Current trends in solid dispersions techniques

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Mr. P.D.Chaudhari

Mr. P.D.Chaudhari

In recent years due to application of combinational chemistry and high-throughput screening during drug discovery, a majority of new drug candidates exhibits poor aqueous solubility, compounds to be very challenging for formulation scientists in development of bioavailable dosage forms for such.

A poorly water soluble compound has classically been defined as one dissolving in less than 1part per 10000 part of water 1 A poorly water soluble drug, more recently, has been defined in general terms to require more time to dissolve in the gastrointestinal fluid than it take to be absorbed in the gastrointestinal tract2. Thus a greater understanding of dissolution and absorption behaviors of drugs with low aqueous solubility is required to successfully formulate them into bioavailable drug products.

Although salt formation, partical size reduction, etc. have commonly been used to increase dissolution rate of the drug, there are practical limitation with these techniques the desired bioavailability enhancement may not always be achieved. Therefore formulation approaches are being explored to enhance bioavailability of poorly water-soluble drugs. One such formulation approach that has been shown to significantly enhance absorption of such drugs is to formulate/prepare solid dispersion.

Chiou and Riegelman defined the term solid dispersion as

“a dispersion involving the formation of eutectic mixtures of drugs with water soluble carriers by melting of their physical mixtures”3.

The term solid dispersion refers to the dispersion of one or more active ingredient in an inert carrier or matrix at solid state prepared by melting (fusion), solvent, or the melting solvent method. Sekiguchi and Obi suggested that the drug was present in a eutectic mixture in a microcrystalline state4, after few years Goldberg et.al. reported that all drug in solid dispersion might not necessarily be presents in a microcrystalline state, a certain fraction of the drug might be molecular dispersion in the matrix, thereby forming a solid solution.5 Once the solid dispersion was exposed to aqueous media & the carrier dissolved, the drug was released as very fine, colloidal particles. Because of greatly enhanced surface area obtained in this way, the dissolution rate and the bioavailability of poorly water-soluble drugs were expected to be high. The commercial use of such systems has been limited primarily because of manufacturing problems with solid dispersion systems may be overcome by using surface active and self-emulsifying carriers. The carriers are melted at elevated temperatures and the drugs are dissolved in molten carriers.6

Surface-active agents are substances that at low concentrations adsorb onto the surfaces or interfaces of a system and alter the surface or interfacial free energy and the surface and the interfacial tension.7 Surface-active agents have a characteristic structure, possessing both polar (hydrophilic) and non-polar (hydrophobic) regions in the same molecule. The surface active carriers are said to be amphipathic in nature.

Surface active carriers uses in Pharmaceutical 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.7

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 Figure 1. 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.

solid dispersions techniques figure 1

Figure 1. A schematic representation of the comparative dissolution of a poorly water-soluble drug from surface-active versus non surface-active vehicle.8 

Block Copolymers as Pharmaceutical Surface active carriers:

The toxicity of many pharmaceutical surface active carriers has led to the search of more acceptable solubilizers. Soluble surface-active block copolymers of polyoxyethylene and polyoxypropylene have been used widely in pharmaceuticals and significantly found favor for such critical applications as emulsifiers for intravenous lipids and as priming agents for heart lung apparatus. A range of commercial block copolymer surface active carriers are available under the Pluronic, Pluronic R, Tetronic, and pluradot trade names; their preparation and properties have been reviewed by schmolka. The corresponding nonproprietary names of the first three types are Poloxamer, Meroxapols and Poloxamine, respectively, there being no equivalent name for the plurodot compounds.

Poloxamers are polyoxyethylene-polyoxypropylene-polyoxyethylene (ABA) block copolymers; The Meroxapols are polyoxypropylene-polyoxyethylene- polyoxypropylene (BAB) copolymers; The Poloxamine structure, (AB)2NCH2CH2N(BA) 2, is in full form as below.

[H (C2H4O) a (C3H6O) b]2NCH2CH2N[(C3H6O)b (C2H4O)aH]2

The Poloxamers have been most widely studied to date, yet there has been considerable confusion in the literature over the exact nature of their colloidal behavior, in particular whether micelles are formed. Recently, surface tension measurement on a series of Poloxamers in aqueous solution and photon correlation spectroscopy has helped to resolve some of these problems, but as benefits their structure their behavior patterns tend to be complex. At low concentrations, approximating those at which more conventional nonionic detergents form micelles, the Poloxamers monomers are thought to form monomolecular micelles by a change in configuration in solution. At higher concentration these monomolecular micelles associate to form aggregates of varying size, which have the ability to solubilize drugs and to increase the stability of solubilized agents.10

solid dispersions techniques fig 3

Figure 2. Schematic representation of block and random copolymer micelles10

The solubilities of some parasubstituted acetanilide in aqueous Poloxamers solutions increase with increasing ox ethylene content of the polymer, although the more hydrophobic solutes do not show this trend. The results show that, e.g., 4-nitroacetanilide is less soluble in more hydrophilic Poloxamers, and this is the general trend shown by the halogenated derivatives. Pluronic F68 solubilizes some benzocaine, which above an apparent CMC of 0.23% w/v has a slope for the solubility curve K, of 0.019, i.e., S= SO + K (Csurfactant - CMC) =SO +0.019(Csurfactant – CMC). The order for solubilization of benzocaine is Triton WR1339 (a tert-octylphenol with ethylene oxide) > Brij 35 > Tetronic 908 > Pluronic F68. At 3% levels the half-life of benzocaine is increased 4 times by Brij 35 and triton WR1399, but the limited solubility of benzocaine in Pluronic solutions results in only a marginal increase in half-life. Pluronic F68 lowers blood viscosity and has been advocated. Intravenous administration of Pluronic F38 is followed by rapid excretion in the urine; F68 appears in bile to the extent of 6% of the injected IV dose. Poloxamers 108 (Pluronic F38), although rapidly phagocytosed, is well tolerated even when administered intravenously in large doses.11

Pluronic block copolymers are synthesized by sequential polymerization of propylene oxide and ethylene oxide. It consists of combined chain of oxyethylene with oxy propylene where oxyethylene impart hydrophillicity whereas oxypropylene impart lipophilicity. Each molecule is synthesized as long segment of the hydrophilic portion combined with long segment of hydrophobic portion referred to as block copolymer. A defining property of Pluronic is ability of individual block copolymer molecules termed as “unimers “ to self assemble into micelles in aqueous solution. The “unimers” form a molecular dispersion in water at block copolymer concentrations below the critical micelle concentration. At concentration above CMC, the unimers molecule aggregate, forming micelles with propylene oxide bock in the inner core of micelles covered by the hydrophilic corona from ethylene oxide block. The water insoluble compounds are transpired into the propylene core of the micelles.

Block copolymer micelles are aggregates that resemble many properties of micelles formed by low molecular weight surface active carriers. They are the consequence of a self-assembling tendency displayed by block copolymers when dissolved in a so-called selective solvent, which is a good solvent for one of the blocks, but a poor one for the other. Solvent selectivity and, hence, copolymer self-assembling, have been observed for a variety of block copolymers in water, polar and non-polar organic solvents and, more recently, in supercritical fluids. For this generality and for the possibility of tuning the aggregate properties by varying either the kind of monomer or the size and proportion of the constituting blocks, these aggregates are able to provide a much wider range of applications than that observed for normal surface active carriers, involving solubilization of drugs or pollutants, as nonreactors, in controlled drug delivery and as potential DNA carriers, among others.9

Limitations of Surface active carrier based Solid Dispersions:

Solid dispersion in surface-active carriers may not be the answer to all bioavailability problems with poorly water-soluble drug. One of the limitations of bioavailability enhancement by this method might be the low solubility of drug in available carriers. The desired dose of a drug cannot be solubilized and filled into the hard gelatin capsules if adequate solubility in a carrier cannot be obtained. Dordunoo et al12 reported that the particle size of a drug in a solid dispersion remained unchanged if it is just mixed with the carrier instead of dissolving in it. On the other hand, if the drug is dissolved by heating in excess of its solubility in a carrier under normal storage condition, it may subsequently crystallize out from the solid dispersion. Either situation would defect the purpose of bioavailability enhancement of poorly water-soluble drugs by solid dispersion.

Another possible limitation of the use of surface-active carrier reported by Aungst et al.13 is that the bioavailability of a drug may vary depending on the amount of carrier administered along with it. This variation is because different amounts of a surface-active carrier may have different solubilization or dispersion effects on a drug in the gastrointestinal fluid. Serajuddin et al. reported a method whereby the rate and efficiency of dispersion of drug in aqueous media from different formulations can be studied.14

Newer techniques: -

The two important breakthrough in formulation of solid dispersion are, the development of technologies to fill solid dispersions directly in to hard gelatin capsule and the ability of surface active & self-emulsifying agents carriers. The technique to fill solid dispersion directly into hard gelatin capsule as melts, which gets solidify at room temperature, was first described by Francol’s & Jones in 1978. But the potential application of that technique was fully realized by Chatham. For ease of manufacturing the carriers must be amenable to liquid filling into hard gelatin capsules as melts. The melting temperature of carriers should be such that the solutions do not exceed ~70°C which is the maximum acceptable temperature for hard gelatin capsule shells.8

The water soluble carriers dissolves more rapidly than the drug, the drug rich layer has to form over the surface of dissolving plug, which prevent further dissolution of drug from solid dispersion because of this directly filled hard gelatin capsule is not a good method of preparation of solid dispersion unless the formation of drug rich layer on the surface of dissolving plug can be prevented.14

The self-emulsifying agent will act as dispersing or self –emulsifying agent on drug through which the dissolution of drug can be increase by preventing the formation of any water insoluble surface layer, although the liberated drug remain undissolved in the dissolution medium. When its concentration exceeded its saturation solubility, it will disperse or emulsify into a finely divided state because of the surface activity of the dissolved vehicle the high surface area will be made available which will facilitate its dissolution in gastrointestinal fluid.14 Serajuddin et al. has also studied improve dissolution of dispersions of REV-5901. He prepared solid dispersion of poorly water-soluble REV-5901 (alpha-pentyl-3- (2-quinolinylmethoxy) benzene methanol) in various PEG’s & in Gelucire ® 44/14 filled in to hard gelatin capsule, Gelucire® 44/14 formulation were able to promote complete & rapid drug dispersion in water & simulated gastric fluid. The PEG’s formulations by contrast were only effective in achieving partial drug dispersion. When the formulation with Gelucire® 44/14 can be filled into soft gelatin capsule without any change in solubilization characteristic of REV-5901 conversely the formulation with PEG-400 gives rise to drug crystallization due to water migration from the gelatin envelop to the fill, which lead to a 45% reduction in REV-5901 solubility.15

The most commonly used surface-active carrier is Gelucire® 44/14 & other grades of Gelucire® the carriers are prepared to have a high melting point but not more than 700 C so as to compatible to be filled in hard gelatin capsule. The grades of Gelucire® denote different no like Gelucire® 44/14, Gelucire® 50/13 in that first digit denote the melting point of carrier and second digit denote HLB value of carrier, on which the grades are differentiated & used as per for its different applications. Gelucire® 44/14 is a mixture of glyceryl & PEG-1500 ester of long-chain fatty acid  & is official in European pharmacopoeia as a lauryl macrogolglycerides.21

Dordunoo et al studied the effect of Gelucire® 44/14 for improving the solubility of Temazepam in comparison with various PEG’s & found Gelucire® 44/14 has shown large increase in its water solubility. Dordunoo et al has also studied the comparative dissolution of the hard gelatin capsule contain 12.5% of Triamterene dispersion in various PEG’s or in Gelucire® 44/14 with that of capsule containing the drug alone. The result of dissolution studies shown that dissolution of Triamterene without excipients was limited upto 30% only & with Gelucire® 44/14 or PEG-1000 was found to be 100% of active ingredient in less than an hour.18
For in-vivo study Aungst B.J. et al & his co-worker has work on improvement of oral bio-availability of an HIV Protease inhibitor using Gelucire® 44/14 & Labrasol vehicle.

DMP-323 is an HIV-Protease inhibitor exhibiting poor water solubility (< 10 micrograms /ml.). Aungst et al measured the apparent solubility of DMP-323 in aqueous dispersion of Gelucire® 44/14 or PEG-400 as a function of excipients concentration Gelucire® clearly improved the apparent solubility of drug while PEG-400 had no solubilization effect on the drug. 21

Chen et al improved the dissolution and bioavailability of ABT-963, a poorly water-soluble compound by preparing solid dispersion using Pluronic F-68 as a carrier by evaporation and hot melt method. The results show that solid dispersion is a promising approach for increasing oral bioavailability.17

Passerini et al prepared granules containing ibuprofen a poorly soluble model drug by melt granulation. The aim was to improve dissolution and its availability; using lactose as a diluent’s and Poloxamer 188 (Lutrol F68) as a new metastable hydrophilic binder. In the conclusion, it was suggested that melt granulation technique is a easy and a fast method to improve the dissolution rate of ibuprofen, using Poloxamer 188 as a new hydrophilic metastable binder.18

Vippagunta et al characterized the nature and solid state properties of solid dispersion system of Nifedipine in a polymer matrix consisting of Pluronic F 68 and Gelucire 50/13 in 1:1:1 ratio. The results indicate that the Nifedipine solid dispersion is physically stable. The release of Nifedipine was faster in solid dispersion than pure crystalline drug of the same particle.19

Chutimaworapan et al studied the enhancement in the dissolution rate of nifedepine with PEG 4000, PEG 6000 HP β-CD and Poloxamer 407 in different ratios and different methods. The solubility and wettability markedly improved in the Poloxamer 407 system.20

Table. Examples of surface-active carriers used for dissolution enhancement.

Sr. No.

Carrier

Drug

Scientist

1.

Poloxamer 188

Ibuprofen

Passerini et al

2.

Poloxamer 188

ABT-963

Chen et al

3.

Poloxamer 407

Nifedipine

Chutinawarapan et al

4.

Poloxamer 188, Gelucire 50/13

Nifedipine

Vippagunta et al

5.

Gelucire 44/14

REV 5901

Sheen et al

6.

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Gelucire 44/14

LAB-687

Serajuddin et al

7.

Mixture Gelucire 44/14-lecithin

Ubidecarenone

Pozi et al

8.

Gelucire 44/14 and PEG 6000

Glibenclamide

Tashtoush

9.

Gelucire 44/14, Vitamin E TPGS

Carbamazepine

Squillanate et al

10.

Gelucire, Capmul, Capmul MCM C10

Ceftriaxone

Seong-Wan CHO et al

11.

Polyethylene glycol

DMP 323

Aungst et al

12.

Mixture of Gelucire 50/13, Polysorbate 80, Polyoxyl 35 castor oil

Ritonavir

---

13.

PEG 3350- Labrasol-Polysorbate 80

RP 69698

Sheen et al

14.

PEG, Myrj 2, Eudragit E 100

Indomethacin

Hadi et al

Future 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.8

One major focus of future research will be identification of new surface-active carriers and self-emulsifying carriers for solid dispersion. Only a small number of such carriers are currently available for oral use. Some carriers that are used for topical application of drug only may be qualified for oral use by conducting appropriate toxicological testing. One limitation in the development of solid dispersion system may be the inadequate drug solubility in carriers, so a wider choice will increase the success of dosage form development. Research should also be directed toward identification of vehicles or excipients that would retard or prevent crystallization of drugs from supersaturated systems. Attention should also be given to any physiological and pharmacological effects of carriers used. Many of the surface-active and self-emulsifying carriers are lipidic in nature, so potential roles of such carriers on drug absorption, especially on their p-glycoprotein-mediated drug efflux, will require careful consideration. In addition to bioavailability enhancement, much recent research on solid dispersion systems was directed towards the development of extended-release dosage forms. It may be pointed out that this area of research has been reinvigorated by the availability of surface-active and self-emulsifying carriers and the development of new capsule filling processes. Because the formulation of solid dispersion for bioavailability enhancement and extended release of drugs may employ essentially similar processes, except for the use of slower dissolving carriers for the later use, it is expected that the research in these two areas will progress simultaneously and be complementary to each other.

References

  1. Martin.A.1993.Physical pharmacy. Pennsylvania: Lea&Febiger. 213.
  2. Horter D, DressmanJB.1997.influence of physicochemical properties on dissolution of drug in the gastrointestinal tract. Adv Drug del Rev53: 3-14.
  3. Chiou, W.L., Rielman, S., 1971.Pharmaceutical application of solid dispersion system.J.Pharm.Sci.60, 1281-1302.
  4. Sekiguchi, K; Obi, N. Studies on absorption of eutectic mixture. I A comparison of the behavior of eutectic mixture of sulfathiazole and that of ordinary sulfathiazole in man. Chem. Pharm. Bull., 1961, 9, 866-872.
  5. Goldberg, A. H.; Galbaldi, M.; Kanig, K, L. Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures III. Experimental evaluation of griseofulvin-succinic acid solution. J. Pharm. Sci. 1966, 55, 487-492.
  6. Serajuddin, A. T. M. Bioavailability enhancement of poorly water-soluble drugs by solid dispersion in surface active and self-emulsifying vehicles. Bull. Technique Gattefosse 1997, 90, 43-50. 
  7. Corrigan OI, Healy AM. Surface active carriers in pharmaceutical products and system: in “Encyclopedia of pharmaceutical technology”, New York, 2nd edition, Marcel Dekker Inc., 2002(3): 2639-2653.
  8. Christensen KL, Design of Redispersible Dry Emulsion: A Potential Oral Drug Delivery System. PhD Thesis 2000: 35-45.
  9. Loh W, Block Copolymer Micelle, Encyclopedia of Surface and Colloid Science, Marcel Dekker 2002: 802-813.
  10. Jones MC, Leroux JC. Polymeric Micelles- a new generation of colloidal drug carriers. Eur J Pharm Biopharm. 1999 (48): 101-111.
  11. Yalkowsky SH. “Techniques of solubilization of drugs”. New York. Marcel Dekker Inc. 1981: 77-80.
  12. Dordunoo SK, Ford JL, Rubinstein MH. Drug Dev Ind Pharm. 1991(17): 1685-1713.
  13. Ahmad M, Fattah A, Bhargava HN. Preparation and in vitro evaluation of solid dispersions of halofantrine. Int J Pharm. 2002(235): 17-33.
  14. Serajuddin ATM. Solid Dispersion Of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems, And Recent Breakthroughs. J Pharm Sci 1999; 88(10): 1058
  15. Serajuddin ATM, Sheen PC, Mufson D, Bernstein DF, Augustine MA. Effect of vehicle amphiphilicity on the dissolution and bioavailability of the poorly water-soluble drug from solid dispersion. J Pharm Sci. 1988(77): 414-417.
  16. Dordunoo SK, Ford JL, Rubinstein MH. Drug Dev Ind Pharm. 1991(17): 1685-1713.
  17. Chen Y, Zhang GGZ, Neilly J, Marsh K, Mawhinney D, Sanzgiri YD, Enhancing the bioavailability of ABT – 963 using solid dispersion containing Pluronic F –68. Int J Pharm. 2004; 286 (1-2): 69 – 80.
  18. Passerini N, Albertini B, Gonzalez-Rodriguez ML, Cavallari C, Rodriguez L. Preparation and characterization of ibuprofen-Poloxamer 188 granules obtained by melt granulation. Eur J Pharm Sci. 2002(15): 71 – 78.
  19. Vippagunta SR, Maul KA, Tallavajhala S, Grant DJW, Solid-State Characterisation Of Nifedepine Solid Dispersion. Int. J. Pharm 2002(236):111-123.
  20. Chutinawarapan S, Ritthidej GC, Yonemochi E, Oguchi T, Yamamoto K, Effect of water soluble carriers on the dissolution characteristics of Nifedipine Solid dispersions. Drug Dev Ind Pharm. 2000; 26(11): 1141-1150
  21. Gattefosse technical brochure, Pharmaceutical excipient for oral semisolids formulations.1999: 12-15.

 

About Authors

P.K.Sharma1*, P.D.Chaudhari2, M.M.Badagale2, K.D.Dave2, P.A.Kulkarni2 and N.S.Barhate2

 1 University institute of Pharmacy, Bundelkhand University, Jhansi, (UP), India.

2 Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune-18 (MS), India.

2Author Address of Correspondence:

Mr. P.D.Chaudhari, Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune-18 (MS), India. Email:pdchaudhari_21@rediffmail.com

Telephone - + 91 – 020 – 27420026, 27420261 Fax No.-  + 91 – 020 - 27420261

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Dr. P.K.Sharma*

M.Pharm, Ph.D, Head and Director of Pharmacy, University institute of Pharmacy, Bundelkhand University, Jhansi, (UP), India.

Mr. P.D.Chaudhari

Mr. P.D.Chaudhari

Asst. Professor, Dept. of Pharmaceutics,Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune-18 (MS), India

Mr. M.M.Badagale

Mr. M.M.Badagale

R & D Officer, Dr. Reddy’s Laboratory, Andhra Pradesh, India.

Miss. K.D.Dave

Miss. K.D.Dave

M.Pharm , Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune-18 (MS), India

Mr. P.A.Kulkarni

Mr. P.A.Kulkarni

M.Pharm, Sem IV, Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune-18 (MS), India


Mr. N.S.Barhate

Mr. N.S.Barhate

M.Pharm, Sem IV , Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune-18 (MS), India

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