Mechanodegradation of Polymers: A Limiting Factor of Mechanochemical Activation in the Production of Amorphous Solid Dispersions by Cryomilling.

In this study, we report on the influence of mechanochemical activation on the chemical stability of amorphous solid dispersions made up of indomethacin and hydroxypropyl methyl cellulose (HPMC), poly(vinylpyrrolidone) (PVP), poly(vinylpyrrolidone vinylacetate) (PVPVA), or Soluplus. In agreement with our recently published work, all applied carriers were found to be prone to polymer degradation. Covalent bonds within the polymers were cleaved and mechanoradicals were generated. Furthermore, decomposition of indomethacin was also observed but occurred only in the presence of polymers. Hence, it is proposed that the generated mechanoradicals from the polymers are responsible for the chemical degradation of indomethacin. Our study also strongly suggests the existence of a critical polymer- and process-dependent molecular weight limit "M∞", below which only limited mechanodegradation takes place since the lower-molecular-weight polymer PVP K12PF had a less profound influence on the degradation of indomethacin in comparison to PVP K25.

Preparation of Amorphous Solid Dispersions by Cryomilling: Chemical and Physical Concerns Related to Active Pharmaceutical Ingredients and Carriers.

In this work, a chemical (and physical) evaluation of cryogenic milling to manufacture amorphous solid dispersions (ASDs) is provided to support novel mechanistic insights in the cryomilling process. Cryogenic milling devices are considered as reactors in which both physical transitions (reduction in crystallite size, polymorphic transformations, accumulation of crystallite defects, and partial or complete amorphization) and chemical reactions (chemical decomposition, etc.) can be mechanically triggered. In-depth characterization of active pharmaceutical ingredient (API) (content determination) and polymer (viscosity, molecular weight, dynamic vapor sorption, Fourier transform infrared spectroscopy, dynamic light scattering, and ANS and thioflavin T staining) chemical decomposition demonstrated APIs to be more prone to chemical degradation in case of presence of a polymer. A significant reduction of the polymer chain length was observed and in case of BSA denaturation/aggregation. Hence, mechanochemical activation process(es) for amorphization and ASD manufacturing cannot be regarded as a mild technique, as generally put forward, and one needs to be aware of chemical degradation of both APIs and polymers.

Gastro-resistant encapsulation of amorphous solid dispersions containing darunavir by coaxial electrospraying.

The relatively simple technique of coaxial electrospraying allows to produce core-shell microparticles with potentially high encapsulation efficiencies. In this study, amorphous solid dispersions of a hydroxypropyl methylcellulose or polyvinlypyrrolidone based polymer matrix containing the active pharmaceutical ingredient darunavir were coated with a gastro-resistant shell polymer that does not dissolve at lower pH present in the stomach, but only later at a higher pH in the small intestine. A multitude of shell polymers were tested with the aim to identify a material that limits the drug release to less than 10% after two hours at a pH of 1 to comply with the European Pharmacopoeia regarding gastro-resistant formulations. In parallel, the core-shell structure of the particles was determined with confocal imaging and their surface morphology with SEM imaging. While the structural analysis revealed significant differences between the different formulations, all investigated shell polymers exhibited a burst drug release followed by a slow release for the remainder of a two hour period. Ultimately, the shell copolymer poly(methacrylic acid-co-methyl methacrylate), in particular for a monomer ratio 1/2, resulted consistently in darunavir release below the 10% upper limit compared to the other tested polymers, where such low releases were inaccessible. Further investigation of this shell polymer revealed that both the monomer ratio of methacrylic acid to methyl methacrylate in the copolymer and the utilized solvent are determining factors in the release performance of the final particles.

Amorphous solid dispersions of darunavir: Comparison between spray drying and electrospraying.

The interest in using electrospraying as a manufacturing method for amorphous solid dispersions has grown remarkably. However, the impact of formulation and process parameters needs further clarification. In this study, amorphous solid dispersions of darunavir and hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS) and polyvinylpyrrolidone K-30 (PVP) were prepared with electrospraying and spray drying, in order to compare both solvent based manufacturing techniques. Our results revealed that electrospraying was as successful as spray drying. The formulations prepared with the two methods were amorphous and had similar characteristics concerning the residual solvent and drug release. Although differences in the morphology and the particle size distributions were observed, this was not reflected in the pharmaceutical performance of the formulations. Electrosprayed amorphous solid dispersions made up of darunavir and PVP were studied in more detail by means of a full factorial experimental design. The impact of two process and two formulation parameters on the properties of the amorphous solid dispersions was determined. The feed flow rate had a significant effect on the diameter and morphology of the particles whereas the tip-to-collector distance had no significant impact within the tested range. The drug loading influenced the homogeneity and the residual solvent, and the total solids concentration had an impact on the homogeneity and the morphology.