Miscibility as a Factor for Component Crystallization in Multisolute Frozen Solutions

The relationship between the miscibility of formulation ingredients and their crystallization during the freezing segment of the lyophilization process was studied. The thermal properties of frozen solutions containing myo-inositol and cosolutes were obtained by performing heating scans from −70°C before and after heat treatment at −20°C to −5°C. Addition of dextran 40,000 reduced and prevented crystallization of myo-inositol. In the first scan, some frozen solutions containing an inositol-rich mixture with dextran showed single broad transitions (T_g′s: transition temperatures of maximally freeze-concentrated solutes) that indicated incomplete mixing of the concentrated amorphous solutes. Heat treatment of these frozen solutions induced separation of the solutes into inositol-dominant and solute mixture phases (T_g′ splitting) following crystallization of myo-inositol (T_g′ shifting). The crystal growth involved myo-inositol molecules in the solute mixture phase. The amorphous–amorphous phase separation and resulting loss of the heteromolecular interaction in the freeze-concentrated inositol-dominant phase should allow ordered assembly of the solute molecules required for nucleation. Some dextran-rich and intermediate concentration ratio frozen solutions retained single T_g′s of the amorphous solute mixture, both before and after heat treatments. The relevance of solute miscibility on the crystallization of myo-inositol was also indicated in the systems containing glucose or recombinant human albumin.     

Investigation of PEG Crystallization in Frozen PEG-Sucrose-Water Solutions. I. Characterization of the Nonequilibrium Behavior during Freeze-Thawing

Our objective was to characterize the nonequilibrium thermal behavior of frozen aqueous solutions containing PEG and sucrose. Aqueous solutions of (i) sucrose (10%, w/v) with different concentrations of PEG (1–20%, w/v), and (ii) PEG (10%, w/v) with different concentrations of sucrose (2–20%, w/v), were cooled to ? 70°C at 5°C/min and heated to 25°C at 2°C/min in a differential scanning calorimeter. Annealing was performed at temperatures ranging from ? 50 to ? 20°C for 2 or 6 h. Similar experiments were also performed in the low-temperature stage of a powder X-ray diffractometer. A limited number of additional DSC experiments were performed wherein the samples were cooled to ? 100°C. In unannealed systems with a fixed sucrose concentration (10%, w/v), the T′_g decreased from ? 35 to ? 48°C when PEG concentration was increased from 1% to 20% (w/v). On annealing at ? 25°C, PEG crystallized. This was evident from the increase in T′_g and the appearance of a secondary melting endotherm in the DSC. Low- temperature XRD provided direct evidence of PEG crystallization. Annealing at temperatures ≤?40°C did not result in crystallization and a devitrification event was observed above the T′_g. In unannealed systems with a fixed PEG concentration (10%, w/v), the T′_g increased from ? 50 to ? 40°C when sucrose concentration was increased from 5% to 50%, w/v. As the annealing time increased (at ? 25°C), the T′_g approached that of a sucrose-water system, reflecting progressive PEG crystallization. A second glass transition at ~? 65°C was evident in unannealed systems [10%, w/v sucrose and 10 (or 20%), w/v PEG] cooled to ? 100°C. Investigation of the nonequilibrium behavior of frozen PEG-sucrose-water ternary system revealed phase separation in the freeze-concentrate. Annealing facilitated PEG crystallization.     

Molecular Dynamics Simulation of Amorphous Indomethacin-Poly(Vinylpyrrolidone) Glasses: Solubility and Hydrogen Bonding Interactions

Amorphous drug dispersions are frequently employed to enhance solubility and dissolution of poorly water-soluble drugs and thereby increase their oral bioavailability. Because these systems are metastable, phase separation of the amorphous components and subsequent drug crystallization may occur during storage. Computational methods to determine the likelihood of these events would be very valuable, if their reliability could be validated. This study investigates amorphous systems of indomethacin (IMC) in poly(vinylpyrrolidone) (PVP) and their molecular interactions by means of molecular dynamics (MD) simulations. IMC and PVP molecules were constructed using X-ray diffraction data, and force-field parameters were assigned by analogy with similar groups in Amber-ff03. Five assemblies varying in PVP and IMC composition were equilibrated in their molten states then cooled at a rate of 0.03 K/ps to generate amorphous glasses. Prolonged aging dynamic runs (100 ns) at 298 K and 1 bar were then carried out, from which solubility parameters, the Flory-Huggins interaction parameter, and associated hydrogen bonding properties were obtained. Calculated glass transition temperature (T_g) values were higher than experimental results because of the faster cooling rates in MD simulations. Molecular mobility as characterized by atomic fluctuations was substantially reduced below the T_g with IMC–PVP systems exhibiting lower mobilities than that found in amorphous IMC, consistent with the antiplasticizing effect of PVP. The number of IMC–IMC hydrogen bonds (HBs) formed per IMC molecule was substantially lower in IMC–PVP mixtures, particularly the fractions of IMC molecules involved in two or three HBs with other IMC molecules that may be potential precursors for crystal growth. The loss of HBs between IMC molecules in the presence of PVP was largely compensated for by the formation of IMC–PVP HBs. The difference (6.5 MPa^1/2) between the solubility parameters in amorphous IMC (25.5 MPa^1/2) and PVP (19.0 MPa^1/2) suggests a small, positive free energy of mixing, although it is close to the criterion for miscibility (< 7 MPa^1/2). In contrast to the solubility-parameter method, the calculated Flory-Huggins interaction parameter (? 0.61 ± 0.25), which takes into account the IMC–PVP interaction energy, predicts complete miscibility at all PVP compositions, in agreement with experimental observations. These results from MD simulations were combined with experimental values for the crystalline γ-polymorph of IMC and amorphous IMC to estimate the solubility of IMC in amorphous PVP dispersions and the theoretical enhancement in the aqueous solubility of IMC molecularly dispersed in PVP at various volume fractions. © 2012Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:876–891, 2013     

Molecular Relaxation Behavior and Isothermal Crystallization above Glass Transition Temperature of Amorphous Hesperetin

The purpose of this paper was to investigate the relaxation behavior of amorphous hesperetin (HRN), using dielectric spectroscopy, and assessment of its crystallization kinetics above glass transition temperature (T_g). Amorphous HRN exhibited both local (β-) and global (α-) relaxations. β-Relaxation was observed below T_g, whereas α-relaxation prominently emerged above T_g. β-Relaxation was found to be of Johari–Goldstein type and was correlated with α-process by coupling model. Secondly, isothermal crystallization experiments were performed at 363 K (T_g+ 16.5 K), 373 K (T_g+ 26.5 K), and 383 K (T_g+ 36.5 K). The kinetics of crystallization, obtained from the normalized dielectric strength, was modeled using the Avrami model. Havriliak–Negami (HN) shape parameters, α_HNand α_HN.β_HN, were analyzed during the course of crystallization to understand the dynamics of amorphous phase during the emergence of crystallites. HN shape parameters indicated that long range (α-like) were motions affected to a greater extent than short range (β-like) motions during isothermal crystallization studies at all temperature conditions. The variable behavior of α-like motions at different isothermal crystallization temperatures was attributed to evolving crystallites with time and increase in electrical conductivity with temperature. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:167–178, 2014     

Using dextran of different molecular weights to achieve faster freeze-drying and improved storage stability of lactate dehydrogenase

Freeze-drying of protein formulations is frequently used to maintain protein activity during storage. The freeze-drying process usually requires long primary drying times because the highest acceptable drying temperature to obtain acceptable products is dependent on the glass transition temperature of the maximally freeze-concentrated solution (T_g′). On the other hand, retaining protein activity during storage is related to the glass transition temperature (T_g) of the final freeze-dried product. In this study, dextrans with different molecular weight (1 and 40?kDa) and mixtures thereof at the ratio 3:1, 1:1, and 1:3 (w/w) were used as cryo-/lyoprotectant and their impact on the stability of the model protein lactate dehydrogenase (LDH) was investigated at elevated temperatures (40?°C and 60?°C). The dextran formulations were then compared to formulations containing sucrose as cryo-/lyoprotectant. Because of the higher T_g′ values of the dextrans, the primary drying times could be reduced compared to freeze-drying with sucrose. Similarly, the higher T_g and T_g′ of dextrans relative to sucrose led to benefits during storage which was shown through improved protection of LDH activity.     

Water Sorption Glass Transition Protein-Stabilizing Behavior of an Amorphous Sucrose Matrix Combined With Various Materials

The effects of various additives on the physical properties of an amorphous sugar matrix were compared. Amorphous, sugar-additive mixtures were prepared by freeze-drying and then rehumidified at given RHs. Sucrose and eighteen types of substances were used as the sugar and the additive, respectively, and water sorption, glass-to-rubber transition, and protein stabilization during freeze-drying for the various sucrose-additive mixtures were examined. The additives were categorized into two groups according to their effects on Tg and water sorption. Presence of polysaccharides, cyclodextrins, and polymers (large-sized additives) resulted in a decrease in equilibrium water content from the ideal value calculated from individual water contents for sucrose and additive, and in contrast, low MW substances containing ionizable groups (small-ionized additives) resulted in an increase. The increase in T_g by the addition of large-sized additives was significant at the additive contents > 50 wt.% whereas the T_g was markedly increased in the lower additive content by the addition of small- ionized additives. The addition of small-ionized additives enhanced the decrease in Tg with increasing water content. The protein stabilizing effect was decreased with increasing additive content in the cases of the both groups of the additives.     

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3 μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50 μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27 μg/ml) over 24 h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low T_g (113 °C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8 MPa^0.5) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.     

Investigation of PEG Crystallization in Frozen PEG–Sucrose–Water Solutions: II. Characterization of the Equilibrium Behavior During Freeze-Thawing

Our objective was to characterize, by DSC and XRD, the equilibrium thermal behavior of frozen aqueous solutions containing polyethylene glycol (PEG) and sucrose. Aqueous solutions of (i) PEG (2.5–50% w/w), (ii) sucrose (10% w/v) with different concentrations of PEG (1–20% w/v), and (iii) PEG (2% or 10% w/v) with different concentrations of sucrose (2–20% w/v), were cooled to ? 70°C at 5°C/min and heated to 25°C at 2°C/min in a DSC. Annealing was performed for 2 or 6 h at temperatures, ranging from ? 50 to ? 20°C. Experiments under similar conditions, on select compositions, were also performed in a powder X-ray diffractometer. Two endotherms, observed during heating of a frozen PEG solution (10% w/v), were attributed to PEG–ice eutectic melting and ice melting, and were confirmed by XRD. At higher PEG concentrations (> 37.5% w/w), only the endotherm attributed to the PEG–ice eutectic melting was observed. Inclusion of sucrose decreased both PEG–ice melting and ice melting temperatures. In unannealed systems with a fixed sucrose concentration (10% w/v), the PEG–ice melting event was not observed at PEG concentration < 5% w/v. Annealing for 2–6 h facilitated PEG crystallization. In unannealed systems with a fixed PEG concentration (10% w/v), an increase in the sucrose concentration increased the devitrification but decreased the PEG–ice melting temperature. The PEG–ice melting temperatures obtained by DSC and XRD were in good agreement. In ternary systems at a fixed PEG to sucrose ratio, the T_g^′ as well as the PEG–ice melting temperature were unaffected by the total solute concentration. XRD confirmed the absence of a PEG–sucrose–ice ternary eutectic. When the PEG to sucrose ratio was systematically varied, the PEG–ice and ice melting temperatures decreased with an increase in the sucrose concentration. However, at a fixed PEG to sucrose ratio, the PEG–ice melting temperature, was unaffected by the total solute concentration.     

Toxicological effects of clofibric acid and diclofenac on plasma thyroid hormones of an Indian major carp,Cirrhinus mrigala during short and long-term exposures

In the present investigation, the toxicity of most commonly detected pharmaceuticals in the aquatic environment namely clofibric acid (CA) and diclofenac (DCF) was investigated in an Indian major carp Cirrhinus mrigala. Fingerlings of C. mrigala were exposed to different concentrations (1, 10 and 100 μg L⁻¹) of CA and DCF for a period of 96 h (short term) and 35 days (long term). The toxic effects of CA and DCF on thyroid hormones (THs) such as thyroid stimulating hormone (TSH), thyroxine (T₄) and triiodothyronine (T₃) levels were evaluated. During the short and long-term exposure period TSH level was found to be decreased at all concentrations of CA (except at the end of 14^th day in 1 and 10 μg L^−l and 21^st day in 1 μg L^−l) whereas in DCF exposed fish TSH level was found to be increased when compared to control groups. T₄ level was found to be decreased at 1 and 100 μg L^−l of CA exposure at the end of 96 h. However, T₄ level was decreased at all concentrations of CA and DCF during long-term (35 days) exposure period. Fish exposed to all concentrations of CA and DCF had lower level of T₃ in both the treatments. These results suggest that both CA and DCF drugs induced significant changes (P < 0.01 and P < 0.05) on thyroid hormonal levels of C. mrigala. The alterations of these hormonal levels can be used as potential biomarkers in monitoring of pharmaceutical drugs in aquatic organisms.     

Use of Manometric Temperature Measurements (MTM) to Characterize the Freeze-Drying Behavior of Amorphous Protein Formulations

The freeze-drying behavior and cake morphology of a model protein in an amorphous formulation were studied at varying protein concentrations using conservative (? 25°C) and aggressive (+ 25°C) shelf temperatures at constant chamber pressure during primary drying. The two cycles were characterized by manometric temperature measurements (MTM) in a SMART^TM freeze dryer that estimates the sublimation rate (dm/dt), product temperature at the freeze-drying front (T_p-MTM) and product resistance (R_p) during a run. The calculated sublimation rates (dm/dt) were 3–4 times faster in the aggressive cycle compared to the conservative cycle. For conservatively dried cakes R_p increased with both dry layer thickness and protein concentration. For aggressively dried cakes (where freeze-drying occurs at the edge of microcollapse), R_p also increased with protein concentration but was independent of the dry layer thickness. The sublimation rate was influenced by R_p, dry layer thickness and T_p-mtm in the conservative cycle, but was governed mainly by T_p-MTM in the aggressive cycle, where R_p is independent of the dry layer thickness. The aggressively dried cakes had a more open and porous structure compared to their conservatively dried counterparts.     

The use of dynamic mechanical analysis (DMA) to evaluate plasticization of acrylic polymer films under simulated gastrointestinal conditions

PurposeGlass transition temperature (T_g) measurements of polymers are conventionally conducted in the dry state with little attention to the environment they are designed to work in. Our aim was to develop the novel use of dynamic mechanical analysis (DMA) to measure the T_g of enteric polymethacrylic acid methylmethacrylate (Eudragit L and S) polymer films formulated with a range of plasticizers in the dry and wet (while immersed in simulated gastric media) states.MethodsPolymer films were fabricated with and without different plasticizers (triacetin, acetyl triethyl citrate, triethyl citrate, polyethylene glycol, propylene glycol, dibutyl phthalate, dibutyl sebacate). T_g was measured by a dynamic oscillating force with simultaneous heating at 1 °C/min. This was conducted on films in the dry state and while immersed in 0.1 M HCl to simulate the pH environment in the stomach.ResultsThe T_g of unplasticized Eudragit L and S films in the dry state was measured to be 150 and 120 °C, respectively. These values were drastically reduced in the wet state to 20 and 71 °C for Eudragit L and S films, respectively. The plasticized films showed similar falls in T_g in the wet state. The fall in T_g of Eudragit L films to below body temperature will have far-reaching implications on polymer functionality and drug release.ConclusionsImmersion DMA provides a robust method for measuring T_g of polymer films in the wet state. This allows better prediction of polymer behaviour in vivo.     

Through-Vial Impedance Spectroscopy of the Mechanisms of Annealing in the Freeze-Drying of Maltodextrin: The Impact of Annealing Hold Time and Temperature on the Primary Drying Rate

The study aims to investigate the impact of annealing hold time and temperature on the primary drying rate/duration of a 10% (w/v) solution of maltodextrin with an emphasis on how the mechanisms of annealing might be understood from the in-vial measurements of the ice crystal growth and the glass transition. The electrical impedance of the solution within a modified glass vial was recorded between 10 and 10⁶ Hz during freeze-drying cycles with varying annealing hold times (1–5 h) and temperatures. Primary drying times decreased by 7%, 27% and 34% (1.1, 4.3 and 5.5 h) with the inclusion of an annealing step at temperatures of –15 °C, –10 °C and –5 °C, respectively. The glass transition was recorded at approximately –16 °C during the re-heating and re-cooling steps, which is close to the glass transition (T_g′) reported for 10% (w/v) maltodextrin and therefore indicates that a maximum freeze concentration (~ 86%, w/w, from the Gordon–Taylor equation) was achieved during first freezing, with no further ice being formed on annealing. This observation, coupled to the decrease in electrical resistance that was observed during the annealing hold time, suggests that the reduction in the drying time was because of improved connectivity of ice crystals because of Ostwald ripening rather than devitrification. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1799–1810, 2014     

Differences in the interaction between aryl propionic acid derivatives and poly(vinylpyrrolidone) K30: A multi-methodological approach

The present work aims at the application of several methods to explain differences in the physical interaction of some aryl propionic acid derivatives (ibuprofen [IBP], ketoprofen [KET], flurbiprofen [FLU], naproxen [NAP], fenbufen [FEN]) with poly(vinylpyrrolidone) (PVP) K30, stored together at 298 ± 0.5 K and 22% RH. X-ray powder diffractometry and ¹³C-solid state NMR demonstrated that IBP was able to strongly interact with the polymer, while weak interaction was observed for KET, FLU, NAP, and the least for FEN. The interaction of comelted drug and PVP was studied by differential scanning calorimetry by applying the Gordon–Taylor equation, which revealed that small molar drug volumes may favour the drug diffusion through the PVP amorphous chains increasing the polymer free volume and decreasing the mixture T_g. The molecular docking study revealed that intermolecular energy is mainly due to the contribution of van der Waals energy component, causing the differences among the drugs, and is related to the drug–PVP surface contact area in the complex formed. Solid-state kinetic study demonstrated that IBP molecules are involved in a three-dimensional diffusion mechanism within the polymer favoured by its low molar volume that reduces molecular hindrance, and by the weakness of its crystal lattice, which facilitates crystallinity loss and stabilisation of the amorphous phase. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4216–4228, 2009     

Development of PVP/PEG mixtures as appropriate carriers for the preparation of drug solid dispersions by melt mixing technique and optimization of dissolution using artificial neural networks

The effect of plasticizer’s (PEG) molecular weight (MW) on PVP based solid dispersions (SDs), prepared by melt mixing, was evaluated in the present study using Tibolone as a poorly water soluble model drug. PEGs with MW of 400, 600, and 2000 g/mol were tested, and the effect of drug content, time and temperature of melt mixing on the physical state of Tibolone, and the dissolution characteristics from SDs was investigated. PVP blends with PEG400 and PEG600 were completely miscible, while blends were heterogeneous. Furthermore, a single T_g recorded in all samples, indicating that Tibolone was dispersed in a molecular lever (or in the form of nanodispersions), varied with varying PEG’s molecular weight, melt mixing temperature, and drug content, while FTIR analysis indicated significant interactions between Tibolone and PVP/PEG matrices. All prepared solid dispersion showed long-term physical stability (18 months in room temperature). The extent of interaction between mixture components was verified using Fox and Gordon–Taylor equations. Artificial neural networks, used to correlate the studied factors with selected dissolution characteristics, showed good prediction ability.     

Preparation of an amorphous sodium furosemide salt improves solubility and dissolution rate and leads to a faster Tmax after oral dosing to rats

Amorphous forms of furosemide sodium salt and furosemide free acid were prepared by spray drying. For the preparation of the amorphous free acid, methanol was utilised as the solvent, whereas the amorphous sodium salt was formed from a sodium hydroxide-containing aqueous solvent in equimolar amounts of NaOH and furosemide. Information about the structural differences between the two amorphous forms was obtained by Fourier Transform Infrared Spectroscopy (FTIR), and glass transition temperature (T_g) was determined using Differential Scanning Calorimetry (DSC). The stability and devitrification tendency of the two amorphous forms were investigated by X-ray Powder Diffraction (XRPD). The apparent solubility of the two amorphous forms and the crystalline free acid form of furosemide in various gastric and intestinal stimulated media was determined. Moreover, the dissolution characteristics of the two amorphous forms and of crystalline free acid were investigated.FTIR confirmed molecular differences between the amorphous free acid and salt. The amorphous salt showed a T_g of 101.2 °C, whereas the T_g for the amorphous free acid was found to be 61.8 °C. The amorphous free acid was physically stable for 4 days at 22 °C and 33% relative humidity (RH), while the amorphous salt exhibited physical stability for 291 days at the same storage conditions. When storing the amorphous forms at 40 °C and 75% RH both forms converted to crystalline forms after 2 days.The apparent solubility of the amorphous salt form was higher than that of both amorphous and crystalline free acid in all media studied. All three forms of furosemide exhibited a greater solubility in the presence of biorelevant media as compared to buffer, however, an overall trend for a further increase in solubility in relation to an increase in media surfactant concentration was not seen. The amorphous salt demonstrated an 8- and 20-fold higher intrinsic dissolution rate (IDR) when compared to amorphous and crystalline free acid, respectively.The promising properties of the amorphous salt in vitro were further evaluated in an in vivo study, where solid dosage forms of the amorphous salt, amorphous and crystalline free acid and a solution of furosemide were administered orally to rats. The amorphous salt exhibited a significantly faster T_max compared to the solution and amorphous and crystalline free acid. C_max for the solution was significantly higher compared to the three furosemide forms. No significant difference was found in AUC and absolute bioavailability for the solution, crystalline free acid and the two amorphous forms of furosemide. It can be concluded that the higher IDR and higher apparent solubility of the amorphous salt resulted in a faster T_max compared to the amorphous and crystalline free acid.     

Continuous versus intermittent infusion of cefepime in neurosurgical patients with post-operative intracranial infections

Cefepime is administered as an intermittent infusion (II); however, continuous infusion (CI) may be advantageous because β-lactam antibiotics exhibit time-dependent antibacterial activity. This retrospective, non-randomised, comparative study included 68 neurosurgical patients with post-operative intracranial infections treated with 4 g/day cefepime over 24 h as a CI (n = 34) or 2 g every 12 h as II (n = 34). CI controlled the intracranial infection more rapidly and effectively than II (6.6 ± 1.9 days vs. 7.8 ± 2.6 days; P = 0.036). By considering the minimum inhibitory concentrations (MICs) to be 4 μg/mL and 8 μg/mL, the percentage of time when the cefepime plasma or CSF concentrations were higher than the MIC (%T_>MIC) was calculated for each patient. For plasma cefepime concentrations, the %T_>MIC in the CI group was higher than in the II group (for MICs of 8 μg/mL, 100% vs. 75%, respectively). The mean calculated area under the curve (AUC) in the CI group was similar to the II group (1197.99 ± 72.15 μg h/mL vs. 890.84 ± 140.78 μg h/mL; P = 0.655). For CSF cefepime concentrations, the %T_>MIC in the CI group was higher than in the II group (for MICs of 4 μg/mL and 8 μg/mL, 83.3% and 75% vs. 25% and 0%, respectively). The mean calculated AUC for the CI group was higher than the II group (220.56 ± 13.59 μg h/mL vs. 86.34 ± 5.69 μg h/mL; P = 0.003). Therefore, CI of cefepime significantly enhanced the antibacterial effect and reduced the treatment duration in neurosurgical patients with post-operative intracranial infections.     

Pilot toxicokinetic study and absolute oral bioavailability of the Fusarium mycotoxin enniatin B1 in pigs

The aim of present study was to reveal the toxicokinetic properties and absolute oral bioavailability of enniatin B1 in pigs. Five pigs were administered this Fusarium mycotoxin per os and intravenously in a two-way cross-over design. The toxicokinetic profile fitted a two-compartmental model. Enniatin B1 is rapidly absorbed after oral administration (T_1/2a = 0.15 h, T_max = 0.24 h) and rapidly distributed and eliminated as well (T_1/2elα = 0.15 h; T_1/2elβ = 1.57 h). The absolute oral bioavailability is high (90.9%), indicating a clear systemic exposure. After intravenous administration, the mycotoxin is distributed and eliminated rapidly (T_1/2elα = 0.15 h; T_1/2elβ = 1.13 h), in accordance with oral administration.     

Development of fully amorphous dispersions of a low Tg drug via co-spray drying with hydrophilic polymers

The aim of the study was to prepare molecular dispersions of a physically highly unstable amorphous drug, paracetamol (acetaminophen with a T_g of ca. 25 °C) via co-spray drying with a variety of polymers. Solid dispersions at a range of drug loadings (10–90%w/w) using hydroxypropyl methylcellulose/acetate succinate (HPMC/HPMC AS), polyvinylpyrrolidone (PVP) and copovidone were produced and characterised by modulated temperature differential scanning calorimetry (MTDSC), thermogravimetric analysis (TGA), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). PVP-based polymers showed a greater tendency than the HPMC-based group to generate temperature-stable dispersions. In particular, copovidone (Plasdone® S-630) was found to be the most effective of the polymers studied and could formulate molecular dispersions at drug loadings up to and including 40%w/w. However, no evidence for direct drug–polymer interactions was found for such systems as a possible stabilising mechanism. The expected relationship of a higher T_g of the polymer leading to greater stabilisation was not observed, while there was an inverse relationship between viscosity grade and amorphous phase generation. The study has therefore shown that temperature-stable amorphous dispersions of a low T_g drug may be prepared by co-spray drying, particularly using PVP-based polymers.     

Alteration of pharmacokinetics of proguanil in healthy volunteers following concurrent administration of efavirenz

Efavirenz and proguanil are likely to be administered concurrently for the treatment of patients with HIV and malaria. The metabolism of proguanil is mediated principally by CYP2C19 while efavirenz is known to inhibit this enzyme. This study therefore investigated the effect of efavirenz on proguanil disposition. Fifteen healthy volunteers were each given 300 mg single oral doses of proguanil alone or with the 9th dose of efavirenz (400 mg daily for 11 days) in a crossover fashion. Blood samples were collected at pre-determined time intervals and analyzed for proguanil and its major metabolite, cycloguanil, using a validated HPLC method. Co-administration of proguanil and efavirenz resulted in significant increases (p < 0.05) in C_max, T_max, AUC_T and elimination half-life (T_1/2β) of proguanil compared with values for proguanil alone [C_max: 2.55 ± 0.24 mg/l vs 3.75 ± 0.48 mg/l; T_max: 2.80 ± 0.99 h vs 4.80 ± 0.99 h; AUC_T: 45.58 ± 12.75 mg h/l vs 97.00 ± 23.33 mg h/l; T_1/2β: 16.50 ± 4.55 h vs 23.24 ± 4.08 h]. Also, efavirenz caused a pronounced decrease in the AUC(metabolite)/AUC(unchanged drug) ratio of proguanil along with a significant decrease (p < 0.05) in C_max and AUC of the metabolite.These results indicate that efavirenz significantly alters the pharmacokinetics of proguanil. These suggest that the protection against malaria by proguanil may be decreased when the drug is co-administered with efavirenz and the antimalarial efficacy is dependent on cycloguanil plasma levels.     

The Effect of the Physical States of Binders on High-Shear Wet Granulation and Granule Properties: A Mechanistic Approach Toward Understanding High-Shear Wet Granulation Process. Part II. Granulation and Granule Properties

The objective is to provide mechanistic understanding of a preferred wet granulation process that a binder is added in a dry state. Blends of CaCO₃ and binders were prepared and used as model systems, and they were exposed to either 96% RH (rubbery/solution state) or 60% RH (glassy state) at room temperature to control the physical state of the binders, followed by high-shear granulation and particle size measurement. The blends of PVP K12, PVP K29/32, and HPC showed a significant increase in particle size after exposure to 96% RH. An increase of aspect ratio was also observed for the blend of HPC. In contrast, the blends being exposed to 60% RH did not exhibit any increase in particle size or aspect ratio. Regarding the effect of binder molecular weight on the mechanical strength of granules, granules of PVP K29/32 had higher strength than granules of PVP K12. This can be explained using polymer entanglement theory, in which the degree of polymerization (DP) of (N ～ 440–540) of PVP K29/32 is above the critical value (N_c ～ 300–600) for entanglement; while DP of PVP K12 (N ～ 20–30) is below it. Finally, a water sorption-phase transition-diffusion induced granule growth model for granulation has been suggested.