The evaluation of modified microcrystalline cellulose for the preparation of pellets with high drug loading by extrusion/spheronization

The performance of microcrystalline cellulose (MCC) which had been modified by the inclusion of various levels of sodium carboxymethylcellulose (SCMC) in the wet cake prior to drying, in terms of their ability to form pellets by a standardised extrusion/spheronization process has been assessed. Initial screening of the ability of the modified MCCs to form pellets with an 80% level of lactose as a model drug identified two potential products containing 6 or 8% of SCMC (B 6 and B 8). These two products were compared with a standard grade of MCC (Avicel PH101) in terms of their ability to produce pellets with 80% of model drugs of low (ibuprofen), intermediate (lactose) and high (ascorbic acid) water solubility when subjected to a standardised extrusion/spheronization process. Also assessed was their ability to retain water with applied pressure using a pressure membrane technique and their ability to restrict water migration during extrusion with a ram extruder. The two new types of MCC (B 6 and B 8) were able to form good quality pellets with all three model drugs, whereas Avicel PH101 could not form pellets with this high level of ibuprofen. This improved performance was related to the ability of the new types of MCC to hold higher levels of water within their structure and restrict the migration of water in the wet mass when subjected to pressure applied during the process of preparing the pellets. There is evidence to show that the two new types of MCC can function over a wider range of water contents than Avicel PH101 and that they have an improved performance if the extrusion process is rapid and if, after incorporation of the water into the powder, the sample is stored for some time before extrusion.     

Pharmaceutical applications of size reduced grades of surfactant co-processed microcrystalline cellulose

New grades of ultra-fine microcrystalline cellulose (MCC), without (grade X) or with variable percentage sodium lauryl sulphate (SLS; grades Y), were prepared by an ultrasonic homogenisation process from Avicel® PH-101 (grade C), prior to recovery by spray-drying. Both new grade types were found to be inferior compared with grade C in a tableting application for paracetamol, resulting largely from poor flow of the feed material. However, both new grades proved superior to grade C in an aqueous extrusion/spheronisation application for the preparation of indomethacin pellets, producing smoother pellets in greater yield. Grade Y was particularly effective at delaying drug dissolution, due mainly to decreased porosity in the pellets formed and retardation of their break-up.     

Improved bioavailability of darunavir by use of κ-carrageenan versus microcrystalline cellulose as pelletisation aid

The aim of this study was to produce pellet formulations containing a high drug load (80%) of the poorly soluble HIV-protease inhibitor darunavir, using wet extrusion/spheronisation with κ-carrageenan or microcrystalline cellulose (MCC) as pelletisation aid. Drug release was assessed in vitro by a standardized paddle-dissolution test and in vivo by a single-dose pharmacokinetic study in dogs. Mean dissolution time (MDT) was 78.2 ± 3.5 h from MCC pellets (1301 ± 301 μm) and 6.1 ± 0.7 min from κ-carrageenan pellets (966 ± 136 μm). In contrast to κ-carrageenan pellets, MCC pellets did not disintegrate and showed a diffusion-controlled drug release. In line with the in vitro findings, the darunavir peak plasma levels and exposure after the administration of a 300 mg dose were more than 60-fold higher when formulated with κ-carrageenan pellets when compared with MCC pellets, and 10-fold higher after co-administration with 10 mg/kg of ritonavir. The relative bioavailability of darunavir versus the reference tablet (F_rel) was 155% with κ-carrageenan pellets and 2% with MCC pellets without ritonavir, while 78% and 9%, respectively, in presence of ritonavir. In conclusion, when compared with MCC pellets, the bioavailability of darunavir was substantially improved in κ-carrageenan pellets, likely due to their better disintegration behavior.     

Use of fine particle ethylcellulose as the diluent in the production of pellets by extrusion-spheronization

The effect of small ethylcellulose particle size on the manufacture and properties of pellets produced by extrusion-spheronization was investigated. A factorial design revealed the effects of microcrystalline cellulose (MCC), polyethylene oxide (PEO), water, and spheronization speed and time on pellet properties. Response surface modeling allowed optimization of the responses with expansion to a central composite design. Pellet yield, size, shape, friability and drug release profile were studied, along with surface and interior morphology. Pellets were spherical irrespective of the formulation and process variables and exhibited physical and mechanical characteristics appropriate for further processing. Yield in the 12/20 mesh cut was lower with FPEC than observed with coarse particle ethylcellulose (CPEC), but FPEC-containing pellets were more rugged and the PEO to obtain optimal pellets was lower for FPEC compared to CPEC. Immediate release products were obtained and ethylcellulose particle size was of no consequence to drug release. Observed responses for the optimized product agreed with predicted values, demonstrating the success of the optimization procedure. These results suggest that FPEC is a good diluent for extrusion-spheronization.     

Drug release from MCC- and carrageenan-based pellets: Experiment and theory

Microcrystalline cellulose (MCC) is a well-established pelletisation aid. However, MCC pellets generally do not disintegrate, resulting in prolonged drug release, especially in the case of drugs with poor/low aqueous solubility. The major objectives of this study were (i) to modify the prolonged matrix-type drug release from MCC pellets by addition of a disintegrant (croscarmellose Na) or pore former (PEG 6000), (ii) to evaluate carrageenan as potential alternative pelletisation aid for manufacturing high-dose immediate release pellets, and (iii) to better understand the underlying drug release mechanisms. Pellets containing 77–90% drug with poor/low aqueous solubility (vatalanib succinate, SAG/ZK, or theophylline) were prepared by extrusion–spheronisation. All batches showed acceptable yields, aspect ratios, tensile strengths, and porosities. Drug release from MCC pellets was predominantly controlled by pure diffusion and limited drug solubility and could be quantitatively described using Fick’s law. Importantly, the apparent drug diffusivity could effectively be adjusted by adding small amounts of a disintegrant or pore former, allowing for release periods ranging from a few minutes to several hours. The drug diffusion coefficients varied between 0.36 and 29 × 10⁻⁶ cm²/s. In contrast, carrageenan-based pellets very rapidly disintegrated upon contact with aqueous media and released high doses of drugs with poor/low aqueous solubility within a few minutes.     

Supercritical fluid impregnation of microcrystalline cellulose derived from the agricultural waste with ibuprofen

The present study was aimed to investigate the feasibility of loading microcrystalline cellulose derived from the agricultural waste with poorly water-soluble drug by using supercritical carbon dioxide as impregnation medium. Operating parameters of supercritical impregnation process (pressure, temperature and time) were varied to in order to maximize loading of ibuprofen used as a model drug into microcrystalline cellulose. The efficiency of ibuprofen loading using supercritical impregnation and release kinetics studies of microcrystalline cellulose in two pharmaceutical forms, powder and tablets, were investigated.The highest amount of ibuprofen was impregnated in microcrystalline cellulose powder by using supercritical impregnation at 25 MPa and 40 °C for 24 h (9.43%). Increasing pressure in the range of 10 MPa–25 MPa and time from 2 h to 24 h favours loading of ibuprofen into microcrystalline cellulose. A higher loading efficiency at the same impregnation conditions was observed for powdered microcrystalline cellulose. Temperature change in range of 40–60 °C had negligible influence on loading efficiency. FT-IR spectroscopy analysis showed no evidence of chemical modification of microcrystalline cellulose after processing. In vitro drug release study showed that impregnated powder formulations released the total amount of ibuprofen immediately, while the impregnation of microcrystalline cellulose powder in the form of tablets led to the achievement of the sustained release profile.     

A statistical design to evaluate the influence of manufacturing factors on the material properties and functionalities of microcrystalline cellulose

The aim of this study is to statistically evaluate the effects of manufacturing factors on the material properties and functionalities of microcrystalline cellulose (MCC) products. How the material properties of MCC products dominate their functionalities was further explored. Results demonstrate that the desired material properties and functionalities of MCC products can be obtained by manipulation of the manufacturing factors using proper polynomial equations, and the key manufacturing factor is temperature. On the other hand, the functionalities can be quantitatively predicted by material properties. Meanwhile, the key material property is molecular mass in controlling MCC functionalities. The particle morphologies may also serve as important material properties. In conclusion, the careful control of temperature during the manufacture of MCC might minimize inter-batch variation. The correlation of the material properties of MCC products with their functionalities might help the formulation designer rationally select proper MCC products. The universal harmonization of MCC products might be achieved by the regulation of their molecular mass, surface roughness, and roundness.     

A comparison of ram extrusion by single-holed and multi-holed dies for extrusion-spheronisation of microcrystalline-based pastes

The use of multi-holed dies as an alternative to single-holed dies for generating extrudates for spheronisation was investigated both in terms of extrusion and spheronisation performance. A model 45 wt% microcrystalline cellulose (MCC)/water paste was employed in ram extrusion tests with square-ended dies with 1, 6, 33 and 137 holes, all of diameter 1 mm and length 2 mm. The extrudates generated using the multi-holed dies yielded pellets with comparable sphericity to those using the single-holed die. Multi-holed dies could also be operated with lower paste flow rates before encountering liquid phase migration (LPM). The characteristic processing velocity for the onset of LPM was determined for each die configuration and supported the hypothesis that LPM was caused by suction effects. A simple model of the flow pattern in a lab-scale Fuji-Paudal frontal screen extruder is presented which yields estimates of velocities and shear rates involved in these devices. The pressure required to extrude the paste through multi-holed dies was compared with the model proposed by Benbow and co-workers. The paste rheology was characterised using the Benbow-Bridgwater approach, employing 1, 2 and 3 mm diameter dies of various lengths. The Benbow et al. model under-predicted the observed extrusion pressure, which was attributed to its failure to account for the redundant work contribution in these complex flows.     

An evaluation of microcrystalline cellulose and lactose excipients using an instrumented single station tablet press

The objective of this study was to evaluate the effects of microcrystalline cellulose of two particle sizes from two suppliers at two concentration levels, in combination with anhydrous lactose or Fast-Flo lactose on various properties of hydrochlorothiazide tablets. The powder blends before compression were evaluated for flow, density and compressibility. Tablets were compressed at three hardnesses and evaluated for friability, disintegration and hydrochlorothiazide dissolution. Powder blends containing Fast-Flo lactose exhibited a flow rate predicted to be sufficient for high-speed tableting whereas only when anhydrous lactose was used with the larger particle size microcrystalline cellulose was the same degree of flowability obtained. Density was affected by the concentration of microcrystalline cellulose. Fast-Flo lactose markedly increased density at the lower level of microcrystalline cellulose concentration. No difference was found in blend compressibility as a result of microcrystalline cellulose particle size or supplier source at medium to high tablet hardness levels, however, anhydrous lactose blends were more compressible than Fast-Flo lactose blends. At all hardness levels, tablets from all blends exhibited excellent friability. In most instances, tablet disintegration seemed to be more rapid when Fast-Flo lactose was present. Hydrochlorothiazide dissolution from all tablets easily met USP specifications. The microcrystalline cellulose from the two sources are interchangeable within particle size classification. Anhydrous lactose is more compressible than Fast-Flo lactose but Fast-Flo lactose is more flowable and its use results in more rapid drug dissolution at the higher microcrystalline cellulose levels.     

Tableting properties of microcrystalline cellulose obtained from wheat straw measured with a single punch bench top tablet press

The objective of this work was to study the relation between the manufacturing conditions of microcrystalline cellulose (MCC), its physicochemical properties and its tableting behavior. Two different preparation procedures were used to produce MCC from wheat straw, utilizing an acid hydrolysis method, either using only sulfuric acid or combination of sulfuric and hydrochloric acid. The tableting behavior of obtained MCC samples and mixtures of MCC with ibuprofen was studied using a dynamic powder compaction analyzer. It was observed that some of the obtained MCC samples showed better flowing properties than commercially available Vivapur® PH101 and also very high values of tensile strength, solid fraction and elastic recovery. This can be linked with its good compaction behavior, but on the other hand it can cause problems with the disintegration of the tablets. In mixtures with ibuprofen, MCC samples showed lower values of tensile strength, while on the other hand elastic recovery did not seem to be much affected, still exhibiting very high values. According to the obtained results, it can be concluded that MCC obtained from the agricultural waste could have satisfactory properties for tablet preparation by the direct compression method. Further studies are needed to optimize process conditions in order to achieve better physicochemical characteristics, especially in terms of elastic recovery.     

Optimization and evaluation of Lisinopril mucoadhesive sustained release matrix pellets: In-vitro and ex-vivo studies

Lisinopril (LIS) is antihypertensive drug, classified as a class III drug with high water solubility and low permeability. To overcome the low permeability, 3² factorial designs aimed to formulate LIS as a sustained-release (LIS-SR) matrix pellet by extrusion/spheronization. Matrix pellets were composed of wet mass containing Avicel® and polymeric matrix polymers (sodium alginate (SA) and chitosan (CS)). Evaluation of the effect of two independent variables, matrix-forming units (SA and CS) on mean line torque, on pellet size, dissolution rate after 6 h, and mucoadhesion strength of the pellets were assessed using Statgraphics software. The tested formulations (F1-F9) showed that mean line torque ranged from 1.583 to 0.461 Nm, with LIS content in the LIS-SR pellets ranged from 87.9 to 103%, sizes varied from 1906 to 1404 µm and high percentages of drug released from pellets formulations (68.48 to 74.18 %), while the mean zeta potential value of mucoadhesive range from −17.5 to –22.9 mV.The selection of optimized formulation must have the following desirability: maximum peak torque, maximum pellets’ particle size, and minimum % LIS release after 6hr. LIS optimized sustained release pellet formula composed of 2,159 % SA and 0.357 % CS was chosen as optimized formula. It’s showed a 1.055 Nm mean line torque was responsible for the increased pellet size to 1830.8 μm with decreased release rate 56.2 % after 6 hr, and −20.33 mV average mucin zeta potential.Ex-vivo mucoadhesion studies revealed that that the optimize formulation, exhibited excellent mucoadhesive properties, after 1 h, about 73% of the pellets were still attached to the mucus membrane. Additionally, ex-vivo permeation determination of LIS from the optimized LIS-SR formulation was found to be significantly higher (1.7-folds) as compared to free LIS.In conclusion: LIS-SR matrix pellets, prepared with an extrusion/spheronization have desirable excellent characteristics in-vitro and ex-vivo sustained-release pellet formulation of LIS-SR was able to sustain the release of LIS for up to 8 h.     

Alginate-based pellets prepared by extrusion/spheronization: Effect of the amount and type of sodium alginate and calcium salts

Pellets containing microcrystalline cellulose (MCC), a model drug (theophylline) and a range of levels of sodium alginate (i.e., 10–50% w/w) were prepared by extrusion/spheronization. Two types of sodium alginate were evaluated with and without the addition of either calcium acetate or calcium carbonate (0, 0.3, 3 and 10% w/w). The effects of amount and type of sodium alginate and calcium salts on pellet properties, e.g., size, shape, morphology and drug release behavior, were investigated. Most pellet formulations resulted in pellets of a sufficient quality with respect to size, size distribution and shape. The results showed that the amounts of sodium alginate and calcium salts influenced the size and shape of the obtained pellets. However, different types of sodium alginate and calcium salt responded to modifications to a different extent. A cavity was observed in the pellet structure, as seen in the scanning electron micrographs, resulting from the forces involved in the spheronization process. Most of pellet formulations released about 75–85% drug within 60 min. Incorporation of calcium salts in the pellet formulations altered the drug release, depending on the solubility of the calcium salts used. The drug release data showed a good fit into both Higuchi and Korsmeyer–Peppas equations.     

Investigate the effect of solvents on wet granulation of microcrystalline cellulose using hydroxypropyl methylcellulose as a binder and evaluation of rheological and thermal characteristics of granules

Wet granulation is the most commonly used technique in the pharmaceutical industry for delivering oral solid dosage forms. In wet granulation, the binder solvent is one of the critical factors affecting granule properties. In the current study, an attempt was made to investigate the effect of solvents (aqueous and hydro-alcoholic) on thermal and flow properties of Microcrystalline Cellulose (MCC) granules prepared using two different grades of Hydroxypropyl Methylcellulose (HPMC), which served as an effective binder. The granulation endpoint was evaluated using thermal effusivity sensor. Rheometer and Modulated Differential Scanning Calorimetry (mDSC) was used to study the flow and thermal properties of wet and dried granules. Furthermore, physical characterization was carried out by granule strength, particle size distribution and tablet hardness for all granules under the study. Thermal effusivity sensor results indicate 55% w/w concentration of binder solution as the endpoint by measuring thermal effusivity for both binders. Additionally, powder rheometer results show that the wet granules of hydro-alcoholic batches show greater resistance to flow whereas the dried granules display excellent flow characteristics as evident from Basic flowability energy values and specific energy values. Permeability results suggest that the granules formed with hydro-alcoholic binder solvent exhibit better porosity and permeability. Tablet hardness data showed that tablets formulated using hydro-alcoholic solvent granules have greater hardness than tablets formulated using water based solvent granules. The granule strength for water based granules is relatively higher than that of hydro-alcoholic based granules. mDSC thermograms show a sharp rise in enthalpy value at 55% w/w binder solution which is indicative of a more significant amount of solvent being present on the surface of granules and formation of optimal granules. To summarize, we have determined a technique to measure endpoint determination and simultaneously investigate the role of solvent systems on the rheology of MCC granules, which could assist in selecting an appropriate solvent system for granulation.     

New insights on how to adjust the release profile from coated pellets by varying the molecular weight of ethyl cellulose in the coating film

The major aims of this work were to study the effect of the molecular weight (Mw) of ethyl cellulose (EC) on the drug release profile from metoprolol succinate pellets coated with films comprising EC and hydroxypropyl cellulose (HPC) with a weight ratio of 70:30, and to understand the mechanisms behind the different release profiles. A broad range of Mws was used, and the kinetics of drug release and HPC leaching followed. The higher the Mw of EC, the slower the HPC leaching and the drug release processes. Drug release occurred by diffusion through the pores created in the coating by the HPC leaching. A novel method was used to explain the differences in the release profiles: the effective diffusion coefficient (D_e) of the drug in the coating film was determined using a mechanistic model and compared to the amount of HPC leached. A linear dependence was found between D_e and the amount of HPC leached and, importantly, the value of the proportionality constant decreased with increasing Mw of EC. This suggests that the Mw of EC affects the drug release profile by affecting the phase separated microstructure of the coating and the hindrance it imparts to drug diffusion.     

Compression force/time-profiles of microcrystalline cellulose, dicalcium phosphate dihydrate and their binary mixtures-a critical consideration of experimental parameters

Compression force/time-profiles of microcrystalline cellulose and dicalcium phosphate dihydrate and mixtures thereof were compared on a modern rotary press by three different methods of compression: compression to a constant tablet weight, compression to a constant tablet height and compression from a constant filling depth. Compression was carried out at three different compression force levels. The differences obtained by analysing the area under the curve in the compression, dwell and decompression phase could be explained by differences of the in-die working density of the powders and their respective compression behaviour. From data of the compression phase as well as from the area-quotient-index obtained from the dwell time it was possible to estimate the percolation threshold of dicalcium phosphate dihydrate in a mixture with microcrystalline cellulose to ˜ 50% (w/w) corresponding to 30% (v/v).     

A new self-emulsifying drug delivery system (SEDDS) for poorly soluble drugs: Characterization, dissolution, in vitro digestion and incorporation into solid pellets

The aim of the current study was the development of a new pellet based self-emulsifying (SE) drug delivery system for the oral delivery of poorly soluble drugs. Furthermore, we wanted to investigate the influence of physiological dilution media and enzymatic digestion on the solubilization capacity of the formulation for the model drug Progesterone.Lipid mixtures composed of Solutol^® HS 15 and medium chain glycerides were optimized with respect to their self-emulsifying properties. The liquid SE lipid was mixed with microcrystalline cellulose and transformed into pellets by extrusion/spheronization. The pellets were characterized for size, shape, surface characteristics and friability. In vitro dissolution and digestion experiments were carried out using physiological dissolution media.The droplet diameter of the dispersed SE mixtures was largely affected by changing the oil to Solutol^® HS 15 ratio. Moreover, digestion of SE mixtures changed the solubilization capacity for Progesterone. Pellets with good properties (size, shape and friability) have been produced through the incorporation of a selected SE mixture into MCC.In conclusion, extrusion/spheronization is a suitable process to produce solid self-emulsifying pellets with up to 40% load of a liquid SE mixture. Digestion induces a change in lipid composition which affects the solubilization capacity of the lipid phase.     

Combining experimental design and orthogonal projections to latent structures to study the influence of microcrystalline cellulose properties on roll compaction

Roll compaction is gaining importance in pharmaceutical industry for the dry granulation of heat or moisture sensitive powder blends with poor flowing properties prior to tabletting. We studied the influence of microcrystalline cellulose (MCC) properties on the roll compaction process and the consecutive steps in tablet manufacturing. Four dissimilar MCC grades, selected by subjecting their physical characteristics to principal components analysis, and three speed ratios, i.e. the ratio of the feed screw speed and the roll speed of the roll compactor, were included in a full factorial design. Orthogonal projection to latent structures was then used to model the properties of the resulting roll compacted products (ribbons, granules and tablets) as a function of the physical MCC properties and the speed ratio. This modified version of partial least squares regression separates variation in the design correlated to the considered response from the variation orthogonal to that response. The contributions of the MCC properties and the speed ratio to the predictive and orthogonal components of the models were used to evaluate the effect of the design variation. The models indicated that several MCC properties, e.g. bulk density and compressibility, affected all granule and tablet properties, but only one studied ribbon property: porosity. After roll compaction, Ceolus KG 1000 resulted in tablets with obvious higher tensile strength and lower disintegration time compared to the other MCC grades. This study confirmed that the particle size increase caused by roll compaction is highly responsible for the tensile strength decrease of the tablets.     

利用海带渣制备药用辅料微晶纤维素的研究

目的为了高效利用海洋生物资源,降低环境污染,以海带加工废弃海带渣为原料制备药用辅料微晶纤维素。方法利用海带渣纤维素与HCl进行水解反应制备微晶纤维素,并研究反应时间对微晶纤维素制备的影响。利用扫描电子显微镜观察微晶纤维素的形貌,利用X射线衍射仪分析微晶纤维素的物相组成的表征。测定产品和市售样品的溶胀性,并将产品和市售样品以阿司匹林为主药进行压片,按照中国药典的规定对其进行硬度、崩解度、溶出度对比考察。结果在酸料比为1∶10,,盐酸浓度为2mol.L-1,水解温度为100℃的条件下,最佳水解时间为40min。海带渣微晶纤维素呈不规则的颗粒状,结晶度为79%,晶粒尺寸为3.9nm。与市售样品相比较,产品压片后崩解时限短、溶出速度快。结论以海带渣为原料用于药用辅料微晶纤维素的制备是可行的,所制备的微晶纤维素性能良好。     

浒苔微晶纤维素的制备及其在药用辅料中的应用

目的 浒苔是一种常见的多细胞绿藻,属于石莼科,是绿潮的主要组成物质,为了更好的利用浒苔资源,缓解绿潮带来的生态问题,本文利用浒苔为原料制备微晶纤维素,并探究其作为辅料进行压片的优势。方法 以浒苔为原料制备微晶纤维素并检测其外观,官能团与电导率等理化性质,再以微晶纤维素作辅料以阿司匹林作为主药进行压片,并对其质量进行检查。结果 微晶纤维素的理化指标均符合《中国药典》2020年版规定,且与市售微晶纤维素具有相同或相似官能团结构;以微晶纤维素作辅料制备的片剂色泽均匀,具有适宜的硬度与耐磨性。