Joseph G. Stowell

Advances in pharmaceutical materials and processing

Abstract Advances in pharmaceutical materials and processing require new generations of pharmaceutical technologies, which in turn require an improved understanding of each step in the unit processes of dosage form development. The unit processes range from raw material qualification to final product release using process monitoring of critical steps. The authors illustrate some recent research trends in understanding and improving pharmaceutical materials and processing through the use of experience obtained within several research programs at Purdue University (West Lafayette, IN, USA).

Modeling and Monitoring of Polymorphic Transformations During the Drying Phase of Wet Granulation

AbstractPurpose. The purpose of this work was to monitor polymorphic transformations of glycine during the drying phase of a wet granulation and model the polymorphic conversions using a time-based reconciliation model. Methods. Near-infrared spectroscopy (NIR) was used for quantitation of polymorphs, and X-ray powder diffraction (XRPD) was used for qualitative analysis of polymorphs. Results. The data show that the faster the granulation was dried, the more kinetic trapping of the metastable α-glycine polymorph, as predicted by reconciliation of the time scales of both the drying rate and the rate of the solution-mediated conversion. Conclusions. By knowing basic properties of the drug substance (solubility of the polymorphic forms and the rate of the solution-mediated conversion), processing conditions, such as the drying rate, can be adjusted to anticipate and prevent potential polymorphic transformations.

Accelerated fluid bed drying using NIR monitoring and phenomenological modeling

A “fast-drying” method to accelerate the fluid bed drying process is presented. It relies on concepts of heat and mass transfer with real-time near-infrared (NIR) monitoring of moisture. Triplicate trials show that fast drying can reduce granulation drying time by half over single-temperature cycles. The product is equivalent in every way tested to material made using a conventional cycle even though the inlet temperature throughout the constant-rate stage was higher than the melting point of the compound. Tablets made from the fast-dried granulation exhibit equivalent physical characteristics to tablets made from granulations dried at a single, lower temperature.

In situ monitoring of wet granulation using online X-ray powder diffraction.

AbstractPurpose. Polymorphic transformations during the wet granulation of a metastable polymorph of flufenamic acid were monitored in situ using online X-ray powder diffraction. The resulting data were used in testing a proposed process induced transformation rate model, which allows the extent and occurrence of polymorphic transformations during wet granulation to be controlled by adjusting the granulation time. Methods. A small-scale, top mixing granulator was designed for compatibility with novel X-ray powder diffraction equipment (available from X-Ray Optical Systems of East Greenbush, NY). Results. The unique polycapillary optic and X-ray source allowed the transformation of the metastable to the stable polymorph to be followed during the granulation. Following a diffraction peak each for the metastable and stable forms demonstrated that polymorphic transformations during the wetting phase of granulation follow the trends predicted by the model. Conclusions. The advanced online monitoring may allow real-time control of the process by the adjustment of process parameters, such as granulation time, and clearly qualifies as a PAT (process analytical technology).

Conformational color polymorphism and control of crystallization of 5-methyl-2-[(4-methyl-2-nitrophenyl)amino]-3-thiophenecarbonitrile

5-Methyl-2-[(4-methyl-2-nitrophenyl)amino]-3-thiophenecarbonitrile is an example of conformational and color polymorphism. The compound crystallizes in red (R), dark red (DR), light red (LR), and orange (O) modifications. There are two specific goals for this study. One is to characterize the complex thermodynamic relationship among these four known forms, and the other is to use the knowledge of the thermodynamic relationship to control the crystallization of these forms. The different forms were characterized by X-ray powder diffractometry as well as Fourier-transform infrared (FT-IR) and Raman spectroscopy; their complex thermodynamic relationships were determined by thermal analysis, solubility measurements, and slurry conversion studies. According to the solubility results, all forms are enantiotropically related: R is the thermodynamically most stable form above 60 degrees C, O is the most stable form between room temperature and 60 degrees C, LR is the most stable form below -15 degrees C, and DR is metastable throughout the entire temperature range. DR, LR, and O have very similar free energy at ambient temperature, which is the reason for the complex transition behavior. Finally, a schematic energy-temperature diagram was constructed that combines all experimental data in a comprehensive thermodynamic picture and provides insights into how to control the crystallization of the individual forms.

Drug-oligonucleotide conjugates

Abstract In this review, drug oligonucleotide conjugates synthesized and characterized in our laboratories will be discussed. An idealized view of a complex between an acridine-oligonucleotide conjugate and RNA is shown above. In addition, other related conjugates will be reviewed. The goal of this review is to establish that it is now feasible to synthesize a wide range of drug oligonucleotide conjugates. The testing of these molecules will provide important information on the pharmacological usefulness of targeting drugs to specific sequences using oligonucleotides.

Crystal Quality and Physical Reactivity in the Case of Flufenamic Acid (FFA)

In reality, no crystal is perfect. Crystals bear defects both in the bulk and on the surface. The purpose of this project is to study the correlation between crystal defect density and reactivity of physical transformation. The hypothesis is that larger crystals have the opportunity to pick up more defects during crystal growth than smaller crystals, therefore, have higher reactivity. Flufenamic acid (FFA) was used as a model compound. Phase transformation of crystal Form I (white) to Form III (yellow) of FFA was studied, and observed that larger crystals of FFA Form I transform faster. Furthermore, the etching pits identified on the major crystal faces (1 0 0) using atomic form microscopy (AFM) also showed that larger crystals had higher surface defect density than smaller ones, which correlates with the finding that larger crystals transforms faster than smaller ones.

Structural characterization of a metal-based perfusion tracer : copper(II) pyruvaldehyde bis(N4-methylthiosemicarbazone)

Copper(II) pyruvaldehyde bis(N4-methylthiosemicarbazone), Cu(PTSM), has been obtained as a dark red crystalline solid from EtOH-DMSO solvent mixture and structurally characterized by x-ray crystallography. The molecule possesses the expected pseudo-square planar N2S2 metal coordination sphere; however, the copper center also interacts through its axial coordination site with the sulfur atom of an adjacent Cu(PTSM) molecule in the crystal lattice. The structure of this compound is compared with the structures of other metal complexes that have been proposed in the nuclear medicine literature as perfusion tracers.

The crystallization of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile in the presence of structurally similar compounds

Abstract The lab-scale crystallization of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) has been investigated either alone or in the presence of structurally similar derivatives. Derivatives have been prepared that either change the crystal form or morphology of the product crystals as compared to 100% ROY crystallization experiments.

Solid-State Stability of Indomethacin Solvates

Abstract Desolvation kinetics of two indomethacin (IMC) solvates namely methanolate and tert−butyl alcohol (TBA) solvate were studied at 60–100 °C by isothermal thermogravimetric analysis. The solvates can transform to one of two true polymorphic forms, α or γ Solid-state desolvation of IMC predominantly proceeds by a nucleation-limited mechanism as described by Avrami-Erofeev kinetics. The activation energies of desolvation as determined from these kinetic data were 34 1 kcal/mol and 17.6 kcal/mol for the methanol and TBA solvates respectively. The rank order of activation energy correlates well with the hydrogen-bonding strength and the crystal packing of the solvates. The methanolate desolvates to the metastable a form, whereas the TBA solvate desolvates to the equilibrium γ form at all the temperatures studied.