REVIEW ARTICLE MELT GRANULATION: AN ALTERNATIVE TO TRADITIONAL GRANULATION TECHNIQUES Desai U.S.*, Chaudhari P.D., Bhavsar D.B. and Chavan R.P. (Received 20 September 2012) (Accepted 23 February 2013) ABSTRACT Melt granulation is a size enlargement process in which the addition of a binder that melts or softens at relatively low temperatures (about 600C) is used to achieve agglomeration of solid particles in the formulation. The process utilizes materials that are effective as granulating agents when they are in the softened or molten state. This process can be used for the preparation of sustained released dosage forms by using lipophilic polymers, such as glycerol monostearate, a combination of a hydrophobic material such as a starch derivative and stearic acid. It also can be used to prepare fast release melt granules by utilizing water-soluble polymers and surfactants, such as PEG and poloxomers. Melt granulation is one of the most widely applied processing techniques in the array of pharmaceutical manufacturing operations.
INTRODUCTION
Fluidised hot melt granulation
Industrial application of extrusion processes dates back to 1930’s. Hot-melt extrusion (HME) is one of the most widely applied processing technologies in the plastic, rubber and food industry. Currently, more than half of all plastic products, including plastic bags, sheets and pipes are manufactured by this process. Recently, melt extrusion has found its place in the array of the pharmaceutical manufacturing operations. Several research groups have evaluated this technology to achieve enhancement in dissolution rates for poorly water soluble drugs, to modify drug release and for transdermal passage of the drug. Extrusion is the process of converting a raw material into a product of uniform shape and density by forcing it through a die under pressure 1-8.
Fluidised hot melt granulation (FHMG) has received considerable attention in recent years with the majority of these processes involving the spraying of molten binder onto a bed of •uidised particles. Schaefer’s group has shown that the granule growth mechanism is dependent on the ratio of binder droplet size to powder particle size2. A low ratio led to a nucleation mechanism, which then gave rise to coalescence and further granule growth. Kidokoro and co-authors have shown that the increase in granule size during FHMG is in•uenced by viscosity of the binder melt. They further showed that the physical properties of tablets pressed from the •uidized hot melted granules were in•uenced by the properties of the binder material9. Advantages Neither solvent nor water used in this process. Therefore good alternative for water sensitive drugs.
l *For correspondence Department of Pharmaceutics Modern College of Pharmacy, Sector No.21 Yamuna Nagar , Nigdi, Pune – 411044 E-mail:
[email protected]
INDIAN DRUGS 50(03) MARCH 2013
l
Fewer processing steps needed since wetting & drying phases eliminated, thus less time consuming. 5
There are no requirements on compressibility of active ingredients, entire procedure simple, continuous and ef!cient.
2. Controlling or modifying the release of the drug.
l
Uniform dispersion of !ne particle occurs.
l
Good stability at varying pH and moisture levels.
4. Enhancing the tabletting compactability of poorly compactible high dose drugs.
l
Safe application in humans due to their nonswellable and water insoluble nature1, 3.
5. Enhancing the chemical stability of highly water soluble drugs.
l
Clinically advantaged dosage forms, such as drug abuse and dose dumping deterrent technology.
6. Preparation of fast dissolving tablets of poorly water soluble drugs.
l
Sustained, modified and targeted release capabilities.
7. Preparation of sustained release floating tablets1,4,6,11-15.
l
Better content uniformity was obtained from HME process among granules of different size ranges.
Materials used in melt granulation
l
Reduced number of unit operations.
l
Production of a wide range of performance dosage forms1-4,10,11.
In hot-melt extruded drug delivery systems, the active compound is embedded in a carrier formulation, often comprised of one or more “meltable” substances and other functional excipients. The meltable substance is generally a polymer or low melting point wax16.
l
Disadvantages l Thermal process (drug/polymer stability). l
Requires high energy input.
l
The melt technique is such that the process cannot be applied to heat-sensitive materials owing to the elevated temperatures involved.
l
Lower-melting-point binder risks situations where melting or softening of the binder occurs during handling and storage of the agglomerates
l
Higher-melting-point binders require high melting temperatures and can contribute to instability problems especially for heat-labile materials.
l
Flow properties of the polymer are essential to processing.
l
Limited number of available polymer1,4.
Applications in the pharmaceutical industry In pharmaceutical industry, melt extrusion has been used for various purposes, such as 1. Improving the dissolution rate and bioavailability of the drug by forming a solid dispersion or solid solution. 6
3. Masking the bitter taste of an active drug.
Binders or matrix carriers
Lipids are considered as an alternative to polymer in the design of sustained drug delivery system due to their advantages such as low melt viscosity (thus avoiding the need of organic solvents for solubilization), absence of toxic impurities such as monomer catalysis and initiator, potential biocompatibility and biodegradability. The various meltable binders used for sustained drug delivery system are mentioned in following Tables I & II. Plasticizers Plasticizers are typically low molecular weight compounds capable of softening polymers to make them more •exible. The use of polymeric carriers in melt granulation often requires the incorporation of a plasticizer into the formulation to improve the processing conditions during the manufacturing of the extruded dosage form or to improve the physical and mechanical properties of the !nal product. Plasticization of the polymer is generally attributed to the inter-molecular secondary valence forces INDIAN DRUGS 50(03) MARCH 2013
Table I : Hydrophilic Meltable Binders in the Melt Granulation Technique10,17 Sr. No. 1 2 3 4 5 6 7 8 9
Hydrophilic Meltable Typical Melting Binders Range(oC) Gelucire 50/13 44-50 Poloxamer 188 50.9 Polyethylene glycol 2000 42-53 Polyethylene glycol 3000 48-63 Polyethylene glycol 6000 49-63 Polyethylene glycol 8000 54-63 Polyethylene glycol 10000 57-64 Polyethylene glycol 20000 53-66 Stearate 6000 WL 1644 46-58
Table II : Hydrophobic Meltable Binders in the Melt Granulation Technique4,16 Sr. No. 1 2 3 4 5 6 7 8 9 10 11 12
Hydrophobic Meltable Binders Beeswax Carnuba wax Cetyl palmitate Glycerin monostearate Paraf!n wax Stearic acid Glyceryl behenate Glyceryl palmitostearate Glyceryl stearate Hydrogenated castor oil Microcrystalline wax Stearyl alcohol
Typical Melting Range(oC) 56-60 75-83 47-50 47-63 47-65 46-69 67-75 48-57 54-63 62-86 58-72 56-60
between the plasticizer and the polymer. Plasticizers are able to decrease the glass transition temperature and the melt viscosity of a polymer by increasing the free volume between polymer chains. In doing so, the ease of movement of polymer chains with respect to each other is dramatically reduced. Plasticizers were also found to facilitate the fusion process of semicrystalline polymers. Less energy is usually required to melt semi-crystalline polymers following the addition of one or more plasticizers. With the INDIAN DRUGS 50(03) MARCH 2013
addition of a plasticizer, a melt granulation process can be conducted at lower temperatures and with less torque. Generally, both the active ingredient and the polymer will be more stable during the granulation process due to these improved processing conditions11. Materials commonly used as plasticizers that are approved by the Food and Drug Administration for use in pharmaceutical dosage forms are listed in Table III . Table III : Plasicizers used in Melt Granulation Technique18 Sr. Type Examples No. 1 Citrate esters triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate 2 Fatty acid butyl stearate, glycerol monostearate, stearyl alcohol esters 3 Sebacate Dibutyl sebacate esters 4 Phthalate diethyl phthalate, dibutyl esters phthalate, dioctyl phosphate 5 Glycol Polyethylene glycol, derivatives propylene glycol 6 Others triacetin, mineral oil, castor oil 7 Vitamin E D-α-tocopheryl polyethylene TPGS glycol 1000 succinate OTHER PROCESSING AIDS •
Anti-oxidants
The excessive temperatures needed to process unplasticized or under plasticized polymers may lead to polymer degradation. The stability of polymers that are susceptible to degradation can be improved with the addition of antioxidants, acid receptors and or light absorbers during HME. Antioxidants are classified as preventive antioxidants or chain-breaking antioxidants based upon their mechanism. Preventive antioxidants include materials that act to prevent initiation of free radical chain reactions. Reducing agents, such as 7
ascorbic acid, are able to interfere with autoxidation in a preventive manner since they preferentially undergo oxidation. The preferential oxidation of reducing agents protects drugs, polymers, and other excipients from attack by oxygen molecules. Chelating agents such as edetate disodium (EDTA) and citric acid are another type of preventive antioxidant that decrease the rate of free radical formation by forming a stable complex with metal ions that catalyze these reduction reactions. Hindered phenols and aromatic amines are the two major groups of chain breaking antioxidants that inhibit free radical chain reactions. Commonly used antioxidants such as butylated hydroxyanisole, butylated hydroxytoluene and vitamin E are hindered phenols. Because the O-H bonds of phenols and the N-H bonds of aromatic amines are very weak, the rate of oxidation is generally higher with the antioxidant than with the polymer18. •
Table IV : Examples of drug substances processed by Melt Granulation Technique Sr. No. 1
Drug
TM(0C)
Diclofenac sodium
284
2
Theophyllin
255
3
Nifedipine
175
4
Carbamazepine
192
Lubricants
Lubricants such as magnesium stearate, Aerosil 1000 etc. are used. Waxy materials like glyceryl monostearate have been reported to function as lubricant in hot-melt-processing18. Active pharmaceutical ingredient The properties of the active drug substance often limit the formulation and processing choices available to the pharmaceutical scientist in the development of dosage forms. Hydrolysis, solvolysis, and oxidation are three primary mechanisms of drug degradation. Drugs containing carboxylic acids, phosphoric acids or carbonyl functional groups are vulnerable to hydrolysis. Water or a solvent must be present for hydrolysis or solvolysis to occur. Melt granulation is an anhydrous process, which avoids potential hydrolytic degradation pathways. In addition, poorly compactable materials can be prepared as tablets without a compression process by cutting an extruded rod to the desired dimensions. The only restriction is that it is not suitable for the drug substances which melt under the HME processing 8
conditions18. The examples of drug substances which has been processed by melt granulation technique are given in Table IV.
References Bhavsar D.B. et al., 2010; Lyons. J.G., 2006; Sato et al., 1997 Bhavsar D.B. et al., 2010; Henrist, D. et al., 1999, 1999a 1999b; Sprockel et al., 1997; Young Cr, 2005; Young et al., 2002; Zhang et al., 2000 Forster et al., 2001a, 2001c; Nakamichi et al., 2002 Perissutti et al., 2002
Effect of Process Variables on Granulation 1. Effect of initial particle size and size distribution: It has been shown that a narrow distribution of feed particles to the granulator increases the sphericity and decreases the porosity of the granular products. Porosity, and its shape, orientation and size distribution have a large effect on the breakage behaviour and strength of granules. A high granule porosity results in lower the granule strength. The pores can be regarded as crack release zones, where the highest local tensile stress is generated and where fracture initiates. 2. Effect of binder content: Correlations have been developed to estimate the required binder content, but these have proved unsuccessful for powder INDIAN DRUGS 50(03) MARCH 2013
mixtures with more than one component, or with powders that have varying diameter and particle shape. Moreover, during granulation, some solid may dissolve partially in the liquid, which leads to very complicated binding forces. 3. Effect of binder viscosity: proposed the extent of the granulation is dependent upon the viscosity of the binder solution within the granulation vessel. In general, a higher binder viscosity leads to a higher degree of granulation. The viscosity of binders may be controlled by varying the temperature within the granulation vessel indicating that the binder viscosity affected both the rate of size enlargement and the mechanism of size enlargement. 4. Effect of particle deformability during granulation: The Ennis theory postulates that the probability of successful coalescence between colliding granules is a function of the granule deformability and inertia have studied the impact deformation of wet granules and correlated granule formation to solid liquid ratio, particle size, binder viscosity and granulation time. 5. Effect of granulation time: As one would expect, a longer granulation time produces larger granules. However, the rate at which the average particle size increases is very dependent on the binder content of the feed and deformability of the granulation mix19. Melt Agglomeration Melt agglomeration is a process by which the solid !ne particles are bound together into agglomerates, by agitation, kneading and layering in the presence of a molten binding liquid. Dry agglomerates are obtained as the molten binding liquid solidi!es by cooling. Typical examples of melt agglomeration processes are melt pelletization and melt granulation. During the agglomeration process, a gradual change in the size and shape of the agglomerates would take place. It is usually not possible to clearly distinguish between granulation and pelletization. Thus granulation is considered a pelletization process when highly spherical agglomerates of narrow size distribution are INDIAN DRUGS 50(03) MARCH 2013
produced. Conversely, an unsuccessful pelletization process may be classi!ed as granulation15. The equipment for melt agglomeration include rotating drums or pans, •uid-bed granulators, lowshear mixers such as Z-blade, planetary mixers, and high-shear mixers. Presently, the more popular agglomeration equipment for industrial-scale production are high-shear mixers and •uid-bed granulators. In both methods, a gradual buildup of agglomerates occurs during the process. The marked difference between the methods is the absence of shearing forces in the •uid-bed process, whereas very high shearing forces are generated in high-shear mixing20,21. During a melt agglomeration process, the meltable binder may be added as molten liquid, or as dry powder or •akes. In the latter, the binder may be heated by hot air or by a heating jacket to above the melting point of the binder. Alternatively, the melt agglomeration process exploits an extremely high shear input, of a high-shear mixer, where the heat of friction alone raises the temperature of the binder and effects melting. Typically, the melting points of meltable binders range from 50 to 80°C. A lowermelting-point binder risks situations where melting or softening of the binder occurs during handling and storage of the agglomerates22. In assessing the in•uence of meltable materials on the formative and growth processes of melt agglomerates, it is imperative to have a thorough understanding of the melt agglomeration process. The mechanism of melt agglomeration is similar to that of wet agglomeration. The agglomerate formation and growth mechanisms for a melt agglomeration process have been studied in high shear mixers and conventional •uid bed granulators. The formation mechanism has been described as a distribution or an immersion mechanism. By the distribution mechanism, small agglomerates (nuclei) are formed by initial solid particles being wetted by distribution of molten binder on their surface enabling agglomerate formation by 9
coalescence between the wetted solid particles. Further agglomerate growth occurs by coalescence between the nuclei, provided that the liquid saturation is suf!ciently high. By the immersion mechanism, initial solid particles become immersed in the surface of a molten binder particle, and further immersion of initial particles gives rise to agglomerate growth. Agglomerate growth by coalescence between agglomerates will primarily occur when no more initial particles are available. This is because the tendency for coalescence between initial particles or between initial particles and agglomerates is larger than the tendency for coalescence between two agglomerates since the tendency is inversely proportional to the size. Agglomerate growth by coalescence will only occur until a critical agglomerate size is reached. This size depends on a balance between coalescence and breakage and can be increased by e.g. using smaller powder particles, by increasing the binder viscosity, and by reducing the energy input. For melt agglomeration in high shear mixers and •uid bed granulators, it has been found that a binder particle size being smaller than that of the solid particles promotes the distribution mechanism. On the other hand, a binder particle size being larger than that of the solid particles, promotes the immersion mechanism. Furthermore, it has been found for high shear mixers that a low viscosity of the binder and/or high shearing forces will promote the distribution mechanism whereas a high viscosity of the binder and/or low shearing forces will promote the immersion mechanism. Consequently, the immersion mechanism can be promoted by keeping the process temperature within or slightly below the melting range of the meltable binder since this will increase the viscosity of the binder markedly. In a melt agglomeration process, both mechanisms might be active simultaneously, although one of the mechanisms will normally be dominant. In high shear mixers, the dominant mechanism will usually be the distribution mechanism because of the high shearing forces. In •uid bed granulators, the agglomerate formation occurs to a larger extent by the immersion mechanism due to the lower shearing forces. A rotary processor, which is a •uid bed 10
granulator equipped with a rotating friction plate, has been shown to be suitable for a melt agglomeration process. For optimum use of a melt agglomeration process in the rotary processor, it is necessary to be able to control the agglomerate size. This requires an understanding of the in•uence of process conditions on agglomerate properties and of the fundamental mechanisms of agglomerate formation and growth. Process conditions such as binder concentration, massing time, friction plate rotation speed, and surface of the friction plate signi!cantly in•uenced the agglomerate size. However, no fundamental studies of the mechanisms of agglomerate formation and growth in a melt agglomeration process in a rotary processor have been carried out23. Modes of melt agglomeration
Fig. 1 : Modes of melt agglomeration : (a) Distribution and (b) Immersion
These are based on the elementary mechanisms— distribution and immersion. In agglomeration by the distribution mode, a distribution of molten binding liquid on the surfaces of primary particles will occur, and agglomerates are formed via coalescence between the wetted nuclei (Fig. 1). In agglomeration by the immersion mode, nuclei are formed by immersion of the primary particles onto the surface of a droplet of molten binding liquid (Fig. 1). The distribution of molten binding liquid to surfaces of nuclei has to be effected by densi!cation prior to coalescence between the nuclei. Depending on the relative size between the solid particles and the molten binding liquid droplets, the distribution will be a dominant mode INDIAN DRUGS 50(03) MARCH 2013
when the molten binding liquid droplets are smaller than the solid particles or of a similar size. On the other hand, the immersion mode will dominate when the molten binding liquid droplets are larger than the solid particles. The distribution mode is promoted by a low molten binding liquid viscosity. In the case of immersion, it is more favorable for molten binding liquid of high viscosity, which could resist breakup by dispersive forces4. Techniques for Melt Granulation Spray Congealing Spray congealing is a melt technique of high versatility. In addition to manufacture multiparticulate delivery system, it can be applied to process the raw meltable materials into particles of de!ned size and viscosity values for the melt agglomeration process. Processing of meltable materials by spray congealing involves spraying a hot melt of wax, fatty acid, or glyceride into an air chamber below the melting point of the meltable materials or at cryogenic temperature. Spraycongealed particles (10–3000 µm in diameter) are obtained upon cooling. The congealed particles are strong and nonporous as there is an absence of solvent evaporation. Ideally, the meltable materials should have de!ned melting points or narrow melting ranges. Viscosity modi!er, either meltable or nonmeltable at the processing temperature, may be incorporated into the meltable matrix to change the consistency of the molten droplets24. Tumbling Melt Granulation A newer melt agglomeration technique, i.e., tumbling melt granulation, for preparing spherical beads has been reported. A powdered mixture of meltable and non-meltable materials is fed onto the seeds in a •uid-bed granulator (Fig. 2). The mixture adheres onto the seeds with the binding forces of a melting solid to form the spherical beads. In preparing the spherical beads, both viscosity and particle size of the meltable materials should be kept at an optimum value. The particle size of a meltable material should be 1/6 or lower than the diameter of the seeds. HighINDIAN DRUGS 50(03) MARCH 2013
viscosity meltable materials should not be employed to avoid agglomeration of seeds and producing beads of low sphericity25. Both particle size and viscosity of the meltable materials play a significant role in the melt agglomeration process. The control of the melt agglomeration process is best initiated by using meltable materials of controlled properties. For the melt pelletization and melt granulation processes, it is desirable that meltable materials have a high viscosity to improve the mechanical strength of the agglomerates, but a reduced particle size to prevent uncontrollable agglomerate growth. In tumbling melt granulation, small meltable particles with suf!cient viscous binding forces are obligatory for the production of spherical beads26,27.
Fig. 2: Process of Tumbling Melt Granulation
Marketed Products The interest in HME is growing rapidly. The US and Germany hold approximately more than half (56%) of all issued patents. In spite of this increased interest, there are few commercialized HME pharmaceutical products currently marketed. There are a number of companies using HME as a drug delivery technology including Pharma Form (TX, USA) and SOLIQS (Germany). SOLIQS has developed a proprietary Meltrex formulation and redeveloped a protease inhibitor combination product, Kaletra, for the treatment of human immunode!ciency virus (HIV). Moreover, HME Kaletra tablets were shown to have signi!cant advantages for the patient compared 11
with the previous soft gel capsule formulation, such as reduced dosing frequency and improved stability. SOLIQS has also developed a fast-onset ibuprofen system and a sustained release formulation of verapamil (Isoptin SRE) that was the !rst directly shaped HME product on the market. There are a number of products which have been developed by several companies using HME as drug delivery technology and this technology is gaining importance in the !eld of pharmaceuticals19. Future Trends The application of HME technology in the pharmaceutical industry has tended to focus on the development of bio-enhanced formulations to increase the ef!cacy of poorly water soluble compounds. There has also been an increase in the application of HME for the development of controlled release formulations, in the form of pellets, beads or minimatrices, and as a means to facilitate the continuous processing of products to reduce the number of manufacturing unit operations. Moreover, there have been several articles investigating the application of HME technology for the production of bio adhesive hot-melt extruded !lm for topical and mucosal adhesion applications and drug delivery. Recent studies have also demonstrated the production of biocompatible shape-memory polymers for use in biomedical applications, using HME as a manufacturing process. The production of multiparticulate dosage forms using HME has been investigated using hot melt pelletization and, lately, the use of die, face-cutting the polymer extrudate to produce HME pellets shows the continuing utilization of technology from the plastics industry for pharmaceutical manufacturing. The scope of the technology has also been broadened to expand the range of polymers and APIs that can be processed through application of HME. The growing market in medical devices, including those that incorporate drugs such as biodegradable stents and drug loaded catheters, might require HME manufacturing processes to be commercialized, and may lead to new areas of collaboration across pharmaceutical, medical device and biotechnology research. HME is 12
a versatile processing technology for pharmaceutical industry and has broad prospectus for future19. CONCLUSION & OUTLOOK Today, melt extrusion technology represents an ef!cient pathway for manufacture of drug delivery systems resulting in products mainly found among semi-solid and solid preparations. The potential of the technology is re•ected in the wide scope of different dosage forms including oral dosage forms, implants, bioadhesive ophthalmic inserts, topical !lms, and effervescent tablets. In addition, the physical state of the drug in an extrudate can be modi!ed with the help of process engineering and the use of various polymers. The drug can be present in crystalline form for sustained release applications or dissolved in a polymer to improve dissolution of poorly water-soluble drugs. The possible use of a broad selection of polymers starting from high molecular weight polymers to low molecular weight polymers and various plasticizers has opened a wide !eld of numerous combinations for formulation research. Drawbacks of the technology are often related to high energy input mainly related to shear forces and temperature. This is where process engineering becomes signi!cant. The design of screw assemblies and extruder dies are two major areas which have signi!cant impact on product quality and degradation of drug and polymers. Drugs which are sensitive to elevated temperatures can be processed successfully when the residence time is short compared to conventional processes like sterilization. Work in this !eld is increasing and the literature published reveals many novel and interesting aspects of this technology such as in-situ salt formation, fast dispersing systems with foam like structures, complex formation in the melt and nanoparticles released from molecular dispersions manufactured by melt extrusion. REFERENCES 1. 2.
Chokshi R. and Zia H., “Hot melt extrusion technique: a review,” Iranian J. Pharm. Res. 2002, 3, 3-16. Schafer T., Holm P., Kristensen H.G., “Melt granulation in a laboratory scale high shear mixer,” Drug Devl. Ind. Pharm.1990, 16 (8), 1249 – 1277. INDIAN DRUGS 50(03) MARCH 2013
3.
Crowley M.M. and Zhang F., “Pharmaceutical Applications of Hot-Melt Extrusion: Part II,” Drug Devl. Ind. Pharm. 2007, 33, 909–926.
4.
http://www.pharmainfo.net/reviews/melt-granulationtechnique-review
5.
Sundaramoorthy K., Kavimani S., Vetrichelman T., Manna P.K., and Venkappayya D., “Formulation and evaluation of extended release dosage form of metformin hydrochloride using combined hydrophobic and hydrophilic matrix”, ijper, 2008, 232-241.
6.
Campisi B., Vojnovic D., Chicco D. and Phan-Tan-Luu R., “Melt granulation in a high shear mixer: optimization of mixture and process variables using a combined experimental design ,” Chemom. Intell. Lab. Syst. 1999, 48, 59–70.
7.
Brabander C.D., Vervaet C. and Remon J.P., “Development and evaluation of sustained release minimatrices prepared by hot melt extrusion,” J. Control Rel. 2003, 89, 235 – 247.
17. Singh C., Jain A.K. and Agrawal K., “Formulation and evaluation of extended release tablet of pioglitazone by melt granulation,” Indian Drugs. 2008, 45(6), 461-468. 18. Crowley M.M. and Zhang F., “Pharmaceutical Applications of Hot-Melt Extrusion: Part I,” Drug Dev. Ind. Pharm. 2007, 33, 909–926. 19. Singhal S., Lohar V.K., Arora V., “Hot Melt Extrusion Technique”, Webmed Central Pharmaceutical Sciences 2011; 2,1. 20. Al-Suwayeh A. A., El-Shaboury H. M., Al-Baraki M. S., Elgorashy S. A., and Taha I. E., “In vitro and in vivo Evaluation of Sustained Release Hydralazine Hydrochloride Tablets Prepared by Thermal Granulation Technique,” Aust. J. Basic Appl. Sci 2009, 3(3), 28662875.
8.
Breitenbach J., “Melt extrusion: from process to drug delivery technology,” Eur. J. Pharm. Biopharm. 2002, 54, 107 – 117.
21. Ochoa L., Igartua M., Rosa M., Hernandez, Gascon A.R. and Pedraz J.L., “Preparation of sustained release hydrophilic matrices by melt granulation in a highshear mixer,” J. Pharm. Pharmaceut. Sci. 2005, 8(2), 132-140.
9.
Walker G.M., Andrews G., and Jones D., Effect of process parameters on the melt granulation of pharmaceutical powders, Powder Technol. 2006, 165,161–166.
22. Royce A., Suryawanshi J., Shah U., and Vishnupad K.,” Alternative Granulation Technique: Melt Granulation” Drug Dev. Ind. Pharm. 1996, 22(9&10), 917-924.
10. Haider S.S., Monnujan N.and Shahriya S.M., “Sustained release preparation of metoclopramide hydrochloride based on fatty matrix,” Indian Drugs. 2002, 39 (2), 7380.
23. Vilhelmsen T., Schæfer T.,” Agglomerate formation and growth mechanisms during melt agglomeration in a rotary processor”, Int. J. Pharm. 2005, 304,152– 164.
11. Heng W.S. and Wong T.W., “Melt processes for oral solid dosage forms,” Pharm. Tech. 2003, 1-6. 12. Evrard B.and Delattre L., “In vitro evaluation of lipid matrices for the development of a sustained–release sulfamethazine bolus for lambs,” Drug Dev. Ind. Pharm. 1996, 22 (2), 111-118. 13. Kowalski J., Kalb O., Joshi Y.M. and Abu T.M., “Application of melt granulation technology to enhance stability of moisture sensitive immediate-release drug product”, Int. J. Pharm. 2009, 381, 56–61. 14. Tayel S.A., Soliman I.I. and Louis D., “Formulation of ketotifen fumarate fast-melt granulation sublingual tablet”, AAPS Pharm. Sci. Tech. 2010, 11(2), 679-685. 15. Kumar R., Patil S., Patil M.B., Patil S.R. and Paschapur M.S., “Design and in vitro evaluation of oral •oating matrix tablets of aceclofenac”, Int. J. ChemTech Res. 2009, 1(4), 815-825. 16. Eliasen H., Kristensen H.G. and Schafer T., “Growth mechanism in melt agglomeration with low viscosity binder,” Int. J. Pharm. 1999, 186, 149-159.
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24. Passerini N., Perissutti B., Monoghini M., Voinovich D., Albertini B., Cavallari C. and Rodriguez L., “Characterization of carbamazepine–Gelucire 50/13 microparticles prepared by a spray congealing process using ultrasounds,” J. Pharm. Sci. 2002, 91(3), 699-707. 25. Maejima T., Osawa T., Nakjima K. and Kobayashi M., “Application of tumbling melt granulation method for preparing controlled release beads coated with hydrogenated castor oil,” Chem. Pharm. Bull. 1997, 45(5), 904-910. 26. Kidokoro M., Sasaki K., Haramiishi Y. and Matahira N., “Effect of crystallization behavior of polyethylene glycol 6000 on the properties of granule prepared by •uidized hot melt granulation (FHMG),” Chem. Pharm. Bull. 2003, 51(5), 487–493. 27. Walkera G.M., Hollanda C.R., Mohammad , Ahmada M.N., Duncan Q.M. Craig, In•uence of process parameters on •uidised hot-melt granulation and tablet pressing of pharmaceutical powders”, Chem. Eng. Sci. 2005,60, 3867 – 3877.
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