Sealed Heating Method Research Articles

Adsorption of a poorly water-soluble drug onto porous calcium silicate by the sealed heating method

To improve the bioavailability of orally-administered drug, solubilization of poorly water-soluble drug is important. The solubility of a drug in its amorphous form is known to be higher than in its crystalline form. In this study, we attempted to adsorb a sublimable drug onto porous calcium silicate (Florite®, FLR) or non-porous calcium silicate (NPCS) by the sealed heating (SH) method and evaporated (EV) method. Ibuprofen (IBU) was used as the poorly water-soluble, sublimable drug. The physicochemical properties of samples were investigated using powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and dissolution test. From the PXRD and DSC results, IBU crystals were adsorbed and amorphized by the SH and EV methods with FLR. From the results of FTIR, the shift to a higher frequency by the carbonyl stretching vibration band of IBU suggests an intermolecular interaction between IBU and FLR. In SH with FLR, improved solubilization was observed. IBU adsorbed onto FLR showed a greater dissolution rate than the IBU crystals or NPCS. Thus, the petal-like structure of FLR may be an effective method to adsorb IBU onto FLR using the SH method.

Design Features in the Molecular-level Development of Solid Pharmaceutical Formulations Based on Supramolecular Structures

We focused on the crystal structure of cyclodextrin (CD) to develop new solid CD complexes. There are two large spaces in the columnar structure of CD crystals: one inside a CD cavity and another between CD columns. New solid CD complexes can be designed by incorporating guest drugs between the CD columns. We succeeded in preparing a solid drug/[polyethylene glycol (PEG)/γ-CD-polypseudoraxane (PPRX)] complex by a sealed-heating method via the gas phase. A drug/(PEG/γ-CD-PPRX) complex has a structure in which PEGs are included in a γ-CD cavity, and guest drugs are incorporated between the γ-CD columns. Screening by a sealed-heating method determined that a variety of guest drugs with varying molecular size and log P could be incorporated into the spaces between γ-CD columns, following a stoichiometric rule. Another method, via solid phase using cogrinding and subsequent heating, was developed to prepare drug/(PEG/γ-CD-PPRX) complex. This method enabled us to prepare the complex with a thermally unstable drug, as well as a drug/(PEG/α-CD-PPRX) complex not formed using the sealed-heating method. Both the structure and molecular state of each drug in the complexes were characterized by powder X-ray diffraction and solid-state NMR measurements. The dissolution character and thermal stability of the drug incorporated in the complex could be improved by the specific complex formation. The solid CD complexes thus developed have potential for drug-encapsulation and as drug-release carriers, owing to their unique structural and pharmaceutical properties.

Preparation and structural characterization of different amylose–flavor molecular inclusion complexes

Flavor microencapsulation has been widely used in foods, medicines, cosmetics, and other fields. The use of amylose‐based complexes is receiving increasing attention because they are biodegradable, non‐toxic, and biocompatible, and these complexes provide a new way to develop and impart flavors. In this study, with the aim of investigating the properties of amylose–flavor complexes, linear aliphatic alcohols (C6–C9) and the aromatic alcohol naphthol were used to prepare inclusion complexes by the sealed heating method in yields ranging from 45 to 50%. In addition, scanning electron microscopy (SEM), X‐ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) were utilized to investigate the structural characteristics of these inclusion complexes, and it was found that the amylose‐n‐heptanol inclusion complex was most stable. Furthermore, nuclear magnetic resonance (NMR) spectroscopy revealed that V‐type crystals existed in the amylose–flavor complexes. Moreover, TGA showed that all amylose–flavor inclusion complexes have excellent thermal stability. The encapsulation efficiency of the complexes increased with decreasing chain length, but the encapsulation efficiency of the complexes with the aromatic alcohol naphthol was lower than that of the complexes with some linear alcohols. This indicated that the stereoscopic confirmation of α‐naphthol may influence the complexes being formed.

Solid-Phase Mediated Methodology To Incorporate Drug into Intermolecular Spaces of Cyclodextrin Columns in Polyethylene Glycol/Cyclodextrin-Polypseudorotaxanes by Cogrinding and Subsequent Heating

In this study, a new preparation method was developed to obtain drug/(polyethylene glycol/cyclodextrin-polypseudorotaxane (PEG/CD-PPRX)) complexes in which drugs were incorporated into the intermolecular spaces of CD columns in PEG/CD-PPRXs. This method was solid-phase mediated and used cogrinding and subsequent heating. Guest drug and CD in PEG/CD-PPRX were amorphized by cogrinding, and then crystallization of CD was promoted by subsequent heating. A previously reported sealed-heating method using the gas phase was not applicable for poorly sublimated and thermally unstable drugs such as piroxicam (PXC) and hydrocortisone, whereas this new method allowed these drugs to be incorporated into the intermolecular spaces of γ-CD columns. Furthermore, salicylic acid (SA) and salicylamide were successfully incorporated into the intermolecular spaces of CD columns using α-CD instead of γ-CD. Powder X-ray diffraction and solution-state 1H nuclear magnetic resonance measurements revealed that complexation followed ...

Application of Intermolecular Spaces between Polyethylene Glycol/γ-Cyclodextrin-Polypseudorotaxanes as a Host for Various Guest Drugs

Eleven guest drugs with planar structures were incorporated into the intermolecular spaces between polyethylene glycol/γ-cyclodextrin (γ-CD)-polypseudorotaxanes by a sealed-heating method. Drug incorporation changed the crystal packing of γ-CD from hexagonal- to monoclinic-columnar forms, without dependence on the guest species. The incorporation of guest drugs was size dependent and stoichiometric. Guest drugs with one benzene ring and maximum cross sectional areas of ca. 40–55 Å2 exhibited a drug to γ-CD stoichiometry of 2:1. Meanwhile, the stoichiometry was 1:1 for drugs with 2–3 benzene rings and maximum cross sectional areas of ca. 60–75 Å2. More sterically bulky drugs (four and five benzene rings) did form complexes, though the complexation efficiency was insufficient to form stoichiometric complexes, due to steric hindrance. The volume of intermolecular space of the host was estimated to be larger than that of a β-CD cavity and as large as that of a γ-CD cavity. Hydrophobic and van der Waals interactions worked as driving forces for the complexation because polycyclic aromatic hydrocarbons with high log P values formed the complex. The dissolution property of the hydrophobic pharmaceutical drug naproxen was clearly improved by the complexation because naproxen existed in a monomolecular state in the complex.

Improvement of thymol properties by complexation with cyclodextrins: In vitro and in vivo studies

Thymol, an effective agent for microbial diseases, has a low aqueous solubility and a strong bitter/irritating taste. These physicochemical characteristics need to be improved to develop pharmaceutical preparations. This study evaluates whether β-cyclodextrin and a copolymer based on dimethylaminoethyl methacrylate (DMAEMA) interact with thymol in order to control powderization, solubilization, and taste-masking properties. The thymol–β-cyclodextrin complex was prepared by co-precipitation and sealed-heating methods. The DMAEMA copolymer was mixed with the complex using a new approach, instead of spray coating, to decrease thymol volatility. In vivo studies were performed. Sealed-heating is a suitable method for including thymol in β-cyclodextrin with a good loading efficiency; thymol volatility control is achieved by mixing the complex with the DMAEMA copolymer. β-Cyclodextrin accelerates the in vivo thymol absorption rate compared with the free drug; the thymol half-life is still long. Therefore, a low number of administrations per day are required. Although bioavailability is unchanged with respect to free thymol, high doses could be administered of a selected formulation without compromising the compliance. Furthermore, thymol that is not absorbed is held along the intestine, where it can useful in the treatment and/or prevention of intestinal bacterial diseases.

Analysis of Molecular Interactions in Solid Dosage Forms; Challenge to Molecular Pharmaceutics

The molecular states of active pharmaceutical ingredients (APIs) in pharmaceutical dosage forms strongly affect the properties and quality of a drug. Various important fundamental physicochemical studies were reviewed from the standpoint of molecular pharmaceutics. Mechanochemical effects were evaluated in mixtures of APIs and pharmaceutical additives. Amorphization, complex formation and nanoparticle formation are observed after grinding process depending on the combination of APIs and pharmaceutical additives. Sealed-heating method and mesoporous materials have been used to investigate drug molecular interactions in dosage forms. Molecular states have been investigated using powder X-ray diffraction, thermal analysis, IR, solid state fluorometry, and NMR.

Salicylic Acid/γ-Cydodextrin 2:1 and 4:1 Complex Formation by Sealed-Heating Method

A novel complex of salicylic acid (SA) and gamma-cyclodextrin (gamma-CD) was obtained via the sealed-heating method. The influence of the water content of gamma-CD on the complex formation with SA by sealed-heating process was investigated. Quantitative determination of SA revealed that sealed-heated samples of SA and gamma-CD with low water content (0.8-5.4%) formed the SA/gamma-CD = 2:1 complex, while the samples with high water content (8.5-11.5%) formed the SA/gamma-CD = 4:1 complex. The molecular arrangements of gamma-CD in 2:1 and 4:1 complexes were determined by powder X-ray diffraction measurements to be in monoclinic-columnar and tetragonal-columnar forms, respectively. The results of infrared spectroscopy and (13)C solid-state NMR measurements showed that two types of SA molecules resided in the 4:1 complex, whereas only one type of SA molecules existed in the 2:1 complex. The obtained 2:1 complex was assumed to contain two SA molecules per one gamma-CD, with the SA molecules existing in the intermolecular spaces formed by the gamma-CD columns. In the case of the 4:1 complex, two SA molecules were incorporated into the intermolecular spaces while the other two SA molecules were included within the gamma-CD cavity.

Preparation of borneol–methyl-β-cyclodextrin inclusion complex by supercritical carbon dioxide processing

In this work, the complex of borneol–methyl-β-cyclodextrin was prepared both by supercritical carbon dioxide processing and by the sealed heating treatment at mild pressure and temperature. An amorphous complex was obtained by the sealed heating treatment. A crystalline inclusion complex was obtained by the supercritical carbon dioxide processing. The crystalline complex is more stable than the amorphous complex. The apparent aqueous solubility of borneol could be enhanced about 70 times by complexation with methyl-β-cyclodextrin. In this work, a 1:1 crystalline inclusion complex between borneol and methyl-β-cyclodextrin was obtained by supercritical carbon dioxide processing at temperature about 100 °C and pressure about 100 bar. This inclusion complex is more stable than the amorphous complex prepared by the sealed heating method. The apparent aqueous solubility of borneol could be enhanced about 70 times by complexation with methyl-β-cyclodextrin. The possible complex structure is shown below:

Solid-State Complexation of Cholic Acid and L-Phenylalanine

Solid-state complexation of cholic acid(CA)/L-phenylalanine(PAA) using a sealed-heating method was investigated.Powder X-ray diffractometry,IR spectroscopy,powder fluorescence spectroscopy,and differential thermal analysis(DTA) were used to characterize the CA-PAA complex.The result showed that PAA,as a guest,was assumed to be included in the channel of the complex formed by CA.While,grinding and co-precipitation methods were also compared to the sealed-heating method for the formation of the CA-PAA complex.It was shown that parts of the PAA were included into the channel of the CA complex during grinding and some solvents were also preferentially included into the guest compounds,which formed a stable cholic acid-solvent complex when co-precipitation method was used.

Complex of shikonin and β-cyclodextrins by using supercritical carbon dioxide

In this work, the complex of shikonin-methyl-β-cyclodextrin and shikonin-2-hydroxypropyl-β-cyclodextrin were studied in supercritical carbon dioxide (sc CO2) at moderate pressure and temperature much lower than the melting point of shikonin. For comparing, the complex was also prepared by sealed heating method. Complex efficiency between shikonin and 2-hydroxypropyl-β-cyclodextrin (HPBCD) was quite low. Partly formation of shikonin—methyl-β-cyclodextrin (MBCD) was obtained by sealed heating method. Complete formation of shikonin—MBCD was obtained in sc CO2 media in short reaction time. This complexation was accelerated and enhanced by the rise in both the reaction temperature and carbon dioxide pressure up to 100 °C 100 bar. The physical state of cyclodextrins in complex reaction has remarkable influence on the complex. The aqueous solubility of shikonin could be enhanced about 75 times by complexing with MBCD. In this work, the complex of shikonin-methyl-β-cyclodextrin and shikonin-2-hydroxypropyl-β-cyclodextrin were studied in supercritical carbon dioxide (sc CO2) at moderate pressure and temperature much lower than the melting point of shikonin (SK). For comparing, the complex was also prepared by sealed heating method. Complex efficiency between SK and 2-hydroxypropyl-β-cyclodextrin (HPBCD) was quite low. Partly formation of SK—methyl-β-cyclodextrin (MBCD) complex was obtained by sealed heating method. Complete formation of SK—MBCD was obtained in sc CO2 media in short reaction time. This complexation was accelerated and enhanced by the rise in both the reaction temperature and carbon dioxide pressure. The physical state of cyclodextrins in sc CO2 has remarkable influence on the complex. The aqueous solubility of SK could be enhanced about 75 times by complexing with MBCD.

Complex formation of cinnamaldehyde-methyl-β-cyclodextrin and muscone-methyl-β-cyclodextrin by supercritical carbon dioxide processing and sealed heating method

Firstly, the interaction between cinnamaldehyde (CIN) and methyl-β- cyclodextrin (MBCD) was studied in aqueous solution. 1:1 inclusion complex was formed and the association constant was 187 ± 9 M−1. Then the complex of CIN–MBCD and muscone–MBCD was prepared both by sealed heating method and by supercritical carbon dioxide (sc CO2) approach. Complete complex was obtained by both methods for CIN–MBCD. Some CIN molecules was weakly associated with MBCD molecules in products by sealed heating method, all CIN molecules was strongly associated with MBCD molecules in products by sc CO2 processing. Complete complex between muscone and MBCD was not obtained. The choice for the size of guest molecule still existed for MBCD cavity in sealed heating method and sc CO2 processing.

Physicochemical characterization of drug-cyclodextrin complexes prepared by supercritical carbon dioxide and by conventional techniques

The objective of this study was to investigate the effectiveness of supercritical carbon dioxide (SC CO2) technique for preparing solid complexes between β-cyclodextrin and three local anesthetic agents (benzocaine, bupivacaine, and mepivacaine) by comparing it to more traditional methods such as kneading, co-evaporation, co-grinding, and sealed-heating. Effects of variation of experimental conditions, i.e. temperature, pressure and exposure time, on the products prepared by SC CO2 method were also examined. The products obtained were characterized by powder X-ray diffractometry and Fourier transform infrared spectroscopy, and tested for dissolution properties. Results suggested the possibility of complex formation between β-cyclodextrin and the three anesthetic agents, and indicated that it was influenced by the preparation technique. The co-grinding method was the only one resulting in completely amorphous products for all three drugs. Almost amorphous products, with only limited residual crystallinity, were obtained by co-evaporation and kneading techniques, while SC CO2 and sealed-heating methods gave rise to more crystalline systems. As for the SC CO2 method, temperature (for benzocaine and bupivacaine) or exposure time (for mepivacaine) had significant effects on the solid-state properties of the final products. Dissolution studies indicated that all the examined methods were more effective than the simple physical mixing in improving drug dissolution properties, but the different rank orders observed for the different drugs suggested that there is no general rule for the selection of the most effective preparation method, which depends on the type of drug-Cyd system considered. Nevertheless, in all cases, products obtained by the SC CO2 method showed satisfactory dissolution properties.

Preparation and characterisation of liposomes encapsulating ketoprofen–cyclodextrin complexes for transdermal drug delivery

Multilamellar vesicle (MLV) liposomes containing ketoprofen–cyclodextrin complexes intended for drug topical delivery were prepared, with the aim of simultaneously exploiting the favourable properties of both carriers. Drug complexes with β-cyclodextrin (βCyd) and hydroxypropyl-βCyd (HPβCyd), prepared by coevaporation and sealed-heating methods, were characterised by differential scanning calorimetry, hot stage microscopy, scanning electron microscopy and tested for dissolution properties. The coevaporated system with HPβCyd was the most effective, enabling an about 11-fold increase in drug dissolution. Drug and drug-Cyd systems were incorporated in MLV liposomes prepared by the thin layer evaporation technique. All liposomal formulations were characterised for encapsulation efficiency, particle size and morphology, using dialysis, light scattering and transmission electron microscopy techniques, respectively. MLV formation was negatively influenced by the presence of Cyd; nevertheless, it was possible to prepare stable MLVs containing ketoprofen-Cyd complexes. The presence of the Cyd complex affected MLV dimensions but not their lamellar structure. The complex with HPβCyd, in virtue of its greater stability than the βCyd one, allowed higher percentages of encapsulation and gave rise to more stable MLV systems. Permeability studies of drug and drug-Cyd complexes, as such or incorporated in liposomes, performed both across artificial membranes and rat skin, highlighted a favourable effect of Cyd on drug permeation rate, due to its solubilizing action; by contrast, unexpectedly, no skin-permeation enhancer property of liposomes has been evidenced. Confocal laser scanning microscopy studies carried out with the rhodamine-Cyd complex as fluorescent marker, confirmed such results, showing that the label permeated deeper across rat skin layers when it was in solution than when entrapped in liposomes.

Effect of Pore Size of FSM-16 on the Entrapment of Flurbiprofen in Mesoporous Structures

The interaction between FSM-16 and flurbiprofen (FBP) in the mesopores of FSM-16 was investigated by using three types of FSM-16 with different pore diameters, i.e., FSM-16(Oc), FSM-16(Do) and FSM-16(Doc) (pore diameters 16.0, 21.6, 45.0 A, respectively). Solid dispersions of 30% FBP-70% FSM-16 were prepared by solvent evaporation and sealed-heating of the physical mixture at 100 degrees C for 6 h. Changes in the molecular state of FBP were investigated using powder X-ray diffractometry, thermal analysis and FT-IR spectroscopy. The changes in pore diameter and specific surface area of FSM-16 systems were investigated by small angle X-ray scattering and nitrogen gas adsorption. Powder X-ray diffractometry and thermal analysis revealed that FBP was adsorbed onto the mesopores of FSM-16(Do) and FSM-16(Doc), leading to an amorphous state, while no change was observed for FSM-16(Oc). Fourier-transformed IR spectroscopy showed a hydrogen bond interaction between the carbonyl groups of FBP and the silanol groups of FSM-16. The pore diameter and specific surface area of FSM-16 in solid dispersions decreased due to the adsorption of FBP. Improved dissolution of FBP from solid dispersions prepared by the evaporation and the sealed-heating methods was observed in comparison with FBP crystals.

Inclusion Behavior of Benzoic Acid Analogues to Linear Amylose by the Sealed-Heating Method

Inclusion Behavior of Benzoic Acid Analogues to Linear Amylose by the Sealed-Heating Method

Effects of the Host Cavity Size and the Preparation Method on the Physicochemical Properties of Ibuproxam-Cyclodextrin Systems

The effect of cyclodextrin (Cd) complexation on ibuproxam (IBUX) dissolution properties was studied by evaluating both the influence of Cd cavity size and the preparation method used for obtaining solid inclusion complexes. Binary systems of IBUX with natural Cds, prepared using different techniques (kneading, sealed-heating, spray-drying), were studied by differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and their dissolution behavior was evaluated according to the dispersed amount method. The nature and the dissolution performance of the end product appeared to be related to both steric factors of host molecule and preparation method of the solid system. The αCd cavity size was less suitable for accommodating the IBUX molecule, whereas spray-drying and sealed-heating methods led to a true inclusion complex of IBUX in the βCd and γCd cavity. In contrast, the kneading method did not lead in any case to a real inclusion complex. Spray-dried systems with βCd and γCd were the most effective in achieving the enhancement of the IBUX dissolution rate.

Complex Formation between Deoxycholic Acid and Menadione by Grinding and Sealed Heating Methods.

Complex formation between deoxycholic acid (DCA) and menadione (MND) by grinding and sealed heating was investigated. The complex between DCA and MND was prepared by coprecipitation and showed a stoichiometry of 2 : 1 (DCA : MND). The IR spectrum of the complex suggested that MND molecules were located in the channel formed by DCA molecules. The 10 min ground mixture of DCA-MND gave the same X-ray diffraction pattern as the DCA-MND coprecipitate. Differential scanning calorimetry (DSC) and IR spectroscopy also demonstrated the identical results between the ground mixture and the complex, confirming the complex formaiton between DCA and MND by grinding. The DSC data suggested that the complex formation was expected during heating process of the DCA-MND physical mixture. The sealed heated samples were prepared and compared with the complex prepared by coprecipitation. After heating in a sealed ampoule at 110°C for 10 min or at 80°C for 24h, samples demonstrated the same X-ray diffraction patterns, DSC curves and IR spectra as the complex. These results indicated that the complex formation took place between DCA and MND by sealed heating as well as by grinding.

Improvement of clofibrate dissolution by complexation with cyclodextrin

Inclusion complexes of clofibrate with β-cyclodextrin (βCD) were prepared by coprecipitation, kneading and sealed heating methods and characterized by UV spectrophotometry, differential scanning calorimetry, X-ray diffractometry and infrared spectroscopy. All results were in keeping with the formation of 1:1 inclusion complex. Dissolution studies showed that clofibrate entrapped in inclusion complexes dissolved much faster than uncomplexed liquid clofibrate. The complex prepared by the sealed heating method showed the greatest improvement in dissolution rate: this complex released 50 mg of clofibrate into water within 10 min. These results show that a more easily manipulated, solid form of clofibrate may be obtained through formation of its inclusion complex with flCD, and that complex formation simultaneously enhances the solubility and dissolution rate of this drug.

Preparation and Characterization of Sealed Heated Mixture of Ethenzamide and Porous Calcium Silicate.

A sealed heated mixture of ethenzamide (EZ) and porous calcium silicate (Florite[○!R]RE : FR) was prepared by heating the physical mixture in a sealed container. No diffraction peaks due to EZ crystals were observed in the powder X-ray diffraction pattern of the sealed heated mixture (FR : EZ=9 : 1) nor was an endothermic peak observed on the differential scanning calorimetric measurement of the sealed heated mixture (FR : EZ=9 : 1), indicating the amorphization of the EZ crystals caused by heating in a sealed container. The sealed heated mixture with FR showed a greater dissolution rate than EZ crystals or the sealed heated mixture with nonporous calcium silicate (CS). The sealed heating method using porous FR thus provides a promising way of amorphizing EZ crystals without using any solvents and of improving the dissolution rate of EZ.