Pradeep Karatgil is from Custom Pharmaceutical Services, Dr Reddy's Laboratories Ltd (India).

Pradeep Karatgi

In the quest to maintain market share and brand equity following patent expiries, many major pharmaceutical companies are focusing on effective product life cycle management as an important growth strategy. Of the various drug delivery technologies available to develop a line extension with improved therapeutic benefit, orally disintegrating tablets (ODTs) provide an attractive alternate to conventional solid oral dosage forms.  

ODTs disintegrate rapidly in the mouth (<30 s) without water, and are an attractive dosage form for a wide range of patients, including children, elderly subjects, and patients with behavioural disorders, persistent nausea, Parkinson's disease or cancer who have difficulty swallowing.

  The FDA's Center for Drug Evaluation and Research defines ODT as: "A solid dosage form containing medicinal substances which disintegrates rapidly usually within seconds, when placed upon the tongue".

  The global ODT market is flourishing and growing steadily, with more than 100 products sold worldwide and sales exceeding €3 billion.

  Recently conducted surveys indicate that many patients prefer ODTs to other dosage forms; approximately 70% of patients would purchase ODTs, or prefer ODTs, rather than regular tablets or liquids.

 Table 1: Advantages of ODTs - patient benefits and business opportunities. 

The key benefits of and indications for ODTs are shown in Tables 1 and 2, respectively.      

An ODT is intended to be placed on the tongue and ingested without water. Upon contact with saliva, it disintegrates rapidly. Depending on the disintegration technology used, several mechanisms can play a role in the process. Following ingestion, the drug reaches the gastrointestinal tract (GIT) where it is absorbed based on its physicochemical and biopharmaceutical properties. In some instances, the drug is released in the mouth and a significant fraction is absorbed through the local oromucosal tissues. Resins or sweeteners are also used in the formulation to aid taste-masking of the API. The sequence of events that typically follows administration of an ODT is shown Figure 1. 

Figure 1: Flowchart depicting the disintegration and delivery mechanism of an ODT following oral administration. 

Despite the advantages of ODTs, the technology is often restricted by the amount of drug that can be incorporated into each solid unit dose (lower than 400 mg for insoluble drugs and less than 60 mg for soluble drugs in the case of lyophilized dosage forms).

  As these dosage forms disintegrate rapidly in the mouth, it is desirable to adequately mask the taste of the API to provide a good mouth feel. The contents should also not be released until they reach the GIT. Another important factor to consider is whether they can be manufactured using conventional equipment and processes, as this will have a positive influence on manufacturing costs. Some products, however, may require a more costly, special unitdose packaging if the dosage form is fragile.  

If the ODT is a line extension, it is necessary to demonstrate bioequivalency to the existing dosage form to avoid clinical studies. Proving bioequivalence can be challenging if the method used for taste-masking impacts drug release. 

Dr Reddy's has several ODTs in various stages of the approval process. A partial list of products developed, including indications and the technology used, is summarized in Table 3. In some instances, ionexchange resins in conjunction with sweeteners were used for taste-masking. These products use conventional processes and traditional processing equipment, resulting in lower development and manufacturing cost. 

Table 3: List of products developed by Dr Reddy's Laboratories. 

The hardness of the products developed by Dr Reddy's is in the 3–8 kp range, indicating their ability to withstand stress during handling. This also results in reduced costs as the products can be packaged in conventional packaging configurations. The products listed in Table 3 are generic versions of innovator products and meet the bioequivalency criteria of the reference products. Some of the reference products were developed using specialized technologies, such as Zydis and Orasol, which require specialized packaging. These technologies may also call for a complicated manufacturing process (sometimes involving lyophilization) and customized packaging that increases costs. 

ODT technologies for sparingly soluble drugs

An ODT can also serve as a preferred delivery system for sparingly soluble compounds or compounds where absorption is solubilitylimited (BCS class II). With proper selection of formulation excipients (solubilizers, resins, disintegrants, etc.) and processing technology, any issues relating to wettability, solubility and absorption could be overcome to obtain a product with good organoleptic properties that still meets bioequivalency criteria. In our opinion, the formulation approaches and technology used at Dr Reddy's overcome these challenges and offer unique applications for improved therapeutic benefit. Some of the technologies are detailed below. Figure 2 shows the dissolution profile of a sparingly soluble drug developed in-house as an ODT dosage form. 

Figure 2: Dissolution profiles of an ODT developed at Dr Reddy's Laboratories. 

Granulation with rapidly disintegrating agents

The formulation comprises an API with appropriately selected solubilization excipients and rapidly disintegrating agents that aid drug disintegration in the mouth and dissolution in the GIT, thus overcoming bioequivalence problems. Examples of disintegrating agents include crosscarmelose sodium, crosspovidone and sodium starch glycolate. 

Table 4: List of preferred drug substance properties for ODT doasge form development. 

Loosely compressed ODTs usually rely on watersoluble excipients and/or super disintegrants to achieve rapid disintegration. However, to produce a less friable ODT, a stronger binder is required, which in turn requires a more effective disintegrating agent for the tablet to release its contents. Thus, the appropriate selection of formulation excipients and process can give a faster disintegrating tablet.  

Following ingestion, these tablets disintegrate into granules and further into powder. Various physicochemical properties of the drug substance, such as solubility, ionization constant and partition coefficient, aid drug dissolution and absorption through the GIT. 

Ionexchange resins have been used in pharmaceutical formulations for several reasons, including tablet disintegration, taste-masking, stabilization and extended release. One of the most important properties of ionexchange resins is imparted by the functional groups that are attached to a polymer backbone that can exchange ions with drugs in solution. Examples of ionexchange resins include amberlite IRP88 and amberlite IRP64. These resins are practically insoluble in all solvents and at all pH levels, which, combined with their particle size, results in limited absorption by the body. Because of this, these resins are generally recognized as nontoxic and safe.  

The drugloaded resin is called a resinate. Resinates are free flowing powders that contain the active in a particular salt form. The exchange of ions is reversible and is dependent on the environment in which the drug and ionexchange resin are found. The insolubility of resinate means it has no effect on taste buds and, hence, provides a tastemasking effect. Tablet disintegration is achieved through the swelling that occurs when the dried resin is put in an aqueous medium, as water penetrates the 3D structure of resin.  

Cyclodextrins are a class of cyclic oligosaccharides made from starch. They usually have a truncated cone structure and a lipophilic cavity with a hydrophilic exterior. Cyclodextrin can form molecular inclusion complexes with a wide variety of drugs, incorporating the lipophilic moiety of the drug molecule in its cavity. The complex provides an effective means of increasing its solubility. The complex is prepared by solubilizing both the drug substance and cyclodextrin in a suitable medium. The drug complex is converted into solid intermediates for tableting using techniques such as spray drying or layering onto pharmaceutical carriers and/or diluents. The solid intermediate is blended with disintegrants, sweeteners and other tableting excipients, and then compressed into tablets. The synergistic effect of disintegrants and complexation supports faster disintegration, dissolution and bioavailability enhancement. Because of the limitation of using cyclodextrin bulk in the blend, the technology is limited to relatively potent actives where the therapeutic dose is <50 mg. 

When delivering sparingly soluble drugs, solubility and dissolution can often be enhanced by formulating the drug as nanometersized particles. This approach can be used for developing ODT forms of moderately potent drugs without compromising the organoleptic properties.  

The nanoparticles are prepared using techniques such as wet bead milling or highpressure homogenization, and then stabilized using suitable surface modifiers that are either polymers and/or surfactants. The nanoparticle dispersion is converted into solid intermediates using spray granulation, drug layering or spray drying, and then incorporated into solid oral dosage forms with suitable additives to aid rapid disintegration. The ODT formed provides a pharmacokinetic profile that is bioequivalent to its original reference product, but with the improved patient benefits. 

Selection of drug substance and excipients

The excipients used in the formulation of ODTs must support the desired organoleptic properties and, simultaneously, allow rapid disintegration when placed on the tongue. For generic products, the excipients should ensure bioequivalence to the reference dosage form. Excipients are selected based on compatibility studies and/or a thorough understanding of the drug structure to minimize or prevent interaction with excipients that can impact physical and chemical stability upon storage. Binders provide cohesiveness during compression to develop an ODT with the required strength to maintain its physical integrity (friability and hardness) during handling and storage. In a fastdissolving formulation, the choice of binder is also critical to achieve the desired sensory and melting characteristics, while also enabling rapid release of the API. 

The choice of drug substance that can be formulated as an ODT is dependent on various physicochemical properties as detailed in Table 4. The properties that need to be addressed during development of an ODT are detailed below. 

When developing an ODT, it is advantageous to have tablets with acceptable hardness at a given compression force to obviate the need for specialized packaging without compromising production speed. Therefore, a more compactable disintegrant can produce stronger and lessfriable tablets. 

The drug substance should be chemically stable, with the selected excipients and drug product physically stable during processing and handling. 

To achieve patient compliance, it is essential that an ODT is palatable and has a good mouth feel. Small particles are preferable as large particles cause grittiness in the mouth. If the drug substance has a tendency to gel upon contact with water, it could result in patient noncompliance. 

As the tablet disintegrates when placed on the tongue, the ODT should be palatable by incorporating appropriate tastemasking agents and, sometimes, sweeteners. 

Rate of disintegration of drug formulation in saliva

The disintegrants must allow rapid penetration of saliva into the tablet to generate the necessary volume expansion and hydrostatic pressures for rapid disintegration when placed in the mouth. 

Rate of absorption from the saliva solution and overall bioavailability

The physicochemical properties (i.e., ionization constant, partition coefficient and solubility) determine drug dissolution and absorption from the GIT. However, for sparingly soluble compounds, surface modifiers, solubilizers and resins may aid drug dissolution and absorption. 

Today, ODTs are more widely available as OTC products for treating various common symptoms. Many ODTs have been successfully commercialized and the market for this particular dosage form is likely to expand because of patient demand and increasing market acceptance. 

As new technologies are becoming available that do not add to the manufacturing costs, the future prospect for ODTs as an alternative to traditional tablets and capsules is promising, especially as the technology could be modified to deliver large molecular weight biopharmaceutical therapeutics, such as proteins and peptides that are unstable at gastric pH. Nowadays, these classes of molecules are developed as injectable drugs because of the limited solubility and propensity to degrade at gastric pH conditions when administered as an immediate release dosage form. With recent advances in processing technologies, pharmaceutical companies can take advantage of ODTs for innovative products, as well as product line extensions to maintain market share following patent expirations. 

 is Vice President, Integrated Product development, Dr. Reddys Laboratories Ltd (India). 

Articles

Orally disintegrating tablets offer numerous advantages compared with traditional tablets and capsules, and can be an effective solution for developing line extensions of currently marketed therapies.

Orally disintegrating tablets: the path to improved patient compliance and enhanced life cycle management

Rapid advances in drug discovery have led to the identification of a number of compounds with good therapeutic potential. However, because of their complex chemistry, the majority of these compounds have poor aqueous solubility resulting in reduced and variable bioavailability.

  Current marketed formulations of sparingly water-soluble drugs such as Ketoconazole (KC), a imidazole antifungal agent used for treatment of fungal infections,

  Fenofibrate (FF), a fibric acid derivative used for the treatment of hypertriglyceridimia,

  and Candesartan cilexetil (CC) a non-peptide angiotensin II type 1 receptor antagonist used in the treatment of hypertension, are suboptimal.

  Following oral administration, absorption of these drugs from the gastrointestinal (GI) tract is dependent on their solubility in Gl fluids. Poorly soluble drugs generally have low dissolution velocity and exhibit a small concentration gradient across the intestinal mucosa, which can result in low, variable absorption and a poor therapeutic response. 

Based on the understanding that the rate of drug dissolution is the primary driving force behind improved pharmacokinetic properties, these drugs were formulated as nanometer-sized particles — particles <1 μm. The increase in surface area because of the reduction in particle size can substantially increase dissolution rate if the formulation disperses into discrete particles.

Nanocrystalline dispersion comprises drug, water and stabilizers. Stabilizers used to aid the dispersion of particles are either polymers and/or surfactants. Polymers act as the primary stabilizer whereas surfactants are used as the secondary stabilizer. To be effective, the stabilizers must wet the drug crystals and provide a steric and ionic barrier to prevent agglomeration. The concentration of polymeric stabilizers can range 1–10% w/v and the concentration of surfactants is generally <2% w/v.

  If required, other excipients, such as buffers, salts and diluents, such as sugar, can be added to enhance physical stability and further processing. 

The bead milling process used for the production of drug nanoparticles can be described as a simple procedure comprising attrition media, suspension and agitation. The extent of size reduction is governed by the grinding energy, which is determined by the intrinsic hardness of the drug, grinding media and milling power. The nanoparticulate dispersion was converted into solid intermediates for tabletting by granulating with water-soluble carriers. The dissolution characteristics of tablet formulations containing drug nanoparticles were compared with commercial formulations in physiologically relevant dissolution media. 

FF, KC and CC were procured from Dr. Reddy's Laboratories (India). Lactose monohydrate was purchased from Roquette Frères (France). Hydroxypropyl methylcellulose (HPMC, 6cps) was purchased from Colorcon (India). Sodium lauryl sulphate was purchased from Qualigen Fine Chemicals (India). Crospovidone (Polyplasdone) and sodium starch glycolate were obtained from International Specialty Products (Wayne, NJ, USA [ISP]) (USP) and Grain Processing Corp. (Muscatine, IA, USA), respectively. All other chemicals were of analytical reagent grade. 

Preparation of nanosuspension on a laboratory scale.

 A glass apparatus mimicking the media milling machine was fabricated in-house for identifying the appropriate stabilizer, along with its concentration, for the preparation of nanoparticulate dispersions with adequate physical stability and the production of solid intermediates required for solid dosage form processing.

Scale-up of manufacturing process for production of nanosuspensions. 

The selected compositions were scaled-up using a bead mill (Lab Star 1 Netzsch Mill; Netzsch, Germany). The milling media comprised 0.2 mm yttrium-stabilized zirconium beads. The suspension flowed axially through the milling chamber where the shear forces generated during impaction of the milling media with the drug provided the energy input to fracture the drug crystals into nanometer-sized particles. The milling operation was performed in a recirculation mode with the suspension fed at a rate of 150 mL/min. The mill and pump speeds were operated at 2500 and 120 rpm, respectively. The temperature inside the milling chamber was controlled by circulating cooling water through the outer jacket. After milling, the suspension was collected and stored at a temperature below 25 °C until further processing.  

Conversion of nanosuspensions into solid intermediates.

 The nanoparticulate and microparticulate dispersions of FF, KC and CC were converted into solid intermediates by spray granulation process (GPCG 1.1 fluidized bed coater; Glatt GmbH, Germany). The suspensions were layered at a predetermined spray rate (6 g/min) onto lactose particles using a top spray fluid bed processor. The drying temperature and atomization speed were set at 40–45 °C and 1.2 bar, respectively. The granules were dried as they moved upward, and small droplets and low viscosity of the spray medium ensured that distribution was uniform resulting in granules with a narrow size distribution.  

 Thermal properties of powder were investigated using a PerkinElmer (Waltham, MA, USA) differential scanning calorimeter (DSC)-7/thermal analysis controller (TAC)-7 with an intracooler-2 cooling system. For this analysis, approximately 3–5 mg of product were placed in perforated aluminum-sealed 50-μL pans and the heat runs for each sample were set from 40 to 200 °C at 5 °C/min under an inert environment using nitrogen. The apparatus was calibrated using indium. 

Powder x-ray diffractograms of unmilled and milled formulations were recorded using a Panalytical Xpert Pro Diffractometer (PANalytical, The Netherlands) with a Cu line as the source of radiation. Standard runs using a 40 kV voltage, a 40 mA current and a scanning rate of 0.02°/min with a 2θ range of 3 to 40 °C were used. 

The granules containing drug nanoparticles of KC, FF and CC were blended with extra-granular excipients using a double cone blender. The blend was subsequently compressed into tablets at the desired strength, and the physical properties of tablets — hardness, friability and disintegration time — were measured.  

 The dissolution characteristics of tablets containing drug nanoparticles and marketed product were determined using a USP dissolution apparatus (DISSO 2000; Labindia, India) type II, fitted with a paddle that operated at 50 rpm. The dissolution media comprised 0.1 N HCl (pH 1.2), acetate buffer (pH 4.5), phosphate buffer (pH 6.8) and purified water. The volume and temperature of the dissolution medium were 500 mL and 37 °C. Samples were withdrawn at predetermined time intervals, filtered in-line and assayed using an HPLC method (Alliance HPLC System; Waters Corp., Milford, MA, USA). A discriminating dissolution media was identified based on its ability to differentiate impact of composition and particle size on dissolution velocity. 

The formula composition for producing nanosuspensions of FF, KC and CC for scale-up trials using the media mill is summarized in Table 1. The primary and secondary stabilizers selected produced stable nanosuspensions for conversion to solid intermediates required for solid dosage form processing. 

Table 1: Formula composition of drug nanosuspensions for scale-up trials.			

The key property of granules is their recovery (i.e., their ability to reconstitute into nanometer-sized particles when dispersed in an aqueous medium or physiologically relevant media). The particle size distribution of nanosuspensions and granules following redispersion in an aqueous medium that is summarized in Table 2 indicated complete recovery. 

Table 2: Particle recovery from granules.			

The DSC thermogram and x-ray diffraction spectra showed no solid state transitions, indicating that drug crystallinity was maintained upon milling. 

Tablet compositions incorporating drug nanoparticles are shown in Table 3. The dissolution characteristics of tablet formulations incorporating drug nanoparticles in discriminating dissolution media are shown in Figures 1–3. The rate and extent of drug dissolution for the nanoparticle FF formulation was comparable to the marketed product (Tricor). The dissolution profile of tablet formulations incorporating drug nanoparticles of KC and CC were significantly higher compared with commercial formulations. 

Figure 1: Fenofibrate tablets containing drug nanoparticles, micronized drug and commercial tablet formulation.			

The results from these studies demonstrate that the wet bead milling process coupled with spray granulation is a viable approach for developing nanoparticle formulations of biopharmaceutics classification system (BCS) class II compounds with enhanced solubility and faster dissolution. Enhancing solubility and dissolution velocity of sparingly soluble compounds correlates with an improved pharmacokinetics profile and a concomitantly improved therapeutic outcome. 

Figure 2: Ketoconazole tablets containing drug nanoparticles, micronized drug and commercial formulation.			

Part of the work pertaining to development of KC nanoparticles was adjudged as the best original work in the area of pharmaceutical technology by a panel of independent judges from academia and industry at the 59th Indian Pharmaceutical Association Annual Conference (2–23 December 2007), held at Banaras Hindu University (India). This work was selected from approximately 1400 papers presented in the conference from India and abroad. The work related to development of CC nanoparticles has been accepted for presentation at the AAPS 2008 Annual Meeting in Atlanta (GA, USA), which will be held 16–20 November. 

Figure 3: Candesartan cilexetil tablets containing drug nanoparticles, micronized drug and commercial formulation.			

 is Assistant Manager, NCE Product Development, Dr. Reddy's  Laboratories Ltd (India).			

 is Deputy Manager, CPS Product Development, Dr. Reddy's  Laboratories Ltd (India).			

is Vice President, NCE and CPS Product Development, Dr. Reddy's Laboratories Ltd 

Ketoconazole in the Management of Fungal Disease

 (Adis Press, New York, NY, USA,1982). 			

et al., Journal of Chromatography B: Biomedical Sciences and Applications

7. E.M. Liversidge, G.G. Liversidge and E.R. Cooper, 

 (2008) DOI: 10.1080/03639040802005024.  

Rapid advances in drug discovery have led to the identification of a number of compounds with good therapeutic potential.