Investigating physical properties of solid dosage forms during pharmaceutical processing : Process analytical applications of vibrational spectroscopy

In order to improve and continuously develop the quality of pharmaceutical products, the process analytical technology (PAT) framework has been adopted by the US Food and Drug Administration. One of the aims of PAT is to identify critical process parameters and their effect on the quality of the final product. Real time analysis of the process data enables better control of the processes to obtain a high quality product. The main purpose of this work was to monitor crucial pharmaceutical unit operations (from blending to coating) and to examine the effect of processing on solid-state transformations and physical properties. The tools used were near-infrared (NIR) and Raman spectroscopy combined with multivariate data analysis, as well as X-ray powder diffraction (XRPD) and terahertz pulsed imaging (TPI). To detect process-induced transformations in active pharmaceutical ingredients (APIs), samples were taken after blending, granulation, extrusion, spheronisation, and drying. These samples were monitored by XRPD, Raman, and NIR spectroscopy showing hydrate formation in the case of theophylline and nitrofurantoin. For erythromycin dihydrate formation of the isomorphic dehydrate was critical. Thus, the main focus was on the drying process. NIR spectroscopy was applied in-line during a fluid-bed drying process. Multivariate data analysis (principal component analysis) enabled detection of the dehydrate formation at temperatures above 45°C. Furthermore, a small-scale rotating plate device was tested to provide an insight into film coating. The process was monitored using NIR spectroscopy. A calibration model, using partial least squares regression, was set up and applied to data obtained by in-line NIR measurements of a coating drum process. The predicted coating thickness agreed with the measured coating thickness. For investigating the quality of film coatings TPI was used to create a 3-D image of a coated tablet. With this technique it was possible to determine coating layer thickness, distribution, reproducibility, and uniformity. In addition, it was possible to localise defects of either the coating or the tablet. It can be concluded from this work that the applied techniques increased the understanding of physico-chemical properties of drugs and drug products during and after processing. They additionally provided useful information to improve and verify the quality of pharmaceutical dosage forms

Analytical studies of gain optimization in CO2-N2 gasdynamic lasers employing two-dimensional wedge nozzles

An analytical method has been proposed to optimise the small-signaloptical gain of CO2-N2 gasdynamic lasers (gdl) employing two-dimensional (2D) wedge nozzles. Following our earlier work the equations governing the steady, inviscid, quasi-one-dimensional flow in the wedge nozzle of thegdl are reduced to a universal form so that their solutions depend on a single unifying parameter. These equations are solved numerically to obtain similar solutions for the various flow quantities, which variables are subsequently used to optimize the small-signal-gain. The corresponding optimum values like reservoir pressure and temperature and 2D nozzle area ratio also have been predicted and graphed for a wide range of laser gas compositions, with either H2O or He as the catalyst. A large number of graphs are presented which may be used to obtain the optimum values of small signal gain for a wide range of laser compositions without further computations.

Expansivity of liquid (cyclohexane + acetic anhydride) near its critical solution point

A simple volume dilatometer is described for the precise measurements of volume changes as a function of temperature in liquid mixtures. The expansivity of (cyclohexane + acetic anhydride) in the critical region was measured. The critical solution temperature Tc was approached to within 9 mK. For T > (Tc + 0.3 K), the results results follow both a logarithmic and a power-law behaviour with an exponent ≈ 1/8. But for T < (Tc + 0.3 K), the results seem to be affected possibly by gravity or temperature gradients. In this region, the expected expansivity anomaly is rounded off to a cusp. The expansivity shows a reduced anomaly for off-critical compositions. A discussion of the local extremum and a correlation between negative expansivity and the resistivity anomaly are also given.

Solution conformations of penta and heptapeptides containing repetitive α-aminoisobutyryl-Image -alanyl and α -aminoisobutyryl-Image -valyl sequences

The presence of folded solution conformations in the peptides Boc-Ala-(Aib-Ala)2-OMe, Boc-Val-(Aib-Val) 2-OMe, Boc-Ala-(Aib-Ala)3-OMe and Boc-Val-(Aib-Val)3-OMe has been established by 270MHz 1H NMR. Intramolecularly H-bonded NH groups have been identified using temperature and solvent dependence of NH chemical shifts and paramagnetic radical induced broadening of NH resonances. Both pentapeptides adopt 310 helical conformations possessing 3 intramolecular H-bonds in CDCl3 and (CD3)2SO. The heptapeptides favour helical structures with 5 H-bonds in CDCl3. In (CD3)2SO only 4 H-bonds are readily detected.

Optimal hydrothermal load flow: Formulation and a successive approximation solution for fixed head systems

This paper deals with the optimal load flow problem in a fixed-head hydrothermal electric power system. Equality constraints on the volume of water available for active power generation at the hydro plants as well as inequality constraints on the reactive power generation at the voltage controlled buses are imposed. Conditions for optimal load flow are derived and a successive approximation algorithm for solving the optimal generation schedule is developed. Computer implementation of the algorithm is discussed, and the results obtained from the computer solution of test systems are presented.

On the direct parallel solution of systems of linear equations: New algorithms and systolic structures

The paper presents two new algorithms for the direct parallel solution of systems of linear equations. The algorithms employ a novel recursive doubling technique to obtain solutions to an nth-order system in n steps with no more than 2n(n −1) processors. Comparing their performance with the Gaussian elimination algorithm (GE), we show that they are almost 100% faster than the latter. This speedup is achieved by dispensing with all the computation involved in the back-substitution phase of GE. It is also shown that the new algorithms exhibit error characteristics which are superior to GE. An n(n + 1) systolic array structure is proposed for the implementation of the new algorithms. We show that complete solutions can be obtained, through these single-phase solution methods, in 5n−log2n−4 computational steps, without the need for intermediate I/O operations.

Two-dimensional solidification in a cylindrical mold with imperfect mold contact

A two-dimensional axisymmetric problem of solidification of a superheated liquid in a long cylindrical mold has been studied in this paper by employing a new embedding technique. The mold and the melt has an imperfect contact and the heat transfer coefficient has been taken as a function of space and time. Short-time exact analytical solutions for the moving boundary and temperature distributions in the liquid, solid and mold have been obtained. The numerical results indicate that with the present solution, for some parameter values, substantial solidified thickness can be obtained. The method of solution is simple and straightforward, and consists of assuming fictitious initial temperatures for some suitable fictitious extensions of the actual regions. Sufficient conditions for the commencement of the solidification have been discussed.

Experimental and Analytical Investigations of the actions taking place in a Synchronous machine during the starting period when the starting Is effected by means of alternating current

The literature on the subject of the present investigation is somewhat meagre. A rotary converter or synchronous motor no! provided with any special starting devices forms, when started from the alternating current side, a type of induction motor whoso Htator is provided with a polyphase winding, and whoso rotor has a single-phase (or single magnetic axis) winding.

Mössbauer studies of the corrosion products of iron formed in aqueous ammonium nitrate solution

The products of corrosion reaction of electrolytic iron in 45% ammonium nitrate solution formed under various conditions of time, temperature and pH have been analysed mainly by Mössbauer spectroscopy, in combination with X-ray diffraction, infrared absorption and electron microscopy techniques. γ-Fe00H is found to be the major product of hydrolytic precipitation at pH > 5.6 while only α-FeOOH is formed at pH < 3.0. In the pH range 3.0 < pH < 5.0, α-Fe00H and ferrihydrite are both formed. However, once the nuclei of α-Fe00H are formed under low pH conditions, their growth is favoured even in the otherwise unfavourable slightly acidic medium, resulting in a hydrous α-Fe00H which has two distinct hyperfine fields at the 57Fe nucleus. Magnetite is always formed in the vicinity of the metal and its rate of formation on the surface increases with temperature. α-Fe203 is the major product of hydrolytic precipitation at temperatures >80C. The possible mechanisms for the formation of each of the corrosion products are discussed.

Treatment of distal intestinal obstruction syndrome in cystic fibrosis with a balanced intestinal lavage solution

Conventional treatment of distal intestinal obstruction syndrome (DIOS) with high doses of pancreatic enzymes, mucolytic agents, and enemas is neither predictably effective nor rapid in action. In 6 cystic fibrosis patients with DIOS a balanced, non-absorbable intestinal lavage solution produced clinical and radiological improvement and striking improvement in DIOS scores. It is suggested that a balanced intestinal lavage solution should be considered as an alternative treatment for DIOS in patients with cystic fibrosis.

Semi-similar solution of an unsteady compressible three-dimensional stagnation point boundary layer flow with massive blowing

A semi-similar solution of an unsteady laminar compressible three-dimensional stagnation point boundary layer flow with massive blowing has been obtained when the free stream velocity varies arbitrarily with time. The resulting partial differential equations governing the flow have been solved numerically using an implicit finite-difference scheme with a quasi-linearization technique in the nodal point region and an implicit finite-difference scheme with a parametric differentiation technique in the saddle point region. The results have been obtained for two particular unsteady free stream velocity distributions: (i) an accelerating stream and (ii) a fluctuating stream. Results show that the skin-friction and heat-transfer parameters respond significantly to the time dependent arbitrary free stream velocity. Velocity and enthalpy profiles approach their free stream values faster as time increases. There is a reverse flow in the y-wise velocity profile, and overshoot in the x-wise velocity and enthalpy profiles in the saddle point region, which increase as injection and wall temperature increase. Location of the dividing streamline increases as injection increases, but as the wall temperature and time increase, it decreases.

Stereochemistry of Peptides Containing 1-AminocyclopentanecarboxylicA cid ( Am5): Solution and Solid-state Conformations of Boc-Acc '-Acc'-NHMe

The conformational analysis of a protected homodipeptide of 1-aminocyclopentanecarboxylic acid (Acc5) has been carried out. 1H-nmr studies establish a -turn conformation for Boc-Acc5-Acc5-NHMe in chloroform and dimethylsulfoxide solutions involving the methylamide NH in an intramolecular hydrogen bond. Supportive evidence for the formation of an intramolecular hydrogen bond is obtained from ir studies. X-ray diffraction studies reveal a type III -turn conformation in the solid state stabilized by a 4 1 hydrogen bond between the Boc CO and methylamide NH groups. The , values for both Acc5 residues are close to those expected for an ideal 310-helical conformation ( ± 60°, ±30°).

Conformations of the amino aterminal tetrapeptide of emerimicins and antiamoebins in solution and in the solid state

The conformations of Boc-l-Phe-(AiB)3-OH (1) and Boc-l-Phe-(Aib)3-OMe (2) which correspond to the amino terminal sequence of the emerimicins and antiamoebins have been studied in solution using 270 MHz 1H n.m.r. In dimethyl sulphoxide solution both peptides show the presence of two strongly solvent shielded Aib NH groups, consistent with a consecutive β-turn conformation, involving the Aib(3) and Aib(4) NH groups in intramolecular 4 → I hydrogen bonds. This folded conformation is maintained for 2 in chloroform solution. Nuclear Overhauser effect studies provide evidence for a Type II Phe-Aib β-turn. An X-ray diffraction study of Boc-(d,l)-Phe-(Aib)3-OH establishes a single type III(III′) β-turn conformation with Aib(2)-Aib(3) as the corner residues. A single intramolecular 4 → I hydrogen bond between Phe(I) CO and Aib(4) NH groups is observed in the crystal. The solution conformation may incorporate a consecutive type II-III′ structure for the Phe(1)-Aib(2)-Aib(3) segment, with the initial type II β-turn being destabilized by intermolecular interactions in the solid state.

Cyclic Peptide Disulfides - Solution And Solid-State Conformation Of Boc-Cys-Pro-Aib-Cys-S-S-Bridge-Nhme,A Disulfide-Bridged Peptide Helix

The solution and solid-state conformations of the peptide disulfide Boc-Cys-Pro-Aib-Cys-NHMe have been determined by NMR spectroscopy and X-ray diffraction. The Cys(4) and methylamide NH groups are solvent shielded in CDCI3 and (CD,),SO, suggesting their involvement in intramolecular hydrogen bonding. On the basis of known stereochemical preferences of Pro and Aib residues, a consecutive @-turn structure is favored in solution. X-ray diffraction analysis reveals a highly folded 310 helical conformation for the peptide, with the S-S bridge lying approximately parallel to the helix axis, linking residues 1 and 4. The backbone conformational angles are Cys(1) 4 = -121.1', $ = 65.6"; Pro(2) 4 = -58.9', 4 = -34.0'; Aib(3) 4 = -61.8', $ = -17.9'; Cys(4) 4 = -70.5', $ = -18.6'. Two intramolecular hydrogen bonds are observed between Cys(1) CO--HN Cys(4) and Pro(2) CO--HNMe. The disulfide bond has a right-handed chirality, with a dihedral angle (xss) of 82'.

Self-similar solution of unsteady compressible three-dimensional stagnation-point boundary layers

The self-similar solution of the unsteady laminar compressible boundary-layer flow with variable properties at a three-dimensional stagnation point with mass transfer has been obtained when the free-stream velocity varies inversely as a linear function of time. The resulting ordinary differential equations have been solved numerically using an implicit finite-difference scheme. The results are found to be strongly dependent on the parameter characterizing the unsteadiness in the free-stream velocity. The velocity profiles show some features not encountered in steady flows.