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Biomedical subjects

P York

Publications and source records attributed to P York.

At least 37 records · Page 2Linked to original sources
PubMed1999

Resolution of ephedrine in supercritical CO(2): A novel technique for the separation of chiral drugs.

Racemic ephedrine has been resolved by diastereomeric salt formation with mandelic acid using supercritical CO(2) as precipitating agent. Crystallizations were performed using the Solution Enhanced Dispersion by Supercritical Fluids (SEDS) technique. Temperature was varied between 35 and 75 degrees C, and pressures ranged from 100 to 350 bar. Resolution, determined by chiral capillary electrophoresis, is described as a function of temperature and density of the supercritical fluid. A comparison of SEDS-produced material with a conventional resolution method shows that SEDS-crystallized material exhibits identical properties to conventionally crystallized material.

Carbon Dioxide↗
PubMed1999

Hydroxypropyl-beta-cyclodextrin inhibits spray-drying-induced inactivation of beta-galactosidase.

The single-step, fast spray-drying process may represent a valuable alternative to the multistep, time-consuming freeze-drying process in the area of formulation and processing of biopharmaceuticals. In this study, we tested the use of sucrose and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) as stabilizing excipients in the spray-drying of a model protein, beta-galactosidase. The solutions were processed using a Büchi 190 cocurrent Mini Spray Dryer at an outlet temperature of 61 +/- 2 degrees C. The powders were redissolved and analyzed for catalytic activity, aggregation, chemical decomposition, and thermal susceptibility as observed by high-resolution calorimetry. Spray-drying significantly inactivated beta-galactosidase. Spray-drying beta-galactosidase in the presence of sucrose did not prevent inactivation. However, after spray-drying beta-galactosidase in the presence of HP-beta-CD, or HP-beta-CD and sucrose, full catalytic activity was exhibited on reconstitution. Furthermore, the reconstituted product was unchanged in terms of molecular weight, charge, and thermal stability. These findings are consistent with a hypothesis that the change responsible for inactivation of beta-galactosidase was mainly a monomolecular, noncovalent change, i. e., the formation of incorrect structures, that arose from surface denaturation. This study clearly demonstrates that cyclodextrins can be useful stabilizing excipients in the preparation of spray-dried protein pharmaceuticals.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1999

Oleate salt formation and mesomorphic behavior in the propranolol/oleic acid binary system.

Thermal analysis of propranolol/oleic acid mixtures prepared by solvent evaporation enabled construction of the binary system phase diagram. This allowed both physical and chemical interactions to be identified, including complex formation at the equimolar composition. An incongruent melting complex with a characteristic reaction point was identified in excess oleic acid compositions, a common property of fatty acid/fatty acid salt binary systems. The equimolar complex was confirmed to be propranolol oleate using infrared spectroscopy. Wide-angle X-ray powder diffractometry demonstrated that propranolol oleate possessed long-range positional order ( approximately 25 A d spacing) accompanied by a degree of disorder over shorter d spacings. Such a pattern suggested mesophase formation, explaining the unctuous nature of propranolol oleate at room temperature. Accurate measurement of the long-range d spacing was achieved using small-angle X-ray scattering, permitting differentiation of the three different phases identified (phase I: 25.4 A, phase II: 24.6 A, phase III: 25.4-25.5 A). The implications of drug fatty acid salt formation and also mesomorphism in pharmaceutical systems are discussed.

Adrenergic beta-Antagonists↗
PubMed1999

Solubility parameters as predictors of miscibility in solid dispersions.

This paper reports interactions and possible incompatibilities in solid dispersions of hydrophobic drugs with hydrophilic carriers, with solubility parameters employed as a means of interpreting results. Systems containing ibuprofen (IB) and xylitol (XYL) in varying proportions and systems of IB with other sugars and a sugar polymer were produced using solvent evaporation and fusion methods. Additionally, bridging agents were employed with IB/XYL systems to facilitate the production of a solid dispersion. Results show that IB formed no interactions with any of the sugar carriers but interacted with all the bridging agents studied. The bridging agents were immiscible with XYL in the liquid state. Results of other reported drug/carrier systems and those from the systems studied in this paper were interpreted using Hildebrand solubility parameters. A trend between differences in drug/carrier solubility parameters and immiscibility was identified with incompatibilities evidence when large solubility parameter differences exist between drug and carrier. It was concluded that Hildebrand parameters give an indication of possible incompatibilities between drugs and carriers in solid dispersions, but that the use of partial solubility parameters may provide a more accurate prediction of interactions in and between materials and could provide more accurate indications of potential incompatibilities.

Analgesics, Non-Narcotic↗
PubMed1999

Phase behavioral effects on particle formation processes using supercritical fluids.

The application of supercritical fluid (SF) processing in pharmaceutical research is increasing particularly in the field of particle formation for drug delivery systems. The SF processes have benefits over the existing particle formation methods in terms of improved control, flexibility and operational ease. This review highlights the fundamental concepts of fluid phase behaviour and their influence on the various processes involving particle formation with supercritical fluids. Several phase behaviour systems are discussed to provide an insight into the factors influencing the process paths and their effects on the characteristics of the particles.

Chemistry, Pharmaceutical↗
PubMed1999

A central composite design to investigate the thermal stabilization of lysozyme.

PURPOSE: The formulation and processing of protein drugs requires the stabilization of the native, biologically active structure. Our aim was to investigate the thermal stability of a model protein, lysozyme, in the presence of two model excipients, sucrose and hydroxypropyl-beta-cyclodextrin (HP-beta-CD). METHODS: We used high sensitivity differential scanning calorimetry (HSDSC) in combination with a central composite design (CCD). As indicators of protein thermal stability, the measured responses were the unfolding transition temperature (Tm), the onset temperature of the denaturation (To), and the extrapolated onset temperature (To,e). RESULTS: A highly significant (F probability <0.001) statistical model resulted from analysis of the data The largest effect was due to pH (over the range 3.2-7.2), and the pH value that maximized Tm was 4.8. Several minor but significant effects were detected that were useful for mechanistic understanding. In particular, the effects of protein concentration and cyclodextrin concentration on Tm and To,e were found to be pH-dependent This was indicative of the partially hydrophilic nature of protein-protein interactions and protein-cyclodextrin interactions, respectively. CONCLUSIONS: Response surface methodology (RSM) proved efficient for the modeling and optimization of lysozyme thermal stability as well as for the physical understanding of the protein-sugar-cyclodextrin system in aqueous solution.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1999

Scaleup of a pharmaceutical granulation in planetary mixers.

The scaleup of a pharmaceutical granulation in a series of planetary mixers with increasing bowl capacity between 5 and 200 liters has been studied by applying the classical dimensionless numbers of Power, Reynolds, and Froude to define the power consumption profile of each mixer as a function of the processing conditions in dimensionless form. Experiments were performed using a formulation based on dicalcium phosphate dihydrate containing pregelatinized starch, with water being added at a fixed rate. Samples were taken at different power consumptions and assessed using mixer torque rheometry. Geometrically similar machines gave the same dimensionless relationship, but when similarity was compromised by the use of modified bowls and blades, different relationships occurred. The results show that, for geometrically similar machines, it is possible to calculate the power consumption at a predefined granulation endpoint at any given operating condition at any scale.

Chemistry, Pharmaceutical↗
PubMed1998

Solid-state characterization of chlordiazepoxide polymorphs.

A novel crystal form (form II) of the benzodiazepine chlordiazepoxide is reported. The new polymorphic phase was characterized and distinguished from the standard form (form I) by X-ray diffractometry, differential scanning calorimetry, infrared spectroscopy, microscopy, solution calorimetry, and solid-state nuclear magnetic resonance. The formation of form II was dependent on the crystallizing solvent, being the predominant form isolated from methanol. Recrystallization from other alcoholic solutions (ethanol, propanol, and butanol) and toluene yielded form I. Differential scanning calorimetry and powder X-ray diffraction indicated that the two forms were enantiotropically related with a transition of form II to form I occurring between 200 and 225 degreesC. Visual examination by hot stage microscopy in this temperature range revealed a dramatic solid-state transition. Single-crystal X-ray analysis was performed on form II which was found to crystallize in the triclinic space group P1 with a = 10.736(2) A, b = 16.921(4) A, c = 17.041(4) A, alpha = 100.76(1) degrees, beta = 95.27(1) degrees, gamma = 97.53(1) degrees, Z = 8, and dcal = 1.33 g/cm3. When compared with the published crystal structure of form I, the cell symmetry, volume, and density were similar. Both structures consisted of four crystallographically independent molecules linked in pairs through intermolecular hydrogen bonding. Differences were observed in the packing arrangement of the dimers in the polymorphs. The small heat of transition calculated from solution calorimetry (1.5 kJ mol-1) was sufficient to effect a crystallographic rearrangement of the dimers.

Calorimetry, Differential Scanning↗
PubMed1998

Characterization of the phase transitions of trehalose dihydrate on heating and subsequent dehydration.

Many pharmaceutical compounds of interest form hydrates. The phase behavior of different particle size fractions of trehalose dihydrate was studied as the sugar was dehydrated by heating. Hot-stage microscopy, X-ray powder diffraction, thermogravimetric analysis, and differential scanning calorimetry were used to characterize the phase changes. Small particles (<45 microm) formed an amorphous phase on dehydration and subsequently liquefied at temperatures above the glass transition temperature of amorphous trehalose. Crystallization to the anhydrate was observed from this supercooled liquid. Large particles (>425 microm) underwent a solid-solid conversion from the dihydrate to the anhydrate at temperatures as low as 80 degrees C. This solid-solid conversion was explained by a catalytic effect of the liberated dihydrate water on the rearrangement of the dehydrated phase to the anhydrate. The large surface area-to-volume ratio of the small particles resulted in dehydration prior to attaining the threshold temperature for rearrangement, explaining why solid-solid conversion was absent for these particles.

Calorimetry, Differential Scanning↗
PubMed1998

Particle size dependent molecular rearrangements during the dehydration of trehalose dihydrate in situ FT-Raman spectroscopy.

PURPOSE: (1) To characterise the different phases of trehalose using FT-Raman spectroscopy. (2) To monitor the changes in the structure of trehalose dihydrate on isothermal heating at 80 degrees C. METHODS: Different phases of trehalose were prepared and FT-Raman spectra obtained. Trehalose dihydrate was sieved to < 45 microns and > 425 microns particle size fractions and FT-Raman spectra were obtained at various time intervals during heating at 80 degrees C. RESULTS: During heating at this temperature, the spectra of a < 45 microns particle size fraction showed a loss of peak resolution with time and after 210 minutes resembled the spectrum of amorphous trehalose prepared by lyophilisation, indicating that the material was rendered amorphous by heating. In contrast, spectra obtained from a > 425 micron particle size fraction altered with time and became characteristic of the crystalline anhydrate. The approximate kinetics of this transformation to the anhydrate were monitored by analysis of peak intensity ratios with time. A two state rearrangement was indicated; some functional groups appeared to manoeuvre into the spatial arrangement found in the anhydrate initially before the rest of the ring structure relaxed into this conformation. This may be due to some parts of the molecule being immediately affected by the loss of the water molecules on dehydration prior to the subsequent reorientation of the entire molecule into the anhydrate crystal lattice. CONCLUSIONS: The < 45 micron particle size fraction becomes disordered on dehydration induced by heating at 80 degrees C whilst the > 425 micron particle size fraction crystallises to the anhydrate under the same conditions.

Calorimetry, Differential Scanning↗
PubMed1998

Supercritical fluid processing of materials from aqueous solutions: the application of SEDS to lactose as a model substance.

PURPOSE: The objective of the work was to study the factors influencing the crystallisation of alpha-lactose monohydrate from aqueous solution using the Solution Enhanced Dispersion by Supercritical Fluids (SEDS) technique. METHODS: An aqueous solution of alpha-lactose monohydrate is dispersed with a homogeneous mixture of carbon dioxide-ethanol/methanol using a co-axial nozzle. Crystallised lactose particles were analysed for water content by Karl-Fisher analysis, anomeric composition by Differential Scanning Calorimetry (DSC) and characterised for crystallinity by powder X-ray diffraction and morphology by scanning electron microscopy. RESULTS: Water content in the lactose recrystallised with ethanol was higher compared to the product obtained with methanol as cosolvent. Rate of crystallisation could be altered by varying the CO2 flow thereby modifying the water content in the lactose. At low flow rates of CO2, the crystallisation occurred in a cosolvent rich antisolvent phase causing rapid crystallisation whereas high flow rates of CO2 favoured a much slower crystallisation mechanism in the water rich phase. As a consequence, the morphology changed from thin long bands to large agglomerated chunks with mean particle size between 5 and 31 microns. CONCLUSIONS: The SEDS process is an efficient method for forming micron sized particles of water-soluble compounds with controlled physico-chemical properties.

Calorimetry, Differential Scanning↗
PubMed1998

Viewing preferences, symptoms of psychological trauma, and violent behaviors among children who watch television.

OBJECTIVE: To examine the extent to which children's television-viewing practices are associated with symptoms of psychological trauma and aggressive behaviors. The following three hypotheses were tested: (1) children who report watching greater amounts of television per day will report higher levels of trauma symptoms than children who report lesser amounts of television viewing; (2) children who report watching greater amounts of television per day will report higher levels of violent behaviors than children who report watching lesser amounts of television per day; and (3) children who report a preference for action and fighting programs will report higher levels of violent behaviors than children who report a preference for other types of television programs. METHOD: The study used a survey design in which an anonymous self-report questionnaire was administered to students in grades 3 through 8 in 11 Ohio public schools during the 1995-1996 school year (N = 2,245). RESULTS: All three hypotheses were supported. CONCLUSION: Heavy television viewing by children may indicate the presence of problems such as depression, anxiety, and violent behaviors; such viewing should be screened for by psychiatrists and other mental health professionals working with children.

Aggression↗
PubMed1998

A methodology for the optimization of wet granulation in a model planetary mixer.

This paper investigates a methodology for the optimization of wet granulation processes in planetary mixers. A model formulation was granulated in a planetary mixer (two different bowl sizes). The wet masses were characterized by their bulk density and consistency (as measured by mixer torque rheometry), and the feasibility of scale-up from one mixer bowl to the other was studied using a dimensionless numbers approach for the estimation of the power consumption at the granulation end point. Both bowls gave the same dimensionless power relationships (a relationship between the power number, Reynolds number, Froude number, and bowl fill ratio), which could therefore be used for calculating the power consumption level when the wet mass achieves its target values of density and consistency, i.e., the point at which granulation should be stopped. It was also shown that batches granulated in different conditions (batch size, blade speed) in two planetary mixers, but presenting similar wet mass characteristics (bulk density and consistency) led to dry granules of similar properties: granule size distribution, density, friability, and flow. This work suggests that it is possible to characterize the wet mass by only two parameters which describe the quality of the downstream granules. The scale-up procedure based on the use of dimensionless numbers was found to be applicable to planetary mixers, provided they give one common dimensionless power relationship.

Technology, Pharmaceutical↗
PubMed1997

Improved bioavailability and clinical response in patients with chronic liver disease following the administration of a spironolactone: beta-cyclodextrin complex.

AIMS: To compare the absorption and clinical effect of spironolactone from an inclusion complex with beta-cyclodextrin (SP-COMP) to Aldactone tablets (ALD) in chronic liver disease. METHODS: Patients, admitted with chronic liver disease, completed a randomized crossover steady state study. They received their spironolactone dose as either daily SP-COMP or ALD for 7 days. Serial blood samples were drawn over a 24 h period from day 7 of each therapy. Accurate fluid balance was recorded on days 5-7 and 12-14. Thirteen (six females) whose mean (s.d.) age and weight was 58.4(9.3) years and 74.3(19.0) kg completed the study. RESULTS: The mean (95% confidence limits) relative bioavailability for SP-COMP (compared with ALD) from steady state serum concentrations of canrenone, 6beta-hydroxyl 7alpha-thiomethyl spironolactone and 7alpha-thiomethyl spironolactone was 310.0 (265.4, 336.7), 233.4(212.9, 250.8) and 254.8(230.8, 279.0)%, respectively. Improvements in clinical status and fluid balance occurred over the last 3 days of SP-COMP with a mean (s.d.) net loss, in fluid balance, of 1370(860)ml compared with a gain of 228(936)ml during ALD. CONCLUSIONS: Better absorption of spironolactone from the spironolactone: beta-cyclodextrin complex formulation should lead to a reduction in dosage and perhaps a more consistent effect in patients with chronic liver disease.

Biological Availability↗
PubMed1997

Characterization of frozen glucose solutions.

Reducing sugars may be used as additives in freeze-dried formulations. The purpose of this study is to examine the effect of freezing on nonequilibrated glucose solutions using FT-Raman spectroscopy. The methods used solutions freshly prepared from either alpha- or beta-crystalline glucose, frozen at different time intervals after dissolution. Solutions frozen immediately after dissolution showed peaks in the anomeric region of the spectrum characteristic of those observed for the parent crystalline form. No change occurred in these spectra after 24 hr in the frozen state. Solutions prepared from either alpha- or beta-crystalline glucose and left for 24 hr at room temperature before freezing showed the presence of both anomers. The glass transition temperature of maximally freeze-concentrated solutions of beta-glucose, frozen immediately after dissolution, was found to be approximately 3 degrees C lower than for solutions prepared from alpha-glucose. Freezing appears to halt the interconversion of glucose anomers, enabling the formation of predominantly alpha- or beta-frozen solutions which exhibit different properties. Freezing of nonequilibrated solutions of reducing sugars may lead to variation in the properties of freeze-dried formulations.

Calorimetry, Differential Scanning↗
PubMed1996

Characterization of dihydrates prepared from carbamazepine polymorphs.

To clarify earlier literature suggesting its existence in more than one solid form, carbamazepine dihydrate was prepared from individual anhydrous carbamazepine polymorphs I and III. The resultant materials were characterized by thermal and spectroscopic techniques, including variable-temperature Fourier transform (FT) Raman spectroscopy. On thermal dehydration, the carbamazepine dihydrates formed different anhydrous polymorphs depending on both starting material and dehydration conditions. Under conditions where liberated hydrate water cannot readily escape from around the sample, the dihydrate originating from polymorph III reverted to polymorph III, but under conditions of lower humidity/moisture, this dihydrate reverted to polymorph I. The dihydrate originating from polymorph I reverted to polymorph I irrespective of dehydration conditions. These observations could be due to a trace amount of nonhydrated original polymorph existing in the dihydrate phase that acts as a seed to regenerate the original polymorph under conditions where liberated hydrate water cannot readily escape from around the sample during dehydration. No evidence was generated that supported the existence of true polymorphs of carbamazepine dihydrate.

Calorimetry, Differential Scanning↗
PubMed1995

Sucrose reduces the efficiency of protein denaturation by a chaotropic agent.

Sugars and polyols are used to stabilize proteins. The degree of stabilization conferred on a model protein by sucrose was calculated in terms of the free energy of folding. Phosphoglycerate kinase (PGK) was denatured by guanidine hydrochloride (GuHCl) in different sucrose concentrations. The linear extrapolation method [1,2] was used to calculate the free energy of folding in the absence of denaturant. Although sucrose increased the concentration of GuHCl required to unfold the protein, the free energy of folding in water was unchanged. In order to probe the nature of the stabilizing effect of sucrose, an FT-Raman spectroscopic study of denaturant-polyol systems was undertaken. Investigations of interactions between GuHCl, urea or formamide and polyhydric compounds, revealed no evidence for hydrogen bonding or dipole-dipole associations. Polyhydric compounds caused minor changes in denaturant spectra although the converse was not observed. The structure of deuterated water changed on addition of denaturants. For non-ionic denaturants, addition of polyhydric solutes countered this change in water structure. Thus polyhydric compounds oppose the effect of denaturants on water structure. The observed increase in GuHCl concentration required to unfold PGK in the presence of sucrose may be attributed to this property of sucrose.

Formamides↗