Robert A. Carlton

Preparation and Structural Characterization of Amorphous Spray-Dried Dispersions of Tenoxicam with Enhanced Dissolution

Tenoxicam is a poorly soluble nonsteroidal anti-inflammatory drug. In this work, the solubility of tenoxicam is enhanced using amorphous spray-dried dispersions (SDDs) prepared using two molar equivalents of l-arginine and optionally with 10%-50% (w/w) polyvinylpyrrolidone (PVP). When added to the dispersions, PVP is shown to improve physical properties and also assists in maintaining supersaturation in solution. The dispersions provide a twofold increase over equilibrium solubility at the same pH. The dispersions are characterized using electron microscopy, vibrational spectroscopy, diffuse-reflectance visible spectroscopy, and X-ray powder diffraction. The structures of the dispersions are probed using solid-state nuclear magnetic resonance (SSNMR) experiments applied to the (1) H, (13) C, and (15) N nuclei, including two-dimensional dipolar correlation experiments that detect molecular association and the formation of a glass solution between tenoxicam, l-arginine, and PVP. Other aspects of the amorphous structure, including hydrogen-bonding interactions and the ionization state of tenoxicam and l-arginine, are also explored using SSNMR methods. These methods are used to show that the SDDs contain an amorphous l-arginine salt of tenoxicam in a glass solution that also includes PVP when present. Finally, the dispersions show only a minor decrease in chemical stability during accelerated stability studies relative to a crystalline form of tenoxicam.

Enantiotropically-related polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid: Crystal structures and multinuclear solid-state NMR

Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and solid-state NMR (SSNMR) techniques are used to analyze the structures of two nonsolvated polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid. These polymorphs are enantiotropically-related with a thermodynamic transition temperature of 35 +/- 3 degrees C. The crystal structure of Form 1, which is thermodynamically more stable at lower temperatures, was determined by SCXRD. The crystal structure of Form 2 was determined using PXRD structure solution methods that were assisted using two types of SSNMR experiments, dipolar connectivity experiments and chemical shift measurements. These experiments determined certain aspects of local conformation and intermolecular packing in Form 2 in comparison to Form 1, and provided qualitative knowledge that assisted in obtaining the best possible powder structure solution from the X-ray data. NMR chemical shifts for 1H, 13C, 15N, and 19F nuclei in Forms 1 and 2 are sensitive to hydrogen-bonding behavior, molecular conformation, and aromatic pi-stacking interactions. Density functional theory (DFT) geometry optimizations were used in tandem with Rietveld refinement and NMR chemical shielding calculations to improve and verify the Form 2 structure. The energy balance of the system and other properties relevant to drug development are predicted and discussed.

Characterization, selection, and development of an orally dosed drug polymorph from an enantiotropically related system.

Solid-state characterization methods are used to study a dimorphic pharmaceutical compound and select a form for development. Polymorph screening found that [4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl] acetic acid can crystallize into two non-solvated polymorphs designated Forms 1 and 2. Physical methods including vibrational spectroscopy, X-ray powder diffraction, solid-state NMR (SSNMR), thermal analysis, and gravimetric water vapor sorption are used to fully characterize the two polymorphs. Temperature-dependent competitive ripening experiments and solubility measurements indicated that the polymorphs in this system exhibit enantiotropy with a thermodynamic transition temperature of 35+/-3 degrees C. This complicates the selection of a polymorph to progress in drug development. Both forms had undesirable qualities; however, a particular drawback of Form 1 was found in its tendency to convert to Form 2 upon milling. Combining this effect and the desired formulation approach with physical property results led to a rationale for the choice of Form 2 for further development. Because this form is thermodynamically metastable at room temperature, analytical approaches were developed to ensure its exclusive presence, including a quantitative infrared spectroscopic method for drug substance and (13)C and (19)F solid-state NMR limit tests for the undesired form in drug product at drug loads of 8.3% (w/w).

Preparation, structural analysis, and properties of tenoxicam cocrystals

Cocrystals of tenoxicam, a non-steroidal anti-inflammatory drug, are screened, prepared, and characterized in this study. Nine tenoxicam cocrystals were identified using solvent-drop grinding (SDG) techniques. Structural characterization was performed using powder X-ray diffraction (PXRD), differential scanning calorimetry, and multinuclear solid-state NMR (SSNMR). Thermal analysis, PXRD, and 1D SSNMR are used to detect solvates and phase mixtures encountered in SDG cocrystal screening. 2D SSNMR methods are then used to confirm cocrystal formation and determine structural aspects for selected cocrystals formed with saccharin, salicylic acid, succinic acid, and glycolic acid in comparison to Forms I and III of tenoxicam. Molecular association is demonstrated using cross-polarization heteronuclear dipolar correlation (CP-HETCOR) methods involving (1)H and (13)C nuclei. Short-range (1)H-(13)C CP-HETCOR and (1)H-(1)H double-quantum interactions between atoms of interest, including those engaged in hydrogen bonding, are used to reveal local aspects of the cocrystal structure. (15)N SSNMR is used to assess ionization state and the potential for zwitterionization in the selected cocrystals. The tenoxicam saccharin cocrystal was found to be similar in structure to a previously-reported cocrystal of piroxicam and saccharin. The four selected cocrystals yielded intrinsic dissolution rates that were similar or reduced relative to tenoxicam Form III.

Polarized Light Microscopy

The optical microscope is used extensively in pharmaceutical development with the primary application being solid-state analysis. The applications range from simple images of drug substance to illustrate particle size and shape to full optical crystallography. The range of utility of the microscope is considerably extended by the use of polarized light which allows us to obtain crystallographic data on small individual crystals. I will use the term Polarized Light Microscopy (PLM) for all light microscopy discussions in this chapter.

Charge neutralization in the ESEM for quantitative X-ray microanalysis.

Quantitative chemical analysis by energy-dispersive X-ray spectrometry (EDS) in the environmental scanning electron microscope (ESEM) is difficult. This analysis is complicated by the spread of the electron beam by chamber gas molecules and the necessity for surface charge neutralization. Without charge neutralization, errors in quantitative analysis can range up to 15-20% relative. It is possible to achieve the error expected of traditional EDS, +/- 5% relative error, using a newly developed surface charge neutralization scheme for the ESEM. Estimates of accuracy and precision are based on studies of the National Bureau of Standards (now National Institutes for Science and Technology) Standard Reference Material 482, a series of certified copper-gold alloys. The scheme for charge neutralization requires an independent path to ground at or near the surface of the specimen. The current through the ground path must be maintained at zero by adjusting the voltage on the Gaseous Secondary Electron Detector when the sample chamber is at a gas pressure of 1-2 torr. This procedure forms the exact number of chamber gas positive ions to neutralize negative electrical charge on the specimen surface from electron bombardment.

Specialized Microscopy Techniques

There are quite a few types of microscopy and microscopical techniques that are used occasionally in pharmaceutical microscopy but do not deserve chapter status. In some cases, these techniques are quite useful in biological applications but have only a few limited uses in pharmaceutics. In other cases, you simply need to be aware of the nature of the technique and the appropriate applications in case you get asked if that technique is applicable to the problem at hand. A pet peeve of mine is that it seems to be the considered the essence of good scientific management today to suggest alternative ways of looking at a problem – even if the manager has very little idea of the nature and limitations of the technique. I cannot count the number of times a manager, director, or vice-president has asked a question such as “Have you considered using cyclotron radiation for your IR experiment?” “Well, no I haven’t because it’s a really dumb idea and won’t help solve the problem in any way, shape or form.” Of course, I do not say those things, but I sure think them. Some of the techniques below have, as I mentioned, important applications in biological science or other fields but only limited applications in physical pharmacy. Some of these techniques, I think, are under-utilized in our industry and I think it may be worth our time to work them into our projects. A prime example of the latter is defect analysis by TEM. There are significant hurdles to this application but I think it is an under-studied area.

Scanning Electron Microscopy and Energy-Dispersive X-Ray Spectrometry

The scanning electron microscope (SEM) is used extensively in pharmaceutical development for both drug substance (DS) and drug product (DP). The vast bulk of the work is examination of size and shape of the individual particles making up the drug substance powder. Some of this work is quantitative in the sense that the size and shape of the particles are measured using image analysis (see Chaps. 7 and 9), but most of the work is more qualitative in nature. It is somewhat amazing that the SEM produces images that are readily interpreted by our visual system when you consider we are looking at the interaction of electrons with matter and that, in fact, there is no true optical system to the SEM. Even without numbers, one can get a sense of how the DS powder will behave based just on the appearance of the particles. If well-crystallized with sharp crystal edges, we may suppose the material will flow well. If it is highly agglomerated, with what appear to be particles fused together, we might suppose the powder will not flow as well. Even if those initial suppositions are somewhat naive and general, just having an image of the particles can help workers understand the system they are dealing with. By the way, it is a rare technical presentation on drug substance that does not include at least one SEM image.

Infrared and Raman Microscopy

Infrared (IR) and Raman spectroscopy are invaluable tools in pharmaceutical development since both yield information on the chemical structure of pharmaceutical molecules. IR and Raman are used for drug identification, for determination of molecular structure (along with nuclear magnetic resonance, mass spectrometry, single crystal X-diffraction, among other techniques), for solid-state analysis, for contaminant/particulate identification, and for chemical imaging of pharmaceutical dosage forms. IR and Raman microscopy are generally applied to the last three areas.

Comparison of SiLi and SDD Detectors for Pharmaceutical Applications

Silicon Drift Detectors (SDD) have a number of advantages over Lithium Drifted Silicon (SiLi) detectors in energy dispersive spectrometry [1]. The primary advantage is the high count rates of SDD compared with SiLi detectors. The majority of the applications have been to non-beam sensitive, high atomic number materials such as metals, ceramics and minerals. There has been some question as to the possible advantages of SDDs to low atomic number and beam sensitive materials such as pharmaceuticals. The purpose of this investigation is to evaluate SDDs for pharmaceutical applications and to the generation of EDS maps of pharmaceutical tablets.