Generation of high drug loading amorphoussolid dispersions by Spray Drying
Poorly water-soluble drugs have steadily grown on the global pharmaceutical industry. The technological approach focused on rendering the drug amorphous to improve apparent solubility remains a challenge since amorphous state is metastable in nature with a potential to undergo recrystallization . In order to prevent this conversion, amorphous materials have been stabilized as solid dispersions using generally hydrophilic carriers for stabilization . An amorphoussolid dispersion (ASD) refers to drug–carrier systems in which the mechanism of drug dispersion is the key to understand its behavior. Such formulations impart an antiplasticizing effect on the amorphous compound yielding an increase in the glass transition temperature thereby reducing molecular mobility . However, in order to achieve adequate stabilization, solid dispersions are often produced with a relatively low drug load (<30 wt%) dispersed in the carrier at molecular level. The problem is that a low drug-loaded ASD requires a large dose to ensure therapeutic efficacy.
Faculty of Natural Sciences and Life, Abderrahmane-Mira University, Targua Ouzemmour road, 06000 Bejaia, Algeria
Abstract: The present work focused on the solubility enhancement of the poorly water-soluble anti-cancer agent camptothecin which, in its natural state, presents poor solubility inducing lack of activity with a marked toxicity. A new approach is adopted by using a ternary system including camptothecin (CPT) and cyclodextrins (CDs) dispersed in polyethylene glycol (PEG) 6000. Camptothecin solubility variations in the presence of α- CD, β-CD, γ-CD, hydroxypropyl-α-CD (HPα-CD), hydroxypropyl-β-CD (HPβ-CD), permethyl-β-CD (PMβ- CD) and sulfobutyl ether-β-CD (SBEβ-CD), were evaluated by Higuchi solubility experiments. In the second part, the most efficient camptothecin/β-CDs binary systems, mainly HPβ-CD and PMβ-CD, were dispersed in PEG 6000. In addition to a drug release and modeling evaluation, the CPT interactions with CDs and PEG 6000 to prepared the amorphoussolid dispersion in the binary and ternary systems were investigated by Fourier trans- formed infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermogravimetric analyses (TGA) and X-ray powder diffraction (XRPD). The results showed that HPβ-CD and PMβ-CD were the most efficient for camptothecin solubilization with highest apparent equilibrium constants. Dissolution studies showed that percentage of CPT alone after two hour in 0.1 M HCl medium, did not exceed 16%, whereas under the same conditions, CPT/PMβ-CD complex reached 76%. When dispersing the binary systems CPT/β-CDs in PEG 6000, the velocity and the percentage of CPT release were considerably improved whatever the CD used, reaching the same value of 85%. The binary and ternary systems characterization demonstrated that CPT inclused into the CDs cavity, replacing the water molecules. Furthermore, a drug transition from crystalline to amorphous form was obtained when solid dispersion is realized. The present work demonstrated that ternary complexes are promising systems for CPT encapsulation, and offer opportunities to use non toxic and com- monly solubilizing carriers: βCD and PEG 6000 to improve bioavailability.
A B S T R A C T
Amorphoussolid dispersions (ASDs) are found to be a well-established strategy for overcoming limited aqueous solubility and poor oral bioavailability of active pharmaceutical ingredients (APIs). One of the main parameters aﬀecting ASDs physical stability is the API solubility in the carrier, because this value determines the maximal API load without a risk of phase separation and recrystallization. Phase-diagrams can be experimentally obtained by following the recrystallization of the API from a supersaturated homogeneous API-polymer solid solution, commonly produced by processes as solvent casting or comilling, which are very time-consuming (hours). The work deals with the construction of a temperature-composition EFV-Soluplus® phase diagram, from a thermal study of recrystallization of a supersaturated solid solution (85 wt% in EFV) generated by spray drying. This supersaturated solution is kept at a given annealing temperature to reach the equilibrium state and the amount that still remains dispersed in the polymer carrier at this equilibrium temperature is determined by means of the new glass transition temperature of the binary mixture. From our knowledge, this is the ﬁrst study employing a fast process (spray drying) to prepare a supersaturated solid solution of an API in a polymer aiming to determine a temperature-composition phase diagram. The EFV solubility in Soluplus ranges from 20 wt% at 25 °C to 30 wt % at 40 °C. It can be a very useful preformulation tool for researchers studying amorphoussolid dispersions of Efavirenz in Soluplus, to assist for predicting the stability of EFV-Soluplus ASDs at diﬀerent EFV loadings and under diﬀerent thermal conditions.
Here we approach the problem in a different way. In one of the first works on supersolidity, Leggett showed how one can derive an upper bound for the fraction of su- perfluid density of a generic many-body system in which translational invariance is broken, by means of a varia- tional computation . The output of Leggett’s compu- tation is a formula that needs as only input the average density profile of the solid. This formula has been ap- plied to Helium crystals, and the aim of this work is to use it to study the amorphoussolid. At present, there is not yet any reliable first principle computation or experi- mental measurements of the density profile of amorphous Helium 4. We endeavor to generate robust estimates of it using a number of different techniques, in particular by investigating a model of zero-point Gaussian fluctuations around classical configurations, and PIMC simulations without exchange (which should be closer to the classical dynamics). Checking whether these techniques all give roughly similar orders for the bound is a way to assess the robustness of our result. In the following, we will denote the fraction of superfluid density by “superfluid fraction” and we always refer to Leggett’s upper bound to this quantity, unless otherwise specified.
DOI: 10.1103/PhysRevLett.89.195506 PACS numbers: 62.20.Fe, 61.43.-j
In contrast with crystalline solids, amorphous mate- rials display a plasticity which cannot be attributed to the motion of well identified defects such as dislocations. Consequently, the microscopic description of amorphous plasticity still lacks a consistent framework. Recent stud- ies [1– 4] have focused on the fact that global plastic deformation is mostly due to local rearrangements. Starting from a molecular dynamics study of a bidimen- sional Lennard-Jones glass and measurements of the mechanical response under shear stress, Falk and Langer  introduced ‘‘shear transformation zones’’ hav- ing a bistable character to build a mean field theory of plastic deformation in an amorphous material. Initially applied by Bulatov and Argon [2 – 4] for amorphoussolid materials, this approach can be extended to granular materials or dense suspensions [5,6].
The formation of magnesium silicate is instantaneous. The synthesis length depends on the addition mode (from few minutes with the mixing system to one hour and half with the slow addition). The amorphoussolid obtained is made up of two kinds of agglomerates (primary and secondary). The size distributions are very dependent on mixing conditions and reactants’ concentrations. The parallel addition with mixing system would enable to synthesize the product made up of smaller particles and agglomerates. Moreover, low concentrations and ultrasound used during the synthesis would enable to synthesize smaller particles too. The measured smallest size is about 4 µm but it should be agglomerates size. Primary particles size is difficult to estimate but it would be about 100 nm. A study perspective is to make product disaggregation in the polymer easy and to “release” small primary particles in order to reach the objective size. Moreover by decreasing reactants’ concentrations, synthetic product is less compact. The dried product disperses best in polar solvents. The product appears to be hydrophilic.
This work has shown that strain induces a history- dependent polarization of local yield thresholds in an amorphoussolid under AQS shear. The Bauschinger ef- fect then appears to arise because the backward-yielding barrier distribution vanishes only (and quasilinearly) at threshold, so that unloading causes reverse plasticity of growing amplitude (i.e. softening), jointly with the emer- gence of a pseudogap in the forward barrier distribution, guaranteeing nearly elastic reloading. Although we used a 2D model, we expect these conclusions to carry over to 3D since our main qualitative results (forward-reverse symmetry breaking, and presence of near-threshold re- verse barriers) are not dimension dependent.
Phase equilibrium has been studied for many process design problems. We have noted its potential use in product design problems in fat systems within a CAM b D framework as it is possible to model
solid-liquid equilibrium in triacylglycerol mixtures. This approach can allow a thermodynamic approach for computer solid fat content and melting range in edible fat products, substituting classical empirical calculations and allowing mixtures development in a Computer Aided Mixture and Blend Design environment for structured lipids. Solid-liquid equilibrium for TAG systems has therefore a scientifically and technological importance.
The present work, although it does not and cannot solve all these issues, brings hope that they can be addressed rigorously in the near future. It will not alleviate the need to rely on simplifying assumptions, and neither is it intended to provide a recipe for the construction of mesoscopic model—a still distant goal. But it probes the rejuvenation process of atomic- scale yield stresses in a model glass undergoing deformation. Thus, it brings direct observations that strongly constrain both model assumptions, especially about the effect of re- juvenation, and model predictions concerning the dynamics of local thresholds. Thanks to the focus on a system un- dergoing shear banding, i.e., comprising quite different local packings, we could demonstrate that there was indeed a well- defined postyield yield stress distribution, quite insensitive to the initial ensemble, and we could access it numerically. This is evidently a key input for theories of amorphous plasticity.
not allow a more thermodynamically stable state to be found during the final quenching process, limited aging proceeds, and the T c value is shifted to a lower temperature (Fig. 2(a)).
The levels of aging and rejuvenation are relative quantities and depend on the choice of reference amorphous state. Thus, if we choose a perfectly rejuvenated amorphous state as the reference amorphous state, which is supposedly constructed through melt quenching at an infinitely fast cooling rate, then fur- ther rejuvenation will not occur. In reality, however, it is impossible to realize such a perfectly rejuvenated state; even though a near-perfectly rejuvenated state can be realized, we would not be able to observe it because of the extremely short lifetime of the highly excited state. For this reason, the discussions above are valid for actual glass systems in general, in which both aging and rejuvenation can be realized.
As it was revealed in  and is shown on Figure 4.26, the short quadrupolar kernel features localization, the emerging shear bands are however short, and by no means they percolate through the system. On the other hand, for the long range kernels shear bands are long. While percolating shear bands are soft modes of the short quadrupolar kernel, the short range nature of the interaction just does not allow for them to develop entirely. This observation helps clarifying the mystery between the similarities of scaling properties, in particular, avalanche distributions between line depinning (τ = 1.25) and plasticity (τ = 1.3): both for the long range quadrupolar and dipolar kernels most of the activity happens along narrow bands. In the depinning pictures this scenario indeed corresponds to the propagation of a one dimensional line in a random landscape. Of course, eventually the activity moves to other bands, thus the collective eﬀect of these loosely coupled bands may be at the origin of the discrepancies. With that in mind, the considerable diﬀerence in the scaling properties of the short range quadrupolar kernel arises from the diﬀerent localization it exhibits. Soft modes are thus necessary, but not enough to reproduce scaling properties of amorphous plasticity: a long range kernel is indeed necessary.
 and molecular dynamics  , the cooperativity of the alpha relaxation process has been particularly investigated when the relaxation dynamics of the amorphous phase are modi ﬁed by orientation  , crystallization  , or even plasticization  . However, the impact of several microstructural modi ﬁcations on the amorphous phase dynamics remains unknown. For example, as illustrated by several authors [18 e20] , given conditions for drawing or thermal crystallization may induce the development of an in- termediate ordering structure called a mesophase which pre ﬁgures the crystallization. The observation of the mesophase is generally reported for semi-crystalline materials [18 e22] for which crystals strongly impact the investigation of the molecular mobility. Consequently, no study deals with the impact alone of the meso- phase on the molecular dynamics of the amorphous phase. One of the challenges to carry out such a study lies in obtaining a unique microstructure where the mesophase is only dispersed in the ori- ented amorphous phase, without the presence of crystals. In the current study, we propose to electrospin polylactide (PLA) ﬁbers to create this speci ﬁc microstructure. Electrospinning is a simple technique to implement in order to produce polymer ﬁbers with diameters ranging from the micro-to the nanoscale [23 e25] . The technique has emerged as a useful technique to produce micro- and nano- ﬁbers that have found wide applications in ﬁelds such as tissue engineering  , biomedical  , ﬁltration  , or elec- tronic  . Despite the simplicity of the technique, many factors in ﬂuence the ﬁber morphology including the solution ﬂow rate, the distance between the syringe and the collector, solution concen- tration and the spinning voltage among others. In addition, very complex processes are involved that in ﬂuences the ﬁber structure including the very rapid solvent evaporation as well as the me- chanical and electrical forces which
pre-buckling as well as unstable buckling behavior. The material behavior is considered isotropic, linearly elastic for the six test problems.
The developed element is compared to the Abaqus linear shell element S4R5; this should be the most appropriate Abaqus linear element for the selected tests as shown in a recent study by Leahu-Aluas et al. . Then, one of the most accurate Abaqus linear solid elements, denoted C3D8I, is also used for comparison purposes, since it shares with the SHB8PS element the same three-dimensional geometry. Finally, the solid–shell element SC8R is also investigated. It is noteworthy that the latter element has been only recently introduced in this commercial software and it has not been specifically designed for buckling applications. The main features of the Abaqus elements used for comparison are summarized in Table 1. The SHB8PS characteristics have been briefly described in Section 2: this is an eight-node hexahedron with three displacement degrees of freedom per node and it is provided with a physical stabilization scheme. Also, the SHB8PS employs 1 n × int integration points (i.e., one single in-plane integration point, and n points through the int
reaction. Our method may be applied to further distinguish the difference.
Besides the fast diffusion of solid-state lithium ions (polarons) along the  channels, 35, 39-41 the de- wetting of lithium ions from the largest and most active (010) facet of FePO 4 particles to lower the surface energy 36, 46 implies that constant low concentration of intercalated lithium is maintained at the interface. We conclude that small variations of the concentrations in the logarithm term should not cause significant voltage change, 2, 27 consistent with the success of our reaction-limited model. Voltage fluctuations due to the contact resistance are also negligible. The contact resistances of the coin cells measured by
process, supported by TEM observations of crystal nucleation and growth on the spherules of ACP  . It has been suggested, based on ionic products in the solution, that at neutral pH OCP is ﬁrst formed, which is then converted to apatite through a topotactic reaction. This process is in accordance with the Ostwald’s step rule. At alkaline pH, however, the conversion of ATCP leads directly to hydroxylated apatite. The OCP intermediate phase does not seem to have been identiﬁed under all conversion conditions. This mech- anism supposes a change in the Ca/P ratio of the solid, which has to be compensated for either by a change in the Ca/P ratio of the solu- tion (an increased Ca/P ratio relative to the 1.5 initial value) or the simultaneous formation of another solid phase with a higher Ca/P ratio, which could be apatite, however, this phase, which is ther- modynamically more stable than OCP, would be favoured. Analy- ses of the solution at the beginning of conversion generally led to higher Ca/P ratios, in part supporting this mechanism.
Thick amorphous PEEK films (250 µ m) were purchased. Films were characterized in the as received condition and after 24h drying.
Amorphization level was checked by wide angle X-ray scattering, using a Philips PW 1700 in reflection mode with CuK.. radiation. The crystalline degree was calculated by integrating the area of the narrow peaks on the halo region of the amorphous phase.
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