Thermodynamic solubility measurement without chemical analysis.

In this work, the optical imaging based single particle analysis (SPA) and the gold standard shake-flask (SF) solubility methods are compared. We show that to analyze pharmaceutical compounds spanning 7 log units in solubility and a diverse chemical space with limited resources, several analytical techniques are required (HPLC-UV, LC-MS, refractometry and UV-Vis spectrometry), whereas solely the SPA method is able to analyze all the same compounds. SPA experiments take only minutes, while for SF, it may take days to reach thermodynamic equilibration. This decreases the time span needed for the solubility experiment from initial preparations to obtaining the result from roughly three days to less than three hours. The optimal particle size for SPA ranges from approximately one to hundreds of microns. Challenges include measuring large particles, very fast dissolving compounds and handling small sample sizes. Inherent exclusion of density from the SPA measurement is a potential source of error for compounds with very low or high density values. The average relative difference of 37 % between the two methods is very good in the realm of solubility, where 400 % interlaboratory reproducibility can be expected.

Fast imaging-based single particle analysis method for solubility determination.

The solubility and dissolution rates of chemical compounds are crucial properties in several fields of industry and research. However, accurate, rapid and green methods for their measurement, which only consume micrograms of compound, are lacking. Here, the unique approach of non-specific, image-based single particle analysis (SPA) for solubility testing is directly compared to and thus validated on the mid-solubility range with the current gold standard shake-flask method with UV-Vis spectroscopy employed for determining sample concentrations. Five biologically active compounds representing a range of physicochemical properties including pKa and logP were analyzed with both methods. The comparison of SPA and the shake-flask (SF) analysis shows excellent linear correlation (R2 = 0.99). Higher variability of the SPA method is attributed to variability between the properties of individual particles, which cannot be detected with traditional methods. Due to the similar average solubility values compared to those produced with SF, it is concluded that the SPA method has great potential as an analytical tool for small-scale solubility studies. It also has several practical advantages over the current gold standard shake-flask method, such as speed, low consumables consumption, and no requirement for prior knowledge of compound chemistry.

Comparison of Traditional and Ultrasound-Enhanced Electrospinning in Fabricating Nanofibrous Drug Delivery Systems.

We investigated nozzleless ultrasound-enhanced electrospinning (USES) as means to generate nanofibrous drug delivery systems (DDSs) for pharmaceutical and biomedical applications. Traditional electrospinning (TES) equipped with a conventional spinneret was used as a reference method. High-molecular polyethylene oxide (PEO) and chitosan were used as carrier polymers and theophylline anhydrate as a water-soluble model drug. The nanofibers were electrospun with the diluted mixture (7:3) of aqueous acetic acid (90% v/v) and formic acid solution (90% v/v) (with a total solid content of 3% w/v). The fiber diameter and morphology of the nanofibrous DDSs were modulated by varying ultrasonic parameters in the USES process (i.e., frequency, pulse repetition frequency and cycles per pulse). We found that the USES technology produced nanofibers with higher fiber diameter (402 ± 127 nm) than TES (77 ± 21 nm). An increase of a burst count in USES increased the fiber diameter (555 ± 265 nm) and the variation in fiber size. The slight-to-moderate changes in a solid state (crystallinity) were detected when compared the nanofibers generated by TES and USES. In conclusion, USES provides a promising alternative for aqueous-based fabrication of nanofibrous DDSs for pharmaceutical and biomedical applications.

Melt-electrospinning as a method to improve the dissolution and physical stability of a poorly water-soluble drug.

The present study introduces a modified melt-electrospinning (MES) method for fabricating the melt-electrospun fibers (MSFs) of a poorly water-soluble drug and carrier polymer. The MES of poorly water-soluble model drug indomethacin (IND) and hydrophilic carrier polymer, Soluplus® (SOL) were prepared at a 1:3 drug-polymer weight ratio. Water was used as an external plasticizer to regulate a MES processing temperature and to improve fiber formation. The fiber size, surface morphology, physical solid state, drug-polymer (carrier) interactions, thermal and chemical stability and dissolution behavior of MSFs were investigated. Solid state nuclear magnetic resonance spectroscopy (NMR) was used to measure T1(1H), and the domain size of IND in MSFs (25-100 nm) was calculated from these results. Solid-state and thermal analysis confirmed the presence of amorphous solid dispersions of IND and SOL. IND was found to be chemically stable during an entire MES process. Only small drug content variability of different MSF batches was detected with high performace liquid chromatography (HPLC). Given findings were verified with the liquid NMR spectroscopy. The dissolution of MSFs was significantly faster than that of physical mixtures (PMs) or pure drug. The enhanced dissolution of MSFs was caused by high surface area, amorphous state of the drug and solubilizing properties of the carrier polymer (SOL).

Interdependence of particle properties and bulk powder behavior of indomethacin in quench-cooled molten two-phase solid dispersions.

Solid dispersions (SDs) hold a proven potential in formulating poorly water-soluble drugs. The present paper investigates the interfacial phenomena associated with the bulk powder flow, water sorption, wetting and dissolution of the SDs prepared by a modified melt and quench-cooling (QC) method. Poorly water-soluble indomethacin (IND) was QC molten with solubilizing graft copolymer (Soluplus®) or polyol sugar alcohol (xylitol, XYL). The interfacial interactions of SDs with air/water were found to be reliant on the type (amorphous/crystalline) and amount of the carrier material used. The final SDs were composed of fused agglomerates (SOL) or large jagged particles (XYL) with good wetting and powder flow properties. The initial dissolution of IND was accelerated by both carrier materials studied. The QC molten SDs with amorphous Soluplus® significantly improved the dissolution rate of IND at pH 6.8 (79.9 ±â€¯0.2% at 30 min) compared to that of pure crystalline drug. The substantial improvement in the dissolution rate of IND was in connection with the amorphous state of the drug being stabilized by Soluplus® in the QC molten SDs. However, it is evident that a strong H-bond formation between the components in some regions of the QC molten SDs can limit the dissolution of IND. The QC molten two-phase SDs with a polyol carrier (XYL) showed rapid and continuous drug release without reaching a plateau.

The formation and physical stability of two-phase solid dispersion systems of indomethacin in supercooled molten mixtures with different matrix formers.

Amorphous solid dispersions (SDs) are a promising approach to improve the dissolution rate of and oral bioavailability of poorly water-soluble drugs. In some cases multi-phase, instead of single-phase, SD systems with amorphous drug are obtained. While it is widely assumed that one-phase amorphous systems are desirable, two-phase systems may still potentially exhibit enhanced stability and dissolution advantages over undispersed systems. The objective of the present study was to understand the solid-state properties of two-phase SDs with amorphous drug and their relation to physical stability. Two different types of excipients for SD formation were used, one being a polymer and the other a small molecule excipient. The supercooled molten SDs of a poorly water-soluble indomethacin (IND) with a graft copolymer, Soluplus® (SOL) and sugar alcohol, xylitol (XYL) were prepared. Supercooled molten SDs of IND with SOL were two-phase glassy suspension in which the amorphous drug was dispersed in an amorphous polymer matrix. A short-term aging of the SDs led to the formation of glassy suspensions where the crystalline drug was dispersed in an amorphous polymer matrix. These were physically stable at room temperature for the time period studied (RT, 23±2°C), but aging at high-humidity conditions (75% RH) recrystallization to metastable α-IND occurred. Interestingly, the SDs with XYL were two-phase amorphous precipitation systems in which the drug was in an amorphous form in the crystalline sugar alcohol matrix. The SDs of IND and XYL exhibited fast drug recrystallization. In conclusion, the preparation method of two-phase systems via co-melting in association with the rapid quench cooling is a feasible method for the formulation of poorly water-soluble drugs. The physical stability of these two-phase systems, however, is dependent on the carrier material and storage conditions.

Towards improved solubility of poorly water-soluble drugs: cryogenic co-grinding of piroxicam with carrier polymers.

Amorphous solid dispersions (SDs) open up exciting opportunities in formulating poorly water-soluble active pharmaceutical ingredients (APIs). In the present study, novel catalytic pretreated softwood cellulose (CPSC) and polyvinylpyrrolidone (PVP) were investigated as carrier polymers for preparing and stabilizing cryogenic co-ground SDs of poorly water-soluble piroxicam (PRX). CPSC was isolated from pine wood (Pinus sylvestris). Raman and Fourier transform infrared (FTIR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were used for characterizing the solid-state changes and drug-polymer interactions. High-resolution scanning electron microscope (SEM) was used to analyze the particle size and surface morphology of starting materials and final cryogenic co-ground SDs. In addition, the molecular aspects of drug-polymer interactions and stabilization mechanisms are presented. The results showed that the carrier polymer influenced both the degree of amorphization of PRX and stabilization against crystallization. The cryogenic co-ground SDs prepared from PVP showed an enhanced dissolution rate of PRX, while the corresponding SDs prepared from CPSC exhibited a clear sustained release behavior. In conclusion, cryogenic co-grinding provides a versatile method for preparing amorphous SDs of poorly water-soluble APIs. The solid-state stability and dissolution behavior of such co-ground SDs are to a great extent dependent on the carrier polymer used.