The oral route remains the most well-liked route of drug administration because of its convenience, good patient compliance and low medicine production costs. In order for a drug to be absorbed into the systemic circulation following oral administration, the drug must be dissolved in the gastric fluids. The active pharmaceutical ingredient in a good dosage form must undergo dissolution before it is designed for absorption from the gastrointestinal tract. 1
Currently, approximately 40% of the marketed immediate release (IR) oral drugs are categorized as practically insoluble (<100 g/ml) (Takagi et al. , 2006). So, there is an urgent need to develop strategies that can overcome the condition of less aqueous solubility. To generally describe "solubility" the Pharmacopoeia (USP) uses seven different solubility expressions as shown in Table 1. The European Pharmacopoeia uses similar solubility definitions except the 'practically insoluble' characteristic, which is not specified. 4
1. 1 Biopharmaceutics classification system
The Biopharmaceutical Classification System (BCS) was introduced in the mid-1990s to classify the drug substances regarding their aqueous solubility and membrane permeability. BCS is a useful tool for decision-making in formulation development from a biopharmaceutical point of view.
Solubility improvement strategies are necessary for Class II and Class IV drugs.
1. 2 Approaches to increase the solubility or even to raise the available surface for dissolution
- Particle size
- Modifications of the crystal habit
- Pseudopolymorphs (including solvates)
- Use of surfactants
- Use of cyclodextrins
- Drug dispersion in carriers
- Eutectic mixtures
- Solid dispersions (non-molecular)
- Solid solutions
- Soluble prodrugs
1. 3 Solid Dispersions
The term solid dispersion refers to several solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles (clusters) or in crystalline particles. 7
Much of the study that has been reported on solid dispersion technologies involves drugs that are poorly water-soluble and highly permeable to biological membranes as with these drugs dissolution is the rate limiting step to absorption. Hence, the hypothesis has been that the pace of absorption in-vivo will be concurrently accelerated with a rise in the speed of drug dissolution. Therefore, solid dispersion technologies are particularly promising for enhancing the oral absorption and bioavailability of BCS Class II drugs.
1. 3. 1 Types of solid dispersions
A. Simple eutectic mixture: Eutectic mixture is made by rapid solidification of fused melts of two components that show a total liquid miscibility with negligible solid-solid solubility. It involves loose atomic or molecular interaction rather than on the forming of chemical bonds. If the eutectic mixture is exposed to gastrointestinal fluids, both poorly soluble drug and the carrier may simultaneously crystallize out as an extremely small particles cause an increased the top area and improved dissolution and absorption of the drug.
B. Solid solution: A good solution represents a homogenous one phase system, where the solid solution is dissolved in a solid solvent and the two components crystallize together. The solid solution achieves faster dissolution when compared to a eutectic mixture because the drug particles in a good solution are reduced to molecular size and dissolution of the drug occurs in the solid state before the contact with the liquid medium.
C. Glass solution: It really is a homogenous glassy system in which a solute dissolves on glassy solvent results in increased dissolution and absorption of the drug. It really is seen as a a transparency and brittleness below the glass forming temperature. Glass solution is a metastable and the effectiveness of the chemical bonding is a lot less when compared with solid solution. Therefore, the discharge of the drug was found to be faster when compared to a solid solution.
D. Amorphous precipitations in crystalline carrier: An amorphous form of the drug produces faster dissolution rate. The drug may precipitate out within an amorphous form in a crystalline carrier from solid dispersions prepared by melting or solvent method. A solid interaction between the drug and carrier leading to the formation of channels within the matrix appears to be a possible mechanism for improved dissolution of the drug.
E. Compound or complex formation: The formation of a complex between the drug and the carrier may either loss of boost the dissolution and the absorption rate of the drug. The formation of soluble complex with low association constant resulted in increased rate of dissolution and absorption.
The enhancement in dissolution rate of the drug can be ascribed to
An increasing solubility of the drug due to its amorphous state or small particle size (Kelvin's law)9, 10
An increased surface designed for drug dissolution due to small size of the drug particles11, 12
An improvement in wetting of the drug caused by the hydrophilic carrier13, 14
1. 3. 2 Advantageous properties of solid dispersions
Management of the drug release profile using solid dispersions is achieved by manipulation of the carrier and solid dispersion particle properties. Parameters such as carrier molecular weight and composition, drug crystallinity and particle porosity and wettability, when successfully controlled, can produce improvements in bioavailability. 16
a. Particles with reduced particle size: Molecular dispersions, as solid dispersions, represent the last state on particle size reduction, and after carrier dissolution the drug is molecularly dispersed in the dissolution medium. Solid dispersions apply this principle to drug release by creating an assortment of a poorly water soluble drug and highly soluble carriers. A higher surface area is formed, resulting in an elevated dissolution rate and therefore, improved bioavailability.
b. Particles with improved wettability: Strong contribution to the enhancement of drug solubility is related to the drug wettability improvement in solid dispersions. It had been observed that even carriers with no surface activity, such as urea improved drug wettability. Carriers with surface activity, such as cholic acid and bile salts, when used, can significantly increase the wettability properties of drugs. Moreover, carriers can influence the drug dissolution profile by direct dissolution or co-solvent effects.
c. Particles with higher porosity: Particles in solid dispersions have been found to have a higher degree of porosity. The upsurge in porosity also depends upon the carrier properties, for instance, solid dispersions containing linear polymers produce larger and even more porous particles than those containing reticular polymers and, therefore, cause an increased dissolution rate. The increased porosity of solid dispersion particles also hastens the drug release profile.
d. Drugs in amorphous state: Poorly water soluble crystalline drugs, when in the amorphous state will have higher solubility. The enhancement of drug release can usually be performed using the drug in its amorphous state, because no energy is required to split up the crystal lattice through the dissolution process.
1. 3. 3. Carriers used in solid dispersions
Many carriers of natural, semi-synthetic and synthetic types are being used which include natural carbohydrates, semi-synthetic and synthetic hydrophilic polymers.
S. No: 1
Nature of carrier: Sugars
Name of the carrier: Dextrose, sorbitol, sucrose, fructose, maltose, galactose, xylitol, mannitol
S. No: 2
Nature of carrier: Acids
Name of the carrier: Citric acid, tartaric acid and succinic acid
S. No: 3
Nature of carrier: Polymorphic materials
Name of the carrier: Polyvinyl pyrrolidone (PVP), polyethylene glycols, hydroxyl propylmethylcellulose (HPMC), guargum, xanthan gum, sodium alginate, methyl cellulose, pectin, hydroxyl ethyl cellulose (HEC), hydroxyl propyl cellulose (HPC) and dextrins.
S. No: 4
Insoluble or enteric
Nature of carrier: polymer
Name of the carrier: Hydroxy propyl methyl cellulosepthalate, eudragit RL, eudragit L 100, eudragit S100, eudragit RS.
S. No: 5
Nature of carrier: Surfactants
Name of the carrier: Polyethylene stearate, poloxamer 188, tweens and spans.
S. No: 6
Nature of carrier: Miscellaneous
Name of the carrier: Nicotinic acid, succinamide, dextrans, gelatin, poly vinyl alcohol, urea, cyclodextrins, skimmed milk etc. ,
Table 1. 2 Various carriers found in solid dispersions
1. 3. 4. Preparation techniques of solid dispersions
The following will be the major processes for the preparation of solid dispersions.
A. Solvent evaporation method: In this technique, the physical combination of two components is dissolved in a typical solvent and followed by the evaporation of solvent. The advantages of this technique are low temperature requirements for the preparation of dispersion and thermal decomposition of drugs and carriers can be prevented. The bigger cost of production, incomplete removal of solvent, undesireable effects of solvent on the chemical stability of the drug and selection of common solvent are the drawbacks of this method.
B. Melting method (Fusion method): The physical mixture of drug and water- soluble carrier was heated to melt and the molten mixture was then cooled and solidified mass was crushed, pulverized and sieved. The melting point of a binary system will depend on its composition and proper manipulation of drug carrier ratios. Decomposition should be avoided due to fusion time and the speed of cooling.
C. Kneading method: The physical combination of drug and carrier were triturated using small level of organic and natural solvent and water mixture, usually alcohol and water (1:1v/v). The slurry is kneaded for 45 minutes and dried at 45C. The dried mass is pulverized and sieved through sieve no. 60 and the fraction was collected. The benefits of this technique are low temperature requirements for solid dispersion preparation and use of organic solvent is less. This technique of preparation avoids thermal degradation of drug and employs less level of organic and natural solvents.
D. Melting solvent method: This method involves dissolving the drug in the right solvent and the incorporation of the solution straight into the molten carrier. This technique possesses the benefits of both solvent and melting methods.
E. Supercritical fluid methods: Supercritical fluid methods are mostly applied with skin tightening and (CO2), which is utilized as the solvent for drug and matrix or as an antisolvent. This system consists of dissolving the drug and the carrier in the solvent that is introduced into a particle formation vessel by way of a nozzle, simultaneously with CO2. When the solution is sprayed, the solvent is rapidly extracted by the SCF, leading to the precipitation of solid dispersion particles on the walls and bottom of the vessel. This system will not require the use of organic and natural solvent and since CO2 is considered environmentally friendly, this system is known as 'solvent free'. This technique is recognized as Rapid Expansion of Supercritical Solution (RESS).
F. Lyophilization/ Freeze Drying: This system is an alternative to the solvent evaporation method. Here the drug and carrier are dissolved in common solvent, frozen and sublimed to obtain a lyophilized molecular dispersion.
G. Melt agglomeration process: This technique is used to get ready solid dispersion in which a binder acts as a carrier. The solid dispersion is prepared by heating binder, drug and excipient to a temperature above the melting point or spraying the dispersion of drug in the molten binder on the heated excipients utilizing a high shear mixer. The effect of binder type, method preparation and particle size are the critical factors influencing the solid dispersion preparation by this technique. These parameters results in a variety of dissolution rates, mechanism of agglomerate formation and growth, agglomerate size and distribution.
1. 3. 5. Limitations of solid dispersion systems:
- Problems limiting the commercial application of solid dispersions are:
- Laborious and expensive method of preparation.
- Reproducibility of physico-chemical characteristics.
- Difficulty in incorporating into the formulation of dosage forms.
- Crystallization of the amorphous drug in the dispersion.
- Poor scale up of manufacturing process and physical and chemical stability of drug and the automobile.
1. 4 FDT's:
Fast-disintegrating and fast-dissolving tablets have become popular as novel delivery systems for drug administration. These are far more convenient for children, elderly patients, patients with swallowing difficulties, and in the absence of potable liquids. The most desirable formulation for use by older people is the one which is easy to swallow easy to handle. Taking these requirements into consideration, attempts have been made to develop a fast-disintegrating tablet. Since such a tablet can disintegrate in only a little amount of water in the mouth, it is simple to take for just about any age patient, no matter time or place. For example, it could be taken anywhere whenever by anyone who do not have easy access to water. Additionally it is easy to dose the aged, bedridden patients, or infants who have problems swallowing tablets and capsules. Recently, many companies have researched and developed numerous kinds of fast-disintegrating dosage forms. 18
These tablets display an easy and spontaneous de-aggregation in the mouth, soon after the connection with saliva, though they can be handled or extracted from the package without alteration. The active agent can thus rapidly dissolve in the saliva and become absorbed through whatever membrane it encounters, during deglutition, unless it is protected from pre-gastric absorption. To fulfill these requirements, tablets must be highly porous, incorporating hydrophilic excipients, able to rapidly absorb water for a rapid deaggregation of the matrix. Different technological techniques, such as freeze drying or molding or direct compression are employed to prepare the formulations of the type present on the pharmaceutical market.
1. 4. 1 Advantages of Fast Disintegrating Drug Delivery System (FDDS) 19, 20
- Ease of administration to patients who won't swallow a tablet, such as pediatric and geriatric patients, mentally ill, disabled and uncooperative.
- Convenience of administration and accurate dosing when compared with liquids.
- No need of water to swallow the dosage form, which is highly convenient feature for patients who are traveling, nor have immediate usage of water.
- Good mouth feel property of FDDS really helps to change the essential view of medication as "bitter pill", particularly for pediatric patients.
- Ability to supply the advantages of liquid medication by means of solid preparation.
- Rapid dissolution of drug and absorption, which might produce rapid onset of action.
- Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the stomach; in such instances bioavailability of drugs is increased.
- Pregastric absorption can cause improved bioavailability and as a result of reduced dosage, improved clinical performance by having a reduction of unwanted side effects.
1. 4. 2 Approaches for fast disintegrating tablets
A. Patented technologies
- Zydis (R. P. Scherer, Inc. )
- WOWTAB (Yamanouchi Pharma Technologies, Inc. )
- OraSolv (Cima Labs, Inc. )
- DuraSolv (Cima Labs, Inc. )
B. Three others are available outside the U. S.
- Flash Dose (Fuisz Technologies, Ltd. ),
- Flash tab (Prographarm Group),
- OraQuick (KV Pharmaceutical Co. , Inc. )
- Nanocrystal Technology
C. Conventional technologies
- Freeze -drying or lyophilization
- Tablet Molding
- Direct compression
- Spray drying
- Mass extrusion
- Direct compression
It is the easiest way to manufacture tablets. Conventional equipment, commonly available excipients and a restricted range of processing steps are involved in direct compression. Also high doses can be accommodated and final weight of the tablet can simply exceed that of other production methods. Directly compressed tablet's disintegration and solubilization will depend on the single or combined action of disintegrates, water soluble excipients and effervescent agent. Disintegrate efficacy is strongly affected by tablet size and hardness. Large and hard tablets have a disintegration time more than that always required. As consequences, products with optimal disintegration properties often have medium to small size and /or high friability and low hardness. Breakage of tablet edges during handling and tablet rupture during the opening of blister, all results from insufficient physical resistance.
Disintegrants have a major role in the disintegration and dissolution procedure for mouth dissolving Tablets made by direct compression. To ensure a high disintegration rate, choice of suitable type and an optimal amount of disintegrant is important. Other formulation components such as water soluble excipients or effervescent agents can further enhance dissolution or disintegration properties. But the main drawback of using effervescent excipients is their highly hygroscopic nature.
The knowledge of disintegrant properties and their effect on formulation has advanced over the last couple of years, particularly regarding so called superdisintegrants. Disintegration efficiency is dependant on a force equivalent concept, which is the combined measurement of swelling force development and amount of water absorption. Force equivalent expresses the ability of disintegrant to transform absorbed water into swelling force. The optimization of tablet disintegration was defined through disintegrant critical concentration. Below this concentration, the tablet disintegration time is inversely proportional to disintegrate concentration and above that disintegration time remains approximately continuous or even increases.
The simultaneous occurrence of disintegrate with a high swelling force called disintegrating agent and substances with low swelling force ( starch, cellulose and direct compression sugar) defined as, "swelling agent" was claimed to be always a key factor for the rapid disintegration of the tablet, which offers physical resistance.
1. 4. 3 Mechanism of tablet disintegration and water absorption
When mouth dissolving tablets located in the mouth, upon connection with saliva the tablet disintegrates or dissolve instantaneously. The mechanisms involved in the tablet disintegration mechanisms are
- Wicking (capillary)
- Particle repulsive forces
- Chemical reaction (acid base reaction)
Not all disintegrates swell in contact with water swelling is thought to be a mechanism in which; certain disintegrating agents (like starch) impart their disintegrating effect. By swelling in touch with water, the adhesiveness of other ingredients in a tablet is overcome causing the tablet to disintegrate.
b. Wicking (porosity and capillary action)
Effective disintegrants that do not swell are thought to impart their disintegrating action through porosity and capillary action. Tablets porosity offers a method for the penetration of fluid into tablets. The disintegrants particles (with cohesiveness and compressibility) themselves act to enhance porosity and provide these capillaries in to the tablets. Liquid is drawn up or wicked into these ways by capillary action and rupture the inter-particulate bonds triggering the tablet to break into small parts.
Starch grains are usually thought to be "elastic" in nature this is the grains that are deformed under great pressure will return to their original form when that pressure is removed. But, with the compression forces involved in tabletting, these grains are permanently deformed and are reported to be "energy rich" with these energies being released upon exposure to water, that is the ability for starch to swell is higher in "energy rich" starch grains than in starch grains that contain not been deformed under pressure. It is believed that no single mechanism is in charge of the action of most disintegrants. But instead, it is much more likely the results of interrelationships between these major mechanisms.
d. Due to disintegrating particle/particle repulsive forces:
Another mechanism of disintegration attempts to clarify the swelling of tablets made with 'non-swellable' disintegrants. Guyot-Hermann has proposed a particle repulsion theory based on the observation that nonswelling particle also causes disintegration of tablets. The electric repulsive forces between particles will be the mechanism of disintegration and water is required for this. Researchers discovered that repulsion is secondary to wicking.
e. Chemical reaction (acid base reaction)
Disintegration of tablet included with citric acid and tartaric acid along with the sodium bicarbonate, sodium carbonate, potassium carbonate; these react in contact with water to liberate carbon dioxide that disrupts the tablet.
Name of the Product: Imodium Lingual
Active Ingredients: Loperamide hydrochloride
Dose: 2 mg
Name of the Product: Pepcidin Rapitab
Active Ingredients: Famotidine
Dose: 20mg and 40 mg
Name of the merchandise: Mosid - MT
Active Ingredients: Mosapride citrate.
Dose: 2. 5mg and 5mg
Name of the Product: Calritin Reditabs
Active Ingredients: Loratadine
Dose: 10 mg
Name of the merchandise: Nimulid - MD
Active Ingredients: Nimesulide
Dose: 50mg and 100mg
Name of the Product: Zyrof Meltab
Active Ingredients: Rofecoxib
Dose: 50 mg
Name of the merchandise: Feldene Melt
Active Ingredients: Piroxicam
Dose: 10mg and 20 mg
Name of the Product: Maxalt-MLT
Active Ingredients: Rizatriptan
Dose: 5mg and 10 mg
Name of the Product: Pepcid RPD
Active Ingredients: Famotidine
Dose: 20mg and 40 mg
Name of the merchandise: Zyprexa Zydis
Active Ingredients: Olanzapine
Dose: 5mg, 10mg, 15mg and 20 mg
Name of the merchandise: Zofran ODT
Active Ingredients: Ondansetron
Dose: 4 mg and 8 mg
Name of the Product: Remeron Soltab
Active Ingredients: Mirtazepine
Dose: 15mg, 30mg and 45 mg
Name of the Product: NuLev
Active Ingredients: Hyoscyamine sulfate
Dose: 0. 125 mg
Table 1. 3 Marketed fast disintegrating tablets
Piroxicam, a non-steroidal anti inflammatory agent, owned by BCS class II is trusted as an initial - line drug in the symptomatic relief of arthritis rheumatoid and osteoarthritis. It's low aqueous solubility should be overcome through formulation strategies.
Skimmed milk can be utilized as a drug carrier as it is inexpensive, easily available, biodegradable, and does not exhibit toxicity problems as familiar with PEG and PVP. 24-26
Polymers as carriers likewise have limitations in boosting the solubility of poorly soluble drugs due to their high viscosity. Therefore the use of skimmed milk in the formulation of the SD of the drugs with limited aqueous solubility may be considered a potential and cost effective way to overcome the challenge. 27
Skimmed milk is a colloidal suspension of casein micelles, globular proteins and lipoprotein particles. The main casein fractions are a-s1, a-s2, b-casein and k-casein. b-casein is amphiphilic and acts as a detergent molecule with surfactant property. The milk also includes whey proteins with principle fractions of the b-lacto globulin, a-lactalbumin, bovine serum albumin and immunoglobulins. These molecules were found to be surface active with a superior solubility than caseins. 28
Aminoacids have been suggested either as additives in peroral application or by means of aminoacid salts to lessen gastrointestinal disorders arising due to piroxicam like NSAID's. The top active agents and amino acid content are anticipated to be the explanation of increased permeation of the drug from the solid dispersion. 29, 30
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