Microsoft word - abushammala_nanocon2010_networked-cellulosic

12. - 14. 10. 2010, Olomouc, Czech Republic, EU NETWORKED CELLULOSIC GEL MATERIAL AS A PHARMACEUTICAL EXCIPIENT
a Materials Science and Engineering, Masdar Institute of Science and Technology, Abu Dhabi, UAE P.O. Box 54224, Abu Dhabi, UAE, rhashaikeh@masdar.ac.ae Abstract
Networked cellulosic (NC) material was prepared in a gel form via sulfuric acid dissolution and hydrolysis of microcrystalline cellulose (MCC) and then regeneration in ethanol. The regenerated material was utilized as tablet excipient. Prepared tablets have shown interesting properties regarding hardness. Tablets were prepared via slip casting of formulas mixed with different NC gel concentrations. The hardness of prepared tablets was measured using tablet hardness tester. It was noticed that the hardness of the tablets increased over a wide range and up to 420 N. The hardness was mainly controlled by the concentration of the NC gel material. Despite of their high hardness, prepared tablets have shown full drug release capabilities. The new technique to prepare these tablets can be implemented in a continuous process that minimizes the Keywords: Cellulose, Sulfuric acid, Hydrolysis, Hardness, Drug delivery.
INTRODUCTION
Cellulose is an abundant, sustainable, and biodegradable biopolymer.[1] It exhibits very interesting properties that can be utilized in many applications in addition to extra ones that can be gained by modification and derivation. Therefore, scientists are paying attention to this inexhaustible material. Also pharmacists have been utilizing cellulose in tablets formulation for a long period of time.[2] It is biocompatible cheap material and widely used as filler and binder in the excipient matrix.[3] Tablets are the most popular dosage forms because they can be produced easily and accurately dosed, easily administered by patients, and have good chemical and mechanical stability.[4] But there are many challenges that face tablets production such as formulation difficulty, batch processing problems, and active ingredients sensitivity. Tablets are required to be hard enough to tolerate the stresses to which they are exposed during packaging and transportation. Such requirement can badly affect the main purpose of tablet production, i.e. drug delivery. Tablets have to disintegrate in the place of action to deliver the active ingredients they contain. Preparing tablets with suitable hardness and drug delivery requires the pharmacist to prepare large number of formulas to achieve this target. Also optimized formulas mostly consist of more than one material which raises the problem of product homogeneity. Manufacturing problems, wasted time and effort in addition to the varying quality of the finished product are important concerns in the formulation Tablets are currently prepared using solid-state mixing of active ingredients with excipients such as starch, gelatin, and sugars. Wet or dry granulation is then performed to prepare the mixture for tablet compression using punch machines. This current technology of production of granules is based on batch processing.[5] Batch processing has many disadvantages including the variety of required equipments and batch-to-batch differences.[6] Continuous processing is a promising technology that is used mainly in the food industry. It is expected to be more economical and uses less equipment, labor and utilities.[7] 12. - 14. 10. 2010, Olomouc, Czech Republic, EU Tablets are produced by the compression of active ingredients with some excipients. The compression requires high pressures that may increase the temperature of the formula. Degradation of active ingredients can be a consequence for such thermal stresses which will affect the tablets content and uniformity. Also the related substances produced due to this degradation could be harmful materials for human and environment. Consequently, Temperature-sensitive active ingredients are not producible in the tablet form but in the capsule form or as injection. On the other hand, capsules production is very expensive compared to tablet production and the injections are not preferable to patients. These issues promoted scientists to look for tablet production techniques that do not include any thermal stresses. A work done by Pachulski et al. showed that the casting of formulas of gel material of colloidal silica and binding agents with Paracetamol, without the need for a pressure, can be used to prepare tablets with good properties.[8] Another work done by Hashaikeh et al. showed that cellulose can be hydrolyzed and processed to a gel form of networked cellulose. The properties of the resultant gel are controlled by the hydrolysis process. This gel material was suggested as an interesting material that can be used to continuously fabricate tablets.[9] In this paper we will investigate the preparation of networked cellulose gel material and its utilization in tablets fabrication via slip casting. The proposed method for tablet fabrication promises to produce uniform product that can be prepared easily. The proposed method can facilitate introducing continuous manufacturing into the pharmaceutical industry while maintaining control over the properties of the finished EXPERIMNETAL METHODS
Cellulose Hydrolysis
Microcrystalline Cellulose (MCC) powder was mixed with 70% (w/w) H2SO4 using Varian Dissolution System (VK7010) at 5°C with 250 rpm agitation. The mixing ratio is 1g cellulose for each 10 ml of H2SO4. After 30 minutes, a white material was precipitated by adding equivalent volume of cold ethanol (-17 °C) as anti- solvent. The product was collected and centrifuged at 4ºC three times for 10 minutes at 4700 rpm using Allegra™ 25R Centrifuge. The precipitate was collected again and dialyzed for three days until the pH is almost neutral. The resultant white suspension was weighed then sonicated using Hieschler Ultrasonic Processor UP400S for 30 minutes. After dialysis the yield was calculated by withdrawing a known amount of small sample and obtaining its oven-dried weight. The yield is calculated based on the solid product weight after hydrolysis and drying compared to the starting weight. The yield was 97.1%. NC suspensions, with different concentrations, were prepared either by drying or diluting to a given weight. Placebo Tablets Preparation
Placebo tablets were prepared by mixing 75g of each of the previously prepared NC suspensions with 15g of MCC. The concentration of the NC suspensions were 2.00%, 4.72%, 6.25%, 8.02%, 9.20%, and 11.66%. The formulas were slip-casted and left to dry for one day. 12. - 14. 10. 2010, Olomouc, Czech Republic, EU Paracetamol Tablets Preparation
Paracetamol tablets were prepared by mixing 75g of 2% NC suspension with 12.6g of MCC and 2.4g of Paracetamol. The formulas were slip-casted and left to dry for one day. The tablets were prepared in order to Evaluation of Tablets
The hardness of the prepared tablets was measured as per USP XXIV monograph for uncoated tablets using Dr.Schleunger® Pharmaton 8M Tablet Tester. Friability testing was conducted by Erweka® TA220 as per USP XXIV monograph. As per USP XXIV monograph, twenty tablets were weighed individually to For content uniformity, the tablets were powdered and 30mg equivalent weight of Paracetamol was transferred into a 250mL volumetric flask. 200mL of water was added to the flask and sonicated for 5 minutes and then completed up to volume with water. 10mL of the stock solution was transferred into a 50mL volumetric flask and completed up to volume by water. A portion was filtered using 0.2µm PTFE filter. The absorbance of the filtrate was measured at 243nm using Thermo UV spectrophotometer with a cell length of 1.0cm. The Paracetamol content was measured against standard with the same final concentration. Paracetamol tablet release was studied using Varian VK7010 Dissolution System connected to Cary 50 Bio UV-Visible Spectrophotometer by Fiber Optics Cords. The release was measured in 900mL of water at 37.0°C using paddle agitation of 50rpm. The absorbance of the medium was measured directly from the vessel at different time intervals at 243nm using cell length of 1.0cm. Accordingly, the percentage Paracetamol release was measured against standard with a concentration of 0.033mg/mL. The test was RESULTS AND DISCUSSION
Previous work done by the authors [refer to the paper in carbohydrate polymers] the conditions for networked cellulose (NC) production were optimized to produce the NC material in a high yield. Also the NC suspension was characterized using X-ray diffraction, transmission electron microscopy, thermogravemetric analysis, and nanoindentation. The material showed a network behavior and the cellulose crystallinity changed from cellulose I to the more stable cellulose II. It is believed that cellulose II crystals are the joinings of amorphous network of randomly distributed fibers.[9] Fig. 1. shows the hardness – concentration curve for the prepared placebo tablets. It is noticed that the hardness of the placebo tablets increased over a wide range and up to 420N, which is a high value for a cellulosic material. Also the hardness was mainly controlled by the concentration of the NC suspension. Such characteristics make the properties of the finished product easily controlled. The curve exhibits a plateau at 420N since it is the maximum limit for the tablet tester. Tablets prepared by mixing MCC with water disintegrated directly during the drying process. 12. - 14. 10. 2010, Olomouc, Czech Republic, EU This behavior shows the significance of introducing the NC particles in the tablet formula. Also the tablets showed shrinkage in volume that depended on the concentration of the used NC suspension. Using the 11.66% NC suspension, the resultant tablets’ average diameter was 7.7mm compared to 10.8mm for the tablets produced using the 2.00% NC The high hardness values, which can achieved by low concentrations, is the reason behind introducing MCC in the formula. MCC can dilute the tablets to enhance their size and weight in one hand. In the Fig. 1. Hardness curve for the placebo tablets.
other hand, it can decrease the hardness of the tablets to suit some drug deliveries. MCC is already used as diluent in pharmaceuticals. Furthermore, it has some lubricant and disintegrant properties that make it useful for tablet production. The hardness of the Paracetamol tablets showed an increase in the hardness values. The tablets showed an average hardness of 58N, which is 31N higher that for the placebo tablets. This change, due to the replacement of some of MCC by Paracetamol, obtained hardness values that can be explained by looking at the diameter difference between the two tablets formulas. Paracetamol tablet’s diameter reduced to 9.6mm compared to 10.8mm for the placebo tablet. This reduction in diameter increased the density of fibers network and consequently increased the hardness of Paracetamol tablets. A friability test was conducted on Paracetamol tablets. The weight loss percent was significantly less than 1%. Mass variation and content uniformity are very important to evaluate the efficiency of the production technique. The average weight of twenty Paracetamol tablets was 178.2mg and the RSD was 1.5%. The average measured content of ten Paracetamol tablets was 99.8% and the RSD was 0.56%. The very small RSD values of mass variation and content uniformity prove the high homogeneity of the tablets produced by slip casting. The RSD values are not easily achieved by the current tablets production technology especially with low label claims like the one we Fig. 2. shows the dissolution profile for the 30mg Paracetamol tablets. Despite of their hardness, Paracetamol tablets showed a full and gradual drug release in six hours. This delivery rate can be important for many active ingredients where there is a need for gradual release over a long period of time. Also we can notice the precise data we got from the six tablets. This is another proof for the Fig. 2. Dissolution profile for Paracetamol tablets.
excellent homogeneity of the finished product. 12. - 14. 10. 2010, Olomouc, Czech Republic, EU It is expected to have different drug release profiles for different NC suspensions since the hardness significantly varies with concentration. Furthermore, changing the mixing ratio can vary the drug release. For example, introducing more MCC in the tablet formula can increase the release rate and make it more suitable for immediate delivery systems. As conclusion, the drug release can be controlled over a wide range of time by changing the concentration of the used NC suspension and the ratio of MCC in the formula. CONCLUSION
NC gel material was prepared via sulfuric acid dissolution and hydrolysis of MCC and then regeneration in ethanol. Tablets, prepared using this gel as an excipient, have shown interesting hardness values. Tablets were prepared via slip casting of MCC mixed with different NC gel concentrations. It was noticed that the hardness of the tablets increased over a wide range and was mainly controlled by the concentration of the NC gel. Despite of their high hardness, prepared tablets have shown full drug release capabilities that can be suitable for different active ingredients. The precise content, uniformity, and mass variation values proved the slip casting of gel formulas as a useful technique for the production of homogeneous tablets. REFERENCES
Li, L., et al. A novel cellulose hydrogel prepared from its ionic liquid solution. Chinese Science Bulletin, 2009, year 54, nr. 38, page 1622. Kamel, S., et al. Pharmaceutical significance of cellulose: A review. Express Polymer Letters, 2008, year 2, nr. 85, page 758. Rowe, R., Sheskey, P., Weller, P. Handbook of pharmaceutical excipients. 6. ed. Pharmaceutical press London, UK, 2003. 136 p. Joshi, A., Duriez, X. Added functionality excipients: an answer to challenging formulations. Pharmaceutical Technology, 2004, year nr. 79, page 12. Rudnic, E., Schwartz, J. Oral Solid Dosage Forms, Remington: The Science and Practice of Pharmacy. 21st. ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005. 892 p. Leuenberger, H. New trends in the production of pharmaceutical granules: batch versus continuous processing. European journal of pharmaceutics and biopharmaceutics, 2001, year 52, nr. 5, page 289. Pellek, A., Arnum, P. Continuous Processing: Moving with or against the Manufacturing Flow. Pharm. Technol, 2008, year 9, nr. 74, page 52. Pachulski, N., Ulrich, J. Production of Tablet-Like Solid Bodies Without Pressure by Sol-Gel Processes. Letters in Drug Design & Discovery, 2007, year 4, nr. 80, page 78. Hashaikeh, R., Abushammala, H. Acid Mediated Networked Cellulose: Preparation and Characterization. Carbohydrate Polymers, 2010, year.

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