Norfloxacin, a nalidixic acid analog with antimicrobial properties, exists in different hydrated ... more Norfloxacin, a nalidixic acid analog with antimicrobial properties, exists in different hydrated forms. Three of these crystal forms were reproducibly prepared and characterized by analytical techniques that included infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, solution microcalorimetry and pulsed nuclear-magnetic resonance spectroscopy. These studies showed that the dihydrate is the thermodynamically stable entity at ambient temperatures and humidities.
The effects of heptakis(2,6-di-Omethyl)-c CHL) is an aryl-substituted nitrogen mustard deriv- ati... more The effects of heptakis(2,6-di-Omethyl)-c CHL) is an aryl-substituted nitrogen mustard deriv- ative useful in the treatment of several human malignancies including chronic lymphocytic leukemia and Hodgkin's and non-Hodgkin's lymphomas. Chlorambucil (CHL) is a labile drug which in aqueous solution undergoes two consecutive unimolecular hydrolysis reactions leading to the formation of cyclic ethyleneimmonium ions and the loss of chloride ions.13 The rate-limiting step in the degradation of CHL is an intramolecular cyclization reaction to give the corresponding ethyleneimmonium ion. Etliyleneimmonium ions are highly susceptible to substitulion reactions with nucleophiles and, in aqueous solution, attack by hydroxide ions or w ater takes place readily, with productilon of the mono- and dihydroxylat- ed analogues. This degradation occurs rapidly at 25 "C, pH 6.5, with a shelf-life (t!,b%) of only 9 mine4 In addition to its poor stability, CHL is practiically insoluble in wat...
In this work, diesel soot has been characterized chemically using a diffuse reflectance infrared ... more In this work, diesel soot has been characterized chemically using a diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) technique. Diesel soot samples were generated under combustion conditions reproducing the typical urban operating mode of a diesel engine. Initial experiments performed to ensure the repeatability of the DRIFTS analysis and the sample preparation method showed that the standard deviations were always lower than 20% for the DRIFTS analysis itself, and lower than 25% when sample preparation was included. This is of special interest as regards application of the DRIFTS technique for quantitative analysis. The functional groups on the soot surface were identified on the basis of the infrared bands observed in the spectra at room temperature, indicating that the diesel soot analyzed comprises a mixture of aromatic hydrocarbons, carboxylic compounds, hydroxyl species, ether groups, and methylene and methyl groups. Analyses were also carried out at different temperatures in the interval of 298-858 K in order to analyze the thermal stability of the functional groups, with carbonyl groups, lactones and ethers appearing to be the most thermally stable compounds.
PDA journal of pharmaceutical science and technology / PDA
DSC: A Perkin-Elmer DSC-7 with Intracooler I (Per¬ kin-Elmer) was used for subambient DSC analysi... more DSC: A Perkin-Elmer DSC-7 with Intracooler I (Per¬ kin-Elmer) was used for subambient DSC analysis. Cyclohexane and indium were used to calibrate the DSC in the temperature range -40°C to 180°C. To construct an extended phase diagram for FK906, 5% to 98% (w/w) FK906 in water was cooled at a cooling rate of -10°C/min to -40°C. Solid samples of 2 to 3 mg and liquid samples of about 10 μ.L were loaded in sample
The polymorphic and pseudopolymorphic forms of mefloquine hydrochloride have been characterized b... more The polymorphic and pseudopolymorphic forms of mefloquine hydrochloride have been characterized by use of X-ray powder diffractometty, thermal analysis, infrared spectra1 analysis, scanning electron microscopy, and solubility measurements. It was determined that mefloquine hydrochloride can ctystallize in at least eight forms, anhydrous forms (A, B', E and MI, solvate forms (B and I) and hydrate forms (C and D). The acetone solvate (form B) and isopropanol solvate (form I) transform into forms B' and M, respectively, when they are heated on a hot stage. Form E, which was recrystallized from ethanol, showed gradual weight loss on heating, and a small endotherm in the DSC thermogram due to desolvation. However, the X-ray powder diffraction pattern of form E after removal of virtually all the ethanol, showed almost the same pattern. This suggests that ethanol is contained in channels within the crystal lattice of form E. An X-ray powder diffraction study showed that the crystal forms of mefloquine hydrochloride in lots of commercial tablets obtained from two sources were forms E and C. When the tablets were stored at 6o"C, 75% R.H., form E was transformed into form D, but form C did not undergo a significant change. A study of the effect of various excipients on the solid-state crystal transformation revealed that microcrystalline cellulose promotes the transformation from form E into form D. However, methylcellulose, hydroxyethylcellulose, P-cyclodextrin, crospovidone and hydrous lactose have no effect on the crystal transformation.
Cyclopentolate hydrochloride (Cy.HC1) undergoes degradation to give a-(1-hydroxycyclopentyl)-benz... more Cyclopentolate hydrochloride (Cy.HC1) undergoes degradation to give a-(1-hydroxycyclopentyl)-benzeneacetic acid (a B-hydroxy acid, by the expected normal ester hydrolysis pathway) and phenylacetic acid (by an unusual cyclic mechanism). These two products are formed simultaneously by parallel mechanisms. The interaction between cyclopentolate (Cy) and cyclodextrins (CDs) results in the formation of a 1:1 stoichiometric complex. 13-CD and its substituted analogs exhibit the greatest degree of stabilization of Cy against hydrolysis. In the presence of CDs, the parallel mechanism still operates, but the proportion of the reaction proceeding by the two pathways is altered. For the 13-hydroxy acid formation pathway, the complexed drug degrades at a rate ~ 1/10 as rapid as that of the uncomplexed drug in solution, while the decrease in rate constant for the phenylacetic acid formation pathway is substantially less. Apart from the stabilization effect, evidence for complex formation is available from NMR and molecular modeling studies. The optimum structure of the complex is obtained when the aromatic ring of the Cy molecule enters the CD cavity. When this occurs, the rate of normal ester hydrolysis is reduced. The hydroxycyclopentyl group apparently does not penetrate deeply into the CD cavity because of the presence of an intramolecular bond which can form between the hydroxyl group and the carbonyl oxygen. When interaction with CD occurs on the hydroxycyclopentyl end of the molecule the cyclic hydrolysis mechanism is affected, but not appreciably.
Theoretical and experimental studies relating the relative stability of solid vitamin A derivativ... more Theoretical and experimental studies relating the relative stability of solid vitamin A derivatives to their melting points have shown that, in general, resistance toward degradation increases with fusion temperature. This is attributed to the part that crystal lattice energy plays in stabilizing these compounds, and is supported by the fact that the solution stabilities of the derivatives appear to be generally comparable. Of the several compounds studied, vitamin A benzhydrazone and vitamin A succinate triphenylguanidine salt exhibited the greatest stability.
Three polymorphs (forms I–III), a monohydrate (form S2), and three new solvates [4:1 hydrate (for... more Three polymorphs (forms I–III), a monohydrate (form S2), and three new solvates [4:1 hydrate (form S1), monohydrate (form S3), and methanol half-solvate (form S4)] were isolated and characterized by X-ray powder diffractometry (XRPD), IR spectroscopy, differential scanning calorimetry (DSC), hot stage microscopy, solution calorimetry, and their dissolution rates. A new polymorph, designated as form V, melting at 146.5–148°C, was observed by hot stage microscopy. Our results indicate that only forms I and S4 exhibit reproducible DSC thermograms. Five of the isolated modifications undergo phase transformation on heating, and their DSC thermograms are not reproducible. Interpretation of DSC thermograms was facilitated by use of hot stage microscopy. The identification of each modification is based on XRPD patterns (except forms S3 and S4, for which the XRPD patterns are indistinguishable) and IR spectra. In the IR spectra, a significant difference was observed in the OH stretching region for all seven modifications. In a purity determination study, 5% of a contaminant modification in binary mixtures of several modifications could be detected by use of XRPD. To obtain a better understanding of the thermodynamic properties of these modifications, a series of increasing heating rates and different pan types were used in DSC. According to Burger's rule, forms I–III are monotropic polymorphs with decreasing stability in the order form I > form II > form III. The melting onsets and heats of fusion for forms I–III are 149.1 °C, 25.5 kJ/mol; 140.8 °C, 24.6 kJ/mol; and 137.8 °C, 24.0 kJ/mol, respectively. For form III the heat of fusion was calculated from heat of solution and DSC data. In the case of form S1 the melting point, 127.2°C, was obtained by DSC using a hermetically sealed pan. The relative stabilities of the six modifications stored under high humidity conditions were predicted to be, on the basis of the heat of solution and thermal analysis data, form S2 > form S3 > form S1 > form I > form II > form III. However, the results of the dissolution rate determination were inconsistent with the heat of solution data. The stable form I shows a higher initial dissolution rate than the metastable form II and unstable form III. All modifications were converted into the stable monohydrate, form S2, during the dissolution study, suggesting that the moisture level in solid formulations should be carefully controlled.
Norfloxacin, a nalidixic acid analog with antimicrobial properties, exists in different hydrated ... more Norfloxacin, a nalidixic acid analog with antimicrobial properties, exists in different hydrated forms. Three of these crystal forms were reproducibly prepared and characterized by analytical techniques that included infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, solution microcalorimetry and pulsed nuclear-magnetic resonance spectroscopy. These studies showed that the dihydrate is the thermodynamically stable entity at ambient temperatures and humidities.
The effects of heptakis(2,6-di-Omethyl)-c CHL) is an aryl-substituted nitrogen mustard deriv- ati... more The effects of heptakis(2,6-di-Omethyl)-c CHL) is an aryl-substituted nitrogen mustard deriv- ative useful in the treatment of several human malignancies including chronic lymphocytic leukemia and Hodgkin's and non-Hodgkin's lymphomas. Chlorambucil (CHL) is a labile drug which in aqueous solution undergoes two consecutive unimolecular hydrolysis reactions leading to the formation of cyclic ethyleneimmonium ions and the loss of chloride ions.13 The rate-limiting step in the degradation of CHL is an intramolecular cyclization reaction to give the corresponding ethyleneimmonium ion. Etliyleneimmonium ions are highly susceptible to substitulion reactions with nucleophiles and, in aqueous solution, attack by hydroxide ions or w ater takes place readily, with productilon of the mono- and dihydroxylat- ed analogues. This degradation occurs rapidly at 25 "C, pH 6.5, with a shelf-life (t!,b%) of only 9 mine4 In addition to its poor stability, CHL is practiically insoluble in wat...
In this work, diesel soot has been characterized chemically using a diffuse reflectance infrared ... more In this work, diesel soot has been characterized chemically using a diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) technique. Diesel soot samples were generated under combustion conditions reproducing the typical urban operating mode of a diesel engine. Initial experiments performed to ensure the repeatability of the DRIFTS analysis and the sample preparation method showed that the standard deviations were always lower than 20% for the DRIFTS analysis itself, and lower than 25% when sample preparation was included. This is of special interest as regards application of the DRIFTS technique for quantitative analysis. The functional groups on the soot surface were identified on the basis of the infrared bands observed in the spectra at room temperature, indicating that the diesel soot analyzed comprises a mixture of aromatic hydrocarbons, carboxylic compounds, hydroxyl species, ether groups, and methylene and methyl groups. Analyses were also carried out at different temperatures in the interval of 298-858 K in order to analyze the thermal stability of the functional groups, with carbonyl groups, lactones and ethers appearing to be the most thermally stable compounds.
PDA journal of pharmaceutical science and technology / PDA
DSC: A Perkin-Elmer DSC-7 with Intracooler I (Per¬ kin-Elmer) was used for subambient DSC analysi... more DSC: A Perkin-Elmer DSC-7 with Intracooler I (Per¬ kin-Elmer) was used for subambient DSC analysis. Cyclohexane and indium were used to calibrate the DSC in the temperature range -40°C to 180°C. To construct an extended phase diagram for FK906, 5% to 98% (w/w) FK906 in water was cooled at a cooling rate of -10°C/min to -40°C. Solid samples of 2 to 3 mg and liquid samples of about 10 μ.L were loaded in sample
The polymorphic and pseudopolymorphic forms of mefloquine hydrochloride have been characterized b... more The polymorphic and pseudopolymorphic forms of mefloquine hydrochloride have been characterized by use of X-ray powder diffractometty, thermal analysis, infrared spectra1 analysis, scanning electron microscopy, and solubility measurements. It was determined that mefloquine hydrochloride can ctystallize in at least eight forms, anhydrous forms (A, B', E and MI, solvate forms (B and I) and hydrate forms (C and D). The acetone solvate (form B) and isopropanol solvate (form I) transform into forms B' and M, respectively, when they are heated on a hot stage. Form E, which was recrystallized from ethanol, showed gradual weight loss on heating, and a small endotherm in the DSC thermogram due to desolvation. However, the X-ray powder diffraction pattern of form E after removal of virtually all the ethanol, showed almost the same pattern. This suggests that ethanol is contained in channels within the crystal lattice of form E. An X-ray powder diffraction study showed that the crystal forms of mefloquine hydrochloride in lots of commercial tablets obtained from two sources were forms E and C. When the tablets were stored at 6o"C, 75% R.H., form E was transformed into form D, but form C did not undergo a significant change. A study of the effect of various excipients on the solid-state crystal transformation revealed that microcrystalline cellulose promotes the transformation from form E into form D. However, methylcellulose, hydroxyethylcellulose, P-cyclodextrin, crospovidone and hydrous lactose have no effect on the crystal transformation.
Cyclopentolate hydrochloride (Cy.HC1) undergoes degradation to give a-(1-hydroxycyclopentyl)-benz... more Cyclopentolate hydrochloride (Cy.HC1) undergoes degradation to give a-(1-hydroxycyclopentyl)-benzeneacetic acid (a B-hydroxy acid, by the expected normal ester hydrolysis pathway) and phenylacetic acid (by an unusual cyclic mechanism). These two products are formed simultaneously by parallel mechanisms. The interaction between cyclopentolate (Cy) and cyclodextrins (CDs) results in the formation of a 1:1 stoichiometric complex. 13-CD and its substituted analogs exhibit the greatest degree of stabilization of Cy against hydrolysis. In the presence of CDs, the parallel mechanism still operates, but the proportion of the reaction proceeding by the two pathways is altered. For the 13-hydroxy acid formation pathway, the complexed drug degrades at a rate ~ 1/10 as rapid as that of the uncomplexed drug in solution, while the decrease in rate constant for the phenylacetic acid formation pathway is substantially less. Apart from the stabilization effect, evidence for complex formation is available from NMR and molecular modeling studies. The optimum structure of the complex is obtained when the aromatic ring of the Cy molecule enters the CD cavity. When this occurs, the rate of normal ester hydrolysis is reduced. The hydroxycyclopentyl group apparently does not penetrate deeply into the CD cavity because of the presence of an intramolecular bond which can form between the hydroxyl group and the carbonyl oxygen. When interaction with CD occurs on the hydroxycyclopentyl end of the molecule the cyclic hydrolysis mechanism is affected, but not appreciably.
Theoretical and experimental studies relating the relative stability of solid vitamin A derivativ... more Theoretical and experimental studies relating the relative stability of solid vitamin A derivatives to their melting points have shown that, in general, resistance toward degradation increases with fusion temperature. This is attributed to the part that crystal lattice energy plays in stabilizing these compounds, and is supported by the fact that the solution stabilities of the derivatives appear to be generally comparable. Of the several compounds studied, vitamin A benzhydrazone and vitamin A succinate triphenylguanidine salt exhibited the greatest stability.
Three polymorphs (forms I–III), a monohydrate (form S2), and three new solvates [4:1 hydrate (for... more Three polymorphs (forms I–III), a monohydrate (form S2), and three new solvates [4:1 hydrate (form S1), monohydrate (form S3), and methanol half-solvate (form S4)] were isolated and characterized by X-ray powder diffractometry (XRPD), IR spectroscopy, differential scanning calorimetry (DSC), hot stage microscopy, solution calorimetry, and their dissolution rates. A new polymorph, designated as form V, melting at 146.5–148°C, was observed by hot stage microscopy. Our results indicate that only forms I and S4 exhibit reproducible DSC thermograms. Five of the isolated modifications undergo phase transformation on heating, and their DSC thermograms are not reproducible. Interpretation of DSC thermograms was facilitated by use of hot stage microscopy. The identification of each modification is based on XRPD patterns (except forms S3 and S4, for which the XRPD patterns are indistinguishable) and IR spectra. In the IR spectra, a significant difference was observed in the OH stretching region for all seven modifications. In a purity determination study, 5% of a contaminant modification in binary mixtures of several modifications could be detected by use of XRPD. To obtain a better understanding of the thermodynamic properties of these modifications, a series of increasing heating rates and different pan types were used in DSC. According to Burger's rule, forms I–III are monotropic polymorphs with decreasing stability in the order form I > form II > form III. The melting onsets and heats of fusion for forms I–III are 149.1 °C, 25.5 kJ/mol; 140.8 °C, 24.6 kJ/mol; and 137.8 °C, 24.0 kJ/mol, respectively. For form III the heat of fusion was calculated from heat of solution and DSC data. In the case of form S1 the melting point, 127.2°C, was obtained by DSC using a hermetically sealed pan. The relative stabilities of the six modifications stored under high humidity conditions were predicted to be, on the basis of the heat of solution and thermal analysis data, form S2 > form S3 > form S1 > form I > form II > form III. However, the results of the dissolution rate determination were inconsistent with the heat of solution data. The stable form I shows a higher initial dissolution rate than the metastable form II and unstable form III. All modifications were converted into the stable monohydrate, form S2, during the dissolution study, suggesting that the moisture level in solid formulations should be carefully controlled.
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Papers by Keith Guillory