EVA implants for controlled drug delivery to the inner ear.

This study evaluated the potential of poly(ethylene vinyl acetate) (EVA) copolymers as matrix formers in miniaturised implants, allowing to achieve controlled drug delivery into the inner ear. Due to the blood-cochlea barrier, it is impossible to reliably deliver a drug to this tiny and highly sensitive organ in clinical practice. To overcome this bottleneck, different EVA implants were prepared by hot melt extrusion, altering the vinyl acetate content and implant diameter.

Bosentan monohydrate and sildenafil base as two companions in enabling formulations.

Hypothesis: Sildenafil base and bosentan monohydrate are co-administered in a chronic therapy of pulmonary arterial hypertension (PAH). Both drugs are poorly soluble in water, and their bioavailability is limited to ca. 50 %.

In-situ forming PLGA implants: Towards less toxic solvents.

In-situ forming poly(lactic-co-glycolic acid) (PLGA) implants offer a great potential for controlled drug delivery for a variety of applications, e.g. periodontitis treatment.

Drug release from PLGA microparticles can be slowed down by a surrounding hydrogel.

This study aimed to evaluate and better understand the potential impact that a layer of surrounding hydrogel (mimicking living tissue) can have on the drug release from PLGA microparticles. Ibuprofen-loaded microparticles were prepared with an emulsion solvent extraction/evaporation method. The drug loading was about 48%.

Exploration of the physical states of riboflavin (free base) by mechanical milling.

Amorphous riboflavin (free base) could be produced for the first time via high energy ball milling of a commercial crystalline form (Form I). Importantly, this solid state amorphization process allowed to circumvent chemical degradation occurring during melting as well as the lack of suitable solvents, which are required for amorphization via spray- or freeze-drying. The amorphous state of riboflavin was thoroughly characterized, revealing a complex recrystallization pattern upon heating, involving two enantiotropic polymorphic forms (II and III) and a dihydrate.

Analysis of the Dissolution Mechanism of Drugs into Polymers: The Case of the PVP/Sulindac System.

This paper is dealing with the dissolution mechanism of crystalline sulindac into amorphous Polyvinylpyrrolidone (PVP) upon heating and annealing at high temperatures. Special attention is paid on the diffusion mechanism of drug molecules in the polymer which leads to a homogeneous amorphous solid dispersion of the two components. The results show that isothermal dissolution proceeds through the growth of polymer zones saturated by the drug, and not by a progressive increase in the uniform drug concentration in the whole polymer matrix.

High energy ball milling vs. nano spray drying in the development of supersaturated systems loaded with bosentan.

In this study, high energy ball milling and nano spray drying were used to prepare amorphous solid dispersions of bosentan in copovidone for the first time. In particular, the impact of this polymer on the bosentan amorphization kinetics was investigated. Copovidone was shown to facilitate the amorphization of bosentan upon ball milling.

Silicone matrices for controlled dexamethasone release: toward a better understanding of the underlying mass transport mechanisms.

Dexamethasone-loaded silicone matrices offer an interesting potential as innovative drug delivery systems, e.g. for the treatment of inner ear diseases or for pacemakers.

Long term behavior of dexamethasone-loaded cochlear implants: In vitro & in vivo.

The aim of this study was to better understand the long term behavior of silicone-based cochlear implants loaded with dexamethasone: in vitro as well as in vivo (gerbils). This type of local controlled drug delivery systems offers an interesting potential for the treatment of hearing loss. Because very long release periods are targeted (several years/decades), product optimization is highly challenging.

The melting of glucose.

Several sugars are known to undergo a spontaneous liquefaction below their reputed melting point (T), but the origin of this apparent melting is not yet clearly understood. In this paper we address this puzzling behavior in the particular case of the crystalline forms of glucose: Gα and Gβ, involving respectively the glucose-α and glucose-β anomers. We show in particular that the spontaneous melting below their reputed melting point T (∼151 °C for Gα and ∼156 °C for Gβ) corresponds to a horizontal displacement of the system in the eutectic phase diagram of the anomeric mixture glucose-α / glucose-β.

Evidence of transient amorphization during the polymorphic transformation of sorbitol induced by milling.

In this paper, we show that the polymorphic transformation γ → α of sorbitol upon milling involves a transient amorphization of the material. This could be done by comilling sorbitol with a high Tg amorphous material (Hydrochlorothiazide, Tg = 115 °C) to stabilize any transient amorphous fractions of sorbitol through the formation of a molecular alloy. The results indicate that for large sorbitol concentration (50%), the comilling leads to a heterogeneous mixture made of sorbitol crystallites in the form α embedded into an amorphous molecular alloy sorbitol / HCT.

Thinking of bosentan repurposing - A study on dehydration and amorphization.

New clinical indications for an orphan drug bosentan are prompting the improvement of the drug formulation. Since bosentan is available as monohydrate, the information on its anhydrous form together with the assessment of its glass forming ability is necessary when developing enabling formulations. The aim of this research was, therefore, to analyze the phenomena occurring upon dehydration and amorphization of bosentan.

Structure determination of riboflavin by synchrotron high-resolution powder X-ray diffraction.

The crystal structure of the stable form of vitamin B2 or riboflavin (CHNO) was solved using high-resolution powder X-ray diffraction (PXRD). The high-resolution PXRD pattern of riboflavin was recorded at room temperature at the European Synchrotron Radiation Facility (Grenoble, France). The starting structural model was generated using a Monte Carlo simulated annealing method.

Dexamethasone-loaded cochlear implants: How to provide a desired "burst release".

Cochlear implants containing iridium platinum electrodes are used to transmit electrical signals into the inner ear of patients suffering from severe or profound deafness without valuable benefit from conventional hearing aids. However, their placement is invasive and can cause trauma as well as local inflammation, harming remaining hair cells or other inner ear cells. As foreign bodies, the implants also induce fibrosis, resulting in a less efficient conduction of the electrical signals and, thus, potentially decreased system performance.

Kinetics and mechanism of polymorphic transformation of sorbitol under mechanical milling.

In this paper, we present a kinetic investigation of the polymorphic transformation γ → α of sorbitol under milling in the objective to identify the microscopic mechanisms that govern this type of solid-state transformation. The milling was performed with a high energy planetary mill and the milled material was analysed by DSC, PXRD and Raman spectrometry. The transformation kinetics was found to be sigmoidal with a noticeable incubation time.

Contribution of low-frequency Raman spectroscopy to determine the solubility curves of drugs in polymers: The case of paracetamol/PVP.

A new method for determining solubility lines of drugs in polymers, based on low-frequency Raman spectroscopy measurements, is described and the results obtained by this method are compared with those obtained using a more classical method based on differential scanning calorimetry investigations. This method was applied to the paracetamol/PVP system using molecular and crystalline dispersions (MCD) rather than usual physical mixtures to reach faster the equilibrium saturated states and make the determination of the solubility line more rapid.

Mechanistic explanation of the (up to) 3 release phases of PLGA microparticles: Diprophylline dispersions.

The aim of this study was to better understand the root causes for the (up to) 3 drug release phases observed with poly (lactic-co-glycolic acid) (PLGA) microparticles containing diprophylline particles: The 1st release phase ("burst release"), 2nd release phase (with an "about constant release rate") and 3rd release phase (which is again rapid and leads to complete drug exhaust). The behavior of single microparticles was monitored upon exposure to phosphate buffer pH 7.4, in particular with respect to their drug release and swelling behaviors.

Morphological and Structural Properties of Amorphous Lactulose Studied by Scanning Electron Microscopy, Polarized Neutron Scattering, and Molecular Dynamics Simulations.

Morphological and structural properties of amorphous disaccharide lactulose (CHO), obtained by four different amorphization methods (milling, quenching of the melt form, spray-drying, and freeze-drying), are investigated by scanning electron microscopy, polarized neutron scattering, and molecular dynamics simulations. While major differences on the morphology of the different amorphous samples are revealed by scanning electron microscopy images, only subtle structural differences have been found by polarized neutron scattering. Microstructure of the milled sample appears slightly different from the other amorphized materials with the presence of remaining crystalline germs which are not detected by X-ray diffraction.

Impact of Amorphization Methods on the Physicochemical Properties of Amorphous Lactulose.

The influence of the amorphization technique on the physicochemical properties of amorphous lactulose was investigated. Four different amorphization techniques were used: quenching of the melt, milling, spray-drying, and freeze-drying, and amorphous samples were analyzed by differential scanning calorimetry, NMR spectroscopy, and powder X-ray diffraction analysis. Special attention was paid to the tautomeric composition and to the glass transition of amorphized materials.

Interest of molecular/crystalline dispersions for the determination of solubility curves of drugs into polymers.

We present here a method to increase the dissolution rate of drugs into polymers in order to make easier and faster the determination of the solubility curves of these mixtures. The idea is to prepare molecular/crystalline dispersions (MCD) where the drug is dispersed into the polymer, partly at the molecular level and partly in the form of small crystallites. We show that this particular microstructure greatly increases the dissolution rate of crystallites since: (1) The molecular dispersion has a plasticizing effect which greatly increases the molecular mobility in the amorphous matrix.

Polymorphism versus devitrification mechanism: Low-wavenumber Raman investigations in sulindac.

The polymorphism of sulindac was investigated by Raman investigations, mainly in the low-wavenumber region in order to analyze the influence of the amorphization method on recrystallization and crystalline form stability. By devitrification of the quenched liquid, it was found that the undercooled liquid crystallizes into Form I, and a polymorphic transformation by cooling Form I toward Form IV, was clearly revealed. The low-wavenumber spectra of polymorphic forms are direct fingerprints of crystals, indicating a degree of disorder of Form IV intermediate between those of the ordered Form II (commercial form) and the relatively disordered Form I.

Using Milling to Explore Physical States: The Amorphous and Polymorphic Forms of Sulindac.

This article shows how milling can be used to explore the phase diagram of pharmaceuticals. This process has been applied to sulindac. A short milling has been found to trigger a polymorphic transformation between form II and form I upon heating which is not seen in the nonmilled material.

Lactulose: A Model System to Investigate Solid State Amorphization Induced by Milling.

In this article, we show that crystalline lactulose can be amorphized directly in the solid state by mechanical milling. Moreover, compared to similar materials, the amorphization kinetics of lactulose is found to be very rapid and the amorphous state thus obtained appears to be very stable against recrystallization on heating. These features make lactulose a model compound for this type of solid state transformation.

Scaling laws and size effects for amorphous crystallization kinetics: Constraints imposed by nucleation and growth specificities.

In the present paper we review different aspects of the crystallization of amorphous compounds in relation to specificities of the nucleation and growth rates. Its main purpose is: i) to underline the interest of a scaling analysis of recrystallization kinetics to identify similarities or disparities of experimental kinetic regimes. ii) to highlight the intrinsic link between the nucleation rate and growth rate with a temperature dependent characteristic transformation time τ(T), and a characteristic size ξ(T).

Structure determination of phase II of the antifungal drug griseofulvin by powder X-ray diffraction.

Two new crystalline polymorphs of the widely used antifungal drug griseofulvin (phases II and III), which originate from the crystallization of the melt, have been detected recently. The crystal structure of phase II of griseofulvin {systematic name: (2S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H,4'H-spiro[1-benzofuran-2,1'-cyclohex-2-ene]-3,4'-dione}, CHClO, has been solved by powder X-ray diffraction (PXRD). The PXRD pattern of this new phase was recorded at room temperature using synchrotron radiation.