Robert M. Wenslow

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.

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.

A Spectroscopic and Crystallographic Study of Polymorphism in an Aza‐Steroid

The crystal structures of two enantiotropic polymorphs of the aza-steroid finasteride (N-(1-1-di-methylethyl)-3-oxo-4-aza-5 alpha-and rost-1-ene-17 beta-carboxam ide ) have been determined. The solid-state nuclear magnetic resonance spectra, infrared spectra, and physical property data of these two polymorphs are discussed in relation to both their solid-state structures and hydrogen-bonding networks.

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.

ABSTRACT 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.

Solid-State Nuclear Magnetic Resonance Determination of the Physical Form of BHA on Common Pharmaceutical Excipients

AbstractPurpose. 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.

Polymorphic behavior of an NK1 receptor antagonist

Four anhydrous polymorphic forms (I, II, III and IV) of an NK1 receptor antagonist, Compound A, have been discovered. The pure compound can exist as either Forms I or II at room temperature and Forms III or IV at elevated temperatures. The four polymorphs were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis, X-ray powder diffraction (XRPD) and solid-state NMR spectroscopy (SSNMR). Polymorphic transformations in the solid phase were studied using DSC, hot stage XRPD, temperature-modulated SSNMR and hot stage optical microscopy. The solubilities of Forms I and II in tert-butyl acetate at different temperatures were measured and the relative stability of the two forms was established. The thermodynamic transformation temperatures between Forms I and III, as well as Forms II and IV, were estimated by DSC. Transformation from Form III to IV, which is undetectable in a normal calorimetric run, was revealed through careful thermal programming. An interesting conversion route from Form I, a more stable form at room temperature, to Form II, a less stable form at room temperature was discovered.

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.