Poorly water-soluble drugs often show poor bio availability because of low and erratic levels of absorption. Drugs that undergo dissolution rate limited gastrointestinal absorption generally show improved dissolution and bio availability as a result of reduction in particle size. However, micronizing of drugs often leads to aggregation and agglomeration of particles, which results in poor wettability.
Solid dispersions of poorly water-soluble drugs with water-soluble carriers have been reduced the incidence of these problems and enhanced dissolution. To increase the rate of dissolution and gastrointestinal absorption of poorly water-soluble drugs by the application of solid dispersion technique was firstly demonstrated by Sekiguchi and Obi. They proposed the faster absorption of poorly water-soluble drugs such as sulfathiazole by the formation of eutectic mixture with a water-soluble and physiologically inert carries like urea. Upon exposure to aqueous fluids the active drug released into fluids is fine, dispersed particles because of fine dispersion of the drug in the solid eutectic mixture and the faster dissolution of the soluble matrix. The eutectic mixture contained 52 per cent w/w of sulfathiazole and 48 per cent w/w of urea. The possibility of using solid solution approach in which a drug is molecularly dispersed in soluble carrier was subsequently introduced. Chiou and Regelman comprehensively reviewed the pharmaceutical application of solid dispersion system.
Definitions of solid dispersion
The term solid dispersion refers to the dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting (fusion), solvent or melting solvent method. The dispersion of a drug or drugs in a solid diluent or diluents by traditional mechanical mixing is not included in this category. The solid dispersion, a first stated by Mayersohn and Gibaldi.
Uses of surface active carriers in pharma preparation
Because of their unique functional properties, surface active carriers find a wide range of uses in pharmaceutical preparations. These include, depending on the type of product, improving the solubility or stability of the drug in the liquid preparation, stabilizing and modifying the texture of semisolid preparations, or altering the flow properties of the final tablet dosage form. In addition to their use as excipients to improve the physical and chemical characteristics of the formulation, surface active carriers may be included to improve the efficacy or the bioperformance of the product. The properties of surfactant are such that they can alter the thermodynamic activity, solubility, diffusion, disintegration, and dissolution rate of a drug. Each of these parameters influences the rate and extent of drug absorption. Further more, surface active carriers can exert direct effects on biological membranes thus altering drug transport across the membrane.
The advantage of a surface-active carrier over a non-surface-active one in the dissolution of drug from a capsule formulation is shown schematically in the figure. The physical state of drug if a solid dispersion must, however, is carefully considered an evaluating the advantage of a surface-active vehicle. As mentioned earlier, the drug can be molecularly dispersed in the carrier to form a solid solution or it can be dispersed as particles. It can also be both partially dissolved and partially dispersed in the carrier. The potential for the formation of a continuous drug rich surface layer is possibly greater if the drug is molecularly dispersed, whereas the drug dispersed, as particulates may be more prone to dissociation from the water-soluble matrix. It is however, rare that the drug is dispersed just as particulates and is not at least partially dissolved in the vehicle. Therefore, a surface-active carrier is preferably in almost all cases for the solid dispersion of poorly water-soluble drugs.
Figure depicting a schematic representation of the comparative dissolution of a poorly water-soluble drug from surface-active versus non surface-active vehicle.
Selection of the carrier
The selection of the carrier has the influence on the dissolution characteristics of the dispersed drug, since the dissolution rate of one component from the surface is affected by the other component in a multiple component mixture. Therefore, a water-soluble carrier results in a faster release of the drug from the matrix. A poorly soluble or insoluble carrier leads to slower release of a drug from the matrix. If the active drug present is a minor component in the dispersion, faster release of a drug can be achieved from matrix.
Classification of solid dispersion systems
It is appropriate to classify various systems of solid dispersion on the basis of their major fast release mechanisms. Chiou and Riegelman classified solid dispersions into the following six representative types: Simple eutectic mixtures, solid solutions, glass solutions and glass suspensions, amorphous precipitations in a crystalline carrier, compound or complex formation, and combinations of the previous five types.
Simple eutectic mixtures
These are prepared by rapid solidification of the fused melt of two components that show complete liquid miscibility and negligible solid-solid solubility. Thermodynamically, such a system is an intimately blended physical mixture of its two crystalline components. Thus the X-ray diffraction pattern of a eutectic constitutes an additive composite of two components.
Solid solutions
In a solid solution the two components crystallize together in a homogeneous one phase system. The particle size of the drug in the solid solution is reduced to its molecular size. Thus, a solid solution can achieve a faster dissolution rate than the corresponding eutectic mixture. Solid solutions can be classified by two methods. According to the extent of miscibility of the two components, they may be classified as continuous or discontinuous. In continuous solid solutions, the two components are miscible in the solid state in all proportions.
According to the criterion of molecular size of the two components, the solid solutions are classified as substitutional or interstitial. In the substitutional type, the solute molecule substitutes for the solvent molecule in the crystal lattice. The molecular size of the two components should not differ by more than 15%. This class is represented by solid solutions of p-dibromobenzene-p-chlorobromobenzene.
● An interstitial solid solution is obtained when the solute (guest) molecule occupies the interstitial space in the solvent (host) lattice. For this to occur, the solute molecule diameter should be less than 0.59 that of solvent molecule; therefore, the volume of the solute molecule should be less than 20% of the solvent molecule. Owing to their large molecular size, polymers favour the formation of interstitial solid solutions. Examples of this type include solid solutions of digitoxin, methyltestosterone, prednisolone acetate and hydrocortisone acetate in the matrix of PEG 6000. They all exhibit a faster rate of dissolution.
Glass solutions and suspensions
A glass solution is a homogeneous glassy system in which a solute dissolves in the glassy system. A glass suspension refers to a mixture in which precipitated particles are suspended in a glassy solvent. The glassy state is characterized by transparency and brittleness below the glass transition temperature. Glasses do not have sharp melting points, instead, they soften progressively on heating. The lattice energy, which represents a barrier to rapid dissolution, is much lower in glass solutions than in solid solutions.
Amorphous precipitations in a crystalline carrier
● The difference between this group of solid dispersions and the simple eutectic mixture is that the drug is precipitated out in an amorphous form in the former as opposed to a crystalline form in the latter. Sulfathiazole was precipitated in the amorphous form in crystalline urea.
Common methods used for preparation of solid dispersion
● Melt method.
● Solvent method.
● Melting solvent method.
● Solvent-deposition method.
Mechanism of faster dissolution rates
● Reduction in particle size provides the larger specific area, thereby increasing the dissolution and oral absorption of poorly soluble drugs.
● A possible solubilization effect by the carrier may operate in the microenvironment (diffusion layer) immediately surrounding the drug particles in the early stage of dissolution, since the carrier completely dissolves in a short time.
● The absence of aggregation between fine crystallites of the pure hydrophobic drug plays an important role in increasing rate of dissolution. Drug surface area is markedly reduced because of aggregation and agglomeration. Serious drawbacks of aggregations, agglomeration and lumping in the dissolution medium between pure drug and particle are, however, rarely present in most solid dispersions, because individually dispersed particles are surrounded in the matrix by carrier particles.
● Excellent wettability and dispersability of a drug from an eutectic or other solid dispersion system prepared with water soluble matrix result in an increased dissolution rate of the drug in aqueous media. This is due to the fact that each single crystalline particle of the drug is very intimately encircled by the soluble carrier which can readily dissolve and cause the water to contact and wet the drug particle. As a result a fine homogeneous solution of a drug can be easily obtained with minimum stirring.
● An increased dissolution and absorption may also occur if a drug crystallized in a metastable form after solidification which in turn leads to faster dissolution rate.
Applications of solid dispersion
Apart from absorption enhancement, the solid dispersion technique may have numerous pharmaceutical applications, which should be further explored.
It is possible that such a technique be used:
● To obtain a homogeneous distribution of a small amount of drug in solid state.
● To stabilize the unstable drug.
● To dispense liquid (up to 10%) or gaseous compounds in a solid dosage.
● To formulate a fast release primary dose in a sustained released dosage form.
● To formulate sustained release regimen of soluble drugs by using poorly soluble or insoluble carriers.
● To reduce pre systemic inactivation of drugs like morphine and progesterone.
● Polymorphs in a given system can be converted into isomorphous, solid solution, eutectic or molecular addition compounds.
Methods of determination of type of solid dispersion system
Many methods are available that can contribute information regarding the physical nature of solid dispersion system. A combination of two or more methods is required to study its complete picture.
1. Thermal analysis. 4. Spectroscopic method.
2. X-ray diffraction method. 5. Dissolution rate method.
3. Microscopic method. 6. Thermodynamic method.
Conclusion
Solubility is a most important parameter for the oral bio availability of poorly soluble drugs. Dissolution of drug is the rate determining step for oral absorption of the poorly water soluble drugs, which can subsequently affect the in vivo absorption of drug. Currently only 8% of new drug candidates have both high solubility and permeability. Because of solubility problem of many drugs the bio availability of them gets affected and hence solubility enhancement becomes necessary. Solid dispersion technology is one of the possible modes that increases the solubility of poorly soluble drugs.
(The authors, Kamal Dua is with Dept of Pharmaceutical Technology, Faculty of Medicine & Health, International Medical University, Malaysia, VK Sharma, UV Singh Sara, MV Ramana are with D. J. College of Pharmacy, Modinagar, UP and Kavita Pabreja is with ISF College of Pharmacy, Moga, Punjab)