No abstract

The objective of this study was to investigate the phase behavior of amorphous solid dispersions composed of a hydrophobic drug and a hydrophilic polymer following exposure to elevated relative humidity. Infrared (IR) spectroscopy, differential scanning calorimetry (DSC) and moisture sorption analysis were performed on five model systems (nifedipine-poly(vinylpyrrolidone) (PVP), indomethacin-PVP, ketoprofen-PVP, droperidol-PVP, and pimozide-PVP) immediately after production of the amorphous solid dispersions and following storage at room temperature and elevated relative humidity. Complete miscibility between the drug and the polymer immediately after solid dispersion formation was confirmed by the presence of specific drug-polymer interactions and a single glass transition (T(g)) event. Following storage at elevated relative humidity (75-94% RH), nifedipine-PVP, droperidol-PVP, and pimozide-PVP dispersions formed drug-rich and polymer-rich amorphous phases prior to crystallization of the drug, while indomethacin-PVP and ketoprofen-PVP dispersions did not. Drug crystallization in systems exhibiting amorphous-amorphous phase separation initiated earlier (<6 days at 94% RH) when compared to systems that remained miscible (>or=46 days at 94% RH). Evidence of moisture-induced amorphous-amorphous phase separation was observed following storage at as low as 54% RH for the pimozide-PVP system. It was concluded that, when an amorphous molecular level solid dispersion containing a hydrophobic drug and hydrophilic polymer is subjected to moisture, drug crystallization can occur via one of two routes: crystallization from the plasticized one-phase solid dispersion, or crystallization from a plasticized drug-rich amorphous phase in a two-phase solid dispersion. In the former case, the polymer is still present in the same phase as the drug, and can inhibit crystallization to a greater extent than the latter scenario, where the polymer concentration in the drug phase is reduced as a result of the amorphous-amorphous phase separation. The strength of drug-polymer interactions appears to be important in influencing the phase behavior.

The three techniques mentioned complement each other in establishing drug-polymer miscibility in amorphous solid dispersion systems. In particular, IR spectroscopy and PXRD are sensitive to changes in local chemical environments and local structure, which makes them especially useful in elucidating the nature of miscibility in binary mixtures when DSC results are inconclusive or variable.

Abstract. Formulation of an amorphous solid dispersion (ASD) is one of the methods commonly considered to increase the bioavailability of a poorly water-soluble small-molecule active pharmaceutical ingredient (API). However, many factors have to be considered in designing an API-polymer system, including any potential changes to the physical stability of the API. In this study, the tendency of ASD systems containing a poorly water-soluble API and a polymer to undergo amorphous-amorphous phase separation was evaluated following exposure to moisture at increasing relative humidity. Infrared spectroscopy was used as the primary method to investigate the phase behavior of the systems. In general, it was observed that stronger drug-polymer interactions, low-ASD hygroscopicity, and a less hydrophobic API led to the formation of systems resistant to moisture-induced amorphous-amorphous phase separation. Orthogonal partial least squares analysis provided further insight into the systems, confirming the importance of the aforementioned properties. In order to design a more physically stable ASD that is resistant to moisture-induced amorphous-amorphous phase separation, it is important to consider the interplay between these properties.

It has been previously observed that exposure to high relative humidity (RH) can induce amorphous-amorphous phase separation in solid dispersions composed of certain hydrophobic drugs and poly(vinylpyrrolidone) (PVP). The objective of this study was to investigate if this phenomenon occurred in solid dispersions prepared using less hygroscopic polymers. Drug-polymer miscibility was investigated before and after exposure to high RH using infrared (IR) spectroscopy and differential scanning calorimetry (DSC). PVP, poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), and hypromellose acetate succinate (HPMCAS) were selected as model polymers, and felodipine, pimozide, indomethacin, and quinidine were selected as model drugs. Drug-polymer mixing at the molecular level was confirmed for all model systems investigated. Moisture-induced drug-polymer demixing was observed in felodipine-PVPVA, quinidine-PVP, quinidine-PVPVA, pimozide-PVPVA, and pimozide-HPMCAS systems, but was absent in the other HPMCAS dispersions and for indomethacin-PVPVA. It is concluded that the balance between the thermodynamic factors (enthalpy and entropy of mixing) in a ternary water-drug-polymer system is the important factor in determining which solid dispersion systems are susceptible to moisture-induced amorphous-amorphous phase separation. Systems with strong drug-polymer interactions and a less hygroscopic polymer will be less susceptible to moisture-induced phase separation, while more hydrophobic drugs will be more susceptible to this phenomenon even at low levels of sorbed moisture.

The physical stability of solid dispersions as a function of RH is highly dependent on the polymer used to form the solid dispersion, with PVP-containing dispersions being much less physically stable at high RH than HPMCAS-containing dispersions.

Variations in the physical stability of the two compounds could not be explained by differences in Tg. However, the relative physical stability is consistent with differences in the degree of supersaturation of each drug in the solid dispersion, treating the polymer and water as a co-solvent system for each drug compound.

Abstract. The solid-state properties of pharmaceutical salts, which are dependent on the counterion used to form the salt, are critical for successful development of a stable dosage form. In order to better understand the relationship between counterion and salt properties, 11 salts of procaine, which is a base, were synthesized and characterized using a variety of experimental and computational methods. Correlations between the various experimental and calculated physicochemical properties of the salts and counterions were probed. In addition to investigating the key factors affecting solubility, the hygroscopicity of the crystalline salts was studied to determine which solid-state and counterion properties might be responsible for enhancements in moisture uptake, thus providing the potential for adverse chemical stability. Multivariate principal components and partial least squares projection to latent structures analyses were performed in an attempt to establish predictive models capable of describing the relationships between these characteristics and both measured and calculated properties of the counterion and salt. Some success was achieved with respect to modeling crystalline salt solubility and the glass transition temperature of the amorphous salts. Through the modeling, insight into the relative importance of various descriptors on salt properties was achieved. The solid-state properties of crystalline and amorphous salts of procaine are highly dependent on the nature of the counterion. Important properties including aqueous solubility, melting point, hygroscopicity, and glass transition temperature were found to vary considerably between the different salts.