Formulation Development of Directly Compressed Orally Disintegrating Tablets - Term Paper Example

Proposal Tittle: FОRMULАTIОN DЕVЕLОРMЕNT ОF DIRЕСTLY СОMРRЕSSЕD ОRАLLY DISINTЕGRАTING TАBLЕTS - RОLЕ ОF DISINTЕGRАNTS Name: Institution: 1. Proposal Summary The aim of this project will be to investigate the effect of various factors that influence the formulation of directly compressed orally disintegrating tablets (ODTs), particularly the type and concentration of disintegrants. Three types of disintegrants will be used, namely: sodium starch glycolate, croscarmellose sodium and crospovidone. The project mainly focuses on the study of different processes and excipients related parameters that influence the formation of clopidogrel as an ODT. Manufacture of clopidogrel by compression method has been proposed for various fractions of disintegrant using ten tablet formulas. The three types of disintegrants and variation of concentration of these disintegrants in the total composition of the tablets to be prepared will enable us investigate how the type and concentration of disintegrant affect the physical properties and intended action of the ODT tablets. The key evaluations that will be carried out in the analysis of the tablet prepared include: the manufacture process of tablet, particle size determination and particle distribution, hardness testing, drug dissolution and disintegration, as well as disintegration time analysis. Particle size and distribution will be determined using a laser particle counter and sieve analysis methods. A USP disintegration and dissolution apparatus will be used in the evaluation of disintegration time and dissolution of the clopidogrel tablet samples that will be prepared. 2.0 Background General Context Oral solid dosage drug delivery remains the most common route for administering drugs to patients because of ease of administration, pain evasion, self-medication, accurate dosage and patient compliance. Traditional capsules and tablets have been found to be inconvenient for some geriatric patients due to changes in different neurological and physiological conditions that are linked with ageing, swallowing difficulties, weakening of eyesight, memory and hearing problems, risk of chocking and many others (Desai, et al., 2016). ODTs have emerged to be one of the novel oral solid dosage forms with ability to deliver numerous drug candidates to both geriatric and pediatric patient populations, mentally retarded, children, nauseated, and uncooperative patient groups. They are designed to readily dissolve in the mouth without requiring water, and because of their convenience, ODTs have been gaining popularity as one of the most preferred oral dosage forms that are user friendly. ODTs combine the advantage of both conventional and liquid formulations that allow for easy administration in the form of a liquid dosage. Solid ODT doses provide improved storage, dose accuracy and stability advantages compared to liquid preparations (McLaughlin, et al., 2009). Compression of excipients is one of the most translatable and cost-effective methodology used for the manufacture of ODTs. Disintegrants, diluents and sweetening agents are used in the formulation of the tablets. Disintegrants are agents that are added to oral tablet formulations to improve the breakup of the tablets into smaller particles to increase their surface area in an aqueous environment and promote the rate of drug substance release rate (Carter, 2009). The active constituents in ODT must be released efficiently for rapid action as the therapeutic action depends on the amount of drug released. In most conventional and novel ODT preparation methods, the impact of disintegrants provide a new dosage form like mouth dissolving tablets or rapid disintegrating tablets. Therefore, the choice of type of disintegrants has a greater impact on the formulation of ODTs to enhance the drug’s bio-availability (Tanuwijaya & Karsono, 2013). Previous Scientific Literature ODT products were developed by pharmaceutical manufacturers in an effort to provide a more convenient drug product to address issues related to patient non-compliance and product indications for certain patient populations (Ghosh & Pfister, 2005). The first ODT drug was provided by the Zedis lyophilization technology and was approved by the U.S Food and Drug Administration in 1996. Development of ODTs provided a new and convenient method of drug delivery to a broad range of patients with problems of drug compliance. According to Mahrous, et al., (2016) a prevous study in which a solid dispersion of clopidogrel was formulated into fast dissolving tablets, it was found that such formulations were characterized by reduced palatability as a result of rapid dissolution on tongue. The type and concentration of disintegrants in ODTs have significant effect on the mechanical integrity of the tablets developed. Bad taste was one hurdle to the development of ODTs because as the tablet quickly disintegrates and intensifies the bad taste in the mouth. This leaves a patient with a disagreeable taste feeling. However, today different taste-adding strategies have been employed to tackle the problem, such as cyclodextrins molecular inclusion and encapsulation. Another failure in in the early development of ODTs was to formulate tablets with a short disintegration time times upon placing in the mouth (Desai, et al., 2014). One of the most important pre-requisites for oral tablets is achieving the shortest disintegration time. During the early developments, ODTs did not achieve disintegration at an optimum speed. Most patients have the best sensation when the drug disintegrates quickly and last between 30-45 seconds. With recent advancements, ODTs can disintegrate as fast as 5 seconds after coming into contact with saliva. The tablet size was approximately also high 500 g. The variation in disintegration times and tablet size were attributed to the emergence of several ODT formulation and manufacturing technologies (Patil & Das, 2011). Recent Literature and Current developments Recent developments in novel ODT delivery system focus on improving the efficacy and safety of the drug molecule through formulation of a dosage form that is convenient for administration to all patients. Dysphagia (difficulty in swallowing) is experienced by pediatric, geriatric, disabled, mentally ill, bedridden, travelling patients, as well as patients with sudden allergy attacks and motion sickness. These leads to increased incidences of drug noncompliance, and non-effective therapy. In order to improve life quality and drug compliance of these patients, fast dissolving tablet dosage form requires substances that can disintegrate rapidly within few seconds after placing upon tongue, without need for water to facilitate swallowing (Mittapalli, et al., 2010). Researchers are developing new disintegrating agents that can disintegrate a tablet at a crushing strength of more than 3.5 Kg (Arnum, 2007). Khinchi, et al., (2011) carried out a study to formulate ODTs of Famotidine by direct compression technique. with better mechanical integrity and faster disintegration in the cavity. To achieve this, excipient base was spray dried and used for formulation of ODTs. There were attempts to improve the rate of dissolution and faster disintegration by use of superdisintegrants, such as Ac-Di-Sol, Crospovidone and sodium starch glycolate in the fomulation of tablets. Famotidine, a H2 receptor antagonist, was used as a model drug in the study. The model drug was analyzed using different physicochemical, organoleptic and spectrophotometric methods. It was found that Famotidine possessed the same taste, color, texture and odor as provided in officials. Khinchi, et al., (2011) concluded from their findings that amongest different combinations of superdisintegrants used, tablets that were formulated by direct compression using Sodium starch glycolate and Crospovidone exhibited quicker tablet disintegration as opposed to tablets formulated using Crosscarmellose sodium and L-HPC. Pahwa & Gupta (2011) analyzed the behavour of disintegration time and wetting time in the oral cavity bysurface free energy. They report that for faster wetting to occure, a molecule should possess high polar component of surface free energy, a special requirement that is met by agents called superdisintegrants. According to Pahwa & Gupta (2011), the availability of these agents as well as the simplicity of the direct compression method indicate that their use in the formulation of ODTs can greatly enhance the bioavailability of the drug. ODTs have a number of challenges that include: costly production process, poor physical resistance in blister packs, and limited ability to increase the concentration of active ingredients in the drug. According to Yapar (2014), ODTs are made of soft molded matrices which need peel-off bluster packing. This increases their cost of production.Generally, it is difficult to a chieve a stable ODT under environmental conditions such as temperature and humidity. This is due to the fact that most ingredients used in ODTs dissolve in small quantity of water. Cost-effective patented production technology - from processing to packaging – is of concern. Generally, all tablet drugs are subject to standard control tests such as size, shape, thickness, apperance and clical studies. However, for ODTs, weight variation, friability, hardness, mechanical strength, disintegration, water absorption ratio and wetting time, uniformity of dispersion, in vitro dissolution time, in vitro disintegration time and stability properties have to be evaluated (Arnum, 2007). In addition, there is need to establish compatibility between active ingredients with exciients and the manufacturing process. The mouthfeel characteristics and specific taste of the tablet are particularly relevant in their intended oral dispersion, requiring a palatable formulation. This may need additional taste formulation strategies. Last but not least, ODTs are not very robust in comparison to the conventional solid-oral dosage drugs since considerations have to be made from their formulation to packaging requirements. What must be done to address the problem? Concentration of the active ingredient and the method of manufacturing are some of the main factors that affect the dissolution of a drug released from tablets and capsules (Mohanachandran, et al., 2011). In the prsent work, raidly disintegrating clopidogrel tablets will be prepared by direct compression method. The drug will be blended with varous excipients, lubricated, and subsequently, directly compressed into a tablet. In this formulation, a disintegrant used need to break the tablet to expose the substance of the drug for dissolution. Studies will then be carried out on the role played by the type and concentration of the disintegrant on the physical properties of the tablet, such as particle size, hardness test and disintegration time analysis. The direct compression technique is prefered as a method of preparing the ODT due to the porous nature of the resulting tablet, a condition that provides faster disintegration. 3.0 Intended design and methods of investigation Experimental Design Crafting of an optimal design will comprise of variable fractions of mixture components of sodium starch glycolate, croscarmellose sodium and crospovidone, and clopidogrel hydrogen sulphate (clopidogrel), and compression pressure. Our main aim will be to use disintegrant mixtures representing variable fraction as part of the tablet composition. For each disintegrant, five variable fraction components will be set to range from 0 to 10% of the total tablet composition. All the components should be 10% of the total tablet composition. Dried mannitol will be sprayed to be used as a filler in the remainder of the total composition of the tablet. Magnesium stearate, sodium hydroxide and pottassium dihydrogen orthophosphate will be used at 0.5%. The samples will be compressed into tablets by applying a discrete compression pressure. The tablets prepared will be evaluated for particle size, hardness, drug dissolution and disintegration, as well as disintegration time analysis to establish the effect of type and concentration of disintegrants on these parameters. Materials and Methods Materials: Clopidogrel hydrogen suphate, microcrystalline cellulose, spray dried mannitol (a filler), croscarmellose sodium, crospovidone and sodium starch glycolate, magnesium sterate, sodium hydroxide and pottassium dihydrogen orthophosphate. These materials will be sourced from known manufacturers and suppliers. Methodology: Preparing clopidogrel hydrogen sulphate tablets by direct compression The amounts of disintegrants, clopidogrel, and microcrystalline cellulose to be used in this study are shown in Table 1. All the components will be accurately weighed and then blended in a mixer for about 5 minutes (Mahrous, et al., 2016). Thereafter, the weight of mannitol will be mixed with the microcrystalline cellulose superdisintegrant for about 10 minutes. In the final step, a measured asmount of magnesium stearate will be mixed using a powder blend for about 2 minutes. When mixing is done, the powder blend will then be compressed into concave tablets using a single 9 mm punch machine. The tablet and all the components will weigh 300 mg. Table 1: Composition of different clopidogrel hydrogen sulphate (CL) ODT Formula CL MCC Mannitol CCS SSG CPV Aspartame & magnesium sterate F1 25 36 36 - - - 2,1 F2 25 35.5 35.5 2.0 - - 2,1 F3 25 33.5 33.5 5.0 - - 2,1 F4 25 31.0 31.0 10.0 - - 2,1 F5 25 35.0 35.0 - 2.0 - 2,1 F6 25 33.5 33.5 - 5.0 - 2,1 F7 25 31.0 31.0 - 10.0 - 2,1 F8 25 35.0 35.0 - 2.0 2,1 F9 25 33.5 33.5 - 5.0 2,1 F10 25 31.0 31.0 - 10.0 2,1 Evaluation of the Clopidogrel Tablet Hardness Testing Hardness (tablet crushing strength) will be investigated by subjecting the tablet on a hardness tester for each of the 10 compressed tablet formula samples. The average weight standard deviation will be recorded. Determination of Particle Size and Particle size distribution Particle size distribution was determined by sieve analysis with a series of sieves.The avaerage particle size of the clopidogrel tablets will be measured using a laser particle counter. The tested clopidogrel granules will be sieved using a mesh size of 500 m and measured via dry dispersion method. In this method, about 5 g of the tested sample tablets will be introduced into the dry dispenser (Velmurugan & Vinushitha, 2010). A series of sieves will be used to carry out sieve analysis of the particles, to determine the particle size distribution of the granules. In vitro disintegration time analysis The tablets that will be prepared will be evaluated for disintegration times in vitro by use of a USP disintegration apparatus at 37Oc, and using a phosphate buffer at pH 6.8 as a medium of disintegration. The time needed for a tablet to completely disintegrate will be recorded and the average time standard deviation of all the tablets will be calculated. In vitro dissolution Test This test will be performed using a USP dissolution apparatus through the paddle apparatus at 50 rpm. At predetermined time intervals of 5, 10, 15, 20 and 30 minutes, a sample of 5 mL will be replaced with a dissolution medium. The samples withdrawn will be subjected to spectrophotometric absorbance measurements at 240 nm to calculate the amount of drug dissolved. 4.0 Project Management Gantt chart Bibliography The author of this article provides an overview of ODTs, from definition to desired properties, advantages and disadvantages, challenges of ODT formulation, drug candidates and excipients. The recent developments of taste making, superdisintegrants, and manufacturing techniques and evaluation parameters have also been presented. Read More