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Biomedical subjects

R Suryanarayanan

Publications and source records attributed to R Suryanarayanan.

At least 37 records · Page 2Linked to original sources
PubMed1998

Characterization of phase transitions during freeze-drying by in situ X-ray powder diffractometry.

The purpose of this research was to develop the technique of in situ freeze-drying in the sample chamber of an X-ray powder diffractometer (XRD) and to monitor the phase transitions during the freeze-drying of aqueous solutions of sodium nafcillin (I) and mannitol (II). Aqueous solutions of I and II were frozen under controlled conditions in the sample chamber of an XRD. This variable temperature XRD was modified so that the sample chamber could be evacuated and the samples dried under reduced pressures. Thus the entire freeze-drying cycle was carried out in the XRD holder and the solid-state was monitored during the various stages of the process. Frozen solutions of I when annealed at -4 degrees C, resulted in crystallization of the solute as 'sodium nafcillin hydrate' (unknown stoichiometry). Primary drying at -10 degrees C, resulted in partial dehydration to a poorly crystalline sodium nafcillin hemihydrate. There was no crystallization of mannitol when solutions of II were cooled and subjected to primary drying at -50 degrees C. During the drying, the intensities of the characteristic X-ray lines of ice (d-spacings of 3.94, 3.70 and 3.48 A) were quantified. This enabled real time monitoring of the complete sublimation of crystalline ice. When the secondary drying was carried out at -25 degrees C, mannitol crystallized as an anhydrous mixture of the delta- and beta-polymorphs. In a second set of experiments, the frozen solutions were warmed to -25 degrees C and subjected to primary drying. Mannitol crystallized and its XRD pattern matched that of mannitol hydrate reported recently (Yu et al., Pharm. Res., 14S (1997) S-445). When the secondary drying was carried out at -10 degrees C, there was no change in the XRD pattern suggesting the formation of a dehydrated hydrate. This in situ XRD technique enabled us to characterize the phase transitions during freeze-drying. It would be useful in developing a mechanistic understanding of the alterations in the solid-state during freeze-drying of complex, multi-component, pharmaceutical systems.

Crystallization↗
PubMed1998

Influence of environmental conditions on the kinetics and mechanism of dehydration of carbamazepine dihydrate.

The object of this project was to study the influence of temperature and water vapor pressure on the kinetics and mechanism of dehydration of carbamazepine dihydrate and to establish the relationship between the dehydration mechanism and the solid-state of the anhydrous phase formed. Three experimental techniques were utilized to study the kinetics of dehydration of carbamazepine dihydrate (C15H12N2O.2H2O)-thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and variable temperature powder X-ray diffractometry (VTXRD). These techniques respectively provide information about the changes in weight, heat flow and solid-state (phase) during the dehydration process. The instrumental setup was modified so that simultaneous control of both the temperature and the water vapor pressure was possible. The experiments were carried out at different temperatures, ranging from 26 to 64 degrees C. In the absence of water vapor, the dehydration followed the 2-dimensional phase boundary controlled model at all the temperatures studied. In the next stage, the water vapor pressure was altered while the studies were carried out at a single temperature of 44 degrees C. The dehydration was 2-dimensional phase boundary controlled at water vapor pressures < or = 5.1 torr while the Avrami-Erofeev kinetics (3-dimensional nucleation) was followed at water vapor pressures > or = 12.0 torr. In the former case, the anhydrous phase formed was X-ray amorphous while it was the crystalline anhydrous gamma-carbamazepine in the latter. Thus a relationship between the mechanism of dehydration and the solid-state of the product phase was evident. The dehydration conditions influence not only the mechanism but also the solid-state of the anhydrous phase formed. While the techniques of TGA and DSC have found extensive use in studying dehydration reactions, VTXRD proved to be an excellent complement in characterizing the solid-states of the reactant and product phases.

Anticonvulsants↗
PubMed1997

Applications of pressure differential scanning calorimetry in the study of pharmaceutical hydrates. I. Carbamazepine dihydrate.

The dehydration of carbamazepine dihydrate (C(15)H(12)N(2)O.2H(2)O) was studied by both conventional differential scanning calorimetry (DSC) and by pressure differential scanning calorimetry. Variable temperature powder X-ray diffractometry (VTXRD) and thermogravimetric analysis were used as complementary techniques. By performing DSC at elevated pressures, the dehydration and vaporization endotherms were separated and it was possible to determine the enthalpy of dehydration. Over the range of 100-600 psi, the enthalpy of dehydration was unaffected by pressure. However, the solid-state of the anhydrous phase formed was influenced by the DSC conditions. At ambient pressure, dehydration resulted in the formation of the gamma-form of anhydrous carbamazepine while at elevated pressures, the anhydrous beta-form appeared which converted to the gamma-form at higher temperatures. At high pressures, the water liberated on dehydration is not immediately removed and its presence appears to be responsible for the formation of beta-carbamazepine. VTXRD permitted in situ study of dehydration and this confirmed the DSC results. A specially fabricated sample holder permitted VTXRD studies at elevated pressures.

Journal Article↗
PubMed1997

Identification of drugs in pharmaceutical dosage forms by X-ray powder diffractometry.

A simple X-ray powder diffractometric (XRD) method was developed for the identification of the active ingredient in a variety of dosage forms. The method was successfully used to unambiguously identify the active ingredient(s) in tablet, capsule, suppository and ointment formulations. The unique feature of the method is that it provides information about the solid-state of the drug. Thus, a capsule formulation containing anhydrous ampicillin was readily distinguished from that containing ampicillin trihydrate. The USP stipulates the use of the beta-polymorphic form of anhydrous carbamazepine in carbamazepine tablets. Contamination by the alpha-polymorph (down to a level of 1.4% w/w of the formulation) could be detected. In some of the multicomponent formulations, there was a pronounced overlap of the powder patterns of ingredients which made identification difficult. This problem was solved by using a pattern subtraction technique, which permitted selective subtraction of the XRD pattern of the constituents of the formulation from the overall XRD pattern. Such an approach enabled identification of the drug even when it constituted only 5% w/w of the formulation. The method also permitted simultaneous identification of the multiple active ingredients in trimethoprim-sulfamethoxazole and acetaminophen-aspirin-caffeine formulations.

Capsules↗
PubMed1997

A novel X-ray powder diffractometric method for studying the reaction between pseudoephedrine enantiomers.

The opposite enantiomers of pseudoephedrine were observed to react in the solid state to form the racemic compound. A novel powder X-ray diffractometric method was developed for studying the kinetics and mechanism of this reaction. The powder X-ray diffraction patterns of the enantiomers were identical, but the racemic compound exhibited a different pattern because of its different crystal structure. The powder patterns of the enantiomers and the racemic compound revealed that the 4.62 and 4.25 A lines were unique to the enantiomers and the racemic compound, respectively. Teflon holders were filled with equimolar mixtures of the two enantiomers, and the integrated intensities of the 4.62 and 4.25 A lines were measured at 30-min intervals over a period of 8 h. Thus, the disappearance of the crystalline enantiomers and the appearance of the crystalline racemic compound were quantified simultaneously. The rate of disappearance of the crystalline enantiomers followed a diffusion-controlled reaction model originally proposed by Jander in 1927. During the kinetic experiment, the sum of the weight fractions of the enantiomers and the racemic compound progressively decreased from an initial value of unity suggesting the existence of an intermediate noncrystalline phase. The presence of the noncrystalline phase was confirmed by a steady increase in the background of the X-ray patterns. Thus, the unique ability of the X-ray method to quantify only the crystalline phases has demonstrated the existence of a non-crystalline amorphous intermediate in this solid-solid reaction.

Crystallography, X-Ray↗
PubMed1997

Polymorphism in anhydrous theophylline--implications on the dissolution rate of theophylline tablets.

The objects of this investigation were (i) to prepare and characterize a new anhydrous theophylline phase that is metastable under ambient conditions, and (ii) to prepare model tablet formulations containing either this metastable anhydrate (I*) or stable anhydrous theophylline (I), store them under different relative humidity (RH) conditions, and compare their dissolution behavior. I* was prepared by dehydration of theophylline monohydrate (II). Variable temperature X-ray powder diffractometry of II revealed the following series of transitions: II-->I*-->I. The metastable anhydrate, I*, which has not yet been reported in the literature, appears to be related monotropically to I. It was characterized by ambient and variable temperature X-ray powder diffractometry, Karl Fischer titrimetry, and thermoanalytical techniques (differential scanning calorimetry and thermogravimetric analysis). Tablet formulations containing either I* or I were prepared and stored at 33 and 52% RH (room temperature). The solid state of the drug was monitored by X-ray powder diffractometry and the tablets were subjected to the USP dissolution test. In tablets, I* completely converted to I in < or = 10 days when stored at either 33 or 52% RH. Scanning electron microscopy provided direct visual evidence of recrystallization. This recrystallization was accompanied by a decrease in the dissolution rate of the stored formulations that was so pronounced in the formulations stored at 52% RH that they failed the USP dissolution test. The in situ solid-state transition appears to be responsible for the decrease in dissolution rate observed following storage. Stored tablets containing I showed neither a phase transition nor an alteration in their dissolution behavior.

Microscopy, Electron, Scanning↗
PubMed1997

Simultaneous quantification of an enantiomer and the racemic compound of ibuprofen by X-ray powder diffractometry.

PURPOSE: An X-ray powder diffractometric method was developed for the simultaneous quantification of the relative amounts of the racemic compound (+/-) of ibuprofen (I) and S(+)-ibuprofen (II), when they occur as a mixture. METHOD: The X-ray powder diffraction patterns of I and II show pronounced differences. This formed the basis for the determination of the relative amounts of I and II when they occur as a mixture. X-ray lines with d-spacings of 14.41 and 4.37 A were unique to I and II, respectively. Mixtures containing different proportions of I and II were prepared which also contained lithium fluoride (III) as an internal standard. RESULTS: A linear relationship was obtained when the intensity ratio (intensity of the 4.37 A line of II/intensity of the 2.01 A line of III) was plotted as a function of the weight fraction of II in the mixture. Similar results were obtained in the case of I. Using these standard curves, the weight fractions of I and II in "unknown" mixtures were determined. The experimentally determined analyte concentration ranged between 98 and 104% of the true value. The relative error in the analyses of individual samples was < 10%. The minimum detectable weight fraction of I and II and II in I were 0.032 (3.2% w/w) and 0.034 (3.4% w/w), respectively. The minimum quantifiable weight fractions were 0.136 for I and 0.112 for II. Since the X-ray diffraction patterns of S(+)-ibuprofen and R(-)-ibuprofen are identical, the conclusions drawn regarding mixtures of I and II will also hold true in the quantitative analyses of mixtures of I and R(-)-ibuprofen.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

An implantable dosage form for the treatment of bone infections.

The object of this investigation was the development of an implantable sustained-release dosage form, for the treatment of bone infections. Cross-linked polydimethylsiloxane (PDMS) was used as the matrix material. The drug delivery system was prepared by incorporating tobramycin, as a free base (C18H37N5O9.H2O) or as a sulfate salt [(C18H37N5O9)2.5H2SO4], into the matrix and molding into spherical beads. Following in vitro studies, the cumulative amount of drug released when plotted as a function of the square root of time was linear for both the base and the salt. The addition of glycerol to the matrix substantially accelerated the rate of drug release and the plots of cumulative amount of drug released continued to be linear as a function of the square root of time. The glycerol-incorporated beads swelled in contact with the aqueous medium but a negligible amount of glycerol was released even after exposure to the medium for 20 days. 13C solid-state and high-resolution NMR studies indicated that a fraction of the added glycerol participated in the cross-linking reaction of the polymer. The effect of the initial molecular weight of PDMS and the effect of the concentration of the cross-linker on the kinetics of drug release were investigated.

Cross-Linking Reagents↗
PubMed1992

Sustained release of nerve growth factor from biodegradable polymer microspheres.

Although grafted adrenal medullary tissue to the striatum has been used both experimentally and clinically in parkinsonism, there is a definite need to augment long-term survival. Infusion of nerve growth factor (NGF) or implantation of NGF-rich tissue into the area of the graft prolongs survival and induces differentiation into neural-like cells. To provide for prolonged, site-specific delivery of this growth factor to the grafted tissue in a convenient manner, we fabricated biodegradable polymer microspheres of poly(L-lactide)co-glycolide (70:30) containing NGF. Biologically active NGF was released from the microspheres, as assayed by neurite outgrowth in a dorsal root ganglion tissue culture system. Anti-NGF could block this outgrowth. An enzyme-linked immunosorbent assay detected NGF still being released in vitro for longer than 5 weeks. In vivo immunohistochemical studies showed release over a 4.5-week period. This technique should prove useful for incorporating NGF and other growth factors into polymers and delivering proteins and other macromolecules intracerebrally over a prolonged time period. These growth factor-containing polymer microspheres can be used in work aimed at prolonging graft survival, treating experimental Alzheimer's disease, and augmenting peripheral nerve regeneration.

Adrenal Medulla↗
PubMed1991

Kinetics of transition of anhydrous carbamazepine to carbamazepine dihydrate in aqueous suspensions.

When suspended in water, anhydrous carbamazepine (C15H12N2O; 1) was transformed to carbamazepine dihydrate (C15H12N2O.2H2O; 2). Compound 1 was dispersed in water at 25 degrees C, and an aliquot of the slurry was taken at periodic intervals and immediately filtered under conditions which removed all the physically bound water from the solid. The weight fractions of 1 and 2 in the solid were quantified by two methods: (a) by determining the weight loss on drying the solid at 60 degrees C under reduced pressure to a constant weight and (b) by a quantitative powder X-ray diffraction technique. There was good agreement between the above two methods. More than 95% (w/w) of 1 was converted to 2 in 1 h and the decrease in the weight fraction of 1 with time was approximately a first-order process.

Carbamazepine↗
PubMed1991

A liquid-chromatographic method for the determination of tobramycin.

A rapid and sensitive liquid-chromatographic method was developed to quantify the release of tobramycin from polymeric drug delivery systems in vitro. Pre-column derivatization of tobramycin and kanamycin B sulphate (internal standard) was carried out with 2,4,6-trinitrobenzenesulphonic acid. The sample volume required was only 50 microliters. The chromatographic separation was achieved on an octyl reversed-phase column with UV detection at 340 nm. This isocratic method was performed at ambient temperature and required only 8 min of chromatography time. The standard curves were linear over the concentration range 0.50-50.0 mg l-1. Inter-day and intra-day relative standard deviations ranged from 3.6 to 9.3% and from 1.6 to 6.8%, respectively. The assay method was used to determine the tobramycin content in different pharmaceutical formulations and to study the stability of the drug both in the solid-state and in solution.

Buffers↗
PubMed1991

Quantitative analysis of the active tablet ingredient by powder X-ray diffractometry.

A powder X-ray diffraction technique has been developed for the quantitative analysis of the active ingredient in intact tablets. Two model drugs were used: lithium carbonate (LC) and carbamazepine (CBZ). Mixtures containing various weight fractions of each drug and microcrystalline cellulose were compressed into tablets and the integrated intensities of several diffraction lines of each were used for quantitative purposes. The ratio of the integrated intensity of these lines in tablets, made from mixtures of drug and microcrystalline cellulose, to the intensity of the same lines in tablets made from only drug was calculated as a function of the weight fraction of the drug in the mixture. These ratios were also experimentally determined and the relative error in the determination of LC was less than 12%. CBZ tablets containing starch were also prepared. In the CBZ tablets containing microcrystalline cellulose or starch, the relative error in the determination of CBZ was less than 10% only when the weight fraction of CBZ in the tablets was greater than or equal to 0.4.

Antiviral Agents↗
PubMed1990

Quantitation of the relative amounts of anhydrous carbamazepine (C15H12N2O) and carbamazepine dihydrate (C15H12N2O.2H2O) in a mixture by solid-state nuclear magnetic resonance (NMR).

The application of solid state nuclear magnetic resonance (NMR) for the quantitation of the relative amounts of carbamazepine anhydrate (I) and carbamazepine dihydrate (II) in a mixture is presented. The techniques of cross polarization, dipolar decoupling, and magic angle spinning have been used to obtain high-resolution NMR spectra of the samples in the solid state. Although the chemical shifts of I and II were similar, the proton spin lattice relaxation time of II was much shorter than that of I. A delay time of 10 sec between pulses resulted in saturation of the signal from I and in a spectrum arising solely from II. The dependence of the observed signal intensity on the contact time was evaluated for II and glycine, the internal standard, to allow theoretical estimation of the peak area ratios. Various molar ratios of I and II were then mixed with glycine, and the resulting peak area ratios of II to the area of the alpha and the carbonyl carbons of glycine was linearly related to the relative proportion of II in the mixture.

Carbamazepine↗
PubMed1989

Determination of the relative amounts of anhydrous carbamazepine (C15H12N2O) and carbamazepine dihydrate (C15H12N2O.2H2O) in a mixture by powder x-ray diffractometry.

A powder x-ray diffraction technique has been developed to quantify the relative amounts of anhydrous carbamazepine (C15H12N2O) (I) and carbamazepine dihydrate (C15H12N2O.2H2O) (II) when they occur as a mixture. The theoretical basis of this technique was developed by Alexander and Klug (Anal. Chem. 20:886-889, 1948). The powder x-ray diffraction patterns of I and II revealed that the lines with d-spacings of 6.78 and 9.93 A were unique to I and II, respectively. The ratio of the integrated intensity of the 6.78 A line in a mixture of I and II to the intensity of the 6.78 A line in a sample consisting of only I was calculated as a function of weight fraction of I in the mixture. These ratios were also experimentally determined, and there was a good agreement between the theoretical and the experimental intensity ratios. Similarly good agreements between the theoretical and the experimental intensity ratios for the 9.93 A line of II were obtained. The samples were compressed into tablets and subjected to x-ray analysis. When compressed to a certain pressure, the particles tended to orient the same way in replicate samples resulting in highly reproducible intensity values. Compression into tablets was necessary because the powder samples yielded unsatisfactory results.

Calorimetry, Differential Scanning↗
PubMed1984

Precipitation of calcium gluceptate from aqueous solutions.

A precipitate encountered in solutions of calcium gluceptate was identified as hydrated calcium gluceptate. Precipitation was associated with a change from a very soluble amorphous anhydrous form to a sparingly soluble crystalline hydrate, the presence of seed crystals inducing crystallization, and unsuitable proportions of the alpha- and beta-epimers of calcium gluceptate. Various commercial samples and the corresponding precipitates were examined by elemental analysis, thermal analysis, X-ray diffraction, IR spectroscopy, and GC-MS. The proportion of the alpha- and beta-epimers in commercial samples was quantitated by GC. In this method, an aqueous solution of calcium gluceptate was converted into a mixture of glucoheptonic acids and their corresponding lactones by passage through a cation-exchange resin. The solution was freeze-dried, the acid-lactone mixture converted to the gamma-lactones using concentrated hydrochloric acid, and the resulting material trimethylsilylated with trimethylsilylimidazole. Stability studies of solutions prepared from calcium gluceptate obtained from various commercial sources indicate that above approximately 50% alpha-epimer, stability decreased with an increase in the relative proportion of the alpha-epimer. Material complying with USP specifications (pure alpha-epimer) is the least stable in solution. It is suggested that calcium gluceptate containing approximately equal proportions of the alpha- and beta-epimers be introduced in the USP monograph together with a method for estimating the proportions of the epimers.

Chemical Phenomena↗