Enhancement of solubility and oral bioavailability of manidipine by formation of ternary solid dispersion with d-α-tocopherol polyethylene glycol 1000 succinate and copovidone

Context: Low bioavailability of oral manidipine (MDP) is due to its low water solubility.

Objective: The objective of this study was to increase the solubility and bioavailability of MDP by fabricating ternary solid dispersion (tSD) with d-α-tocopherol polyethyleneglycol-1000-succinate and copovidone.

Methods: In this study, solid ternary phase diagram was applied in order to check the homogeneity of tSD prepared by melting and solidifying with dry ice. The physicochemical properties of different formulations were determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR) and hot stage microscopy. Their solubility, dissolution, stability and bioavailability were also investigated.

Results and discussion: The results demonstrated that tSD obtained from ternary phase diagram divided into homogeneous and non-homogeneous regions. In the homogenous region, the transparent characteristics of tSD was observed and considered as a glass solution, which have a higher MDP solubility than that in non-homogenous region. The hot stage microscopy, DSC and PXRD confirmed that solid dispersion was formed in which MDP was molecularly dispersed in the carriers, especially in the homogenous region of phase diagram. FTIR analysis demonstrated strong hydrogen bonding between amine groups of MDP and carbonyl groups of copovidone, which supported a higher solubility and dissolution of tSD. The pharmacokinetic study in Wistar rats showed that the tSD had the greatest effect on oral bioavailability. Immediate hypotensive effect of tSD was also observed in vivo.

Conclusions: The improvement of stability, dissolution and oral bioavailability of MDP could be achieved by using tSD technique.     

Stability enhancement of shellac by formation of composite film: Effect of gelatin and plasticizers

The objective of the present study was to reduce the polymerization of shellac by the formation of composite films with gelatin. The 6% w/w of composite film based on shellac and gelatin was prepared by the incorporation of different concentrations of gelatin and was prepared by film casting method. The stability of the composite films was then studied at 40 °C, 75% RH for 180 days in a stability chamber and the physicochemical properties were investigated. The results demonstrated that the higher concentrations of gelatin (30%, 40% and 50%) contributed to slight change in the acid value and the percentage of insoluble solids upon 180 days of storage. These results were due to the protection at the active sites of the shellac, carboxyl and hydroxyl groups, by the electrostatic interaction between the negative charge of shellac and the positive charge of gelatin, resulting in the stabilized shellac. However, the mechanical properties could not withstand the storage time; further investigation was required to improve the stability in terms of mechanical properties of the composite film by the addition of a plasticizer. Two types of plasticizers were used: polyethylene glycol (PEG) and diethyl phthalate (DEP) represented hydrophilic and hydrophobic plasticizers at the concentrations of 5% and 10%, respectively. The addition of both types and concentrations of plasticizers could improve the poor mechanical properties and brittleness of the composite film for a longer storage time. However, only PEG 400 at 5% and 10% w/w acted as a good plasticizer capable of improving the stability of the composite film under the longer periods of storage. Therefore, the attempt to improve the stability in terms of polymerization and mechanical properties of shellac by the formation of the composite film and the addition of the plasticizer could be achieved. The result could be used to develop a new material for the various applications of edible films for coating in food and pharmaceutical industries.     

Improved stability of solid dispersions of manidipine with polyethylene glycol 4000/copovidone blends: application of ternary phase diagram

Context: Manidipine (MDP) is generally used clinically as an antihypertensive agent; however, the bioavailability of orally administered MDP is limited due to their very low water solubility.

Objective: The objectives of this research were, therefore, to increase the solubility of MDP by the formation of ternary solid dispersions (tSD) with polyethylene glycol 4000 (PEG4000) and copovidone and to improve their stability.

Methods: Solid ternary phase diagram was constructed to find homogeneous solid dispersion region after melting and solidifying at low temperature with different quenching substances. The pulverized powder of solid dispersions was then determined, for their physicochemical properties, by differential scanning calorimetry, powder X-ray diffractometry, Fourier transform infrared (FTIR) spectroscopy and hot stage microscopy. The solubility and dissolution of MDP from the tSD were investigated. The physical stability of tSD was also determined under accelerated condition at 40?°C/75% relative humidity (RH) for 6 months.

Results and discussion: The results showed that MDP was molecularly dispersed in PEG4000 and copovidone when the tSD was created from homogeneous region of solid ternary phase diagram. FTIR results confirmed that strong hydrogen bonding was presented between MDP and copovidone, leading to a significant increase in the solubility and dissolution of MDP. After storage at accelerated condition (40?°C/75%RH) for 6 months, the tSD still showed a good appearance and high solubility.

Conclusion: The results of this study suggest that tSD prepared by melting has promising potential for oral administration and may be an efficacious approach for improving the therapeutic potential of MDP.     

Effect of mineral admixtures and curing periods on shrinkage and cracking age under restrained condition

This paper presents the test results on cracking behavior at medium age of uniaxially restrained specimens containing different types of mineral admixture, namely fly ash and limestone powder. In this study, the uniaxially restrained shrinkage, free shrinkage and strength tests were conducted to study the potential of cracking of concrete under restrained shrinkage condition. The influences of water to binder ratio, mineral admixtures and curing period of concrete on cracking behavior were investigated in this study. The investigation showed that cracking age and cracking strain of restrained specimens vary with mix proportion, mineral admixture and curing period. The potential of shrinkage cracking is not influenced only by cracking strain and amount of shrinkage but also on shrinkage rate and tensile creep. Mixture with lower water to binder ratio (w/b = 0.35) shows shorter cracking age than the mixture with higher water to binder ratio (w/b = 0.55). Fly ash and limestone powder significantly increase cracking age of concrete. The cracking age increases with the increase of the replacement ratio of fly ash. The higher shrinkage rate, when exposed to drying, of mixture with longer curing period leads to shorter cracking age.     

Biohydrogen production from xylose by Thermoanaerobacterium thermosaccharolyticum KKU19 isolated from hot spring sediment

A thermophilic hydrogen producer was isolated from hot spring sediment and identified as Thermoanaerobacterium thermosaccharolyticum KKU19 by biochemical tests and 16S rRNA gene sequence analysis. The strain KKU19 showed the ability to utilize various kinds of carbon sources. Xylose was the preferred carbon source while peptone was the preferred organic nitrogen source. The optimum conditions for hydrogen production and cell growth on xylose were an initial pH of 6.50, temperature of 60 °C, a carbon to nitrogen ratio of 20:1, and a xylose concentration of 10.00 g/L. This resulted in a maximum cumulative hydrogen production, hydrogen production rate and hydrogen yield of 3020 ± 210 mL H₂/L, 3.95 ± 0.20 mmol H₂/L h and 2.09 ± 0.02 mol H₂/mol xylose consumed, respectively. Acetic and butyric acids were the main soluble metabolite products suggesting acetate and butyrate type fermentation.     

Co-digestion of oil palm trunk hydrolysate with slaughterhouse wastewater for thermophilic bio-hydrogen production by Thermoanaerobacterium thermosaccharolyticm KKU19

The key factors influencing a co-digestion of the oil palm trunk (OPT) hydrolysate with a slaughterhouse wastewater (SHW) to produce hydrogen by Thermoanaerobacterium thermosaccharolyticum KKU19 were investigated. The OPT hydrolysate was obtained by the hydrolysis of OPT by microwave-H₂SO₄ method using 1.56% (w/v) H₂SO₄ and 7.50 min reaction time at 450 W. The Plackett–Burman method was used to screen the key factors that influenced the hydrogen production potential (P_s). Results indicated that initial cell concentration, tCOD/TN (total COD/total nitrogen) ratio and CuSO₄ concentration influenced the P_s. These factors were further optimized using response surface methodology (RSM) with central composite design (CCD). A maximum P_s of 2604 ± 86 mL H₂/L substrate was achieved at an initial cell concentration of 224 mg dry cell/L, tCOD/TN ratio of 49.87 and CuSO₄ concentration of 13.33 mg/L. The main soluble metabolite products were butyric and acetic acids. The P_s obtained when the hydrolysate was supplemented with SHW (2604mL ± 86 mL H₂/L substrate) was comparable to the P_s obtained when it was supplemented with yeast extract at the same tCOD/TN (2802 ± 87 mL H₂/L substrate). This result suggests that SHW can be used to replace the costly nitrogen source.     

Effect of heat on characteristics of chitosan film coated on theophylline tablets

The effect of heat on the characteristics of chitosan film coated on theophylline tablets was studied. Chitosan of high viscosity grade with molecular weight in the range of 800,000-1,000,000, 80-85% degree of deacetylation was used as a film former by dissolving in 1% v/v acetic acid solution. The coated tablets had been cured at 40, 60, and 100°C for 6, 12, and 24 hr. The morphology of the film at the edge and surface of coated tablets was investigated using scanning electron microscopy. Film cracking was increased and clearly observed in the coated tablets cured at 100°C for 24 hr. As a result, more water could be absorbed into the tablets, followed by faster disintegration and faster drug release. The evidence of partial conversion of chitosonium acetate to chitin in the ¹³C nuclear magnetic resonance (NMR) spectra of chitosan films cured at 40, 60, and 100°C was observed, but it had no effect on drug release behavior. Theophylline tablets coated with chitosan films gave sustained release behavior in various media, i.e., distilled water, 0.1 N hydrochloric acid, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer. In addition, the film coating temperature at 55-60°C and curing process at 40 and 60°C had no effect on the drug release from theophylline tablets coated with chitosan polymer. Finally, it might be concluded that both the physical and chemical properties of chitosan films were affected by heat.     

An approach for the enhancement of the mechanical properties and film coating efficiency of shellac by the formation of composite films based on shellac and gelatin

The purpose of this study was to enhance the mechanical properties and film coating efficiency of shellac by the formation of composite films with different concentrations of gelatin. The composite films were prepared by the casting method and their mechanical and physicochemical properties were investigated. The results demonstrated that the puncture strength and percentage elongation of the composite film increased from 3.61 to 15.58 MPa and from 3.80% to 32.47% as the gelatin concentration increased to 50% w/w, respectively, indicating the enhancement of the strength and flexibility of the shellac film. The efficiency of the composite film over two model substrates, i.e., hydrophilic and hydrophobic substrates, respectively, was also studied. The work of adhesion and spreading coefficient of the composite film increased from 66.42 to 83.53 mN/m and from −8.14 to −3.07 mN/m for the hydrophilic substrate, indicating the improvement of the coating efficiency whereas the hydrophobic substrate showed the opposite trend with the increase in gelatin concentration. Therefore, the formation of the composite film not only improved the mechanical properties of shellac but also enhanced the efficiency of film coating by the modification of different concentrations of hydrocolloid polymer to suit with the type of coating substrate. Hence the knowledge of composite film could make beneficial contributions to the various applications in film coating for the food and pharmaceutical industries.