Lubricant sensitivity in function of paddle movement in the forced feeder of a high-speed tablet press.

CONTEXT: The negative impact of magnesium stearate (MgSt) on the hardness of tablets is a well-known phenomenon, but the influence of paddle movement in the forced feeder on the lubricant effect during tablet compression is often neglected. OBJECTIVE: The purpose of this research was to investigate the influence of paddle speed in the forced feeder on tablet tensile strength (TS). MATERIALS AND METHODS: Mixtures of microcrystalline cellulose (MCC) and MgSt (0.5%) were blended using different methods (low & high shear). After blending, the formulations were compressed into tablets. All parameters of the tableting cycle were kept constant except the speed of the paddles in the forced feeder. RESULTS AND DISCUSSION: The blending technique affected the sensitivity of the formulation to the paddle speed. The TS of pure MCC tablets did not change in function of paddle speed, while tablets prepared by low shear mixing became softer at higher paddle speed. The TS of tablets manufactured using the high-shear mixed blend was low and did not vary in function of paddle speed, suggesting that overlubrication already occurred during the initial blending step. Furthermore, analysis of the machine parameters allowed evaluation of the influence of the paddles on the flowability, initial packing, and compactability of the powder mixtures. CONCLUSION: The results elucidated that during manufacturing of tablets using MgSt-containing blends care should not only be taken during the blending step prior to tableting, but also during the tableting process itself, as paddle speed can affect tablet TS, a critical quality attribute.

Studying the API Distribution of Controlled Release Formulations Produced via Continuous Twin-Screw Wet Granulation: Influence of Matrix Former, Filler and Process Parameters.

Hydroxypropyl methylcellulose (HPMC) is a preferred hydrophilic matrix former for controlled release formulations produced through continuous twin-screw wet granulation. However, a non-homogeneous API distribution over sieve fractions with underdosing in the fines fraction (<150 µm) was previously reported. This could result in content uniformity issues during downstream processing. Therefore, the current study investigated the root cause of the non-homogeneous theophylline distribution. The effect of process parameters (L/S-ratio and screw configuration) and formulation parameters (matrix former and filler type) on content uniformity was studied. Next, the influence of the formulation parameters on tableting and dissolution behavior was investigated. Altering the L/S-ratio or using a more aggressive screw configuration did not result in a homogeneous API distribution over the granule sieve fractions. Using microcrystalline cellulose (MCC) as filler improved the API distribution due to its similar behavior as HPMC. As excluding HPMC or including a hydrophobic matrix former (Kollidon SR) yielded granules with a homogeneous API distribution, HPMC was identified as the root cause of the non-homogeneous API distribution. This was linked to its fast hydration and swelling (irrespective of the HPMC grade) upon addition of the granulation liquid.

The viscosity-enhancing effect of carob bean gum and sodium carboxymethylcellulose when added to infant formula.

Despite limited supporting evidence, the practice of thickening breast milk or infant formula with commercially available thickening agents is prevalent. This study explored the viscosity-enhancing impact of carob bean gum (CBG) and sodium carboxymethylcellulose (NaCMC) when added to infant formula at various concentrations and for different thickening durations. The findings indicate that thickening leads to an exponential increase in milk viscosity, from 25% of the recommended dosage onward. This suggests that minor adjustments in dosage can significantly impact formula thickness, underscoring the importance of accurately dosing and preparing infant milk. The considerable variability in viscosity also emphasizes the need for thoughtful selection of teat size, considering the energy expenditure of the sucking infant. When using 50% of the recommended CBG dose or 25% of NaCMC, the resulting viscosity matches that of a commercially available casein-based formula containing CBG for anti-regurgitation. In the case of CBG, a viscosity plateau is only reached after 30 min. Therefore, educating parents on the correct handling and preparation steps for CBG-thickened infant milk is crucial, including a 30-min waiting period to achieve the intended thickening effect.

Modified Release 3D-Printed Capsules Containing a Ketoprofen Self-Nanoemulsifying System for Personalized Medical Application.

This study explores the realm of personalized medicine by investigating the utilization of 3D-printed dosage forms, specifically focusing on patient-specific enteric capsules designed for the modified release of ketoprofen, serving as a model drug. The research investigates two distinct scenarios: the modification of drug release from 3D-printed capsules crafted from hydroxypropyl methylcellulose phthalate:polyethylene glycol (HPMCP:PEG) and poly(vinyl alcohol) (PVA), tailored for pH sensitivity and delayed release modes, respectively. Additionally, a novel ketoprofen-loaded self-nanoemulsifying drug delivery system (SNEDDS) based on pomegranate seed oil (PSO) was developed, characterized, and employed as a fill material for the capsules. Through the preparation and characterization of the HPMCP:PEG based filament via the hot-melt extrusion method, the study thoroughly investigated its thermal and mechanical properties. Notably, the in vitro drug release analysis unveiled the intricate interplay between ketoprofen release, polymer type, and capsule thickness. Furthermore, the incorporation of ketoprofen into the SNEDDS exhibited an enhancement in its in vitro cylooxygenase-2 (COX-2) inhibitory activity. These findings collectively underscore the potential of 3D printing in shaping tailored drug delivery systems, thereby contributing significantly to the advancement of personalized medicine.

Influence of formulation variables on the processability and properties of tablets manufactured by fused deposition modelling.

The present work studied the influence of different formulation variables (defined also as factors), namely, different polymers (HPC EF, PVA and HPMC-AS LG), drugs with different water solubilities (paracetamol, hydrochlorothiazide and celecoxib) and drug loads (10 or 30 %) on their processability by HME and FDM. Both filaments and tablets were characterized for physic and chemical properties (DSC, XRPD, FTIR) and performance properties (drug content, in vitro drug release). Experiments were designed to highlight relationships between the 3 factors selected and the mechanical properties of filaments, tablet mass and dissolution profiles of the model drugs from printed tablets. While the combination of hydrochlorothiazide and HPMC-AS LG could not be extruded, the combination of paracetamol with HPC EF turned the filaments too ductile and not stiff enough hampering the process of printing. All other polymer and drug combinations could be successfully extruded and printed. Models reflected the influence of the solubility of the drug considered but not the drug load in formulations. The ranking of the drug release rates was in good agreement with their solubilities. Furthermore, PVA presenting the fastest swelling rate, promoted the fastest drugs' releases in comparison with the other polymers studied. Overall, the study enabled the identification of the key factors affecting the properties of printed tablets, with the proposal of a model that has valued the relative contribution of each factor to the overall performance of tablets.

Screening of lubricants towards their applicability for external lubrication.

Internal lubrication is associated with decreasing tensile strength and prolonged disintegration. These effects can be minimized using external lubrication. In current study, six lubricants (magnesium stearate, sodium stearyl fumarate, stearic acid, glyceryl dibehenate, poloxamer 188 and sucrose monopalmitate) were processed with an external lubrication system implemented in a compaction simulator. The effect of process parameters related to the tableting process (main compaction pressure and tableting speed) and external lubrication system (spraying time, atomizing pressure and dust extraction system) on the responses was studied for a placebo formulation (80% mannitol - 20% microcrystalline cellulose). Internally lubricated blends (0.75 - 4%) were processed as reference. All lubricants proved successful in reducing ejection forces through external lubrication while yielding substantially lower lubricant concentrations compared to internal lubrication. No negative effect of external lubrication on tensile strength and disintegration time was observed, irrespective of lubricant type. Similar tensile strengths and disintegration times were measured for the different lubricants. This was in contrast to internal lubrication where a decrease in tensile strength and prolonged disintegration was generally observed. Additionally, the lubricant types affected tensile strength and disintegration differently. This study demonstrates the versatility of external lubrication as an alternative lubrication method for production of pharmaceutical tablets.

Upscaling of external lubrication from a compaction simulator to a rotary tablet press.

External lubrication is a highly valuable alternative lubrication method as it minimizes the negative impact on tablet properties encountered when using internal lubrication. In current study, experiments were performed with automated external lubrication systems implemented in a compaction simulator and rotary tablet press using three lubricants (magnesium stearate (MgSt), sodium stearyl fumarate (SSF) and glyceryl dibehenate (DBHG)). The effect of process parameters related to the tableting process (main compaction pressure and tableting speed) and external lubrication systems (spraying time, atomizing pressure, dust extraction system and lubricant feed rate) on the responses was studied for a placebo formulation which is non-processable without lubrication. Low and comparable ejection forces were recorded for all lubricants on both tablet presses. No negative effect on tensile strength was observed for process parameters of both external lubrication systems, irrespective of lubricant type. Disintegration times were slightly higher for SSF compared to MgSt and DBHG for the tablets produced on the rotary tablet press, linked to higher lubricant concentrations on the tablets for SSF, while disintegration times were similar for all lubricant types on the compaction simulator. The potential of external lubrication for implementation on production scale tableting equipment and during scale-up was demonstrated for multiple lubricants.

Solvent electrospinning amorphous solid dispersions with high itraconazole, celecoxib, mebendazole and fenofibrate drug loading and release potential.

In this work, the feasibility of ultra-high drug loaded amorphous solid dispersions (ASDs) for the poorly soluble itraconazole, mebendazole and celecoxib via solvent electrospinning in combination with poly(2-ethyl-2-oxazoline) and fenofibrate in combination with polyvinylpyrrolidone is demonstrated. By lowering the polymer concentration in the electrospinning solution below its individual spinnable limit, ASDs with a drug content of up to 80 wt% are obtained. This is attributed to drug-polymer interactions not being limited by default to hydrogen bonds, as also Van der Waals interactions can result in high drug loadings. The theoretically predicted miscibility by the Flory-Huggins theory is corroborated by the experimental findings based on (modulated) differential scanning calorimetry and x-ray diffraction. Globally, the maximally obtained amorphous drug loadings are higher compared to the loadings found in literature. Additionally, non-sink dissolution tests demonstrate an increase in solubility of up to 50 times compared to their crystalline counterparts. Moreover, due to the lack of precipitation biocompatible PEtOx succeeds in stabilizing the dissolved drug and inhibiting its instant precipitation. The current work thus demonstrates the broader applicability of the electrospinning technique for the production of physically stable ASDs with ultra-high drug loadings, a result which has been validated for several Biopharmaceutics Classification System class II drugs.

The effect of particle size on the sublimation behavior of butylhydroxytoluene as antioxidant in tablets during storage and coating.

The effect of particle size on the sublimation behavior of butylhydroxytoluene (BHT) was investigated when BHT was included as antioxidant in tablets. Sublimation of pure BHT was found to be independent of its particle size, with pore formation on the surface of all tablets after storage at room temperature and above. Moreover, a higher residual BHT content after storage was detected in tablets containing a larger size fraction. X-ray µCT scans revealed the formation of peripherally larger pores at higher BHT particle sizes, implying a slower sublimation rate in the tablet core. A stability study indicated an increase in the extent of BHT sublimation at higher temperature and longer exposure time for all size fractions. The influence of BHT particle size was more pronounced when the tablets were stored at higher temperature, but the effect receded with longer exposure time. Similar trends were seen in film-coated tablets. Due to the short exposure time to elevated temperatures, a gradient in pore size was also observed at smaller particle sizes, with peripheral pores being larger in uncoated tablets. Superficial pores disappeared when a film coating was deposited onto the tablets. After storage of the film-coated tablets, less BHT had sublimated compared to the uncoated tablet. The coating layer did not prevent sublimation, but the process was slowed down.

Smart hydrogels delivered by high pressure aerosolization can prevent peritoneal adhesions.

Postoperative peritoneal adhesions occur in the majority of patients undergoing intra-abdominal surgery and are one of the leading causes of hospital re-admission. There is an unmet clinical need for effective anti-adhesive biomaterials, which can be applied evenly across the damaged tissues. We examined three different responsive hydrogel types, i.e. a thermosensitive PLGA-PEG-PLGA, a pH responsive UPy-PEG and a shear-thinning hexapeptide for this purpose. More specifically, their potential to be homogeneously distributed in the peritoneal cavity by high pressure nebulization and prevent peritoneal adhesions was evaluated. Solutions of each polymer type could be successfully nebulized while retaining their responsive gelation behavior in vitro and in vivo. Furthermore, none of the polymers caused in vitro toxicity on SKOV3-IP2 cells. Following intraperitoneal administration, both the PLGA-PEG-PLGA and the hexapeptide hydrogels resulted in local inflammation and fibrosis and failed in preventing peritoneal adhesions 7 days after adhesion induction. In contrast, the pH sensitive UPy-PEG formulation was well tolerated and could significantly reduce the formation of peritoneal adhesions, even outperforming the commercially available Hyalobarrier® as positive control. To conclude, local nebulization of the bioresponsive UPy-PEG hydrogel can be considered as a promising approach to prevent postsurgical peritoneal adhesions.

Effect of feed frame on lubricant sensitivity during upscaling from a compaction simulator to a rotary tablet press.

Internal lubrication can be associated with reduced tabletability. Deformation mechanism, lubricant type, lubricant blending time and paddle speed (PS) of the forced feeder are known to be influenceable factors. This study investigated the effect of lubricant blending time and PS of forced feeders on the tensile strength of lubricated microcrystalline cellulose (MCC) and lactose tablets. Magnesium stearate (MgSt), sodium stearyl fumarate (SSF) and stearic acid (SA) were used as lubricants. Tablets were produced on a compaction simulator and a rotary tablet press to investigate lubricant sensitivity during upscaling. Lubricant sensitivity was found higher for MCC compared to lactose which was attributed to the higher plasticity of MCC. The reduction in tensile strength upon lubricant addition followed the order: MgSt > SSF > SA; which could be linked to particle size, specific surface area and particle shape of the lubricants. Although differences in tensile strength were observed between the lubricant types, comparable ejection forces were obtained. The impact of PS on tensile strength was higher compared to lubricant blending time for both tableting machines. A good correlation of tensile strength and lubricant sensitivity between the compaction simulator and rotary tablet press was observed based on the calculation of paddle passes (NPP).

The Precision and Accuracy of 3D Printing of Tablets by Fused Deposition Modelling.

Tablet manufacture by fused deposition modelling (FDM) can be carried out individually (one tablet printed per run) or as a group (i.e., 'multiple printing' in one run) depending on patient's needs. The assessment of the process of printing must take into consideration the precision and the accuracy of the mass and dose of tablets, together with their solid-state properties and drug dissolution behaviour. Different mixtures made of either poly(vinyl alcohol) and paracetamol or hydroxypropylcellulose EF and hydrochlorothiazide were used to evaluate multiple printing of tablets by manufacturing batches of 30 tablets with nozzles of 0.4 and 0.7 mm, in two different printers. Besides testing for mass, drug content, density and dissolution performance, tablets were analysed for their thermal (DSC) and spectroscopic (NIR and FTIR) properties. Low standard deviations around mean values for the different properties measured suggested low intra-batch variability. Statistical analysis of data revealed no significant differences between the batches for most of the properties considered in the study. Inter-batch differences (p<0.05) were observed only for mass of tablets, possibly due to deviation on filament's diameter. The use of a smaller nozzle or a different printer enabled the manufacture of more reproducible tablets within a batch. Multiple printing revealed a significant saving on manufacturing time (>35%) in comparison to individual printing.

Impact of alternative lubricants on process and tablet quality for direct compression.

Internal lubrication with magnesium stearate (MgSt) is associated with a reduced tensile strength and prolonged disintegration and dissolution times. In the current study, alternative lubricants to MgSt were compared with regard to lubrication efficacy and their impact on tablet properties. The lubricants were combined in different concentrations (0.5-5% w/w) with three fillers (lactose, mannitol and microcrystalline cellulose (MCC)). The high lubrication efficiency of MgSt was associated with the highest reduction of tensile strength. The micronized stearic acid (SA) grades proved good alternatives as they showed a good lubrication efficiency in combination with a limited negative effect on tensile strength. The hydrophobic lubricants (e.g., MgSt and SA) did not prolong disintegration. In contrast, delayed disintegration was observed for sucrose monopalmitate combined with all three fillers and for several other hydrophilic lubricants (sodium lauryl sulfate, poloxamers 188 and P407) combined with MCC. These unexpected findings were explained by the competition-for-water hypothesis. The potential of alternative lubricants to MgSt was demonstrated in this study. Nevertheless, the impact of lubricant addition on process and tablet quality depended on lubricant (type and concentration) and formulation (lubrication need, deformation mechanism and disintegration behavior) properties. Therefore, lubricant selection should be carefully considered in formulation development.

Poly(2-alkyl-2-oxazoline)s: A polymer platform to sustain the release from tablets with a high drug loading.

Sustaining the release of highly dosed APIs from a matrix tablet is challenging. To address this challenge, this study evaluated the performance of thermoplastic poly (2-alkyl-2-oxazoline)s (PAOx) as matrix excipient to produce sustained-release tablets via three processing routes: (a) hot-melt extrusion (HME) combined with injection molding (IM), (b) HME combined with milling and compression and (c) direct compression (DC). Different PAOx (co-)polymers and polymer mixtures were processed with several active pharmaceutical ingredients having different aqueous solubilities and melting temperatures (metoprolol tartrate (MPT), metformin hydrochloride (MTF) and theophylline anhydrous (THA)). Different PAOx grades were synthesized and purified by the Supramolecular Chemistry Group, and the effect of PAOx grade and processing technique on the in vitro release kinetics was evaluated. Using the hydrophobic poly (2-n-propyl-2-oxazoline) (P n PrOx) as a matrix excipient allowed to sustain the release of different APIs, even at a 70% (w/w) drug load. Whereas complete THA release was not achieved from the P n PrOx matrix over 24 â€‹h regardless of the processing technique, adding 7.5% w/w of the hydrophilic poly (2-ethyl-2-oxazoline) to the hydrophobic P n PrOx matrix significantly increased THA release, highlighting the relevance of mixing different PAOx grades. In addition, it was demonstrated that the release of THA was similar from co-polymer and polymer mixtures with the same polymer ratios. On the other hand, as the release of MTF from a P n PrOx matrix was fast, the more hydrophobic poly (2-sec-butyl-2-oxazoline) (P sec BuOx) was used to retard MTF release. In addition, a mixture between the hydrophilic PEtOx and the hydrophobic P sec BuOx allowed accurate tuning of the release of MTF formulations. Finally, it was demonstrated that PAOx also showed a high ability to tune the in vivo release. IM tablets containing 70% MTF and 30% P sec BuOx showed a lower in vivo bioavailability compared to IM tablets containing a low PEtOx concentration (7.5%, w/w) in combination with P sec BuOx (22.5%, w/w). Importantly, the in vivo MTF blood level from the sustained release tablets correlated well with the in vitro release profiles. In general, this work demonstrates that PAOx polymers offer a versatile formulation platform to adjust the release rate of different APIs, enabling sustained release from tablets with up to 70% w/w drug loading.

Stable amorphous solid dispersion of flubendazole with high loading via electrospinning.

In this work, an important step is taken towards the bioavailability improvement of poorly water-soluble drugs, such as flubendazole (Flu), posing a challenge in the current development of many novel oral-administrable therapeutics. Solvent electrospinning of a solution of the drug and poly (2-ethyl-2-oxazoline) (PEtOx) is demonstrated to be a viable strategy to produce stable nanofibrous amorphous solid dispersions (ASDs) with ultrahigh drug-loadings (up to 55 wt% Flu) and long-term stability (at least one year). Importantly, at such high drug loadings, the concentration of the polymer in the electrospinning solution has to be lowered below the concentration where it can be spun in absence of the drug as the interactions between the polymer and the drug result in increased solution viscosity. A combination of experimental analysis and molecular dynamics simulations revealed that this formulation strategy provides strong, dominant and highly stable hydrogen bonds between the polymer and the drug, which is crucial to obtain the high drug-loadings and to preserve the long-term amorphous character of the ASDs upon storage. In vitro drug release studies confirm the remarkable potential of this electrospinning formulation strategy by significantly increased drug solubility values and dissolution rates (respectively tripled and quadrupled compared to the crystalline drug), even after storing the formulation for one year.

Advances in Twin-Screw Granulation.

Twin-screw granulation (TSG) is an emerging process technology that allows both wet and dry granulation of powders with a wide range of properties [...].

Continuous Twin Screw Granulation: A Review of Recent Progress and Opportunities in Formulation and Equipment Design.

Continuous twin screw wet granulation is one of the key continuous manufacturing technologies that have gained significant interest in the pharmaceutical industry as well as in academia over the last ten years. Given its considerable advantages compared to wet granulation techniques operated in batch mode such as high shear granulation and fluid bed granulation, several equipment manufacturers have designed their own manufacturing setup. This has led to a steep increase in the research output in this field. However, most studies still focused on a single (often placebo) formulation, hence making it difficult to assess the general validity of the obtained results. Therefore, current review provides an overview of recent progress in the field of continuous twin screw wet granulation, with special focus on the importance of the formulation aspect and raw material properties. It gives practical guidance for novel and more experienced users of this technique and highlights some of the unmet needs that require further research.

Effect of binder type and lubrication method on the binder efficacy for direct compression.

The effect of different binders for direct compression on tablet critical quality attributes was investigated. Dicalcium phosphate, lactose and microcrystalline cellulose were used as fillers and combined with ten binders (10, 20 and 30% w/w). Binder properties were linked to tensile strength via partial least square analysis. Tablets containing VA64F and PH105 exhibited the highest tensile strength which was linked to their compaction properties (specific work of compaction, elasticity, cohesion index) and particle size. In contrast, S1500 and E15 exhibited the lowest tensile strength of all binders. Lubrication method influenced the tensile strength as lubricant sensitivity was observed to some extent for all binders. Tensile strength was significantly higher applying external compared to internal lubrication. Fast disintegration was observed for MCC (PH105 and PH200) and starch (S1500 and NMSt) grades, whereas HPC (KEXF and KEF) and E15 resulted in delayed disintegration. Wettability measurements, via determination of contact angle, correlated well with the disintegration behaviour of the binders and can therefore be used as an indicative measurement for tablet disintegration. This study revealed the effect of binder properties, filler type and lubrication method on tablet critical quality attributes. In addition, the potential of dry binder addition for direct compression was highlighted.

Influence of Print Settings on the Critical Quality Attributes of Extrusion-Based 3D-Printed Caplets: A Quality-by-Design Approach.

Extrusion-based 3D-printing is an easy-to-use, cheap manufacturing technique that could be used to produce tailored precision medicines. The technique has an almost unlimited versatility since a multitude of print parameters can easily be adapted. Unfortunately, little is known of the effect of these print parameters on the critical quality attributes of the resulting printlets. In this study, practical guidelines and means to adapt certain parameters in order to achieve the desired outcome (e.g., acceptable visual quality and flexible dosing) are stipulated for medical 3D-printing using a design-of-experiments approach. The current study aims at elucidating the effect of five print parameters (infill, overlap, number of shells, layer height and layer pattern) on the mechanical properties, dimensions, weight, porosity and dissolution characteristics of a fixed-size caplet consisting of Eudragit EPO (69.3%), Polyox WSR N10 (29.7%) and zolpidem hemitartrate (1%). In terms of the mechanical properties, 3D-printed caplets possessed anisotropy where the vertical compression strength and Brinell hardness exceeded the diametral strength. In general, all 3D-printed caplets possessed acceptable mechanical strength except for a small region of the knowledge space. Dimensional analysis revealed small, statistical significant differences between different runs, although the clinical relevance of this variation is likely negligible. The weight or dose of a caplet can be varied mainly using the infill and overlap and, to a lesser extent, via the layer height and number of shells. The impact on porosity was complicated as this was influenced by many factors and their interactions. Infill was the only statistically relevant factor influencing the dissolution rate of the current formulation. This study unravels the importance of the print parameter overlap, which is a regularly neglected parameter. We also discovered that small dose variations while maintaining the same dissolution profile were possible via modifying the overlap or number of shells. However, large dose variations without affecting the dissolution behaviour could only be accomplished by size modifications of the printlet.

Identifying Critical Binder Attributes to Facilitate Binder Selection for Efficient Formulation Development in a Continuous Twin Screw Wet Granulation Process.

The suitability of pharmaceutical binders for continuous twin-screw wet granulation was investigated as the pharmaceutical industry is undergoing a switch from batch to continuous manufacturing. Binder selection for twin-screw wet granulation should rely on a scientific approach to enable efficient formulation development. Therefore, the current study identified binder attributes affecting the binder effectiveness in a wet granulation process of a highly soluble model excipient (mannitol). For this formulation, higher binder effectiveness was linked to fast activation of the binder properties (i.e., fast binder dissolution kinetics combined with low viscosity attributes and good wetting properties by the binder). As the impact of binder attributes on the granulation process of a poorly soluble formulation (dicalcium phosphate) was previously investigated, this enabled a comprehensive comparison between both formulations in current research focusing on binder selection. This comparison revealed that binder attributes that are important to guide binder selection differ in function of the solubility of the formulation. The identification of critical binder attributes in the current study enables rational and efficient binder selection for twin-screw granulation of well soluble and poorly soluble formulations. Binder addition proved especially valuable for a poorly soluble formulation.