1. INTRODUCTION:

The oral route of drug administration is the most common and preferred method of delivery due to convenience and ease of ingestion. From a patient’s perspective, swallowing a dosage form is a comfortable and a familiar means of taking medication. As a result, patient compliance and hence drug treatment is typically more effective with orally administered medications as compared with other routes of administration, for example, parenteral.

Although the oral route of administration is preferred, for many drugs it can be a problematic and inefficient mode of delivery for a number of reasons. Limited drug absorption resulting in poor bioavailability is paramount amongst the potential problems that can be encountered when delivering an active agent via the oral route. Drug absorption from the gastrointestinal (GI) tract can be limited by a variety of factors with the most significant contributors being poor aqueous solubility and/or poor membrane permeability of the drug molecule.

When delivering an active agent orally, it must first dissolve in gastric and/or intestinal fluids before it can then permeate the membranes of the GI tract to reach systemic circulation. Therefore, a drug with poor aqueous solubility will typically exhibit dissolution rate limited absorption, and a drug with poor membrane permeability will typically exhibit permeation rate limited absorption. Hence, two areas of pharmaceutical research that focus on improving the oral bioavailability of active agents include: (i) enhancing solubility and dissolution rate of poorly water-soluble drugs and (ii) enhancing permeability of poorly permeable drugs. This article focuses on the former, in particular, the use of solid dispersion technologies to improve the dissolution characteristics of poorly water-soluble drugs and in turn their oral bioavailability. Numerous solid dispersion systems have been demonstrated in the pharmaceutical literature to improve the dissolution properties of poorly water-soluble drugs.

Other methods, such as salt formation, complexation with Cyclodextrins, solubilization of drugs in solvent(s) and particle size reduction have also been utilized to improve the dissolution properties of poorly water-soluble drugs; however, there are substantial limitations with each of these techniques. On the other hand, formulation of drugs as solid dispersions offers a variety of processing and excipient options that allow for flexibility when formulating oral delivery systems for poorly water soluble drugs (table-1).

Much of the research that has been reported on solid dispersion technologies (Table-2) 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 rate of absorption in vivo will be concurrently accelerated with an increase in the rate of drug dissolution. In the Biopharmaceutical Classification System (BCS) drugs with low aqueous solubility and high membrane permeability are categorized as Class II drugs (Amidon et al., 1995). Therefore, solid dispersion technologies are particularly promising for improving the oral absorption and bioavailability of BCS Class II drugs.^1,2

Table: 1 List of Poorly Soluble Drugs with Hydrophilic Carriers

Sr. No.	Carrier	Drug
1.	Polyethylene glycol (PEG)	Griseofulvin
2.	Polyvinylpyrrolidone (PVP)	Flufenamic acid
3.	Hydroxypropylmethylcellulose (HPMC)	Albendazole, Benidipine
4.	Sorbitol	Predinisolon
5.	Urea	Ofloxacin

2.1. TYPES OF SOLID DISPERSION:

2.1.1. Eutectic Mixtures:

A simple eutectic mixture consists of two compounds which are completely miscible in the liquid state but only to a very limited extent in the solid state. It is prepared by rapid solidification of fused melt of two components that show complete liquid miscibility but negligible solid-solid solution (Fig.-1)^{8, 4}

Figure 1: Phase diagram for a eutectic system.⁵

2.1.2. Amorphous Precipitation In Crystalline Matrix:

This is similar to simple eutectic mixtures but only difference is that drug is precipitated out in an amorphous form.⁶

2.1.3. Solid Solution:

Solid solutions are comparable to liquid solutions, consisting of just one phase irrespective of the number of components. In the case of solid solutions, the drug's particle size has been reduced to its absolute minimum viz. the molecular dimensions⁷ and the dissolution rate is determined by the dissolution rate of the carrier. Classified according to their miscibility (continuous versus discontinuous solid solutions) or second, according to the way in which the solvate molecules are distributed in the solvendum (substitutional, interstitial or amorphous).

2.1.3.1. Continuous Solid Solutions:

In a continuous solid solution, the components are miscible in all proportions. Theoretically, this means that the bonding strength between the two components is stronger than the bonding strength between the molecules of each of the individual components. Solid solutions of this type have not been reported in the pharmaceutical world till date.

2.1.3.2. Discontinuous Solid Solutions:

In the case of discontinuous solid solutions (Fig.-2), the solubility of each of the components in the other component is limited. Due to practical considerations it has been suggested by Goldberg et al.⁷ that the term `solid solution' should only be applied when the mutual solubility of the two components exceeds 5%.

Figure 2: Phase diagram for a discontinuous solid Solution.⁵

2.1.3.3. Substitutional Solid Solutions:

Substitution is only possible when the size of the solute molecules differs by less than 15% or so from that of the solvent molecules⁶. Classical solid solutions have crystalline structure (fig.-3), in which the solute molecules can either substitute for solvent molecules in the crystallattice or fit into the intrsticies between the solvent molecules.

Figure 3: Substitutional crystalline solid solution.³

2.1.3.4. Interstitial Solid Solutions:

In interstitial solid solutions (fig.-4), the dissolved molecules occupy the interstitial spaces between the solvent molecules in the crystal lattice. Solute molecule diameter should be less than 0.59 times than that of solvent molecular diameter.⁸

Figure 4: Interstitial crystalline solid solution.⁹

2.1.4. Glass Solution and Suspensions:

Glass solutions are homogeneous glassy system in which solute dissolves in glass carrier. Glass suspensions are mixture in which precipitated particles are suspended in glass solvent. Lattice energy is much lower in glass solution and suspension.⁶

3. OTHER TYPES OF SOLID DISPERSION:

3.1. Binary solid dispersion: It consists of drug and a polymeric carrier.

3.2. Ternary solid dispersion: It consists of drug, a polymeric carrier and a surfactant. Generally used surfactant is Polysorbate 80 which plays an important positive role in dissolution of the solid dispersion.

Both the binary and ternary solid dispersions enhanced the dissolution of poorly water soluble drugs. Moreover, the dissolution of ternary solid dispersion is found faster compared with that of binary solid dispersion 43.This was because of polysorbate 80, which improved the wettability and solubilized the non-molecularly dispersed or crystalline fraction of drug (ex. Ofloxacin ).³⁶

3.3 Surface solid dispersion: Surface solid dispersion is formulated with polymers such as polyvinyl pyrrolidone, polyethylene glycol and polyvinyl pyrrolidone-vinyl acetate copolymer by fusion technique to improve its solubility. Preparation of surface solid dispersion, a technique that provides deposition of the drug on the surface of certain materials, can alter the dissolution characteristics of drug. Deposition of drug on the surface of an inert carrier leads to reduction in particle size of drug, therapy providing faster rate of dissolution. ³⁷

4. METHOD OF PREPARATION:

1. Solvent evaporation method

2. Modified solvent evaporation method

3. Melting method

4. Melt-solvent method

5. Kneading method

6. Co-grinding method

7. Co-precipitation method

8. Co-precipitation with supercritical fluid

9. Spray drying method

10. Gel entrapment technique

4.1. Solvent evaporation method: Drug and carrier both are dissolved in organic solvent. After complete dissolution, the solvent is evaporated. The solid mass is ground, sieved and dried.

Ex. Solid dispersion of Ofloxacin with polyethylene glycol was prepared by solvent evaporation method .¹¹

4.2. Modified solvent evaporation method: Drug is dissolved in organic solvent at its saturation solubility with continued stirring for some time. Polymer is suspended in sufficient amount of water (up to wet mass of polymer). The drug solution is poured at once into polymer suspension. The entire solvent is evaporated. The mass obtained is dried. ¹⁰

4.3. Melting method: Accurately weighed drug and carrier are mixed using glass mortar and pestle. The mixture is heated at or above the melting point of all the components to achieve a homogenous dispersion. It is then cooled to obtain a congealed mass. It is pulverized and sieved.

Ex. Albendazole and urea solid dispersion was prepared this method ¹²

4.4. Melt-solvent method: Accurately weighed drug is dissolved in organic solvent and the solution is incorporated into the melt of mannitol by pouring into it. It is suddenly cooled. The mass is kept in desiccator for complete drying. The solidified mass is crushed, pulverized and passed through sieve ¹³

4.5. Kneading method: A mixture of accurately weighed drug and carrier is wetted with solvent and kneaded thoroughly for some time in a glass mortar. The paste formed is dried and sieved.

Ex. furosemide and crospovidone solid dispersion was prepared by this method ¹⁴

4.6. Co-Grinding method: Accurately weighed pure drug powder and the carrier are physically mixed for some time using a blender at a specified speed. The mixture is then charged into the chamber of a vibration ball mill. A certain number of steel balls are added.

The powder mixture is ground. Then the sample is collected and kept at room temperature in a screw capped glass vial until use.

Ex. chlordiazepoxide and mannitol solid dispersion was prepared by this method.

4.7. Co-precipitation method (co-evaporates): Accurately weighed carrier is dissolved in water and drug in organic solvent. After complete dissolution, the aqueous solution of carrier is then poured into the organic solution of the drug. The solvents are then heated and evaporated. The dispersion is pulverized with pestle and mortar, sieved and dried.¹⁵

4.8.Co-precipitation with supercritical fluid: Conventional methods for the preparation of solid dispersions include either the fusion or solvent processes, with supercritical fluid processing (SCP) emerging as an alternative solvent- evaporation method for formulating co precipitates of smaller particle size, lower residual organic solvent and better flowability. A supercritical fluid exists as a single fluid phase above its critical temperature and pressure. Carbon dioxide is currently the most commonly used supercritical fluid because of its low critical temperature of carbon dioxide makes it attractive for processing heat labile pharmaceuticals. In the context of manufacturability, rate of cooling and solvent removal is stringently controlled, resulting in acceptable batch to batch variation. A precipitation vessel with a nominal capacity of 50ml was loaded with a 7ml solution of pure drug or drug: polymer (carbamazepine: polyethylene glycol) in acetone. The supercritical carbon dioxide was added from the bottom of the chamber and when the liquid phase expanded, the formed particles were retained in the vessel by a suitable filter. During the co-precipitate formation, the pressure was fixed at 70bar and the temperature at 40^OC ¹⁶

4.9. Spray drying method: Accurately weighed amount of drug with lipid carrier are dissolved in methanol to obtain a clear solution. This solution is then spray dried using a laboratory scale dryer. The sample is stored over silica gel in a vacuum desiccators.⁹

4.10. Gel entrapment technique: Carrier for example hydroxyl propyl methyl cellulose is dissolved in organic solvent (dichloromethane) to form a clear and transparent gel. Then drug for example carbamazepine is dissolved in gel by sonication for few minutes. Organic solvent is evaporated under vacuum. Solid dispersions are reduced in size by glass mortar and sieved .¹⁷

5. CHARACTERIZATION OF SOLID DISPERSION:^26-35

5.1. Detection Of Crystallinity In Solid Dispersions:

Several different molecular structures of the drug in the matrix can be encountered in solid dispersions. Many attempts have been made to investigate the molecular arrangement in solid dispersions. However, most effort has been put into differentiate between amorphous and crystalline material. For that purpose many techniques are available which detect the amount of crystalline material in the dispersion. The amount of amorphous material is never measured directly but is mostly derived from the amount of crystalline material in the sample. It should be noted that through the assessment of crystallinity as method to determine the amount of amorphous drug it will not be revealed whether the drug is present as amorphous drug particles or as molecularly dispersed molecules.

5.2. Currently, The Following Techniques Are Available To Detect The Degree Of Crystallinity:

Powder X-ray diffraction can be used to qualitatively detect material with long range order. Sharper diffraction peaks indicate more crystalline material. Recently developed X-ray equipment is semi quantitative. Infrared spectroscopy (IR) can be used to detect the variation in the energy distribution of interactions between drug and matrix. Sharp vibrational bands indicate crystallinity. Fourier Transformed Infrared Spectroscopy (FTIR) was used to accurately detect crystallinities ranging from 1 to 99% in pure material. However in solid dispersions only qualitative detection was possible. Water vapor sorption can be used to discriminate between amorphous and crystalline material when the hygroscopicity is different, this method requires accurate data on the hygroscopicity of both completely crystalline and completely amorphous samples. Isothermal Microcalorimetry measures the crystallization energy of amorphous material that is heated above its glass transition temperature (Tg). However, this technique has some limitations. Firstly, this technique can only be applied if the physical stability is such that only during the measurement crystallization takes place. Secondly, it has to be assumed that all amorphous material crystallizes. Thirdly, in a binary mixture of two amorphous compounds a distinction between crystallization energies of drug and matrix is difficult. Dissolution Calorimetry measures the energy of dissolution, which is dependent on the crystallinity of the sample. Usually, dissolution of crystalline material is endothermic, whereas dissolution of amorphous material is exothermic. Macroscopic techniques that measure mechanical properties that are different for amorphous and crystalline material can be indicative for the degree of crystallinity. Density measurements and Dynamic Mechanical Analysis (DMA) determine the modulus of elasticity and viscosity and thus affected by the degree of crystallinity. However, also these techniques require knowledge about the additivity of these properties in intimately mixed binary solids. A frequently used technique to detect the amount of crystalline material is Differential Scanning Calorimetry (DSC). In DSC, samples are heated with a constant heating rate and the amount of energy necessary for that is detected. With DSC the temperatures at which thermal events occur can be detected. Thermal events can be a glass to rubber transition, (re)crystallization, melting or degradation. Furthermore, the melting- and (re)crystallization energy can be quantified. The melting energy can be used to detect the amount of crystalline material. Possibly, the recrystallization energy can be used to calculate the amount of amorphous material provided, that all amorphous material is transformed to the crystalline state. If during DSC-measurements, amorphous material crystallizes, information is obtained on the crystallization kinetics and on the physical stability of the amorphous sample. To quantify the amount of crystalline material, measurements should be completed before crystallization of amorphous material has started. In some cases, this can be established applying high scanning rates.

5.3. Detection Of Molecular Structure In Amorphous Solid Dispersions:

The properties of a solid dispersion are highly affected by the uniformity of the distribution of the drug in the matrix. The stability and dissolution behaviour could be different for solid dispersions that do not contain any crystalline drug particles, i.e. solid dispersions of type V and VI or for type II and III. However, not only the Knowledge on the physical state (crystalline or amorphous) is important; the distribution of the drug as amorphous or crystalline particles or as separate drug molecules is relevant to the properties of the solid dispersion too. Nevertheless, only very few studies focus on the discrimination between amorphous incorporated particles versus molecular distribution or homogeneous mixtures.

1. Confocal Raman Spectroscopy was used to measure the homogeneity of the solid mixture of ibuprofen in PVP. It was described that a standard deviation in drug content smaller than 10% was indicative of homogeneous distribution. Because of the pixel size of 2 μm3, uncertainty remains about the presence of nano-sized amorphous drug particles.

2. Using IR or FTIR, the extent of interactions between drug and matrix can be measured. The interactions are indicative for the mode of incorporation of the drug, because separately dispersed drug molecules will have more drug-matrix interactions than when the drug is present in amorphous clusters or other multi-molecule arrangements.

3. Temperature Modulated Differential Scanning Calorimetry (TMDSC) can be used to assess the degree of mixing of an incorporated drug. Due to the modulation, reversible and irreversible events can be separated. For example, glass transitions (reversible) are separated from crystallization or relaxation (irreversible) in amorphous materials. Furthermore, the value of the Tg is a function of the composition of the homogeneously mixed solid dispersion. It has been shown that the sensitivity of TMDSC is higher than conventional DSC. Therefore this technique can be used to assess the amount of molecularly dispersed drug, and from that the fraction of drug that is dispersed as separate molecules is calculated.

6. USES OF SOLID DIPERSION:

1. Solid dispersion improves dissolvability in water of a poorly water soluble drug in a pharmaceutical composition.⁵³

2. Drug is formulated with hydrophilic carrier (ex. poly ethylene glycol) as a solid dispersion to increase its aqueous solubility and dissolution. Then superdisintegrant (ex.croscarmellose sodium) is used in tablet formulation to achieve rapid disintegration of tablets prepared by wet granulation method. Thus solid dispersion is used in preparing rapid disintegration oral tablets. These rapidly disintegrating tablets can be used as an alternative to parenteral therapy enabling patient for self medication even without the aid of water.⁵⁴

3. Solid dispersion is used as formulation vehicle to facilitate the preclinical safety and early clinical studies on new chemical entities with very low aqueous solubility. A compound with extremely low or negligible aqueous solubility may significantly limit the dose range or exposure of the drug achievable in the preclinical and clinical studies when formulated via traditional means. In these cases, solid dispersion formulations may provide a means to rapidly assess the safety and efficacy profile of the drug substance that may be otherwise difficult to obtain.⁵⁵

4. In improving immunosuppressive therapy in lung transplant patients, dry powder formulation consisting of a solid dispersion (ex. CyclosporineA) for inhalation iss prepared. It can avoid many problems

ex. i.) With dry powder inhalation the use of local anesthesia and irritating solvents can be avoided.

ii.) The higher deposition efficiency of dry powder inhalation compared with nebulization reduces the need for high metered doses.

Solid dispersions are known for their dissolution rate enhancing properties of poorly soluble drugs such as CyclosporineA.⁵⁶

7. BENEFITS OF SOLID DISPERSION SYSTEM:

Solid dispersion systems can provide numerous additional benefits to oral drug therapy beyond improving bioavailability such as:

1. Solid dispersion formulations were demonstrated to accelerate the onset of action for drugs such as Nonsteroidal anti inflammatory drugs where immediacy of action is crucial to relieving acute pain and inflammation.

2. For anti-cancer drugs in particular, solid dispersion systems were shown to provide bioavailable oral dosage forms which could be substituted for standard injections to improve patient comfort and compliance.

3. Solid dispersion systems were also found to reduce food effect on drug absorption, thus increasing the convenience of drug therapy as the need for some drugs to be taken with food was eliminated.

4. It was also demonstrated that a solid dispersion- based dosage form allowed for greater drug loading per dose and improved stability over a soft gelatin capsule formulation which thereby improved the convenience of drug therapy by reducing the dosing regime and eliminating the need for refrigerated storage.

5. Additionally, the improved absorption efficiency demonstrated for solid dispersion systems allows for a reduction in the content of active agent per dose, thus decreasing the cost associated with these drug therapies.

6. Finally it was demonstrated the solid dispersion systems can be produced utilizing functional carriers that offer the added benefit of targeting the release of highly soluble forms of poorly water soluble drugs to an optimum site for absorption.

7. These benefits demonstrate the current contributions and future potential of solid dispersion systems toward improving drug therapies for a variety of important medical conditions whose treatment involves poorly water soluble drugs ³⁸

8. APPLICATIONS OF SOLID DISPERSIONS :^19-25

1. To increase the solubility of poorly soluble drugs thereby increase the dissolution rate, absorption and bioavailabilty.

2. To stabilize unstable drugs against hydrolysis, oxidation, recrimination, isomerisation, photo oxidation and other decomposition procedures.

3. To reduce side effect of certain drugs.

4. Masking of unpleasant taste and smell of drugs.

5. Improvement of drug release from ointment, creams and gels.

6. To avoid undesirable incompatibilities.

7. To obtain a homogeneous distribution of a small amount of drug in solid state.

8. To dispense liquid (up to 10%) or gaseous compounds in a solid dosage.

9. To formulate a fast release primary dose in a sustained released dosage form.

10. To formulate sustained release regimen of soluble drugs by using poorly soluble or insoluble carriers.

11. To reduce pre systemic inactivation of drugs like morphine and progesterone.

9. LIMITATIONS: ^42-52

Usually solid dispersions are prepared with water soluble low melting point synthetic polymers such as polyvinyl pyrrolidone, mannitol or polyethylene glycol. These polymers show superior results in drug dissolution enhancement, but the amount of these polymers required is relatively large, around 1:2 to 1:8 (drug/ polymer) ratio. In certain similar experiments it has been observed that, polyvinyl pyrrolidone and polyethylene glycol get first dissolved in dissolution media (owing to their high water solubility) leaving the drug back in undissolved state. In such case, though the drug is in controlled crystallization state or amorphous state, the polymers are unable to provide wetting ability of the drug particles. In such cases, there may be the possibility of rapid reversion of amorphous drug to the more stable crystalline state in presence of small amount of plasticizers such as water. So to avoid these problems hydrophilic swellable polymers for example sodium carboxy methyl cellulose, sodium starch glycolate and pregelatinized starch are used.

An obstacle of solid dispersion technology in pharmaceutical product development is that a large amount of carrier, i. e, more than 50% to 80% wt/wt, was required to achieve the desired dissolution. This high percentage of carrier causes consistency of product performance at the time of manufacturing. This is a major consideration in that the number of market products arising from this approach has been less than expected.

Recently, combined carriers have been used and a higher increase in drug dissolution was reported. However, those reported solid dispersions were still a very low percentage of drugs loading in the system, which required an extremely high amount of carrier. High drug-loaded solid dispersion with high drug dissolution enhancement is not an easy task since the drug presented in such a system is in complete crystal has high crystallinity.

Destabilization of solid dispersion systems results in decreased dissolution rate, due to a number offactors. For ex. Solid dispersion systems may be destabilized through physical treatment such as pulverization and aging. Upon melting a drug and polyethylene glycol, unpulverizable, sticky, metastable or glassy solids may form after cooling. Pulverization has resulted in the conversion of amorphous drugs in solid dispersion to crystalline forms.

Solid dispersion is a high energy metastable form. Phase separation, crystal growth or conversion from the amorphous to the crystalline form during storage decrease solubility and dissolution rate and result in variable oral bioavailability.

10. FEUTURE PROSPECTS:

Despite many advantages of solid dispersion, issues related to preparation, reproducibility, formulation, scale up, and stability limited its use in commercial dosage forms for poorly water-soluble drugs. Successful developments of solid dispersion systems for preclinical, clinical and commercial use have been feasible in recent years due to the availability of surface-active and self-emulsifying carriers with relatively low melting points. The preparation of dosage forms involves the dissolving of drugs in melted carriers and the filling of the hot solutions into gelatin capsules. Because of the simplicity of manufacturing and scale up processes, the physicochemical properties and as expected to change significantly during the scale up. For this reason, the popularity of the solid dispersion systems to solve difficult bioavailability issues with respect to poorly water-soluble drugs will grow rapidly. Because the dosage form can be developed and prepared using small amounts of drugs substances in early substances in early stages of the drug development process, the system might have an advantage over such other commonly used bioavailability enhancement techniques as micronization of drugs and soft gelatin encapsulation.¹⁸

11. RECENT ADVANCES:

Serrajuddin particularly emphasize on self emulsifying system. Commercial development of drug products based on solid dispersion by advances in filling solid dispersion directly into hard gelatin capsule and availability of surface active agent and self emulsifying agent. For ease manufacturing carrier must be amenable to liquid filling into hard gelatin capsules as melts. Melting temperature should not exceed 70ºC (because maximum acceptable temperature for hard gelatin capsule is 70ºC).

12. MARKETED PREPARATIONS OF SOLID DISPERSION:

1) Solid dispersion of VALDECOXIB (NSAID) using PVP by Solvent Evaporation method. ³⁹

2) Solid dispersion of TERBINAFINE HYDROCHLORIDE (synthetic allyl amine derivative, broad spectrum antifungal activity when used orally/topically) using Polyvinyl Pyrollidone K30 by Solvent Evaporation method^{. 40}

3) Surface Solid Dispersion Of GLIMEPIRIDE (third generation sulphonylurea, antidiabetic drug which stimulates insulin release) using Crospovidone, Pregelatinised starch, Croscarmellose sodium and Avicel PH 101 by Solvent Evaporation method. ⁴¹

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Received on 18.11.2011 Modified on 30.11.2011

Research J. Pharm. and Tech. 5(2): Feb. 2012; Page 190-197

Class	Example of carriers
Sugars	dextrose, Sucrose, Galactose, Sorbitol, Maltose, Xylitol, Mannitol, Lactose
Acids	Citric acid, Succinic acid
Polymeric materials	Polyvinylpyrrolidone (PVP), Polyethylene glycols (PEG), Hydroxypropyl-methylcellulose, Methylcellulose, Hydroxyethylcellulose, Hydroxypropylcellulose, Cyclodextrins, Pectin, Galactomannan
Insoluble or enteric polymers	Hydroxypropylmethylcellulosephthalate, Eudragit L-100, Eudragit S-100, Eudragit RL, Eudragit RS
Surfactants	Polyoxyethylene stearate, Polyoxyethylene stearate, Poloxamer 188, Deoxycholic acid, Tweens, Spans
Miscellaneous	Pentaerythritol, Pentaerythrityltetracetate, Urea, Urethane, Hydroxyalkylxanthins