INTRODUCTION:

Product development scientists often encounter significant difficulties in solving the problem of poor water solubility of drug candidates in the development of pharmaceutical dosage forms^1-4. As a matter of fact, more than one third of the drugs listed in the U.S. Pharmacopoeia fall into the poorly water soluble or water insoluble categories⁵.It was reported a couple of decades ago that more than 41% of the failures in new drug development have been attributed to poor biopharmaceutical properties, including water insolubility^{6, 7},while it was still indicated recently that about 50% failure of drug candidates was due to poor “drug - like” properties ⁸. It is commonly recognized in the pharmaceutical industry that on average more than 40% of newly discovered drug candidates are poorly water soluble.

Drug absorption from the gastrointestinal tract (GIT) can be limited by a variety of factors with the most significant contributors being poor aqueous solubility 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 GIT to reach systemic circulation.

Therefore, a drug with poor aqueous solubility will typically exhibit dissolution rate limited absorption. Modified Noyes-Whitney equation ^{9, 10} (eqⁿ-1) provides some hints as to how the dissolution rate of poorly soluble drugs might be improved:

(1)

Where dc/dt is the rate of dissolution, A is the surface area available for dissolution, D is the diffusion coefficient of the compound, Cs in the solubility of the compound in the dissolution medium, C is the concentration of drug in the medium at time t and h is the thickness of the diffusion boundary layer adjacent to the surface of the dissolving compound.

The main possibilities for improving dissolution according to this analysis are to increase the surface area available for dissolution by decreasing the particle size of the solid compound. However, micronization has several disadvantages like limited opportunity to control size, shape, morphology, surface properties and electrostatic charges of final particles. Therefore, the most attractive option for increasing the release is improvement of the solubility through formulation approaches. Various formulation approaches have been developed for solubility enhancement for poorly water soluble drugs including salt formation, use of surfactant, use of prodrug, alteration in pH, complexation with polymers, change in physical form, inclusion complexation with cyclodextrin derivatives and the formation of solid dispersions with water soluble carriers¹¹.

Among the various strategies, formulations of solid dispersions with carriers have been successfully used for enhancing dissolution of poorly water soluble drugs ^12-15. Studies revealed that drugs in solid dispersion need not necessarily exist in the micronized state. A fraction of the drug might molecularly disperse in the matrix, thereby forming a solid dispersion^{16, 17}. When the solid dispersion is exposed to aqueous media, the carrier dissolves and the drug releases as fine colloidal particles. The resulting enhanced surface area produce higher dissolution rate and bioavailability of poorly water soluble drugs. In addition, in solid dispersion, a portion of drug dissolves immediately to saturate gastrointestinal tract fluid and enters drug precipitates as fine colloidal particles. This review is devoted to a discussion of the various carrier used for the preparation of solid dispersion.

CARRIERS USED IN SOLID DISPERSIONS:

Polyethylene Glycol (PEG):

The polyethylene glycols (PEG) are a series of water soluble synthetic polymers obtained by catalytic condensation of ethylene oxide and water. The general formula of these compounds belongs to:

HO – CH₂ – CH₂ – [O - CH₂ – CH₂]_n – OH

Where n represents the average number of oxyethylene groups (- OCH₂CH₂-), i.e. the degree of polymerization ¹⁸. PEGs are available in a wide molecular weight range (MW), ranging at room temperature from liquids (MW: 200-600), semi solids with a vaseline like consistency (MW: 800-1500), waxy (MW: 2000-6000) and above 20000, they form hard and brittle crystals. The average molecular weight and melting point of some commonly PEGs are given in Table 1.

Table1: Molecular weight and melting point of typical polyethylene glycol polymers.

Grade	Average molecular weight	Melting point
PEG – 1000	950-1050	37 – 40⁰C
PEG – 1500	1300 – 1600	44 – 48⁰C
PEG – 1540	1300 – 1600	40 – 48⁰C
PEG – 2000	1800 – 2200	45 – 50⁰C
PEG – 3000	2700 – 3300	48 – 54⁰C
PEG – 4000	3000 – 4800	50 – 58⁰C
PEG – 6000	7000 – 9000	55 – 63⁰C
PEG – 8000	7300 – 9300	60 – 63⁰C
PEG – 20000	15000 – 25000	60 – 63⁰C

Their solubility in water is generally good, but decreases with molecular weight. These polymers have a wide range of applications in the pharmaceutical field. Although around thirty different materials including polymers have been proposed as carriers for the elaboration of solid dispersions, in particular PEG based polymers have been extensively used with advantages due to their favorable solution properties, low toxicity and low cost^19-21. Moreover, they are the carriers of selection in the preparation of solidified melts, because they display a low melting point and their molecular size favors the formation of interstitial solid solutions with drugs. Besides this, the high viscous nature of the melts tends to entrap the drug in a molecular state or to form micro particles.

The polyethylene glycols used for the majority of solid dispersion studies (molecular weight 4000 – 2000) may exist in more than one crystal form, exhibiting multiple melting points in the region of 55 – 65⁰C^22,23. It has been suggested that many of the dual melting points described in the literature ascribed to eutectic behavior may in fact be chain folded forms of the PEG itself ²⁴. Polyethylene glycol is a hydrophilic polymer often used to prepare solid dispersions with the melting method. After melting, the next difficult step in the preparation of solid dispersions was the hardening of melts so that they could be pulverized for subsequent formulation into powder filled capsules or compressed tablets. Chiou and Riegelman ²⁵ facilitated hardening of the griseofulvin-PEG 6000 solid dispersion by blowing cold air after spreading it on a stainless steel plate and then storing the material in a desiccators for several days. Nifedipine – PEG 6000 solid dispersion²⁶ prepared by blending physical mixtures of the drug and the carrier in a v-shaped blender and then heating the mixture on a hot plate at 80 – 85⁰C until they were completely melted. The melts were rapidly cooled by immersion in a freezing mixture of ice and sodium chloride, and the solids were stored for 24 hours in desiccators over silica gel before pulverization and sieving. Mura at al¹³ solidified naproxen – PEG melts in an ice bath and the solids were then stored under reduced pressure in desiccators for 48 hours before they were ground into powders with a mortar and pestle. Mefenamic acid – PEG solid dispersion²⁷ were prepared by heating the drug carrier mixture on a hot plate to a temperature above the melting point of mefenamic acid and then cooling the melt to room temperature under a controlled environment.

Another commonly used method of preparing a solid dispersion is the dissolution of drug and carriers in a common organic solvent, followed by the removal of solvent by evaporation. Because the drug used for solid dispersion is usually hydrophobic and the carrier is hydrophilic, it is often difficult to identify a common solvent to dissolve both components. Chiou and Riegelman ²⁵ used 500 ml of ethanol to dissolve 0.5 g of griseofulvin and 45 gm of PEG 6000. The resultant ethanolic solution of griseofulvin and PEG 6000 was dried in an oil bath at 115⁰C until there was no evolution of ethanol bubbles. The viscous mass was then allowed to solidity by cooling in a stream of cold air.

McGinity et al²⁸ prepared solid dispersions of tolbutamide in PEG 6000 by flash cooling in a bath of dry ice and acetone or by gradual cooling over a period of several hours by immersion in an oil bath. In the powder X-ray diffraction patterns of tolbutamide-PEG 6000 solid dispersions, peaks for both tolbutamide and PEG 6000 were observed; however, their degree of crystallinity in flash cooled samples were less than that in the slow cooled samples. In another study, a metastable amorphous form of nifedipine was formed in its solid dispersions in PEG 4000 and PEG 6000 when the drug carrier melts were cooled rapidly, whereas slow cooling of melts or powdering of solidified mass resulted in the crystallization of drug ²⁹. Gines et at³⁰ studied the effect of fusion temperature on oxazepam-PEG 4000 solid dispersions. Macroscopic examination revealed the presence of crystalline oxazepam and the spherulitic form of PEG 4000 in solid dispersions prepared by fusion at 100⁰C. In contrast, a fusion temperature of 150⁰C produced a solid dispersion with no crystalline form of the drug and the presence of PEG 4000 in a hedritic form. Complete dissolution of drug in the carrier at 150⁰C in contrast to 100⁰C was reported to be responsible for such a difference in physico-chemical properties of the solid dispersions produced.

Corrigan ^31,32 provided a very valuable contribution by not only measuring the dissolution rate of the incorporated drug but also assessing that of the polymer itself, in this case PEG. The author found that the dissolution rate of the drug in the polymer and the polymer alone were in part equivalent, leading to the suggestion of carrier controlled dissolution whereby the dissolution rate of the drug is controlled by that of the inert carrier. This finding was supported by the work of Dubois and Ford ³³ who noted that the dissolution rates of a range of drugs in a single carrier, prepared under comparable conditions, were identical in most cases. This again implies that it is the dissolution rate of the carrier and not the drug that may dominate the process. Similarly, a study by Craig and Newton ³⁴ indicated that a log-linear relationship existed between the molecular weight of the PEG carrier and the dissolution rate, again implying that the properties of the polymer were dominating the dissolution process. Lloyed et al ³⁵ argued that it dissolution was dominated by the properties of the carrier and not the drug (at least in some cases) then the physical form of the drug should be irrelevant to the release rate. These authors examined the released of paracetamol from PEG 6000 dispersions, using different drug size fractions in the initial preparation processes and different manufacturing methods which were known to alter the physical properties of the drug³⁶. First inspection of the dissolution data indicated a higher release from the larger size fraction systems. However, these authors also measured the concentration of drug at the dissolving surface, finding that settling had occurred during the solidification process on cooling from the melt. Once this had been corrected for, the dissolution rates were found to be independent of manufacturing conditions or initial particle size.

The drug/carrier ratio in a solid dispersion is one of the main influences on the performance of a solid dispersion. If the percentage of the drug is too high, it will form small crystals within the dispersion rather than remaining molecularly dispersed. On the other hand, if the percentage of the carrier is very high, this can lead to the complete absence of crystallinity of the drug and thereby enormous increase in the solubility and release rate of the drug. Lin and Cham ²⁶ showed that solid dispersions of naproxen in PEG 6000 released drug faster when a 5 or 10% naproxen loading was used than when a 20, 30 or 50% loading was used. These results could be explained on the basis of X-ray diffraction results, which indicated that dispersions with low loading levels of naproxen were amorphous whereas those with high loadings were partly crystalline. An increase in the release rate by formulation as a solid dispersion in PEG has been observed for many drugs partial (Table-2):

Table 2: List of drugs forming solid dispersion with PEG

Drug	Reference
Oxazepam	30
Piroxicam	37
Zolpidem	38
Glyburide	39
Triamterene	40
Nitorfurantoin	41
Norfloxacin	42
Ketoprofen	43
Nifedipine	44
Phenytoin	45
Fenofibrate	46
Prednisolone	47

Some of the challenges in the dosage from development of PEGs are difficulty of pulverization and sifting of the dispersions, which are usually soft and tacky, poor flow properties of powders thus prepared, poor compressibility, drug carrier incompatibility, and poor stability of dosage form. In developing a tablet formulation for the indomethacin – PEG 6000 solid dispersion ⁴⁸, the solid dispersion was not amenable to wet granulation because water could disrupt its physical structure. In addition, the dispersion was soft and tacky. To overcome these problems, the authors adopted an in situ dry granulation method where the excipients (calcium hydrogen phosphate and sodium starch glycolate), were preheated and rotated a water jacketed blender at 70⁰C and the indomethacin – PEG 6000 mixture that melted at 100⁰C was then added to the moving powder. After mixing, the granules were passed through a 20 mesh sieve and allowed to harden at 25⁰C for 12 hours. Then the granules were mixed with a relatively high concentration of magnesium stearate and compressed into tablets. To process 100 mg of solid dispersion, 506 mg of other excipients were used thus making the final weight of a 25 mg indomethacin tablet 606 mg.

The lack of disintegration and the slow dissolution of tablets prepared from solid dispersions could be related to the soft and waxy nature of carriers used (e.g., PEG) in many of the reported studies. Such carriers essentially act as strong binders within tablets. During compression, the carriers could plasticize, soften or melt, filling the pores with in tablets and thus making them non-disintegrating. It is also possible that the soften and melted carriers coat the disintegrants and other ingredients used in tablets, and such a coating, along with the reduction of porosity of tablets, make the disintegrants ineffective. Use of a very high ratio solid dispersion to added excipient might alleviate the problem.

Polyvinyl pyrrolidone (PVP):

The USP describes polyvinyl pyrrolidone as a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidone groups. Polymerization of vinyl pyrrolidone leads to polyvinyl pyrrolidone of various molecular weights. It is characterized by its viscosity in aqueous solution, relative to that of water, expressed as a K-value, ranging from 10 to 120. The K-value is calculated using Fikentschis equation ⁴⁹. Approximate molecular weights for different PVP grades are shown in Table 3.

Table 3: Approximate molecular weight for different grades of PVP ⁴⁹.

K-Value	Approximate molecular weight
12	2,500
15	8,000
17	10,000
25	30,000
30	50,000
60	4,00,000
90	10,00,000
120	30,00,000

PVP is widely used excipients in the field of pharmaceutics as a binder and coating agent in solid dosage formulations and as a suspending, stabilizing, and viscosity increasing agent in liquid and semisolid formulations ^{50, 49}. Moreover PVP has been proposed for the dissolution enhancement of very slightly soluble drug substances by the solid dispersion technique and by its ability to interact with certain drug molecules⁵⁰. The glass transition temperature of PVP is high. For this reason PVPs have only limited application for the preparation of solid dispersions by melting method. Due to their good solubility in a wide variety of organic solvents, they are particularly suitable for the preparation of solid dispersions by the solvent method. Solid dispersions of andrographolide with PVP-K30 were prepared by a spray drying technique using different ratios of drug to polymer ⁵¹. A five-fold increase in saturation solubility of andrographolide was observed in different dissolution mediums. This was attributed to the formation of amorphous nature and intermolecular hydrogen bonding between drug and PVP K30. The stability showed there to be no significant change in molecular pharmaceutical properties and dissolution profile over the period of 3 months. Kubo et al ⁵² prepared solid dispersion system of probucol-PVP in various weight ratios. Dissolution of probucol was markedly increased in the solid dispersions system. Following the administration of solid dispersion system in rabbits, a marked increase in the area under the plasma concentration time curve (AUC) was observed. When the weight ratio of PVP to probucol was larger, a larger AUC was also observed. Pharmaceutical availability of dispersion, oxazepam and nitrazepam from solid dispersion of PVP have been studied in comparison to those of the corresponding physical mixtures and pure benzodiazepins⁵³. The solubility of diazepam, oxazepam and nitrazepam from its solid dispersion has been found to increase in presence of PVP. Solid dispersions of piroxicam in PVP were prepared by precipitation with compressed antisolvent (PCA) and spray drying techniques ⁵⁴. Physico-chemical characterization by X-RD, FTIR and DSC showed that piroxicam was amorphously dispersed in both solid dispersion systems with the drug to polymer weight ration of 1:4. PCA- processed solid dispersions showed distinctly superior performance in that piroxicam dissolved completely within the first 5 minutes and the dissolution rate was at least 20 times faster than raw drug did within the first 15 minutes.

Doharty and York⁵⁵studied the release behaviors of furosemide/PVP dispersions as a function of the degree of crystallinity of the preparation. When solid comprising 50% furosemide was prepared, crystalline regions could be detected by X-ray diffraction. In contrast, when the drug/carrier ration was 2:3, the dispersion was amorphous. Dispersions containing crystalline areas exhibited biphasic release profiles, with the amorphous areas dissolving quickly and the crystalline areas more slowly. In one study, the release rates from solid dispersion of etopiside in PEGs and PVPs were compared ⁵⁶. PVP K25 produced faster released than PEG 3400, 6000 or 8000. On the other hand, the released rate from PEG 3400 and 6000 was higher than from PVP K17. Studies with coevaporate of chloramphenicol and PVP revealed that the dissolution of chloramphenicol was slower when PVPs of higher MW were used as the carrier ⁵⁷. Similarly, the slower dissolution of indomethacin from PVP K90 compared to PVP K12 was attributed to the higher viscosity generated by PVP K90 in the diffusion boundary layer adjacent to the dissolving surface of the dispersion ⁵⁸.

Marsac et al ⁵⁹ studied the effects of temperature and relative humidity on the miscibility of a felodipine-PVP solid dispersion. Solid dispersion showed evidence of adhesive hydrogen bonding interactions at all compositions studied. The dug polymer intermolecular interactions were weakened and/or less numerous on increasing the temperature, but persisted up to the melting temperature of the drug. Changes in the hydrogen bonding interactions were found to be reversible with changes in temperature. In contrast, the introduction of water into amorphous molecular level solid dispersions at room temperature irreversibly disrupted interactions between the drug and the polymer resulting in amorphous-amorphous phase separation followed by crystallization. In one study ⁶⁰ compared the effects of polymer type and storage relative humidity on the crystallization kinetics of felodipine from amorphous solid dispersions. Felodipine crystallization rates from PVP containing dispersions were found to be very sensitive to changes in storage RH, while crystallization rates from HPMCAS- containing dispersions were not. PVP and HPMCAS were similar in terms of their ability to inhibit crystallization at low RH, but when the storage RH was increased to 75% or above, felodipine crystallization from PVP-containing solid dispersions proceeded much faster. Rumondor et al ⁶¹ investigated the phase behavior of amorphous solid dispersions composed of some hydrophobic drugs with PVP. Complete miscibility between the drug and the polymer immediately after solid dispersion formation was confirmed by the presence of specific drug polymer interactions and a single glass transition event. Following storage at elevated relative humidity (75-94% RH), nifedipine-PVP, droperidol-PVP, and pimozide-PVP dispersions formed drug rich and polymer- rich amorphous phases prior to crystallization of the drug, while indomethacin PVP and Ketoprofen-PVP dispersions did not. Papageorgiou et al ⁵³ evaluated the effect of PVP, eudragit RS100, and chistosan on fluvastatine stability during storage. The characterization by DSC and wide angle X-ray diffractometry (WAXRD) showed that amorphization of the drug occurred in all of the solid dispersions of fluvastatine as a result of drug dissolution into polymer matrices and due to physical interactions (hydrogen bonding) between the polymer matrix and fluvastatine. SEM and Mino-Raman spectroscopy showed that fluvastain was interspersed to the polymer matrices in the form of molecular dispersion and nanodispersion, too. Marasac et al ⁶²compared the physical stability of amorphous molecular level solid dispersions of nifidipine and felodipine, in the presence of PVP and small amounts of moisture. Nifedipine crystallizes more easily than felodipine at any given polymer concentration and in the presence of moisture. The glass transition temperatures of each compound, alone and in the presence of PVP, are statistically equivalent at any given water content. The nifedipine systems are significantly more hygroscopic than the corresponding felodipine systems. Table 4 list some of the drugs used to prepare solid dispersion with PVP.

Table 4: Drugs used to prepare solid dispersion with PVP.

Drug	Method of preparation	Carriers	Reference
Diazepam and Nifedipine	Lyophilizaion	PVP K12, K30 and K60	63
Andrographolide	Spray-drying	PVP-K30	51
Piroxicam	Precipitation with compressed anti solvent and spray drying	PVP	54
Esomeprazole Zinc	Solvent evaporation method	PVP-K30	64
Indomethacin	Solvent evaporation method	PVP-K30, K90	65
Lovastatine	Solvent evaporation method	PVP-K30	66
Etoricoxib	Solvent evaporation method	PVP-K30	67
Cefuroxime axetil	Solution enhanced dispersion by super initial fluids	PVP-K30	68

Hydroxypropyl methylcellulose (HPMC):

HPMCs are mixed ethers of cellulose, in which 16.5-30% of the hydroxyl groups are methylated and 4-32% is derivatized with hydroxypropyl groups. HPMC defined in the USP specifies the substitution type by appending a four digit number to the nonproprietary name; e.g., HPMC 1828. The first two digits refer to the approximate percentage content of the methoxy group (OCH₃). The second two digits refer to the approximate percentage content of the hydroxypropoxy group (OCH₂CH (OH) CH3), calculated on the dry basis. The molecular weight of the HPMCs ranges for about 10,000 to 1,500,000 and they are soluble in water and mixture of ethanol with dichloromethane and methanol with dichloromethane⁶⁹. Engers et al ⁷⁰prepared itraconazole solid dispersion with different polymers at varied concentration. Among the various formulations, a 1:2 (w/w) itraconazole/HPMC dispersion showed best result. They compared a simple formulation of 1:2 (w/w) itraconazole/HPMC dispersion in a capsule to crystalline itraconazole in a capsule in dogs bioavailability study, with the dispersion being significantly more bio-available. Ibuprofen loaded solid dispersions with HPMC and poloxamer were reported to enhance solubility and bioavailability ⁷¹. The solid dispersion composed of ibuprofen /HPMC/Poloxamer at the weight ratio of 10:3:2 improved the drug solubility approximately 4 fold. It gave significantly higher initial plasma concentration, AUC and C_max of drug than did ibuprofen powder in rats. Douroumis et al ⁷²studied the dissolution behavior and interactions of various drugs with HPMC in solid dispersion. The FTIR spectra of carbamazepine and oxcarbazepine demonstrated drug interactions with HPMC through hydrogen polymer bonds. Thus solid dispersions of these drugs had on improved dissolution profile. In contrast, solid dispersions of rufinamide showed modest enhancement of dissolution, suggesting negligible drug polymer interactions. The different dissolution behaviors are attributed to the extent of interactions between the polymer hydroxyl group and the drug amide groups. In one study, HPMC was used to improve the dissolution rate and bioavailability of albendazole, as poorly water soluble drug, in beagles ⁷³. In another study, solid dispersion of HPMC with nifedipine showed a higher nifedipine dissolution rate when compared to solid dispersions prepared with methyl cellulose and hydroxyproply cellulose⁷⁴. HPMC was applied to a number of poorly soluble drugs including UC 781⁷⁵, Cerbemezepine⁷⁶, Itraconazole⁷⁷, Sibustramine⁷⁸, to improve solubility.

Crospovidone:

Crospovidone is a water insoluble synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidinone. It rapidly exhibits high capillary activity and pronounced hydration capacity, with little tendency to form gels. With the technique of co-evaporation, crospovidone can be used to enhance the solubility of poorly soluble drugs. The drug is adsorbed on to crospovidone in the presence of a suitable solvent and the solvent is then evaporated. This technique results in faster dissolution rate. In one study, a 1:2 ratio of furosemide to crospovidone led to an increase in the dissolution rate by a factor of 5.8⁷⁹ in comparison with either the drug powder or a physical mixture of furosemide with crosspovidone. The mechanism of the increase in the release rate of furosemide proved to be the presentation of the drug in the amorphous form in the dispersion, as shown by X-ray diffraction studies. Mohammadi et al ⁸⁰compared dissolution profile of ibuprofen from its solid dispersion with crospovidone, microcrystalline cellulose, and oleaster powder. The efficiency of the carriers for dissolution enhancement was in the order of: crospovidone > oleaster powder > microcrystalline cellulose. The DSC thermo grams and X-ray diffraction patterns revealed a slight reduced crystallinity in the SDs. Solid dispersion of indomethacin with crospovidone was prepared using a twin-screw extruder or Kneader ⁸¹. The solubility of solid dispersion powders of indomethacin was improved about four-fold compared to crystalline indomethacin. Xu et al ⁸²prepared and evaluated ibuprofen solid dispersion systems with crospovidone using a pulse combustion dryer system. The dissolution property of ibuprofen in the solid dispersions was markedly enhanced. The dissolution test showed that after 5 minutes of dissolution, the concentration of ibuprofen in the solid dispersion with Kollidon CL as the carrier was 43.81 mg/ml, corresponding to 13 times that of pure ibuprofen. Powder X-ray diffraction showed that the crystal diffraction peaks of ibuprofen in solid dispersions disappeared completely. Hirasawa et al ⁸³stabilized the nilvadipine-crospovidone solid dispersion by the use of ternary systems. XRD and DSC studies showed that re-crystallization occurred during storage and that the dissolution of nilvadipine greatly decreased, compared with that of the initial finding. The dissolution properties of nilvadipine/crosponidone/methyl cellulose solid dispersion system were characterized by crospovidone markedly enhancing the dissolution of nilvadipine and methyl cellulose inhibiting the change of the dissolution of nilvadipine during storage.

Polyvinyl Alcohol (PVA):

Polyvinyl alcohol is water soluble synthetic polymer represented by the formula (C₂H₄O)_n. The value of n for commercially available materials lies between 500 and 5000, equivalent to a molecular weight range of approximately 20,000-2, 00,000. When solid dispersions of nifedipine were prepared with carrier mixtures consisting of nicotinamide and PVP, HPMC or PVP in a drug/nicotinamide/polymer ratio of 1:3:1, those prepared with PVA dissolved 20 time as fast as the drug alone ⁸⁴. However, the other carriers, HPMC and PVP, yielded even better results.

Eudragit:

Polyacrylates and polymethacrylates on glassy substances that are produced by the polymerization of acrylic and methacrylic acid, and derivatives of these polymers such as esters, amides and nitriles. Commonly they are referred to by the trade name Eudragit⁸⁵. Several different types are commercially available and may be obtained as the dry powder, as an aqueous dispersion, or as an organic solution. Eudragit E is cationic polymer based on dimethyl-amino ethyl methacrylate and other neutral methacrylic acid esters. It is soluble in gastric fluid as well as in weakly acidic buffer solutions (up to pH~5). Eudragit L and S, also referred to as methacrylic acid co-polymers, are anionic copolymerization products of methacrylic acid and methyl methacrylate. The ratio of free carboxyl groups to the ester is approximately 1:1 in Eudragit L and approximately 1:2 in Eudragit S. Both polymers are readily soluble in neutral to weakly alkaline conditions (pH 6-7) and form salts with alkalis, thus affording film coats that are resistant to gastric media but soluble in intestinal fluid. Eudragit RL and Eudragit RS, also referred to as ammonio methacrylate copolymers, are copolymers synthesized from acrylic acid and methacrylic esters, with Eudragit RL having 10% of functional quartarnary ammonium groups and Eudragit RS having 5% of functional quaternary ammonium groups. The ammonium groups are present as salts and give rise to P^H- independent permeability of the polymers. The dissolution rate of piroxicam was improve from its solid dispersion with Eudragit S100⁸⁶. XRD and DSC analysis indicated that the drug was in the amorphous state. That amorphous piroxicam in the solid dispersion particles did not crystallize under storing at 40⁰C, 75% RH for 3 months. Goddeceris et al ⁸⁷enhanced dissolution of the anti HIV drug UC 781 by formulation in a ternary solid dispersion with TPGS 1000 and Eudragit E100. The release of UC 781 in a medium simulating the gastro intestinal lumen was markedly enhanced, reaching a release of 70% w/w after 4 hours. Zhing et al ⁸⁸prepared nimodipine solid dispersion by hot-melt extrusion using HPMC, PVP/VA, and Eudragit EPO. Solid dispersion prepared by hot-melt extrusion improved the dissolution rate of nimodipine. From the XRPD and DSC data it was showed that, nimodipine acted as a plasticizer for PVP/VA and EPO and was miscible with the polymers, because a single T(g) was observed in these extrudes. In one study, Zheng et al ⁸⁹studied bioavailability in beagle dogs of nimodipine solid dispersion prepared by hot-melt extrusion. The mean bioavailability of nimodipine was comparable after administration of the Eudragit EPO solid dispersion and marketed product Nimotop, but the HPMC and PVP/VA dispersions inhibited much lower bioavailability. However, the AUC (0-12 hours) values of all three solid dispersions were significantly higher than physical mixtures with the same carriers and nimodipine powder. Valizadeh et al ⁹⁰prepared and characterized solid dispersions of piroxicam with hydrophilic carriers. The dissolution rate of piroxicam was markedly increased in solid dispersion of myrj 52, Eudragit E 100 and mannitol. The solubility and dissolution rate of various drugs can be increased with Eudragit including metoprolol⁹¹, propranolol hydrochloride⁹², indomethacin⁹³, ibouprofen⁹⁴, coenzyne 10⁹⁵, furosemide⁹⁶.

Hydroxypropyl methyl cellulose phthalate (HPMCP):

HPMCP is cellulose in which some of the hydroxyl groups are replaced with methyl ethers, 2-hydroxy-propyl ethers, phthalyl esters. Several different types of HPMC are commercially available with molecular weight in the range 20,000 – 2,00,000⁹⁷, HPMC is insoluble in gastric fluid but will swell and dissolve rapidly in the upper intestine. Solid dispersion of nitrendipine-carbopol and nitrendipine-HPMC systems were prepared using a twin screw extruder ⁹⁸. Nitrendipine carbopol solid dispersion were found to give somewhat higher dissolution than crystalline nitrendipine and physical mixtures, while the dissolution of nitrendipine – HPMC solid dispersions was markedly decreased compared with the crystalline nitrendipine and physical mixture. Using a spray drying technique to form a solid dispersion in HP55, the dissolution rate of the anti-fungal drug MFB 1041 could be increased by a factor of 12.5 as compared to the best possible dissolution achievable by micronizing the drug⁹⁹. Furthermore, the oral bioavailability in beagles was almost 17 times better following administration of the drug in solid dispersions form.

Urea:

Urea is the end product of human protein metabolism, has a light diuretic effect and is regarded as non-toxic. Its solubility in water is greater than 1 in 1 and it also exhibits good solubility in many common organic solvents. The studies as dissolution enhancement of rofecoxib using urea were showed dissolution improvement of the drug¹⁰⁰.Suzuki at al ¹⁰¹compared dissolution of nifedipine solid dispersion using nicotinamide, ethylurea and polyethylene glycol as carriers. Compared with the physical mixtures, the solid dispersion with ethyl urea or PEG led to a higher dissolution rate of the drug, whereas the difference in drug release between the physical mixtures and the solid dispersions with nicotinamide was not clear. In one study tablets were prepared using amylobarbitone-urea solid dispersion¹⁰². Dissolution rate studies showed that the urea/amylobarbitone (80:20) solid dispersion exhibited better rates of dissolution than those of the pure drug. The drug releases from these tablets were 7.6 times greater than that form tablets prepared from pure amylobarbitone. In the case of ursodeoxycholic acid the release rate from urea dispersion prepared by the hot melt method were faster than from other carriers studied, including PEG 6000¹⁰³. A two-fold increase in the dissolution rate of phenytoin has also been achieved with urea; however, in this case PEG 6000 was more efficient ¹⁰⁴.

Carboxy methyl cellulose sodium (Na-CMC):

Carboxy methyl cellulose sodium is the sodium salt of a polycarboxymethyl ether of cellulose. A number of grades of carboxymethylcellulose sodium are commercially available. These have a degree of substitution (DS) in the range 0.7-1.2. The DS is defined as the average number of hydroxyl groups substituted per anhydroglucose unit and it is this that determines the aqueous solubility of the polymer. Park et at¹⁰⁵prepared tacrolimus – loaded solid dispersion with Na-CMC and sodium lauryl sulphate. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulphate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. Similarly Ugaowkar et al¹⁰⁶ enhanced dissolution of carbamazepine using Na-CMC in solid dispersion.

Hydroxy propyl cellulose (HPC):

Hydroxypropyl cellulose is partially substituted poly (hydroxypropyl) ether of cellulose. HPC is commercially available in a number of different grades that have various solution viscosities. HPC is freely soluble in water below 38⁰C, forming a smooth, clear, colloidal solution. In hot water, it is insoluble and is precipitated as a highly swollen flock at a temperature between 40 and 45⁰C. HPC is soluble in many cold or hot polar organic solvents such as dimethyl formamide, dimethyl sulfoxide, dioxane, ethanol, methanol, proprane-2-ol (95%), and propylene glycol. Yamada et al ¹⁰⁷ prepared solid dispersion of anti-osteoporosis drug KCA-098 using HPC by the solvent method. The KCA-098/HPC (1:2) solid dispersion capsule showed a 3.5 fold increase in the initial concentration and 2.5 fold increase initial concentration of dissolved drug after 60 minutes, compared with the values for a physical mixture. The area under the plasma concentration curve of KCA-098 after oral administration of the KCA-098/HPC (1:2) solid dispersion capsule was three fold greater than that for the drug itself. Yuasa et al ¹⁰⁸ carried out intensive studies of the influence of the chain length and proportion of HPC in the solid dispersion on the release behavior of flurbiprofen. The release rate improved as the proportion of HPC was increased and when lower molecular weights HPCs were used as the carrier.

Surface active and self emulsifying carrier:

Fusion and solvent evaporation are most commonly used techniques to prepare solid dispersion in the laboratory scale. However, these methods have practical limitation in the scale to commercial production. Even methods such as hot melt extrusion, spray drying and super critical fluid technique have many challenges. For example, the drug and/or the carrier may not be stable at the high temperature needed for melt extrusion, a common solvent to dissolve both the relatively hydrophobic drug and the relatively hydrophilic carrier for the purpose of spray drying may not be available, and the super critical fluid technology may not be amenable and cost efficient in most cases. The introduction of surface active and self emulsifying excipients that are solid at room temperature represents a breakthrough in commercial development of solid dispersions. It has been reported that formulations incorporating these new excipients may not only increase dissolution rates of poorly water soluble drugs, but they may also be filled as their molten mass directly into hand gelatin capsules, this eliminating the need for additional unit operations such as milling, blending, sieving, and so forth.

Gelucire 44/14 is the surface active carrier used for the preparation of solid dispersion. Gelucire 44/14 is a mixture of glycerol and PEG 1500 esters of long chain fatty acids and is official in the European Pharmacopoeia as lauryl macrogol glycerides; the suffixes 44 and 14 in its name refer, respectively, to its melting point and hydrophilic-lipophilic balance (HLB) value. A solid dispersion of poorly soluble REV 5901 in Gelucire 44/11 under a fasting regimen had much higher bioavailability in human volunteers than that of a tablet formulation even though the micronized form of drug and a wetting agent were used in the tablet ¹¹⁸. The bioavailability of ubidecarenone in dogs from solid dispersion in Gelucire 44/14 and the Gelucire 44/14 lecithin mixture were 2 and 3 times higher, respectively, than that of commercially available tablet ¹¹⁰.

Another surface active carrier useful for preparing solid dispersion formulation is tocopheryl polyethylene glycol 1000 succinate (TPGS). Koo et al ¹¹¹reported that a solid dispersion of an anti-malarial drug, halofantrin, provided 5.7 times higher bioavailability than a conventional tablet formulation. In another study conducted in rats, the effect of TPGS on the solubility and permeability of paclitaxel was demonstrated by improving the bioavailability by four to six folds by co-administration with TPGS as compared to a formulation without TPGS ¹¹².

A commonly used surfactant, polysorbate 80, when mixed with solid PEG, has also been reported to be an alternative surface active carrier ^113,114. Polysorbate 80 is liquid at room temperature; it forms a solid matrix when it is mixed with a PEG because it incorporates within the amorphous regions of PEG solid structure. As much as 75% (w/w) poly sorbate 80 was incorporated, PEG remained semisolid, and the lowering of the melting temperature of the PEG used was <12⁰C ¹¹⁴. The PEG polysorbate carriers have been found to enhance dissolution ¹¹⁵, and bioavailability ¹² of drugs from the solid dispersions.

CONCLUSION:

The solubility of drugs in aqueous media is a key factor highly influencing their dissolution rate and bioavailability following oral administration, solid dispersions have attracted considerable interest as on efficient means of improving the dissolution rate and hence the bioavailability of a range of hydrophobic drugs. Many of the carriers that can be applied are already extensively used in the pharmaceutical industry as excipients, so additional toxicity studies above and beyond what is required for the drug itself should not be required. The possibility of combining several carriers to produce an optimized product further extends the range of possibilities for formulation.

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Received on 25.10.2010 Modified on 02.11.2010

Research J. Pharm. and Tech. 4(3): March 2011; Page 356-366

KEYWORDS: solid dispersion, polyethylene glycol, polyvinyl pyrrolidone, surface-active carriers