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ENVIRONMENTAL FRIENDLY PHARMACEUTICAL EXCIPIENTS TOWARDS GREEN MANUFACTURING

Seema Pushkar1*, Nikhil K Sachan1, S.K. Ghosh2


2

University Institute of Pharmacy, C.S.J.M. University, Kanpur-208024 U.P. India Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh- 786004 Assam, India

ABSTRACT Drugs are rarely administered as pure chemical substances alone and are almost always given as formulated preparations or medicines. Drug dosage forms contain many components in addition to the active pharmaceutical ingredient(s) to assist in the manufacturing process as well as to optimize drug delivery. Nature has provided us a wide variety of materials to help improve and sustain the health of all living things either directly or indirectly. In recent years there have been important developments in different dosage forms for existing and newly designed drugs and natural products, and semi-synthetic as well as synthetic excipients often need to be used for a variety of purposes. The components employed as excipients must present the characteristics required by their technological function but, as with any substance administered to man, they must also correspond to suitable safety requirements. Since pharmaceutical natural excipients may be comply with many requirements such as nontoxicity, stability, availability and renewability they are extensively investigated for use in the development of solid oral dosage forms.

KEYWORDS: Pharmaceutical excipients, Natural excipients, Green pharmacy

OVERVIEW OF PHARMACEUTICAL EXCIPIENTS The International Pharmaceutical Excipients Council (IPEC, www.ipec.gov) defines an excipient as any substance other than the active drug or prodrug that is included in the manufacturing process or is contained in a finished pharmaceutical dosage form (1). Today's commercially available excipients provide a gamut of required functions, from processing aids that increase lubricity, enhance flowability, and improve compressibility and compatibility to agents that impart a specific functional property to the final product (e.g., modifying drug release). The US PharmacopeiaNational Formulary (USPNF) categorizes excipients as binders, disintegrants, diluents, lubricants, glidants, emulsifyingsolubilizing agents, sweetening agents, coating agents, antimicrobial preservatives, and so forth. In addition to their functional performance, ideally, excipients should be chemically stable, nonreactive with the drug and other excipients, inert in the human body, have low equipment and process sensitivity, have pleasing organoleptic properties, and be well characterized and well accepted by the industry and regulatory agencies. A limited choice of excipients with all of these attributes and presently available in the market can make formulation design and excipient selection challenging. Excipients are categorized as compendial or noncompendial materials. Compendial excipients have composition consistent with monographs published in compendia such as USPNF. Generally speaking, compendial excipients are the better characterized excipients and most likely to possess the desirable qualities previously stated. These materials are recognized as preferred excipients for pharmaceutical formulations. Noncompendial excipients might also be applied in pharmaceutical formulations. The use of these noncompendial materials is supported by Type IV drug master files (DMFs) in regulatory dossiers (i.e., new drug applications, abbreviated new drug applications, and investigational new drug applications). These files are maintained by excipient manufacturers with the agency and support the safety of the excipient as well as the quality and consistency of excipient manufacturing. There may be approved drug products containing noncompendial excipients, thereby demonstrating the acceptance of these excipients by the US Food and Drug Administration or other agencies in the major markets. For materials in which toxicity is a possible concern, formulators can gain information about the excipient's regulatory acceptance and allowable amount by consulting with excipient manufacturers and toxicology experts. This information also may be found in the Food Chemicals Codex, Code of Federal Regulations (CFR), FDA Inactive Ingredients Guide (2), and other references. In addition, 21 CFR parts 182 and 184 list generally regarded as safe (GRAS) food ingredients. PHARMACEUTICAL DEVELOPMENT: For lifecycle management, improved formulations replace or are marketed with already available products. By setting up an excipient formulary, which includes a sufficient number of carefully selected excipients and links to various unit processes, efforts can be geared toward a better understanding of excipients, functionality-test development, vendor relationships (e.g., vendor qualification), and second-vendor identification and qualification.The establishment of an excipient formulary can lead to more efficient use of available assets, decreased development times, harmonized specifications, worldwide formulation acceptance, and economy in product manufacturing.

Excipient selection in the drug productdevelopment phase focuses on the desirable characteristics (e.g., functionality, material consistency, regulatory acceptance, cost, availability, and sources). Ingredients derived from natural animal sources (e.g., gelatin, starch) have raised concerns of transmissible spongiform encephalopathy/bovine spongiform encephalopathy/genetically modified organism (TSE/BSE/GMO). A verification letter from a vendor of these natural materials is sufficient to support non-GMO or TSE/BSE implication for consumer protection. Some vendors also provide prionics-check certification for ingredients from animal sources. Imprudent selection of excipients and excipient vendors may lead to process-development problems (see sidebar "Potential problems related to excipients"). Excipient and vendor selections can greatly influence development time, performance, quality, and acceptance of final products. Consequently, quality excipient suppliers should:
y y y y

maintain drug master files with FDA for noncompendial items; consistently conform to monograph requirements; manufacture in ISO 9000certified facilities; pass FDA inspection and auditing by either pharmaceutical companies or International Pharmaceutical Excipient Audit (IPEA, www.ipeainc.com).

Inattention to excipients, excipient suppliers, and regulations may lead to product development failure. Quality-by-design concepts, which have recently been initiated by FDA, emphasize the need for characterizing material properties (e.g., micromeritic, chemical, thermal, rheological, and mechanical properties) and elucidate their vital role in formulation and manufacturing processes (3-6). NEW EXCIPIENTS: Currently available excipients are sufficient to support typical formulation development. A significant number of drug entities under development, however, have physicochemical, permeation, and pharmacokinetic properties that are less than ideal. These drugs present formulation challenges and may require either the discovery of new excipients or new applications of existing excipients. Regulatory agencies require new excipients to undergo a series of toxicology tests, which may be costly. Few new excipients of new chemical entity have been introduced into the market, primarily because of the economic hurdles associated with toxicology testing. Instead, excipient manufacturers have improved excipient performance and have expanded product lines by modifying already approved products (see Table I). Excipients undergoing these approaches may be advantageous in their formulation, manufacture, and marketing. In formulation, these excipients may decrease strain rate sensitivity, increase rework potential, increase dilution potential, decrease lubricant sensitivity, enhance flow properties, enhance the blending process, optimize content uniformity, increase compression ratio, facilitate material handling, require smaller quantities, decrease environmental concerns, and improve stability. These formulation benefits can lead to manufacturing advantages such as enable direct compaction to avoid time-consuming wet granulation, increase production capacity using excipients with enhanced flow and compaction behavior, reduce tablet tooling and machine wear, and eliminate the facility need of solvent recovery. Benefits such as rapid

formulation development, smaller tablet size, better quality products, and no solvent residues may be possible by using these excipients with proven functionality. Many APIs under development have less than ideal physicochemical and absorption properties, resulting in poor bioavailability. Excipient manufacturers have developed enabling excipients such as various solubilizers and absoption enhancers for these hard-todeliver compounds. Table 1: Natural Products, including naturally occurring polymers and derivatives Name Use

DRUG DELIVERY: Drug delivery is highly innovative in terms of materials to assist delivery, excipients, and technology which allow fast or slow release of drugs. For example analgesics, which often involve as much as five or six tablets a day, can be reduced to a single dose by using appropriate excipients, based on carbohydrate polymers. Polymers are classified in several ways; the simplest classification used for pharmaceutical purposes is into natural and synthetic polymers. Polysaccharides, natural polymers, fabricated into hydrophilic matrices remain popular biomaterials for controlled-release dosage forms and uses of a hydrophilic polymer matrix is one of the most pop- ular approaches in formulating an extended-release dosage forms (7-9). This is due to the fact that these formulations are relatively flexible and a well designed system usually gives reproducible release profiles. Since drug release is the

process by which a drug leaves a drug product and is subjected to absorption, distribution, metabolism, and excretion (ADME), eventually becoming available for pharmacologic action, hence drug release is described in several ways as follows: a) Immediate release refers to the instantaneous availability of drug for absorption or pharmacologic action in which drug products allow drugs to dissolve with no intention of delaying or prolonging dissolution or absorption of the drug. b) Modified-release dosage forms include both delayed and extended-release drug products. Delayed release is defined as the release of a drug at a time other than immediately following administration, while extended release products are formulated to make the drug available over an extended period after administration. c) Controlled release includes extended-release and pulsatile-release products. Pulsatile release involves the release of finite amounts (or pulses) of drug at distinct intervals that are programmed into the drug product. One of the most commonly used methods of modulating tablet drug release is to include it in a matrix system. The classification of matrix systems is based on matrix structure, release kinetics, controlled release properties (diffusion, erosion, swelling), and the chemical nature and properties of employed materials. Matrix systems are usually classified in three main groups: hydrophilic, inert, and lipidic (10). In addition, the drug release is a function of many factors, including the chemical nature of the membrane, geometry and its thickness, and the particle surface area of the drug device, the physico-chemical nature of the active substance and the interaction between the membrane and the permeating fluids are also important (11-13). In fact, the mechanism probably varies from membrane to membrane, depending on the membrane structure as well as on the nature of the permeating solution. It is believed that several different mechanisms are involved in the drug release through a non disintegrating polymer coat (14): a) Permeation through water-filled pores; in this mechanistic model, the release of the drug involves transfer of the dissolved molecule through water-filled pores. The coating membrane is not homogeneous. The pores can be created by the incorporation of leachable components, such as sugars or incompatible water soluble polymers into the original coating material (15) or can be produced by an appropriate production process. b) Permeation through membrane material; in this mechanism, the release process involves the consecutive process of drug partition between the core formulation and the membrane. The drug molecules are dissolved in the membrane at the inner face of the coat, representing equilibrium between a saturated drug solution and the membrane material. The transport of drug across the coat is then driven by the concentration gradient in the membrane. Outside the membrane, the drug is dissolved in an aqueous environment. c) Osmotic pumping; this release mechanism is driven by a difference in osmotic pressure between the drug solution and the environment outside the formulation. In addition to the above, controlled release of drug from the matrix is dependent on particle size and type of the polymer wetting, polymer hydration, polymer dissolution, and drug: polymer ratio (16 19). The hydration rate depends on the nature of the constituents, such as the molecular structure and the degree of substitution. The viscosity of the aqueous solution can be increased by increasing the average molecular weight of the polymer, the concentration of the polymer or decreasing the temperature of the solution [7, 20]. So, the factors associated with polymers, such as molecular weight type (nominal viscosity), concentration, degree of substitution, and particle size [2128]; have been shown to have a significant influence on drug release. For example, in tablet formulations containing hydrophilic polymers like HPMC, the release of active drug is controlled by the rate of formation of a partially hydrated gel layer of the tablet surface formed upon contact with aqueous gastric media following ingestion and the continuous formation of additional gel layers. In addition to this, process

variables like method of granulation, amount of binder added during granulation, use of high or low shear mixer, granule size distribution, compression force during tableting, etc., are also important for extended-release [29-39]. POLYSACCHARIDES IN PHARMACEUTICALS: Natural polysaccharides are extensively used for solid form formulations. They are highly stable, safe, nontoxic, and hydrophilic and gel forming in nature. Pectin, starch, guar gum, amylase and karaya gums are a few polysaccharides commonly used in dosage forms. Nonstarch, linear polysaccharides remain intact in the physiological environment of the stomach and the small intestine,but are degraded by the bacteria present in human colon which make them potentially useful in targeted drug delivery systems to the colon (40). a) Pectins: Pectin are non-starch.linear polysaccharides extracted from plant cell walls. They are predominantly linear polymers of mainly linked D-galacturonic acid resides interrupted by 1,2-linked L-rhamnose residues with a few hundred to about one thousand building blocks per molecule, corresponding to an average molecular weight of about 50,000 to about 1,80,000 Being soluble in water, pectin is not able to shield its drug load effect effectively during its passage through the stomach and small intestine. It was found that a coat of considerable thickness was required to protect the drug core in simulated in vivo conditions. Mixed films of pectin with ethylcellulose were investigated as a coating material for colonspecific drug delivery. Sungthongjeen et al investigated the high-methoxy pectin for its potential value in controlled-release matrix formulations (41). The effects of compression force,ratio of drug to pectin, and type of pectin on drug release from matrix tablets were also investigated. A very low solubility pectin-derivative (pectinic acid, degree of methoxylation 4%) was found to be well suited as an excipient for pelletisation by extrusion/spheronisation. Pectin microspheres of piroxicam were prepared by the spray dying technique. In vivo tests in rabbits with dispersions of piroxicam-loaded microspheres also indicated a significant improvement of piroxicam bioavailbility in the aqueoushumuor (2.5-fold) when compared with commercial piroxicam eye drops (42). b) Alginates: Alginates are natural polysaccharide polymers isolated from the brown sea weed (Phaeophyceae). Alginic acid can be converted into its salts, of which sodium alginate is the major form currently used. A linear polymer consisting of D-mannuronic acid and Lguluronic acid residues arranged in blocks in the polymer chain, these homogenous blocks (composed of either acid residue alone) are separated by blocks made of random or alternating units of mannuronic and guluronic acids. Alginates offer various applications in drug delivery, such as in matrix type alginate gel beads, in liposomes, in modulating gastrointestinal transit time, for local applications and to deliver the bio molecules in tissue engineering application[43]. c) Starches: It is the principal form of carbohydrate reserve in green plants and especially present in seeds and underground plant organs. Starch occurs in the form of granules (starch grains), the shape and size of which are characteristic of the species, as it is also the ratio of the content of

principal constituents, amylase andamylopectin. A number of starches are recognized for pharmaceutical use. These include maize(Zeamays),rice(Oryza sativa),wheat(Triticum aestivum) and potato(Solanum tuberosum) (44). Modified starch was tested for general applicability of a new pregelatinized starch product in directly compressible controlledrelease matrix systems.It was prepared by enzymatic degradation of potato starch followed by precipitation (retrogradation), filtration and washing with ethanol. The advantages of the material include ease of tablet preparation, the potential of a constant release rate(zero- order) for an extended period of time and its ability to incorporate high percentages of drugs with different physicochemical properties (45). Acetylating of starch considerably decreases its swelling and enzymatic degradation. Thus, starch acetate (SA) based delivery systems were tested for controlled drug delivery (46). B. GUMS: a) Gum: Gums are considered to be pathological products formed following injury to the plant or owing to unfavourable conditions, such as drought, by a breakdown of cell walls (extra cellular formation; gummosis). Gums are pathological products(47). Acacia, tragacanth, and guar gum are examples of gums. Gums are plant hydrocolloids. They are also translucent amorphous substances and polymers of a monosaccharide or mixed monosaccharides and many of them are combined with uronic acids. Gums constituents and on hydrolysis yield a mixture of sugars and uronic acids. Gums and hydrophilic molecules, which can combine with water to form viscous solutions or gels. The nature of the compounds involved influences the properties of different gums. Linear polysaccharides occupy more space and are more viscous than highly branched compounds of the same molecular weight. The branched compounds form gels more easily and are more stable because extensive interaction along the chains is not possible.

a)

Gellan gum:

Deacylated Gellan gum (Gellan) is an anionic microbial polysaccharide, secreted from Sphingomonas elodea, consisting of repeating tetrasaccharide units of glucose, glucuronic acid and rhamnose residues in a 2:1:1 ratio: [ 3)Dglucose(1 4)Dglucuronic acid (1 4)D glucose(1 4) Lrhamnose(1 ]. In the native polymer two acyl substituents, L-glyceryl at O(2) and acetyl at O(6), are present on the 3-linked glucose. On average, there is one glyceryl per repeating unit and one acetyl for every two repeating units. Deacylated Gellan gum is obtained by alkali treatment of the native polysaccharide. Both native and deacylated Gellan gum are capable of physical gelation (48). To induce Gellan gelation it is necessary to warm up preliminarily a concentrated water solution of the polysaccharide: when the temperature is decreased, the chains undergo a conformational transition from random coils to double helices (Coil-Helix Transition). Then a rearrangement of the double helices occurs leading to the formation of ordered junction zones (Sol-Gel Transition) (49) thus giving a thermo-reversible hydrogel (50). Much stronger physical thermo-reversible hydrogels are also obtained by addition of mono and divalent ions to Gellan solutions or in acidic conditions (51). The physical gelation properties make this polysaccharide suitable as a structuring and gelling agent.

C. VOLATILE OILS: a) Methanol: Methanol is obtained by steam distillation of the flowering tops of Mentha piperita belonging to the family Labiatae. A membrane- moderated transdermal therapeutic system(TTS)of nimodipine using 2%w/w hydroxypropylmethylcellulose (HPMC) gel as a reservoir system containing menthol as penetration enhancer and 60%v/v ethanol- water as solvent system (52). Methanol was tested for improving the bioavailability of poorly watersoluble ibuprofen in the rectum with poloxamer (52,53). b) Caraway: Caraway fruit consists of the dried, ripe fruits of Carum carvi (Umbelliferae).The volatile oil consists of ketone carvone and the terpene limonene. In another attempt, a limonenebased transdermal therapeutic system (TTS) was prepared to study its ability to provide the desiredsteady-state plasma concentration of nicorandil in human volunteers (54).

DRUGEXCIPIENT AND EXCIPIENTEXCIPIENT INTERACTIONS: Interactions between drugs and excipients can occur by means of several possible mechanisms, including adsorption, complexation, chemical interaction, pH effects, and eutectic formation, resulting in drug products with desired or undesired properties. Water-insoluble cellulose-type excipients such as microcrystalline cellulose and croscarmellose sodium can adsorb APIs during wet granulation or in dissolution testing, thereby leading to incomplete dissolution. This incomplete dissolution, however, usually is not present at an alarmingly high level when only van der Waals forces are operative. Substantial electrostatic interactions can occur between oppositely charged excipients and drugs, for example. Negatively charged excipients may not be compatible with positively charged drugs or excipients and positively charged excipients can interact with negatively charged drugs and excipients. Based on the Henderson-Hasselbalch equation, alkalinizing agents (e.g., sodium bicarbonate, calcium carbonate, magnesium oxide) and acidifiers (e.g., citric acid, tartaric acid, malic acid, fumaric acid) can influence the microenvironment pH significantly and may have a major influence on drug solubility or dissolution for acidic and basic drugs. Drugexcipient interaction examples have been reviewed (55). Furthermore, formulation scientists should evaluate the possibility of excipientexcipient interactions and their influence on drug-product attributes. An excipientexcipient interaction sometimes can be used as a formulation strategy to achieve desired product attributes. For example, the viscosity of xanthan gum is increased in the presence of ceratonia (56), and the viscosity of non-ionic cellulose derivatives (hydroxypropyl methylcellulose and hydroxypropyl cellulose) is enhanced by the incorporation of sodium lauryl sulfate (57). These excipientexcipient interactions are used synergistically in controlled-release drug delivery systems.

CONCLUSION: In addition to conventional pharmaceutical excipients as bulking agents, substance use for masking taste/texture or as a substance use to aid during manufacturing process, Novel excipients offer broad range of additional properties suitable to preserve the integrity of active constituents of the formulation and enhances its self life. New and modified excipients, irrespective of its source (synthetic or herbal) produces formulation that offer better drug delivery performance, reliability, negligible toxicity, enhances stability, improve bioavailability and patient acceptability. It also avoids dependence of pharmaceutical industry on rapidly perishing non renewable resources like fossil fuel. The synthetic polymers can be designed or modified as per requirement of the formulation; by altering polymer characteristics and on the other hand herbal pharmaceutical excipients are biocompatible, non toxic, environment friendly and economical. It seems conceivable that in the near future, kilogram quantities of fusion proteins, fibronectin, poly (lysine), or hemolysin could become available as off-the-shelf excipients or as designer excipient kits. This scenario is even more plausible considering that moieties that were unheard of a decade ago are now routinely available for use as excipients or in biochemical research (e.g., Lipofectamine, poly (lactideco-glycolide), PAMAM dendrimers, tocopherol PEG succinate, etc.). Excipients that have never been used before must pass formidable regulatory requirements before being incorporated into approved dosage forms. Such requirements include, but are not limited to, comprehensive toxicology (including acute, chronic, and reproductive) and pharmacokinetic and carcinogenic studies as outlined in the ICH S7, S3A, S3B, S2B, and S5A and the US Pharmacopeia REFERENCES: 1. International Pharmaceutical Excipients Council-Americas, "What are Pharmaceutical Excipients?" www.ipecamericas.org/public/faqs.html#question1. 2. . Center for Drug Evaluation and Research (CDER), "Inactive Ingredient Search for Approved Drug Products," www.accessdata.fda.gov/scripts/cder/iig/index.cfm. 3. CDER, Quality Systems Approach to Pharmaceutical Good Manufacturing Practices, Draft Guidance (Rockville, MD, 2004). 4. S.U. Ahmed, V.Naini, and S.R. Vaithiyalingam, "Physicochemical Characteristics of Drugs and Excipients: An Overview," Amer. Pharm. Rev. 9 (3), 47 52 (2006). 5. J.R. Johanson, "Defining the Physical Functionality of Excipients, Bulk Drugs and Formulations," Innovations in Pharmaceutical Technology 1 (2), 136146 (1999). 6. D. Bugay and W.P. Findlay, Pharmaceutical Excipients: Characterization by IR, Raman, and NMR Spectroscopy (Marcel Dekker, Inc., New York, NY, 1999). 7. Alderman D. A. A.: Review of cellulose ethers in hydrophilic matrices for oral controlled-release dosage forms. International Journal of Pharmaceutical Technology and Product Manufacture, 5, 19 (1984). 8. Heller J.: Use of polymers in controlled release of active agents. in Controlled Drug Delivery. Fundamentals and Applications (eds.: Robinson J. R., Lee V. H. L.) Marcel Dekker, New York, 179212 (1987). 9. Longer M. A., Robinson J. R.: Sustained-release drug delivery systems. in Remingtons Pharmaceutical Sciences (Ed.: Remington J. P.) Mack Publishing, Easton, 16761693 (1990). 10. Sandip B. T., Ali R.: Extended-release oral drug delivery technologies: monolithic matrix systems. Methods of Molecular Biology, 437, 217243 (2008).

11. Liu J., Lin S., Li L., Liu E.: Releases of theophylline from polymer blend hydrogels. International Journal of Pharmaceutics, 298, 117125 (2005). 12. Prokop A., Kozlov E., Carlesso G., Davidson J. M.: Hydrogel-based colloidal polymeric system for protein and drug delivery: physical and chemical characterization, permeability control and applications. Advances in Polymer Science, 160, 119173 (2002). 13. Zaikov G. E., Iordanskii A. P., Markin V. S.: Diffusion of electrolytes in polymers. VSP Science Press, Utrecht (1988). 14. George S. C., Thomas S.: Transport phenomena through polymeric system. Progress in Polymer Science, 26, 9851017 (2001). 15. Lindholm T., Juslin M.: Controlled release tablets 3: Ethylcellulose coats containing surfactant and powdered matter. Pharmaceutical Industry, 44, 937941 (1982). 16. Rodriguez C. F., Bruneau N., Barra J., Alfonso D., Doelker E.: Hydrophilic cellulose derivatives as drug delivery carriers: Influence of substitution type on the properties of compressed matrix tablets. in Handbook of Pharmaceutical Controlled Release Technology (ed.: Wise D. L.) Marcel Dekker, New York, 130 (2000). 17. Lapidus H., Lord N. G.: Drug release from compressed hydrophilic matrices. Journal of Pharmaceutical Sciences, 57, 12921301 (1968). 18. Bettini R., Colombo P., Massimo G., Catellani P. L., Vitali T.: Swelling and drug release in hydrogel matrices: Polymer viscosity and matrix porosity effects. The European Journal of Pharmaceutical Sciences, 2, 213219 (1994). 19. Campos-Aldrete M. E., Villafuerte-Robles L.: Influence of the viscosity grade and the particle size of HPMC on metronidazole release from matrix tablets. European Journal of Pharmaceutics and Biopharmaceutics, 43, 173178 (1997). 20. Amaral H. M., Lobo S. J. M., Ferreira D. C.: Effect of hydroxypropyl methylcellulose and hydrogenated castor oil on naproxen release from sustained-release tablets. AAPS Pharmaceutical Science Technology, 2, 1421 (2001). 21. Ford J. L., Rubinstein M. H., Hogan J. E.: Formulation of sustained release promethazine hydrochloride tablets using hydroxypropyl methylcellulose matrices. International Journal of Pharmaceutics, 24, 327338 (1985). 22. Cheong L. W. S., Heng P. W. S., Wong L. F.: Relationship between polymer viscosity and drug release from a matrix system. Pharmaceutical Research, 9, 15101514 (1992). 23. Tahara K., Yamamoto K., Nishihata T.: Overall mechanism behind matrix sustained release (SR) tablets prepared with hydroxypropyl methylcellulose. Journal of Controlled Release, 35, 5966 (1995). 24. Krgel I., Bodmeier R.: Development of a multifunctional matrix drug delivery system surrounded by an impermeable cylinder. Journal of Controlled Release, 61, 4350 (1999). 25. Shah N., Zhang G., Apelian V., Zeng F., Infield M. H., Malick A. W.: Prediction of drug release from hydroxypropyl methylcellulose (HPMC) matrices: Effect of polymer concentration. Pharmaceutical Research, 10, 16931695 (1993). 26. Xu G., Sunada H.: Influence of formulation change on drug release kinetics from hydroxypropyl methylcellulose matrix tablets. Chemical and Pharmaceutical Bulletin, 43, 483487 (1995). 27. Velasco M. V., Ford J. L., Rowe P., Rajabi-Siahboomi A. R.: Influence of drug: Hydroxypropyl methylcellulose ratio, drug and polymer particle size and compression force on the release of diclofenac sodium from HPMC tablets. Journal of Controlled Release, 57, 7585 (1999).

28. Mitchell K., Ford J. L., Armstrong D. J., Elliot P. N. C., Hogan J. E., Rostron C.: The influence of substitution type on the performance of methyl cellulose and hydroxypropyl methylcellulose in gels and matrices. European Journal of Pharmaceutics and Biopharmaceutics, 100, 143154 (1993). 29. Sheskey P. J., Williams D. M.: Comparison of lowshear and high-shear wet granulation techniques and the influence of percent water addition in the preparation of a controlled-release matrix tablet containing HPMC and a highdose, highly watersoluble drug. Pharmaceutical Technology, 20, 8192 (1996). 30. Bettini R., Colombo P., Massimo G., Catellani P. L., Vitali T.: Swelling and drug release in hydrogel matrices: Polymer viscosity and matrix porosity effects. The European Journal of Pharmaceutical Sciences, 2, 213219 (1994). 31. Ford J. L., Rubinstein M. H., Hogan J. E.: Formulation of sustained release promethazine hydrochloride tablets using hydroxypropyl methylcellulose matrices. International Journal of Pharmaceutics, 24, 327338 (1985). 32. Selkirk A. B., Ganderton D.: The influence of wet and dry granulation methods on the pore structure of lactose tablets. Journal of Pharmaceutical and Pharmacology, 22, 86S94S (1970). 33. Huber H. E., Christenson G. L.: Utilisation of hydrophilic gums for the control of drug substance release from tablet formulations II. Influence of tablet hardness and density on dissolution behavior. Journal of Pharmaceutical Sciences, 57, 164166 (1968). 34. Genc L., Bilac H., Gler E.: Studies on controlled release dimenhydrinate from matrix tablet formulations. Pharmaceutical Acta Helvetiae, 74, 4349 (1999). 35. Chalmers A. A., Elworthy P. H.: Oxytetracycline tablet formulations: The influence of excipients and the method of granulation. Journal of Pharmaceutical and Pharmacology, 28, 234238 (1976). 36. Chowhan Z. T., Yang I-C.: Effect of intergranular versus intragranular corn starch on tablet friability and in vitro dissolution. Journal of Pharmaceutical Sciences, 72, 983 988 (1983). 37. Khattab I., Menon A., Sakr A.: Effect of mode of incorporation of disintegrants on the characteristics of fluid-bed wet-granulated tablets. Journal of Pharmaceutical and Pharmacology, 45, 687691 (1993). 38. Li J. Z., Rekhi G. S., Augsburger L. L., Shangraw R. F.: The role of intra- and extragranular microcrystalline cellulose in tablet dissolution. Pharmaceutical Development and Technology, 1, 343355 (1996). 39. Zhang Y. E., Tchao R., Schwartz J. B.: Effect of processing methods and heat treatment on the formation of wax matrix tablets for sustained drug release. Pharmaceutical Development and Technology, 6, 131144 (2001). 40. Sinha VR, Rachana K. Polysaccharides in colon specific drug delivery. Int. J.Pharm. 2001; 224: 19-38. 41. Sinha VR, Rachana K. Polysaccharides in colon specific drug delivery. Int. J.Pharm. 2001; 224: 19-38. 42. Giunchedi P, Conte U, Chetom P, Saettone MF. Pectin microspheres as ophthalmic carriers for piroxicam: Evaluation in vitro and in vivo in albino rabbits. Eur. J. Pharm. Sci. 1999; 9: 1-7. 43. Tonnesen HH, Karlssen J. Alginate in drug delivery system Drug Develop. Ind. Pharm. 2002; 28: 620-31. 44. Trease GE, Evans WC editors. Text Book of Pharmacognosy, 15th ed., 2002. London, Balliere.

45. Te-Wierik GH, Eissens AC, Bergsma J, Arends-Scholte AW, Bolhuis GK. A new generation starch product as excipient in pharmaceutical tablets III: Parameters affecting controlled drug release from tablets based on high surface area retrograded pregelatinized potato starch. Int. J. Pharm. 1997; 157: 181-7. 46. Tuovinen L, Peltonen S, Jarvinen K. Drug release from starch-acetate films. J. Control Release. 2003; 91: 345-54. 47. J. S. Qadry. Shah and Qadrys Pharmacognosy. Ahmedabad, India: B S Shah Prakashan; 2008. 48. Coviello, T.; Matricardi, P.; Marianecci, C.; Alhaique, F. Polysaccharide hydrogels for modified release formulations. J. Control. Release 2007, 119, 5-24. 49. Peppas, N.A.; Bures, P.; Leobandung, W.; Ichikawa, H. Hydrogels in pharmaceutical formulations. Eur. J. Pharm. Biopharm. 2000, 50, 27-46. 50. Pollock, T.J. Sphingas Groups of Exopolysaccharides (EPS). In Biopolymers Polysaccharides I; Vandamme, E.J., De Baets, S., Steinbchel, A. Eds.; Wiley-VCH Verlag GmbH: Weinheim Germany, 2002; pp. 239-253. 51. Miyoshi, E.; Takaya, T.; Nishinari, K. Rheological and thermal studies of gel-sol transition in Gellan gum aqueous solutions. Carbohydr. Polym. 1996, 30, 109-119. 52. Kokate CK, Purohit AP, Gokhle SB, editors. Pharmacognosy. 22nd ed. Nrali Parkashan, India. 2003; pp. 133-66. 53. Krishnaiah YS, Satyanarayana S, Prasad YV. Studies of guar gum compressioncoated 5 aminosalicylic acid tablets for colon-specific drug delivery. Drug Develop. Ind. Pharm. 1999; 25: 651-7. 54. Yong CS, Yang CH, Rhee JD, Lee BJ, Kim DC, Kim DD. Enhanced rectal bioavaility of ibuprofen in rats by poloxamer 188 and menthol. Int. J. Pharm. 2004; 269: 169-76. 55. K. Jackson, D. Young, and S. Pant, "DrugExcipient Interactions and Their Affect on Absorption," PSTT 3 (10), 338345 (2000). 56. P.J. Weller, "Ceratonia," in Handbook of Pharmaceutical Excipients, R.C. Rowe, P.J. Sheskey, and P.J. Weller, Eds. (Pharmaceutical Press and American Pharmaceutical Association, Chicago, IL, 2003), pp. 123124. 57. B. Wittgren, M. Stefansson, and B. Porsch, "Interactions between Sodium Dodecyl Sulphate and Non-Ionic Cellulose Derivatives Studies by Size Exclusion Chromatography with Online Multiangle Light Scattering and Refractometric Detection," J. Chromatogr. A. 1082 (2), 166175 (2005).