Andrey V. Peresypkin

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.

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.

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.