The Increase in the Plasticity of Microcrystalline Cellulose Spheres' When Loaded with a Plasticizer.

Compaction pressure can induce an undesirable solid-state polymorphic transition in drugs, fragmentation, loss of coated pellet integrity, and the decreased viability and vitality of microorganisms. Thus, the excipients with increased plasticity can be considered as an option to decrease the undesirable effects of compaction pressure. This study aims to increase the plasticity (to reduce the mean yield pressure; Py) of dried microcrystalline cellulose (MCC) by loading it with a specially selected plasticizer. Diethyl citrate (DEC), water, and glycerol were the considered plasticizers. Computation of solubility parameters was used to predict the miscibility of MCC with plasticizers (possible plasticization effect). Plasticizer-loaded MCC spheres with 5.0 wt.% of water, 5.2 wt.% of DEC, and 4.2 wt.% glycerol were obtained via the solvent method, followed by solvent evaporation. Plasticizer-loaded formulations were characterised by TGA, DSC, pXRD, FTIR, pressure-displacement profiles, and in-die Heckel plots. Py was derived from the in-die Heckel analysis and was used as a plasticity parameter. In comparison with non-plasticized MCC (Py = 136.5 MPa), the plasticity of plasticizer-loaded formulations increased (and Py decreased) from DEC (124.7 MPa) to water (106.6 MPa) and glycerol (99.9 MPa), and that was in full accordance with the predicted miscibility likeliness order based on solubility parameters. Therefore, water and glycerol were able to decrease the Py of non-plasticized MCC spheres by 16.3 and 30.0%, respectively. This feasibility study showed the possibility of modifying the plasticity of MCC by loading it with a specially selected plasticizer.

Mechanical approach for the evaluation of the crispiness of food granular products.

Crispiness of food products is a key parameter for consumer acceptance. Available methods to evaluate this attribute are subjective and have limitations. They are particularly difficult to implement when granular products are considered. The present study aims to provide a physical characterization of the crispiness of food granular products (gari and grinded corn flakes) based on the compression cycle modeling and the determination of the Py (yield pressure) parameter of the Heckel model. High Py values attributed to the brittle behavior, are indicative of product crispiness. Furthermore, Py parameter showed sensitivity to the plasticizing effect of water. This developed physical method was validated through sensory analysis and acoustic measurements which are both considered as reference methods for crispiness evaluation. The brittle/plastic behavior attributed to crispy/non crispy products respectively was confirmed through image analysis using X-ray microcomputed tomography. The latter made it possible to distinguish the brittle from the plastic behavior through the particle size distribution evolution. This work suggests that the Py value is a relevant indicator for the crispiness evaluation of granular products. This physical characterization is expected to contribute in food engineering as an alternative method for granular products crispiness in a simpler and a more objective way.

Compression Modulus and Apparent Density of Polymeric Excipients during Compression-Impact on Tabletability.

The present study focuses on the compaction behavior of polymeric excipients during compression in comparison to nonpolymeric excipients and its consequences on commonly used Heckel analysis. Compression analysis at compaction pressures (CPs) from 50 to 500 MPa was performed using a compaction simulator. This study demonstrates that the particle density, measured via helium pycnometer (ρpar), of polymeric excipients (Kollidon®VA64, Soluplus®, AQOAT®AS-MMP, Starch1500®, Avicel®PH101) was already exceeded at low CPs (<200 MPa), whereas the ρpar was either never reached for brittle fillers such as DI-CAFOS®A60 and tricalcium citrate or exceeded at CPs above 350 MPa (FlowLac®100, Pearlitol®100SD). We hypothesized that the threshold for exceeding ρpar is linked with predominantly elastic deformation. This was confirmed by the start of linear increase in elastic recovery in-die (ERin-die) with exceeding particle density, and in addition, by the applicability in calculating the elastic modulus via the equation of the linear increase in ERin-die. Last, the evaluation of "density under pressure" as an alternative to the ρpar for Heckel analysis showed comparable conclusions for compression behavior based on the calculated yield pressures. However, the applicability of Heckel analysis for polymeric excipients was questioned in principle. In conclusion, the knowledge of the threshold provides guidance for the selection of suitable excipients in the formulation development to mitigate the risk of tablet defects related to stored elastic energy, such as capping and lamination.

Molecular Understanding and Implication of Structural Integrity in the Deformation Behavior of Binary Drug-Drug Eutectic Systems.

In eutectic, a lamellar microstructure offers better tableting than that of the nonreacted physical mixture. However, bulk deformation remains elusive in two binary eutectics. We hypothesized that the binary eutectic of a drug with different components, having different H-bonding dimensionalities and crystal structure, shall allow the understanding of the structural integrity in the bulk deformation behavior. The shearing molecular solid (FXT Q) shared a common composition with the viscoelastic crystal (ASP I) and brittle (PCM I), forming EM-1 (ϕ1 = 41.27:58.73% w/w) and EM-2 (ϕ2 = 41.10:58.90% w/w), respectively. The excess thermodynamic functions were contributed by high energy microstructures (nonbonding interactions) along incoherent phase boundaries (visualized under CLSM). The energy dispersive analysis enabled the recognition of the relative distribution of higher atoms over the heterogeneous surface. EM-1 (FXT Q-ASP I) demonstrated higher compressibility, tensile strength, and compactibility (CTC profile) compared to those of EM-2 (FXT Q-PCM I) over a range of applied compaction pressures. The lower true yield strength (σ0(EM-1) = 138.66 MPa) of EM-1 as compared to that of EM-2 (σ0(EM-2) = 166.66 MPa) suggested a better deformation performance and incipient plasticity quantified from the "out-of-die" Heckel analysis. From Ryshkewitch analysis, the tensile strength at zero porosity (τ01 = 3.83 MPa) was predicted to be higher for EM-1 than EM-2 (τ02 = 2.54 MPa). The higher bonding strength of EM-1 was contributed to the additional influence of true density and isotropic van der Waals interactions of ASP I (0D). In contrast, EM-2 demonstrated lower compressibility and compactibility, having herringbone molecular packing of PCM I (1D) with a common shearing component (FXT Q (1D)). This study confirmed that the intrinsic deformational and chemical nature of the second component defined the compressibility and compactibility tendency to a greater extent in the tableting performance of conglomerates of crystalline solid solution.

A hybrid approach to predict the relationship between tablet tensile strength and compaction pressure using analytical powder compression.

The objective was to present a hybrid approach to predict the strength-pressure relationship (SPR) of tablets using common compression parameters and a single measurement of tablet tensile strength. Experimental SPR were derived for six pharmaceutical powders with brittle and ductile properties and compared to predicted SPR based on a three-stage approach. The prediction was based on the Kawakita b-1 parameter and the in-die Heckel yield stress, an estimate of maximal tensile strength, and a parameter proportionality factor α. Three values of α were used to investigate the influence of the parameter on the SPR. The experimental SPR could satisfactorily be described by the three stage model, however for sodium bicarbonate the tensile strength plateau could not be observed experimentally. The shape of the predicted SPR was to a minor extent influenced by the Kawakita b-1 but the width of the linear region was highly influenced by α. An increased α increased the width of the linear region and thus also the maximal predicted tablet tensile strength. Furthermore, the correspondence between experimental and predicted SPR was influenced by the α value and satisfactory predictions were in general obtained for α = 4.1 indicating the predictive potential of the hybrid approach.

Increased yield pressure in the anal canal during sacral nerve stimulation: a pilot study with the functional lumen imaging probe.

BACKGROUND: Sacral nerve stimulation (SNS) is a well-established treatment for fecal incontinence but its mode of action remains obscure. Anal sphincter function is usually evaluated with manometry but resistance to distension may be a more appropriate parameter than luminal pressure. The functional lumen imaging probe allows detailed description of distension properties of the anal canal. Our objective in this study was to characterize the impact of SNS on distension properties of the anal canal in patients with idiopathic fecal incontinence. METHODS: We studied 10 women (median age 64 [44-79] years) with idiopathic fecal incontinence at baseline and during SNS. The luminal geometry of the anal canal was examined with the FLIP at rest and during squeeze and the distensibility of the anal canal was investigated during filling of the bag. KEY RESULTS: All patients were successfully treated with SNS and the mean Wexner Incontinence Score was reduced from 14.9 ± 4 to 7.1 ± 4.8 (P<.001). The pressure required to open the narrowest point of the anal canal during distension (yield pressure) increased from 14.5 ± 12.2 mmHg at baseline to 20.5 ± 13.3 mmHg during SNS (P<.01). The pressure-strain elastic modulus increased non-significantly from 2.2 ± 0.5 to 2.9 ± 1.6 kPa, indicating increased stiffness of the anal canal. CONCLUSION AND INFERENCES: The yield pressure and the resistance to distension increased in response to SNS for idiopathic fecal incontinence. This will inevitably increase the resistance to flow through the anal canal, which may contribute to the benefits of sacral nerve stimulation.

Powder compression mechanics of spray-dried lactose nanocomposites.

The aim of this study was to investigate the structural impact of the nanofiller incorporation on the powder compression mechanics of spray-dried lactose. The lactose was co-spray-dried with three different nanofillers, that is, cellulose nanocrystals, sodium montmorillonite and fumed silica, which led to lower micron-sized nanocomposite particles with varying structure and morphology. The powder compression mechanics of the nanocomposites and physical mixtures of the neat spray-dried components were evaluated by a rational evaluation method with compression analysis as a tool, using the Kawakita equation and the Shapiro-Konopicky-Heckel equation. Particle rearrangement dominated the initial compression profiles due to the small particle size of the materials. The strong contribution of particle rearrangement in the materials with fumed silica continued throughout the whole compression profile, which prohibited an in-depth material characterization. However, the lactose/cellulose nanocrystals and the lactose/sodium montmorillonite nanocomposites demonstrated high yield pressure compared with the physical mixtures indicating increased particle hardness upon composite formation. This increase has likely to do with a reinforcement of the nanocomposite particles by skeleton formation of the nanoparticles. In summary, the rational evaluation of mechanical properties done by applying powder compression analysis proved to be a valuable tool for mechanical evaluation for this type of spray-dried composite materials, unless they demonstrate particle rearrangement throughout the whole compression profile.

Compaction behavior and deformation mechanism of directly compressible textured mannitol in a rotary tablet press simulator.

Textured mannitol powder is widely used as a pharmaceutical excipient for tablet compaction. In order to choose the right tableting parameters, it is necessary to understand its mechanical behavior during deformation under industrial tableting conditions. The aim of this study was to evaluate the mechanical behavior during deformation of a textured mannitol using a rotary tablet press simulator. Mean yield pressure (Py) obtained by Heckel modeling, Walker coefficients (W) and Stress Rate Sensitivity (SRS) were compared to reference excipients, known for either their plastic (microcrystalline cellulose) or fragmentary (lactose and dibasic calcium phosphate) deformation behavior. Py, W and SRS values showed that the studied textured mannitol has a fragmentary deformation mechanism. Furthermore, this mechanical behavior was not sensitive to lubrication, which is characteristic of fragmentary excipients.

Use of in-die powder densification parameters in the implementation of process analytical technologies for tablet production on industrial scale.

The use of process analytical technologies (PAT) to ensure final product quality is by now a well established practice in pharmaceutical industry. To date, most of the efforts in this field have focused on development of analytical methods using spectroscopic techniques (i.e., NIR, Raman, etc.). This work evaluated the possibility of using the parameters derived from the processing of in-line raw compaction data (the forces and displacement of the punches) as a PAT tool for controlling the tableting process. To reach this goal, two commercially available formulations were used, changing the quantitative composition and compressing them on a fully instrumented rotary pressing machine. The Heckel yield pressure and the compaction energies, together with the tablets hardness and compaction pressure, were selected and evaluated as discriminating parameters in all the prepared formulations. The apparent yield pressure, as shown in the obtained results, has the necessary sensitivity to be effectively included in a PAT strategy to monitor the tableting process. Additional investigations were performed to understand the criticalities and the mechanisms beyond this performing parameter and the associated implications. Specifically, it was discovered that the efficiency of the apparent yield pressure depends on the nominal drug title, the drug densification mechanism and the error in pycnometric density. In this study, the potential of using some parameters derived from the compaction raw data has been demonstrated to be an attractive alternative and complementary method to the well established spectroscopic techniques to monitor and control the tableting process. The compaction data monitoring method is also easy to set up and very cost effective.

Monitor de pressão e volume gástricos: estudo experimental em suínos / Monitor pressure and gastric volume: an experimental study in pigs

The gastric pressure monitor was developed by the Biomedical Engineering Div. of the HCPA. It helps to evaluate Gastric Yield Pressure (GYP) in a swine model for gastroesophageal reflux (GER). A dual lumen 20 Fr Foley catheter is passed through a gastrostomy into the swine stomach...