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. METHODS: The maximum release of clotrimazole, a weakly basic drug, from ASDs formulated with insoluble and pH-responsive polymers, was determined as a function of solution pH. Drug-polymer interactions in ASDs were probed using melting point depression, moisture sorption, and solid-state Nuclear Magnetic Resonance spectroscopy (SSNMR) measurements. RESULTS: The extent of solubility suppression was dependent on polymer type and drug loading. The strength of drug-polymer interactions was found to correlate well with the degree of solubility suppression. For the same ASD, the degree of solubility suppression was nearly constant across the solution pH range studied, suggesting that polymer-drug interactions in residual ASD solids was independent of solution pH. The total drug release agrees with the Henderson-Hasselbalch relationship if the suppressed amorphous solubility of the free drug is independent of solution pH. CONCLUSIONS: The mechanism of solubility suppression at different solution pHs appeared to be drug-polymer interactions in the solid-state, where the concentration of the free drug remains the same at variable pHs and the total drug concentration follows the Henderson-Hasselbalch relationship.

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. This review will discuss methods of preparation and characterization of ASDs with an emphasis on understanding and predicting stability. Theoretical understanding of supersaturation and predicting in vivo performance will be stressed. Additionally, a summary of preclinical and clinical development efforts will be presented to give the reader an understanding of risks and key pitfalls when developing an ASD.

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. The intermolecular interaction between FEL and PVP/VA in SDs was investigated by Fourier transform infrared spectroscopy, (15) N CP/MAS NMR, and (1) H high-resolution MAS NMR. Furthermore, a single glass transition temperature (Tg ) was detected by differential scanning calorimetry in addition to a single (1) H T1 or T1rho relaxation time detected by (13) C NMR signals. These results confirm that the extrudates contain FEL dispersed into the polymer matrix at a molecular level with no detectable phase separation. This molecular-scale mixing results in a significantly faster dissolution rate compared with the pure crystalline FEL. Additionally, the molecular-scale mixing prevents the amorphous drug from recrystallizing even after being stored at 40°C/75% Relative Humidity for 2 months.

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. To the best of our knowledge, the observed bis-HCl salt appears to be the first example of an active pharmaceutical ingredient in a form of a stable HCl complex. The paucity of stable complexes of APIs with HCl is likely due to the fact that HCl is a gas at ambient conditions and can easily evaporate compromising physical (and chemical) stability of a drug. The bis-HCl salt was chemically/physically stable at low humidity and the molecular HCl stays in the lattice until heated above 140 degrees C under nitrogen flow. Structure solution from powder diffraction using the Monte Carlo simulated annealing method as well as variable temperature ATR-FTIR suggest the possibility of weak hydrogen bonding between the molecular HCl and the nitrogen atom of the amide group. Two years later after the search for a suitable pharmaceutical salt began, the elusive conventional mono-HCl salt was obtained serendipitously concluding the lengthy quest for a regular salt. This work emphasizes the necessity to be open-minded during the salt selection process. It also highlights the difficult, lengthy and often serendipitous path of finding the most appropriate form of an API for pharmaceutical development.

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. It is advantageous to control positional isomers in the early stages of the synthetic process, as rejection and analysis of these isomers will likely become more difficult in later stages. The current work reports the development of a chromatographic analysis of 2- and 3-fluorophenylacetic acid positional isomer impurities in 4-fluorophenylacetic acid (4-FPAA), a building block in the synthesis of an active pharmaceutical ingredient. The method is employed as a part of a Quality by Design Approach to control purity of the starting material in order to eliminate the presence of undesirable positional isomers in the final drug substance. During method development, a wide range of chromatographic conditions and structurally related positional isomer probe molecules were exploited in an effort to gain insight into the specifics of the separation mechanism. For the systems studied it was shown that the choice of organic modifier played a key role in achieving acceptable separation. Further studies encompassed investigation of temperature influence on retention and selectivity of the FPAA isomers separation. Thermodynamic analysis of these data showed that the selectivity of the 2- and 4- fluorophenylacetic acids separation was dominated by an enthalpic process, while the selectivity of the 4- and 3-fluorophenylacetic acids separation was exclusively entropy driven (Delta(DeltaH degrees approximately 0). Studies of chromatographic behavior were complemented by solid state NMR experiments which provided valuable information regarding the relationship between stationary phase solvation and selectivity.

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). The results demonstrate that the area of the 19F CP/MAS signal obtained in 25 min at 25 degrees C is linearly dependent (R2=0.997) on the mass of I within the ssNMR rotor. Slopes of CP-MAS peak area versus mass of I in the rotor were nearly identical for the solid mixture and slurry suspension. Signal-to-noise ratio for the low potency slurry suggest detection and quantitation of 0.1 mg of crystalline I in the rotor, corresponding to 2 mg/g of crystalline material within the slurry suspension.

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). According to the FTIR and (29)Si NMR spectra, molecules in the SAMs demonstrated "horizontal" cross-linking (Si-O-Si and Si-OH.HO-Si bonds) and little or no "vertical" bonds with the metal oxide forming an amorphous, yet ordered film. Also, approximately 3 mol of H(2) was formed per each mole of grafted C(18), indicating complete hydrolysis of C(18)H(37)SiH(3) during the reaction. On the basis of the activity of different metal oxides, we concluded that the hydrolysis of C(18)H(37)SiH(3), the key step in the reaction mechanism, is catalyzed by water adsorbed on acidic and basic centers (Lewis and Brönsted) of the surface of metal oxide. Metal oxides and solids with weak acidic and basic properties, like silica, carbon, and organic polymers, do not react with C(18)H(37)SiH(3). Increasing the temperature of the reaction or doping neutral surfaces with acids or bases greatly increases their activity in the reaction with RSiH(3).

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. After air drying under ambient conditions, the mixtures were examined by 13C MAS and CP/MAS nuclear magnetic resonance (NMR) spectroscopy to evaluate the physical form of the BHA. RESULTS: The data suggested that BHA could exist as either a crystalline or an amorphous component and that amorphous material was either bound to excipients or relatively mobile during the time of the NMR experiment. At 0.1% loading, BHA appeared to be amorphous and mobile in the freshly prepared blends. At 0.5% loading, BHA was shown to be amorphous on microcrystalline cellulose (MCC) and hydroxypropylmethylcellulose (HPMC) while remaining crystalline on lactose, mannitol, calcium phosphate dihydrate, and croscarmellose sodium. CONCLUSIONS: Solid-state NMR spectroscopy has been used to probe the physical forms of 13C-labeled BHA granulated onto common pharmaceutical excipients. The techniques described in this paper may be applied to help explain stability changes in formulations containing BHA.

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. Preparation of pyridine N-oxide amine 4 was accomplished via a selective oxidation of the corresponding pyridinylamine 6. Pyridinylthioimidate 27 was prepared from pyrazinone 7 via a two-step one-pot process in near quantitative yield. Chlorination of the pyrazinone ring in 3 followed by hydrolysis and amide coupling completed the synthesis of 1. This chromatography-free synthesis was used successfully to prepare multikilogram quantities of the drug with reproducibility and high purity.

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. The conformational transition was controlled by a single kinetically driven process, as evidenced by the chromatographic studies. Solid-state NMR was used to study the effect of the temperature on the conformational change of the solvated phase (with or without the DHP acid enantiomers and TFA) and provided some viable structural information about the CSP and the enantiomers.

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. CPMAS spectra of Chiralpak AD flushed with the mobile phases displayed clear evidence of solvent incorporation into the CSP. When alcohol modifiers with varying size and bulkiness were used in the mobile phase, differences in structure and chiral selectivity were observed on Chiralpak AD based on solid-state NMR and chromatographic data. The change of t-butanol concentration in the t-butanol/hexane mobile phase caused changes of structure and chiral selectivity of the Chiralpak AD. These data further support our belief that the different chiral selectivities of the CSP associated with the use of different alcohol modifiers are due to different alterations of the steric environment of the chiral cavities in the CSP by the different mobile-phase modifiers.

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. To investigate the feasibility of ATR-FT-IR for quantitation of polymorphic forms of Aprepitant, a calibration plot was constructed with known mixtures of the two polymorphs by plotting the peak ratio of the second derivative of absorbance spectra against the weight percent of form II in the polymorphic mixture. Using this novel approach, 3 wt % of one crystal form could be detected in mixtures of the two polymorphs. The accuracy of ATR-FT-IR in determining polymorph purity of the drug substance was tested by comparing the results with those obtained by X-ray powder diffractometry (XRPD). Indeed, polymorphic purity results obtained by ATR-FT-IR were found to be in good agreement with the predictions made by XRPD and compared favorably with actual values in the known mixtures. The present study clearly demonstrates the potential of ATR-FT-IR as a quick, easy, and inexpensive alternative to XRPD for the determination of polymorphic identity and purity of solid drug substances. The technique is ideally suited for polymorph analysis, because it is precise, accurate, and requires minimal sample preparation.

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. Additionally, elevated-temperature 19F MAS NMR further characterized solid forms through 19F resonance narrowing brought about by the phenomenon of solvent escape. Similar solvent dynamics at elevated temperatures were utilized in combination with ambient-temperature 19F MAS NMR analysis to provide excipient-free spectra to unambiguously identify the active pharmaceutical ingredient (API) conversion from crystalline Form I to the amorphous form in low-dose tablets. It is shown that 19F solid-state NMR is exceptionally powerful in distinguishing amorphous and crystalline forms in both bulk and formulation samples.