Fabrication and characterization of dexibuprofen nanocrystals using microchannel fluidic rector.

PURPOSE: Dexibuprofen is an enantiomer of ibuprofen with low bioavailability which results from its hydrophobic nature. Nanosuspensions have developed a podium to solve the in vitro dissolution problem that frequently occurs in current research. MATERIALS AND METHODS: The drug and polymer solutions were mixed in a microchannel fluid reactor and the successive embryonic nanosuspension was decanted into a vial having the polymer solution. The impact of different process and formulation parameters including inlet angle, antisolvent and solvent flow rate(s), mixing time, drug concentration, polymer type and concentration was evaluated. RESULTS AND DISCUSSION: Stable dexibuprofen nanocrystals with a particle size of 45±3.0 nm and polydispersity index of 0.19±0.06 were obtained. Differential scanning calorimetry and powder X-ray diffraction confirmed the crystallinity. The key parameters observed were inlet angle 10°, antisolvent to solvent volume of 2.0/0.5 mL/min, 60 minutes mixing with 5 minutes sonication, Poloxamer-407 with a concentration of 0.5% w/v and drug concentration (5 mg/mm). The 60-day stability studies revealed that the nanocrystals were stable at 4°C and 25°C. The scanning electron microscopy and transmission electron microscopy images showed crystalline morphology with a homogeneous distribution. CONCLUSION: Stable dexibuprofen nanocrystals with retentive distinctive characteristics and having marked dissolution rate compared to raw and marketed formulations were efficiently fabricated. In future perspectives, these nanocrystals could be converted to solid dosage form and the process can be industrialized by chemical engineering approach.

Investigation of the potential application of sodium bentonite as an excipient in formulation of sustained release tablets.

In this study, the application of sodium bentonite (SB) in formulation of tablets prepared by direct compression for oral administration was tested. Three different model drugs with different solubilities: paracetamol, diclofenac sodium and metformin HCl were tested. Each drug was mixed with SB at ratio of 50% and the mixtures were subsequently compressed. Compatibility studies were conducted using both Deferential Scanning Calorimeter (DSC) and Fourier Transform Infrared Spectroscopy (FTIR). The dissolution profile for each drug was determined in USP-buffers at different time intervals. Diclofenac sodium in pH 6.8 buffer and paracetamol in both pH 6.8 and pH 4.5 buffers showed extended release. However, metformin HCl showed immediate release at the different pH values. The study showed that using SB was possible to prepare tablets with different release profiles. However, these profiles differ depending on dissolution media and drug type.

Effect of mechanical denaturation on surface free energy of protein powders.

Globular proteins are important both as therapeutic agents and excipients. However, their fragile native conformations can be denatured during pharmaceutical processing, which leads to modification of the surface energy of their powders and hence their performance. Lyophilized powders of hen egg-white lysozyme and ß-galactosidase from Aspergillus oryzae were used as models to study the effects of mechanical denaturation on the surface energies of basic and acidic protein powders, respectively. Their mechanical denaturation upon milling was confirmed by the absence of their thermal unfolding transition phases and by the changes in their secondary and tertiary structures. Inverse gas chromatography detected differences between both unprocessed protein powders and the changes induced by their mechanical denaturation. The surfaces of the acidic and basic protein powders were relatively basic, however the surface acidity of ß-galactosidase was higher than that of lysozyme. Also, the surface of ß-galactosidase powder had a higher dispersive energy compared to lysozyme. The mechanical denaturation decreased the dispersive energy and the basicity of the surfaces of both protein powders. The amino acid composition and molecular conformation of the proteins explained the surface energy data measured by inverse gas chromatography. The biological activity of mechanically denatured protein powders can either be reversible (lysozyme) or irreversible (ß-galactosidase) upon hydration. Our surface data can be exploited to understand and predict the performance of protein powders within pharmaceutical dosage forms.

Equation to Line the Borders of the Folding-Unfolding Transition Diagram of Lysozyme.

It is important for the formulators of biopharmaceuticals to predict the folding-unfolding transition of proteins. This enables them to process proteins under predetermined conditions, without denaturation. Depending on the apparent denaturation temperature (Tm) of lysozyme, we have derived an equation describing its folding-unfolding transition diagram. According to the water content and temperature, this diagram was divided into three different areas, namely, the area of the water-folded lysozyme phase, the area of the water-folded lysozyme phase and the bulk water phase, and the area of the denatured lysozyme phase. The water content controlled the appearance and intensity of the Raman band at ∼1787 cm(-1) when lysozyme powders were thermally denatured at temperatures higher than Tm.

An equation to calculate the actual methylene middle parameter as a function of temperature.

Methylene middle parameter [Formula: see text] , the product of the methylene group's cross-sectional area ( [Formula: see text] ) and the root square of its dispersive free energy ( [Formula: see text] ), is the key parameter to calculate the dispersive surface components of solids (γs(d)) using inverse gas chromatography (IGC) at different temperatures. The only method reported to calculate [Formula: see text] as a function of temperature is the Dorris-Gray method. However, the conventional values of [Formula: see text] calculated by the Dorris-Gray method depend heavily on theoretical aspects. This paper establishes a novel equation calculating the actual [Formula: see text] as a function of temperature using the latest and most accurate surface parameters of seven successive n-alkanes. The obtained actual [Formula: see text] values are slightly higher those of the conventional [Formula: see text] . At 20°C, the actual [Formula: see text] generates γs(d) values less than those generated using the conventional [Formula: see text] by ∼3%, and this reduction in calculated γs(d) values increases linearly to become ∼5% at 100°C. Therefore, using the new actual [Formula: see text] seems to mitigate the discrepancy between the γs(d) values measured by IGC and those measured by the contact angle method.

Mapping the solid-state properties of crystalline lysozyme during pharmaceutical unit-operations.

Bulk crystallisation of protein therapeutic molecules towards their controlled drug delivery is of interest to the biopharmaceutical industry. The complexity of biotherapeutic molecules is likely to lead to complex material properties of crystals in the solid state and to complex transitions. This complexity is explored using batch crystallised lysozyme as a model. The effects of drying and milling on the solid-state transformations of lysozyme crystals were monitored using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), FT-Raman, and enzymatic assay. XRPD was used to characterise crystallinity and these data supported those of crystalline lysozyme which gave a distinctive DSC thermogram. The apparent denaturation temperature (Tm) of the amorphous lysozyme was ∼201 °C, while the Tm of the crystalline form was ∼187 °C. Raman spectra supported a more α-helix rich structure of crystalline lysozyme. This structure is consistent with reduced cooperative unit sizes compared to the amorphous lysozyme and is consistent with a reduction in the Tm of the crystalline form. Evidence was obtained that milling also induced denaturation in the solid-state, with the denatured lysozyme showing no thermal transition. The denaturation of the crystalline lysozyme occurred mainly through its amorphous form. Interestingly, the mechanical denaturation of lysozyme did not affect its biological activity on dissolution. Lysozyme crystals on drying did not become amorphous, while milling-time played a crucial role in the crystalline-amorphous-denatured transformations of lysozyme crystals. DSC is shown to be a key tool to monitor quantitatively these transformations.

Accuracy verification of surface energy components measured by inverse gas chromatography.

Inverse gas chromatography (IGC) measures the retention times of probes which are then used to calculate the surface properties of solids. No method is available to verify how much the measured values are close to their accurate values. According to the chromatographic adhesion law, the accurate determination of the dispersive retention factor (K(a)(CH2)) is a necessary prerequisite to obtain accurate surface components. Employing two equations in this paper, %ΔγS(d), which is the percentage deviation of dispersive component (γS(d)) from its accurate value (γS0(d)), was correlated firstly to %CV(ln K(a)(CH2)), the percentage coefficient of variation of ln K(a)(CH2), and secondly to FEK(a)(CH2), the factor error of K(a)(CH2), via two linear equations. The first equation is to outline the upper and lower limits of the uncertainty range of γS0(d), and the second equation is to estimate γS0(d). To minimize the uncertainty range of γS0(d) to less than ±5%, %CV(ln K(a)(CH2)) should be less than 0.7%. Then considering the sign of FEK(a)(CH2) narrows the uncertainty range to either its upper or lower half.

Chromatographic adhesion law to simplify surface energy calculation.

The calculated data of inverse gas chromatography (IGC) vary depending on the calculation methods and the n-alkane series. To overcome IGC data variability, this paper combines the Van Oss­Good­Chaudhury concept, the Dorris­Gray equation, the Schultz equation, the Fowkes equation and group contribution theory to establish the chromatographic adhesion law and its equation is K(a)(i) =e(ΔEai /kT) . In the equation, K(ai) is the adhesion retention factor of a chemical group, ΔE(ai) represents the increased chromatographic adhesion energy due to this group and kT expresses the thermal kinetic energy of the molecule contain-ing this group. The dispersive component (γ(dS) ), the electron acceptor component (γ(+S) ) and the electron donor component (γ(−S)) of a solid surface are then calculated from ΔE(ai) . Through correlating the retention time with the adhesion energy, this law expresses mathematically the chromatographic adhesion phenomenon of IGC at the infinite dilution region. This paper also derives a new equation to calculate the retention time of a non-adsorbing probe (dead retention time).

Hansen solubility parameter as a tool to predict cocrystal formation.

The objective of this study was to investigate whether the miscibility of a drug and coformer, as predicted by Hansen solubility parameters (HSPs), can indicate cocrystal formation and guide cocrystal screening. It was also our aim to evaluate various HSPs-based approaches in miscibility prediction. HSPs for indomethacin (the model drug) and over thirty coformers were calculated according to the group contribution method. Differences in the HSPs between indomethacin and each coformer were then calculated using three established approaches, and the miscibility was predicted. Subsequently, differential scanning calorimetry was used to investigate the experimental miscibility and cocrystal formation. The formation of cocrystals was also verified using liquid-assisted grinding. All except one of the drug-coformers that were predicted to be miscible were confirmed experimentally as miscible. All tested theoretical approaches were in agreement in predicting miscibility. All systems that formed cocrystals were miscible. Remarkably, two new cocrystals of indomethacin were discovered in this study. Though it may be necessary to test this approach in a wide range of different coformer and drug compound types for accurate generalizations, the trends with tested systems were clear and suggest that the drug and coformer should be miscible for cocrystal formation. Thus, predicting the miscibility of cocrystal components using solubility parameters can guide the selection of potential coformers prior to exhaustive cocrystal screening work.