Tableting of coated ketoprofen pellets

Ketoprofen pellets were prepared by the method of extrusion-spheronization, and a film coating of guar gum and Eudragit NE was applied to drug cores using pan technology. In an attempt to design a tablet which, on peroral administration, disintegrates rapidly, releasing intact coated pellets which maintain the integrity of both the cores and their release retarding membrane, Avicel PH101, lactose DT and magnesium stearate were used as excipients to prepare tablets comprising ketoprofen pellets or microcapsules. Preliminary experiments were conducted on uncoated pellets to determine the optimum compression force required to prepare tablets of satisfactory mechanical properties and release profiles. Coated pellets containing ketoprofen were used to investigate the influence of excipients levels. In an attempt to minimize problems associated with blending and segregation of microcapsules and excipients, placebo spheres of Avicel PH101 and lactose DT were produced by the method of extrusionspheronization. The use of placebo spheres produced tablets with improved drug content uniformity and disintegration time. The tensile strength of such compacts was enhanced by excluding magnesium stearate from the mixes without significant problems of sticking or picking. The use of placebo pellets resulted in significant damage to drug microcapsules, which was attributed to the higher hardness and density of the excipients pellets. The role of membrane coating in protecting the drug core during compression was also evaluated.     

Influence of formulation and excipient variables on the pellet properties prepared by extrusion spheronization

Four commercial grades of microcrystalline cellulose, Avicel PH 101, Avicel PH 102, Avicel PH 112 and Avicel PH 302 were compared for extrusion spheronization. Model mixes containing Avicel PH 101 with different proportions of fillers like lactose and dicalcium phosphate dihydrate (DCPD) were also compared to observe the influence of these fillers on the pellet properties. The amount of water used for granulation of Avicel/ Avicel mixes was kept constant so as to evaluate and quantitate the influence of these excipients/fillers on the pellet properties. The various pellet properties evaluated included, drug release, size and size distribution, shape, density, friability and flow. Mean pellet diameter did not vary among the Avicel grades. Pellets prepared with different proportions of Avicel PH 101 and lactose were more or less similar in mean diameter. The same phenomena were observed in case of DCPD as well. Plain lactose pellets were the largest in size. Therefore, it can be inferred that the presence of Avicel suppressed the change in pellet size. Circularity was found to be significantly linear function of log of bulk density of Avicel powders. As revealed by the SEM photographs, pellets of Avicel PH 101 were fairly round where as those containing Avicel PH 302 were dumbbell shaped. Formulations containing DCPD showed the highest circularity. Drug release rate varied in all the formulations. Among the Avicel grades, Avicel PH 302 showed the highest drug release rate where as Avicel PH 101 showed the least. Drug release also varied as a function of the type of filler and their proportion in the pellets. For both the fillers, the drug release increased with an increase in their proportion. Less water was required for formulations containing higher amounts of lactose and DCPD. Plain DCPD failed to spheronize, although pellets of plain lactose could be formed at the investigated level of water.     

Development and in vitro evaluation of an enteric-coated multiparticulate drug delivery system for the administration of piroxicam to dogs.

The aim of the study was to develop enteric-coated pellets for the administration of piroxicam (a poorly water-soluble drug) to small animals in order to avoid local gastrointestinal irritation, one of the major side effects of nonsteroidal anti-inflammatory drugs after oral ingestion. Pellets were made by an extrusion-spheronization process. The influence of several excipients on the in vitro drug release was evaluated. Piroxicam release from the uncoated pellets was measured in phosphate buffer (pH 6.8) using the paddle dissolution method (USP XXIII). The enteric-coated pellets were tested in 0.1 N HCl and phosphate buffer, pH 6.8. The addition of sodium croscarmellose (Ac-Di-Sol) did not influence the piroxicam release from microcrystalline cellulose pellets. Sodium carboxymethyl starch (Explotab) increased the release from 30 to 65% at 45 min. The incorporation of sodium carboxymethyl cellulose on its own or as a co-processed blend with microcrystalline cellulose (Avicel RC 581 and CL 611) enhanced the release of piroxicam at 45 min from 30% (pure Avicel PH 101) to 95% (combination of Avicel PH 101 and CL 611 in a ratio of 1:3). Additional use of cyclodextrins had only a minor influence on the dissolution rate. An Eudragit L 30 D-55 and FS 30 D (6/4) film was applied to the core pellets (containing 2.5% (w/w) piroxicam and a combination of Avicel PH 101 and CL 611 in a ratio of 1:3) in order to obtain gastroresistant properties. The coated pellets retained their dissolution characteristics after compression into fast disintegrating tablets because waxy cushioning beads were added to minimize film damage.     

Compatibility study between acetylcysteine and some commonly used tablet excipients.

Differential scanning calorimetry (DSC), Fourier transform infra-red spectroscopy (FT-IR), HPLC and TLC were used to investigate the interactions between the mucolytic drug acetylcysteine and a number of commonly used tablet and capsule excipients. Acetylcysteine was found to be compatible with microcrystalline cellulose (Avicel PH 101), sodium carboxymethylcellulose, amorphous silicon dioxide (Aerosil), PVP, cross-linked PVP (Polyplasdone XL), corn starch, saccharose and magnesium stearate. Acetylcysteine thermal stability (onset degradation temperature) was decreased in mixtures with corn starch, magnesium stearate, saccharose and lactose. Interactions of acetylcysteine with lactose, PEG 4000 and 6000, glycine, adipic acid and saccharin sodium were found using DSC and studied in detail with FT-IR, HPLC and TLC. The results suggest that acetylcysteine in mixtures with PEG 4000, glycine or saccharin sodium is degraded during storage at conditions of high temperature and humidity.     

Differential scanning calorimetry to investigate the compatibility of ciprofloxacin hydrochloride with excipients

The compatibility between ciprofloxacin hydrochloride (CFX) and some excipients was evaluated using differential scanning calorimetry (DSC). Physical mixture, coground mixture, compressed mixture and kneaded mixture were prepared to study the effect of sample manipulation. In addition, the samples of physical mixture were also accelerated at 55 degrees C for three weeks to obtain more reliable conclusions. Different types of excipients currently used in tablet or capsule formulations namely, calcium phosphate dibasic dihydrate (Emcompress), magnesium stearate lactose, sorbitol, mannitol, croscarmellose sodium (Ac-Di-Sol), sodium carboxymethyl starch (Primojel), microcrystalline cellulose (Avicel PH 101, Emcocil) were examined. The DSC scan of CFX displayed two endothermic peaks probably as a result of a fusion process followed by a decomposition process. CFX appeared to interact with sorbitol, mannitol, Ac-Di-Sol, Primojel, Avicel PH 101 and Emcocil.     

Some factors affecting properties and dissolution behavior of tableted furosemide microspheres.

Furosemide (1) microspheres prepared by using Eudragit RS (1:4 and 1:2 drug:polymer ratios) were tableted. Microspheres were compressed with or without excipients (lactose, Avicel PH 101 or Emcompress). The thickness and crushing strength of tablets containing excipients were also found to be affected by the type of excipients. Dissolution characteristics of furosemide from tableted microspheres with or without excipients depended on the applied compression force but showed a controlled release behavior. Compression slowed down the release of 1. Addition of excipients to the formulation increased drug dissolution. The release from tablets followed Higuchi matrix model kinetics.     

Studies on flufenamic acid capsules and tablets

In this study, the in vitro dissolution rate of flufenamic acid was investigated in two different dosage forms, tablets and capsules, and the influence of the commonly used additives (lactose, corn starch, magnesium stearate, sodium lauryl sulphate). Using lactose, starch, Avicel PH 101, and methyl cellulose as additives, direct compression and wet granulation techniques were tried for preparing flufenamic acid tablets. The rotating basket method of U.S.P. XIX was used for determination of release rate. The findings were compared to the dissolution rate results of the commercial flufenamic acid capsules.     

Development of disintegrating multiple-unit tablets on a high-speed rotary tablet press.

Enteric coated bisacodyl pellets were compressed into divisible disintegrating tablets on a high speed rotary tablet press and investigated for pellet damages. The degree of pellet damages was examined via the bisacodyl dissolution during the acid treatment of' the drug release test for enteric coated articles according to USP 23. The damages depended on the type of filler-binder used and settings of the tablet press. Avicel PH 101 proved to be the most suitable filler-binder, effecting homogeneous distribution of the pellets within the tablets, as could be shown by image analysis of coloured pellets. The speed of the tablet press had noo influence on the pellet damages using Avicel PH 101 as a filler-binder, however, tablets containing 70% (w/w) of coated pellets did not fulfil the requirements of USP 23, despite optimum elasticity and coating thickness of a new Eudragit FS 30 D coating. Reducing the proportion of pellets to 60% per tablet, less than 10% of bisacodyl were released within 2 h during acid treatment thus fulfilling the requirements of the USP 23.     

Release Kinetics of Papaverine Hydrochloride from Tablets with Different Excipients

The influence of excipients on the disintegration times of tablets and the release of papaverine hydrochloride (PAP) from tablets were studied. Ten different formulations of tablets with PAP were prepared by direct powder compression. Different binders, disintegrants, fillers, and lubricants were used as excipients. The release of PAP was carried out in the paddle apparatus using 0.1 N HCl as a dissolution medium. The results of the disintegration times of tablets showed that six formulations can be classified as fast dissolving tablets (FDT). FDT formulations contained Avicel PH 101, Avicel PH 102, mannitol, (3-lactose, PVP K 10, gelatinized starch (CPharmGel), Prosolv Easy Tab, Prosolv SMCC 90, magnesium stearate, and the addition of disintegrants such as AcDiSol and Kollidon CL. Drug release kinetics were estimated by the zero- and first-order, Higuchi release rate, and Korsmeyer-Peppas models. Two formulations of the tablets containing PVP (K10) (10%), CPharmGel (10% and 25%), and Prosolv Easy Tab (44% and 60%) without the addition of a disintegrant were well-fitted to the kinetics models such as the Higuchi and zero-order, which are suitable for controlled- or sustained-release.     

The effect of the particle size of microcrystalline cellulose on tablet properties in mixtures with magnesium stearate

Magnesium stearate was mixed with different sieved fractions (80–180, 180–250, 250–350 μm) of microcrystalline cellulose (Avicel PH 102). The influence of mixing time on crushing strength and disintegration of tablets compressed from these mixtures were studied. The disintegration time increased and the crushing strength decreased with increasing particle size of the Avicel fractions. When magnesium stearate is mixed with table excipients the size of these materials could have an effect on the deterioration of the tablet properties as a function of mixing time.     

Evaluation of drug-excipient interaction in the formulation of celecoxib tablets

In the present study, the possible interactions between celecoxib and some excipients (colloidal silicon dioxide (Aerosil), microcrystalline cellulose (Avicel PH 102), lactose anhydrous, magnesium stearate, cross-povidone and talc) were evaluated by examining the pure drug or drug-excipient powder mixtures which were stored under different conditions (25 +/- 2 degrees C, 60% RH +/- 5% RH or 40 + 2 degrees C, 75% RH +/- 5% RH) and different period (30 or 60 days) using DSC, FT-IR and HPLC. In order to investigate the possibility of celecoxib-excipient interaction in aqueous medium, dispersions of the pure drug or drug in physical powder mixture (1:1 w/w) in water (1%, w/v) were also prepared and evaluated by FT-IR and HPLC at day 0 and day 7 (40 +/- 2 degrees C). The interaction between celecoxib and magnesium stearate or colloidal silicon dioxide were determined in the aqueous dispersions by FT-IR. Different tablet formulations with or without excipients tested were prepared, and assessed for drug dissolution and permeability.     

Influence of wet granulation and lubrication on the powder and tableting properties of codried product of microcrystalline cellulose with beta-cyclodextrin.

The individual influence of wet granulation and lubrication on the powder and tableting properties of codried product of microcrystalline cellulose (MCC) with beta-cyclodextrin (beta-CD) was examined in this study. Avicel PH 101 and 301 were included for comparison. The codried product, Avicel PH 101 and 301 were granulated with water, and the granules were milled to retain three different size fractions: 37-60 microm, 60-150 microm, and 150-420 microm. The original Avicels and codried product were lubricated with magnesium stearate in three different percentages (0.2, 0.5, and 1.0%). The results showed that the powder flowability and disintegration of codried product and Avicels were significantly improved after wet granulation. However, the compactibility of codried product and Avicels decreased with increasing particle size. Nevertheless, the compactibility of the codried excipient after granulation was still better than the non-granulated Avicel PH 101 and 301. On the other hand, codried product and Avicels were sensitive to lubrication and resulted in decreasing compactibility and increasing disintegration. Because of the rounder shape of particles, the codried excipient was more sensitive to magnesium stearate and produced weaker tablets than did Avicels.     

The properties of tablets containing microcrystalline cellulose.

Tablets have been prepared from mixtures of microcrystalline cellulose (Avicel) and spray dried lactose. Tests on these showed that a maximum value of dissolution rate occurred as the percentage of the cellulose increased. This maximum was at 4% w/w for mixtures containing Avicel PH 101 and coincided with the point of maximum liquid penetration rate. With grade PH 105 this maximum was at 2% w/w and corresponded to the optimum balance between the opposing factors of disintegration and liquid penetration rate. Addition of up to 2% w/w magnesium stearate to the formulation containing 4% w/w PH 101 grade had little effect on pore structure, but decreased the dissolution rate by retarding water penetration. Similar concentrations of Carbowax 4000 caused no such decrease.     

The properties of tablets containing microcrystalline cellulose

Tablets have been prepared from mixtures of microcrystalline cellulose (Avicel) and spray dried lactose. Tests on these showed that a maximum value of dissolution rate occurred as the percentage of the cellulose increased. This maximum was at 4% w/w for mixtures containing Avicel PH 101 and coincided with the point of maximum liquid penetration rate. With grade PH 105 this maximum was at 2% w/w and corresponded to the optimum balance between the opposing factors of disintegration and liquid penetration rate. Addition of up to 2% w/w magnesium stearate to the formulation containing 4% w/w PH 101 grade had little effect on pore structure, but decreased the dissolution rate by retarding water penetration. Similar concentrations of Carbowax 4000 caused no such decrease.     

Formulation and release of dihydralazine sulphate from tabletted microcapsules

One of the principal uses suggested for the microencapsulation of pharmaceuticals has been the preparation of the sustained release dosage form. The finished microcapsules have usually been presented in the form of suspensions or gels, but in order to obtain greater sustained release effect a non-disintegrating tablet would be a better formulation. Dihydralazine sulphate (Nepresol) is a dihydralazine-1,4-phthalazine derivative and used as an antihypertensive drug. This work was planned to prepare sustained action preparations of dihydralazine sulphate by microencapsulation and by tabletted microcapsules. Microcapsules were prepared from the microcapsule fractions using biconvex punches with 0.81 cm diameter fitted into a single punch by hand compressor. Avicel PH 101 and lactose were used as disintegrating materials in tablets having 2 kg hardness. Dissolution from both suspended microcapsules and the tablets was studied using the USP XX basket method. A study of in vitro release for both the free and tabletted microcapsules showed basically the same pattern but the time for the release was extended in the case of the tabletted preparations. Dissolution of dihydralazine sulphate was found to be governed by the core: wall ratio, microcapsule size, and the amount and kind of disintegrating agents. Dissolution kinetics were studied and evaluated.     

Developing a study method for producing 400 microm spheroids

The aim of this work was to obtain 400 microm spheroids that can be sprinkled on food to improve patient compliance particularly in the case of children and old people. A methodology to select wet masses for extrusion-spheronization through a 400 microm orifice was developed. The first step was to define the parameters that make it possible to assess the qualities required by the wet mass and the extrudates and evaluation norms: plasticity, cohesiveness, brittleness of the mass and the extrudates, and appearance of extrudates. A feasibility assay was then performed on the cylinder extruder, showing that extrusion of the lactose/Avicel PH 101/water (50/50/60) mass is not feasible through the 400 microm orifice. Precirol ato 5 and Gelucire 50/02 wetted with a sodium lauryl sulfate solution at 0.5% show plastic flow through the 400 microm diameter orifice. The presence of Avicel PH 101 does not improve plasticity for this orifice. Micropellets of 400 microm have been proved feasible as long as excipients with suitable pharmaceutical technological properties are used. After proving the feasibility of 400 microm spheroids of Gelucire 50/02, we considered the association of a drug with it.     

快速崩解茶碱包衣小丸骨架片的研制

用挤出／滚圆法以茶碱主模型药物研制快速崩解包衣小丸骨架片,以Ｅｕｄｒａｇｉｔ ＮＥ３０Ｄ或ＲＬ／ＲＳ３０Ｄ为包衣材料,用底喷式流化床包衣,再压制成骨架片,对包衣材料的种类、压片辅料的组成和用量,压片力等因素进行了考察优化,得到了符合美国药典释放度要求的包衣小丸骨架片。     

Compatibility study between ketoprofen and pharmaceutical excipients used in solid dosage forms

Thermogravimetry/derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC) techniques were used for assessing the compatibility between ketoprofen (KT) and several excipients as: corn starch, microcrystalline cellulose (PH 101 and PH 102), colloidal silicon dioxide, lactose (monohydrate and anhydre), polyvinylpyrrolidone K30, magnesium stearate and talc, commonly used in the pharmaceutical form.In order to investigate the possible interactions between the components, the thermal curves of KT and each selected excipients were compared with those of their 1:1 (w/w) physical mixtures.For KT, the DSC curves have shown a sharp endothermic peak at 96.8 °C which corresponds to the melting process (literature value: 94-97 °C), respectively the TG curves demonstrated a simple stage of mass loss in the temperature range of 235-400 °C.FT-IR spectroscopy and X-ray powder diffraction (XRPD) were used as complementary techniques to adequately implement and assist in interpretation of the DSC results.On the basis of thermal results, a possible interaction was found between the KT with polyvinylpyrrolidone K30 and magnesium stearate, which could influence the stability of the KT in the binary mixtures. These possible incompatibilities were confirmed by FT-IR and X-ray analysis.     

Application of near-infrared spectroscopy for nondestructive analysis of Avicel powders and tablets

The purpose of this study was to use near-infrared spectroscopy (NIRS) as a nondestructive technique to (a) differentiate three Avicel products (microcrystalline cellulose [MCC] PH-101, PH-102, and PH-200) in powdered form and in compressed tablets with and without 0.5% w/w magnesium stearate as a lubricant; (b) determine the magnesium stearate concentrations in the tablets; and (c) measure hardness of tablets compressed at several compression forces. Diffuse reflectance NIR spectra from Avicel powders and tablets (compression forces ranging from 0.2 to 1.2 tons) were collected and distance scores calculated from the second-derivative spectra were used to distinguish the different Avicel products. A multiple linear regression model was generated to determine magnesium stearate concentrations (from 0.25 to 2% w/w), and partial least squares (PLS) models were generated to predict hardness of tablets. The NIRS technique could distinguish between the three different Avicel products, irrespective of lubricant concentration, in both the powdered form and in the compressed tablets because of the differences in the particle size of the Avicel products. The percent error for predicting the lubricant concentration of tablets ranged from 0.2 to 10% w/w. The maximum percent error of prediction of hardness of tablets compressed at the various compression forces was 8.8% for MCC PH-101, 5.3% for MCC PH-102, and 4.6% for MCC PH-200. The NIRS nondestructive technique can be used to predict the Avicel type in both powdered and tablet forms as well as to predict the lubricant concentration and hardness.     

伏立康唑片的制备及其质量评价

目的制备并评价伏立康唑片。方法采用预胶化淀粉、一水乳糖、交联羧甲基纤维素钠、聚维酮、硬脂酸镁制备伏立康唑片,并对其进行薄膜包衣。采用正交设计法确定最佳处方。对其硬度、脆碎度和溶出度进行考察并与市售伏立康唑片比较。结果预胶化淀粉、一水乳糖、交联羧甲基纤维素钠、硬脂酸镁的用量分别为片重的40%,21%,3%和1%,采用5%聚维酮K90水溶液做黏合剂,片芯硬度为15 kg.cm 2,包衣厚度为4%左右时,伏立康唑片的溶出度接近原研产品。结论伏立康唑片的制备工艺简单,重现性好,药物的溶出行为达到预期目的。