) and carboxymethyl cellulose (CMC) as model hydrocolloids. The rheological properties of the hydrocolloids were characterised to investigate the effect of consistency and shear thinning behaviour on their performance as administration media. Palatability attributes and ease of swallowing of the vehicles alone and formulations containing model multiparticulates were evaluated in healthy volunteers.
2. Materials and methods
2.1. Materials
Microcrystalline cellulose pellets (CELLETS® 200 and CELLETS® 700) were provided by Pharmatrans Sanaq (Basel, Switzerland). Xanthan gum (“XG”, Xantural 180, 1% gum in 1% KCl aqueous solution: 1200–1600 cP) was supplied by CP Kelco (Leatherhead, Surrey, UK); sodium carboxymethyl-cellulose (“CMC”, Blanose 7HF-PH, 1% aqueous solution: 1500–2500 cP) was provided by Ashland (Covington, Kentucky, USA); and vanillin was procured from Sigma-Aldrich (Irvine, Ayrshire, UK).
2.2. Preparation of administration media
Polymeric hydrogels in the range of 0.15–1.50% (w/v) were prepared by slow addition of hydrophilic polymer (XG or CMC) into 100 ml of water under continuous stirring at room temperature. Previous research indicate that some hydrocolloids may impart a noticeable foreign taste or off-flavour to water and other liquid vehicles (Matta et al., 2006, Ong et al., 2018, Pelletier, 1997, Saha and Bhattacharya, 2010). For this reason, a small amount of vanillin (0.1% w/v) was added to mask any potential taste and smell of the polymers which could negatively impact results. Samples were left stirring overnight to ensure complete polymer hydration and stored in the refrigerator at 5 ± 0.5 °C. Samples were allowed to equilibrate to room temperature before testing.
For the sensory evaluation study, the viscosity of the XG and CMC vehicles were targeted to meet the International Dysphagia Diet Standardisation Initiative (IDDSI) descriptors (Cichero et al., 2017, IDDSI, 2015). According to this framework, Level 1 fluids are “thicker than water but flow through a teat/nipple and straw”, Level 2 fluids “require effort to drink through a straw and flow quickly off a spoon” and Level 3 fluids are “difficult to suck through a straw and pour slowly off a spoon”.
2.3. Rheological characterisation
A Bohlin CVO rotational rheometer system (Malvern Instruments Ltd, Malvern, UK) was used to investigate the flow properties of the samples using a cone and plate geometry (40 mm diameter, 4° angle; gap size adjusted to 250 µm). A shear sweep measurement mode was employed, whereby the shear rate of the sample was advanced across the range of 0.1–200 s−1, with ascendant logarithmic progression. The temperature of the samples was maintained at 25 ± 0.2 °C throughout testing. This procedure was repeated three times for each sample.
The resulting data (shear rate vs. shear stress) was fitted to the power law model (Eq. (1)) to describe the flow properties of the samples:(1)σ=Kγnwhere σ is the shear stress (Pa), γ is the shear rate (1/s), K is the consistency index (Pas), and n is the flow behaviour index (dimensionless). The consistency index (K) corresponds to the viscosity at a shear rate of 1 s−1; whereas the flow behaviour index (n) provides an indication of the deformation behaviour, where a value of 1 indicates Newtonian behaviour, 0–1 indicates shear-thinning behaviour and values greater than 1 indicate shear-thickening (O’Leary et al., 2010). In addition, the apparent viscosity at 50 s−1 (ƞ at 50 s−1), a reference shear rate for oral processing and swallowing, and the apparent viscosity at 0.1 s−1 (ƞ at 0.1 s−1), a reference shear rate of the sample at rest, were measured by the rheometer along the ascendant shear ramp.
2.4. Sedimentation experiments
The ability of the administration media to maintain multiparticulates in suspension was calculated based on sedimentation experiments. A sample containing 500 mg of CELLETS® and 50 ml of administration media was filled into a 50-ml graduated plastic tube. The tube was turned upside down until homogeneous dispersion of the particles. Then, the sample was left standing and the time taken for CELLETS® to clarify the top 15 ml of the dispersant (approximately one third of the media volume) was determined. This experiment was adapted from that described by Kluk and co-workers (Kluk and Sznitowska, 2014). Experiments were repeated using multiparticulates of two extreme particle sizes, CELLETS® 200 (200–355 µm) and CELLETS® 700 (700–1000 µm), to account for the effect of particle size on sedimentation. The experiment was conducted in triplicate.
2.5. Sensory evaluation study
2.5.1. Study design
Thirty healthy adult volunteers (aged 19–33 years, average 23.2 ± 4.4 years; 21 females) were enrolled in a randomised, single-blind, single-centre, 3-treatment, crossover sensory evaluation. The study was approved by UCL Research Ethics Committee (Project ID: 4612-011). All participants received a detailed information sheet and provided written consent to participate in the study. The study was conducted in three sessions taken place on three separate days. On each day, participants tested samples of liquid vehicles without particles (T1: ‘no particles’), with 200–355 µm particles (T2: ‘smaller particles’) and with 700–1000 µm particles (T3: ‘larger particles’). Participants were divided into six groups to ensure that all possible sequence orders between treatments were considered. In each session, participants were handed eight samples, including XG and CMC samples and water as a control (Table 1), in a randomised order.
Table 1. List of liquid vehicles assessed in sensory evaluation experiments.
For samples containing multiparticulates, 250 mg of solid particles were pre-dispersed in the administration media (approximately 3 ml, for a total volume of 5 ml) using a spatula immediately before administration. Microcrystalline cellulose pellets used in this investigation were non-disintegrating in water or in the mouth. Samples were provided onto 5-ml plastic medicine spoons that were handed to participants of the study. During the evaluation of the samples, participants had free access to spring water to complete sample intake and clean their palate. To minimise subject discomfort and carryover effect 5–10-minute intervals were respected between samples.
2.5.2. Evaluation tool and outcome measures
A digitalized questionnaire (Qualtrics.com) was used for data collection. Immediately after swallowing the sample, volunteers were asked to rate several sample attributes, including appearance, ease of swallowing, mouth-feel and taste, using a 5-point hedonic scale (1 – extremely liked, 5 – extremely disliked). In addition, the feeling of particles in the mouth during sample intake (i.e. grittiness perception) and the feeling of particles in the mouth after sample intake and after rinsing their mouth with water (i.e. residue in mouth) was assessed using a 5-point magnitude scale (1 – not perceptible, 5 – extremely perceptible). Participants could also provide voluntary feedback of each sample attribute using their own words.
2.5.3. Data analysis
The different categories of the 5-point scales were assigned numeric scores (1–5) from lowest to highest stimuli perception, respectively. Statistical analysis was performed using the non-parametric Kruskal-Wallis one-way analysis of variance followed by Dunn’s test as post hoc for pairwise comparison, both with a 95% confidence level. Minitab 17 (Minitab Inc., State College, Pennsylvania, USA) was used for data analysis.
3. Results and discussion
3.1. Development of administration media for multiparticulates
3.1.1. Rheological properties
The rheological properties of the administration media require especial attention as these will have an impact on several critical quality attributes, such as suspendability and palatability (particularly appearance and mouth-feel). XG and CMC were selected as model excipients to develop polymeric hydrogels for the administration of multiparticulates, being Generally Regarded As Safe (GRAS) excipients commonly used in oral formulations.
The rheological properties of XG and CMC hydrogels were investigated as a function of the hydrocolloid concentration (Table 2). The consistency index of XG and CMC-based polymeric hydrogels increased as the hydrocolloid concentration increased, as it can be expected. The increase in viscosity was more pronounced for XG than it was for CMC, revealing the higher ‘thickening power’ of XG. In addition, XG hydrogels exhibited a strong shear thinning behaviour whereas CMC hydrogels showed a much lower degree of shear thinning; the flow behaviour index (n-value) of XG-based hydrogels was lower than that of CMC-based hydrogels throughout the range of concentrations tested.
Table 2. Rheological characteristics of XG and CMC hydrogels prepared at concentrations 0.15–1.50% w/v.
The contrasting rheological characteristics of XG and CMC made them ideal candidates to investigate the effect of shear thinning behaviour on their performance as administration media for the administration of multiparticulates. Previous research indicate that Newtonian fluids require greater effort in oral processing and swallowing than shear thinning fluids (Steele et al., 2015). However, it could be hypothesised that shear thinning fluids would be less effective in ‘masking’ the presence of particles since the viscosity of these fluids will decrease under the relatively high shear rates experienced during oral processing (50–300 s−1) (Steele et al., 2015).
3.1.2. Ability to maintain multiparticulates in suspension
An ideal vehicle should be able to maintain multiparticulates in suspension from dispersion of the particles in the media until administration. Sedimentation time of multiparticulates in polymeric hydrogels was determined by measuring the time lapse between homogeneous dispersion of multiparticulates and clearance of the top layer of the liquid vehicle. Results of sedimentation time as a function of the media viscosity are summarised in Table 3. The time needed for manipulation and administration of a medicine is usually less than 5 min but can take longer than 10 min in some cases (Ruiz et al., 2016), thus appropriate administration media should maintain multiparticulates in suspension for at least 10–15 min.
Table 3. Sedimentation time (minutes) of CELLETS® 200 and CELLETS® 700 in XG and CMC hydrogels.
Sedimentation time increased with increasing viscosity of the media and decreased with increasing size of the multiparticulates, in accordance to Stoke’s law. XG hydrogels prepared at 0.25% w/v would be sufficient to maintain both 200–355 and 700–1000 µm particles in suspension for at least 10–15 min, whereas a higher concentration of CMC (1.00% w/v) would be required to maintain the larger particles in suspension for the same time. The lower concentration of XG required to maintain multiparticulates in suspension could be expected based on its stronger thickening power and its shear thinning character, which means that the viscosity of XG hydrogels at low shear rates (i.e. shear rates relevant during sedimentation) is higher than that of CMC hydrogels.
3.2. Sensory evaluation studies
3.2.1. Liquid vehicles without multiparticulates
Participants of the sensory evaluation study tested liquid vehicles without multiparticulates in one of the three sessions of the study. The analysis of liquid vehicles without multiparticulates was performed in order to gain fundamental understanding of the properties of the liquid vehicles, such as appearance, mouthfeel, taste and ease of swallowing.
All samples evaluated received average appearance ratings in the neutral to positive range of the scale, except for XG L3 (average appearance rating = 3.17). According to participants responses to hedonic scales, the appearance of XG hydrogels was worse than the appearance of water and CMC hydrogels (p < 0.001), as shown in Fig. 1. This was adscribed to the opaque appearance of XG hydrogels (in contrast with the transparent aspect of water and CMC hydrogels), as supported by anecdotal feedback provided by the participants: e.g. “I personally prefer when the sample is limpid, this one was a bit opaque and it gives you an idea of dirt” (Participant 11, XG L3). Appearance ratings worsened as the consistency level increased. This indicates that the appearance of very thick samples (which retain their shape when placed on a spoon) was considered less appealing than thinner fluids.
Fig. 1. Interval plot for appearance, mouthfeel, taste and ease of swallowing of different liquid vehicles. Markers represent the population mean for the hedonic ratings (where 1 is the best possible rating and 5 is the worst possible rating) and bars show the 95% CI for the mean. Water + v. represents water to which 0.1% w/v vanillin was added; the consistency level of XG and CMC hydrogels is described as L1 (Level1), L2 (Level 2) and L3 (Level 3).
The taste of all liquid vehicles evaluated received average ratings between 2 and 3 (range: 2.33–2.63; XG L1 – Water), which indicates acceptable neutral taste (Fig. 1). The very small differences between samples confirmed that the level of vanillin used was appropriate to mask any potential foreign taste from the polymer without having a significant impact on results (as it was intended). However, the fact that average ratings for taste were closer to the centre of the scale than to the positive end of the scale may indicate participants’ expectations of a more intense, sweetened or flavoured taste for samples intended as a medicinal product. This was reinforced by voluntary feedback; e.g. “if this had added sugar/sweetener it would be a more enjoyable medicine to take” (P05, CMC L3).
Mouthfeel ratings of XG and CMC hydrogels worsened as the consistency of the sample increased, revealing preference for thinner vehicles (Fig. 1). This is consistent with previous research which reported that thinner fluids are perceived as less viscous, less adhesive and easier to manipulate in the mouth than thicker fluids (Ong et al., 2018). However, all samples received average ratings in the neutral to positive range of the scale (range: 1.67–2.90), suggesting all vehicles prepared had an acceptable mouthfeel to be used as media for the administration of multiparticulates. CMC hydrogels received slighly worse mouthfeel ratings than XG samples, which was attributed to a “greasy” or “oily” feeling in the mouth, as reported by the volunteers. The mouth-coating texture of CMC hydrogels has been reported in previous research and attributed to its low degree of shear thinning (high n-value) (Cho et al., 2015, Szczesniak and Farkas, 1962). On the contrary, xanthan gum samples have been perceived as less adhesive and easier to manipulate in the mouth (Ong et al., 2018). Nevertheless, mouthfeel differences between XG and CMC vehicles were not statistically significant, despite their contrasting rheological profiles. The inability to clearly identify preference between samples can be explained by consumers, including patients, having different criteria for personal preferences (Matta et al., 2006).
All samples evaluated were considered ‘easy to swallow’ by healthy volunteers, receiving average ratings in the neutral to positive range of the scale (range: 1.07–2.57). However, samples were considered relatively more difficult to swallow as the consistency level increased (p < 0.001), as depicted in Fig. 1. This can be attributed to the greater effort required to convey thicker fluids through the oral cavity and greater effort required for the throat muscles to swallow thicker fluids (Ong et al., 2018). In their open-ended feedback, participants described the need to swallow repetitively to achieve full ingestion of thicker samples; e.g. “the sample is very viscous and is difficult to swallow, it remains in my mouth after swallowing a few times” (P22, CMC L3). This is in line with previous research as thicker liquids have been shown to increase the risk of post-swallow residue in the mouth and pharynx (Steele et al., 2015). It is also well established that fluids with higher viscosity exhibit prolonged oral transit times as compared to thinner fluids such as water (Soares et al., 2015). Moreover, the ratings of ease of swallowing indicate that XG hydrogels were slightly easier to swallow than CMC hydrogels (p < 0.018), which was supported by anecdotal feedback; e.g. “this sample (CMC L2) is more difficult than the previous one (XG L2) in swallowing it as a whole, as it remains in my mouth after the first swallow” (P10, CMC L2). This can be explained by the stronger shear thinning behaviour of XG hydrogels. Shear thinning fluids can be expected to be easier to swallow due to lower resistance to flow under shear (Ong et al., 2018, Steele et al., 2015).
3.2.2. Multiparticulates dispersed in liquid vehicles
The appearance of multiparticulate samples dispersed in different vehicles received average ratings around the neutral range of the scale (range: 2.70–3.40), as shown in Fig. 2. The size of the multiparticulates had no influence on the ratings of appearance (p = 0.074), whereas the vehicle used had a significant impact on the appearance of the final formulation (p < 0.001). The appearance of samples dispersed in polymeric hydrogels (2.96 for XG and 2.77 for CMC hydrogels, on average) was considered better than that of samples dispersed in water (3.33 with and 3.40 without vanillin). This was explained by the more homogenous appearance of samples dispersed in thickened vehicles as compared to multiparticulates dispersed in water. Multiparticulates precipitated very quickly in water, due to its very low viscosity, leading to heterogenous samples with particles settled down on the bottom of the spoon. On the contrary, CELLETS® remained homogeneously dispersed in thicker hydrogels, which was considered a positive feature by the volunteers. Moreover, samples prepared in XG vehicles thickened to the highest consistency were rated more negatively than samples dispersed in other hydrogels, which can be expected based on the negative ratings of appearance received by this vehicle when evaluated on its own.
Fig. 2. Interval plot for appearance, taste, mouthfeel and ease of swallowing as a function of the vehicle used as suspending media and the size of the dispersed multiparticulates: 200–355 µm (CELLETS® 200) or 700–1000 µm (CELLETS® 700). Markers represent the population mean for the hedonic ratings (where 1 is the best possible rating and 5 is the worst possible rating) and bars show the 95% CI for the mean. Water + v. represents water to which 0.1% w/v vanillin was added; the consistency level of XG and CMC hydrogels is described as L1 (Level1), L2 (Level 2) and L3 (Level 3).
The taste of the samples worsened when multiparticulates where added into the formulation and when the multiparticulate size increased (Fig. 2); from 2.44 on average without presence of multiparticulates to 2.63 and 2.89 on average with smaller and larger multiparticulates, respectively. In addition, the taste of formulations with vanilla flavour was deemed better than the taste of samples prepared with pure water (p < 0.001). On the contrary, no significant differences were found between XG and CMC samples in terms of taste which, again, confirmed the successful masking of any potential inherent taste of the polymer by addition of a small quantity of vanillin. Although microcrystalline cellulose pellets are expected to be tasteless, negative taste ratings in hedonic scales have been previously reported and attributed to the poor mouthfeel of the formulation (Lopez et al., 2018). This can be explained by a common cognitive bias in sensory evaluation by which perception of a salient attribute influences the ratings of other (independent) sample attributes (Clark and Lawless, 1994).
The mouthfeel of multiparticulates dispersed in liquid vehicles also received average ratings around the neutral range of the scale (Fig. 2). Both the size of the multiparticulates and the vehicle used to disperse them had a significant impact on mouthfeel of the final formulation (p = 0.001 and p < 0.001, for size and vehicle, respectively). The mouthfeel of samples containing smaller multiparticulates was on average 0.30 points better than that of samples containing larger multiparticulates. An increasing grittiness sensation or rough mouthfeel with increasing size of the multiparticulates have also been reported on previous studies (Kimura et al., 2015, Kluk and Sznitowska, 2014, Lopez et al., 2018, Lopez et al., 2016). In terms of the vehicle used, participants showed preference for samples dispersed in thickened vehicles over samples dispersed in water. In addition, participants preferred the samples with low and middle-range consistencies (Level 1 and Level 2) over the extremely thick ones (Level 3). According to the participants of the study, those samples achieved a good balance by “concealing the presence of particles in the mouth” but not being too thick (which has a detrimental impact on mouthfeel). Samples thickened to Level 1 and Level 2 consistencies were rated on average 0.62 and 0.54 points better than water, respectively, whereas samples with Level 3 consistency were rated only 0.34 points better than water, on average.
As depicted in Fig. 2, swallowing of multiparticulates was considered more difficult with increasing particle size, from 2.36 on average for smaller multiparticulates to 2.91 on average for larger multiparticulates (p < 0.001). Multiparticulates dispersed in polymeric hydrogels were easier to swallow than multiparticulates dispersed in water (by approximately 0.50 points), irrespectively of the size of the particles. Both XG and CMC hydrogels were similarly efficient in facilitating swallowing of the multiparticulates (2.52 and 2.49 on average, respectively). Therefore, no significant differences were found between XG and CMC hydrogels in terms of ease of swallowing when administered with multiparticulates, despite their different rheological properties and the differences found when administered without multiparticulates. This might indicate that the sensory properties of the samples were dominated by the presence of particles in suspension at relatively high concentration (Mueller et al., 2010), thus differences between vehicles became negligible. The rheological properties of the samples could be dramatically affected by addition of multiparticulates; the inclusion of the solid particles is expected to produce and increase in consistency and in shear thinning behaviour (Mueller et al., 2010). In agreement with the results for mouthfeel perception, participants showed preference for swallowing samples with thin and middle-range consistencies (Levels 1 and 2) as opposed to thicker samples. These samples performed best at “carrying the particles together” as a bolus and “providing cushioning”, facilitating swallowing, while not being too thick to “linger around” in the oral cavity for long. The contrast between samples of different consistency was reported in open-ended responses; e.g.: “the liquid in this sample was too runny and was unable to carry the particles along with it, so the liquid part was consumed first, leaving behind the solid part of the sample” (P02, CELLETS® 200 in Water); or “I feel that this sample has the correct viscosity that is able to hold the particles together and is able to be easily swallowed” (P10, CELLETS® 200 in XG L1).
As discussed above, grittiness perception increased with increasing size of the multiparticulates (p < 0.001) in agreement with previous studies (Kimura et al., 2015, Kluk and Sznitowska, 2014, Lopez et al., 2018, Lopez et al., 2016); samples of smaller multiparticulates obtained an average grittiness score of 2.50 compared to 3.31 scored on average by samples containing larger multiparticulates. The feeling of residual particles in the mouth also increased with increasing size of the multiparticulates, 1.67 on average for CELLETS® 200 compared to 2.14 on average for CELLETS® 700 (Fig. 3). Participants ratings of ‘grittiness perception’ confirmed the results obtained for mouthfeel and ease of swallowing in that polymeric hydrogels masked the presence of multiparticulates. Grittiness perception was lower for polymeric hydrogel formulations than for samples dispersed in water by approximately 1.0 point, on average, both for smaller and larger multiparticulates. This was supported by voluntary feedback; e.g. “without a thick solution to act as a lubricant and carry the particles along with it, the ‘grainy’ feeling was enhanced, making it very unpleasant to take” (P02, CELLETS® 200 in water); compared to samples in thickened vehicles, e.g. “it is viscous, but that masks the overall ‘particles feel’, which is good” (P12, CELLETS® 200 in CMC L2). The use of polymeric hydrogels to disperse multiparticulates also reduced the ‘residue in mouth’, i.e. the feeling of particles in the mouth after swallowing (p < 0.001), for multiparticulates of both sizes evaluated. The residual feeling of particles was reduced by approximately 0.5 points on average when using polymeric hydrogels as vehicles, as compared to water.
Fig. 3. Interval plot for grittiness and residue of multiparticulates in mouth after swallowing as a function of the vehicle used as suspending media and the size of the multiparticulates: 200–355 µm (CELLETS® 200) or 700–1000 µm (CELLETS® 700). Markers represent the population mean for the 5-point magnitude scale (where 1 is the lowest possible and 5 is the highest possible intensity of the stimulus) and bars show the 95% CI for the mean. Water + v. represents water to which 0.1% w/v vanillin was added; the consistency level of XG and CMC hydrogels is described as L1 (Level1), L2 (Level 2) and L3 (Level 3).
According to the ratings on the 5-point scale, no significant differences were found between XG and CMC hydrogels in their ability to mask the grittiness of particles, either during sample intake or after swallowing of the samples; although the trend suggests that CMC vehicles performed better when using multiparticulates of larger size. As previously discussed, this indicates that the sensory properties of the samples were dominated by the presence of multiparticulates rather than the shear thinning behaviour of the vehicles. Moreover, no significant differences were found between vehicles thickened to different consistency levels based on scale ratings, although anecdotal feedback indicated that thicker hydrogels performed better than thinner vehicles in terms of masking the presence of particles, e.g. “less thick than other samples, thus I can feel the particles when I swallowed it; need to drink water to remove the particles” (P16, CELLETS® 200 in XG L1). Disagreement between grittiness ratings and voluntary feedback suggests that scale ratings were influenced by the overall appreciation of the sample, an issue commonly encountered in sensory evaluation studies (Clark and Lawless, 1994, Prescott et al., 2011). As the concentration of hydrocolloid in de sample increased, the perception of particles decreased but other organoleptic attributes worsened. As such, mouthfeel and grittiness perception were driven by a balance between those opposing phenomena, which explains the similar ratings obtained by samples of different consistency despite their different organoleptic attributes. These findings highlight the multifactorial nature of palatability and mouthfeel perception which poses a challenge to evaluate sample attributes independently (Clark and Lawless, 1994, Popper et al., 2004, Prescott et al., 2011).
The results of these trial are summarised in Fig. 4, where the radar charts show the mean result for each palatability attribute as a function of the size of the multiparticulates and the administration media (water with vanillin, which was used as a control, was excluded from the graphs to aid clarity). The use of polymeric hydrogels as administration media resulted in an overall improvement of the samples: appearance, taste, mouthfeel, ease of swallowing and residue in the mouth improved by ca. 0.5 points, and oral grittiness perception improved by ca. 1 point. Overall, polymeric hydrogels thickened to medium consistency (Level 2) demonstrated the best performance by virtue of their ability to conceal the grittiness of multiparticulates in the mouth and to aid swallowing of the formulation as a bolus, while maintaining a balanced consistency (not too thick) to ensure appropriate mouthfeel. These findings were in line with previous research in the field in that vehicles of very thick consistency tend to be disliked despite their ability to mask the presence of multiparticulates in the formulation (Kluk and Sznitowska, 2014, Lopez et al., 2016). Further investigation of the physicochemical properties of the samples, such as adhesiveness, ductility and lubrication properties could provide a more rigorous insight into the physical drivers for mouthfeel perception (Stokes et al., 2013). Differences in palatability and acceptability can be expected in different sub-sets of the population (Lopez et al., 2018, Mennella et al., 2012), thus future work should investigate the acceptability of these vehicles in paediatrics and patients with swallowing difficulties, those who could benefit the most from these formulations.
Fig. 4. Radar chart for appearance, taste, grittiness, mouthfeel, ease of swallowing and residue of multiparticulates in mouth as a function of the vehicle used as suspending media and the size of the multiparticulates: 200–355 µm (CELLETS® 200) or 700–1000 µm (CELLETS® 700). Each palatability item is described by its population mean for the 5-point scale (where 1 is the lowest possible and 5 is the highest possible intensity of the stimulus). The consistency level of XG and CMC hydrogels is described as L1 (Level1), L2 (Level 2) and L3 (Level 3).
4. Conclusion
The use of hydrogels as administration media for multiparticulates improved a range of sample attributes compared to water formulations, including appearance, taste, mouthfeel, ease of swallowing and grittiness perception during and after sample intake. This improvement was apparent for samples containing multiparticulates of both sizes investigated (those over 200 and those over 700 µm). Polymeric hydrocolloids provided ‘cushioning and lubrication’ of the particles and acted as an effective vehicle by ‘carrying the particles together’, concealing the gritty feeling of the multiparticulates and assisting swallowing. Participants also reported that additional intake of water after administration of the gel formulation was beneficial to facilitate swallowing of the full dose of multiparticulates. Polymeric hydrogels thickened to medium consistency (Level 2, XG 0.5% and CMC 1.0% w/v) were preferred over either thinner or thicker vehicles. A balanced consistency reduced the gritty feeling of multiparticulates while not being overly thick, which would hinder sensory attributes. Meanwhile, differences between XG and CMC hydrogels were minimal despite their opposing shear thinning behaviour. These findings suggest that the consistency of the vehicle was an attribute of greater importance than its shear thinning behaviour. However, XG brings the added value of its strong thickening power, requiring very low concentrations to produce hydrogels of adequate consistency. Results of this study indicate that polymeric hydrogels could be used to improve palatability, facilitate swallowing and enhance patient acceptability of multiparticulate formulation.
5. Author contribution statement
Felipe L. Lopez: Methodology, Investigation, Formal Analysis, Visualization, Writing- Original draft preparation. Terry B. Ernest: Funding Acquisition, Conceptualization, Methodology, Supervision, Writing – Review & Editing. Mine Orlu: Funding Acquisition, Conceptualization, Methodology, Supervision, Writing – Review & Editing. Catherine Tuleu: Funding Acquisition, Conceptualization, Methodology, Validation, Supervision, Writing – Review & Editing.
Acknowledgement
The authors are grateful to the EPSRC for providing funding through a studentship within the CDT in Targeted Therapeutics and Formulation Sciences (EPSRC grant: EP/I01375X/1).
Conflict of interest statement
The authors declare no conflict of interest other than their disclosed affiliations and acknowledged funding.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.ijpharm.2018.08.021.
License
Creative Commons license CC BY 4.0.
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https://cellets.com/wp-content/uploads/2025/08/Titelbild-Lopez-2018.jpg6271200Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2026-09-25 09:17:382026-09-25 09:17:38The effect of administration media on palatability and ease of swallowing of multiparticulate formulations
This article [1] on the development of an innovative method to improve the dissolution performance of rivaroxaban was first published here.
Abstract
The dissolution performance of rivaroxaban has become a critical focus in pharmaceutical research, as this hydrophobic drug is practically insoluble in water, limiting its absorption and therapeutic effectiveness. Recent advancements in formulation strategies have explored the use of drug–cyclodextrin complexes to overcome solubility challenges, but traditional solid-state inclusion methods often result in incomplete encapsulation. To address this limitation, researchers have developed an innovative technique to integrate liquid-state rivaroxaban–hydroxypropyl-β-cyclodextrin complexes into solid dosage forms. By dispersing the drug complex with hydroxypropyl-cellulose and coating cellulose pellets under precisely controlled processing conditions, this approach enhances drug stability, compressibility, and flowability. Comprehensive physicochemical characterization confirmed successful complexation, while dissolution studies demonstrated significantly improved release rates, particularly within the first 10 minutes, when compared to conventional rivaroxaban tablets.
A method to improve the dissolution performance of rivaroxaban
Recent advances in solid dosage form design with active ingredient–cyclodextrin complexes have attracted strong interest in pharmaceutical research. However, most earlier studies focused on solid-state complexes, which often caused incomplete inclusion. Therefore, new methods became necessary to improve drug incorporation.
In this study, the researchers developed a novel way to integrate liquid-state drug–cyclodextrin complexes into solid dosage forms. Specifically, their work centered on rivaroxaban, a poorly water-soluble and hydrophobic drug. To achieve this, Ozon et al. combined rivaroxaban with hydroxypropyl-β-cyclodextrin at a 1:1 molar ratio and kept the mixture in a liquid state. Furthermore, to increase viscosity, the team added 2% hydroxypropyl-cellulose. Finally, they sprayed the resulting dispersion onto cellulose pellets (CELLETS® 780) using a Caleva Mini Coater.
Improved Process Strategies for Rivaroxaban Dissolution
The researchers carefully controlled the process conditions. Specifically, atomization air pressure stayed at 1.1 atm, while fluidizing airflow ranged between 35–45 m³/h. After coating, they analyzed the pellets and raw materials using FTIR, XRD, SEM, and DSC techniques. As a result, these tests confirmed that rivaroxaban successfully formed inclusion complexes with hydroxypropyl-β-cyclodextrin. Furthermore, the final pellets showed excellent flowability, good compressibility, and adequate hardness.
In addition, HPLC-DAD analysis confirmed a drug loading of 10 mg rivaroxaban per 750 mg of coated pellets. For dissolution testing, the researchers used two distinct media: sodium acetate buffer pH 4.5 with 0.2% sodium dodecyl sulfate, and phosphate buffer pH 6.8 without surfactants. They then compared the new capsules with both reference capsules and conventional tablets. Consequently, results showed that the experimental capsules matched the release profile of Xarelto® 10 mg. Moreover, they released rivaroxaban at a faster rate within the first 10 minutes.
Conclusion
In conclusion, this research introduces an effective method to create solid dosage forms from liquid-state drug–cyclodextrin complexes. More importantly, this innovative approach significantly improves the dissolution performance of rivaroxaban. Therefore, it opens promising new possibilities for enhanced drug delivery and greater oral bioavailability. This breakthrough highlights the potential of liquid-state inclusion complexes to optimize the dissolution performance of rivaroxaban, paving the way for more efficient drug delivery systems and enhanced oral bioavailability.
References
[1] E. A. Ozon, E. Mati, Oana Karampelas, V. Anuta, I. Sarbud, A. M. Musuc, R.-A. Mitran. D. C. Culita, I. Atkinson, M. Anastasescu, D. Lupuliasa, M. A. Mitu, Heliyon 10(12), 2024, e33162; doi: 10.1016/j.heliyon.2024.e33162
Connecting information
Are you working on dissolution performance of rivaroxaban or similar API, as well? Get in touch with us. We supply material support for educational research activities.
https://cellets.com/wp-content/uploads/2024/10/Anmerkung-2024-10-17-165154.png397527Bastian Arlthttps://cellets.com/wp-content/uploads/2016/10/Logo_Cellets_2016_website.pngBastian Arlt2026-08-18 14:35:252026-08-18 14:35:25The development of an innovative method to improve the dissolution performance of rivaroxaban
Control Strategy for Wurster Coating and Its Importance in Modern Drug Formulation
Control Strategy for Wurster Coating plays a central role in the production of high-quality pharmaceutical pellets for extended-release drug products. In multiparticulate formulations, coating efficiency and coating accuracy determine the final drug release profile. Therefore, manufacturers must control coating thickness with high precision. Even small differences in pellet size can affect coating uniformity and alter dissolution behavior. As a result, coating consistency directly influences product quality, therapeutic performance, and patient safety. Modern pharmaceutical manufacturing increasingly relies on Quality by Design (QbD) principles and Process Analytical Technology (PAT). Consequently, advanced control strategies help manufacturers achieve reliable and reproducible coating results while reducing process variability.
Understanding the Wurster Process and Bottom-Spray Fluid-Bed Technology
The Wurster process is a specialized bottom-spray fluid-bed coating technology used for pellets, beads, and granules. During the process, conditioned air fluidizes the particles inside the coating chamber. At the same time, a spray nozzle applies the coating suspension from below. The characteristic Wurster column creates a controlled particle circulation pattern. As a result, each pellet repeatedly passes through the spray zone and receives a uniform coating layer. This mechanism enables highly accurate film formation on large numbers of particles. Therefore, the technology has become the preferred solution for extended-release, delayed-release, and taste-masked formulations. Compared with many alternative coating methods, the Wurster process delivers superior coating uniformity and process reproducibility.
How a Modern Control Strategy for Wurster Coating Improves Process Performance
Traditional coating processes often rely on spraying a predefined amount of coating material. However, pellet size variations can influence the final coating thickness. Consequently, manufacturers may achieve different coating results even when they use the same coating quantity. A modern Control Strategy for Wurster Coating addresses this challenge through real-time process monitoring. Instead of focusing only on coating mass, the strategy measures particle growth during the coating process. Manufacturers can then continue spraying until the target coating thickness is reached. As a result, the process directly controls a critical quality attribute rather than an indirect process parameter. Furthermore, this approach compensates for substrate variability and improves batch-to-batch consistency. It also strengthens process robustness and supports regulatory expectations for advanced pharmaceutical manufacturing.
The Function of CELLETS® 500 in Wurster Coating Studies
CELLETS® 500 microcrystalline cellulose pellets serve as highly spherical starter cores for coating development and process evaluation. In the referenced study, researchers used CELLETS® 500 as a model substrate to investigate coating performance. This approach eliminated the influence of active pharmaceutical ingredients and allowed a focused assessment of coating behavior. In addition, the pellets provided a reproducible and well-characterized surface for coating application. Researchers compared different pellet size populations to examine the impact of substrate dimensions on coating thickness. Consequently, CELLETS® 500 helped validate the effectiveness of a PAT-based Control Strategy for Wurster Coating and demonstrated the importance of controlling particle growth during processing.
Benefits for Pharmaceutical Products and Patients
A modern Control Strategy for Wurster Coating offers significant advantages for both manufacturers and patients. First, it improves coating uniformity and dissolution profile consistency. Second, it reduces batch variability and minimizes the risk of product deviations. Moreover, precise coating control supports predictable drug release throughout the intended dosing period. This consistency helps ensure reliable therapeutic outcomes. At the manufacturing level, companies can reduce waste and improve production efficiency. In addition, advanced process control supports continuous improvement initiatives and data-driven decision-making. Ultimately, patients benefit from consistent drug performance, improved treatment reliability, and enhanced product quality.
Conclusion and Outlook
Control Strategy for Wurster Coating has become a key element of modern pharmaceutical pellet manufacturing. The combination of bottom-spray fluid-bed technology and real-time process monitoring enables highly accurate coating control. Furthermore, PAT-based approaches allow manufacturers to target coating thickness directly and compensate for pellet size variability. This capability improves product quality and strengthens process reliability. Looking ahead, digitalization, automation, and advanced analytics will further enhance Wurster coating operations. As pharmaceutical manufacturing continues to evolve, modern Control Strategy for Wurster Coating concepts will support more efficient production processes and more consistent extended-release drug products for patients worldwide.
References
[1] Edward Godek, Chris O’Callaghan, Ian Jones, Piyush Patel, Pharmaceutical Technology, 08 Feb 2018, 43(8)
The Role of Pellets in Advanced Oral Drug Delivery
Formulation and design of multiunit particulate systems play a central role in modern oral drug delivery. Pellets used in Multiunit Particulate Systems (MUPS) distribute the active ingredient into many small units. As a result, they reduce the risk of dose dumping and minimize local irritation. In addition, they improve content uniformity and gastric emptying reproducibility. Therefore, patients benefit from safer therapy and lower variability in plasma levels. Moreover, pellet-based systems allow functional coating and precise release control. This advantage becomes critical for acid-labile drugs. Consequently, the formulation and design of multiunit particulate systems offer clear technological and therapeutic benefits. The uploaded publication applies this concept to Pantoprazole and uses a Quality by Design framework to achieve a robust MUPS tablet.
Summary of the Study: QbD-Based Development Strategy
The publication by G. S. Sonar and S. Rawat [1]describes a structured QbD-driven development of an oro-dispersible Pantoprazole MUPS tablet. First, the authors defined a Quality Target Product Profile. Then, they identified critical quality attributes such as acid resistance, buffer-stage dissolution, hardness, friability, and disintegration time.
Next, the team performed risk assessment using cause-and-effect diagrams and Failure Mode and Effects Analysis. This step identified three critical formulation variables. These variables included the quantity of dry enteric polymer, the amount of PlasACRYL® HTP20, and the percentage of pellets in the final tablet. Subsequently, they applied a 2³ full factorial design to study main and interaction effects. This statistical model allowed precise evaluation of formulation influences.
The results showed that the enteric polymer mainly controlled acid-stage drug release. In contrast, PlasACRYL® HTP20 improved film flexibility and reduced pellet rupture during compression. Furthermore, the pellet percentage strongly influenced mechanical strength and disintegration time. Because compression can damage coated pellets, the authors introduced a cushioning layer with PEG 6000. This modification reduced acid-stage drug release significantly.
The optimized formulation achieved less than 10% release in 0.1 N HCl and 70–80% release in pH 6.8 buffer. In addition, the tablets showed acceptable hardness and friability below 1%, a disintegration time at 17 s. Composition was of 100 mg dry polymer, 34 mg PlasACRYL HTP20 and 35% of MCC pellets in a tablet. Starter cores can be used such as CELLETS® 150-300.
for formulation V4. The similarity factor f2 reached 56.5, which confirmed pharmaceutical equivalence to the reference product. Finally, the researchers defined a validated design space with robust operating ranges. Therefore, the study demonstrates how QbD strengthens the formulation and design of multiunit particulate systems.
API, QbD Principle, and Final Formulation
Design Pantoprazole: API Type, BCS Class, and Indication
Pantoprazole is a proton pump inhibitor and a substituted benzimidazole derivative. It irreversibly blocks the H⁺/K⁺-ATPase in gastric parietal cells. Consequently, it suppresses gastric acid secretion. Clinicians prescribe it for gastroesophageal reflux disease, peptic ulcer disease, and Zollinger–Ellison syndrome. Pantoprazole is acid-labile and degrades rapidly at low pH. Therefore, manufacturers formulate it as an enteric-coated dosage form. According to the Biopharmaceutics Classification System, Pantoprazole belongs to BCS Class II. Thus, it shows low solubility but high permeability, which makes dissolution control essential.
QbD Principle and Its Formulation Advantage
Quality by Design follows ICH Q8 to Q10 guidelines. It starts with predefined objectives and builds product understanding through risk management and experimental design. Instead of relying on empirical testing alone, developers link critical material attributes and process parameters to critical quality attributes. Consequently, they can predict product performance. In the formulation and design of multiunit particulate systems, QbD reduces development risk and improves robustness. Moreover, it allows regulatory flexibility when operating within the approved design space.
Final Formulation Design and Drug Release Profile
The final MUPS tablet consists of layered pellets compressed into an oro-dispersible matrix. First, the developers applied a drug-loading layer onto microcrystalline cellulose starter cores. Then, they added a seal coat using hypromellose. Afterward, they applied an enteric coat with Eudragit L30D-55 and PlasACRYL® HTP20. To protect the pellets during compression, they added a cushioning layer containing PEG 6000. Finally, they blended the coated pellets with excipients such as microcrystalline cellulose, mannitol, crospovidone, and lubricants before compression.
The optimized formulation delivered less than 10% drug release after 120 minutes in acidic medium. Subsequently, it released 70–80% of the drug within 30 minutes in phosphate buffer pH 6.8. The tablets showed hardness around 47–48 N, disintegration below 20 seconds, and friability under 0.5%. Therefore, the formulation achieved acid protection, rapid intestinal release, and mechanical stability simultaneously.
Conclusion and Outlook
The study clearly demonstrates that formulation and design of multiunit particulate systems benefit from a structured QbD approach. By combining risk assessment, factorial design, and statistical validation, the researchers developed a robust Pantoprazole MUPS tablet. Moreover, they established a well-defined design space that ensures consistent quality. As pharmaceutical development evolves, QbD will further enhance efficiency and regulatory confidence. In the future, integration of process analytical technology and advanced modeling will strengthen pellet-based platforms even more. Consequently, the formulation and design of multiunit particulate systems will remain a key strategy for complex oral drug delivery.
References
[1] G.S. Sonar1, S. Rawat, International Journal of PharmTech Research, CODEN (USA): IJPRIF, ISSN: 0974-4304, Vol.8, No.8, pp 05-23, 2015. (link)
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Introduction to Multilayered Pharmaceutically Active Compound Technology
Multilayered pharmaceutically active compound-releasing microparticles in a liquid dosage form represent an innovative approach to oral drug delivery. This technology combines the benefits of coated pellets with the convenience of liquid administration. Effervescent tablets are solid dosage forms that release carbon dioxide when they dissolve in water. This reaction results from the interaction between an acid source, such as citric acid, and a carbonate or bicarbonate salt. Patients consume the resulting solution or suspension immediately after preparation. Consequently, effervescent tablets improve ease of administration and often enhance patient compliance.
Pellets play an increasingly important role in modern effervescent tablet formulations. Unlike conventional powder blends, pellets can carry individual functional coatings that protect active pharmaceutical ingredients (APIs) from degradation. In addition, pellets can separate incompatible ingredients within the same dosage form. They also improve taste masking and enable modified-release properties. As a result, formulators can develop more stable and effective products. Furthermore, pellet-containing effervescent tablets often reduce gastrointestinal irritation and improve dose uniformity. These advantages benefit both the final pharmaceutical product and the patient.
Multilayered pharmaceutically active compound-large
Summary of EP3117824A1
The European patent EP3117824A1 describes a drug delivery platform based on multilayered pharmaceutically active compound-releasing microparticles suspended in a liquid dosage form. The invention addresses a major challenge in pharmaceutical formulation. Many controlled-release and enteric-coated particles lose functionality when they remain in contact with water for extended periods. Therefore, maintaining stability during storage becomes difficult.
The patented technology uses microparticles that contain an API-loaded core surrounded by multiple functional coating layers. A controlled-release or enteric coating forms the intermediate layer. An additional outer protective layer surrounds this coating. The inventors designed this outer layer from a combination of hydrophilic and hydrophobic materials. Consequently, the layer protects the underlying release-controlling membrane from premature exposure to the liquid environment.
During storage, the protective coating minimizes drug leakage and preserves the integrity of the controlled-release system. As a result, the microparticles maintain their desired release characteristics for extended periods. Once the patient administers the formulation, the outer coating dissolves rapidly in the stomach. Subsequently, the underlying controlled-release coating resumes its intended function. This mechanism allows the formulation to deliver the API at a predefined location or rate within the gastrointestinal tract.
The invention offers particular advantages for drugs that require modified release, intestinal targeting, or protection from acidic gastric conditions. In addition, the technology supports the development of patient-friendly liquid formulations. This feature benefits pediatric, geriatric, and dysphagic patients who often struggle to swallow tablets or capsules. Overall, the patent combines the flexibility of pellet-based drug delivery with improved stability in aqueous dosage forms. Therefore, it represents an important advancement in oral pharmaceutical technology.
Impact of MCC spheres in this Patent
In EP3117824A1, CELLETS® or similar spherical starter cores serve as the fundamental substrate for producing the multilayered pharmaceutically active compound-releasing microparticles. These inert pellet cores, commonly composed of microcrystalline cellulose, provide a highly uniform and mechanically stable surface onto which drug-containing layers and subsequent functional coatings can be applied with high precision.
Their excellent sphericity promotes uniform coating thickness, which is critical for achieving reproducible controlled-release performance and minimizing variability between pellets. Furthermore, Cellets enable high drug loading while maintaining robust processing characteristics during fluid-bed coating operations.
Pellet size also plays an important role in the final product performance. Smaller pellets, typically in the range of 100–500 µm (such as CELLETS® 100, 200, 350), offer a larger surface area and can provide faster or more uniform drug release, whereas larger pellets, often between 500–1500 µm (such as CELLETS® 500, 700, 1000), facilitate the application of multiple coating layers and may support more sophisticated release profiles.
In addition, smaller pellets generally improve content uniformity and patient acceptability, especially in liquid and effervescent dosage forms, because they create a smoother mouthfeel and more homogeneous suspension. Therefore, selecting the appropriate Cellet size represents a key formulation parameter that influences coating efficiency, drug release kinetics, stability, and overall patient experience.
Acetylsalicylic Acid, Paracetamol, and Ascorbic Acid in Pellet-Based Effervescent Formulations
Although EP3117824A1 does not specifically focus on acetylsalicylic acid, paracetamol, or ascorbic acid, the technology applies well to these APIs. Acetylsalicylic acid, commonly known as aspirin, belongs to the nonsteroidal anti-inflammatory drug (NSAID) class. It treats pain, fever, inflammation, and cardiovascular disorders. Depending on the classification source and physiological conditions, aspirin generally falls within BCS Class I or Class III. Because aspirin can irritate the gastric mucosa, pellet-based controlled-release systems may improve gastrointestinal tolerability.
Paracetamol is an analgesic and antipyretic agent that treats pain and fever. It is generally classified as a BCS Class I compound due to its high solubility and permeability. Furthermore, pellet technology can improve taste masking and provide modified-release options. These properties make paracetamol formulations more suitable for pediatric and elderly patients.
Ascorbic acid, also known as vitamin C, functions as a water-soluble vitamin and antioxidant. Healthcare professionals use it to prevent and treat vitamin C deficiency. It exhibits high aqueous solubility and frequently appears in effervescent products. Moreover, pelletization can improve formulation stability by separating ascorbic acid from reactive ingredients. This approach may reduce degradation during storage and improve product quality.
Conclusion and Outlook
Multilayered pharmaceutically active compound technology offers a sophisticated solution for modern oral drug delivery. It combines coated pellet systems with liquid dosage forms while maintaining controlled-release functionality. Moreover, the technology supports improved stability, enhanced patient convenience, and flexible formulation design. When formulators incorporate pellets into effervescent tablets, they can protect sensitive APIs, reduce gastrointestinal side effects, and optimize therapeutic performance. As pharmaceutical research advances, multilayered pharmaceutically active compound systems will likely support more complex formulations and personalized treatment strategies. Consequently, this technology may become an increasingly important platform for next-generation oral medicines.
Patent Summary
Name of Patent: Multilayered pharmaceutically active compound-releasing microparticles in a liquid dosage form
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Introduction to the Formulation and Design of Multiunit Particulate Systems
Formulation and design of multiunit particulate systems focus on oral dosage forms that contain many small, functional subunits instead of one single unit. These systems typically consist of pellets, granules, or coated spheres that are filled into capsules or compressed into tablets. As a result, they allow precise control of drug release and improved robustness during gastrointestinal transit. Moreover, the formulation and design of multiunit particulate systems emphasize a deep understanding of materials, coating technologies, and compression behavior. Therefore, developers can protect sensitive drug layers while ensuring consistent performance. In recent years, Quality by Design approaches have further strengthened this concept by linking formulation variables directly to product quality and clinical relevance.
Functionality and Consumer Compliance Opportunities of Multiunit Particulate Systems
Multiunit particulate systems offer clear functional advantages that directly support consumer compliance. First, the multiparticulate structure distributes the drug dose along the gastrointestinal tract, which improves absorption consistency. In addition, this distribution reduces local irritation and lowers the clinical risk of dose dumping. Furthermore, these systems often improve swallowability because the individual subunits are small and well tolerated. Consequently, patient groups such as children and older adults benefit significantly. At the same time, multiunit particulate systems enable flexible dosing and advanced release profiles. Therefore, they align better with daily routines and long-term treatment needs, which ultimately enhances adherence.
Formulation and Design of Multiunit Particulate Systems
Summary of the Pantoprazole MUPS Tablet Study
The referenced publication examines the formulation and design of multiunit particulate systems (MUPS) through the development of a pantoprazole MUPS tablet using a Quality by Design framework. The study aimed to understand how selected formulation variables affect critical tablet characteristics. To achieve this, the authors used enteric-coated pantoprazole pellets as multiparticulate units and compressed them into tablets with protective excipients. As a result, the formulation needed to balance mechanical strength with coating integrity.
The researchers applied a factorial design of experiments to evaluate three key variables: dry polymer content, matrix-forming polymer concentration, and pellet loading. Subsequently, they measured responses such as dissolution behavior, tablet hardness, friability, and disintegration time. The results showed that each variable influenced tablet quality in a measurable way. For example, higher pellet content increased the risk of coating damage during compression. However, appropriate polymer levels reduced this risk and stabilized drug release.
Based on statistical analysis, the study defined an optimized design space that delivered robust tablets with acceptable mechanical properties. In addition, the optimized formulation demonstrated dissolution behavior comparable to a marketed reference product. Therefore, the study confirmed that a well-designed multiunit particulate system can deliver pantoprazole effectively without compromising enteric protection. Overall, the work highlights how systematic formulation control improves both product performance and development efficiency.
Role of MCC Spheres in the Multiunit Particulate System
MCC spheres (such as CELLETS® 150-300) played a central role as inert starter cores in the multiparticulate formulation. First, they provided a uniform and mechanically stable substrate for drug layering. Moreover, their spherical shape supported homogeneous coating and predictable dissolution behavior. During compression, MCC spheres showed favorable plastic deformation, which helped absorb mechanical stress. As a result, they protected the enteric coating from cracking or rupture. Consequently, MCC spheres enabled the successful conversion of coated pellets into a compressed MUPS tablet while maintaining functional integrity.
Conclusion and Outlook
In conclusion, formulation and design of multiunit particulate systems offer a robust strategy for developing patient-friendly oral dosage forms. The pantoprazole study clearly demonstrates how a Quality by Design approach links formulation variables to tablet performance. Moreover, the use of MCC spheres highlights the importance of selecting suitable core materials for compression stability. Looking ahead, advances in material science and process understanding will further strengthen multiunit particulate systems. Therefore, these systems will continue to play a key role in improving therapeutic consistency and consumer compliance.
References
[1] G.S. Sonar, S. Rawat, International Journal of PharmTech Research, CODEN (USA): IJPRIF, ISSN: 0974-4304, Vol.8, No.8, pp 05-23, 2015. (link)
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Influence of Water on the Structure of MCC describes how moisture reshapes microcrystalline cellulose at both structural and dielectric levels [1]. Water interacts strongly with hydroxyl groups on cellulose chains. Therefore, it changes hydrogen bonding and mobility inside amorphous and crystalline regions. Moreover, the system develops distinct hydration states depending on water content. At low moisture levels, water remains mostly adsorbed on surfaces. However, at higher levels, it forms multilayer hydration shells around crystallites. Consequently, the material shows measurable changes in crystallite order and dielectric relaxation behavior. In addition, a critical hydration threshold appears where the structure shifts toward a continuous interfacial water network. As a result, both permittivity and loss mechanisms change significantly across temperature and frequency ranges.
Technologies and Materials Used in the Study
The study combines structural and dielectric characterization techniques to analyze hydrated cellulose systems. Specifically, X-ray diffraction resolves changes in crystallinity and crystallite dimensions. In addition, thermal analysis distinguishes bound water from loosely adsorbed water fractions. Broadband dielectric spectroscopy then tracks relaxation processes across temperature and frequency domains. Therefore, the researchers connect molecular mobility with macroscopic dielectric response.
The material system consists of microcrystalline cellulose processed into compacted pellets for measurement. Moreover, pellet compaction ensures stable geometry and reproducible dielectric contact. In similar experimental frameworks, standardized spherical MCC pellets such as CELLETS® 1000 are often used. These pellets provide uniform particle size, consistent porosity, and predictable packing behavior. Consequently, they reduce structural variability during pressing. In addition, they improve signal stability in dielectric spectroscopy because they minimize air gaps and heterogeneity effects. As a result, researchers can isolate water-induced changes more reliably and compare hydration states under controlled conditions.
Influence of Water on Structure and Dielectric Behavior
Water strongly controls both structure and dielectric response in MCC. Initially, small water amounts occupy surface sites and weak adsorption layers. However, increasing hydration strengthens hydrogen bonding rearrangements. Moreover, water molecules increase chain mobility in amorphous regions. Consequently, the material shows shifts in crystallite boundary structure and apparent crystallinity.
At moderate hydration, water forms multilayer shells around crystallites. Therefore, interfacial polarization becomes more pronounced. In addition, dielectric permittivity increases due to enhanced dipole alignment. Meanwhile, relaxation processes shift toward lower temperatures because water lowers activation barriers for molecular motion. As a result, β-relaxation associated with surface groups becomes more visible.
At higher hydration levels, the system approaches a percolated water network. Thus, the dielectric response becomes dominated by interfacial water dynamics. Moreover, the cellulose–water system transitions into a more flexible structural regime. Consequently, both structural stability and dielectric dispersion change significantly across frequency ranges.
Conclusion and Outlook
Water governs the structural and dielectric behavior of MCC in a direct and measurable way. Specifically, it modifies hydrogen bonding networks and reorganizes interfacial regions. Therefore, hydration controls crystallite order and molecular mobility at the same time. Moreover, a critical moisture threshold marks a transition into a continuous hydration regime.
In addition, these findings highlight the importance of controlled humidity in cellulose-based systems. Future research should focus on tuning water content to engineer dielectric properties. Moreover, standardized pellet systems, including CELLETS 1000-type MCC materials in comparable studies, can improve reproducibility. Consequently, hydrated cellulose systems may support future applications in bio-based dielectrics, sensors, and adaptive functional materials.
References
[1] Kovalov, K.M., Alekseev, O.M., Lazarenko, M.M. et al. Influence of Water on the Structure and Dielectric Properties of the Microcrystalline and Nano-Cellulose. Nanoscale Res Lett12, 468 (2017); doi: 10.1186/s11671-017-2231-5
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MCC pellets under rheological investigation are ideal model spheres for studying powder behavior. In this study, we revisit the work of V. Mohylyuk and R. Dattani to analyze the effect of pellet size on powder properties. Understanding how pellet size influences flow and handling is essential for optimizing powder performance. Moreover, investigating size variations helps improve material processing and formulation strategies. By focusing on these aspects, researchers can better predict and control the behavior of MCC spheres in different applications.
Rheological behavior has a deep impact
The rheological behavior of powders greatly affects pharmaceutical formulations and processing steps. In particular, when studying MCC pellets under rheological investigation, powder rheology becomes a key area of focus. Typically, powders behave as solids under static conditions; however, they can fluidize under certain circumstances. Consequently, fluidization is widely used in pharmaceutical processes because it enables controlled and uniform coating or layering of starter beads with drugs and functional excipients. Moreover, while fluid behavior in liquids depends on inter- and intra-molecular interactions, network bonds, and temperature, powder fluidization primarily relies on micro-particular properties such as particle size, surface characteristics, and flowability. In addition, the exact gas speed and volume required for powder fluidization must be carefully adjusted for each system. Therefore, a thorough analysis of the powder is essential to achieve precise control and optimal performance.
In this study, CELLETS® are used for the investigation. These pellets consist of Microcrystalline Cellulose, featuring a smooth surface, high sphericity, and minimal friability. Due to these properties, CELLETS® are popular as starter beads in pharmaceutical formulations and are ideal model spheres for rheological studies. Four types—CELLETS® 90, CELLETS® 100, CELLETS® 200, and CELLETS® 350—were examined, with size distributions ranging from 90 µm to 500 µm. The D50 values for these types vary between 94 µm and 424 µm. The specific size distribution of each CELLETS® type is summarized in Table 1.
Table 1: Particle size distribution of selected MCC spheres.
Characterization Methods for MCC Pellets Under Rheological Investigation
First, we measured the particle size distribution of MCC pellets under rheological investigation using optical digital microscopy (Keyence VHX 600). This approach provides precise and reliable data on pellet dimensions, which is essential for understanding their flow and handling properties.
Next, we applied standard pharmacopoeia methods to determine bulk and tapped density, as well as flow rate using a gravitational funnel. In addition, we analyzed the dynamic angle of repose and dynamic cohesivity index with a rotating drum tester (GranuDrum). Furthermore, we used a powder rheometer (FT4 Powder Rheometer) to evaluate basic flowability energy, specific energy, aerated energy, permeability, and compressibility. Altogether, these measurements give a comprehensive understanding of MCC pellets under rheological investigation and offer detailed insights into their performance in pharmaceutical applications.
Results of the rheological investigations
Figure 1 presents the particle size distribution of MCC pellets under rheological investigation, as measured with an optical digital microscope.
With increasing particle size the apparent specific surface area (fig. 2) decreases obviously. Hence, a decrease in pellet size, allow an expectation in increase in mechanical interlocking.
With increasing particle size, the bulk and tapped density of CELLETS® increases; however, the densification kinetics remained approximately the same for all pellet sizes (Fig. 3). Moreover, a few periodic oscillations significantly influenced the density of the pellets, highlighting subtle variations in their behavior.
With increasing particle size the compressibility decreases (fig. 4). The applied force was identical for all pellets sizes. Worsening packing efficiency.
With increasing particle size the permeability increases while applying the same force for all pellet types. (fig. 5). increase in voids between particles.
The gravitational funnel method suggests an absence of correlation between the mass flow rate and pellet size or specific surface area (fig. 6).
Analyzing the dynamic angle of repose
We analyzed the dynamic angle of repose to evaluate the powder flow of MCC pellets under rheological investigation. All pellet sizes showed similar behavior: as the rotation speed increased, the angle of repose rose almost linearly. The measurements for all pellet types formed a funnel shape within the range of analytic errors (Fig. 7). These results clearly characterize the dynamic flow ability of the powders.
With increasing particle size the specific energy decreases (fig. 8). The level of interlocking and friction between powder particles decreased, the flowability increased.
With increasing particle size the basic flowability energy decreases (fig. 9). the flowability in a constrained environment increased.
The aerated energy rises as air velocity decreases (Fig. 10). This parameter helps determine the minimum fluidization velocity, as increasing air velocity alters interparticle interactions.
The aerated energy increased with increasing pellet size (fig. 11). dependent on particle mass and inter-particle interactions (friction).
with increasing pellet size, the cohesive index decreases (fig. 12). an indicator of the sum of inter-particle interaction forces.
Summary
Overall, researchers have now characterized MCC pellets under rheological investigation more comprehensively than ever before, providing new insights into their flow behavior and material properties. Powder rheology methods successfully revealed the bulk powder behavior, flow properties, and inter-particular interactions as a function of pellet size. CELLETS® served as robust model spheres made of Microcrystalline Cellulose, making them ideal for these detailed investigations. This study highlights the importance of pellet size in predicting and optimizing powder performance in pharmaceutical formulations.
References
[1] V. Mohylyuk and R. Dattani, “Assessment of the effect of microcrystalline cellulose (MCC) spheres size on the flow via powder rheology”, Conference: The FORGE: Hybrid Conference on Particle Characterisation (March 2022), doi:10.13140/RG.2.2.14935.75688
Research Advances in MCC Pellet Technology and Applications
Scientific literature on MCC pellets highlights the growing importance of CELLETS® in pharmaceutical and scientific research. These microcrystalline cellulose spheres play a key role in developing reliable multiparticulate drug delivery systems. Researchers have investigated improved rivaroxaban dissolution, efficient film coating kinetics, and their use in orally disintegrating films. In addition, studies focus on colon-targeted vitamin B₂ release and fluidized-bed coating performance. Moreover, academic theses explore uniform hot-melt coating techniques and detailed modeling of tablet disintegration. As a result, MCC pellets continue to prove their versatility across many dosage forms. Consequently, this expanding body of literature reinforces the value of CELLETS® in advancing modern drug delivery technologies.
Selected Scientific literature on MCC pellets
Please, find scientific literature on MCC pellets (CELLETS®), MCC spheres. This list is constantly updated and does not claim to be complete. If you are author, scientist or R&D specialist, please submit your present publication to us for improving the visibility.
Research article Optimising the in vitro and in vivo performance of oral cocrystal formulations via spray coating European Journal of Pharmaceutics and Biopharmaceutics, Volume 124, March 2018, Pages 13-27
Dolores R. Serrano, David Walsh, Peter O’Connell, Naila A. Mugheirbi, Zelalem Ayenew Worku, Francisco Bolas-Fernandez, Carolina Galiana, Maria Auxiliadora Dea-Ayuela, Anne Marie Healy
Conference abstract Multiple-unit orodispersible mini-tablets International Journal of Pharmaceutics, Volume 511, Issue 2, 25 September 2016, Page 1128
Anna Kira Adam, Christian Zimmer, Stefan Rauscher, Jörg Breitkreutz
Research article Asymmetric distribution in twin screw granulation European Journal of Pharmaceutics and Biopharmaceutics, Volume 106, September 2016, Pages 50-58
Tim Chan Seem, Neil A. Rowson, Ian Gabbott, Marcelde Matas, Gavin K. Reynolds, AndyIngram
Research article Physical properties of pharmaceutical pellets Chemical Engineering Science, Volume 86, 4 February 2013, Pages 50-60
Rok Šibanc, Teja Kitak, Biljana Govedarica, StankoSrčič Rok Dreu
Research article Understanding Fluidized-Bed Granulation Pharmaceutical Technology 35 (8), 2011, 63-67 A. Burggraeve, T. Van Den Kerkhof, M. Hellings, J.P. Remon, C. Vervaet, T. De Beer
Research article Labscale fluidized bed granulator instrumented with non-invasive process monitoring devices Chemical Engineering Journal, Volume 164, Issues 2–3, 1 November 2010, Pages 268-274
Jari T. T. Leskinen, Matti-Antero H. Okkonen, Maunu M. Toiviainen, Sami Poutiainen, Mari Tenhunen, Pekka Teppola, Reijo Lappalainen, Jarkko Ketolainen, Kristiina Järvinen
Research article New insights into segregation during tabletting International Journal of Pharmaceutics, Volume 397, Issues 1–2, 15 September 2010, Pages 19-26
S. Lakio, S. Siiriä, H. Räikkönen, S. Airaksinen, T. Närvänen, O. Antikainen, J.Yliruusi
Research article Granule size distribution of tablets Journal of Pharmaceutical Sciences, Volume 99, Issue 4, April 2010, Pages 2061-2069
Satu Virtanen, Osmo Antikainen, Heikki Räikkönen, Jouko Yliruusi
Research article In vivo evaluation of the vaginal distribution and retention of a multi-particulate pellet formulation European Journal of Pharmaceutics and Biopharmaceutics, Volume 73, Issue 2, October 2009, Pages 280-284
Nele Poelvoorde, Hans Verstraelen, Rita Verhelst, Bart Saerens, Ellen De Backer, Guido Lopes dos Santos Santiago, Chris Vervaet, Mario Vaneechoutte, Fabienne De Boeck, Luc Van Borteld, Marleen Temmerman, Jean-Paul Remon
List – Publications with MCC spheres, 2008 and earlier
Research article Attrition strength of different coated agglomerates Chemical Engineering Science, Volume 63, Issue 5, March 2008, Pages 1361-1369
B. van Laarhoven, S.C.A. Wiers, S.H. Schaafsma, G.M.H. Meesters
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