David E. Bugay

Physical Characterization of Pharmaceutical Solids

A general review of the methods available for the physical characterization of pharmaceutical solids is presented. The techniques are classified as being on the molecular level (properties capable of being detected in an ensemble of individual molecules), the particulate level (properties which can be detected through the analysis of an ensemble of particles), and the bulk level (properties which can be measured only using a relatively large amount of material). The molecular-level properties discussed are infrared spectroscopy and nuclear magnetic resonance spectrometry, the particulate-level properties discussed are particle morphology, particle size distribution, powder X-ray diffraction, and thermal methods of analysis, and the bulk-level properties discussed are surface area, porosity and pore size distribution, and powder flow characteristics. Full physical characterization of three modifications of lactose (hydrous, anhydrous, and Fast-Flo) is presented to illustrate the type of information which can be obtained using each of the techniques discussed.

Solid-State Nuclear Magnetic Resonance Spectroscopy: Theory and Pharmaceutical Applications

The theory of solid-state nuclear magnetic resonance (NMR) spectroscopy is reviewed, with specific discussions of magnetic interactions in the solid state. Each magnetic interaction (Zeeman, dipole-dipole, chemical-shift, spin–spin, and quadrupolar) is addressed and manifestations of these interactions in the solid state NMR spectrum are explained. The techniques of high-power decoupling, magic-angle spinning, and cross-polarization, used to acquire highly resolved solid-state NMR spectra, are also illustrated. Application of solid-state NMR to pharmaceutical problem solving and methods development is then briefly reviewed.

Utilization of Fourier transform-Raman spectroscopy for the study of pharmaceutical crystal forms

It is well understood that the solid state physical characterization of a drug substance is necessary for successful development and approval of a pharmaceutical product AAPS [1]. Physical analytical techniques used include: XRD, IR, DSC, TG, and NMR. Recently, Fourier transform (FT) Raman spectroscopy has become a more common technique. Complimentary to IR, FT-Raman can be used to differentiate between different crystal forms of a drug substance. FT-Raman exhibits several advantages over IR and the other physical analytical techniques. Very little sample is required with no preparation (dilution), analysis time is quick, and since water is a weak scatter (Raman spectrum of water contains three low intensity peaks), crystallization studies of drug substances from aqueous solutions can be performed. Additionally, through the use of a variable-temperature accessory, phase diagrams can be determined for crystal systems, leading to further characterization of those systems. This paper introduces the use of FT-Raman spectroscopy for pharmaceutical development activities. Specific examples will be shown for investigations of crystal forms (qualitative and quantitative) and crystallization studies.

Quantitation of cefepime : 2HCl dihydrate in cefepime.2HCl monohydrate by diffuse reflectance IR and powder X-ray diffraction techniques

The identification, characterization and quantitation of crystal forms is becoming increasingly important within the pharmaceutical industry. Multi-disciplinary, physical analytical techniques are necessary for this task. In this work, diffuse reflectance mid-infrared (IR) and powder X-ray diffraction (XRD) analyses were used to identify two different hydrated forms of cefepime.2HCl, a cephalosporin. Characterization of the mono- and dihydrate forms led to separate IR and XRD quantitative assays for the determination of dihydrate content in cefepime.2HCl monohydrate bulk material. For the IR assay, a working range of 1.0-8% (w/w) was established with a minimum quantifiable level (MQL) of 1.0% (w/w) and a limit of detection (LD) of 0.3% (w/w) dihydrate in monohydrate material. The XRD assay displayed a working range of 2.5-15% (w/w) with an MQL of 2.5% (w/w) and an LD of 0.75% (w/w). Cross validation was performed between the two techniques, with a good correlation displayed for each assay as compared with the known concentrations and as compared with each other. In addition, a full evaluation of potential assay errors was made.

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.

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.

Pharmaceutical relationships of three solid state forms of stavudine

Three solid state forms of stavudine designated forms I, II and III have been identified and characterized. Forms I and II are anhydrous polymorphs whereas form III is hydrated and is pseudopolymorphic with forms I and II. Physico-chemical and thermodynamic properties of the three solid state forms have been characterized. Solid-state stability and potential for interconversion of the forms to aid in the selection of preferred form for development and commercialization has been studied. Conditions of recrystallization governing the formation of thermodynamically most stable polymorphic form I devoid of other forms was identified.

Spectral Methods for Determination of Water

Techniques based on the interaction of electromagnetic radiation with materials can be extremely useful for the characterization of water in solids of pharmaceutical interest. When combined with other physical methods, such as calorimetry, thermogravimetry, or titration, spectral techniques can be used to deduce information regarding the nature of water contained within a solid. The spectral methods are particularly useful in the study of hydrate species, and in the differentiation of hydrate water from entrapped or adventitious water. The most useful methods are powder x-ray diffraction, fourier transform infrared spectroscopy, and solid state nuclear magnetic resonance spectroscopy. These particular methods have been used in the study of ampicillin hydrate species.

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.