Biomedical subjects

Raj Suryanarayanan

Publications and source records attributed to Raj Suryanarayanan.

32 records · Page 2Linked to original sources

PubMed2004

Characterization and crystal structure of D-mannitol hemihydrate.

The objectives of this study were (i) to isolate and characterize mannitol hydrate, and (ii) to solve its crystal structure from high-resolution synchrotron X-ray powder diffraction data. Mannitol hydrate was prepared by freeze-drying aqueous mannitol solutions (5% w/v) under controlled conditions. X-ray powder diffractometry, differential scanning calorimetry, and thermogravimetric analyses indicated that mannitol exists as a hemihydrate (C(6)H(14)O(6) . 0.5H(2)O). Synchrotron data were collected on the X3B1 beamline at the National Synchrotron Light Source. The simulated annealing program PSSP was used to solve the structure, which was subsequently refined by Rietveld analysis using the program package GSAS. The compound crystallizes in space group P1, with a = 9.8963 A, b = 10.5424 A, c = 4.7860 A, alpha = 102.589 degrees , beta = 86.092 degrees , and gamma = 116.079 degrees . The unit cell contains two dissimilar D-mannitol molecules and one water molecule, forming a hydrogen bonding pattern significantly different from that seen in the anhydrous polymorphs.

Crystallization↗

PubMed2004

Use of glancing angle X-ray powder diffractometry to depth-profile phase transformations during dissolution of indomethacin and theophylline tablets.

PURPOSE: The purpose of this study was (i) to develop glancing angle x-ray powder diffractometry (XRD) as a method for profiling phase transformations as a function of tablet depth; and (ii) to apply this technique to (a) study indomethacin crystallization during dissolution of partially amorphous indomethacin tablets and to (b) profile anhydrate --> hydrate transformations during dissolution of theophylline tablets. METHODS: The intrinsic dissolution rates of indomethacin and theophylline were determined after different pharmaceutical processing steps. Phase transformations during dissolution were evaluated by various techniques. Transformation in the bulk and on the tablet surface was characterized by conventional XRD and scanning electron microscopy, respectively. Glancing angle XRD enabled us to profile these transformations as a function of depth from the tablet surface. RESULTS: Pharmaceutical processing resulted in a decrease in crystallinity of both indomethacin and theophylline. When placed in contact with the dissolution medium, while indomethacin recrystallized, theophylline anhydrate rapidly converted to theophylline monohydrate. Due to intimate contact with the dissolution medium, drug transformation occurred to a greater extent at or near the tablet surface. Glancing angle XRD enabled us to depth profile the extent of phase transformations as a function of the distance from the tablet surface. The processed sample (both indomethacin and theophylline) transformed more rapidly than did the corresponding unprocessed drug. Several challenges associated with the glancing angle technique, that is, the effects of sorbed water, phase transformations during the experimental timescale, and the influence of phase transformation on penetration depth, were addressed. CONCLUSIONS: Increased solubility, and consequently dissolution rate, is one of the potential advantages of metastable phases. This advantage is negated if, during dissolution, the metastable to stable transformation rate >> dissolution rate. Glancing angle XRD enabled us to quantify and thereby profile phase transformations as a function of compact depth. The technique has potential utility in monitoring surface reactions, both chemical decomposition and physical transformations, in pharmaceutical systems.

Drug Stability↗

PubMed2004

Effect of aging on the physical properties of amorphous trehalose.

PURPOSE: The purpose of this investigation was i) to study the effect of physical aging on crystallization and water vapor sorption behavior of amorphous anhydrous trehalose prepared by freeze-drying, and ii) to determine the effects of water sorption on the relaxation state of the aged material. METHODS: Freeze-dried trehalose was aged at 100 dgrees C for varying time periods to obtain samples with different degrees of relaxation. The glass transition temperature (Tg) and enthalpic relaxation were determined by differential scanning calorimetry, and the rate and extent of water uptake at different relative humidity values were quantified using an automated vapor sorption balance. RESULTS: Annealing below the Tg caused nucleation in the amorphous trehalose samples, which decreased the crystallization onset temperature on subsequent heating. However, no crystallization was observed below the Tg even after prolonged annealing. Physical aging caused a decrease in the rate and extent of water vapor sorption at low relative humidity values. Moreover, the water sorption removed the effects of physical aging, thus effectively causing enthalpic recovery in the aged samples. This recovery occurred gradually in the glassy phase and was not associated with a glass to rubber transition. We believe this aging reversal to be due to volume expansion during water sorption in the amorphous structure. CONCLUSIONS: Thermal history of amorphous materials is a crucial determinant of their physical properties. Aging of amorphous trehalose led to nucleation below the Tg, and decrease in rate and extent of water sorption. Sorption of water resulted in irreversible changes in the relaxation state of the aged material.

Absorption↗

PubMed2004

Effect of preparation method on physical properties of amorphous trehalose.

PURPOSE: To determine the effect of preparation method on the physical properties of amorphous trehalose. METHODS: Amorphous anhydrous trehalose was prepared by four different methods. viz., freeze-drying, spray-drying, dehydration, and melt quenching. The glass transition temperature (Tg), enthalpic relaxation behavior, and crystallization were studied by differential scanning calorimetry, whereas X-ray diffractometry was used for phase identification. The rate and extent of water uptake at different relative humidity values were also obtained. RESULTS: Though the enthalpic relaxation and crystallization behaviors were influenced by the method of preparation of amorphous trehalose, the Tg and fragility were not. The phase prepared by dehydration showed the highest enthalpic recovery at Tg, indicating that aging may have occurred during preparation. Among the four methods used, trehalose prepared by dehydration had the highest tendency to crystallize, whereas there was no crystallization in melt-quenched amorphous trehalose. The method of preparation influenced not only the rate and extent of water sorption but also the phase crystallized. Water vapor sorption removed the effects of structural history in the amorphous phase formed by dehydration. CONCLUSIONS: The method of preparation strongly influenced the pharmaceutically relevant properties of amorphous trehalose. The resistance to crystallization can be rank ordered as trehalose prepared by dehydration < freeze-dried approximately spray-dried < melt-quenched. The rate of water sorption can be rank ordered as trehalose prepared by dehydration < freeze-dried < spray-dried.

Chemical Phenomena↗

PubMed2003

Racemic species of sodium ibuprofen: characterization and polymorphic relationships.

Racemic and homochiral sodium ibuprofen were characterized by thermal analysis and powder X-ray diffractometry. The melting point phase diagram was constructed and thermodynamic calculation was performed. In contrast to racemic ibuprofen, which is a racemic compound, racemic sodium ibuprofen forms both a racemic conglomerate (termed the gamma-form) as well as two polymorphic racemic compounds, alpha and beta, which are less stable monotropes. From the supercooled liquid, alpha and beta crystallized along with the original gamma-form. Forms alpha and beta are "enantiotropically related" with a transition temperature between 75 degrees and 113 degrees C, but can be considered to be metastable monotropes of the racemic conglomerate, the stable gamma-form.

Ibuprofen↗

PubMed2003

Solute crystallization in mannitol-glycine systems--implications on protein stabilization in freeze-dried formulations.

The use of mannitol in combination with glycine has resulted in stable freeze-dried protein formulations. Our objectives were to (1) study solute crystallization in ternary systems containing mannitol, glycine, and water during all the stages of freeze drying as a function of processing conditions and formulation variables; (2) investigate the effect of sodium phosphate buffer salts on the crystallization of both mannitol and glycine and vice versa; and (3) investigate the effects of these excipients in a freeze-dried lactate dehydrogenase (LDH) formulation. X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to study the frozen aqueous solutions. Phase transitions during primary and secondary drying were monitored by simulating the entire freeze-drying process in situ in the sample chamber of the diffractometer. LDH activity after freeze drying was determined spectrophotometrically. In frozen aqueous solutions containing mannitol and glycine, each solute influenced the extent of crystallization of the other. The solutes crystallized as delta-mannitol and beta-glycine during primary drying. Glycine had a stronger tendency to crystallize, while it was easier to influence mannitol crystallization. The buffer salts inhibited the crystallization of mannitol and glycine. However, in some cases, during primary drying, glycine crystallization was followed by that of disodium hydrogen phosphate dodecahydrate. The latter underwent dehydration forming an amorphous anhydrate. It was possible to correlate the extent of crystallization of mannitol and glycine in the lyophile with the retention of protein activity. An increase in buffer concentration decreased the crystallinity of mannitol and glycine. This translated to increased retention of protein activity.

Buffers↗

PubMed2003

The effect of additives on the crystallization of cefazolin sodium during freeze-drying.

PURPOSE: To monitor the phase transitions during freeze-drying of cefazolin sodium (I) as a function of process and formulation variables. METHODS: Aqueous solutions of I were frozen under controlled conditions in the sample chamber of a variable temperature X-ray powder diffractometer (XRD). The instrument was modified so that the chamber could be evacuated and the samples dried under reduced pressures. Thus, the entire freeze-drying process was carried out in the XRD holder with real time monitoring of the phase transitions during the different stages of freeze-drying. RESULTS: When aqueous solutions of cefazolin sodium (10% w/w) were cooled to -40 degrees C, the XRD pattern revealed only the crystallization of ice. Annealing the frozen sample led to the crystallization of I as the pentahydrate. Differential scanning calorimetry revealed that the presence of isopropyl alcohol (IPA) (5% w/w) led to a decrease in the Tg', the glass transition temperature of the system, and lowered the temperature of crystallization. The crystallization was studied at -8 and at -15 degrees C in the XRD, and, as expected, more rapid crystallization was observed at the higher temperature. Primary drying at -8 degrees C led to the dehydration of the pentahydrate, resulting in a poorly crystalline product. Again, XRD permitted real time monitoring of the decrease in intensities of some characteristic peaks of the pentahydrate. The in situ XRD technique also enabled us to study the effects of processing conditions (different primary and secondary drying temperatures) and crystalline bulking agents on the solid-state of I in the lyophile. When I was lyophilized using mannitol or glycine as an additive, without an annealing step, the drug was X-ray amorphous although the additive crystallized. When annealed and freeze-dried, I remained crystalline in the presence of glycine but not in the presence of mannitol. CONCLUSIONS: The in situ XRD technique has enabled us to characterize the phase transitions during freeze-drying of cefazolin sodium in multicomponent systems.

Cefazolin↗

PubMed2003

Effective inhibition of mannitol crystallization in frozen solutions by sodium chloride.

PURPOSE: The purpose of this work was to study the possibility of preventing mannitol crystallization in frozen solutions by using pharmaceutically acceptable additives. METHODS: Differential scanning calorimetry (DSC) and low-temperature X-ray diffractometry (LTXRD) were used to characterize the effect of additives on mannitol crystallization. RESULTS: DSC screening revealed that salts (sodium chloride, sodium citrate, and sodium acetate) inhibited mannitol crystallization in frozen solutions more effectively than selected surfactants, alpha-cyclodextrin, polymers, and alditols. This finding prompted further studies of the crystallization in the mannitol-NaCl-water system. Isothermal DSC results indicated that mannitol crystallization in frozen solutions was significantly retarded in the presence of NaCl and that NaCl did not crystallize until mannitol crystallization completed. Low-temperature X-ray diffractometry data showed that when a 10% w/v mannitol solution without additive was cooled at 1 degrees C/min, the crystalline phases emerging after ice crystallization were those of a mannitol hydrate as well as the anhydrous polymorphs. In the presence of NaCl (5% w/v), mannitol crystallization was suppressed during both cooling and warming and occurred only after annealing and rewarming. In the latter case however, mannitol did not crystallize as the hydrate, but as the anhydrous delta polymorph. At a lower NaCl concentration of 1% w/v, the inhibitory effect of NaCl on mannitol crystallization was evident even during annealing at temperatures close to the Tg' (-40 degrees C). A preliminary lyophilization cycle with polyvinyl pyrrolidone and NaCl as additives rendered mannitol amorphous. CONCLUSION: The effectiveness of additives in inhibiting mannitol crystallization in frozen solutions follows the general order: salts > alditols > polyvinyl pyrrolidone > alpha-cyclodextrin > polysorbate 80 approximately polyethylene glycol approximately poloxamer. The judicious use of additives can retain mannitol amorphous during all the stages of the freeze-drying cycle.

Calorimetry, Differential Scanning↗

PubMed2003

Crystalline to amorphous transition of disodium hydrogen phosphate during primary drying.

PURPOSE: To monitor the phase transitions during freeze-drying of disodium hydrogen phosphate. METHODS: The variable temperature sample stage of the X-ray diffractometer (XRD) was attached to a vacuum pump, which enabled the entire freeze-drying process to be carried out in the sample chamber. The phase transitions during the freeze-drying cycle were monitored in real time by XRD. Aqueous buffer solution (containing disodium hydrogen phosphate and sodium dihydrogen phosphate) was cooled at 2 degrees C/min from room temperature to -70 degrees C. It was then heated to -25 degrees C and subjected to primary drying for 2 h at a chamber pressure of approximately 100 mTorr, followed by secondary drying at -10 degrees C. RESULTS: In the frozen solution, disodium hydrogen phosphate had crystallized as the dodecahydrate (Na2HPO4 x 12H2O) as was evident from its characteristic lines at approximately 5.37, 4.27, and 2.81 angstroms. Primary drying for 2 h resulted in ice sublimation, and the complete disappearance of the dodecahydrate peaks. CONCLUSION: The dehydration of the crystalline dodecahydrate resulted in an amorphous anhydrate. Thus the amorphous nature of the end product is a result of phase transitions during the process and do not reflect the solid-state of the ingredients during the entire process.

Crystallization↗

PubMed2003

Determination of glass transition temperature and in situ study of the plasticizing effect of water by inverse gas chromatography.

PURPOSE: To use an inverse gas chromatographic (IGC) method to determine the glass transition temperature (Tg) of some amorphous pharmaceuticals and to extend this technique for the in situ study of the plasticizing effect of water on these materials. METHODS: Amorphous sucrose and colyophilized sucrose-PVP mixtures were the model compounds. Both IGC and differential scanning calorimetry (DSC) were used to determine their Tg. By controlling the water vapor pressure in the IGC sample column, it was possible to determine the Tg of plasticized amorphous phases. Under identical temperatures and vapor pressures, the water uptake was independently quantified in an automated water sorption apparatus. RESULTS: The Tg of the dry phases, determined by IGC and by DSC, were in very good agreement. With an increase in the environmental relative humidity (RH), there was a progressive decrease in Tg as a result of the plasticizing effect of water. Because the water uptake was independently quantified, it was possible to use the Gordon-Taylor equation to predict the Tg values of the plasticized materials. The predicted values were in very good agreement with those determined experimentally using IGC. A unique advantage of this technique is that it provides complete control over the sample environment and is thus ideally suited for the characterization of highly reactive amorphous phases. CONCLUSIONS: An IGC method was used (a) to determine the glass transition temperature of amorphous pharmaceuticals and (b) to quantify the plasticizing effect of water on multicomponent systems.

Calorimetry, Differential Scanning↗

PubMed2003

Crystallization of D-mannitol in binary mixtures with NaCl: phase diagram and polymorphism.

PURPOSE: To study the crystallization, polymorphism, and phase behavior of D-mannitol in binary mixtures with NaCl to better understand their interactions in frozen aqueous solutions. METHODS: Differential scanning calorimetry, hot-stage microscopy, Raman microscopy, and variable-temperature X-ray diffractometry were used to characterize D-mannitol-NaCl mixtures. RESULTS: NaCl and D-mannitol exhibited significant melt miscibility (up to 7.5% w/w or 0.20 mole fraction of NaCl) and a eutectic phase diagram (eutectic composition 7.5% w/w NaCl; eutectic temperature 150 degrees C for the alpha and beta polymorphs of D-mannitol and 139 degrees C for the delta). The presence of NaCl did not prevent mannitol from crystallizing but, depending on sample size, affected the polymorph crystallized: below 10 mg, delta was obtained; above 100 mg, alpha was obtained. Pure mannitol crystallized under the same conditions first as the delta polymorph and then as the a polymorph, with the latter nucleating on the former. KCl showed similar eutectic points and melt miscibility with D-mannitol as NaCl. LiCl yielded lower eutectic melting points, inhibited the crystallization of D-mannitol during cooling, and enabled the observation of its glass transition. CONCLUSIONS: Despite their structural dissimilarity, significant melt miscibility exists between D-mannitol and NaCl. Their phase diagram has been determined and features polymorph-dependent eutectic points. NaCl influences the polymorphic behavior of mannitol, and the effect is linked to the crystallization of mannitol in two polymorphic stages.

Algorithms↗

PubMed2002

Crystallization of mannitol below Tg' during freeze-drying in binary and ternary aqueous systems.

PURPOSE: To characterize the phase transitions in a multicomponent system during the various stages of the freeze-drying process and to evaluate the crystallization behavior below Tg' (glass transition temperature of maximally freeze-concentrated amorphous phase) in frozen aqueous solutions and during freeze-drying. METHODS: X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to study frozen aqueous solutions of mannitol with or without trehalose. By attaching a vacuum pump to the low-temperature stage of the diffractometer, it was possible to simulate the freeze-drying process in situ in the sample chamber of the XRD. This enabled real-time monitoring of the solid state of the solutes during the process. RESULTS: In rapidly cooled aqueous solutions containing only mannitol (10% w/w), the solute was retained amorphous. Annealing of frozen solutions or primary drying. both below Tg', resulted in crystallization of mannitol hydrate. Similar effects were observed in the presence of trehalose (2% w/w). At higher concentrations (> or =5% w/w) of this noncrystallizing sugar. annealing below Tg' led to nucleation but not crystallization. However, during primary drying, crystallization of mannitol hydrate was observed. CONCLUSIONS: The combination of in situ XRD and DSC has given a unique insight into phase transitions during freeze-drying as a function of processing conditions and formulation variables. In the presence of trehalose, mannitol crystallization was inhibited in frozen solutions but not during primary drying.

Cold Temperature↗

PubMed2002

Crystallization behavior of mannitol in frozen aqueous solutions.

PURPOSE: To study the effect of cooling rate, the influence of phosphate buffers and polyvinylpyrrolidone (PVP) on the crystallization behavior of mannitol in frozen aqueous solutions. METHODS: Low-temperature differential scanning calorimetry and powder X-ray diffractometry were used to characterize the frozen solutions. RESULTS: Rapid cooling (20 degrees C/min) inhibited mannitol crystallization, whereas at slower cooling rates (10 degrees C and 5 degrees C/min) partial crystallization was observed. The amorphous freeze-concentrate was characterized by two glass transitions at -32 degrees C and -25 degrees C. When the frozen solutions were heated past the two glass transition temperatures, the solute crystallized as mannitol hydrate. An increase in the concentration of PVP increased the induction time for the crystallization of mannitol hydrate. At concentrations of > or =100 mM, the buffer salts significantly inhibited mannitol crystallization. CONCLUSIONS: The crystallization behavior of mannitol in frozen solutions was influenced by the cooling rate and the presence of phosphate buffers and PVP.

Crystallization↗

PubMed2002

Investigation of solid-state reactions using variable temperature X-ray powder diffractometry. II. Aminophylline monohydrate.

PURPOSE: The object of this investigation was to demonstrate the utility of X-ray powder diffractometry (XRD) to study the kinetics of a complex pharmaceutical solid-state reaction wherein the reactant, product and intermediate phases were all simultaneously quantified. METHODS: Aminophylline monohydrate (I) decomposed to anhydrous theophylline (III) either directly or through an intermediate (anhydrous aminophylline, II). The reaction kinetics were studied isothermally at several temperatures ranging from 65 to 100 degrees C. By measuring the intensities of the XRD peaks unique to I, II and III, it was possible to simultaneously quantify the 3 phases during the entire reaction. RESULTS: Assuming that all the reaction steps follow first-order kinetics. the three equations describing the concentrations of I, II and III as a function of time, were derived. By fitting the experimental data to these equations, it was possible to obtain the rate constants for the three reaction steps. The rate constants were obtained at different temperatures and were used to draw Arrhenius type plots from which the activation energies were determined. At lower temperatures (< 80 degrees C). the concentration of the intermediate phase, i.e., II, was low throughout the reaction while at higher temperatures (> 90 degrees C), there was rapid formation and accumulation of II during the early stages of the reaction. These differences could be attributed to the fact that k1 (I --> II) had a more pronounced temperature dependence than k2 (I --> III) and k3 (II --> II). The XRD results were confirmed with isothermal thermogravimetry. CONCLUSIONS: Variable temperature XRD is a powerful tool to probe reaction kinetics in crystalline pharmaceuticals since it permits simultaneous quantification of multiple solid phases.

Aminophylline↗