pH-Dependent supersaturation from amorphous solid dispersions of weakly basic drugs.

Purpose: In amorphous solid dispersions (ASDs), the chemical potential of a drug can be reduced due to mixing with the polymer in the solid matrix, and this can lead to reduced drug release when the polymer is insoluble in the dissolution media. If both the drug and the polymer composing an ASD are ionizable, drug release from the ASD becomes pH-dependent. The goal of this study was to gain insights into the pH-dependent solubility suppression from ASD formulations.

Amorphous solid dispersions: a robust platform to address bioavailability challenges.

Amorphous solid dispersions (ASDs) are being used with increasing frequency for poorly soluble pharmaceutical compounds in development. These systems consist of an amorphous active pharmaceutical ingredient stabilized by a polymer to produce a system with improved physical and solution stability. ASDs are commonly considered as a means of improving the apparent solubility of an active pharmaceutical ingredient.

Physicochemical characterization of felodipine-kollidon VA64 amorphous solid dispersions prepared by hot-melt extrusion.

To improve the dissolution and hence the oral bioavailability, amorphous felodipine (FEL) solid dispersions (SDs) with Kollidon® VA 64 (PVP/VA) were prepared. Hot-melt extrusion was employed with an extruding temperature below the melting point (Tm ) of FEL. X-ray powder diffraction (XRPD) and (13) C CP/MAS nuclear magnetic resonance (NMR) measurements show that the extrudates are amorphous.

Discovery of a stable molecular complex of an API with HCl: a long journey to a conventional salt.

We report formation and characterization of the first pharmaceutically acceptable and stable molecular complex of a mono-HCl salt of Compound 1 with HCl. The novelty of this discovery is due to the fact that there is only one major basic site in the molecule. Thus this complex is reminiscent of other noncovalent crystalline forms including solvates, hydrates, cocrystals and others.

Chromatographic selectivity study of 4-fluorophenylacetic acid positional isomers separation.

Unique properties of the fluorine atom stimulate widespread use and development of new organofluorine compounds in agrochemistry, biotechnology and pharmacology applications. However, relatively few synthetic methods exhibit a high degree of fluorination selectivity, which ultimately results in the presence of structurally related fluorinated isomers in the synthetic product. This outcome is undesirable from a pharmaceutical perspective as positional isomers possess different reactivity, biological activity and toxicity as compared to the desired product.

Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid.

We report the first case of a pharmaceutical cocrystal formed between an inorganic acid and an active pharmaceutical ingredient (API), which enabled us to develop a stable crystalline and bioavailable solid dosage form for pharmaceutical development where otherwise only unstable amorphous free form or salts could have been used.

Quantitation of crystalline material within a liquid vehicle using 1H/19F CP/MAS NMR.

A method to detect and quantify a small amount crystalline material within a liquid solution of solubilized material is described. 19F CP-MAS ssNMR was investigated as a technique to detect low levels (0.2 mg/g) of crystalline sodium (2R)-7-{3-[2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy]propoxy}-2-methyl-3,4-dihydro-2H-chromane-2-carboxylate (I) within a solid mixture (with microcrystalline cellulose) and a slurry with a liquid vehicle (capric and caprylic acid triglycerides).

Reaction of organosilicon hydrides with solid surfaces: an example of surface-catalyzed self-assembly.

The solution-phase reactions of octadecylsilane (C(18)H(37)SiH(3)) with 10 high surface area metal oxides (groups II-VIII) were investigated. C(18)H(37)SiH(3) reacted with most metal oxides at room temperature and produced supported monolayers (self-assembled monolayers, SAMs) with a high grafting density of C(18), approximately 4.5-5 groups/nm(2).

Solid-state nuclear magnetic resonance determination of the physical form of BHA on common pharmaceutical excipients.

Purpose: The purpose of this study was to evaluate the physical form of 2-tert-butyl-4-methoxy-phenol (BHA) following wet granulation onto common pharmaceutical excipients.

Methods: A 13C label was incorporated into the methoxy group of BHA, the major isomer in synthetic butylated hydroxyanisole. Solutions of the labeled BHA were used to load the labeled BHA onto common pharmaceutical excipients.

Synthesis of 3-aminopyrazinone mediated by 2-pyridylthioimidate-ZnCl2 complexes. Development of an efficient route to a thrombin inhibitor.

A six-step preparation of thrombin inhibitor drug candidate 1 from pyrazinone 7 in 47% overall yield is described. The problem of low reactivity between weak amine nucleophile 4 and poor electrophile 3-bromopyrazinone 17 was overcome with the use of pyridinylthioimidate 27 in the presence of ZnCl(2) to afford adduct 3 in high yield. Several zinc complexes were characterized by solution and solid-state NMR and X-ray crystallographic analyses, and provided insight into the reaction mechanism.

Characterization of a thermally induced irreversible conformational transition of amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phase in enantioseparation of dihydropyrimidinone acid by quasi-equilibrated liquid chromatography and solid-state NMR.

A thermally induced irreversible conformational transition of amylose tris(3,5-dimethylphenylcarbamate) (i.e., Chiralpak AD) chiral stationary phase (CSP) in the enantioseparation of dihydropyrimidinone (DHP) acid racemate was studied for the first time by quasi-equilibrated liquid chromatography with cyclic van't Hoff and step temperature programs and solid-state ((13)C CPMAS and (19)F MAS) NMR using ethanol and trifluoroacetic acid (TFA)-modified n-hexane as the mobile phase.

Effects of alcohol mobile-phase modifiers on the structure and chiral selectivity of amylose tris(3,5-dimethylphenylcarbamate) chiral stationary phase.

Following a previous publication, the present paper reports additional results on the effects of alcohol mobile-phase modifiers on the structure and chiral selectivity of amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD) chiral stationary phase (CSP). Solid-state NMR (1H/13C CPMAS) was utilized to identify and compare structural differences in Chiralpak AD caused by the various alcohol mobile-phase modifiers, many of which were not studied in the previous publication. The influences of the various alcohol modifiers (in hexane-based mobile phase) on the structure and chiral selectivity of the CSP were studied and compared.

Characterization and quantitation of aprepitant drug substance polymorphs by attenuated total reflectance fourier transform infrared spectroscopy.

In this study, we report the use of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FT-IR) for the identification and quantitation of two polymorphs of Aprepitant, a substance P antagonist for chemotherapy-induced emesis. Mixtures of the polymorph pair were prepared by weight and ATR-FT-IR spectra of the powdered samples were obtained over the wavelength range of 700-1500 cm(-1). Significant spectral differences between the two polymorphs at 1140 cm(-1) show that ATR-FT-IR can provide definitive identification of the polymorphs.

19F solid-state NMR spectroscopic investigation of crystalline and amorphous forms of a selective muscarinic M3 receptor antagonist, in both bulk and pharmaceutical dosage form samples.

The purpose of the following investigation was to display the utility of 19F solid-state nuclear magnetic resonance (NMR) in both distinguishing between solid forms of a selective muscarinic M3 receptor antagonist and characterizing the active pharmaceutical ingredient in low-dose tablets. Ambient- and elevated-temperature solid-state 19F fast (15 kHz) magic-angle spinning (MAS) NMR experiments were employed to obtain desired spectral resolution in this system. Ambient sample temperature combined with rotor frequencies of 15 kHz provided adequate 19F peak resolution to successfully distinguish crystalline and amorphous forms in this system.