Gary mcgeorge - Academia.edu (original) (raw)
Papers by Gary mcgeorge
Journal of Pharmaceutical Innovation
Journal of Pharmaceutical Innovation
ABSTRACT Thesis (Ph. D.)--University of Durham, 1996.
Applied Spectroscopy, 2015
Hyperspectral chemical imaging technologies are frequently applied in the pharmaceutical industry... more Hyperspectral chemical imaging technologies are frequently applied in the pharmaceutical industry to assess the distribution of ingredients in product intermediates and finished products. This article discusses two recognized measures of spatial uniformity in the context of pharmaceuticals. Synthetic images are used to introduce the utility of Ripley's K-function and the Herfindahl-Hirschman index (HHI) for describing image content. These metrics were applied to a commercial-like product to demonstrate the practical interpretation for product development. The simple approaches presented here offer the possibility of reporting objective measures of intra-tablet compositional uniformity with minimal supervision.
AAPS PharmSciTech, Jan 24, 2015
Complete dissolution of the active pharmaceutical ingredient (API) is critical in the manufacturi... more Complete dissolution of the active pharmaceutical ingredient (API) is critical in the manufacturing of liquid-filled soft-gelatin capsules (SGC). Attenuated total reflectance UV spectroscopy (ATR-UV) and Raman spectroscopy have been investigated for in-line monitoring of API dissolution during manufacturing of an SGC product. Calibration models have been developed with both techniques for in-line determination of API potency. Performance of both techniques was evaluated and compared. The ATR-UV methodology was found to be able to monitor the dissolution process and determine the endpoint, but was sensitive to temperature variations. The Raman technique was also capable of effectively monitoring the process and was more robust to the temperature variation and process perturbations by using an excipient peak for internal correction. Different data preprocessing methodologies were explored in an attempt to improve method performance.
ChemInform, 2003
ABSTRACT For Abstract see ChemInform Abstract in Full Text.
With the accelerated pace of drug product development due to fast changes in the pharmaceutical i... more With the accelerated pace of drug product development due to fast changes in the pharmaceutical industry, the quality of the final product and the commercial process relies on the capability of detecting risks early in development and quickly diagnosing issues in routine commercial manufacture. In this particular study, the ability to characterize the behavior of agglomerated API throughout drug product development was enabled by efficient analytical tools to quickly identify risks. Agglomerated API was selected for use over large single particles because the agglomerate manufacturing process offered several advantages such as shorter cycle times and higher yield. However, the use of agglomerated API in the drug product process poses risks to blend uniformity and content uniformity of the final dosage form given that agglomerate properties such as size and strength may vary batch to batch. One such analytical tool that was employed for understanding risk and found to be critical to ...
Near-infrared (NIR) spectroscopy has played a key role in the evolution of pharmaceutical process... more Near-infrared (NIR) spectroscopy has played a key role in the evolution of pharmaceutical process monitoring for the manufacture of drug products. Since NIR spectroscopy is sensitive to chemical and physical attributes of the sample, careful attention needs to be paid to the many variables that impact the spectral response. This presentation will describe: 1) efforts to understand and model these variations to produce robust analytical methods; and 2) applications of NIR techniques (bench, online, and imaging) to understand relationships between processing parameters and pharmaceutical product quality.
Applied spectroscopy, 2014
Transmission near-infrared (NIR) measurements of a 1 mm thick aspirin disk were made at different... more Transmission near-infrared (NIR) measurements of a 1 mm thick aspirin disk were made at different positions as it was moved through a stack of eight 0.5 mm thick disks of microcrystalline cellulose (Avicel). The magnitude of the first derivative of absorbance for the aspirin interlayer at 8934 cm(-1) was lower when the disk was placed at the top or bottom of the stack of Avicel disks, with the largest signal observed when the aspirin was positioned at the central positions. The variation in signal with depth is consistent with that observed previously for transmission Raman spectrometry. In both cases, the trend observed can be attributed to lower photon density at the air-sample interface, relative to the center of the sample, owing to loss of photons to the air. This results in a reduction in the number of photons absorbed or Raman photons generated and subsequently detected when the interlayer occupies a near-surface position.
Journal of the Chemical Society, Perkin Transactions 2, 1996
ABSTRACT Polycrystalline powder samples of an azobenzene disperse dyestuff have been investigated... more ABSTRACT Polycrystalline powder samples of an azobenzene disperse dyestuff have been investigated using solid-state and solution-state 13C and 15N NMR spectroscopy in an attempt to understand the effect of polymorphism. Assignment of the 13C spectra indicates that it is possible to form an intramolecular hydrogen bond resulting in two conformations co-existing in the crystal structure of two of the polymorphs, as well as in solution, and differing by internal rotation of a side-chain acetamido group. This is clearly evident in the solid-state spectra at ambient temperature and in solution at sufficiently reduced temperatures. Each polymorph contains varying amounts of each conformer as a result of different crystal interactions, and conformer interchange can be shown to occur even in the solid state. This remarkable finding is accounted for by the open nature of the crystal structures, resulting from the steric effects of substituents, as attested by packing coefficients and molecular modelling. The conformational variations are confirmed by 15N spectra, and isotopic labelling by 15N allows tensor analysis to be applied which shows that the azo nitrogen's principal shielding components are significantly influenced by the formation of the hydrogen bond in one of the conformations.
Journal of the Chemical Society, Perkin Transactions 2, 1996
ABSTRACT Several complexes between substituted phenols and triphenylphosphine oxide (TPPO) were e... more ABSTRACT Several complexes between substituted phenols and triphenylphosphine oxide (TPPO) were examined both in solution and in the solid state by NMR spectroscopy. The degree of proton transfer from the phenol to TPPO in solution was studied by the 1H chemical shift of the phenolic OH proton and by the 13C chemical shifts of the phenol C–O (C1) and para(C4) carbons. As the pKa of the acid decreases, the 1H signal moves towards higher frequencies as a consequence of the deshielding produced by the proximity of the second oxygen. However, when the hydrogen is largely transferred to the oxide moiety, e.g. in the picric acid complex, the 1H resonance shifts to lower frequencies again. In turn, the 13C chemical shift of C1 is displaced to high frequencies, whereas C4 shifts in the reverse direction. The solid phase was studied through the changes in the 31P shielding tensor of the TPPO residue and by the C1 and C4 13C chemical shifts of the phenols. The proton transfer process follows the same pattern observed in solution. The values of the principal components of the 31P shielding tensor (σii) move towards those corresponding to symmetric tetrahedral phosphorus environments as the pKa of the phenol decreases.
Analytical Profiles of Drug Substances and Excipients, 1999
This chapter discusses the description, methods of preparation, physical properties, excipient st... more This chapter discusses the description, methods of preparation, physical properties, excipient studies, stability, and methods of analysis of sorbitol. Sorbitol is an odorless powder that is white or almost colorless. Various grades based on particle size are available, and it is obtained in various forms such as flakes, granules, pellets, or powder. Sorbitol is a hexahydric alcohol that is isomeric with mannitol. It has been described as a humectant, plasticizer, sweetening agent, and tablet and capsule diluent. It is used extensively in the pharmaceutical, cosmetics, and food industries, because it has a sweet taste and approximately 50–60% the sweetness of sucrose. In pharmaceutical applications, sorbitol is used as a tablet diluent in wet granulation or dry compression formulations. It is commonly used in chewable tablets because of its sweet taste, and it is used as a plasticizer for gelatin in capsule formulations. Sorbitol is utilized in sugar-free liquid preparations and as a stabilizer for drug, vitamin, and antacid suspensions. When it is used in syrups, crystallization around bottle caps is prevented. Sorbitol has also been used in injectable and topical products, and has a therapeutic use as an osmotic laxative.
The Journal of Physical Chemistry A, 1998
ABSTRACT A solid azobenzene dyestuff has been studied by a combination of single-crystal X-ray di... more ABSTRACT A solid azobenzene dyestuff has been studied by a combination of single-crystal X-ray diffraction and 15N CP/MAS NMR. The X-ray work establishes that the crystal structure of one polymorph is disordered. The 15N NMR proves that this is a temporal, rather than a spatial, effect. Three 15N-enriched isotopomers (together with a second polymorph) were examined by NMR, and assignments established by rotational resonance. The shielding tensor components were determined, and the angles of change between their orientations were established by a two-dimensional exchange experiment, the theory of which is discussed. Exchange rates were measured both by selective polarization inversion and by band shape analysis. Thermodynamic parameters for the barrier to exchange are presented. It is demonstrated, by the combination of X-ray and NMR work, that the process is essentially a crankshaft motion of the azo linkage.
Powder Technology, 2014
ABSTRACT In a Quality by Design (QbD) development environment the effect of early process paramet... more ABSTRACT In a Quality by Design (QbD) development environment the effect of early process parameters on downstream manufacturing parameters, and the ultimate effect on drug product quality, need to be understood. For poorly soluble drugs, size reduction is frequently employed to obtain consistent in-vivo exposures. As a result, micronization is a key early stage processing step for many active pharmaceutical ingredients (APIs). This paper demonstrates the effect of varying micronization conditions on an API for which micronization is deemed necessary to ensure consistent drug delivery after human administration. Material micronized to different extents are confirmed as different by surface area, surface energy, particle size analysis, bulk density and surface adhesion measurements. These material characteristics can be correlated with the outcomes from a key processing step, blending. The evolution of the blending process is followed using PAT techniques, so that an overall understanding of the relationship between particle properties and blend uniformity can be demonstrated. Execution of such a study during drug development can enable selection of the appropriate control strategy to ensure production of API in the desired range where consistent optimal bioavailability and downstream processability are achieved.
Molecular Physics, 1998
A sensitive, high-resolution 'FIREMAT' two-dimensional (2D) magic-angle-turning experim... more A sensitive, high-resolution 'FIREMAT' two-dimensional (2D) magic-angle-turning experiment is described that measures chemical shift tensor principal values in powdered solids. The spectra display spinning-sideband patterns separated by their isotropic shifts. The new method's sensitivity and high resolution in the isotropic-shift dimension result from combining the 5pi magic-angle-turning pulse sequence, an extension of the pseudo-2D sideband-suppression data rearrangement, and the TIGER protocol for processing 2D data. TPPM decoupling is used to enhance resolution. The method requires precise synchronization of the pulses and sampling to the rotor position. It is shown that the technique obtains 35 natural-abundance 13C tensors from erythromycin in 19 hours, and high quality naturalabundance 15N tensors from eight sites in potassium penicillin V in three days on a 400MHz spectrometer.
Magnetic Resonance in Chemistry, 1999
ABSTRACT The free acids and sodium salts of a series of sulphonated azobenzene dyestuffs were exa... more ABSTRACT The free acids and sodium salts of a series of sulphonated azobenzene dyestuffs were examined in the solid and solution states by 13C and 15N NMR spectroscopy. In solution the spectra of both the free acids and salts are characteristic of trans-azobenzene structures, as are the spectra of the solid samples of the salts. However, the spectra obtained from solid samples of the free acids are very different and are interpreted in terms of resonance structures of the azonium tautomers. Copyright © 1999 John Wiley & Sons, Ltd.
Journal of Pharmaceutical Innovation
Journal of Pharmaceutical Innovation
ABSTRACT Thesis (Ph. D.)--University of Durham, 1996.
Applied Spectroscopy, 2015
Hyperspectral chemical imaging technologies are frequently applied in the pharmaceutical industry... more Hyperspectral chemical imaging technologies are frequently applied in the pharmaceutical industry to assess the distribution of ingredients in product intermediates and finished products. This article discusses two recognized measures of spatial uniformity in the context of pharmaceuticals. Synthetic images are used to introduce the utility of Ripley's K-function and the Herfindahl-Hirschman index (HHI) for describing image content. These metrics were applied to a commercial-like product to demonstrate the practical interpretation for product development. The simple approaches presented here offer the possibility of reporting objective measures of intra-tablet compositional uniformity with minimal supervision.
AAPS PharmSciTech, Jan 24, 2015
Complete dissolution of the active pharmaceutical ingredient (API) is critical in the manufacturi... more Complete dissolution of the active pharmaceutical ingredient (API) is critical in the manufacturing of liquid-filled soft-gelatin capsules (SGC). Attenuated total reflectance UV spectroscopy (ATR-UV) and Raman spectroscopy have been investigated for in-line monitoring of API dissolution during manufacturing of an SGC product. Calibration models have been developed with both techniques for in-line determination of API potency. Performance of both techniques was evaluated and compared. The ATR-UV methodology was found to be able to monitor the dissolution process and determine the endpoint, but was sensitive to temperature variations. The Raman technique was also capable of effectively monitoring the process and was more robust to the temperature variation and process perturbations by using an excipient peak for internal correction. Different data preprocessing methodologies were explored in an attempt to improve method performance.
ChemInform, 2003
ABSTRACT For Abstract see ChemInform Abstract in Full Text.
With the accelerated pace of drug product development due to fast changes in the pharmaceutical i... more With the accelerated pace of drug product development due to fast changes in the pharmaceutical industry, the quality of the final product and the commercial process relies on the capability of detecting risks early in development and quickly diagnosing issues in routine commercial manufacture. In this particular study, the ability to characterize the behavior of agglomerated API throughout drug product development was enabled by efficient analytical tools to quickly identify risks. Agglomerated API was selected for use over large single particles because the agglomerate manufacturing process offered several advantages such as shorter cycle times and higher yield. However, the use of agglomerated API in the drug product process poses risks to blend uniformity and content uniformity of the final dosage form given that agglomerate properties such as size and strength may vary batch to batch. One such analytical tool that was employed for understanding risk and found to be critical to ...
Near-infrared (NIR) spectroscopy has played a key role in the evolution of pharmaceutical process... more Near-infrared (NIR) spectroscopy has played a key role in the evolution of pharmaceutical process monitoring for the manufacture of drug products. Since NIR spectroscopy is sensitive to chemical and physical attributes of the sample, careful attention needs to be paid to the many variables that impact the spectral response. This presentation will describe: 1) efforts to understand and model these variations to produce robust analytical methods; and 2) applications of NIR techniques (bench, online, and imaging) to understand relationships between processing parameters and pharmaceutical product quality.
Applied spectroscopy, 2014
Transmission near-infrared (NIR) measurements of a 1 mm thick aspirin disk were made at different... more Transmission near-infrared (NIR) measurements of a 1 mm thick aspirin disk were made at different positions as it was moved through a stack of eight 0.5 mm thick disks of microcrystalline cellulose (Avicel). The magnitude of the first derivative of absorbance for the aspirin interlayer at 8934 cm(-1) was lower when the disk was placed at the top or bottom of the stack of Avicel disks, with the largest signal observed when the aspirin was positioned at the central positions. The variation in signal with depth is consistent with that observed previously for transmission Raman spectrometry. In both cases, the trend observed can be attributed to lower photon density at the air-sample interface, relative to the center of the sample, owing to loss of photons to the air. This results in a reduction in the number of photons absorbed or Raman photons generated and subsequently detected when the interlayer occupies a near-surface position.
Journal of the Chemical Society, Perkin Transactions 2, 1996
ABSTRACT Polycrystalline powder samples of an azobenzene disperse dyestuff have been investigated... more ABSTRACT Polycrystalline powder samples of an azobenzene disperse dyestuff have been investigated using solid-state and solution-state 13C and 15N NMR spectroscopy in an attempt to understand the effect of polymorphism. Assignment of the 13C spectra indicates that it is possible to form an intramolecular hydrogen bond resulting in two conformations co-existing in the crystal structure of two of the polymorphs, as well as in solution, and differing by internal rotation of a side-chain acetamido group. This is clearly evident in the solid-state spectra at ambient temperature and in solution at sufficiently reduced temperatures. Each polymorph contains varying amounts of each conformer as a result of different crystal interactions, and conformer interchange can be shown to occur even in the solid state. This remarkable finding is accounted for by the open nature of the crystal structures, resulting from the steric effects of substituents, as attested by packing coefficients and molecular modelling. The conformational variations are confirmed by 15N spectra, and isotopic labelling by 15N allows tensor analysis to be applied which shows that the azo nitrogen's principal shielding components are significantly influenced by the formation of the hydrogen bond in one of the conformations.
Journal of the Chemical Society, Perkin Transactions 2, 1996
ABSTRACT Several complexes between substituted phenols and triphenylphosphine oxide (TPPO) were e... more ABSTRACT Several complexes between substituted phenols and triphenylphosphine oxide (TPPO) were examined both in solution and in the solid state by NMR spectroscopy. The degree of proton transfer from the phenol to TPPO in solution was studied by the 1H chemical shift of the phenolic OH proton and by the 13C chemical shifts of the phenol C–O (C1) and para(C4) carbons. As the pKa of the acid decreases, the 1H signal moves towards higher frequencies as a consequence of the deshielding produced by the proximity of the second oxygen. However, when the hydrogen is largely transferred to the oxide moiety, e.g. in the picric acid complex, the 1H resonance shifts to lower frequencies again. In turn, the 13C chemical shift of C1 is displaced to high frequencies, whereas C4 shifts in the reverse direction. The solid phase was studied through the changes in the 31P shielding tensor of the TPPO residue and by the C1 and C4 13C chemical shifts of the phenols. The proton transfer process follows the same pattern observed in solution. The values of the principal components of the 31P shielding tensor (σii) move towards those corresponding to symmetric tetrahedral phosphorus environments as the pKa of the phenol decreases.
Analytical Profiles of Drug Substances and Excipients, 1999
This chapter discusses the description, methods of preparation, physical properties, excipient st... more This chapter discusses the description, methods of preparation, physical properties, excipient studies, stability, and methods of analysis of sorbitol. Sorbitol is an odorless powder that is white or almost colorless. Various grades based on particle size are available, and it is obtained in various forms such as flakes, granules, pellets, or powder. Sorbitol is a hexahydric alcohol that is isomeric with mannitol. It has been described as a humectant, plasticizer, sweetening agent, and tablet and capsule diluent. It is used extensively in the pharmaceutical, cosmetics, and food industries, because it has a sweet taste and approximately 50–60% the sweetness of sucrose. In pharmaceutical applications, sorbitol is used as a tablet diluent in wet granulation or dry compression formulations. It is commonly used in chewable tablets because of its sweet taste, and it is used as a plasticizer for gelatin in capsule formulations. Sorbitol is utilized in sugar-free liquid preparations and as a stabilizer for drug, vitamin, and antacid suspensions. When it is used in syrups, crystallization around bottle caps is prevented. Sorbitol has also been used in injectable and topical products, and has a therapeutic use as an osmotic laxative.
The Journal of Physical Chemistry A, 1998
ABSTRACT A solid azobenzene dyestuff has been studied by a combination of single-crystal X-ray di... more ABSTRACT A solid azobenzene dyestuff has been studied by a combination of single-crystal X-ray diffraction and 15N CP/MAS NMR. The X-ray work establishes that the crystal structure of one polymorph is disordered. The 15N NMR proves that this is a temporal, rather than a spatial, effect. Three 15N-enriched isotopomers (together with a second polymorph) were examined by NMR, and assignments established by rotational resonance. The shielding tensor components were determined, and the angles of change between their orientations were established by a two-dimensional exchange experiment, the theory of which is discussed. Exchange rates were measured both by selective polarization inversion and by band shape analysis. Thermodynamic parameters for the barrier to exchange are presented. It is demonstrated, by the combination of X-ray and NMR work, that the process is essentially a crankshaft motion of the azo linkage.
Powder Technology, 2014
ABSTRACT In a Quality by Design (QbD) development environment the effect of early process paramet... more ABSTRACT In a Quality by Design (QbD) development environment the effect of early process parameters on downstream manufacturing parameters, and the ultimate effect on drug product quality, need to be understood. For poorly soluble drugs, size reduction is frequently employed to obtain consistent in-vivo exposures. As a result, micronization is a key early stage processing step for many active pharmaceutical ingredients (APIs). This paper demonstrates the effect of varying micronization conditions on an API for which micronization is deemed necessary to ensure consistent drug delivery after human administration. Material micronized to different extents are confirmed as different by surface area, surface energy, particle size analysis, bulk density and surface adhesion measurements. These material characteristics can be correlated with the outcomes from a key processing step, blending. The evolution of the blending process is followed using PAT techniques, so that an overall understanding of the relationship between particle properties and blend uniformity can be demonstrated. Execution of such a study during drug development can enable selection of the appropriate control strategy to ensure production of API in the desired range where consistent optimal bioavailability and downstream processability are achieved.
Molecular Physics, 1998
A sensitive, high-resolution 'FIREMAT' two-dimensional (2D) magic-angle-turning experim... more A sensitive, high-resolution 'FIREMAT' two-dimensional (2D) magic-angle-turning experiment is described that measures chemical shift tensor principal values in powdered solids. The spectra display spinning-sideband patterns separated by their isotropic shifts. The new method's sensitivity and high resolution in the isotropic-shift dimension result from combining the 5pi magic-angle-turning pulse sequence, an extension of the pseudo-2D sideband-suppression data rearrangement, and the TIGER protocol for processing 2D data. TPPM decoupling is used to enhance resolution. The method requires precise synchronization of the pulses and sampling to the rotor position. It is shown that the technique obtains 35 natural-abundance 13C tensors from erythromycin in 19 hours, and high quality naturalabundance 15N tensors from eight sites in potassium penicillin V in three days on a 400MHz spectrometer.
Magnetic Resonance in Chemistry, 1999
ABSTRACT The free acids and sodium salts of a series of sulphonated azobenzene dyestuffs were exa... more ABSTRACT The free acids and sodium salts of a series of sulphonated azobenzene dyestuffs were examined in the solid and solution states by 13C and 15N NMR spectroscopy. In solution the spectra of both the free acids and salts are characteristic of trans-azobenzene structures, as are the spectra of the solid samples of the salts. However, the spectra obtained from solid samples of the free acids are very different and are interpreted in terms of resonance structures of the azonium tautomers. Copyright © 1999 John Wiley & Sons, Ltd.