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Antipsychotics are a class of psychiatric medication that is primarily effective at reducing psychosis symptoms, particularly in schizophrenia and bipolar disorders. This study aims to formulate mixtures of the antipsychotic drugs quetiapine fumarate (QUE), nortriptyline (NOR), propranolol (PROP) and haloperidol (HAL) with excipients urea, niacin (NIA) and niacinamide (NIM) to obtain an enhanced bioavailability and therapeutic effect. The mixtures were prepared by the solvent method and are characterized by various analytical techniques such as differential scanning calorimetry, wide angle X-ray diffraction, scanning electron microscopy and dissolution studies. Out of the various mixtures that have been prepared and tested, five of them showed eutectic behavior and their eutectic points are as follows: quetiapine fumarate–urea (QUE–UREA) 20–80, w/w; nortriptyline–niacin (NOR–NIA) 70–30, w/w; propranolol–niacin (PROP–NIA) 80–20, w/w; propranolol–niacinamide (PROP–NIM) 40–60, w/w; and haloperidol–niacinamide (HAL–NIM) 20–80, w/w. DSC investigation has revealed the formation of an eutectic system and the phase diagrams and Tamman’s triangle construction along with the hot-stage microscopy confirmed their melting points. PXRD study indicated no chemical interaction between either of the mixtures, while SEM study showed the size reduction in these mixtures that has been achieved. In vitro studies of the five mixtures showed an appreciable increase in the dissolution rate compared to that of the drug alone. In conclusion, five simple eutectic mixtures have been formulated by the solvent method and were found to show better dissolution rates than that of the pure form of the drugs, thus improving the bioavailability of these poorly water-soluble drugs.

This project aims to study the nature of interaction and orientation of selected drugs such as dexamethorphan HBr (DXM), diphenhydramine HCl (DPH), and lidocaine HCl (LDC) inclusion complexes with hydroxyl-propyl s-cyclodextrin (HP-s-CD) using 1HNMR spectroscopy, 2D-NMR ROESY and molecular-modeling techniques. Freeze-drying technique was used to formulate the inclusion complexes between DXM, DPH and LDC with HP-s-CD (1:1 M ratio) in solid state. Inclusion complex formation was initially characterized by Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. Further characterization of inclusion complexes to determine the interaction of DXM, DPH and LDC with HP-β-CD was performed using the 1HNMR spectroscopy, 2D-NMR ROESY and molecular modeling techniques. Inclusion complexes of DXM, DPH and LDC with HP-s-CD were successfully prepared using the freeze-drying technique. Preliminary studies with FT-IR, DSC, XRD and SEM indicated the formation of inclusion complexes of DXM, DPH and LDC with HP-β-CD at 1:1 M ratio. 1HNMR study showed a change in proton chemical shift upon complexation. 2D-NMR ROESY (two-dimensional) spectroscopy gave an insight into the spatial arrangement between the host and guest atoms. 2D-ROESY experiments further predicted the direction of orientation of guest molecules, indicating the probability that amino moieties of DXM, DPH and LDC are inside the hydrophobic HP-s-CD cavity. Cross-peaks of inclusion complexes demonstrated intermolecular nuclear Overhauser effects (NOE) between the amino protons in DXM, DPH and LDC and H-atoms of HP-s-CD. Molecular modeling studies further confirmed the NMR data, providing a structural basis of the individual complex formations. Microsecond time-level molecular dynamics and metadynamics simulations indicate much stronger binding of DXM to HP-s-CD and more dynamic behavior for DPH and LDC. In particular, LDC can exhibit multiple binding modes, and even spent some time (∼1-2%) out of the carrier, proving the dynamic nature of the complex. To conclude, 2D-NMR and molecular dynamic simulations elucidate the formation of inclusion complexes and intermolecular interactions of DXM, DPH and LDC with HP-s-CD.

Adaptation refers to the ability of the visual system to adjust to the prevailing conditions of light stimulation in order to maximize sensitivity, reduce the effect of noise, and prevent neural overload or saturation. Many forms of visual adaptation have been identified, occurring at multiple sites within the visual pathway. The types of adaptation that are thought to be retinal in origin are light adaptation, contrast adaptation, chromatic adaptation, and dark adaptation. This article discusses the characteristics of these forms of adaptation and briefly describes the retinal processes that are presumed to underlie them.

Background. Skin infections occur commonly and often present therapeutic challenges to practitioners due to the growing concerns regarding multidrug-resistant bacterial, viral, and fungal strains. The antimicrobial properties of zinc sulfate and copper sulfate are well known and have been investigated for many years. However, the synergistic activity between these two metal ions as antimicrobial ingredients has not been evaluated in topical formulations. Objective. The aims of the present study were to (1) formulate topical creams and gels containing zinc and copper alone or in combination and (2) evaluate the in vitro antibacterial activity of these metal ions in the formulations. Method. Formulation of the gels and creams was followed by evaluating their organoleptic characteristics, physicochemical properties, and in vitro antibacterial activity against Escherichia coli and Staphylococcus aureus. Results. Zinc sulfate and copper sulfate had a strong synergistic antibacterial activity in the creams and gels. The minimum effective concentration was found to be 3 w/w% for both active ingredients against the two tested microorganisms. Conclusions. This study evaluated and confirmed the synergistic in vitro antibacterial effect of copper sulfate and zinc sulfate in a cream and two gels.

A eutectic is formed from a mixture of two or more solids and has a melting point lower than that of each of its constituents. It is generally represented by a phase diagram where the liquid and solid phases impact upon each other with a value known as the eutectic point. In pharmaceuticals, poor water solubility is a major obstacle for releasing new dosage forms into the market. Eutectic formation overcomes these problems. Preparation of a phase diagram by Differential Scanning Calorimetry can determine eutectic properties, but it is tedious. A modified Van't Hoff (VH) equation was used in this study. Devalina Law developed a dimensionless index for the VH equation. The difference in melting points of an excipient polymer and drug are divided by the slope of the VH equation. In previous studies, five excipient-drug compositions were evaluated. The final index relationship was in good agree- ment except for the salt, quinine sulfate. In order to test the validity of the VH index, further studies of PEG with ace- tylsalicylic acid, acetaminophen, diflunisal, dimenhydri- nate, ketoconazole, and mefenamic acid were performed.

Eugenol is the main volatile compound extracted oil from clove bud, Syzygium aromaticum L., and used in traditional medicine, as a bactericide, fungicide, anesthetic, and others. Its extraction was performed using hydrodistillation which is the most common extraction technique. Its components and thermal behavior were evaluated using gas chromatography (GC) and differential scanning calorimetry (DSC), which provide a better characterization of these natural compounds. This extracted product was compared to the standard eugenol results. The GC results suggested ~90% eugenol was found in the total extracted oil, and some of its boiling characteristics were 270.1 °C for peak temperature and 244.1 J g−1 for the enthalpy variation.

Eugenol is an allyl chain-substituted guaiacol in the biosynthesized phenylpropanoid compound class derived from Syzygium aromaticum L. and widely used in folk medicine. Nonetheless, its pharmacological use is limited by some problems, such as instability when exposed to light and high temperature. In order to enhance stability, the eugenol molecule was structurally modified, resulting in eugenyl acetate. The eugenyl acetate’s thermal behavior and crystal structure was then characterized by differential scanning calorimetry (DSC) and X-ray diffraction (XRD) and compared to a commercial sample.

Essential oils are good candidates for the substitution of conventional medicinal treatments. Many articles and patents for their use have been published in recent years. The most attractive aspects of using essential oils as medicaments are their natural source and rapid permeability. Besides permeability, the solubility behavior of a drug is a key determinant of its oral bioavailability. Based on these characteristics, the aim of this study was to synthesize an essential oil derivative compound, using the raw oil extracted from Syzygium aromaticum L., without previous purification. The Eugenol molecular modification may diminish the problems of water solubility and bioavailability. The Eugenyl acetate molecule was characterized and its molecular modification investigated, including its structural properties and stereochemistry. This study was performed applying techniques, such as carbon-13 nuclear magnetic resonance spectroscopy (C-13 NMR), X-ray crystallographic analysis (XRD), powder X-ray diffraction (PXRD) and microscopic recording. Eugenol and its structure have been known for many years, where as Eugenyl acetate’s structure has never been elucidated nor confirmed until now.

A water-insoluble complex between diltiazem HCl and Na deoxycholate was prepared to achieve sustained release dosage forms. Physicochemical characterization of the drug complex was carried out with differential scanning calorimetry, (1)H-nuclear magnetic resonance, and Fourier transform infrared spectroscopy. These techniques showed that the characteristic peaks in both the drug and the complexing agent (protonated amine and carboxylate) disappeared and new peaks appeared upon formation of the ionic complex. The release of diltiazem from drug-complex tablets was sustained for a long period of time (24 h) and was dependent on the pH of the dissolution medium. However, the dependence of drug release on pH was eliminated at pH 6-8 and minimized at pH 1.5 when drug-complex powders were incorporated in hydroxypropylmethylcellulose (HPMC) drug carriers. Unlike the release of diltiazem HCl from HPMC drug carriers, drug release from drug-complex/HPMC tablets was linear or near linear irrespective of the viscosity grade of the polymer (E15 to K4M). This is due to a shift in the controlling mechanism of drug release from drug diffusion to erosion of polymer. Also, drug release kinetics was not significantly affected by the water solubility of cationic drugs (diltiazem HCl, verapamil HCl, propranolol HCl, and labetalol HCl) ranging from 1.6 to 62% and the type of amine (i.e., secondary or tertiary). The same release characteristics were observed from the complexes between anionic drugs (Na salicylate, naproxen Na, and tolmetin Na) and benzathine diacetate as found from the complexes between cationic drugs and Na deoxycholate.

The electroretinogram (ERG) provides a noninvasive, objective measure of retinal function, and is one of the most widely used diagnostic tools in the study of visual disorders. Although rodents are often used in the study of retinal disease, the properties of the flicker ERG of the rodent retina have not been fully characterized. Here, we show that the fundamental response of the rat ERG to sine-wave flicker exhibited a low-pass pattern in the frequency range from 2 to 30 Hz, whereas the second harmonic (F2) showed a more complex frequency response relation. The F2 component represented only a small fraction of the ERG response at low temporal frequencies (below 12 Hz), but it made a substantial contribution to responses at high frequencies. The contrast-response relation was linear when tested with a low-frequency (6 Hz) stimulus, but saturated in response to a high-frequency (20 Hz) stimulus. After intravitreal injection of L-AP4, a specific blocker of the retinal ON pathway, the flicker responses elicited by either 6- or 20-Hz stimuli were greatly reduced in amplitude, whereas only a very slight enhancement was seen after the application of PDA, a drug that blocks retinal OFF-pathway activity. Based on the observed differences in the degree of non-linearity, and contrast-response properties of the rat flicker ERG at low and high frequencies, as well as the pharmacological results, we postulate that sustained and transient ON bipolar cells generate the flicker ERG responses elicited at low and high temporal frequencies, respectively.

This project investigated the interaction between poly-L-lactic acid (PLLA) and several therapeutic agents. Low percentage crystallinity PLLA (melt-pressed, molded and drawn) was studied. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to characterize the crystallinity and thermal properties in a thermal cycling process. Repeatable melting and crystallization events were observed. The thermal properties of a drug-polymer combination using PLLA and an acidic, basic, neutral and zwitterionic material were investigated. A sufficient quantity of the drug must be present in the polymer to be observed thermally. Release of atropine sulfate from a PLLA tablet showed a two-phase process.

Industrial manufacturing of solid oral dosage forms require quality tests, such as friability, hardness, and disintegration. The United States Pharmacopeia (USP) disintegration test uses 900mL of water. However, recent studies of orally disintegrating tablets (ODTs) have shown that this volume does not accurately portray the oral environment. In our study, various tests were conducted with a more moderate amount of water that accurately resembles the oral environment. A simulated wetting test was performed to calculate the water absorption ratio. Results showed that wetting was comparable to disintegration. Although the wetting test worked for most types of ODTs, it had limitations that produced inaccurate results. This led to the use of a modified shaking water bath test. This test was found to work for all types of ODT products and was not subject to the limitations of the wetting test. The shake test could provide disintegration times rather than water permeation times; however, it could not be used to calculate the water absorption ratio. A strong correlation was observed between the standardized shake test and the USP disintegration times for the tablets. This shake test could be used during the development stages and quality tests for ODTs with relative ease.

Granulations of dimenhydrinate (DMH) were prepared using various concentrations of ethyl cellulose (EC) by the solid dispersion technique. Characterization was done using thermal analysis, powder X-ray diffraction, infrared spectroscopy, optical microscopy and dissolution studies. Humidity studies were performed to investigate the effect of moisture on the drug and solid dispersions. It was seen that the crystalline drug was converted into its amorphous form in all the granulations. There was no chemical interaction between the DMH and EC. The thermal decomposition of drug in the granules was not affected. Dissolution studies revealed that the drug release from the granulations was significantly reduced as compared to the pure drug. As the amount of ethyl cellulose increased, the drug release rate decreased and the drug release kinetics showed a better fit to zero-order kinetics. Humidity studies showed that the drug and granulations remained stable in conditions not exceeding 70%RH. At high humidity of 100%RH, there was formation of the hydrate crystal forms of the drug in the pure drug samples and granules with 1:1 DMH-EC content whereas the granules with higher polymer content did not show any significant changes indicating better drug stability in the granules.

Differential scanning calorimetry (DSC) is a thermal analytical tool for preformulation studies. Extrapolated melting temperature (TP) and heat of fusion (ΔHf) can be used as parameters for optimizing the DSC performance. Two model pharmaceuticals acetaminophen and nicotinamide are used in this study. Using a factorial design for the experimental model and matrix analysis the results, the effect of sample mass, heating rate and the nitrogen flow rate were evaluated on the ΔHf values and TP values. Two levels for each of the procedural variables were used as a balanced experimental design with two sample sizes, two heating rates and two nitrogen flow rates. It was found that the change in the heating rate caused significant changes in the ΔHf values but not the Tp values for acetaminophen. However, no significant effect was found for the Tp value but ΔHf value was affected to a certain extent for nicotinamide.

We report three unrelated patients with mutations in the GRM6 gene that normally encodes the glutamate receptor mGluR6. This neurotransmitter receptor has been shown previously to be present only in the synapses of the ON bipolar cell dendrites, and it mediates synaptic transmission from rod and cone photoreceptors to this type of second-order neuron. Despite the synaptic defect, best visual acuities were normal or only moderately reduced (20/15 to 20/40). The patients were night blind from an early age, and when maximally dark-adapted, they could perceive lights only with an intensity equal to or slightly dimmer than that normally detected by the cone system (i.e., 2-3 log units above normal). Electroretinograms (ERGs) in response to single brief flashes of light had clearly detectable a-waves, which are derived from photoreceptors, and greatly reduced b-waves, which are derived from the second-order inner retinal neurons. ERGs in response to sawtooth flickering light indicated a markedly reduced ON response and a nearly normal OFF response. There was no subjective delay in the perception of suddenly appearing white vs. black objects on a gray background. These patients exemplify a previously unrecognized, autosomal recessive form of congenital night blindness associated with a negative ERG waveform.

Solid-state interaction between ibuprofen and nicotinamide was studied using thermal, spectroscopic, and microscopic techniques. Solubility enhancement was calculated by high-performance liquid chromatography and suspension was found to be the suitable choice of formulation. Ibuprofen-nicotinamide binary mixtures were prepared by solvent evaporation method. Differential scanning calorimetry was used to investigate the stoichiometry and thermal properties of the complex between ibuprofen and nicotinamide. A sharp, single endotherm was observed between the melting endotherms of the individual components at a composition of 60% ibuprofen and 40% nicotinamide (w/w). Several spectroscopic techniques such as ultraviolet-visible, Fourier transform infrared, nuclear magnetic resonance, and powder X-ray diffraction were used to investigate the type of interaction between the two components. Optical microscopy was performed to observe changes with regard to particle size and crystal habit. It was concluded that the interaction that occurred was Pi donor-Pi acceptor in nature and too weak to sustain the integrity of the complex in the liquid state. The solubility of ibuprofen was enhanced by 62 times in the suspension when the concentration of nicotinamide was 13.3 mg/mL. The suspension prepared in this study has potential of being a better medication for pain relief in patients with osteoarthritis.

The possibility of obtaining tolbutamide polymorphs was investigated using the solvents acetonitrile and 1-octanol. Tolbutamide is an oral hypoglycemic agent that exists in four polymorphic forms. Characterization of the various polymorphs was carried out by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), infrared spectroscopy (FTIR), optical microscopy and dissolution studies. Form A, crystallized from acetonitrile, resembled the form I polymorph, while form O, crystallized from 1-octanol, resembled the form III polymorph. Tablets of both form A and form O were produced at compression pressures of 2500 lbs and 5000 lbs using cornstarch and talc and were exposed to 40%, 75% and 95% RH conditions. DSC and PXRD studies did not show any significant drug-excipient interaction. Moreover, the change in the crystalline state of either form upon exposure to humidity was not evident. Dissolution studies showed a significantly lower drug release rate from form O tablets compressed at 5000 lbs pressure and exposed to 95% RH. Pressure and humidity had no significant effect on the dissolution profiles on the form A tablets. It was concluded that form A was the robust choice for further formulation development.

The evaporative properties of adipic acid, triethanolamine (TEA), and glycolic acid have been studied by thermal analysis. Samples were heated in a simultaneous thermogravimetric–differential thermal analysis (TG–DTA) unit at 10 °C min −1 in a dry nitrogen atmosphere flowing at 100 mL min −1 . Benzoic acid was used to calculate a calibration constant which could then be inserted into a modified Langmuir equation to calculate vapor pressure curves for adipic acid, TEA, and glycolic acid. The results were compared to vapor pressure curves generated by use of Antoine constants, where these were available. Good correlation was obtained between the two sets of curves for adipic acid and TEA. Glycolic acid decomposed and evaporated in the same temperature range, thus, making calculations invalid.

Purpose To demonstrate the value of a 2-color perimetric procedure for determining cone and rod system contributions to the dark-adapted kinetic visual field (VF). Design Prospective evaluation of perimetric testing procedure. Participants Five patients with retinal diseases and 6 visually normal individuals. Methods Long- and short-wavelength stimuli were presented under dark-adapted conditions in a Goldmann perimeter. Visual fields were measured for the II and V test target sizes with a long-wavelength filter (cut-on at 600 nm) and a short-wavelength filter (cutoff at 510 nm). Light intensities through these filters were matched scotopically for the rod system by producing equal peripheral boundaries on 6 visually normal individuals. To validate the application of this procedure, we tested a patient with congenital achromatopsia and another patient with congenital stationary night blindness (CSNB). We then tested 2 patients with retinitis pigmentosa (RP) and 1 patient with Usher's syndrome to determine the cone and rod contributions to their VF isopters. Main outcome measures Isopters for long- and short-wavelength test stimuli, and the appearance of the test stimuli, whether reported as chromatic or achromatic. Results The patient with congenital achromatopsia showed superimposed isopters for the 2 stimuli, which were reported as achromatic, demonstrating that the peripheral field boundaries were rod mediated. The patient with CSNB showed an isopter in response to the long-wavelength stimulus that was considerably larger than that in response to the short-wavelength stimulus, both stimuli reported as chromatic, showing that the cone system determined peripheral thresholds for both stimuli. In 2 patients with RP, we observed a mixed pattern of cone or rod system detection of the chromatic stimuli. The peripheral isopters were rod mediated, whereas the cone system determined the central field isopters. In an Usher's syndrome patient, cones mediated both the peripheral and the central field isopters. Conclusions A 2-color dark-adapted Goldmann perimetric procedure was able to determine whether the VF isopters were rod or cone mediated in 5 patients with various forms of retinal disease.

Snake skin is a viable and readily available material as a model for human skin. Pharmaceutical applications use shed snake skin to study the effects of sunscreens on exposure to UV radiation (e.g. benzophenone on Boa integument). In order to understand the effects of radiation or drug transport through this model skin, one must determine its basic physical properties. This preliminary study evaluated two types of snake skin, namely Cuban Boa a 'dark' skin (Epicrates angulifer) and Green tree python a 'light' skin (Morelia viridis). Previous studies by other investigators have used pig, rabbit and snake skin as a human skin substitute. The structure of both snake skins was comparable based on IR spectroscopy and were functionally amino acids and moisture. Photomicrography by light and scanning electron microscopy revealed strong anatomic similarities. Morphologically there were two structures visible, namely a cellular and hinge-fibrous area. The thermal techniques indicated a phase transition at 35-75°C, which is associated with lipid melting. There was an 8 and 12% mass loss for the light skin and dark skin, respectively, which is interpreted, in part, as moisture loss at

Five poorly soluble drugs namely hydrochlorothiazide, menadione, propylthiouracil, quinine sulfate and sulfamerazine were used to evaluate the ability of an index (Ic) based on the van't Hoff equation to predict the eutectic composition at a higher heating rate than previously published. The term Ic is a dimensionless index which has been defined in the literature and is used to predict eutectic composition. This current work uses this study to determine if the correlation holds true at the higher heating rate of 10°C min-1. The maximum deviation was observed for quinine sulfate, for which the predicted eutectic composition was 10% lower than what was observed with the DSC. It can be concluded that the Index developed here has a good correlation with the experimentally determined eutectic composition.

This study attempts to identify the degradative process which folic acid undergoes in the solid-state under thermal stress. In order to facilitate the process, the various pieces of the chemical structure, namely, p-amino benzoic acid, pterin and glutamic acid as both its d- and l-isomers were investigated as separate entities. These structured solid-state pieces were then compared to the composite solid state folic acid degradative curves in order to identify the peaks seen and provide direction for the interpolation of the degradative mechanism. It was observed that none of the structural pieces could be superimposed as assumed earlier and hence an attempt was made to identify the decomposition products using various analytical techniques such as infrared spectroscopy, mass spectroscopy and X-ray diffraction which suggested that the glutamic acid fragment is lost first as evidenced by acid loss and amide enhancement in the IR spectra. The vitamin was ultimately degrading to carbon fragments and that further identification was not necessary.

The present study was aimed at determining the kinetics of evaporation and establishing vapor pressure curves for both single and multi-component systems by thermogravimetry (TG) and differential scanning calorimetry (DSC). Essential oils (e.g. lavender oil, orange oil, clove oil and eucalyptus oil, etc.) are typically multi-component systems consisting of various volatile pure components (e.g. linalyl acetate, limonene, cinnamaldehyde, etc.) which resemble single component systems. In this study linalyl acetate was taken as the calibration compound for TG. The vapor pressure curves for the pure substances were plotted using TG and vapor pressure plots for clove oil and eucalyptus oil were constructed using DSC. The thermodynamic and kinetic parameters of the pure compounds were compared to that of the multi-component systems to quantitatively and qualitatively measure the influence of different compounds on each other. The k-value from the vapor pressure data for linalyl acetate was calculated as 112006 Pa kg0.5mol0.5s-1 m-2 K-0.5. The vapor pressure values were used to determine the Antoine constants using the SPSS 10.0 software.

A rapid and sensitive high‐performance liquid chromatographic method was developed for the determination of propylthiouracil. The chromatographic system utilized a C8 column with the detector wavelength set at 276 nm. The mobile phase was composed of water and methanol in a 70:30 (v/v) ratio and was delivered at a flow rate of 0.5 mL/minute. The analytical run time was less than 7 min. The standard curves were linear over a range of 1–100 µg/mL with a correlation coefficient of 0.9958. The limit of quantification was assessed to be 15 ng and the limit of detection 4.5 ng. The RSD values for the intra‐ and inter‐day precision studies were 0.11–1.28% and 1.65%, respectively. The accuracy was ≤5% over the concentration range 1–100 µg/mL. The stability‐indicating nature of the assay method was determined by subjecting a stock solution of propylthiouracil to extremes of acidic and basic degradation. It was found that the method was specific for propylthiouracil. Hence, a simple, rapid, sensitive, stab...

Linezolid is an oxazolidinone antibiotic recently approved for treatment of infections due to antibiotic-resistant strains of Enterococcus faecium , Staphylococcus aureus, and Streptococcus pneumoniae. Because infections with these organisms, particularly vancomycin-resistant E faecium (VREF) and methicillin-resistant S aureus (MRSA), are becoming more common in critically ill neonates, linezolid is likely to play an increasingly important role in the antibiotic treatment of neonates who have antibiotic-resistant gram-positive infections. ### Mechanism of Action Oxazolidinone antibiotics, including linezolid, inhibit bacterial protein translation through a unique mechanism. Linezolid binds to the 23S subunit of the bacterial 50S ribosome. In doing so, the antibiotic blocks formation of the 70S translation initiation complex. Not surprisingly, nonclinical strains that have 23S rRNA mutations have shown linezolid resistance in vitro. ### Spectrum of Action Organisms against which linezolid has proven antibacterial efficacy include: E faecium (vancomycin-resistant strains only), S aureus (including methicillin-resistant strains), S agalactiae , S pneumoniae, and S pyogenes. Linezolid also shows in vitro activity against E faecalis (including vancomycin-resistant strains), E faecium (vancomycin-susceptible strains), S epidermidis (including methicillin-resistant strains), S haemolyticus , S pneumonia (penicillin-resistant strains), viridans-group streptococci, and Pasteurella multocida. In general, linezolid is bacteriostatic for staphylococci and enterococci, but is bactericidal for streptococci. Linezolid has activity against methicillin-sensitive and -resistant strains of S aureus and reportedly is active even against glycopeptide-intermediate and -resistant S aureus strains. ### Absorption Linezolid is administered either intravenously or orally. The intravenous preparation contains 2 mg/mL linezolid in an isotonic citrate buffer; the oral suspension contains 20 mg/mL linezolid. The oral bioavailability of linezolid suspension in older children and adults is 100% and is not altered by food. Neither preparation contains alcohol. No data on oral absorption in neonates are available. ### Distribution Linezolid distributes to well-perfused tissues and has low plasma protein binding (approximately 31%). Studies have shown that linezolid penetrates into osteoarticular tissues well, exceeding the minimum inhibitory …

The present study evaluates the effects of excipients, compression pressure, and relative humidity (RH) on the stability of sulfamerazine polymorphs (referred here as SMZ I and SMZ II) and their release from directly compressed tablets using differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and dissolution analysis. SMZ I and SMZ II tablets were compressed with magnesium stearate (MGST), and microcrystalline cellulose (MCC) at 5000, 7500, and 10,000 lbs. pressures and stored at 40, 75, 95, and 100% RH conditions for 5 weeks. There were indications of possible drug-excipient interaction in the binary mixtures under different relative humidity conditions from the DSC data, but they could not be confirmed by PXRD because the crystal structures of the drug and excipients remained unaltered. The crystal structures of the polymorphs in the tablet also remained unaltered under the above conditions. There were, however, significant differences observed in the drug release properties of the two polymorphs. SMZ II was found in general to have a higher rate of drug release than SMZ I. Extensive gelation of MCC under higher moisture conditions, compression pressure during tableting, and inherent tabletability of the sulfamerazine crystals were factors that affected drug release. All these factors contributed towards prolonging the disintegration and deaggregation of the tablet particles and were therefore concluded to be the rate limiting steps for the dissolution process.

We study the depinning transition of the $1+1$ dimensional directed polymer in a random environment with a defect line. The random environment consists of i.i.d. potential values assigned to each site of $\mathbb{Z}^2$; sites on the positive axis have the potential enhanced by a deterministic value $u$. We show that for small inverse temperature $\beta$ the quenched and annealed free energies differ significantly at most in a small neighborhood (of size of order $\beta$) of the annealed critical point $u_c^a=0$. For the case $u=0$, we show that the difference between quenched and annealed free energies is of order $\beta^4$ as $\beta\to 0$, assuming only finiteness of exponential moments of the potential values, improving existing results which required stronger assumptions., Comment: 22 pages. Changes to Proposition 3.8 make Proposition 4.1 unnecessary; minor corrections made

The importance of the amorphous state in studying bioavailability of poorly water-soluble drugs cannot be over-emphasized. The higher free energy and therefore the apparent high solubility of the amorphous phase are some of the advantages for promoting the amorphous phase, as compared to its crystalline counterpart. It is well known that the amorphous phase is thermodynamically unstable. This might result in the conversion of the metastable form to its stable crystalline form during storage. This conversion might also lead to product failure during storage owing to the poor dissolution properties of the crystalline form. Excipients can play a key role in preventing such a transformation during storage as well as maximizing the therapeutic efficacy of the amorphous material. This book chapter intends to highlight the delivery issues pertaining to amorphous drugs with a special emphasis on the most commonly used excipients in stabilizing amorphous drug substances in formulations.

Four non-polymeric plasticizers, propylene glycol, diethyl phthalate, triacetin, and glycerin have been subjected to rising temperature thermogravimetry for kinetic analysis and vaporization-based thermal stability evaluation. Since volatile loss of a substance is a function of its vapor pressure, the thermal stability of these plasticizers has been analyzed by generating vapor pressure curves using the Antoine and Langmuir equations. Unknown Antoine constants for the sample compounds, triacetin and glycerin have been derived by subjecting the vapor pressure curves to nonlinear regression. For the first time, the entire process of obtaining the unknown Antoine constants through thermogravimetry has been validated by developing an approach called the 'double reference method.' Based on this method, it has been possible to show that this technique is accurate even for structurally diverse compounds. Kinetic analysis on the volatilization of compounds revealed a predominant zero order process. The activation energy values for vaporization of propylene glycol, diethyl phthalate, triacetin, and glycerin, as deduced from the Arrhenius plots, have been determined to be 55.80, 66.45, 65.12, and 67.54 kJ/mol, respectively. The enthalpies of vaporization of the compounds have been determined from the Clausius-Clapeyron plots. Rising temperature thermogravimetry coupled with nonlinear regression analysis has been shown to be an effective and rapid technique for accurately predicting the vapor pressure behavior and thermal stability evaluation of volatile compounds.

It has been observed that hindered settling experiments usually lead to voluminous data, which is usually characterized as “poorly reproducible”. Many factors might affect these techniques. The ability to control these parameters may result in a better analysis of the outcome and the correct estimation of the particle size. An attempt was made to investigate calcium oxalate monohydrate stability in the presence and absence of cholesterol, while determining the factors which may undermine the results obtained. The data may provide interesting information which may be used in other similar investigations to reduce the negative compacts caused by the low reproducibility. *Posthumously.

A new viscosity–capillary dipometer was designed and used in this investigation. Comparing this piece of equipment with other viscometers, the capillary dipometer is accurate, easy to operate, and much less expensive. The viscosities for calcium hydrogen phosphate and calcium oxalate suspensions are determined using the capillary dipometer. The data shows that this method is suitable for suspensions. This method could also be applied to other liquid dosage forms (i.e., emulsions) to provide quick and accurate results.

The drug acetazolamide (C4H6N4O3S2) was studied using a simultaneous thermogravimetric–differential thermal analysis (TG–DTA) unit. The study covered the temperature range of ambient to 600 °C. The DTA showed a melting point of 258.5 °C followed by a three-stage decomposition. The TG–DTG plots clearly show the decomposition when subjected to heat treatment in a nitrogen atmosphere. A kinetic analysis of all stages was attempted, where a zero-order process appeared to be the best fit mechanism and plots of ln k versus T−1 show this. The values of Eact are shown to vary throughout each stage as the reaction progressed.

This study attempts to identify the degradative process which folic acid undergoes under thermal stress. In order to facilitate the process, the various pieces of the chemical structure, namely, p -amino benzoic acid (PABA), pterin and glutamic acid as both its d - and l -isomers were investigated as separate entities. These structured pieces were then compared to the composite folic acid degradative thermogram in order to identify the peaks seen and provide direction for the interpolation of the degradative mechanism [Thermal stability of folic acid and associated excipients, M.Sc. thesis, 2001]. It was observed that none of the structural pieces could be superimposed as assumed earlier, and hence, an attempt was made to identify the decomposition products using various analytical techniques such as infrared (IR) spectroscopy, mass spectroscopy (MS) and X-ray diffraction (XRD) which suggested that the glutamic acid fragment is lost first as evidenced by acid loss and amide enhancement in the IR spectra. The vitamin was ultimately degraded to carbon fragments and that further identification was not necessary.

There are a number of substances used to calibrate various instruments with benzoic acid being an IUPAC recommended calibration material. It has gained recognition as a reference material because it exhibits an ‘‘ideal’’ behavior. Hence, benzoic acid is often used to aid in determining the enthalpy of sublimation values for various organic substances. In this study, the thermal behavior of benzoic acid is observed from a simultaneous thermogravimetry–differential thermal analysis (TG–DTA) unit. A series of tests under various experimental conditions is performed, and the results allow for the determination of the enthalpy of sublimation values for benzoic acid. The purpose of this study is to investigate the influence of experimental parameters, such as sample preparation procedures, heating rates, atmospheric conditions, and gas flow rates, on the calculated enthalpy of sublimation values. Enthalpy of vaporization for benzoic acid was also calculated. # 2002 Elsevier Science B.V. All rights reserved.

The Langmuir equation was used to construct vapor pressure curves for the sublimation phase of nicotinic acid. Three different approaches were used to calculate the pressure values. In the first, the ‘k’ term of the Langmuir equation was eliminated by comparing the sample with the reference compound, in the second, the actual values of the ‘k’ term were used and in the third approach, the ‘k’ term was kept constant. The vapor pressure curve constructed using the actual values of ‘k’ was in close agreement with the first. This indicates that the ‘k’ term of the Langmuir equation cannot be assumed to be constant and the systematic variation in the values of the ‘k’ term with temperature has to be taken into consideration.

The three naturally occurring available carbonates in northwest Ohio are magnesite, calcite and dolomite. Dolomite is a double carbonate containing calcium and magnesium carbonate in equimolar concentrations. All three carbonates decompose via a single stage process in an atmosphere of nitrogen. The thermal behavior and the kinetics of decomposition were studied using the Arrhenius equation applied to solid-state reactions. It was found that calcite and dolomite supposedly decompose via a zero order mechanism while magnesite decomposes via a first order process. The energy of activation for the decomposition of magnesite, calcite and dolomite were 226.34, 192.50 and 175.05 kJ/mol, respectively. Similarly the ln A-values for magnesite, calcite and dolomite decomposition were 30.70, 20.73 and 18.76, respectively. Finally, the effect of procedural variables on the kinetic parameters of dolomite decomposition was investigated. The three procedural variables studied included flow rate, heating rate and sample size. The kinetic parameters and mechanism remain unaffected by a change in these variables. # 2002 Elsevier Science B.V. All rights reserved.

The thermal behavior of cinnamyl alcohol, which is used in the perfume industry to create a sweet, balsamic and hyacinth-like fragrance, was examined with a simultaneous thermogravimetric–differential thermal analysis (TG–DTA) unit. The sample was subjected to a controlled rising temperature regime under a regulated purge gas flow rate. The evaporation rates and coefficient of evaporation were calculated from TG–DTG data. From the DTG curve, it was found that the evaporation of cinnamyl alcohol is a zero-order process. The activation energy and enthalpy of vaporization for the evaporation process were determined by the use of the Arrhenius and Clausius–Clapeyron equations, respectively. The enthalpy value was calculated to be 68.10±0.84 kJ, while the energy of activation was found to be 66.34±0.84 kJ. The Langmuir equation was applied to the evaporation data, enabling the vapor pressure curves to be determined.

This study aims at providing a simple thermogravimetric method in estimating the vapor pressure characteristics using the Antoine equation as the analytical tool. The heat treatment for the majority of benzoic acid derivatives follows zero order rate processes that are in good correlation with their evaporation process. The optimum conditions for the rising temperature experiments were found when the heating rate was 10 8C/min in an atmosphere of dry nitrogen (100 ml/min). Methyl paraben was taken as the calibration compound since its Antoine constants are reported in literature and its selected thermodynamic parameters were evaluated using the Langmuir equation. The coefficient of vaporization k was determined to be 124525 � 0:8, with units being reported in the SI system. The corresponding vapor pressure plots were obtained for the remaining compounds that followed a zero order evaporation process and their Antoine constants were calculated using the Levenberg‐Marquardt least square curve fit method. # 2002 Elsevier Science B.V. All rights reserved.

Differential scanning calorimetry (DSC) is one of the important thermoanalytical techniques for preformulation studies of pharmaceutical substances. DSC studies can be used to characterize the melting behavior, crystallization, solid–solid transitions and chemical reactions of drugs. The attainment of proper results in a DSC experiment is dependant on a number of factors. The purpose of this study was to establish the appropriate condition for DSC performance. Factorial design and matrix analysis was used extensively in this study. The variables considered in this study were the sample size, heating rates, atmosphere, crucible type and relative humidity (RH). Two model drugs, benzoic acid (typical melting range: 121–123 °C, heat of fusion: 147 J/g) and vanillin (typical melting temperature: 81–83 °C, heat of fusion: 135 J/g) with sample size ranges of 3–5 and 10–12 mg were exposed to heating rates of 2 and 10 °C/min with atmospheres of air and nitrogen. The crucible types evaluated were open crucibles, crimped crucibles without pinhole and crimped crucible with pinhole. The samples were stored under 0, 25, 60 and 100% RH to evaluate the effect of RH on DSC performance. The study in this laboratory established a general protocol for DSC performance, which included the use of a small sample size range (3–5 mg), a low heating rate (2 °C/min), nitrogen as the atmosphere, crimped crucible without pinhole, and storage of the samples in a dry atmosphere (0% RH). Exceptions to the established protocols under various conditions are also discussed.

Thermogravimetric analysis is often used to evaluate the evaporation phenomenon of several substances. The present study was designed to characterize the vaporization characteristics of three essential oils; lemon oil, lavender oil and cinnamon oil and their several components. All three oils represent multi-component systems, whereas their main components represent single component systems. Linalyl acetate was used as the calibration compound and the coefficient of vaporization was obtained as 7×107 (SI system). The order of reaction was first determined for each of the compounds under study. Vapor pressure curves were then plotted using Langmuir and Antoine equations for the compounds, which represent single component systems, undergoing zero-order non-activated evaporation processes. The vapor pressure curves obtained were statistically quantified along with the calculations for the Antoine constants using SPSS version 10.0 software. The energies of activation for cinnamon oil, lemon oil and lavender oil were found to be 45.10, 33.2 and 33.9 kJ/mol, respectively.

The objective of this study was to develop and analyze an analytical method in order to evaluate preformulation candidates by their thermodynamic parameters and evaporation characteristics. Ortho, meta and tere-phthalic acids were chosen as model compounds. The relative advantages and disadvantages of a rapid thermogravimetric method have been studied in detail, which would aid in the preformulation characterization for pharmaceuticals. Methyl paraben was taken as the model compound for calibration, as its evaporation characteristics are well known. Using the Antoine and the Langmuir equation for evaporation conjointly, the parameter k, known as the coefficient of evaporation was determined. The value for this constant was validated by three methods simultaneously. Previously the use of such methods for compounds having uninhibited zero order evaporation has been documented. In the present study, phthalic acid was chosen as the model compound since its evaporation is a two-step overlapping phenomenon. In this study we have shown the use of Pressure Differential Scanning Calorimetry in separating such simultaneous endothermic processes. The Clausius-Clapeyron equation seemingly has anomalous behavior for vapor pressure over high temperature ranges. In this study a modification of the equation has been suggested to take into account the changes in the heat capacities that result due to high temperature effects. This study aims at documenting a concise method for rapid pharmaceutical characterization and suggests modifications for some basic thermodynamic parameters over higher temperature ranges.

Objective To compare the extent of intraocular straylight in carriers of choroideremia (CHM) and X-linked recessive retinitis pigmentosa (XLRP) to clarify further the relationship between photoreceptor cell degeneration and intraocular light scatter in retinal diseases. Design Prospective case-control study. Participants Six obligate carriers of CHM, 12 obligate carriers of XLRP, and 30 age-similar control subjects with normal vision. The controls had no posterior subcapsular (PSC) lens opacities, and the carriers had minimal or no PSC lens opacities, as assessed by slit-lamp biomicroscopy. Main outcome measures Straylight levels were measured using a van den Berg Straylightmeter. Visual acuity and Goldmann visual field area using a II/4e target were assessed for both eyes of each carrier. Electroretinogram (ERG) data were available on four of six carriers of CHM and all carriers of XLRP. The extent of retinal pigment epithelial degenerative changes was evaluated by fundus examination. Results All six carriers of CHM had typical fundus abnormalities with normal visual fields. Five of the six carriers of CHM had age-normal levels of intraocular light scatter, and one showed minimally elevated intraocular light scatter. The 12 carriers of XLRP had a spectrum of fundus abnormalities and varying severity of functional impairment as derived from visual field areas and ERG amplitudes. Seven of the 12 carriers of XLRP showed an elevated level of intraocular light scatter in at least one eye. The degree of straylight elevation above the normal mean age value was correlated significantly with both visual field area and amplitude of the maximal-intensity, dark-adapted ERG b-wave. Conclusions The carriers of XLRP who had evidence of photoreceptor cell dysfunction (as determined by visual field loss and reduced ERG amplitudes) had increased levels of intraocular straylight, whereas the carriers of CHM, who showed fundus abnormalities alone, in the absence of demonstrable photoreceptor cell dysfunction, had normal or minimally elevated levels. This finding supports the hypothesis that the increased levels of intraocular light scatter observed in some patients with hereditary retinal degenerations result from subclinical changes in the PSC region of the lens as a consequence of photoreceptor cell degeneration.

The purpose of this study was to identify the degradation products for folic acid which may form under thermal stress. An attempt was made to identify each of the decomposition products using various analytical techniques, such as infrared spectroscopy, mass spectroscopy, and X-ray diffraction, which suggested that the glutamic acid fragment of folic acid is lost first, as evidenced by acid loss and amide enhancement in the IR spectra. The vitamin was ultimately degrading to carbon fragments and further identification was not necessary.

Using yeast forward and reverse two-hybrid analyses, we have discovered that the replication terminator protein Tus of Escherichia coli physically interacts with DnaB helicase in vivo . We have confirmed this protein–protein interaction in vitro . We show further that replication termination involves protein–protein interaction between Tus and DnaB at a critical region of Tus protein, called the L1 loop. Several mutations located in the L1 loop region not only reduced the protein–protein interaction but also eliminated or reduced the ability of the mutant forms of Tus to arrest DnaB at a Ter site. At least one mutation, E49K, significantly reduced Tus–DnaB interaction and almost completely eliminated the contrahelicase activity of Tus protein in vitro without significantly reducing the affinity of the mutant form of Tus for Ter DNA, in comparison with the wild-type protein. The results, considered along with the crystal structure of Tus– Ter complex, not only elucidate further the mechanism of helicase arrest but also explain the molecular basis of polarity of replication fork arrest at Ter sites.

Nicotinic acid belongs to the B group of vitamins and is often referred to as Vitamin B3. It is an essential component of a balanced diet and is prescribed as tablet, and in parenteral dosage forms in cases of vitamin deficiency. This study involves a preliminary preformulation study to assess whether nicotinic acid is a good candidate for tablet and capsule manufacture. The manufacturing process for solid dosage forms involves high energy-intensive processes, which mainly include grinding and compaction. The effect of these high-energy processes on the stability of nicotinic acid was evaluated using thermogravimetry (TG) as the primary analytical tool. The initial stage involved characterizing the thermal behavior of the material. It was found that nicotinic acid shows a solid-solid state phase transition, which is reversible. This transition appears as a small endothermic peak on the differential thermal analysis (DTA) curve, just before the dual sublimation-evaporation stage. This was followed by study...

The heat treatment of parahydroxy benzoic acid esters follows zero order rate processes that are in good correlation with their evaporation process. Rising temperature experiments were performed and the optimum conditions were found when the heating rate was 10°C/min in an atmosphere of dry nitrogen, the flow rate of which was maintained at 100 mL/min. The Antoine constants for methyl paraben were substituted into the Antoine equation to get the corresponding vapor pressures that were then used in the Langmuir equation to obtain the value for the coefficient of evaporation k . The Eact value, obtained from the Arrhenius plot, was 75.1 kJ mol−1; the enthalpy of vaporization (ΔHvap) was calculated to be 77.9 kJ mol−1, in very close agreement with the Eact value. Using the Antoine and Langmuir equations, the value of k was experimentally determined to be 124525 ± 0.8, units being in the S.I. system. Taking the value of k to be independent of the substance, the corresponding vapor pressures were obtained for ...

Dolomite decomposes via a 2-stage mechanism in an atmosphere of CO2. The first stage of the decomposition was analyzed in depth using both isothermal and rising temperature kinetics. It was found that the first stage of decomposition follows the Avrami-Erofeev A2 mechanism for the isothermal experiments. However, for the rising temperature experiment, the reaction follows the Avrami-Erofeev A4 mechanism. The energy of activation (Ea) obtained for the isothermal experiments was determined to be 424.97 kJ/mol, while the value for the rising temperature experiment was 647.20 kJ/mol. Similarly, the ln A-value for the isothermal experiments was found to be 49.22, while the ln A-value for the rising temperature experiment was 74.20. The effect of procedural variables on the thermal behavior of dolomite in a nitrogen atmosphere is investigated. The program design variables include alterations in the flow rate, heating rate, grain size, and sample size. Out of these variables, heating rate, flow rate, and grain s...

Captopril is an antihypertensive drug currently being administered in tablet form. The thermal analysis study was carried out using a simultaneous TG–DTA unit. Both the isothermal and non-isothermal experiments are preformed to investigate the thermal degradation process of captopril in its natural state as a solid. The runs were performed in a flowing nitrogen atmosphere. Captopril melted at 106°C followed by decomposition. Based on the order of reaction, one method is used to identify the reaction mechanism in isothermal kinetics and two methods are used to identify the reaction mechanism in non-isothermal kinetics. These methods use the equations established by Avrami–Erofeev, Arrhenius and Freeman and Carroll. However, a kinetic analysis based on the “method of fit” using zero-order, first-order, and second-order equations showed that a first-order process gave a good fit for the Arrhenius plot at certain specific experimental conditions (i.e. very low sample mass). Overall, a second-order process followed by a first-order reaction for the main decomposition process of captopril showed an even better fit for the experiments. The possible reasons for this kinetic behavior are presented. There was up to 2% carbon remaining at 500°C. Thermal analysis was supplemented using Fourier Transform infrared spectroscopy (FTIR), X-ray diffraction and scanning electron microscopy (SEM) methods to identify the captopril with any degradation products which may have formed.

Allopurinol sublimates when subjected to thermogravimetry in a nitrogen atmosphere. The process is zero order and plots of ln k versus reciprocal temperature (K) give a value of 132.64 kJ mol −1 for the activation energy. On the basis that equilibrium is achieved at all temperatures the data is used to establish a plot of the vapor pressure curve versus temperature from which a Clausius–Clapeyron relationship can be used to establish the Δ H for sublimation. The method requires that the equipment is calibrated and data for p -aminobenzoic acid is used for this purpose.

The thermal analysis of basic magnesium carbonate has been investigated by thermogravimetry (TGA), derivative thermogravimetry (DTGA) and differential thermal analysis (DTA). The end product was magnesium oxide formed from the decomposition of magnesium carbonate. The composition of the samples studied varied, but the general formula that represented them was xMgCO3·yMg(OH)2·zH2O. In the present study, the thermal analysis of such magnesium carbonates in nitrogen, carbon dioxide and air was carried out at different heating rates and the origin of the exothermic peak was studied. Generally, the decomposition peaks were endothermic, but a persistent exothermic peak was noted, always accompanied by a very sharp drop in the TG curve, and the weight loss in this region may be significant. The exothermic DTA peak was found to be strongly influenced by the rate at which the samples were heated, sample size and atmospheric conditions.