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[Display omitted] Paracetamol absorption kinetics show considerable variability in older adults, complicating the development of effective dosing regimens in the advanced-age population. In previous research, sparkling water has been shown to influence absorption-related processes. This study aimed to apply these findings to older adults and investigate the impact of sparkling water on absorption-related variability and early exposure. To this end, fourteen volunteers, with a median age of 72.5, were enrolled in a small-scale, randomised, controlled clinical trial with a cross-over design. A single immediate-release 500 mg paracetamol tablet was administered with sparkling or still water. Venous blood samples were collected regularly over 8 hours and analysed using HPLC-UV. Reduced variability of absorption-related parameters and a trend towards higher early exposure were observed in the sparkling water group, as demonstrated by a 1.6-fold increased AUC 0-30min , a 2-fold reduced geometric coefficient of variation (GCV) for AUC 0-30min , and a reduced median [interquartile range] T max of 25.0 [20.0–30.0] min compared to 30.0 [25.0–45.0] min. Based on our findings, sparkling water as a real-life dosing condition might improve paracetamol absorption kinetics and early exposure in the advanced-age population. [ABSTRACT FROM AUTHOR]

[Display omitted] • Eudragit E was spray dried using 2- and 3-fluid nozzles for taste masking. • Slower drug release occurred from microparticles prepared using the 3-fluid nozzle. • Low yields resulted when drug/Eudragit E were spray dried, irrespective of nozzle. • Yields improved with high glass transition temperature polymer in the inner stream. • Polymers with similar solubility parameters mixed during 3-fluid spray drying. Conventional spray drying using a 2-fluid nozzle forms matrix microparticles, where drug is distributed throughout the particle and may not effectively mask taste. In contrast, spray drying using a 3-fluid nozzle has been reported to encapsulate material. The objective of this study was to spray dry Eudragit® E-PO (EE) with acetaminophen (APAP), a water-soluble model drug with a bitter taste, using 2- and 3-fluid nozzles for taste masking. Spray drying EE with APAP, however, resulted in yields of ≤ 13 %, irrespective of nozzle configuration. Yields improved when Eudragit® L 100–55 (EL) or Methocel® E6 (HPMC) was used in the inner fluid stream of the 3-fluid nozzle or in place of EE for the 2-fluid nozzle. Drug release from microparticles prepared with the 2-fluid nozzle was relatively rapid. Using EE in the outer fluid stream of the 3-fluid nozzle resulted in comparatively slower drug release, although drug release was observed, indicating that encapsulation was incomplete. Results from these studies also show that miscible polymers used in the two fluid streams mix during the spray drying process. In addition, findings from this study indicate that the polymer used in the inner fluid stream can impact drug release. [ABSTRACT FROM AUTHOR]

[Display omitted] This study explores the innovative production of personalized bilayer tablets, integrating two advanced manufacturing techniques: Droplet Deposition Modeling (DDM) and Injection Molding (IM). Unlike traditional methods limited to customizing dense bilayer medicines, our approach uses Additive Manufacturing (AM) to effectively adjust drug release profiles. Focusing on Caffeine and Paracetamol, we found successful processing for both DDM and IM using Caffeine formulation. The high viscosity of Paracetamol formulation posed challenges during DDM processing. Integrating Paracetamol formulation for the over-molding process proved effective, demonstrating IM's versatility in handling complex formulations. Varying infill percentages in DDM tablets led to distinct porosities affecting diverse drug release profiles in DDM-fabricated tablets. In contrast, tablets with high-density structures formed through the over-molding process displayed slower and more uniform release patterns. Combining DDM and IM techniques allows for overcoming the inherent limitations of each technique independently, enabling the production of bilayer tablets with customizable drug release profiles. The study's results offer promising insights into the future of personalized medicine, suggesting new pathways for the development of customized oral dosage forms. [ABSTRACT FROM AUTHOR]

This study demonstrates the applicability of near-infrared (NIR) imaging to evaluating in vivo oral formulation performance. As a NIR probe and model drug, indocyanine green (ICG) and acetaminophen (ACE) were selected, respectively. The fluorescence intensity of ICG greatly increased upon dissolution, with the dissolved ICG passing through the gastrointestinal tract over time. Both compounds (0.05 mg of ICG and 0.5 mg of ACE) were encapsulated in gelatin and hydroxypropyl methylcellulose (HPMC) capsules in the solid form. In vitro, the HPMC capsules showed a disintegration lag time, a feature that was not observed for the gelatin capsules. After oral administration of each capsule to rats, blood samples were collected, followed by fluorescent imaging of the abdominal region. At 0.25 h after HPMC capsule administration, the fluorescence area and intensity were significantly small and relatively weak compared to that of the gelatin capsule. These tendencies resulted from the difference in capsule disintegration times, leading to a change in gastric emptying, which corresponded well with the initial time profile of the plasma concentration of ACE. These results indicate that possibility of NIR imaging with ICG to evaluate in vivo performance of orally administered formulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Graphical abstract Abstract This study describes the preparation of free films of zein with and without acetylated high amylose maize starch (HAS) and their corresponding coated tablets as a novel approach to colonic drug delivery. We hypothesise that the embedding of a digestible starch component within the inert zein would allow the film to remain intact until the large intestine is reached. Free films of zein alone and starch/zein were prepared and characterized. SEM and AFM images of film surface showed that films were morphologically inhomogeneous, particularly at lower HAS/Zein ratios; however, nanothermal analysis data suggested that these differences in appearance within the same film are not compositional differences. Moreover, FT-IR could detect no molecular interaction between the two polymers. Paracetamol tablets were coated with HAS/Zein aqueous based coatings of different compositions to a TWG of 20%. Drug release from zein alone and 1:5 HAS/Zein coated tablets under upper gastrointestinal conditions (pH 1.2, pH 6.8 with pepsin and pancreatin included) was very similar (for example approximately 12% and 14% of the drug was released, respectively, after 6 h in a sequential in vitro test), suggesting that release in this region is limited and is not influenced by the presence of HAS in the ratio to zein under study. Studies using an in vitro colon model showed that under simulated colonic conditions, the drug release was significantly (p < 0.05) more rapid from 1:5 HAS/Zein, compared to the zein alone coating formulation. These data therefore support the potential use of zein-starch mixed films for colonic targeting purposes. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Wet milling coupled with crystallisation has considerable potential to deliver enhanced control over particle attributes. The effect of process conditions and wet mill configuration on particle size, shape and surface energy has been investigated on acetaminophen using a seeded cooling crystallisation coupled with a wet mill unit generating size controlled acetaminophen crystals through an interchangeable rotor-tooth configuration. The integrated wet milling crystallisation platform incorporates inline focused beam reflectance measurement (FBRM) and particle vision measurement (PVM) for in-depth understanding of particle behaviour under high-shear conditions. We used a recently developed computational tool for converting chord length distribution (CLD) from FBRM to particle size distribution (PSD) to obtain quantitative insight into the effect of the competing mechanisms of size reduction and growth in a wet milling seeded crystallisation process for acetaminophen. The novelty of our wet milling crystallisation approach is in delivery of consistent surface energies across a range of particle sizes. This highlights the potential to engineer desirable particle attributes through a carefully designed, highly intensified crystallisation process. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Spironolactone form I melts at about 70 degrees lower than form II, which is very unusual for two co-existing polymorphs. The phase relationships involving this unprecedented case of dimorphism have been investigated by constructing a topological pressure-temperature phase diagram. The transition from polymorph I to polymorph II is unambiguously exothermic while it is accompanied with an increase in the specific volume. This indicates that the d P /d T slope of the I-II equilibrium curve is negative. The convergence of the melting equilibrium lines at high pressure leads to a topological P - T diagram in which polymorph I possesses a stable phase region at high pressure. Thus, forms I and II are monotropically related at ordinary pressure and turn to an enantiotropic relationship at high pressure. Given that polymorph I is the densest form, it negates the rule of thumb that the densest form is also the most stable form at room temperature, similar to the case of paracetamol. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract This work demonstrates the feasibility of the extemporaneous preparation of maltodextrins orodispersible films (ODF) by hot-melt ram-extrusion 3D printing. This method consists of three simple technological operations which can be also implemented in a pharmacy setting. First, maltodextrins, drug, and other excipients are mixed in a mortar and wetted with the plasticizer (i.e. glycerine). Then, the mixture is fed in the chamber of the ram-extruder and heated. ODF are individually printed on the packaging material foil and sealed without further manipulations. The critical formulation attributes and process variables were investigated to define the processability space. In particular, the optimal conditions to print a mixture of maltodextrins/glycerine in a 80/20 w/w ratio resulted: heating temperature: 85 °C; needle gauge: 18 G; needle-packaging material foil distance: 0.6 mm; maximum print rate: 50 mm/s; filling angle: 120°. The maximum drug loading was about 40%, when paracetamol was used as model drug. The compounded ODF complied with USP and Ph. Eur. specifications for disintegration time (<1 min). The dissolution pattern of paracetamol overlapped with that obtained from ODF with a similar composition prepared by the consolidated solvent casting technique, demonstrating the suitability of the proposed technology. [ABSTRACT FROM AUTHOR]

The small intestine is generally considered the major site of absorption after oral drug administration. Absorption from the stomach is often disregarded, though passive diffusion across the gastric mucosal barrier is theoretically possible. In this study, an in situ gastric bolus administration model was used to study the gastric absorption of pharmaceutical compounds in fasted and fed state rats. Three drugs [paracetamol (neutral), diclofenac (acidic) and posaconazole (basic)] were administered directly into the stomach as solution (paracetamol and diclofenac) or suspension (posaconazole). Transfer to the intestine was blocked by ligating the pylorus; as a reference, non-ligated conditions were used. Blood samples were collected and gastric absorption was assessed by the appearance of compounds in the systemic circulation. Paracetamol and diclofenac were readily absorbed from the fasted and fed state rat stomach. For paracetamol, the relative contribution of gastric absorption was higher in the fed state compared to the fasted state. Posaconazole absorption was negligible. Since the ability of the stomach to absorb pharmaceutical compounds was clearly confirmed, the present study warrants further research to quantify the contribution of gastric absorption to total gastrointestinal drug absorption. [ABSTRACT FROM AUTHOR]

Three-dimensional printing (3DP) is gaining momentum in the field of pharmaceuticals, offering innovative opportunities for medicine manufacture. Selective laser sintering (SLS) is a novel, high resolution and single-step printing technology that we have recently introduced to the pharmaceutical sciences. The aim of this work was to use SLS 3DP to fabricate printlets (3D printed tablets) with cylindrical, gyroid lattice and bi-layer structures having customisable release characteristics. Paracetamol-loaded constructs from four different pharmaceutical grade polymers including polyethylene oxide, Eudragit (L100-55 and RL) and ethyl cellulose, were created using SLS 3DP. The novel gyroid lattice structure was able to modulate the drug release from all four polymers. This work is the first to demonstrate the feasibility of using SLS to achieve customised drug release properties of several polymers, in a swift, cost-effective manner, avoiding the need to alter the formulation composition. By creating these constructs, it is therefore possible to modify drug release, which in practice, could enable the tailoring of drug performance to the patient simply by changing the 3D design. [ABSTRACT FROM AUTHOR]

Despite the wide occurrence of crystallization in the pharmaceutical industry, deep understanding and fine control of the process remain a tricky issue. Nevertheless, the successful manufacturing of finished pharmaceutical products, as well as the structural determination of biopharmaceuticals, depend on the size, form, shape and purity of the crystals. The ability of substrates with precise chemistry and topological features to induce nucleation has been thoroughly assessed during the recent years. This paper reviews the major advances and discoveries in controlling small molecule drug and protein crystallization by means of engineered surfaces. By designing superficial properties and morphology, it has been possible to tune the polymorph outcome, shorten the nucleation induction time, impose specific crystal shapes, control the crystal size and carry out crystallization at very low supersaturation levels. Such achievements underline the potential of surface-induced crystallization to provide an ideal platform for the study of the nucleation process and gain control over its stochastic nature. [ABSTRACT FROM AUTHOR]

Selective laser sintering (SLS) is a three-dimensional printing (3DP) technology employed to manufacture plastic, metallic or ceramic objects. The aim of this study was to demonstrate the feasibility of using SLS to fabricate novel solid dosage forms with accelerated drug release properties, and with a view to create orally disintegrating formulations. Two polymers (hydroxypropyl methylcellulose (HPMC E5) and vinylpyrrolidone-vinyl acetate copolymer (Kollidon ® VA 64)) were separately mixed with 5% paracetamol (used as a model drug) and 3% Candurin ® Gold Sheen colorant; the powder mixes were subjected to SLS printing, resulting in the manufacture of printlets (3DP tablets). Modulating the SLS printing parameters altered the release characteristics of the printlets, with faster laser scanning speeds accelerating drug release from the HPMC formulations. The same trend was observed for the Kollidon ® based printlets. At a laser scanning speed of 300 mm/s, the Kollidon ® printlets exhibited orally disintegrating characteristics by completely dispersing in <4 s in a small volume of water. X-ray micro-CT analysis of these printlets indicated a reduction in their density and an increase in open porosity, therefore, confirming the unique disintegration behaviour of these formulations. The work reported here is the first to demonstrate the feasibility of SLS 3DP to fabricate printlets with accelerated drug release and orally disintegrating properties. This investigation has confirmed that SLS is amenable to the pharmaceutical research of modern medicine manufacture. [ABSTRACT FROM AUTHOR]

The manufacture of immediate release high drug loading paracetamol oral tablets was achieved using an extrusion based 3D printer from a premixed water based paste formulation. The 3D printed tablets demonstrate that a very high drug (paracetamol) loading formulation (80% w/w) can be printed as an acceptable tablet using a method suitable for personalisation and distributed manufacture. Paracetamol is an example of a drug whose physical form can present challenges to traditional powder compression tableting. Printing avoids these issues and facilitates the relatively high drug loading. The 3D printed tablets were evaluated for physical and mechanical properties including weight variation, friability, breaking force, disintegration time, and dimensions and were within acceptable range as defined by the international standards stated in the United States Pharmacopoeia (USP). X-ray Powder Diffraction (XRPD) was used to identify the physical form of the active. Additionally, XRPD, Attenuated Total Reflectance Fourier Transform Infrared spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC) were used to assess possible drug-excipient interactions. The 3D printed tablets were evaluated for drug release using a USP dissolution testing type I apparatus. The tablets showed a profile characteristic of the immediate release profile as intended based upon the active/excipient ratio used with disintegration in less than 60 s and release of most of the drug within 5 min. The results demonstrate the capability of 3D extrusion based printing to produce acceptable high-drug loading tablets from approved materials that comply with current USP standards. [ABSTRACT FROM AUTHOR]

Water wettability of pharmaceutical blends affects important quality attributes of final products. We investigate the wetting properties of a pharmaceutical blend lubricated with Magnesium Stearate (MgSt) as a function of the mechanical shear strain applied to the blend. We measure the penetration dynamics of sessile drops deposited on slightly compressed powder beds. We consider a blend composed of 9% Acetaminophen 90% Lactose and 1% MgSt by weight. Comparing the penetration time of water and a reference liquid Polydimethylsiloxane (silicon oil) we obtain an effective cosine of the contact angle with water, based on a recently developed drop penetration method. We repeat the experiments for blends exposed to increasing levels of shear strain and demonstrate a significant decrease in water wettability (decrease in the cosine of the contact angle). The results are consistent with the development of a hydrophobic film coating the powder particles as a result of the increased shear strain. Finally, we show that, as expected dissolution times increase with the level of shear strain. Therefore, the proposed drop penetration method could be used to directly assess the state of lubrication of a pharmaceutical blend and act as a quality control on powder blend attributes before the blend is tableted. [ABSTRACT FROM AUTHOR]

The number of intramuscularly applied dosage forms has been continuously increasing during the last decades. However, up to date no in vitro dissolution test method for parenteral dosage forms has been described in the Ph. Eur. or USP. It was the aim of this study to investigate dissolution test setups based on the compendial flow-through cell and the reciprocating holder for this purpose. Both apparatuses were equipped with dialysis membranes to accommodate the drug formulation. The suitability of the dissolution method was evaluated by comparing release profiles with blood level curves that were obtained previously in an in vivo study in rats by our group. Aqueous solutions and oily suspensions of paracetamol and prednisolone were tested in vitro that were also applied in the in vivo study. In the case of the aqueous solutions in which no formal dissolution occurs, transport from the applied depot across a dialysis membrane was investigated. While the drug transport across the dialysis membrane of both drugs in aqueous solution was similar in all applied test methods, differences in the release behavior of paracetamol and prednisolone as an oily suspension were observed. This was mainly due to sedimentation of the particles within the oily depot. [ABSTRACT FROM AUTHOR]

Low-melting-point substances are widely used to develop temperature-sensitive formulations. In this study, we focused on microcrystalline wax (MCW) as a low-melting-point substance. We evaluated the drug release behavior of wax matrix (WM) particles using various MCW under various temperature conditions. WM particles containing acetaminophen were prepared using a spray congealing technique. In the dissolution test at 37 °C, WM particles containing low-melting-point MCWs whose melting was starting at approx. 40 °C (Hi-Mic-1045 or 1070) released the drug initially followed by the release of only a small amount. On the other hand, in the dissolution test at 20 and 25 °C for WM particles containing Hi-Mic-1045 and at 20, 25, and 30 °C for that containing Hi-Mic-1070, both WM particles showed faster drug release than at 37 °C. The characteristic drug release suppression of WM particles containing low-melting-point MCWs at 37 °C was thought attributable to MCW melting, as evidenced by differential scanning calorimetry analysis and powder X-ray diffraction analysis. Taken together, low-melting-point MCWs may be applicable to develop implantable temperature-sensitive formulations that drug release is accelerated by cooling at administered site. [ABSTRACT FROM AUTHOR]

Many newly developed active pharmaceutical ingredients (APIs) have very low solubility in aqueous media. The preparation of solid dispersions (SDs) is one way of avoiding this problem. However, compound wettability and thus solubility are influenced by surface energy. In this study, we used inverse gas chromatography (IGC) to evaluate the surface energies of prepared SDs, and compared them with those obtained for physical mixtures (PMs). SDs containing different weight ratios of crystalline acetaminophen and one of three polymers (Kollidon ® 12 PF, Kollidon ® VA 64 or Soluplus ® ) were prepared by the melt-quenching of corresponding PMs. In all cases, as the polymer content increased, the surface energy decreased significantly. For the SDs and PMs containing Soluplus ® , this decrease in surface energy showed the same non-linear trend. In the cases of Kollidon ® 12 PF and Kollidon ® VA 64, the trend was linear, with the SDs showing a steeper decrease in surface energy than the corresponding PMs. Typically, such decreases are ascribed to the dissolution of the crystalline structure of an API. Our results suggest that in the case of the Kollidons, the steeper decrease is caused by another mechanism, namely, strong API-Kollidon interaction leading to the less wettable surface of SDs. [ABSTRACT FROM AUTHOR]

In this study, the origins of granule content non-uniformity in the high-shear wet granulation of a model two-component pharmaceutical blend were investigated. Using acetaminophen as the active pharmaceutical ingredient (API) and microcrystalline cellulose as the excipient, the distribution of the API across the granule size classes was measured for a range of conditions that differed in the duration of the initial dry mixing stage, the overall composition of the blend and the wet massing time. The coarse granule fractions were found to be systematically sub-potent, while the fines were enriched in the API. The extent of content non-uniformity was found to be dependent on two factors – powder segregation during dry mixing and redistribution of the API between the granule size fractions during the wet massing phase. The latter was demonstrated in an experiment where the excipient was pre-granulated, the API was added later and wet massed. The content non-uniformity in this case was comparable to that obtained when both components were present in the granulator from the beginning. With increasing wet massing time, the extent of content non-uniformity decreased, indicating that longer wet massing times might be a solution for systems with a natural tendency for component segregation. [ABSTRACT FROM AUTHOR]

The presence of solid matter in polymer melts affects the rheological properties of a drug-polymer mixture, and thus the processability of these mixtures in melt-based processes. The particle morphological changes related to dissolution and crystal growth in the mixtures of paracetamol and ibuprofen with polyethylene oxide and methacrylate copolymer (Eudragit ® E PO) were observed by polarized microscopy simultaneously while measuring their rheological properties within temperature ranges relevant for melt processes, such as hot melt extrusion and fused deposition modeling 3D printing. The dissolution of solid crystalline matter into the molten polymer and its effects on the rheological parameters showed that the plasticization effect of the drug was highly dependent on the temperature range, and at a temperature high enough, plasticization induced by the small-molecule drugs could enhance the flowability even at very high drug loads. Therefore, even supersaturated mixtures can be plasticized efficiently, enabling their melt processing, such as hot melt extrusion or 3D printing. The combination of rheometry and polarized light microscopy proved to be very useful for studying the link between morphological changes in the drug-polymer and the flow behavior of the drug-polymer mixtures at different temperature ranges and deformation modes. [ABSTRACT FROM AUTHOR]

The aim of this study was to manufacture 3D printed tablets (printlets) from enteric polymers by single filament fused deposition modeling (FDM) 3D printing (3DP). Hot melt extrusion was used to generate paracetamol-loaded filaments from three different grades of the pharmaceutical excipient hypromellose acetate succinate (HPMCAS), grades LG, MG and HG. One-step 3DP was used to process these filaments into enteric printlets incorporating up to 50% drug loading with two different infill percentages (20 and 100%). X-ray Micro Computed Tomography (Micro-CT) analysis revealed that printlets with 20% infill had cavities in the core compared to 100% infill, and that the density of the 50% drug loading printlets was higher than the equivalent formulations loaded with 5% drug. In biorelevant bicarbonate dissolution media, drug release from the printlets was dependent on the polymer composition, drug loading and the internal structure of the formulations. All HPMCAS-based printlets showed delayed drug release properties, and in the intestinal conditions, drug release was faster from the printlets prepared with polymers with a lower pH-threshold: HPMCAS LG > HPMCAS MG > HPMCAS HG. These results confirm that FDM 3D printing makes it possible not only to manufacture delayed release printlets without the need for an outer enteric coating, but it is also feasible to adapt the release profile in response to the personal characteristics of the patient, realizing the full potential of additive manufacturing in the development of personalised dose medicines. [ABSTRACT FROM AUTHOR]

Mini-tablets have potential applications as a flexible drug delivery tool in addition to their generally perceived use as multi-particulates. That is, mini-tablets could provide flexibility in dose finding studies and/or allow for combination therapies in the clinic. Moreover, mini-tablets with well controlled quality attributes could be a prudent choice for administering solid dosage forms as a single unit or composite of multiple mini-tablets in patient populations with swallowing difficulties (e.g., pediatric and geriatric populations). This work demonstrated drug substance particle size and concentration ranges that achieve acceptable mini-tablet quality attributes for use as a single or composite dosage unit. Immediate release and orally disintegrating mini-tablet formulations with 30 μm to 350 μm (particle size d 90 ) acetaminophen and Compap™ L (90% acetaminophen) at concentrations equivalent to 6.7% and 26.7% acetaminophen were evaluated. Mini-tablets achieved acceptable weight variability, tensile strength, friability, and disintegration time at a reasonable solid fraction for each formulation. The content uniformity was acceptable for mini-tablets of 6.7% formulations with ≤170 μm drug substance, mini-tablets of all 26.7% formulations, and composite dosage units containing five or more mini-tablets of any formulation. Results supported the manufacturing feasibility of quality mini-tablets, and their applicability as a flexible drug delivery tool. [ABSTRACT FROM AUTHOR]

Active pharmaceutical ingredients (APIs) are predominantly organic solid powders. Due to their bulk properties many APIs require processing to improve pharmaceutical formulation and manufacturing in the preparation for various drug dosage forms. Improved powder flow and protection of the APIs are often anticipated characteristics in pharmaceutical manufacturing. In this work, we have modified acetaminophen particles with atomic layer deposition (ALD) by conformal nanometer scale coatings in a one-step coating process. According to the results, ALD, utilizing common chemistries for Al 2 O 3 , TiO 2 and ZnO, is shown to be a promising coating method for solid pharmaceutical powders. Acetaminophen does not undergo degradation during the ALD coating process and maintains its stable polymorphic structure. Acetaminophen with nanometer scale ALD coatings shows slowed drug release. ALD TiO 2 coated acetaminophen particles show cytocompatibility whereas those coated with thicker ZnO coatings exhibit the most cytotoxicity among the ALD materials under study when assessed in vitro by their effect on intestinal Caco-2 cells. [ABSTRACT FROM AUTHOR]

Capping or lamination is an unsolved common problem in tablet manufacturing. Knowledge gaps remain despite an enormous amount of effort made in the past to better understand the tablet capping/lamination phenomenon. Using acetaminophen – containing formulations, we examined the potential use of a compaction simulator as a material-sparing tool to predict capping occurrence under commercial tableting conditions. Systematical analyses of the in-die compaction data led to insight on the potential mechanism of tablet capping/lamination. In general, capping strongly correlates with high in-die elastic recovery, high Poisson’s ratio, low tensile strength, and radial die-wall pressure. Such insight can be used to guide the formulation design of high quality tablet products that are free from capping problems for challenging active pharmaceutical ingredients. [ABSTRACT FROM AUTHOR]

The main objective of this work was to explore the potential of coupling fused deposition modeling in three-dimensional (3D) printing with hot-melt extrusion (HME) technology to facilitate additive manufacturing, in order to fabricate tablets with enhanced extended release properties. Acetaminophen was used as the model drug and different grades and ratios of polymers were used to formulate tablets. Three-point bending and hardness tests were performed to determine the mechanical properties of the filaments and tablets. 3D-printed tablets, directly compressed mill-extruded tablets, and tablets prepared from a physical mixture were evaluated for drug release rates using a USP-II dissolution apparatus. The surface and cross-sectional morphology of the 3D-printed tablets were assessed by scanning electron microscopy. Differential scanning calorimetry and thermogravimetric analysis were used to characterize the crystal states and thermal properties of materials, respectively. The 3D-printed tablets had smooth surfaces and tight structures; therefore, they showed better extended drug release rates than the directly compressed tablets did. Further, this study clearly demonstrated the feasibility of coupling HME with 3D printing technology, which allows for the formulation of drug delivery systems using different grades and ratios of pharmaceutical polymers. In addition, formulations can be made based on the personal needs of patients. [ABSTRACT FROM AUTHOR]

Partially hydrolysed polyvinyl alcohol (PVA) was evaluated as a pelletisation aid for the production of pellets with a high acetaminophen and metformin hydrochloride concentration (>70%, w/w). Mixtures with varying drug concentration and PVA/microcrystalline cellulose (MCC) ratios were processed via extrusion-spheronisation, either after addition of PVA as a dry powder or as an aqueous solution. Finally, high drug- loaded metformin pellets were coated with a methacrylic acid copolymer (Eudragit™ NM 30D) and evaluated for their sustained release potency in vitro and in vivo . The plasticity index of the wet mass increased by the addition of PVA to the formulation, which resulted in enhanced extrusion-spheronisation properties, even at a high drug load. Although the MCC concentration was successfully lowered by adding PVA, the inclusion of MCC in the formulation was essential to overcome problems related to the tackiness effect of PVA during extrusion. Overall, wet addition of PVA was superior to dry addition, as pellets with a higher mechanical strength and narrower particle size distribution were obtained. Pellets containing 87% (w/w) metformin hydrochloride were successfully layered with 20% (w/w) coating material, yielding sustained release pellets with a final drug load of 70% (w/w). In addition, the sustained release characteristics of the PVA-based pellets with a high drug content were confirmed in vivo as no difference with the Glucophage™ SR reference formulation was observed. [ABSTRACT FROM AUTHOR]

Oral delivery of pharmaceuticals requires that they retain their physical and chemical attributes during transit within the gastrointestinal (GI) tract, for the manifestation of desired therapeutic profiles. Solid lipid nanoparticles (SLNs) are used as carriers to improve the absorption of hydrophobic drugs. In this study, we examine the stability of amphotericin B (AmB) and paracetamol (PAR) SLNs in simulated GI fluids during gastric emptying. On contact with the simulated fluids, the particles increased in size due to ingress of the dissolution media into the particles. Simulated gastric emptying revealed that the formulations had mean sizes <350 nm and neutral surface charges, both of which are optimal for intestinal absorption of SLNs. There was ingress of the fluids into the SLNs, followed by diffusion of the dissolved drug, whose rate depended on the solubility of the loaded-drug in the particular medium. Time-of-flight secondary ion mass spectrometry analyses indicated that drug loading followed the core-shell model and that the AmB SLNs have a more drug-enriched core than the PAR SLNs do. The AmB SLNs are therefore a very suitable carrier of AmB for oral delivery. The stability of the SLNs in the simulated GI media indicates their suitability for oral delivery. [ABSTRACT FROM AUTHOR]

[Display omitted] • Granules containing 30% drug were prepared using novel CGD and BGD methods. • Advantages and disadvantages of CGD and BGD granules were compared. • CGD can produce ellipsoidal granules with excellent flowability and good tabletability. • CGD can produce a larger amount of granules with less energy and space than FG. LaVortex® was developed as a novel free-flow continuous granulation/drying (CGD) system. In this study, we compared the advantages and disadvantages of granules prepared by continuous and batchwise manufacturing systems. Granules containing 30 % acetaminophen were manufactured under various operating conditions using CGD system, with comparison granules manufactured using conventional batch systems that involve a combination of fluid bed granulation (FG), agitation granulation (AG), continuous drying, fluid bed drying, and/or shelf drying, after which the pharmaceutical properties of each type of manufactured granule were evaluated. Cumulative particle-size distributions were determined by sieving, powder flowabilities were determined by angle of repose measurements, and scanning electron microscopy was employed to examine granule morphologies. The CGD system produced fine-to-large spherical or ellipsoidal granules that exhibited excellent powder fluidities and tabletabilities that are almost identical to those of AG granules. Moreover, the CGD granules exhibited better powder flowability than the FG granules. The addition of water promoted CGD-granule growth and improved significantly powder flowability, and did a little in tabletability. Small spherical granules with good fluidity suitable for fine-particle-coating core materials, or large granules with excellent fluidity and tabletability, were prepared by adjusting the values of the elemental parameters of the CGD process. [ABSTRACT FROM AUTHOR]

[Display omitted] The compatibility of drugs with excipients plays a crucial role in the prospective stability of pharmaceutical formulations. Apart from real-time stability studies, conventional analytical tools like DSC, FTIR, NMR, and chromatography help identify the possibilities of drug-excipient interactions. Machine learning can assist in developing a predictive tool for drug-excipient incompatibility. In the present work, PubChem Fingerprint is employed as the descriptor of compounds that thoroughly represents the drug's and excipient's chemistry. The 881-bit binary fingerprints of each drug and excipient make 1762 inputs, and one categorical output makes an instance in the dataset. A dataset of more than 3500 instances of drugs and excipients is carefully selected from peer-reviewed research papers. Rigorous training of the Artificial Neural Network (ANN) model was performed with maximum validation accuracy, minimum validation loss, and maximum validation precision as the checkpoints. The machine learning model (DE-Interact) was trained, achieving training and validation accuracies of 0.9930 and 0.9161, respectively. The performance of the DE-Interact model was evaluated by confirming three incompatible predictions by conventional analytical tools. Paracetamol with vanillin, paracetamol with methylparaben, and brinzolamide with polyethyleneglycol are these instances which are predicted as incompatible by the DE-Interact. DSC, FTIR, HPTLC, and HPLC analysis confirm the prediction. The present work offers a reliable DE-Interact tool for quick referencing while selecting excipients in formulation design. [ABSTRACT FROM AUTHOR]

In this study, we investigated the influence of deformability of specifically-engineered guest particles on the tensile strength of tablets of interactive mixtures. The binder polyvinylpyrrolidone (PVP) of different molecular weights were spray dried with l -leucine to create guest particle formulations. The guest particle formulations were characterized by their particle size, surface l -leucine concentration and glass transition temperature (Tg). These spray-dried particles were then blended with paracetamol to form interactive mixtures, which were compacted into tablets and tablet tensile strength and elastic recovery were determined. The guest particles had particle diameters in the range of 1–10 μm, and surfaces that were l -leucine enriched. The Tg of guest particle formulations increased with increasing molecular weight of the PVP. All the guest particle formulations formed an observed homogeneous interactive mixture with paracetamol. The tensile strength of the tablets of interactive mixtures increased with decreasing Tg of the guest particles. In these interactive mixtures, higher tensile strength was also associated with lower tablet elastic recovery. The elastic recovery of the tablets showed a correlation with the elastic recovery of the tablets of guest particles. Thus, our results indicated that the deformability of guest particles dictates the tensile strength of the tablets of these interactive mixtures. [ABSTRACT FROM AUTHOR]

Amorphous solid dispersions (ASDs) comprising an active pharmaceutical ingredient (API) and polymer are a frequently described approach in the formulation of new drug candidates. This study aimed to evaluate the saturation solubility and dissolution behavior of ASDs consisting of paracetamol (PCM) and polyvinylpyrrolidone/vinyl acetate (PVP/VA) in water and their influence on the transepithelial in vitro permeation of PCM. With increasing amounts of PVP/VA, the water solubility of ASDs containing PCM increased up to six times compared to that of a saturated PCM solution. In the case of preparations with 30 % PCM, two-phase separation was observed in water at room temperature, consisting of a polymer-rich phase with high API loading and an aqueous, polymer-poor phase. This result was attributed to the thermoresponsive behavior of PVP/VA with lower critical solution temperature (LCST). As the PCM content in the ASD increased, the LCST decreased. This behavior was analyzed by measuring the demixing temperature (T dem ) values with differential scanning calorimetry (DSC). Furthermore, the permeation behavior of PCM from these phase-separated preparations through Caco-2 cells was analyzed. Additionally, the effect of these preparations on cell viability was evaluated using the MTT assay. Preparations with relatively high PCM concentrations showed a reduction in cell viability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Fused deposition modeling (FDM) 3–Dimensional (3D) printing is becoming an increasingly important technology in the pharmaceutical sciences, since it allows the manufacture of personalized oral dosage forms by deposition of thin layers of material. Here, a filament extruder was used to obtain filaments of polyvinyl alcohol (PVA) containing paracetamol or caffeine appropriate for 3D printing. The filaments were used to manufacture caplets for oral administration by FDM 3D printing, with the aim of evaluating the effect of the internal structure (micropore volume), drug loading and composition on drug dissolution behaviour. Micropore volume of the caplets was primarily determined by the presence of large pores due to gaps in the printed layers/net while printing, and the porosity of the caplets was 10 fold higher than the porosity of the extruded filament. Dynamic dissolution drug release tests on the caplets in biorelevant bicarbonate media revealed distinctive release profiles, which were dependent on drug solubility and drug loading. Porosity of the caplets did not help to predict the different drug release profiles. This study confirms the potential of 3D printing to fabricate caplets and helps to elucidate which factors influence drug release from this type of new dosage form. [ABSTRACT FROM AUTHOR]

The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate (IAC), is an innovative non- radical scavenger used with success in numerous disease models such as inflammation, neurological disorders, hepatitis and diabetes. The pharmacological treatments have been performed by the intraperitoneal route of administration, representing to date, the main limit for the drug use. The aim of this study was to develop a delivery system that allows the oral administration of IAC while maintaining its therapeutic efficacy. Solid Lipid Microparticles (SLMs) containing a theoretical 18% (w/w) of IAC have been produced by the spray congealing technology; three formulations have been tested (A, B and C) using different low melting point carriers (stearic acid, Compritol ® HD5ATO and carnauba wax) alone or in combination. All IAC loaded SLMs exhibited a spherical shape, encapsulation efficiency higher than 94% and particle size suitable for the oral route. Administered per os at different dosages in an inflammation rat model, all SLMs demonstrated their efficacy in reducing oedema and alleviating pain, compared to the gold standards Indomethacin and Paracetamol. These results suggested that the SLMs are an efficacious delivery system for the oral administration of IAC, potentially useful for the treatment of others diseases related to an over production of free radicals. [ABSTRACT FROM AUTHOR]

A method for predicting dissolution profiles of directly compressed tablets for a fixed sustained release formulation manufactured in a continuous direct compaction (CDC) system is presented. The methodology enables real-time release testing (RTRt). Tablets were made at a target drug concentration of 9% Acetaminophen, containing 90% lactose and 1% Magnesium Stearate, and at a target compression force of 24 kN. A model for predicting dissolution profiles was developed using a 3 4−1 fractional factorial experimental design built around this targeted condition. Four variables were included: API concentration (low, medium, high), blender speed (150 rpm, 200 rpm, 250 rpm), feed frame speed (20 rpm, 25 rpm, 30 rpm), compaction force (8KN, 16KN, 24KN). The tablets thus obtained were scanned at-line in transmission mode using Near IR spectroscopy. The dissolution profiles were described using two approaches, a model-independent “shape and level” method, and a model-dependent approach based on Weibull’s model. Multivariate regression was built between the NIR scores as the predictor variables and the dissolution profile parameters as the response. The model successfully predicted the dissolution profiles of the individual tablets (similarity factor, f 2 ∼72) manufactured at the targeted set point. This is a first ever published manuscript addressing RTRt for dissolution prediction in continuous manufacturing, a novel and state of art technique for tablet manufacturing. [ABSTRACT FROM AUTHOR]

An ultrasound measurement system was employed as a non-destructive method to evaluate its reliability in predicting the tensile strength of tablets and investigate the benefits of incorporating it in a continuous line, manufacturing solid dosage forms. Tablets containing lactose, acetaminophen, and magnesium stearate were manufactured continuously and in batches. The effect of two processing parameters, compaction force and level of shear strain were examined. Young's modulus and tensile strength of tablets were obtained by ultrasound and diametrical mechanical testing, respectively. It was found that as the blend was exposed to increasing levels of shear strain, the speed of sound in the tablets decreased and the tablets became both softer and mechanically weaker. Moreover, the results indicate that two separate tablet material properties (e.g., relative density and Young's modulus) are necessary in order to predict tensile strength. A strategy for hardness prediction is proposed that uses the existing models for Young's modulus and tensile strength of porous materials. Ultrasound testing was found to be very sensitive in differentiating tablets with similar formulation but produced under different processing conditions (e.g., different level of shear strain), thus, providing a fast, and non-destructive method for hardness prediction that could be incorporated to a continuous manufacturing process. [ABSTRACT FROM AUTHOR]

The goal of this study was to test the feasibility to load non-ordered, non-spherical mesoporous silica with the model drug paracetamol, and subsequently coat the loaded particles using one single pilot scale fluid bed system equipped with a Wurster insert. Mesoporous silica particles (Davisil ® ) with a size ranging from 310 to 500 μm and an average pore diameter of 15 nm were loaded with paracetamol to 18.8% drug content. Subsequently, loaded cores were coated with ethylcellulose to obtain controlled drug release. Coating processing variables were varied following a full factorial design and their effect on drug release was assessed. Increasing coating solution feed rate and decreasing fluidizing air temperature were found to increase drug release rates. Increasing pore former level and decreasing coating level were found to increase drug release rates. The release medium’s osmolality was varied using different sodium chloride concentrations, which was found to affect drug release rates. The results of this study clearly indicate the potential of non-ordered, non-spherical mesoporous silica as a reservoir carrier for the controlled release of drugs. Although non-spherical, we were able to reproducibly coat this carrier using a bottom spray fluid bed system. However, a major hurdle that needs to be tackled is the attrition the material suffers from during fluid bed processing. [ABSTRACT FROM AUTHOR]

The aim of this work was to evaluate the suitability of stereolithography (SLA) to fabricate drug-loaded tablets with modified-release characteristics. The SLA printer creates solid objects by using a laser beam to photopolymerise monomers. In this work polyethylene glycol diacrylate (PEGDA) was used as a monomer and diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide was used as a photo-initiator. 4-aminosalicylic acid (4-ASA) and paracetamol (acetaminophen) were selected as model drugs. Tablets were successfully printed and formulations with different properties were fabricated by adding polyethylene glycol 300 (PEG 300) to the printing solution. The loading of paracetamol and 4-ASA in the printed tablets was 5.69% and 5.40% respectively. In a realistic dynamic dissolution simulation of the gastrointestinal tract, drug release from the tablets was dependent on the composition of the formulations, but independent of dissolution pH. In conclusion SLA 3DP technology allows the manufacture of drug loaded tablets with specific extended-release profiles. In the future this technology could become a manufacturing technology for the elaboration of oral dosage forms, for industrial production or even for personalised dose. [ABSTRACT FROM AUTHOR]

As dry granulation as a continuous process becomes steadily more important, the interest of different materials and their processing is growing. Binders are of high importance as they have to compensate granule hardening, reduce the fines, and ensure adequate tablet tensile strengths. A simple formulation was used for roll compaction/dry granulation with subsequent tableting to produce granules and tablets, containing paracetamol (70% w/w), a filler and a binder (10%). With this formulation other influences were negligible and the influence of the binder was almost isolated. Eight different binders were compared with special attention to raw material properties. Six of them were cellulose based and two of them were based on povidone. Granule size distributions were typically bimodal. With the same method of preparation, large differences between the formulations occurred. The median particle size of granules differed from 200 μm, up to barely 700 μm. The larger the resulted particles, the higher was the tensile strength after tableting. Tablets with fine grades of HPC and copovidone achieved highest tensile strength exceeding 2.5 MPa at a compaction pressure of 350 MPa. Formulations with other binders were inferior, but mostly adequate. MCC performed insufficient and led to capping. [ABSTRACT FROM AUTHOR]

Mannitol is a frequently used diluent in the production of tablets due to its non-hygroscopic character and low drug interaction potential. Although the δ-polymorph of mannitol has superior tabletability in comparison to α- and β-mannitol, the latter are most commonly used because large-scale production of δ-mannitol is difficult. Therefore, a continuous method for production of δ-mannitol was developed in the current study. Spray drying an aqueous solution of mannitol and PVP in a ratio of 4:1 resulted in formation of δ-mannitol. The tabletability of a physical mixture of spray dried δ-mannitol with PVP (5%) and paracetamol (75%) was clearly superior to the tabletability of physical mixtures consisting of spray dried α- and β-mannitol with PVP (5%) and paracetamol (75%) which confirmed the excellent tableting properties of the δ-polymorph. In addition, a coprocessing method was applied to coat paracetamol crystals with δ-mannitol and PVP. The tabletability of the resulting coprocessed particles consisting of 5% PVP, 20% δ-mannitol and 75% paracetamol reached a maximal tensile strength of 2.1 MPa at a main compression pressure of 260 MPa. Moreover the friability of tablets compressed at 184 MPa was only 0.5%. This was attributed to the excellent compression properties of δ-mannitol and the coating of paracetamol crystals with δ-mannitol and PVP during coprocessing. [ABSTRACT FROM AUTHOR]

A new formulation method for solid dosage forms with drug loadings from 0.65 ± 0.03% to 39 ± 1% (w/w) of acetaminophen (APAP) as a model drug has been presented. The proposed method involves the production of highly-porous lactose with a BET surface area of 20 ± 1 m 2 /g as an excipient using a templating method and the incorporation of drug into the porous structure by adsorption from a solution of the drug in ethanol. Drug deposition inside the carrier particles, rather than being physically distributed between them, eliminated the potential drug/carrier segregation, which resulted in excellent blend uniformities with relative standard deviations of less than 3.5% for all drug formulations. The results of DSC and XRD tests have shown deposition of nanocrystals of APAP inside the nanopores of lactose due the nanoconfinement phenomenon. FTIR spectroscopy has revealed no interaction between the adsorbed drug and the surface of lactose. The final loaded lactose particles had large BET surface areas and high porosities, which significantly increased the crushing strengths of the produced tablets. In vitro release studies in phosphate buffer (pH 5.8) have shown an acceptable delivery performance of 85% APAP release within 7 minutes for loaded powders filled in gelatin capsules. [ABSTRACT FROM AUTHOR]

The structure of solid drug delivery systems has considerable influence on drug release behaviors from particles and granules and also impacts other properties relevant to release characteristics such as taste. In this study, lipid-based microspheres of acetaminophen were prepared to mask the undesirable taste of drug and therefore to identify the optimal formulation for drug release. Synchrotron radiation X-ray computed microtomography (SR-μCT) was used to investigate the fine structural architectures of microspheres non-destructively at different sampling times during drug release test, which were simultaneously determined to quantitatively correlate the structural data with drug release behaviors. The results demonstrated that the polymeric formulation component, namely, cationic polymethacrylate (Eudragit E100), was the key factor to mask the bitter taste of acetaminophen by inhibiting immediate drug release thereby reducing the interaction intensity of the bitter material with the oral cavity taste buds. The structure and morphology of the microspheres were found to be influenced by the shape and particle size of the drug, which was also an important factor for taste-masking performance. The quantitative analysis generated detailed structural information which was correlated well with drug release behaviors. Thus, SR-μCT has been proved as a powerful tool to investigate the fine microstructure of particles and provides a new approach in the design of particles for taste masking. [ABSTRACT FROM AUTHOR]

We report novel pharmaceutical cocrystal of a popular antipyretic drug paracetamol (PCA) with coformer 5-nitroisophhthalic acid (5NIP) to improve its tabletability. The cocrystal (PCA-5NIP at molar ratio of 1:1) was synthesized by solvent evaporation technique using methanol as solvent. The physicochemical properties of cocrystal were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), fourier transform infrared spectroscopy (FTIR), hot stage polarized microscopy (HSPM) and scanning electron microscopy (SEM). Stability of the cocrystal was assessed by storing them at 40 °C/75% RH for one month. Compared to PCA, the cocrystal displayed superior tableting performance. PCA-5NIP cocrystal showed a similar dissolution profile as compared to PCA and exhibited good stability. This study showed the utility of PCA-5NIP cocrystal for improving mechanical properties of PCA. [ABSTRACT FROM AUTHOR]

Novel orally disintegrating system based on multiparticulate form was developed, offering an alternative to encounter major issues in the design of dosage form for pediatric patients, i.e., the difficulty in swallowing large solid dosage form (tablet or capsule), and the requirement to cover a broad range of doses for different age groups. Microcrystalline cellulose-based pellets containing acetaminophen were prepared via extrusion/spheronization followed by freeze-drying. The in vitro disintegration behavior of these pellets was quantitatively measured with a texture analyzer. Mercury intrusion and gas adsorption techniques, scanning electron microscopy of pellet surface and cross-section were performed in order to characterize their internal porous structure. Pellets characteristics such as size distribution, sphericity, friability and drug release were also determined. The developing process was able to produce pellets containing high drug loading (25, 50 and up to 75%, w/w) with good sphericity (aspect ratio ∼1) and low friability. The pellets exhibited an instantaneous disintegration upon contact with water, which was indicated by two parameters: the disintegration onset was approximating to 0, and the disintegration time less than 5 s. The fast disintegration behavior is correlated with the pellet internal structure characterized by a capillary network with pore diameter varying from 0.1 to 10 μm. Such a structure not only ensured a rapid disintegration but it also offers to freeze-dried pellets adequate mechanical properties in comparison with conventional freeze-dried forms. Due to pellet disintegration, fast dissolution of acetaminophen was achieved, i.e., more than 90% of drug released within 15 min. This novel multiparticulate system offers novel age-appropriate dosage form for pediatric population owing to their facility of administration (fast disintegration) and dosing flexibility (divided and reduced-size solid form). [ABSTRACT FROM AUTHOR]

The influence of active pharmaceutical ingredient (API) hydrophobicity on continuous wet granulation was studied in twin screw granulation utilizing foamed binder delivery. The APIs examined were caffeine, acetaminophen, ibuprofen and griseofulvin and the drug load was maintained constant at 15 wt%. In order to understand the impact of these APIs on the granulation process, API and binder distribution, particle size, porosity, and fracture strength were analyzed on samples collected along the screw length. It was found that the API and binder distributions were uniform along the screws regardless of the hydrophobicity of the formulation, in contrast to literature results with liquid injection. The absence of de-mixing of the hydrophobic ingredient was hypothesized to be a result of the high spread-to-soak ratio of a foamed binder that ‘cages’ those particles within the mass of local hydrophilic solids. [ABSTRACT FROM AUTHOR]