Strength and morphology of solid bridges in dry granules of pharmaceutical powders

This is an experimental study of the tensile strength of solid bridges between primary particles comprising granules of lactose or mannitol. We report on two systems: granules prepared with ethanol granulating solutions, in which the base powders were at most sparingly soluble, and aqueous granulating solutions, in which the base powder solubility was large. Both systems were studied with and without hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (PVP) or surfactants (Triton-X100, sodium lauryl sulfate or polysorbate 80) added to the granulating solution. The interparticle bridge strength was determined from the granule crush strength with a simple model that assumes that solid bridges form by evaporation of solvent from liquid bridges that maintain their shape during drying.Lactose granules prepared with pure ethanol are very weak, with crush strength comparable to that predicted by JKR theory, consistent with its negligible solubility. Mannitol, which is sparingly soluble, forms granules with bridge strength similar to the theoretical (Griffith) strength of a pure mannitol. Addition of HPC or PVP to the granulating solution produces bridges with strength comparable to that of pure polymer films. In comparison, the behavior of granules prepared with aqueous granulating solutions was much more complex due to the high saturation concentration of base powder. Granules produced with pure water had bridge strength approximately 20% of the theoretical strength. Addition of HPC or PVP to lactose granules increased the bridge strength modestly, but the strength was much smaller than that of the corresponding pure polymer films. Addition of HPC to mannitol granules had little effect on bridge strength, while PVP reduced bridge strength by approximately 30%. Addition of surfactants to the granulating solution also reduced dry bridge strength. These results reflect the complex microstructure and resulting mechanical properties of dry bridges produced by coprecipitation of the sugars and polymers (or surfactants).     

Multi-stage crystallization for resolution of enantiomeric mixtures in a solid solution forming system

A systematic procedure for synthesizing the multi-stage crystallization process was developed for resolution of enantiomeric mixtures involving solid solutions in the crystalline phase. The model compound investigated was citalopram oxalate, which revealed a complete solid solution in the solid phase. The counter-current multi-stage batch crystallization was suggested to isolate the target enantiomer from enantiomerically enriched mixtures. The solid–liquid equilibria in the presence of a solvent and the distribution diagrams were quantified and used in designing the crystallization process and defining adequate processing conditions. Different flowsheet schemes were considered and compared with respect to the process performance. The design procedure was verified by the experimental separation of enantiomeric mixtures of citalopram.     

A mathematical model for lactose dissolution

Many users of lactose crystals have to dissolve the sugar before they can use it in processing. To date, the design of the vessels used to perform this operation has been carried out either on an ad hoc basis or based on past experience. There is therefore a need to define the system in terms of its rate-limiting steps so that appropriate design decisions can be made. Here the relevant literature on lactose dissolution is reviewed and the first-order reaction kinetics for the mutarotation of α-lactose to β-lactose are combined with the appropriate mass transfer equations to model the dissolution process. The resultant predictions are compared with experimental data.Three main mechanistic regions are identified: the first is when saturated solutions of lactose are required, the second is when lactose concentrations between the α-lactose solubility limit and saturated solutions are targeted and the third is when solutions below the α=lactose solubility limit are desired. The model, when modified to allow for the variation in α-lactose solubility with β-lactose concentration, has modelled successfully the first two regions, but fitted only poorly the region below the α-lactose solubility limit.     

Development of co-continuous structure in liquid crystalline polyester

We investigated liquid crystallization of liquid crystalline polyester BB-5 during isothermal annealing by digital high-fidelity microscope and light scattering. A liquid crystalline spherical domain having a radius of micrometers appeared by annealing at around 180 °C. The domain grew dendritically in all directions. Neighboring liquid crystalline regions coalesced and then interconnected. The interconnected structure changed to a co-continuous two-phase structure with increasing ordering of the liquid crystalline phase, and the interface between the liquid crystalline phase and the isotropic phase became smoother over time. Liquid crystallization stopped before volume filling the whole space, and the liquid crystalline phase and isotropic phase coexisted. The liquid crystalline region became narrower with an increase in the temperature of the liquid crystallization. Such structural development is different from the liquid-liquid phase separation via spinodal decomposition, and it may be attributed to the segregation of non-liquid crystallizable low molecular weight molecules from the growth front by fractionation of the molecular weight distribution during the liquid crystallization in terms of the instability of the diffusion-controlled interface.     

Manufacturing pharmaceutical granules: Is the granulation end-point a myth?

The moist agglomeration process by high-shear mixing/granulation, i.e. the wet massing, screening and subsequent drying is a wide spread but critical unit operation. Since for decades formulators are looking for the correct “end-point” of this important process, i.e. when do you need to stop massing or stop with the addition of granulating liquid? What is the correct amount of granulating liquid? A similar situation exists in case of the moist agglomeration in fluidized bed equipment. In the latter case the simultaneous drying of the still moist granules have to be taken into account. Recently a science-based virtual equipment simulator could be developed mimicking the granule size evolution in a fluidized bed granulator during the addition of granulating liquid. For the simultaneous drying the Mollier chart is used. With this virtual equipment simulator it is possible to simulate “crash situations”, i.e. by overwetting or by an incorrect use of the parameter setting. However the determination of the “end-point” depends only on the operator, who desires a certain granule size distribution and a well-defined final moisture content of the batch. Thus the existence of a process intrinsic “end-point” has to be questioned. The same situation can be reported in case of high-shear mixing/granulation based on many years of research. In fact nobody could clearly show the existence of an intrinsic “end-point”. However during the continuous addition of a granulating low viscous liquid a sudden increase in power consumption can be measured, which levels off. Such a measurement depends on the formulation and leads to an “early signal” not to the “end-point”. This signal can be used for a tight control of the granulation process and leads to a low batch to batch variability in the final granule size distribution. The latter is the goal of the PAT (Process Analytical Technology) Initiative emphasizing “Quality by Design”.     

Formation of porous poly(ethylene‐co‐vinyl alcohol) membrane via thermally induced phase separation

Crystalline poly(ethylene‐co‐vinyl alcohol) (EVOH) membranes were prepared by a thermally induced phase separation (TIPS) process. The diluents used were 1,3‐propanediol and 1,3‐butanediol. The dynamic crystallization temperature was determined by DSC measurement. No structure was detected by an optical microscope in the temperature region higher than the crystallization temperature. This means that porous membrane structures were formed by solid–liquid phase separation (polymer crystallization) rather than by liquid–liquid phase separation. The EVOH/butanediol system showed a higher dynamic crystallization temperature and equilibrium melting temperature than those of the EVOH/propanediol system. SEM observation showed that the sizes of the crystalline particles in the membranes depended on the polymer concentration, cooling rate, and kinds of diluents. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 79: 2449–2455, 2001     

Rheologically determined negative influence of increasing nucleating agent content on the crystallization of isotactic polypropylene

Dibenzylidene sorbitol (DBS) exists in the form of fibril and usually acts as an effective nucleating agent to facilitate crystallization of polyolefin during manufacturing. In this research, the isothermal crystallization of isotactic polypropylene (iPP) containing different amounts of DBS was followed by dynamic rheometry, and described upon a viewpoint of viscoelastic property evolution. Since the adopted temperatures within the entire sample preparation and characterization process were below the melting point of DBS, the DBS additives played a role of only solid nucleating agent, thus the possible effect of a changed miscibility between iPP and DBS on the viscoelastic properties as change of temperature could be ignored. Although saturation of nucleating iPP was observed at 0.1% DBS concentration, a negative influence with further increasing DBS content on the crystallization of iPP was determined for the first time via time sweep of G′ upon a single angular frequency and application of “inverse quenching” protocol within a wide range of angular frequency. Even more, a largely increased G′ and viscosity were observed in the melt as decreasing the temperature of iPP containing 0.1% DBS, suggesting a strong quasi-solid like behavior before iPP crystallization. A complement for well understanding the crystallization of iPP containing nucleating agent was discussed based on the formation of the DBS fibrils' network, the interfacial tension between crystalline/amorphous phase, and the consistency of crystallizing lamellae. Our study demonstrates clearly that the crystalline characteristic upon saturation of heterogeneous nucleating is difficult to be detected by traditional means, but could be followed reasonably by rheological measurements which is much sensitive to the microstructural changes.     

Solvent-free slack wax de-oiling—Physical limits

In order to get more knowledge about the fundamentals of solvent-free slack wax de-oiling by melt crystallization, investigations on multicomponent paraffin waxes have been performed, which included X-ray powder diffraction and optical microscopy. The tested neutral oil and medium slack waxes consisted mainly of n- and iso-paraffins with different chain lengths. The results suggest that only n-paraffins formed orthorhombic crystals at room temperature with c-axes corresponding to the average chain length of the paraffin waxes. The crystals were surrounded by less crystalline, rather amorphous, solid phase containing mainly iso-paraffins. The typical solid–solid transition of crystal lattice in neutral oil slack waxes from orthorhombic to hexagonal system at temperatures below melting point increases the mobility of the low melting components. This is the key for the applicability of the melt crystallization process. Investigations on sweating suggest a strong influence of the n-paraffins content on mechanical stability of crystal structures and on the separation efficiency of sweating.     

Degradation of nitric acid-treated bulk polyethylene

Summary The Selective removal of Chain Defects (branches, unsaturations) by nitric acid from melt crystallized polyethylene is examined with reference to the question of the distribution of defects between crystalline and amorphous domains. The results obtained using the IR methyl band at 1376 cm^–1 together with weight-loss measurements support the view that the majority of defects, which are situated in the non-crystalline regions, are selectively digested by the nitric acid attack. After removal of the non-crystalline phase the small remaining branch content located within the crystal cores confirms the levels of defect inclusion previously derived from unit cell expansion data.     

Binder liquid distribution during granulation process and its relationship to granule size distribution

The aim of this study is to characterize the impact of binder liquid distribution on granule properties during the wet granulation process. A new parameter, namely the binder liquid transfer coefficient, is used to characterize binder liquid distribution. The relationships between binder liquid distribution coefficient and granule size distribution are discussed. Granules are made of lactose alpha-monohydrate (97.5% w/w, d₅₀ = 31 μm) and polyvinylpyrrolidone (2.5% w/w, d₅₀ = 89 μm) and are manufactured in a Mi-Pro high shear mixer (Pro-C-epT, Belgium). Nigrosine is incorporated as a tracer in the binder liquid in order to detect its distribution in the granules during the process. The results show that the binder liquid is heterogeneously distributed at the beginning of the process whereas it tends to be evenly distributed in the powder during the process. The binder liquid transfer in granule classes obeys a first-order law and the binder liquid transfer coefficient appears to be related to operating conditions: high rotation speed, low liquid flow rate and low liquid viscosity favour the achievement of high liquid transfer coefficient. In addition, the higher the coefficient, the earlier the homogenization and the wider the granule mean diameters. Thus, granule size distribution can be controlled by the binder liquid distribution process. A binder liquid distribution mechanism is proposed, which makes it possible to discuss the influence of the operating parameters on the granule construction process.     

A thermally responsive, rigid, and reversible adhesive

In this paper we present the development of a unique self-adhesive material that, unlike conventional adhesives, maintains a high degree of rigidity at the “adhesive” state while possessing the ability to easily de-bond upon heating. Consequently, the material is both a rigid and a reversible adhesive. The material is an initially miscible blend of poly(?-caprolactone) (PCL) and diglycidyl ether of bisphenol-A/diaminodiphenylsulfone (DGEBA/DDS) epoxy, processed to a unique morphology via polymerization-induced phase separation (PIPS). The fully cured material features a biphasic, “bricks-and-mortar” morphology in which epoxy forms highly interconnected spheres (“bricks”) that interpenetrate with a continuous PCL matrix (“mortar”). When heated to melt the PCL phase (60 °C < T < 200 °C), the epoxy bricks remain rigid due to the high epoxy T_g (>200 °C) while PCL liquefies to become a melt adhesive. Moreover, the PCL liquid undergoes microscopic dilational flow to wet the sample surfaces due to its high volumetric expansion in excess to epoxy bricks expansion, a phenomenon we term “differential expansive bleeding” (DEB). Remarkably, the samples remain rigid at this state and their surfaces become covered by a thin layer of PCL now able to wet, and subsequently bond through cooling, to a variety of substrates. We observe high bonding strengths, which we attribute to a combination of good wetting and subsequent formation of a thin layer of crystalline PCL with high cohesive strength upon cooling. This adhesive layer can be melted again by heating (T > T_m) to easily de-bond and subsequent rebonding capacity was demonstrated, indicating repeated availability of PCL melt adhesive to the surface by the DEB mechanism.     

Parameterization of population balance models for polythermal auto seeded preferential crystallization of enantiomers

For analysis, design and model-based control of crystallization processes typically population balance models or reduced models derived therefrom are used. Usually the kinetic parameters in these models are determined analyzing measured concentration trajectories and/or particle size distributions using parameter estimation procedures. In the case of preferential crystallization of enantiomers the analysis of experiments is complex since there are two “competing” crystal populations. In this field often batch processes are performed using seeds of the desired enantiomer. Currently, it is in particular challenging to quantify and optimize a new concept: e.g. the so-called “auto seeded programmed polythermal preferential crystallization” (“as3pc” [Coquerel, G., Petit, M.-N., Bouaziz, R., 2000. Method of resolution of two enantiomers by crystallization. United States Patent, Patent number: 6,022,409]). In order to design and optimize this process the temperature dependent kinetic constants for crystal growth, nucleation and dissolution have to be known. In this work a reduced model for this auto seeded process is presented. The general identifiability of the model parameters is investigated along with some suggestions on how to reparameterize the kinetic terms involved. The values of the identified key parameters are estimated using conventional least square optimization using experimental data determined for the model system threonine/water. Parameter confidence and cross correlation are discussed and finally the model is validated using experiments not used for parameter estimation.     

Supercooling (ΔT) dependence of nano-nucleation of PE by SAXS and proposal of a new nucleation theory

Degree of supercooling (ΔT) dependence of nano-nucleation was studied by means of small angle X-ray scattering (SAXS) and a new nucleation theory was proposed. We obtained the ΔT dependence of size distribution f(N,t) directly, where N is number of particle and t is time, which concluded that the “induction period” of crystallization is not controlled by so called “spinodal decomposition” but by nucleation one. It clarified that the critical nano-nucleation mainly controls not only the steady nano-nucleation but also macro-crystallization experimentally as the zero-th approximation by using the newly obtained ΔT dependence of f(N,t) and nucleation rate (I) of macroscopic crystal obtained by means of optical microscope (OM). Time evolution of total free energy of nucleation of a huge closed system δG(t) was obtained experimentally for the first time, which clearly confirmed that nano-nucleation is the process where δG(t) passes through an activation barrier and reaches the most stable state by completion of melt-solid (crystal) phase transition due to well known “Ostwald ripening”. We proposed a new nucleation theory by introducing a “mass distribution function Q(N,t) ∝ Nf(N,t)”. We proposed a new basic equation of the mass conservation law, ∂Q(N,t)/∂t=−∂j(N,t)/∂N, where j(N,t) is net flow. This solved the serious problem in classical nucleation theory (CNT), where so called “fundamental kinetic equation” does not satisfy the mass conservation law. The coupling of our “real image” and correct theory will enable us to realize the ultimate structure and physical properties of materials, which should be a very interesting “fruit”.     

A “side-on” liquid crystalline polymer with the cholesterol moiety

Summary Starting from cholesterol a new type of liquid crystalline side-chain polymer is synthesized whose cholesterol moiety is attached laterally to the polymer backbone. Phase structure and phase transformation temperatures were determined, proving that the polymer forms a cholesteric phase and, according to previous results at side-on liquid crystalline polymers, no smectic phases exist.     

Unraveling the droplet drying characteristics of crystallization‐prone mannitol – experiments and modeling

Spray‐dried mannitol is a potential lactose replacement in pharmaceutical formulations, yet the drying behavior of individual mannitol droplets within the spray chamber has not been fully understood. This work explored the drying characteristics of mannitol by employing the reaction engineering approach (REA) in data analysis. A glass filament single droplet drying technique was used to monitor the changes in droplet temperature, mass, and diameter. The drying kinetics data obtained clearly demonstrated the droplet “wet‐bulb” period, the crust formation, and the crystallization phenomena. The master activation‐energy curves developed from REA modeling responded sensitively to varying drying temperatures, which could have led to different crystallization events. The deviation of these plots from the expected norms that do not encounter a phase change was used effectively to discern the physics involved. A REA kinetic model was proposed to assist in process optimization of large‐scale spray‐drying operations. © 2017 American Institute of Chemical Engineers AIChE J, 63: 1839–1852, 2017     

Sintering of fat crystal networks in oil during post-crystallization processes

Several foods contain semi-solid fats that consist of solid crystals dispersed in a liquid oil. In oil-continuous margarine, butter, and chocolate, fat crystals determine properties such as consistency, stability against oiling-out, and emulsion stability. Trends toward foods with less fat and/or less saturated fat create a need for understanding and controlling the properties of fat crystal dispersions. Fat crystals form a network in oil due to mutual adhesion. One source of strong adhesion is formation of solid bridges (sintering), which has been studied in this work through sedimentation and rheological experiments. Results indicate that sintering may be created by crystallization of a fat phase with a melting point between that of the oil and the crystal. Generally speaking, β′ crystals were sintered by β′ fat bridges, favored by rapid cooling, and β crystals by β fat bridges, favored by slow cooling. The existence of the same polymorphic form of the crystal and bridge indicated that solid bridges, rather than bridges formed by small crystal nuclei, were formed. A maximum in sintering ability for an optimal sintering fat concentration occurred due to competition between bridge formation and other crystallization processes. Some emulsifiers influenced the sintering process. For example, monooolein made it more pronounced, while technical lecithin had the opposite effect.     

Foam granulation: Liquid penetration or mechanical dispersion?

There have been significant advances in the understanding of wet granulation processes. Foam granulation is the latest development and an emerging area of interest for pharmaceutical manufacturing.Single foam penetration experiments were carried out on static powder beds, followed by short-nucleation experiments (where nuclei are formed by a nucleation-only mechanism) and full foam granulation experiments (where nucleation, growth and breakage are occurring simultaneously). All experiments were performed with lactose monohydrate powder using a 5 L high shear mixer–granulator. The foam penetration/dispersion behaviour was examined and the granule size distributions were investigated as a function of foam quality (83–97% FQ), impeller speed (105–515 rpm) and wet massing period (0–4 min).Nucleation in foam granulation is postulated to undergo either “foam drainage” or “mechanical dispersion” controlled mechanisms. For “foam drainage” mechanism, the foam penetrates the powder bed to form coarse and broad granule size distributions. For “mechanical dispersion” mechanism, the wetting and nucleation conditions are governed by the powder mixing conditions and similar granule size distributions are produced. Regardless of the mechanism, the initial wetting and nucleation behaviour controls the initial nuclei size distribution, and this initial distribution is retained in the final granule size distribution. This work demonstrated the critical importance of the nucleation and binder distribution in determining the granule size distributions for foam granulation process.     

Mobile amorphous phase fragility in semi-crystalline polymers: Comparison of PET and PLLA

PET and PLLA were cold crystallised at various times and the two polymers were studied by differential scanning calorimetry (DSC), dielectric spectroscopy (DS) and thermally stimulated depolarisation currents (TSDC). The crystalline, the amorphous and the rigid amorphous fraction were quantified. The percentage of rigid amorphous fraction is very large in semi-crystalline PET and very low in semi-crystalline PLLA. From DSC, DS and TSDC data, the values of the relaxation times of four samples were obtained above and below the glass transition. The “strong-fragile” glass former liquid concept was used and the fragility of polymers was obtained. The presence of the crystalline phase and of a rigid amorphous fraction does not significantly modify PLLA fragility parameters and the polymer remains “fragile”, while for PET the semi-crystalline material goes towards a “strong character”. The coupling between phases is much weaker in PLLA than in PET.     

Toughening mechanism of alumina-matrix ceramic composites with the addition of AlTiC master alloys and ZrO2

Titanium carbide and aluminium are introduced in alumina matrix in the form of AlTiC, which is a kind of master alloy. Alumina-matrix ceramic composites are prepared by using transient liquid phase and hot-press sintering. Significant improvements in mechanical properties have been attained due to the good toughening effect of AlTiC master alloys and ZrO₂. The microstructures and toughening mechanisms of the fabricated alumina-matrix ceramic materials are analysed using a scanning electron microscope, a transmission electron microscopy and an electron probe microanalysis, respectively. Results show that the microstructures of “intracrystalline shape” and “intercrystalline shape” are formed and “sublattice” exists in the composites, which may extend crack path and restrain intracrystalline failure, thus improving the fracture toughness of the composites.     

Investigation of the crystallization of m(LLDPE) under shear flow using rheo-optical techniques

Metallocene linear low density polyethylene (mLLDPE) crystallization under shear flow at different controlled shear rates was investigated experimentally between its quiescent crystallization temperature and its melting point temperature (T_m). The evolution of the material optical properties, including turbidity, birefringence and dichroism, was monitored following a temperature jump from a temperature much higher than T_m to a fixed crystallization temperature (T_c). These properties are discussed in terms of the evolution of the polymer semi-crystalline microstructure. In light of the optical properties evolution, the crystallization process can be split into three stages (i) incubation phase in which small (compared to the light wavelength) crystalline nuclei spread over the medium, (ii) isotropic crystallite growth phase and (iii) anisotropic crystallite growth phase. The optical properties evolution due the development of the crystallization is compared to that of the stress under the same thermo-mechanical conditions. It is observed that the optical properties are more sensitive than the stress to follow the crystalline development, in particular during the early stage of the process.