Polymer Delivery Systems Concepts - ACS Symposium Series (ACS

Chapter 1

Polymer Delivery Systems Concepts

Downloaded by OREGON HEALTH & SCIENCE UNIV on November 9, 2014 | http://pubs.acs.org Publication Date: March 5, 1993 | doi: 10.1021/bk-1993-0520.ch001

I. C. Jacobs and N. S. Mason Department of Chemical Engineering, Washington University, One Brookings Drive, St. Louis, M O 63130

Examples of successful applications of controlled release are mentioned and commonly used concepts are defined. The chapter describes how polymers are used in devices and how their properties affect device performance. Processes of wide applicability including those covered in succeeding chapters are summarized. The task of controlled release is deceptively simple: get therightamount of the active agent at therighttime to therightplace. Controlled release is a term that represents an increasing number of techniques by which active chemicals are made available to a specified target at a rate and duration designed to accomplish an intended effect. In their most elegant implementation, these systems can mimic processes of living cells such as secretion of hormones or enzymes. Many other terms besides "controlled" have been used to describe somewhat different delivery system concepts from "continuous" release to "timed" release. Some of the terms are defined more precisely by Ballard (1). Only a few examples will be cited in the paragraphs following. Controlled Release of Drugs. Controlled release is often used to extend the time the effective therapeutic dose is present at the targetfroma single administration, and to avoid or minimize concentrations that exceed therapeutic requirements. It also can decrease the needed dose of an expensive active ingredient. Protecting certain tissues is often desirable, e.g. the stomach from irritation. Targeting tissues may be desirable, avoiding toxic effects. This can make the administration of the drug less invasive. Taste-masking of a drug can improve patient compliance. Incompatibilities between ingredients can be mitigated. A few commercial examples may be mentioned: Occusert, a device for releasing pilocarpine, a drug to treat glaucoma, to the eye (2,3), an implantable osmotic pump capable of delivering a nearly constant 20 mg/hr of solution to the body for almost a day (4) and Norplant, a long-term contraceptive implant (5). Controlled Release Pesticides. Controlled release can increase the effectiveness of an agent, and its specificity. It can decrease the possibility of damage to the environment. 0097-6156/93/0520-0001$06.00/0 © 1993 American Chemical Society

In Polymeric Delivery Systems; El-Nokaly, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1993.

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POLYMERIC DELIVERY SYSTEMS

Penncap M and E. represent examples of microencapsulated forms of methyl and ethyl Parathion (6). Systems have been developed for releasing pheromones to confuse insects (7), collars to keep fleas away from pets (£), even keep mollusks from the hulls o f ships (8).


Controlled Release Fertilizers. Controlled release can decrease the number o f applications. It can make one application last longer. A reduction in run-off into rivers or aquifers may be another benefit. Special C o n t r o l Release Applications. "Carbonless carbon paper" was the first product involving microencapsulation. A latent dye, crystal violet lactone is contained in 5 to 25 micron microcapsules that are coated on the back o f a page. The action of a sharp pencil, typewriter, or impact printer ruptures the microcapsules, releasing the lactone to react with an acid clay present on the copy sheet, activating the color (9). Side effects in the treatment o f diabetes would be decreased, i f encapsulated implants o f islets o f Langerhans from the pancreas could be used. The islets could originate from a different species. Encapsulation would keep the islets from being destroyed by the immune system of the host, allowing the cells to release insulin in response to the concentration of glucose (JO). Improvements in oil well stimulation with hydraulic fracturing fluids have been realized with the use o f controlled release viscosity breakers (77). Increasing the likelihood of germination o f seeds under adverse conditions is another application o f controlled release. Because controlled release is a rapidly changing field, new ideas are being generated and applications are being evaluated every day. Functions o f Polymers i n Controlled Release. Polymers are uniquely suited as materials o f construction for delivery systems because their permeability can be modified and controlled. They can be shaped and applied relatively easily by a large variety o f methods. Active ingredients and property modifiers can be incorporated either physically or chemically. In general, polymers have little or no toxicity. Despite the diversity o f applications, they principally serve as membranes or envelopes, as matrices i n which the active ingredient is dispersed or dissolved, or as carriers which are chemically attached to the active ingredient. Not all controlled release devices use polymers explicitely. For example liposomes do not. Delivery Systems Terms. Devices can range i n size from as small as one molecule to coated tablets and boluses used in cattle. Availability, or bioavailability is an important property o f most dnig-containing devices. Tests i n glass-ware (in vitro) or i n the living system (in vivo) must be conducted to ascertain that the active ingredient is available under specified conditions.



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Biodegradable refers to polymers that under certain conditions undergo a decrease i n molecular weight eventually disintegrating or dissolving in the medium. It is most often applied to polymers and copolymers o f lactic, glycolic, hydroxybutyric acids as well as poly(a-caprolactone). For these substances the degradation is hydrolytic and no enzymes are involved. Kinetics generally follow first order (72, 13) and are often insensitive to p H . Natural polymers such as starch and cellulose are also biodegradable and enzymes are involved i n these cases. Polyphosphazenes, polypeptides, and proteins have also been proposed for drug delivery. Other polymers mentioned as biodegradable were, poly(dihydropyrans), poly(acetals), poly(anhydrides) (14), polyurethanes, and poly(dioxinones). Biocompatible devices are devices that can be applied without causing undesirable effects in living systems. Bioabsorbable devices are those which are degraded by a living system and can be utilized or metabolized by it. E r o d i b l e systems are designed to control the release of the active substance by erosion of the matrix. Zero order release means the active substance is released at a constant rate. B y analogy to reaction kinetics, the rate of release, -dc/dt = k. It can be approximated by a reservoir device containing a saturated solution o f the active ingredient surrounded by a rate-limiting membrane. This requires a supply o f undissolved active ingredient i n the device and a non-changing or zero sink condition (75). First order or pseudo-first order means the release rate is proportional to the concentration remaining in the device i.e., with a rate, -dc/dt = kc. This implies a decrease in rate with time. It would be approximated by a device in which the concentration decreased as the amount remaining in the device decreased. B u r s t effect refers to the tendency o f some devices to release the active substance more rapidly during some period, usually the initial test period, than during the steady-state, or a later period. Time lag is observed when the rate limiting membrane must first establish a concentration gradient before releasing at the designed rate. Therefore some time elapses before the release rate reaches its designed value. Mathematical expressions of this and the above phenomenon are given in (15). Reservoir devices consist of a drug or other active agent enclosed within an inert controlling membrane. Examples would be a tube filled with the active substance, where the wall of the tube would serve as the limiting membrane, a sphere o f the active substance coated with a film controlling the diffusion o f the active substance, or a slab


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of the active substance closed off from the medium by a film which controls the diffusion. Matrix devices in which the active drug is dispersed throughout the polymer are called monolithic devices or monoliths by a number of authors. One can distinguish between monolithic devices in which the active ingredient is dissolved, dispersed, located i n connected pores, or granular. The equations describing the time behavior of such devices predict that initially the fraction released varies as time and the rate o f release is proportional to t i m e ' . Baker and Lonsdale (15) i n their classic paper, treat each of the cases separately including the different geometries such as slab, sphere and cylinders. A s time increases, the release rate is better approximated by an exponential decay (Late time approximation). A more recent review of this material by Roseman may be found in (16). 1/2


m

Targeting of drugs is a concept that is as old as the dream of the magic bullet o f Paul Ehrlich (17). Thies (18) distinguishes between active and passive targeting. Passive targeting takes advantage o f an existing body process such as the rapid concentration of particles smaller than 1 micron i n the liver or spleen after intravenous injection. In active targeting, the natural tendency o f the body to distribute the active substance is altered. The drug or carrier, because it has a special affinity e.g., by certain molecular interactions such as a lock and key mechanism, interacts with specific cells. If this could be implemented, it could improve cancer chemotherapy considerably. Enteric coatings, coatings which are less soluble in acidic aqueous solutions than neutral ones, provide a means for a drug to by-pass the stomach and only become available in the intestine. This is a method to direct rather than target a drug. M a n y enteric coatings are based on polymers containing phthalic acid residues attached to cellulosic or vinyl polymer chains. Reverse enterics, on the other hand, do not dissolve in neutral media such as the mouth, but dissolve very rapidly i n an acid medium such as the stomach. Polymer Properties that Affect the Release of Active Substances. Consider a polymer membrane and a diffusing active substance in solution. The amount o f the substance which diffuses per unit time across the membrane at steady-state is proportional to the diffusion coefficient and to the concentration difference across the membrane measured on each side o f the membrane just inside the membrane. (It is also proportional to the area and inversely proportional to the thickness o f the membrane). Because the concentration inside the membrane is not known and is often much different from the concentration in solution, the concentration difference normally measured in the solution must be multiplied by the distribution coefficient. The distribution coefficient is the ratio o f the solubility o f the agent in the membrane to its solubility in the external medium. The permeability is die


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product of the diffusion coefficient and the solubility coefficient. Its dimensions are the same as the diffusion coefficient, (length) /time. 2

It must be pointed out, as Baker and Lonsdale (15) have done, that the relatively low diffusivity and solubility of large molecules in polymers often constrain the release rates attainable with delivery systems which employ unplasticized dense membranes. Even silicone rubbers which have high diffusion coefficients and solubilities for many organic active molecules of interest, rarely permit maximum daily fluxes greater than 2.5 mg/cm through a 0.1 m m thick membrane. For less permeable polymers, fluxes two orders o f magnitude lower are typical. This is the reason why applications have favored silicone rubbers and only very potent drugs such as steroids. Some values o f these parameters are listed in Table I. It illustrates the range o f values encountered. The diffusion coefficient and the solubility (i.e. distribution coefficients) have very different dependencies i n the polymer phase. This will be discussed below.


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Table I. Selected Values of Diffusion Coefficients and Partition Coefficients i n Polymers Solute

Polymer

Diffusion Coefficient cm /sec

Partition Coefficient (polymer/water)

2

Acetophenone

Polyethylene

3.55 χ ΙΟ*

3.16

Chlormadione Acetate

Silicone Rubber

3.03 χ ΙΟ"

82

Estriol

Poryurethane Ether

2

Fluphenazine

Polymethylmethacrylate

1.74 x l O

1 7

Hydrocortisone

Polycaprolactone

1.58 χ 1 0

1 0

17a-hydroxy-progesterone

Silicone Rubber

5.65 χ ΙΟ"

Progesterone

Silicone Rubber

5.78 χ ΙΟ"

Salicylic A c i d

Polyvinyl Acetate

χ 10"

4.37 χ 1 0

7

133

9

0.89

7

7

45 to 60

1 1

SOURCE: Adapted from ref. 16 with permission. Copyright 1980 C R C Press. Hydrophilic polymers, or polymers that can swell in water or other solvents, are not subject to the limitations o f the dense polymers in the above table and will be covered in a later section. Porous polymers also can have higher fluxes.



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Diffusion Coefficient Diffusion coefficients are much more sensitive to molecular weight o f the diffusing substance in polymers than they are in low viscosity liquids, Figure 1. Diffusion coefficients depend on the mobility of segments of the polymer chain. Table Π summarizes the trend of several factors on the diffusion coefficient. Diffusion of a molecule in a polymer requires the cooperative movement of several polymer chain segments. This is why substances have higher diffusion coefficients in polymers that have lower interchain forces such as silicone rubber and natural rubber in comparison to polystyrene. The lower the molecular weight, or more accurately, the size of the diffusing substance, the smaller is the required segmental motion. Therefore it is more likely for the smaller molecule to find sufficient space for diffusion. For the same reasons, an increase in crystallinity o f the polymer will decrease the diffusion coefficient o f the substance as will an increase in the degree of cross-linking. Plasticizers or solvents that increase the segmental mobility lead to increases in diffusion coefficients, whereas fillers which decrease the segmental mobility lead to decreases in the diffusion coefficient. The diffusing substance itself, i f it plasticizes the polymer, will increase its own diffusion coefficient. Diffusion coefficients are always higher above the glass transition, Τ , o f the polymer than below. (The glass transition temperature is the temperature at which the polymer changes from a glassy to a rubbery state). The activation energy for diffusion decreases above the T as well. Whether above the T or below, the diffusion coefficient increases with temperature. The diffusion coefficient can be increased by copolymerization, e.g. by random insertion of groups especially i f the groups increase the flexibility or decrease the crystallinity. g

g

Table Π - Factors which Change the Diffusion Coefficient Increases in Factor Listed Below

Effect on Diffusion Coefficient

Interchain Forces Segmental Mobility Permeant Molecular Weight Polymer Crystallinity Plasticizer Copolymerization Temperature Glass Transition

+

+ + +

Solubility. The solubility of substances i n polymers is very sensitive to small changes in the molecule such as the addition o f a substituent. The most widely used attempts to predict solubilities i n polymers have been the use o f solubility parameters (19). The closeness of the solubility parameter between the active substance and the polymer



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Figure 1. Dependence of diffusion coefficients on molecular weight (Reproduced with permission from ref. 16. Copyright 1980 C R C Press, Inc.)


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would favor compatibility and solubility. However, the degree o f hydrogen bonding and polarity effects are also important (20).


Structural Considerations. H y d r o p h o b i c Polymers. When active agents are dispersed i n polymers the geometry may play a role regarding availability and release rate. The first models were tortuosity models (21). Pores were assumed to be of uniform cross-section but tortuous. Therefore, a molecule must travel a greater distance than i f the pores were straight. Constriction or corrugation models assume that there are places where the pores become narrower. This geometry may more closely approximate porous polymers. The arrangement of pores can also affect the release, i.e. whether the pores are isolated or connected. As the porosity increases more of the pores connect to each other and availability of the agent increases rapidly. The percolation threshold, which is the value of the porosity at which the availability increases rapidly, ranges from 50 to 70 % for two dimensional matrices and from 20 to 43 % for three dimensional ones (21). This depends to some degree on the pore shape.

H y d r o p h i l i c Polymers and gels are used extensively in controlled release devices. Gelatin is a versatile hydrophilic polymer. It is soluble in water above 30 to 35 C but is a gel below this temperature. It can also be cross-linked so that it is no longer soluble in water at any temperature. Other substances which gel on temperature decrease include agar, agarose, and iota-carrageenan. (22). Hydrophilic polymers that can be cross-linked ionically include alginates, and low methoxyl pectins with calcium ions, and kappa-carrageenan with potassium or calcium ions. A l l these substances have been used in microcapsules as well as other controlled release devices. Hydrogels, e.g., cross-linked copolymers o f hydroxyethyl methacrylate and ethylene dimethacrylate, have been studied extensively for medical applications because o f their biocompatibility (23). Hydrophilicity can be controlled by copolymerization with methyl methacrylate or other less water soluble monomers. Hydrophilic polymer properties can be used to engineer devices which can respond to their environment and thus, potentially could be used as elements i n feed-back control loops. Cross-linked gels that contain ionic groups can show substantial changes i n swelling with small changes in p H (24). Such a gel can respond to the concentration o f glucose i f it also incorporates glucose oxidase. Glucose oxidase catalyzes the oxidation of glucose to gluconic acid changing the p H . Okano (25) constructed interpenetrating gels from N-acryloylpyrrolidine and polyoxyethylene which showed a change i n equilibrium swelling i n water from 150 % to 500 % when the temperature was cycled from 10 to 30°C. The rate of release o f a drug more than doubled in response to the same step change i n temperature. Controlled release devices can be fabricated also from polymers which are normally water soluble but dissolve more slowly than the


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active ingredient. Such polymers can also be cross-linked by a variety o f methods. Diffusion coefficients o f water swollen polymers are much higher than those in non-swollen polymers. In fact they approach diffusion coefficients in solution. A simplified equation from (26) may be useful to correlate data on diffusion o f small molecules in gels. l n ( D / D J = (kA,Xl-H)/H where D and D are the diffusion coefficients in the gel and in water respectively, A is the effective cross-section of the solute molecule, H is the volume fraction o f water in the gel, and k is a constant at constant temperature.


w

e

Processes for Achieving Controlled Release. Methods for the manufacture o f polymer delivery systems may be divided into physical and chemical processes depending upon whether the active ingredient becomes covalently attached during the process. Physical methods are most often used to place the active ingredient into a reservoir or matrix form. O f the many processes described in the literature, the following physical processes are used most often: Spray coating Pan Coating A i r Suspension coating Wall deposition from solution Complex coacervation Polymer-Polymer Induced Coacervation Interfacial polymerization Solid-Gas Liquid-Liquid Interfacial Polycondensation Matrix Solidification Spray Drying Spray Chilling Solvent Evaporation from Emulsions Solvent Evaporation in Castings Castings or Particle Formation using Polymerization Flavor and Fragrance Trapping Centrifugal Methods Annular Jet Encapsulation Suspension Separation



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Spray Coating. Particles to be coated are put i n motion either by rotation as in a drum, or coating pan, or by a carrier gas as in a fluidized bed (also called air suspension coating). The coating as a solution, latex, or low-viscosity melt is sprayed onto or into the bed of particles. The motion of the particles needs to be sufficient to prevent particle agglomeration while the solvent is drying. Coatings are built up in layers on the surface o f the particles and the quality o f the barrier will be affected by the nature o f the coating formulation as well as process conditions. Spraying rates, coating droplet size, bed temperature, humidity, particle motion, and surface wettabilities are all important factors. When latexes are used as alternatives to organic solutions o f polymers, post-heat treatment above the glass transition temperature is often used to improve film formation. Plasticizers which lower the T are also used for the same purpose. For melts, one is limited to low viscosities to obtain sufficiently fine droplets. g

P a n coating is among the most widely used procedures for controlled release, especially pharmaceuticals. The current pan coating designs evolved from confectionary pans invented approximately 140 years ago (27). Newer designs improve mixing efficiency with baffles and improved drying air flow across or through the particle bed with the most well known variants among what are known as side vented coating pans. Lack o f reproducibility and operator error plague the process. A i r suspension or fluidized bed coating may place the spray nozzle on top of the bed, on the side, or near the bottom. The Wurster process (28% which places the nozzle in a draft tube near the bottom of the vessel, can often be fully automated (Figure 2). Coating uniformity is excellent, and irregular small particles can be used with a variety o f coating materials. Particles down to approximately 100 microns can be coated. W a l l Deposition from Solution. Complex Coacervation-phase separation was developed by N C R in 1954 (9). Gelatin and gelatin-gum acacia were described for the wall o f microcapsules containing the dye used in the manufacture of carbonless carbon paper. The technique has been adapted for the controlled release of many materials. For example, an organic phase is dispersed in a dilute aqueous gelatin solution and a second water soluble polymer is added that can associate with the gelatin, e.g., a porycarboxylic compound, or possibly a polysulfonic acid. The p H o f the solution is adjusted below the isoelectric point of the normally amphoteric gelatin making it cationic and thus causing an association of the polymers to occur and the appearance o f a polymer-rich phase or "coacervate". The coacervate droplets must wet the surface of the core particles before coalescing into a continuous coating. Poor wetting of particles and agglomeration o f the capsules during formation and drying are common problems. Coacervation also can be induced by conditions or materials that influence polymer hydration such as temperature, water soluble solvents, or by addition of large amounts


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TOP S P R A Y

COATER

Filter Housing


Expansion Chamber

Produot Container

Expanded View

Lower Plenum

Α - P r o d u c t Container B-Air

Distribution Plate

WURSTER - B O T T O M S P R A Y -

C-Spray Nozzle D-Expansion Chamber

COATER

Product Container Expanded Lower Plenum

View

Α - C o a t i n g Chamber

D-Spray Nozzle

B-Partition

E-Expansibn Chamber

C-Air Distribution

ROTOR - T A N G E N T I A L S P R A Y -

Plate

COATER

Filter Housing

Expansion Chamber

Product Container Lower Plenum

Product Container Expanded View Α - P r o d u c t Chamber

C-Disc Gap or

B - V a r i a b l e Speed Disc

D-Spray Nozzle

Slit

Figure 2. Spray Coating Apparatus. (Reproduced by permission of Glatt Air Techniques)


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o f salts such as sodium sulfate. The resulting gelatin coatings can be cross-linked with formaldehyde or glutaraldehyde.


Polymer-Polymer and Non-Solvent Induced Coacervation. Analogous processes exist for the encapsulation of water soluble solids using organic phase separation (29). In these processes, the core particles are suspended i n an organic solution o f a polymer such as ethyl cellulose or cellulose acetate butyrate that is induced to separate as a coacervate either through cooling, slow addition of non-solvents for the polymer, or the addition o f a more soluble polymer, called a phase inducer. Interfacial Polymerization. Barriers can be formed around liquid droplets or on solid surfaces by causing a chemical reaction to occur at the phase boundary be it a liquid-liquid, solid-liquid, or solid-gas. Solid-Gas. Free radical condensation o f gas phase para-xylylene was developed as a coating process by Union Carbide Corp. during the 1960's (30). Solid para-xylylene is sublimed at 500°C under vacuum to produce free radicals that then undergo polymerization on cold surfaces. Uniform walls o f linear poly (p-xylene) have been deposited on the surfaces o f a variety o f particulate solids. L i q u i d - L i q u i d encapsulation may be applied to any water insoluble liquid, solid or gas. Because the conditions are so mild it has been used for the encapsulation o f living cells. The method involves the formation of droplets o f a sodium alginate solution containing the cells that are then placed into a solution o f calcium chloride converting the drops into gel beads. Encapsulation o f viable insulin producing islet cells for transplantation into diabetics was first disclosed by L i m and Sun (10). The washed gel beads containing the islets are then placed in a solution o f poryrysine for sufficient time to form the association polymer of lysine and alginate on the gel bead surface. The capsules are then placed in a sodium citrate solution to extract the calcium from the bead interior and reliquefy the droplet. Interfacial polycondensation is widely used for the formation o f barriers around organic liquid droplets. Uniform walls of polyureas, polyamides, and mixed systems of the two are widely known. The process involves a polyfunctional electrophile such as a diisocyanate or diacyl chloride dissolved in an organic phase that is then dispersed in an aqueous phase containing the active substance. A water soluble polyfunctional nucleophile is added and the reaction occurs at the boundary o f the phases. One of the two reactants needs to be at least tri-functional for cross-linking o f the walls. These barriers can have good strength and integrity. M a t r i x Solidification. Polymer delivery systems may not necessarily consist o f small particles but also may be slabs or cylinders protecting an active ingredient. Likewise, the processes that involve the formation o f small particles protecting an active ingredient may not be in the form of a single core surrounded by a barrier polymer.


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Products which consist of a dispersed phase, either solid or liquid, contained or imbedded in a particle can be termed matrix particles. These are often less costly to manufacture. Matrix devices can be formed by casting, extrusion or otherwise forming monoliths that contain a dispersed phase. Spray Drying. This process is widely used to produce free flowing granules for the food, pharmaceutical, and agrichemical industries. The material to be dried is suspended or dissolved in a liquid that is atomized by either nozzles or spinning discs at the top o f a chamber (Fig. 3). In most spray dryers hot air flows concurrently with the particles as they fall through the tower. The liquid is evaporated rapidly and the overall drying time is short with production rates varying from a few kilos per hour to tons per hour. Water soluble polymers such as starches, cellulose derivatives, and gums are commonly used. The use o f organic solvents is being replaced with water-based dispersions (latexes) because of environmental health and safety concerns. M u c h work has been done to improve the stability of the oil in water emulsions prepared for drying with the use of modified polymers (31). Latex compositions and plasticizers have been investigated to improve product performance (32). Spray Chilling uses similar equipment as spray-drying but does not require evaporation. The liquid or solid active ingredient is dispersed into a molten continuous phase that is then atomized and cooled to form solid particles. Solvent Evaporation from Emulsions. Here, the active ingredient is dissolved in a polymer solution that is then dispersed in a second immiscible phase. Conditions o f pressure and temperature are adjusted to slowly evaporate the dispersed solvent phase thus converting the mixture into a dispersion o f solid matrix particles containing the active ingredient (33). Control o f the dispersion step is critical to getting the desired particle size. Particle agglomeration during the time-consuming evaporation step is often a problem as the particles can go through a sticky stage in the process. Solvent Evaporation in Castings. Polymer films and slabs can be cast routinely by dissolving the polymer o f interest i n a suitable solvent along with the active ingredient and then forming the film or slab using a Gardner knife or an appropriate mold. The solvent is allowed to evaporate slowly. Some polymers, which swell in water, are loaded with water soluble ingredients by soaking the device i n a concentrated solution o f the active agent, removing the swollen polymer from the solution, and surface washing o f the device. This latter technique allows only low loadings o f active agent, often under 20 %. Castings or Particle Formation using Polymerization Reactions. Monomer mixtures or pre-polymers can be mixed with an active ingredient and poured into molds or otherwise formed into droplets. The polymerization reactions are initiated with heat, ionizing radiation, or catalysts and when completely cured become an effective matrix




Liquid Feed Hot Air

Product and Exhaust Air

Figure 3. Conventional Cocurrent Spray-Dryer.


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for controlled release. The active ingredient generally must be inert to the polymerization process.


Flavor, Fragrance or Pesticide Trapping. Processes have been developed (34) that allow trapping of hydrophobic liquid droplets in a starch matrix. The starches are chemically derivatized, then mixed with the oil droplets and finally dried and ground. In other processes flavor or fragrance/starch mixtures are extruded, subdivided into particles and dried. Centrifugal Processes. A n n u l a r Jet Encapsulation. Southwest Research Institute, in San Antonio, Texas pioneered a technique for microencapsulating droplets from 300 to 1500 microns (35). In this method, the core liquid is pumped through an orifice to form a jet. The coating material is forced through a concentric annular space around the core jet with the velocity matching the velocity of the internal jet. As the concentric jet moves away from the orifice, the stream breaks up into droplets. The droplets are hardened by cooling or solvent removal, or by complexation with calcium in the case of alginate walls. Suspension/Separation Process. In this process, developed at Washington University in St. Louis, Missouri, the core particles are first suspended in a coating liquid that is either a melt or a polymer solution (36). The suspension is delivered to a rotating disk of specific design that separates the now coated particles from the excess coating. The rotational speed o f the disk is adjusted so that the coating material forms a film on the edge o f the disk that is thinner than the diameter of the cores. When the coating film atomizes, it forms droplets smaller than the coated particles that are then cooled or dried to give the product. The smaller particles of excess coating are recycled after separation. The method is useful for particles in the range of 30 micron to 2 mm. Since the process is rapid and continuous, the throughputs can be very high with low operating costs. The same plant also may be used to produce granules up to 600 micron. Chemical Processes. The attachment o f biologically active molecules to polymer backbones for controlled release has been extensively studied since the early 1960's (37). A typical synthesis involves an active ingredient that contains a reactive functional group that can form a bond at sites along the polymer. The bonds are often ester, amide, or anhydride. Hydroxy or carboxy containing natural polymers such as cellulose, chitin, lignin and hyaluronic acid have been studied. Synthetic polymers such as, polyvinyl alcohol, polyethylenimine, and acrylic or methacrylic copolymers have also been used. These processes also can offer the intriguing possibility mat both drug and targeting functionalities can be attached to the polymer chain.



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Literature Cited

1. Ballard, Β. E. In Sustained and Controlled Release Drug Delivery Systems; Robinson J. R. Ed.; Drugs and the Pharmaceutical Sciences Marcel Dekker: New York 1978 Vol 6; pp. 3-6 2. Chandrasekaran, S. K.; Benson, H.; Urquhart, J. In Sustained and Controlled Release Drug Delivery Systems; Robinson, J. R., Ed.; Marcel Dekker: New York 1978, pp 569-72. 3. Yates, F. E.; Benson, H.; Buckles, R.; Urquhart, J.; Zaffaroni, A. In Advances in Biomedical Engineering, Brown, J. H.; Dickson, J. F.,III,Eds; Academic Press, New York, 1975 Vol 5, p 15. 4. Theeuwes, F. In Controlled Release Technologies: Methods, Theory and Applications; Kydonieus, A. F., Ed.; CRC Press New York 1980 Vol. 2; pp 195-205. 5. Woutersz T. B. Int. J. Fertil. 1991 36 Suppl 3 pp. 51-56 6. Koestler R. C. In Controlled Release Technologies: Methods, Theory, and Applications; Kydonieus A. F., Ed.; CRC Press: Boca Raton, FL, 1980, Vol 2; p 130. 7. Brooks, T. W. In Controlled Release Technologies: Methods, Theory, and Applications; Kydonieus A. F., Ed.; CRC Press: Boca Raton, FL, 1980, Vol 2; p 165. 8. Cardarelli, N. F. In Controlled Release Technologies: Methods,Theory, and Applications; Kydonieus, A. F., Ed.; CRC Press: Boca Raton, FL, 1980 Vol1;pp 58-59. 9. Green, Β. K.; Schleicher L. S. U.S. Pat. 2,800,457(July 23, 1957) to NCR Co. 10. Lim, F.; Sun A. M. Science 1980, 210, 908. 11. Walles, W. E.; Williamson T. D.; Tomkinson D. L. U.S. Pat. 4,741,401. 12. Schindler Α.; et al. Biodegradable Polymers for Sustained Drug Delivery, Continuing Topics in Polymer Science; Plenum Press 1977 Vol 2. 13. Mason, N. S.; Miles C. S.; Sparks R. E. In Biomedical and Dental Applications of Polymers; Gebelein, C. G.; Koblitz, F. F., Eds.; Polymer Science and Technology, Plenum: New York 1981 vol 14; pp 279-291. 14. Laurencin, C.; Domb Α.; Langer R. In Proceedings of the 17th International Symposium on Controlled Release of Bioactive Materials; Lee, V. H. L., Ed.; Controlled Release Society: Lincolnshire, IL 1990 pp 158-159. 15. Baker R. W.; Lonsdale H. K. In Controlled Release of Biologically Active Agents; Tanquary A. C.; Lacey R. E. Eds.; Advances in Experimental Medicine and Biology, Plenum: New York, 1974 Vol 47; pp 15 -71. 16. Roseman, T. J. In Controlled Release Technologies: Methods, Theory, and Applications; Kydonieus A. F., Ed.; CRC Press: Boca Raton, FL 1980 pp 21-54. 17. Encyclopedia Britannica; 15th ed, Encyclopedia Britannica Inc. Chicago IL, 1991 Vol 4 p 395.



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