Kenneth R. Morris

An integrated approach to the selection of optimal salt form for a new drug candidate

Abstract A general method was developed to select the optimal salt form for BMS-180431, a novel HMG-CoA reductase inhibitor and a candidate for oral dosage form development, in an expeditious manner at the onset of the drug development process. The physicochemical properties such as hygroscopicity, physical stability of crystal forms at different humidity conditions, aqueous solubility, and chemical stability of seven salts e.g., sodium, potassium, calcium, zinc, magnesium, arginine and lysine, were studied using a multi-tier approach. The progression of studies among different tiers was such that the least time-consuming experiments were conducted earlier, thus saving time and effort. A ‘go/no go’ decision was made after each tier of testing the salts, thus avoiding generation of extensive data on all available salt forms. The hygroscopicities of all BMS-180431 salts were evaluated at tier 1 and four salts (sodium, potassium, calcium and zinc) were dropped from consideration due to excessive moisture uptake within the expected humidity range of pharmaceutical manufacturing plants (30–50% R.H. at ambient temperature). The remaining three salts were subjected to the tier 2 evaluation for any change in their crystal structures with respect to humidity and the determination of their aqueous solubilities in the gastrointestinal pH range. The magnesium salt was dropped from further consideration due to humidity-dependent changes in its crystal structure and low solubility in water (3.7 mg/ml at room temperature). Arginine and lysine salts, which were resistant to any change in their crystalline structures under extremes of humidity conditions (6 and 75% R.H.) and had high aqueous solubilities (> 200 mg/ml), were elevated to tier 3 for the determination of their chemical stability. Based on solid state stability of these two salts under accelerated conditions (temperature, humidity, and presence of excipients), consideration of ease of synthesis, ease of analysis, potential impurities, etc., and input from the marketing group with respect to its preference of counter ion species, the arginine salt was selected for further development. The number of tiers necessary to reach a decision on the optimal salt form of a compound may depend on the physicochemical properties studied and the number of salts available. This salt selection process can be completed within 4–6 weeks and be easily adopted in the drug development program.

Solid-state NMR and IR for the analysis of pharmaceutical solids: Polymorphs of fosinopril sodium

The two polymorphic modifications of fosinopril sodium have been characterized as to their differences in melting behaviour, powder X-ray diffraction patterns, Fourier transform infrared spectra (FTIR), and solid-state 31P- and 13C-NMR spectra. The polymorphs were found to be enantiotropically related based upon melting point, heat of fusion, and solution mediated transformation data. Analysis of the solid-state FTIR and 13C-NMR data indicated that the environment of the acetal side chain of fosinopril sodium differed in two polymorphs, and that there might be cis-trans isomerization about the C6-N peptide bond. These conformational differences are postulated as the origin of the observed polymorphism.

The effect of size and mass on the film thickness of beads coated in fluidized bed equipment

Abstract The relationship between the film thickness on a bead, and the beads size and mass in a polydispersed system was studied. Beads with a size distribution in the no. 14–20 mesh range were coated using Glatt fluidized bed units equipped with a Wurster insert. The coated beads were separated into narrower size fractions and dissolution testing of each fraction was performed using the USP basket method. The larger beads exhibited much slower release rates compared to the smaller beads, and the differences could not be explained by the relative surface areas. Examination of the beads by scanning electron microscope indicated that the larger or heavier beads received a thicker film compared to the smaller or lighter beads. This trend was attributed to differences in the fluidization patterns and velocities of the various sized beads.

Characterization of humidity-dependent changes in crystal properties of a new HMG-CoA reductase inhibitor in support of its dosage form development

Abstract Humidity-dependent changes in the crystal properties of the disodium salt of a new HMG-CoA reductase inhibitor (SQ-33600) were characterized using a combination of gravimetric, thermal, and spectral techniques. The drug substance was found to exhibit rapid moisture sorption and/or desorption, depending on the environmental conditions. Three crystalline solid hydrates and one liquid crystalline phase were identified, each having a definite stability over a range of humidity. The drug substance turned amorphous upon wet granulation, and the amorphous phase reconverted to crystalline hydrates upon exposure to 33–75% relative humidity. To avoid physical instability of dosage forms due to phase changes, manufacturing of solid dosage forms by dry processing below 52% relative humidity was recommended. The dissolution of drug from solid dosage forms was observed to be independent of the crystal form of the active.

Mechanism and Kinetics of Metal Ion-Mediated Degradation of Fosinopril Sodium

Fosinopril sodium (I), a new angiotensin converting enzyme inhibitor, is a diester prodrug of the active moiety II. We report here a novel transformation of fosinopril into β-ketoamide, III, and a phosphonic acid, IV, mediated through metal ion participation. The interaction of fosinopril with magnesium ions was studied in a solution model system in which methanol was used as the solvent and magnesium acetate as the source of metal ions. Kinetic analysis indicated the degradation to be a bimolecular process, with the rate being first order in both metal ion and fosinopril concentration. The degradation products II, III, and IV effectively retarded the magnesium ion mediated reaction of fosinopril. Based on the results of 31P-NMR, 1H-NMR, Mn(II)-EPR spectroscopy experiments and mass spectrometry, a mechanism is postulated for this transformation. A key reactive intermediate has been characterized that supports the proposed mechanism. The results can account for the observed degradation profile of the fosinopril sodium in a prototype tablet formulation.

Characterization of the hydration state of pharmaceuticals by variable-temperature diffuse-reflectance infrared spectroscopy

The characterization of hydrates is exceedingly important for pharmaceuticals since the state of hydration of a drug can effect its solubility, dissolution rate, bioavailability, chemical stability, and the physical stability of subsequent dosage forms. In addition, the United States Food and Drug Administration concerns about the above issue make complete characterization of hydrates a necessary part of investigative new drug filings. A Collector TM Diffuse Reflectance accessory fitted with a controlled Environmental Chamber was used to study drug formulations under varying temperature and humidity conditions.