Influence of dry granulation on compactibility and capping tendency of macrolide antibiotic formulation

The effect of dry granulation (roller compaction and slugging) on compactibility and tablet capping tendency in a formulation with macrolide antibiotic and microcrystalline cellulose (MCC) was investigated. Direct tableting of this formulation revealed a pronounced capping tendency. Both dry granulated systems exhibit better compactibility and significant reductions in capping tendency compared to direct tableting. The capping tendency was also reduced through the use of precompression during direct tableting. The main volume reduction mechanism for macrolide antibiotic is fragmentation; this was confirmed by Heckel analysis, the lubricant sensitivity test, and SEM images. The yield pressure (P_y) of the direct tableting system is lower than the P_y of dry granulated systems, which indicates the lower plasticity of dry granulated systems. These findings do not explain the lower capping tendency of dry granulated systems compared to direct tableting. The main differentiating bonding mechanism is attributed to long distance intermolecular bonds due to the intense amorphization of macrolide antibiotic that occurs during dry granulation. Amorphization leads to a significant increase in surface free energy and consequently stronger long distance bonding between particles, which can withstand elastic relaxation and therefore reduce the capping problem. Solid bridges probably do not make a notable contribution to the mechanical strength of tablets, due to the brittle nature of the particles and the complex molecular structure of macrolide antibiotic.     

Influence of formulation composition and processing on the content uniformity of low-dose tablets manufactured at kilogram scale

The purpose of this study was to investigate the impact of processing, API loading, and formulation composition on the content uniformity of low-dose tablets made using direct compression (DC) and roller compaction (RC) methods at 1?kg scale. Blends of 1:1 microcrystalline cellulose/lactose or 1:1 microcrystalline cellulose/dicalcium phosphate anhydrous with active pharmaceutical ingredient (API) at loadings of 0.2, 1 and 5% were processed either by DC or RC. A statistical analysis showed that DC produced comparable content uniformity results to RC. Microcrystalline cellulose/lactose formulations had improved average potency compared to microcrystalline cellulose/dicalcium phosphate anhydrous formulations for both DC and RC. The impact of segregation in the DC blends and adhesion to equipment surfaces was assessed to aid in understanding potency trends. DC may be as suitable as RC for low-dose regime (e.g. <?1?mg) when manufacturing clinical supplies at small scale provided the API has a suitable particle size and potency loss to equipment is negligible.     

Elucidation of Solution State Complexation in Wet-Granulated Oven-Dried Ibuprofen and β-Cyclodextrin: FT-IR and 1H-NMR Studies

The effect of oven-dried wet granulation on the complexation of β-cyclodextrin with ibuprofen (IBU) in solution was investigated using Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance (¹H NMR), and molecular modeling. Granulation was carried out using 5 mL of three different granulating solvents; water, ethanol (95% v/v), and isopropanol and the granules were oven-dried at 60°C for 2 h. The granules were compared to oven-dried physical mixture and conventionally prepared complex. Phase solubility study was performed to investigate the stability of the granulation-formed complexes in solution. FT-IR was used to examine the complexation in the granules while ¹H NMR, and molecular modeling studies were carried out to determine the mechanism of complexation in the water-prepared granules. The solubility studies suggested a 1:1 complex between IBU and βCD. It also showed that the stability of the complex in solution was in the following order with respect to the granulating solvents: ethanol > water > isopropanol. The FT-IR study revealed a shift in the carboxylic acid stretching band and decrease in the intensities of the C-H bending bands of the isopropyl group and the out-of-plane aromatic ring, of IBU, in granules compared to the oven-dried physical mixture. This indicated that granules might have some extent of solid state complexation that could further enhance dissolution and the IBU–βCD solution state complexation. ¹H NMR showed that water prepared oven-dried granules had a different ¹H NMR spectrum compared to similarly made oven-dried physical mixture, indicative of complexation in the former. The ¹H NMR and the molecular modeling studies together revealed that solution state complexation from the granules occurred by inclusion of the isopropyl group together with part of the aromatic ring of IBU into the βCD cavity probably through its wider side. These results indicate that granulation process induced faster complexation in solution which enhances the solubility and the dissolution rate of poorly soluble drugs. The extent of complexation in the granules was dependent on the type of solvent used.     

Influence of Process Parameters on Pellets Elaborated in a Mi-Pro High-Shear Granulator

The aim of the study was to prepare porous pellets several hundred micrometers in diameter into or onto which drug substances could be embedded. Wet granulation was carried out on a powder mix of α-lactose and polyvinylpyrrolidone in a Mi-Pro high-shear granulator. The process parameters were investigated to point out their influence on pellet physical properties. The reference conditions of granulation that gave the most satisfactory pellets in size and shape were determined by adjusting the volume and the distribution rate of water. Increasing impeller speed resulted in an increase in granule size and granulation yield and in a decrease in proportion of fines. The granules showed easy flowing for all granulation conditions. Adjusting process parameters enabled control of size, shape, surface area, and porosity of the granules and thus the design of ready to use granules to which drug substances could be associated by deposition or inclusion.     

Effect of formulation variables on in vitro drug release and micromeritic properties of modified release ibuprofen microspheres

Modified release microspheres of the non-steroidal anti-inflammatory drug, ibuprofen, were formulated and prepared using the emulsion solvent diffusion technique. The contribution of various dispersed phase and continuous phase formulation factors on in vitro drug release and micromeritic characteristics of microspheres was examined. The results demonstrated that the use of Eudragit RS 100 and Eudragit RL 100 as embedding polymers modified the drug release properties as a function of polymer type and concentration. Eudragit RS 100 retarded ibuprofen release from the microspheres to a greater extent than Eudragit RL 100. The drug/polymer concentration of the dispersed phase influenced the particle size and drug release properties of the formed microspheres. It was found that the presence of emulsifier was essential for microsphere formation. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release properties. Scanning electron microscopy revealed profound distortion in both the shape and surface morphology of the microspheres with the use of magnesium stearate as added emulsifier. The application of an additional Eudragit RS 100 coat onto formed microspheres using fluid bed technology was successful and modulated the drug release properties of the coated microspheres.     

An investigation into the effect of formulation variables and process parameters on characteristics of granules obtained by in situ fluidized hot melt granulation

The aim of this study was to investigate the influence of binder content, binder particle size, granulation time and inlet air flow rate on granule size and size distribution, granule shape and flowability, as well as on drug release rate. Hydrophilic (polyetilenglycol 2000) and hydrophobic meltable binder (glyceryl palmitostearate) were used for in situ fluidized hot melt granulation. Granule size was mainly influenced by binder particle size. Binder content was shown to be important for narrow size distribution and good flow properties. The results obtained indicate that conventional fluid bed granulator may be suitable for production of highly spherical agglomerates, particularly when immersion and layering is dominant agglomeration mechanism. Granule shape was affected by interplay of binder content, binder particle size and granulation time. Solid state analysis confirmed unaltered physical state of the granulate components and the absence of interactions between the active and excipients. Besides the nature and amount of binder, the mechanism of agglomerate formation seems to have an impact on drug dissolution rate. The results of the present study indicate that fluidized hot melt granulation is a promising powder agglomeration technique for spherical granules production.     

Influence of granulation temperature on particle size distribution of granules in twin-screw granulation (TSG)

This study investigated an influence of granulation temperature during twin-screw granulation (TSG) on particle size distributions (PSDs). The influence of the granulation temperature on granule size distributions varied, depending on the liquid to solid (L/S) ratio, the kind of binders, the method of binder addition, and the filler material. The PSD of granules was broad and bimodal at a barrel temperature of 30?°C. Granules size distributions became narrow and second height decreased at high barrel temperature. While the L/S ratio had an effect on the sharpness of granule size distributions, this effect was minor compared to the granulation temperature. Granule size distributions were influenced by binder addition methods. When the binder was added as solution, PSD became broad. In formulations using lactose as filler, PSD became broad and bimodal at 90?°C. Much lactose was dissolved in granulation solution at high temperature, because the solubility of lactose rises significantly with the solution temperature leading to higher effective L/S ratio in the granulator. Hence, granulation was proceeded and large granules were formed. From these results, the granulation temperature is one of important parameters to obtain mono-modal PSD in TSG.     

Comparison of single pot and multiphase granulation. Part 1: Effect of the high shear granulator on granule properties according to the drug substance and its concentration

Pharmaceutical granulations are usually developed with regard to a specific manufacturing process but switching from one piece of equipment to another can be necessary to comply with the available industrial equipment. Investigations were undertaken on formulations differing in the drug substance and in its concentration. Our aim was to highlight the effect of the granulation process on granules manufactured in a pilot scale Moritz® Turbosphere TS50 or in Fielder® PMA 65 and dried in a Glatt® GPCG1 fluid bed dryer. The granulation process and formulation parameters showed a significant impact on granule size distribution, behaviour under pressure, and on tablet mechanical properties and dissolution kinetics.     

Effects of the Method of Preparation on the Compression,Mechanical, and Release Properties of Khaya Gum Matrices

A study has been made of the compression properties of khaya gum matrices and the effects of drug concentration and method of preparation of the material on the compression, mechanical and the drug release characteristics of the matrices. Khaya gum matrix tablets were prepared by direct compression and wet granulation methods. The compression properties of the formulations were assessed using the equations of Heckel and Kawakita. The mechanical properties of the tablets were evaluated using crushing strength and friability of the tablets, whereas the release properties of the tablets were evaluated by using the disintegration and dissolution times. The results obtained show that khaya gum deformed mainly by plastic deformation. The compression properties of the formulations were affected by the concentration of the drug and the method of preparation of the materials for compression. Tablets prepared by wet granulation showed faster onset and higher amount of plastic deformation during compression than those prepared by direct compression. Tablets containing dicalcium phosphate showed higher mechanical strength and disintegration and dissolution times. Wet granulation also increased the mechanical strength of the tablet without significantly affecting the drug release characteristics from the matrix tablets. Thus, the wet granulation method could be useful in the preparation of khaya gum matrix tablet with acceptable mechanical properties and drug release properties.     

血液标本不同处理方法对血糖检测结果的影响

目的探讨血液标本不同的处理方法对血糖检测结果的影响。方法采集65例门诊体检人群空腹静脉血,分别对血样进行有抗凝剂并离心后分离血清（A组）、离心后分离血清（B组）、离心后不分离血清（C组）三种处理方法,在1h、2h．3h．4h、5h等5个时间段分别对血糖进行检测,观察三组各时间段血糖检测结果。结果A组和B组血糖测定值在5h内差异均无统计学意义（均P〉0．05）,C组血糖测定值随着时间的延长而逐渐降低,5h血糖检测值与lh的相比,差异有统计学意义（P〈0．05）,与A组、B组比较差异均有统计学意义（均P〈0．05）。结论血样采集后放置时间、及时分离血浆及加入抗凝剂都影响血糖检测结果,应及时测定,较少误差。     

Effects of drying methods on the physicochemical and compressional characteristics of Okra powder and the release properties of its metronidazole tablet formulation

A study has been made of the effects of sun and oven drying methods on the physicochemical characteristics and compressibility of Okra powder and the release properties of its metronidazole tablet formulation. Corn starch was used as the reference standard. The mechanical properties of the tablets were evaluated using crushing strength and friability, while the release properties were determined using the disintegration times and dissolution rates. The results obtained showed that sun-dried Okra powder had smaller particle size, exhibited good flow and possessed higher hydration and swelling capacities compared to the oven dried samples. The compressibility of Okra powders assessed by the indices of plasticity from Heckel (Py) and Kawakita plots (Pk) showed that sun dried Okra powders had higher Py but lower Pk values than the oven-dried Okra powder. Metronidazole tablets formulated with oven dried Okra powder formed stronger tablets than tablets containing sun dried Okra powder. Generally, tablets containing sun dried Okra powders had faster disintegration and dissolution than tablets formulated with oven-dried powder. The results suggest that the choice of drying method during the processing of pharmaceutical raw materials is critical to its physicochemical properties and the release properties of its tablet formulations.     

不同干燥方式对颗粒粉体性质的影响

目的 探究不同干燥方式对颗粒粉体性质的影响。方法 采用相同的处方进行制粒,采用真空干燥,烘箱干燥及流化床干燥,测定不同干燥方式所得颗粒的流动性指数,综合评价不同干燥方式所得颗粒的粉体性质。结果 三者中烘箱干燥产物的流动性最好,可压性无明显区别。结论 不同干燥工艺造成了干燥产物粉体性质的差异。     

The influence of excipients on physical and pharmaceutical properties of oral lyophilisates containing a pregabalin-acetaminophen combination

Objectives: The purpose of the study was to investigate and characterize the oral lyophilisates containing the pregabalin-acetaminophen drug combination and as xcipients mannitol with microcrystalline cellulose or hydroxypropyl methylcellulose, in order to conclude upon drug-excipient interactions and their stability implications, impact of excipients on drug release and on the physicochemical and mechanical properties of the pharmaceutical formulations.

Methods: The oral tablets were made by using a Christ freeze-dryer alpha 2–4-LSC lyophilizer, and evaluated for stability, drug-excipient compatibility and homogeneity of the prepared pharmaceutical formulations. The formulations were evaluated for in vivo absorption in rabbits by histopathological exams.

Results: FTIR and thermogravimetric analyses, DLS technique, SEM and NIR-CI studies confirmed the compatibility between compounds. From the determined physical and biochemical parameters of the formulations it was established that they are stable, homogeneous, and meet the conditions for orally disintegrating tablets.

Conclusion: In the case of the investigated pharmaceutical formulations the study evidenced the assembling through physical bonds between the excipients and the ‘codrug’ complex, which do not affect the release of the bioactive compounds.     

基于生物碱类成分优选黄连药材的加工方法

目的：探索黄连药材在产地加工过程中不同的干燥方法对其生物碱类成分的影响,以优化和建立适宜的干燥加工方法。方法：采用高效液相色谱（HPLC）法同时测定不同加工方法的黄连药材样品中7种生物碱类成分的含量,并采用主成分分析（PCA）对其进行综合评价。结果：不同加工方法对黄连中生物碱类成分的含量有一定影响,自然干燥综合质量较好。结论：建议黄连在加工时采用低温、不断翻动干燥的方法,为优选黄连适宜的产地加工方法提供了基础研究资料。     

Influence of the roll compactor parameter settings and the compression pressure on the buccal bio-adhesive tablet properties

Miconazole buccal tablets were prepared via a dry granulation process. By applying a factorial design (2⁴), the roll compactor parameters (compaction force, gap between the rolls, type of the rolls (smooth, ribbed) and the sieve aperture) were optimised for the tablet strength. The compaction force and the roll type significantly affected the tablet strength. Afterwards, a quarter fractional factorial design (2^5-2) was applied, consisting of the four compactor parameters and additionally the compression pressure, in order to optimise these parameters for the dissolution profile and the buccal bio-adhesion characteristics (bio-adhesive force and energy). In order to evaluate the dissolution profiles properly, the similarity factor between sample and a zero-order release reference profile was used. The compression pressure and the roll type significantly affected the dissolution profile. The sieve aperture had a significant effect on the buccal adhesion properties and the compaction force had a significant effect on the dissolution profile and the bio-adhesive energy. The gap between the rolls affected the bio-adhesive force significantly.     

Effect of solvents on physical properties and release characteristics of monolithic hydroxypropylmethylcellulose matrix granules and tablets

Effect of solvents on physical characteristics and release characteristics of monolithic acetaminophen (APAP) hydroxypropylmethylcellulose (HPMC) matrix granules and tablets were examined. Various types and amounts of solvents were employed for granulation and cOAting. APAP and other excipients were mixed and were then wet-granulated in a high-speed mixer. The dried granules were then directly compressed and film-coated with low viscosity grade HPMC. As the amount of water increased, the size of granules also increased, showing more spherical and regular shape. However, manufacturing problems such as capping and lamination in tableting occurred when water was used alone as a granulating solvent. The physical properties of HPMC matrix granules were not affected by the batch size. The initial release rate as well as the amount of APAP dissolved had a tendency to decrease as the water level increased. Addition of nonaqueous solvent like ethanol to water resulted in good physical properties of granules. When compared to water/ethanol as a coating solvent, the release rate of film-coated HPMC matrix tablets was more sensitive to the conditions of coating and drying in methylene chloride/ethanol. Most of all, monolithic HPMC matrix tablet when granulated in ethanol/water showed dual release with about 50% drug release immediately within few minutes followed by extended release. It was evident that the type and amount of solvents (mainly water and ethanol) were very important for wet granulation and film-coating of monolithic HPMC matrix tablet, because the plastic deforming and fragmenting properties of material were changed by the different strengths of the different solvents.     

Application of quality by design (QbD) to formulation and processing of naproxen pellets by extrusion–spheronization

Abstract

The aim of this research was to apply quality by design (QbD) to the development of naproxen loaded core pellets which can be used as the potential core for colon-specific pellets. In the early stages of this study, prior knowledge and preliminary studies were systematically incorporated into the risk assessment using failure mode and effect analysis (FMEA) and fishbone diagram. Then Plackett–Burman design was used to screen eight potential high risk factors (spheronization speed, spheronization time, extrusion speed, drying method, CCMC-Na concentration, lactose concentration, water concentration and Tween 80 concentration) obtained from the above risk assessment. It was discovered that out of the eight potential high risk factors only three factors (spheronization speed, extrusion speed and CCMC-Na concentration) had significant effects on the quality of the pellets. This allowed the use of Box–Behnken design (BBD) to fully elucidate the relationship between the variables and critical quality attribute (CQA). Finally, the final control space was established within which the quality of the pellets can meet the requirement of colon-specific drug delivery system. This study demonstrated that naproxen loaded core pellets were successfully designed using QbD principle.     

Effects of different processing methods on digestibility of Scylla paramamosain allergen (tropomyosin)

Crustacean allergy is a significant health problem around the world, and tropomyosin (TM) represents the major allergen of crustaceans. The aim of this study was to evaluate three processing methods (boiling, CUB, HPS) and identify the one method that is most effective in the degradation of TM and reduction of its IgE-binding reactivity, and make it easier to be decomposed during gastrointestinal digestion. SDS-PAGE analysis indicated that boiling had little impact on the digestive stability of TM. In contrast, combined ultrasound and boiling (CUB), and high pressure steaming (HPS) both could accelerate the digestion of TM. Similarly, western blotting and inhibition ELISA also demonstrated that the reactivity of IgG/IgE-binding of TM that was extracted from processed crab was partially decreased after treating with CUB or HPS. Among the three processing methods, HPS was the most effective method to accelerate the digestion of TM in gastrointestinal digestion, and reduce the reactivity of IgG/IgE-binding of TM. These results suggest that proper processing of crab could promote the degradation of TM in simulated gastrointestinal digestion, reduce the reactivity of IgG/IgE-binding of TM, and decrease the incidence of crab hypersensitivity in humans.     

Influence of the formulation components on the properties of the system SLN-dextran hydrogel for the modified release of drugs

A system composed by solid lipid nanoparticles (SLN) entrapped into a chemical hydrogel of dextran was recently proposed for the controlled release of lipophilic drugs in oral formulations. This study reports now an extension of such study focused on the investigation of how the nature and the amount of the formulation components are able to modify the properties of the system. In particular the concentration of the two surfactants used for the nanosuspension stabilization, the nature of the lipid phase used for the nanoparticles preparation, as well as the concentration and the derivatization degree of the polymer employed for the gel preparation were investigated. The effects of these variables on the physicochemical properties of the nanoparticles and/or on the release profiles of the model drug (S)-(+)-2-(4-isobutylphenyl)-propionic acid (ibuprofen) were reported and discussed. Rheological experiments on samples of SLN, dextran hydrogel, and SLN-dextran hydrogel were also performed.     

不同炮制方法对火麻仁饮片中葫芦巴碱含量的影响

目的 以火麻仁饮片中的葫芦巴碱为指标性成分,比较不同炮制方法对葫芦巴碱含量的影响.方法采用清炒法、微波法、烘法对3个不同产地的火麻仁饮片进行炮制,采用高效液相色谱法测定不同炮制品及生品中葫芦巴碱的含量.结果火麻仁经过炮制后葫芦巴碱的含量均有不同程度的升高,其中清炒法提升幅度最大,微波法次之,烘法最小.结论炮制可以提高火麻仁中葫芦巴碱的含量,且以清炒法为最佳.