Structural evolution of indomethacin particles upon milling: Time-resolved quantification and localization of disordered structure studied by IGC and DSC.

The amorphization of indomethacin was induced by milling. The mass fraction of the amorphous phase in the drug milled for various time intervals was determined with differential scanning calorimetry (DSC). Because the surface fraction amorphized by milling can be much higher than the mass fraction, which can have a large impact on the powder properties, a method for quantification of surface fraction amorphized by milling using inverse gas chromatography (IGC) was developed. A calibration curve was constructed by mixing completely amorphous indomethacin (obtained after milling for 120 min) with various amounts of the initial crystalline sample. Linear part of the curve was then used to quantify the surface amorphous content of samples milled for different time intervals. Surface and mass amorphization kinetics were determined and fitted to a first-order model. It was found that the surface amorphization rate is an order of magnitude higher than the mass amorphization rate. Results confirmed that IGC is a sensitive method for detection and quantification of the fraction of amorphous surface of milled indomethacin powder. If suitably combined with other techniques, this method represents a relatively general approach for the localization and quantification of the surface amorphous fraction in crystalline substances that transform into amorphous ones upon intensive milling

Understanding controlled drug release from mesoporous silicates: Theory and experiment.

Based on the results of carefully designed experiments upgraded with appropriate theoretical modeling, we present clear evidence that the release curves from mesoporous materials are significantly affected by drug-matrix interactions. In experimental curves, these interactions are manifested as a non-convergence at long times and an inverse dependence of release kinetics on pore size. Neither of these phenomena is expected in non-interacting systems. Although both phenomena have, rather sporadically, been observed in previous research, they have not been explained in terms of a general and consistent theoretical model. The concept is demonstrated on a model drug indomethacin embedded into SBA-15 and MCM-41 porous silicates. The experimental release curves agree exceptionally well with theoretical predictions in the case of significant drug-wall attractions. The latter are described using a 2D Fokker-Planck equation. One could say that the interactions affect the relative cross-section of pores where the local flux has a non-vanishing axial component and in turn control the effective transfer of drug into bulk solution. Finally, we identify the critical parameters determining the pore size dependence of release kinetics and construct a dynamic phase diagram of the various resulting transport regimes

The phase (trans)formation and physical state of a model drug in mesoscopic confinement.

Compounds embedded into mesoporous or even microporous matrices are interesting for many emerging applications, such as novel catalysts, sensors, batteries, hydrogen storage materials or modern drug delivery devices. We report on two unexpected phenomena regarding the structural and dynamic properties of a model drug substance (indomethacin) when confined in mesoscopic matrices. Firstly, we show that the confinement directs the crystallization of the drug into a stable polymorph that is not otherwise formed at all; its relative amount depends on the pore size. This phenomenon is also explained theoretically using a modified classical heterogeneous nucleation theory. Secondly, we demonstrate that-even at relatively low volume fractions-the confined drug forms a condensed phase in a way that obstructs the passage of the pore channels. This may have far-reaching consequences for understanding the mechanisms of drug release from porous matrices

Vitrification from solution in restricted space: Formation and stabilization of amorphous nifedipine in a nanoporous silica xerogel carrier.

Purpose: The goal was to find thermodynamic criteria that must be satisfied in order to prevent formation of crystalline state of drugs within a confined space (e.g., nanopores of inorganic solid). Similarly, criteria that lead to stabilization of amorphous drug within such pores were investigated. Methods: In the theoretical part, the classical thermodynamics of nucleation is applied to the conditions of a restricted space. The theoretical findings are verified using porous silica as a carrier and nifedipine as a model drug. The amorphicity of the latter is checked using XRD and thermal analysis (DTA, DSC) in combination with BET measurements. Results: It is shown that there exists a critical pore radius of a host below which the entrapped substance will solidify in an amorphous form. There also exists a critical pore radius below which the entrapped amorphous solid will not be able to crystallize. Specifically, incorporation of NIF into a silica xerogel with an average pore diameter of about 2.5 nm produces and stabilizes its amorphous form. Conclusion: Entrapment of drugs into solid nanoporous carriers could be regarded as a potentially useful and simple method for production and/or stabilization of non-crystalline forms of a wide range of drugs

Guest-host van der Waals interactions decisively affect the molecular transport in mesoporous media.

We present clear evidence that the global (macroscopic) transport from/to mesoporous materials is significantly affected by the interactions between the mesoporous host and the guest molecules. The problem is considered in a most general way so the solutions apply for a variety of cases such as the release of a guest from porous matrices, catalysis occurring in porous materials or processes taking place in separation techniques. The concept is proved on the experimentally determined release profiles of a model drug (indomethacin) from accurately designed SBA-15 and MCM-41 mesoporous silicates. In order to allow for a full quantitative analysis, a very high frequency of sampling was carried out at short release times. The agreement between the experimentally determined and the theoretically predicted curves is excellent not only in shape but also in all major trends. In the broadest sense, one might say that the host-guest interactions change the effective cross-section of pores through which the transport of guest occurs. In addition, the interactions lower the efficiency of utilization of the guest. In drug release this is observed as a decrease of released matter at long times, in catalysis this would correspond to a decrease of global turnover efficiency etc. However, it is not only the final outcome that is affected but also the transport pattern (e. g. the shape of release curves) during a wide range of timescales. Our finding might have a profound influence on the design of various devices based on meso- or macroporous materials

Novel hybrid silica xerogels for stabilization and controlled release of drug.

Purpose: The goal was to show that incorporation of a model drug into a porous solid matrix with small enough pores should lead to composites in which the drug would be in the amorphous rather than in the crystalline state. Due to spatial constraints, the amorphous state was expected to be temporally highly stable. Methods: As a porous solid matrix silica was selected, while nifedipine served as a model drug. The silica-drug composites were prepared using a sol-gel procedure at conditions which yielded pores in the range 2-3 nm. To tune the properties of composites, two silica precursors were combined: tetraethoxysiiane (TEOS) and bis-1,2-(triethoxysilyl)ethane (BTSE). Results: In all composites the amorphous state of nifedipine was proven using several analytical methods. The amorphicity was preserved for at least several months. Drug incorporation into purely TEOS-based silica decreased significantly the release rate. Loosening the structure by addition of BTSE, while preserving the amorphicity, increased the drug dissolution rate. The dissolution behaviour was explained using a combination of the Noyes-Whitney and power law model. Conclusion: The observed release patterns could be interesting for therapies requiring a high initial drug concentration in blood plasma, followed by a slower release rate of the remaining drug

The relation between the interfacial contact and SiO₂ coating efficiency and properties in the case of two clarithromycin polymorphs.

Two clarithromycin polymorphs with very similar particle size and morphology were coated with silica using a base-catalyzed sol-gel procedure. It was found that the contact angles, evaluated from measured surface free energies, correlate well with coating efficiency. The connection between interfacial contact (described with the contact angle), nucleation kinetics and coating performance was established using the heterogeneous nucleation theory. The resulting coating thickness and morphology were evaluated by means of thermal analysis. X-ray powder diffraction and scanning electron microscopy. Good agreement was found between the theoretical predictions and experimental findings

Suspensions of modified TiO2 nanoparticles with supreme UV filtering ability.

TiO2 nanoparticles (20-23 nm in size) were coated with a silica layer onto which lauric acid was strongly bound. The strong (probably covalent) bonding was proved using detailed comparative thermal analysis. The functionalized TiO2 nanoparticles exhibited significantly reduced agglomeration, both in dry and in dispersed states (in oily media). The reduced tendency towards agglomeration was consistent with contact angle measurements which showed an increased hydrophobicity of functionalized TiO2. The strong (covalent) bonding also greatly improved the stability of the nanoparticulate sample in suspensions. Finally, the UV filtering efficiency of functionalized samples was much improved when compared to non-functionalized or those functionalized using conventional stabilizers based on adsorption. This effect was consistent with our theoretical prediction in which we correlated the particle size and the UV filtering ability