a novel freeze pelletization technique for preparing...

www.pharmtech.com98 Pharmaceutical Technology OCTOBER 2004

Sreekhar Cheboyina is a PhD student inthe department of pharmaceutics, School ofPharmacy, University of Mississippi. WalterG. Chambliss, PhD, is director oftechnology management and a researchprofessor at the Research Institute ofPharmaceutical Sciences, and professor ofpharmaceutics, University of Mississippi.Christy M. Wyandt, PhD, is associatedean of the Graduate School and associateprofessor of pharmaceutics, School ofPharmacy, University of Mississippi, tel.662.915.7474, fax 662.915.1177,[email protected].

*To whom all correspondence should be addressed.

A Novel Freeze Pelletization Technique for

Preparing Matrix PelletsSreekhar Cheboyina, Walter G. Chambliss, and Christy M. Wyandt*

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A novel and simple freeze-pelletizationtechnique generates immediate- orsustained-release spherical pellets with anarrow particle-size distribution.

elletization involves the agglomeration of active phar-maceutical ingredients and excipients in spherical beadscalled pellets. Pellets have numerous pharmacokineticand biopharmaceutical advantages over tablets (1–3).

Pellets provide an alternative for blending incompatible activeingredients, obtaining various release profiles, and developingmultidrug controlled-release formulations. As a result of thisflexibility, the number of oral drug delivery systems involvingpellets has steadily increased during the past 40 years.

Manufacturers produce pellets using techniques such asballing, extrusion–spheronization, high-speed shear mixing,and drug layering on seeds using coating pans or fluidized-bedequipment (4). These techniques require expensive equipment,labor-intensive processes, and skilled operators. Moreover, theirprocess development and validation are tedious. Other pelleti-zation techniques require introducing liquids or molten solidsinto a cooling fluid as droplets and freezing or solidifying theseinto pellets. The cooling fluid is typically either liquid nitrogenor cooling gases from liquid nitrogen. The most widely usedprocess for producing such solid particles is spray congealing,in which a molten solid mass is sprayed into cooling chambers(5–8). This process may not be feasible in some cases becauseit requires tall cooling chambers for adequate cooling of themolten solids. In cryopelletization, aqueous–organic solutions,suspensions, or emulsions are dropped into liquid nitrogen toform frozen particles. These particles are then freeze-dried orlyophilized to remove water or organic solvents (9–12). A majorlimitation to this process, however, is that it requires liquid ni-trogen, which has a temperature of 2196 8C. Moreover, the im-pact of liquid or semisolid droplets on the surface of the liquidnitrogen create surface irregularities in the pellets. In addition,pellets produced by freeze-drying are highly porous and maynot be spherical.

Freeze pelletizationFreeze pelletization is a new and simple technique for produc-ing spherical pellets for pharmaceutical use. In this technique,a molten-solid carrier/matrix is introduced as droplets into aninert column of liquid in which the molten solid is immiscible.The molten solid moves in the liquid column as droplets andsolidifies into spherical pellets. The molten-solid droplets can

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move upward or downward in the liquid column depending onthe droplets’ density with respect to the liquid in the column.If the density of the molten-solid carrier/matrix is more thanthat of the liquid in the column, then the droplets are intro-duced from the top of the column and pellets solidify in thebottom portion of the column as illustrated in Apparatus I (seeFigure 1). Conversely, if the density of the molten-solidcarrier/matrix is less than that of the liquid in the column, thenthe droplets are introduced from the bottom of the column andpellets solidify at the top portion of the column as shown inApparatus II (see Figure 2).

Molten-solid matrices in this technique are composed ofmolten-solid carriers, in which actives and excipients are dis-persed or dissolved. Excipients in the matrix can be diluents,disintegrating agents, surfactants, or release-modifying agents.Various hydrophilic and hydrophobic solids are suitable as car-riers. Suitable carriers are solid at room temperature and meltbelow 100 8C to minimize the degradation of the actives. A ma-trix can be composed of hydrophilic or hydrophobic carriersor combinations of both.

Potential hydrophilic carriers are polyethylene glycols (PEGs)(molecular weight [MW] >1000), polyvinyl alcohol, sugars (es-pecially low melting-point sugars such as xylitol, dextrose, malt-

ose, and sorbitol), Gelucires of higherhydrophilic–lipophilic balance values(HLB . 14) values, water solublepolyoxyethylene derivatives (e.g.,Brijs), polyethylene–propylene glycolcopolymers (poloxamers), poly (eth-yleneoxide) (PEO) derivatives, PEGderivatives, PEG–PEO derivatives, orvarious combinations. When melted,these solids are completely immisci-ble with silicone oils, mineral oil, veg-etable oils, aliphatic long-chain hy-drocarbons, or various combinations.Commercially available silicone oilshaving a wide range of viscosities aremost suitable as the liquid in the col-umn. They are clear, nontoxic, non-rancidifying, and predominantlyinert. Moreover, they have very lowfreezing points. The densities ofmolten, hydrophilic solids are usuallyhigher than that of these liquids, sousing Apparatus I to form pellets withthese materials would be appropriate.

Potential hydrophobic carriers in-clude glyceryl monostearate, glycerylpalmitostearate (GPS), glyceryldibehenate, ethylene glycol palmi-tostearate, cetostearyl alcohol, cetylalcohol, stearyl alcohol, cholesterol,hydrogenated vegetable oils, phospho-lipids and its derivatives, lanolin,triglycerides, long-chain fatty acids orhydrocarbons, hard fat, oil-soluble

Brijs, cocoa butter and other waxes, and combinations of these.When melted, these solids are completely immiscible with somehydrophilic liquids such as liquid PEGs (MW 200–600), propy-lene glycol, glycerin, ethyl alcohol, water, and various combi-nations. These liquids can serve as cooling liquids. The densi-ties of hydrophobic solids are usually lower than those ofhydrophilic liquids, so using Apparatus II to form pellets wouldbe appropriate.

Some liquids are immiscible with both hydrophobic and hy-drophilic molten solids. This property allows them to serve ascooling liquids for sustained-release pellets containing mixturesof hydrophilic and hydrophobic solids. Examples include sili-cone oils with viscosities .20 cP that are immiscible with hy-drophilic solids such as PEGs and certain hydrophobic solidssuch as glyceryl dibehenate and carnauba wax. Tables I and IIlist the physical properties of some carrier solids and coolingliquids that can affect the freeze-pelletization process (13, 14).

To demonstrate the applicability of this technique, variouspellets were prepared, including immediate-release dexametha-sone pellets, sustained-release theophylline matrix pellets, andplacebo wax pellets. Dexamethasone (a poorly water-solubledrug) and theophylline (a moderately water-soluble drug) servedas the model drugs.

100 Pharmaceutical Technology OCTOBER 2004 www.pharmtech.com

Table I: The physical properties of some carrier solids that can affect the freeze pelletization technique.Carrier solids Melting point (°C) Density (g/cm3) Viscosity (cP)PEG 1000 37–40 1.15–1.21 at 25 8C 18–22 at 99°CPEG 1500 44–48 1.15–1.21 at 25 8C 30–38 at 99 8CPEG 4000 50–58 1.15–1.21 at 25 8C 126–181 at 99 8CPEG 6000 55–63 1.15–1.21 at 25 8C 287–448 at 99 8CPEG 8000 60–63 1.15–1.21 at 25 8C 540–1035 at 99 8CXylitol 92–96 1.52 at 25 8C —Sorbitol 110–112 1.507 at 25 8C —Maltitol 148–151 — —Mannitol 166–168 1.514 at 25 8C —Trehalose 97 — —Gelucire 50/13 46–51 — —Gelucire 44/14 40–50 0.91 at 70 8CPoloxamer 188 52–57 1.06 at 25 8C —Brij 35 33 1.05 at 20 8C —Brij 72 43 — —PEG Stearates 37–47 — —Glyceryl monostearate 55–60 0.88 at 90 8C 21 at 90 8CGlyceryl Palmito– 52–55 0.87 at 90 8C 17 at 90 8Cstearate (Precirol ATO 5)Glyceryl behenate(Compritol 888) 65–67 0.85 at 90 8C —Gelucire 43/01 42–46 — —Carnauba wax 75–83 0.84 at 90 8C 43 at 90 8CMicrocrystalline 60–90 0.79 at 90 8C 17 at 90 8Cwax (Petrolite 195)Beeswax 56–60 0.82 at 90 8C 15 at 90 8CStearyl alcohol 56–60 0.80 at 90 8C 8 at 90 8CCompritol HD 5 60–67 — —


Materials and methodsMaterials. PEGs (MW 1500, 3350, and 8000), dexamethasone,theophylline anhydrous, and propylene glycol were purchasedfrom Spectrum Chemical Manufacturing Corp. (NewBrunswick, NJ). Silicone oils (200 fluid 5-cSt and 200 fluid 20-cSt) were provided by Dow Corning Corp. (Midland, MI). Pre-cirol ATO 5 (glyceryl palmitostearate) and Compritol 888 ATO(glyceryl dibehenate) were supplied by Gattefossé Corp. (Para-mus, NJ). Acetonitrile HPLC grade was obtained from FisherScientific (Pittsburgh, PA).

Preparing matrix pellets. Selecting the appropriate apparatusfor preparing matrix pellets depends on the density of the moltencarrier solids. Carrier solids (hydrophilic or hydrophobic) aremelted with either a water bath or an electric heater (see num-ber 1, Figures 1 and 2). The temperature in the bath is main-tained at 5–10 8C higher than the melting point of the carriersolids. The actives and excipients are added to the molten massand mixed with a stirrer (see number 2, Figures 1 and 2) to forma uniform solution or dispersion. This molten matrix is intro-duced as droplets into the liquid in the column (see numbers3 and 4, Figures 1 and 2) using needles or nozzles (number 5,Figures 1 and 2). The needle’s gauge size can range from 16 toabout 31 depending on the desired pellet size.

In Apparatus I, the molten solid matrix can be dropped froma height of less than an inch to several inches from the top ofthe column. The height is selected such that the droplets remain

intact as they fall. Needles or nozzles also can be immersed inthe liquid. In Apparatus II, the molten solid matrix is intro-duced as droplets using needles that are pierced through therubber septums attached at the bottom portion of the column.

The columns in Apparatus I and Apparatus II is divided intotwo parts: the initial portion and the cooling portion. The ini-tial portion of the column is where the matrix is introducedand is maintained between 25 8C and ;100 8C. The specifictemperature depends on the melting point and other thermalproperties of the carrier solid. This portion of the column al-lows the liquid droplets (see number 6, Figures 1 and 2) to at-tain an equilibrium spherical shape. In addition, it prevents so-lidification of the matrix in the needles and nozzles, especiallyin Apparatus II. As the pellets move, they solidify into hard pel-lets (see number 7, Figures 1 and 2) in the cooling portion ofthe column, which is longer than the initial column to providesufficient cooling. Here, the temperature is maintained at sub-zero, depending on the freezing point of the liquid in the col-umn and on the nature of the matrix. The temperature can bemaintained using cooling mixtures such as acetone–dry ice,acetonitrile–dry ice, or salt–ice.

The lengths of the initial and cooling portions of the columndepend on the size of the apparatus. In the laboratory set updescribed in this article, the total length of the column was 24in., of which the length of the initial column was 8 in. Thecolumns were made of borosilicate glass. Pellets that were so-

8

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Figure 1: Schematic of Apparatus I.

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Figure 2: Schematic of Apparatus II.


lidified at the end of the cooling columns were collected in col-lectors (see number 8, Figures 1 and 2). In Apparatus I, pelletswere collected at the bottom of the column. By using multiplevalves (see numbers 9 and 10, Figures 1 and 2) and collectors, itwas possible to produce pellets continuously in Apparatus I. InApparatus II, pellets were collected at the top and continuouslyremoved. In this work, molten solid was introduced into the liq-uid medium in the column using a 22G stainless steel needle.

Pellets were washed with a suitable solvent to remove thecooling liquid from their surface. The washing solvent should

be easily volatile and should dissolve the cool-ing liquid but not the matrix. Pellets were thendried under vacuum at 25 8C for approxi-mately 24 h to remove any residual washingsolvents.

Preparing immediate-release dexametha-sone matrix pellets using Apparatus IDexamethasone pellets were prepared byadding dexamethasone in a molten PEG base,which was a mixture of 70% w/w PEG 1500,25% w/w PEG 3350, and 5% w/w PEG 8000.The molten matrix was introduced as dropletsinto 200 fluid, a silicone oil with a viscosity of5 cSt (4.5 cP), using a 22G needle (see Figure1). The initial portion of the column was main-tained at room temperature, and the coolingportion of the column was maintained at 2408C using an acetonitrile and dry-ice coolingmixture. The droplets moved down the col-umn and solidified into spherical pellets. Pel-lets were collected at the bottom of the col-umn, removed, and washed three times withether to remove silicone oil from the pellets’surface. The pellets then were dried under vac-uum at 25 8C for 24 h to remove residual ether.Pellets containing 5, 10, and 20% w/w dexam-

ethasone were prepared.

Preparing sustained-release theophylline matrix pellets using Apparatus ITheophylline pellets were prepared by adding10% w/w of theophylline anhydrous to a mix-ture of molten PEG base and increasing propor-tions (10, 20, 30, 40, and 50% w/w) of GPS. Themolten matrix was introduced as droplets into200 fluid, a silicone oil with a viscosity of 20 cSt(19 cP), using a 22G needle (see Figure 1). Theinitial portion of the column was maintained at60 8C, which is 5 8C above the melting point ofGPS, using recirculating hot water. The coolingportion of the column was maintained at –408C using an acetonitrile and dry-ice cooling mix-ture. Pellets were removed from the bottom ofthe column, washed three times with isopropylalcohol, and then dried under vacuum at 25 8Cfor 24 h to remove the alcohol.

Preparing wax pellets using Apparatus IIWax pellets were prepared by melting a mixture of equalamounts of GPS and glyceryl dibehenate. This molten matrixwas introduced as droplets into a column containing propyleneglycol and water (70:30) using a 22G needle (see Figure 2). Inthis case, water was added to reduce the viscosity of the propy-lene glycol. The initial portion of the column was maintainedat 75 8C, which is 5 8C above the melting point of behenate,using recirculating hot water. The cooling portion of the col-

Figure 3: Figure shows (a) a microscopic image (43) of a pellet containingdexamethasone (10% w/w) in a polyethylene glycol (PEG) base; (b) a microscopic image(43) of a pellet containing theophylline (10% w/w) in a PEG base; (c) a microscopic image(43) of a pellet containing theophylline (10% w/w), glyceryl palmitostearate (GPS) (50%w/w), and a PEG base (40% w/w); and (d) a microscopic image (43) of a pellet containingtheophylline (10% w/w), GPS (40% w/w), and a PEG base (50% w/w).

a b

c d

Table II: Properties of some liquids that can affect freeze pelletization.Liquid Freezing point Density Viscosityin the column (8C) (g/cm3) at 20–25°C (cP) at 20–25 8CPropylene glycol 259 1.038 58 Glycerin 17.8 1.26 .110

PEG 300 215 to 28 1.12 77PEG 400 4–8 1.12 101

PEG 600 15–25 1.08 141Mineral oil 212 to 29 0.84–0.89 110–230

Castor oil 212 0.957–0.968 1000Almond oil 218 0.91–0.915 —

Oleic acid 4 0.895 26200 fluid, 5 cs 270 0.913 4.5(silicone oil)

200 fluid, 10 cSt 260 0.935 9.5200 fluid, 20 cSt 252 0.949 19

200 fluid, 50 cSt — 0.959 48


umn was maintained at 240 8C using an acetoni-trile and dry-ice cooling mixture. Pellets collectedat the top of the column were washed three timeswith deionized water and dried under vacuum at25 8C for 24 h. No drug was added to the carriersolids.

Characterization and evaluation of the pelletsThe particle-size distribution of the pellets wasdetermined by sieve fractioning. The shape andsurface morphology of the pellets were observedusing a microscope fitted with a digital camera(Kodak Qualcomm Windows Eudora Version 5.1).The friability of the pellets was evaluated using atablet friabilator and by noting a change in theinitial weight of 500 mg of pellets when the pel-lets were subjected to 100 free falls. The drug con-tent of the pellets and the amount of drug releasedduring dissolution studies were determined usinga UV-spectrophotometer (Lambda EZ 201, PerkinElmer). Dexamethasone was analyzed at 240 nmand theophylline at 271 nm. The solvents usedfor dexamethasone and theophylline were ace-tonitrile–deionized water (1:1) and deionizedwater, respectively. Dissolution studies were con-ducted in 900 mL of deionized water using USPApparatus I at a rotation speed of 100 6 2 rpmand maintained at 37 6 0.5ºC. Samples weretaken at predetermined time intervals, and theamount of drug released was analyzed.

Results and discussionTo use the freeze-pelletization process, the fol-lowing key factors are identified:

• The molten carrier solids should be com-pletely immiscible with the liquid in the col-umn.

• Selection of the apparatus depends on thedensity of the carrier solids.

• The viscosity of the drug matrix should below so as not to cause blockage of the nee-dles or lead to non-homogeneity in the shapeand size of the pellets.

• The particle size of actives and excipients thatare added to the carriers should be smallenough to pass through the needles.

• The liquid in the column should have a lowfreezing point, preferably below 210 8C.

• The optimum viscosity of the liquid should range between4 and 40 cP at 20 8C to obtain spherical pellets. If the vis-cosity is much lower, molten solid droplets move rapidlyin the column and lose their spherical shape. If the viscos-ity is greater, then the pellets move too slowly and they mayform agglomerates.

• The rate at which droplets are introduced into the columnshould be optimized to prevent aggregation of the pellets.

Immediate-release pellets were prepared with hydrophilic

solids, and sustained-release pellets were prepared with a mix-ture of hydrophilic and hydrophobic solids. The physical stateof the drug in the matrix depends on its solubility in the car-rier solids. Accordingly, the drug may be a solid solution, a dis-persion, or both. Analysis of the pellets showed that the size dis-tribution of pellets was very narrow and that the pellets werein the size range of mesh #8 to #10. The diameter of all the pel-lets was 2.15 6 0.25 mm when a 22G needle was used. Micro-scopic studies (see Figure 3a–d) indicated that the pellets were

Figure 5: Dissolution profiles of theophylline pellets sized 2.15 6 0.25 mm containing10% w/w theophylline and increasing proportions of GPS in a PEG base.

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Figure 4: Dissolution profiles of dexamethasone pellets sized 2.15 6 0.25 mmcontaining 5, 10, and 20% w/w dexamethasone in a PEG base.

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nonporous and spherical in shape. The friability of the pelletswas less than 0.5%. The drug content of the pellets was 100 610%, indicating no significant extraction of the drugs into theliquid in the column. The dexamethasone pellets had as muchas a 20% w/w drug loading. The matrix containing dexametha-sone in concentrations above 20% was too viscous for prepar-ing pellets. Figures 4 and 5 show the dissolution profiles. Therewas nearly a 100% release of dexamethasone and theophyllinewithin 30 min from the immediate-release pellets. Figure 5shows that the release of theophylline decreased as the propor-tion of GPS in the matrix increased. To sustain the release oftheophylline for 12 h, at least 50% w/w GPS was required in thematrix pellets. The placebo wax pellets were successfully pre-pared using Apparatus II with acceptable properties, includinga spherical shape, smooth surface, and a friability of ,0.5%. Itshould be possible to incorporate water-soluble drugs in thesewax matrices to obtain sustained-release pellets.

Although the production rate of freeze pelletization may belower than those of conventional industrial methods, it maynot be a major limitation because of the significantly decreasedtime required to process the raw materials. It should be possi-ble to scale-up this process by increasing the number of injec-tors (nozzles), to several hundred if required, to meet the de-sired rate of production. These injectors can be arranged invarious configurations depending on the design of the appara-tus, and they can be static or vibrated electrically. Using freezepelletization, it should be possible to spray the molten solid ma-trix with an atomizer instead of adding it drop-wise into thecolumn to obtain micropellets.

ConclusionFreeze pelletization is a novel and simple technique that offersseveral advantages over other pelletization methods. The pel-lets are nonporous and spherically shaped with a very narrowsize distribution. They are solid at room temperature, so freeze-drying or lyophilization is not required. The technique has fewerprocess variables than other pelletization methods and worksas either a batch or a continuous process. Freeze pelletizationhas many potential applications for preparing immediate- andcontrolled-release matrix pellets. Controlled-release pellets arematrix type and do not require additional coating. Pellets madeusing freeze-pelletization can be subsequently coated with suit-able polymers to produce delayed-release and colon-specificformulations. Various excipients can be used in this technique,and formulations can be easily modified to suit a wide range ofdrug delivery applications.

References1. H. Bechgaard and G.H. Nielson, “Controlled-Release Multiple-Unit

and Single-Unit Doses,” Drug. Dev. Ind. Pharm. 4 (1), 53–67 (1978).2. D. Blok et al., “Scintigraphic Investigation of the Gastric Emptying of

3-mm Pellets in Human Volunteers,” Int. J. Pharm. 73 (2), 171–176(1991).

3. G.A.Digenis,“In Vivo Behavior of Multiparticulate Versus Single-UnitDose Formulations,” in Multiparticulate Oral Drug Delivery, I. Ghe-bre-Sellassie, Ed. (Marcel Dekker, New York, NY, 1994), pp. 333–355.

4. I. Ghebre-Sellassie, Ed., Pharmaceutical Pelletization Technology (Mar-cel Dekker, New York, NY, 1989), pp. 20–120


5. A. Lanterbach, “Production of Spherical Shaped Products of Sublim-ing Substances,” US patent 5,437,691 (1 August 1995).

6. J.A. Uribe and J.G. Flores,“Parental Dosage Form,” US patent 5,643,604(1 July 1997).

7. E. Cervos et al., “Coumarin Spherules/Beads Having Unique Mor-phology,” US patent 5,693,342 (2 December 1997).

8. L. Rodriguez et al., “Apparatus and Method for Preparing Solid Formswith Controlled Release of the Active Ingredient,” US patent 5,707,636(13 January 1998).

9. J. Buchmüller and G. Weyermanns,“Device for the Controlled Freez-ing of Viscous Liquids,” US patent 4,829,783 (16 May 1989).

10. G. Weyermanns,“Process and Device for Pellet Freezing Pourable andFlowable Materials,” US patent 5,694,777,9 (December 1997).

11. J.C. Wunderlich et al., “Solid Bodies Containing Active Substances anda Structure Consisting of Hydrophilic Macromolecules, Plus a Methodof Producing Such Bodies,” US patent 5,876,754 (2 March 1999).

12. Schvester, “Pellet Freezing Device and Process,” International Publi-cation Number WO 01/68231 A1 (20 September 2001).

13. R.C. Rowe, P.J. Sheskey, and P.J.Weller, Eds., Handbook of Pharmaceu-tical Excipients (Pharmaceutical Press, London and American Phar-maceutical Association, Washington DC, 4th ed., 2003), pp. 454–459,260, 267, 447, 596, 679, 683, 694.

14. L.J. Thomsen, T.Schæfer, and H.G. Kristensen, “Prolonged ReleaseMatrix Pellets Prepared by Melt Pelletization II: Hydrophobic Sub-stances as Meltable Binders,” Drug. Dev. Ind. Pharm. 20 (7), 1179–1197(1994). PT

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