Physical and chemical characterization of thermosoftened bases for molten filled hard gelatin capsule formulations

Dynafill, Dynasan-114, Lutrol-F68, PEG-10000 and PEG-20000 have been examined as potential bases for the preparation of fusion formed solid dispersions for molten filling into hard gelatin capsules. Investigations included, an examination of thermal effects on crystal structure by DSC and XRD, a theological study to evaluate capsule filling characteristics, dissolution studies on drug/base formulations, chemical analysis for free fatty acid impurities in Dynafill and Dynasan-114, and detailed studies on selected drug/base formulations. PEG-20000 and Dynasan-114 were not examined in detail, after preliminary investigations had shown high viscosity and poor filling characteristics for PEG-20000 and poor dissolution characteristics for Dynasan-114. Dynafill provided good release profiles when formulated with a variety of model drugs (Acetohexamide, Ibuprofen, Indomethacin, Quinidine sulphate and Theophylline). Results from hot stage photomicrography supported by DSC and XRD were used to construct a phase diagram of the Ibuprofen/Lutrol-F68 system. The evidence from the phase diagram indicated the formulation of a simple eutectic system with no solid solubility and a eutectic composition at approximately 35% w/w Ibuprofen.     

Physical stability and resistance to peroxidation of a range of liquid-fill hard gelatin capsule products on extreme long-term storage

Background: The industrial take-up of liquid-fill hard capsule technology is limited in part by lack of published long-term physical and chemical stability data which demonstrate the robustness of the system.

Objective: To assess the effects of extreme long-term storage on liquid-fill capsule product quality and integrity, with respect to both the capsules per se and a standard blister-pack type (foil–film blister).

Materials and methods: Fourteen sets of stored peroxidation-sensitive liquid-fill hard gelatin capsule product samples, originating ~20 years from the current study, were examined with respect to physical and selected chemical properties, together with microbiological evaluation.

Results and discussion: All sets retained physical integrity of capsules and blister-packs. Capsules were free of leaks, gelatin cross-linking, and microbiological growth. Eight samples met a limit (anisidine value, 20) commonly used as an index of peroxidation for lipid-based products with shelf lives of 2–3 years. Foil–film blister-packs using PVC or PVC–PVdC as the thermoforming film were well-suited packaging components for the liquid-fill capsule format.

Conclusion: The study confirms the long-term physical robustness of the liquid-fill hard capsule format, together with its manufacturing and banding processes. It also indicates that various peroxidation-sensitive products using the capsule format may be maintained satisfactorily over very prolonged storage periods.     

Development of novel spray coated soft elastic gelatin capsule sustained release formulations of nifedipine

Nifedipine release from coated commercially available immediate release soft elastic gelatin capsules was investigated. Capsules were spray coated using two different polymeric combinations, ethylcellulose and hydroxypropylmethylcellulose or pectin, at different coating loads. In vitro drug release studies were conducted in three different dissolution media: with gastric pretreatment, without gastric pretreatment, and in water to investigate the pH effect on nifedipine release. Convolution of in vitro dissolution data for selected formulations and commercially available sustained release nifedipine formulations showed that the tested formulations provided release profiles of nifedipine that are very promising in terms of desirable sustained release formulations.     

Influence of capsule shell composition on the performance indicators of hypromellose capsule in comparison to hard gelatin capsules

The purpose of this study was to assess the in vitro performances of “vegetable” capsules in comparison to hard gelatin capsules in terms of shell weight variation, reaction to different humidity conditions, resistance to stress in the absence of moisture, powder leakage, disintegration and dissolution. Two types of capsules made of HPMC produced with (Capsule 2) or without (Capsule 3) a gelling agent and hard gelatin capsules (Capsule 1) were assessed. Shell weight variability was relatively low for all tested capsules shells. Although Capsule 1 had the highest moisture content under different humidity conditions, all capsule types were unable to protect the encapsulated hygroscopic polyvinylpyrrolidone (PVP) powder from surrounding humidity. The initial disintegration for all Capsule 1 occurred within 3?min, but for other types of capsules within 6?min (n?=?18). Dissolution of acetaminophen was better when the deionized water (DIW) temperature increased from 32 to 42?°C in case of Capsule 1, but the effect of temperature was not significant for the other types of capsules. Acetaminphen dissolution from Capsule 1 was the fastest (i.e. >90% in 10?min) and independent of the media pH or contents unlike Capsule 2 which was influenced by the pH and dissolution medium contents. It is feasible to use hypromellose capsules shells with or without gelling agent for new lines of pharmaceutical products, however, there is a window for capsule shells manufacturing companies to improve the dissolution of their hypromellose capsules to match the conventional gelatin capsule shells and eventually replace them.     

Weight and weight uniformity of hard gelatin capsules filled with microcrystalline cellulose and silicified microcrystalline cellulose

The objective of this study was to investigate the weight and weight uniformity of hard gelatin capsules filled with microcrystalline cellulose (MCC) and silicified microcrystalline cellulose (SMCC) powdered formulations. A tamping-type encapsulation apparatus was used to fill the capsules. The four formulations that were tested included MCC alone, MCC blended with fumed silica, SMCC, and high-density SMCC (SMCC-HD). The mean capsule weight and the average variation in mean capsule weight of each formulation were determined. Both SMCC products exhibited better flow than the MCC alone, with SMCC-HD being the freest flowing of the powders investigated. Capsules filled with the SMCC products had higher fill weights than those containing the MCC powders. The SMCC-containing capsules exhibited the lowest variation in weight, although these findings were not significantly different from either of the MCC-containing capsules. Significantly higher weight variations were found in capsules filled with SMCC-HD. A relationship between Carr's compressibility index and capsule weight variation was found, with more compressible materials producing more uniformly filled capsules. No relationship could be established between powder flow and capsule weight uniformity. These findings suggest that powder flow may not be a critical parameter in ensuring capsule weight uniformity when the encapsulation equipment utilizes a tamping-type filling system.     

Physical and chemical characterization of Dead Sea mud

A laboratory analysis was performed to determine the physical and chemical properties of 24 Dead Sea mud samples collected from three different locations on the eastern shore of the Dead Sea. Several analytical techniques were used to determine the chemical and mineralogical compositions of those samples including atomic absorption spectrometry and X-ray diffraction. Physical parameters such as specific gravity, Atterberg limits, grain size, specific surface area, cation exchange capacity, pH and electrical conductivity were also studied. The main focus of the work was to document mud characteristics and to study the interrelation between physical and chemical properties. The mud samples were quite rich in minerals. Strontium was the most abundant trace element in the samples (range: 410–810 ppm) followed by barium (range: 155–380 ppm), vanadium (range: 209–264 ppm) and lead (range: 108–114 ppm). There were significant differences in the elemental contents of mud samples collected from different locations.     

Formulation and physical properties of thixotropic gels for hard gelatin capsules

Abstract

Thixotropic gels for filling into hard gelatin capsules at room temperature were formulated using Miglyol 829 and colloidal silicon dioxide. Initial studies on several vehicles were undertaken prior to selection of Miglyol 829 for detailed study. The rheological properties of the gels and drug/gel formulations have been investigated in detail and the results are discussed with reference to capsule filling, stability and drug release of a model drug propantheline bromide (PPBr).     

Formulation and physical properties of thixotropic gels for hard gelatin capsules

Thixotropic gels for filling into hard gelatin capsules at room temperature were formulated using Miglyol 829 and colloidal silicon dioxide. Initial studies on several vehicles were undertaken prior to selection of Miglyol 829 for detailed study. The rheological properties of the gels and drug/gel formulations have been investigated in detail and the results are discussed with reference to capsule filling, stability and drug release of a model drug propantheline bromide (PPBr).     

Imprinting on empty hard gelatin capsule shells containing titanium dioxide by application of the UV laser printing technique

The purpose of this study was to examine the application of ultraviolet (UV) laser irradiation to printing hard gelatin capsule shells containing titanium dioxide (TiO₂) and to clarify how the color strength of the printing by the laser could be controlled by the power of the irradiated laser. Hard gelatin capsule shells containing 3.5% TiO₂ were used in this study. The capsules were irradiated with pulsed UV laser at a wavelength of 355?nm. The color strength of the printed capsule was determined by a spectrophotometer as total color difference (dE). The capsules could be printed gray by the UV laser. The formation of many black particles which were agglomerates of oxygen-defected TiO₂ was associated with the printing. In the relationship between laser peak power of a pulse and dE, there were two inflection points. The lower point was the minimal laser peak power to form the black particles and was constant regardless of the dosage forms, for example film-coated tablets, soft gelatin capsules and hard gelatin capsules. The upper point was the minimal laser peak power to form micro-bubbles in the shells and was variable with the formulation. From the lower point to the upper point, the capsules were printed gray and the dE of the printing increased linearly with the laser peak power. Hard gelatin capsule shells containing TiO₂ could be printed gray using the UV laser printing technique. The color strength of the printing could be controlled by regulating the laser energy between the two inflection points.     

Morphological, thermal and annealed microhardness characterization of gelatin based interpenetrating networks of polyacrylonitrile: A hard biopolymer

The present paper reports the preparation of full IPNs of gelatin and polyacrylonitrile. Various compositions of gluteraldehyde crosslinked gelatin and N,N′-methylene-bis-acrylamide crosslinked PAN were characterized by SEM and DSC techniques. The IPNs were also thermally pretreated by the annealing process. The effects of annealing temperature on the microhardness of IPNs were studied using the Vickers method. SEM indicates the homogeneous morphological features for IPN. The role of gelatin, AN and crosslinker on the developed hard biopolymer has been described with the help of DSC thermograms and microhardness measurements of annealed specimens and good correlation is observed.     

Stability study of hard gelatin capsules containing retinoic acid

Retinoic acid (RA) is employed in the therapeutic treatment of acute promyelocytic leukemia (APL). In this paper, the chemical stability and the most favorable storage conditions of RA in hard gelatin capsules containing alpha-lactose monohydrate, used in clinical experimentation, are reported. A secondary goal of this work was to show the usefulness of a robust regression technique, repeated median with replicates (RMWR) in a solid-state shelf life prediction by accelerated studies. The capsules were stored at room temperature and in the freezer. Their residual RA content was assayed for more than 3 years. RA chemical degradation was monitored by high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) stability-indicating methods previously validated and able to detect various potential degradation products. Possible physical modifications were checked by dissolution tests and differential scanning calorimetry (DSC) of the content of the capsules. The shelf life was also predicted by an accelerated isothermal method to confirm room temperature results, and the activation energy estimated through this study was 12.5 +/- 1.1 kcal/mol (95% confidence interval). In the conditions of climatic zone II, the shelf life for the capsules stored at room temperature in light-resistant containers was equal to 678 days, while the capsules stored in the freezer retained the initial content of drug after 1289 days. From the results gathered in this study, the usefulness of RMWR for shelf life prediction in the presence of outliers is evident.     

The preparation of prolonged action formulations in the form of semi solid matrix into hard gelatin capsules of oxprenolol I. Thermocap method

The aim of this study was to obtain prolonged action by preparing semi-solid matrices (SSM) into hard gelatin capsules using Oxprenolol as a model drug.

SSM formulations were prepared by using different lipophilic and hydrophilic pharmaceutical excipients, polyethylene glycols as channeling agent in the semi solid mass and Gelucires. The release kinetic of drug from these formulations was determined and compared with the commercial preparation in the form of polymeric matrix of this drug.

Among the generally used excipients, we have found that Gelucires were the most appropriate excipients for preparation of SSMs and drug release from these dosage forms can be improved by the method mentioned above depending on quantity and type of channeling agent which was used.     

The preparation of prolonged action formulations in the form of semi solid matrix into hard gelatin capsules of oxprenolol I. Thermocap method

Abstract

The aim of this study was to obtain prolonged action by preparing semi-solid matrices (SSM) into hard gelatin capsules using Oxprenolol as a model drug.

SSM formulations were prepared by using different lipophilic and hydrophilic pharmaceutical excipients, polyethylene glycols as channeling agent in the semi solid mass and Gelucires. The release kinetic of drug from these formulations was determined and compared with the commercial preparation in the form of polymeric matrix of this drug.

Among the generally used excipients, we have found that Gelucires were the most appropriate excipients for preparation of SSMs and drug release from these dosage forms can be improved by the method mentioned above depending on quantity and type of channeling agent which was used.     

The preparation of prolonged action formulations in the form of semi solid matrix into hard gelatin capsules of oxprenolol II. Thixocap Method

In this study, it was aimed to obtain prolonged release preparations in the form o f semisolid matrices (SSM) o f Oxprenolol as a model drug into mixtures possessing thixotropic property by filling in the hard gelatin capsules.

The results of this study showed that the formulation, prepared with liquid paraffin and Cutina HR, gave kinetic values close to that of the polymeric matrix preparation of Oxprenolol HCl used for comparison. However, in the thixotropic formulations, prepared with Isopropyl Myristate and Isopropyl Palmitate by adding Arerosil 200, the drug release was slow, there fore the release in expected period of time and level can be ensured by.adding different. proportions of hydrophilic substances forming channels in the mass without damaging thixotropic structure.     

A screening technique to study the mechanical strength of gelatin formulations

A semiquantitative method for measuring the mechanical strength of gelatin ribbons was demonstrated using a universal tensile testing machine (Instron, model 1122). Molten gelatin formulations comprised of acid-bone gelatin, limed-hide gelatin, or their combinations were made, pored as gelatin films, and aged at 50% relative humidity (RH). Viscoelastic properties (mechanical strength) of five gelatin formulations were evaluated by determining elastic modulus, tensile strength, and ratio of tensile strength to elastic modulus of gelatin ribbons. This study demonstrated that a 3:1 ratio of acid-bone to limed-hide gelatin combination showed better viscoelastic properties than the other formulations studied.     

明胶/锂藻土纳米复合材料的制备与性能研究

通过溶液共混和溶剂蒸发的方法制备了明胶/锂藻土纳米复合材料,利用衰减全反射傅立叶红外光谱(ATR-FTIR)、广角X射线衍射(WAXD)、紫外-可见光谱(UV-Vis)、差示量热扫描(DSC)和热重分析(TGA)等仪器方法对材料的结构与性质进行了研究。结果表明:ATR-FTIR曲线中,除Si-O键外,各基团特征峰强度都随锂藻土含量增加而降低。WAXD谱图中未发现锂藻土的层状衍射峰,说明锂藻土完全剥离。锂藻土还对明胶的结晶性和结晶结构产生影响,在2θ=27.1°发现了新的衍射峰,并随着锂藻土含量增加峰强度变强。明胶/锂藻土纳米复合膜表现出良好的透明性,锂藻土含量对材料透明度影响不大。随着锂藻土含量的增加,明胶的熔点(Tm)先增加后降低,含5%锂藻土的纳米复合膜有最高的熔点。纳米复合膜的热稳定性明显好于纯明胶膜,并且随着锂藻土含量的增多,材料的热稳定性也提高,少量锂藻土即可大幅改善明胶的热稳定性。