Handbook of
`Pharmaceutical
`Controlled Release
`Technology
`
`executive editor
`Donald L. Wise
`Cambridge Scientific, Inc.
`Cambridge, Massachusetts
`
`associate editors
`Lisa Brannon-Peppas
`Biogel Technology, Inc.
`Indianapolis, Indiana
`Alexander M. Klibanov
`Robert S. Langer
`Massachusetts Institute of Technology
`Cambridge, Massachusetts
`Antonios G. Mikos
`Rice University
`Houston, Texas
`Nicholas A. Peppas
`Purdue University
`West Lafayette, Indiana
`
`Debra J. Trantolo
`Cambridge Scientific, Inc.
`Cambridge, Massachusetts
`Gary E. Wnek
`Virginia Commonwealth University
`Richmond, Virginia
`Michael J. Yaszemski
`Mayo Clinic
`Rochester, Minnesota
`
`MARCEL
`
`MARCEL q EKKER, INC. (cid:9)
`
`NEW YORK • BASEL
`
`ENDO - Ex. 2040
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`
`

`

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`
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`

`

`page was copied from the collection of the National Library of Medicine by a third party and may be protected by U.S. Copyright law
`
`23
`
`Research and Development Aspects of Oral
`Controlled-Release Dosage Forms
`
`Yihong Qiu
`Abbott Laboratories, North Chicago, Illinois
`
`Guohua Zhang
`Andrx Corportation, Florida
`
`I. INTRODUCTION
`
`Controlled release may be defined as a technique or approach by which active chemicals are
`made available to a specified target at a rate and duration designed to accomplish an intended
`effect. More specifically, an oral controlled release drug delivery system is, in principle, a de-
`vice or dosage form that controls drug release into the absorption site in the gastrointestinal
`(GI) tract. It controls the drug absorption rate to achieve the desired plasma profiles defined by
`the steady-state pharmacology (1). A typical controlled release system is designed to provide
`constant or nearly constant drug levels in plasma with reduced fluctuation via slow release of
`drug over an extended period of time. Controlled release systems are sometimes called ex-
`tended release or sustained release systems. In practical terms, an oral controlled release should
`allow a reduction in dosing frequency as compared to that drug presented as a conventional
`dosage form (2).
`Over the last two decades, controlled technology has received increasing attention from
`the pharmaceutical industry and academia. As new technologies emerge, they not only open up
`a wide range of new therapeutic opportunities, but also offer the benefits of product differenti-
`ation, market expansion, and patent extension. By 1998 over 70 chemical entities had been for-
`mulated into more than 90 oral controlled release products that were approved for marketing by
`the U.S. Food and Drug Administration (FDA) (3).
`Controlled release technology may provide increased clinical value as well as extended
`product life. The advantages of an ideal controlled release dosage form over an immediate re-
`lease product include improved patient compliance due to a reduced dosing frequency, a de-
`creased incidence and/or intensity of the side effects, a greater selectivity of pharmacological ac-
`tivity, and a more constant or prolonged therapeutic effect, as well as an increase of cost
`effectiveness. A typical example is diltiazem hydrochloride, a calcium antagonist for the treat-
`ment of hypertension. To enhance drug therapy and competitiveness, this compound was formu-
`lated into three generations of dosage forms, including immediate release tablets (Cardizem) ap-
`proved from 1982 to 1986, twice-daily controlled release capsules (Cardizem SR) approved in
`1989, and once-daily controlled release capsules (Cardizem CD) approved from 1991 to 1992.
`
`

`

`466 (cid:9)
`
`Qiu and Zhang
`
`With the growing need for optimization of therapy, controlled release technologies pro-
`viding programmable delivery rates other than immediate input have increasingly become more
`important, especially for drugs for chronic use or with a narrow therapeutic index. Thus, un-
`derstanding and utilizing the fundamentals of controlled release technologies is essential to the
`successful formulation research and development of a controlled release product.
`
`11. CONTROLLED RELEASE SYSTEMS FOR ORAL ADMINISTRATION
`
`The basic concepts of controlled release have been reviewed thoroughly in the literature
`(1,4-6). Various physical and chemical approaches have been applied to produce a well-char-
`acterized dosage form that controls drug input into the body within the specifications of the de-
`sired release profile. In this section, commonly used methods based on application of physical
`and polymer chemistry to oral drug delivery systems will be briefly discussed with emphasis on
`polymeric systems.
`
`A. Common Oral Polymeric Controlled Release Systems
`
`The thrust of oral controlled release efforts has been focused mostly on the dosage forms with
`well-defined controlled release profiles. Almost all of the oral solid controlled release prod-
`ucts on today's market are based on the designs of matrix, membrane-controlled, and osmotic
`systems (see Table 1). The application of polymeric systems to the oral controlled release
`dosage form designs and release-controlling mechanisms of these systems have been exten-
`sively investigated (1,7). The mechanisms of these controlled release dosage forms generally
`involve drug diffusion through a viscous gel layer, tortuous channels, or a barrier; drug dis-
`solution via system erosion; and drug solution or suspension forced out of the device by os-
`motic pressure.
`
`1. (cid:9) Matrix Systems
`Both hydrophilic and hydrophobic polymeric matrix systems are widely used to provide con-
`trolled delivery of drug substances because of their versatility, effectiveness, and low cost.
`These types of systems are also suitable for in-house development since they are usually man-
`ufactured using conventional equipment and processing. In a matrix system, a drug is incorpo-
`
`Table 1 Common Oral Controlled Release Polymeric Systems Feasible for Commercial Development
`
`Matrix systems
`
`Reservoir systems
`
`Osmotic systems
`
`Coated beads or tablets
`Microencapsulation
`
`Elementary osmotic pump
`Push-Pull system
`Push-Layer system
`Push-Stick system
`
`Hydrophilic matrix (cid:9)
`• Swellable (cid:9)
`• Swellable and erodible
`Hydrophobic matrix
`n Homogeneous (nonporous)
`• Heterogeneous (porous)
`1. Inert (monolithic)
`2. Erodible
`3. Degradable
`
`-
`
`(cid:9)
`(cid:9)
`

`

`ng
`
`ro-
`
`In-
`the
`
`are
`ar-
`le-
`cal
`on
`
`ith
`)d-
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`en-
`dly
`lis-
`os-
`
`an-
`)st.
`an-
`ao-
`
`rnp
`
`Research and Development of Oral Forms (cid:9)
`
`467 (cid:9)
`
`rated into the polymer matrix by either particle or molecular dispersion. The former is simply a
`suspension of drug particles homogeneously distributed in the polymer matrix, whereas the lat-
`ter is a matrix with drug molecules dissolved in the polymer. Drug release occurs by diffusion
`and/or erosion of the matrix system. (cid:9)
`In a hydrophilic matrix, there are two competing mechanisms involved in the drug re- (cid:9)
`lease: Fickian diffusional release and relaxational release. Diffusion is not the only pathway by
`which a drug is released from the matrix; the erosion of the matrix following polymer relax-
`ation also contributes to the overall release. The relative contribution of each component to the
`total release is primarily dependent on the properties of a given drug. For instance, the release
`of a sparingly soluble drug from hydrophilic matrices involves the simultaneous absorption of
`water and desorption of drug via a swelling-controlled diffusion mechanism. As water pene-
`trates into a glassy polymeric matrix, the polymer swells and its glass transition temperature is
`lowered. At the same time, the dissolved drug diffuses through this swollen rubbery region into
`the external releasing medium. This type of diffusion and swelling generally does not follow a (cid:9)
`Fickian diffusion mechanism. A simple semiempirical equation was introduced to describe drug (cid:9)
`release behavior from hydrophilic matrix systems (8,9):
`
`Q = kt" (cid:9)
`
`(1)
`
`where Q is the fraction of drug released in time t, k is the rate constant incorporating charac-
`teristics of the macromolecular network system and the drug, and n is the diffusional exponent.
`It has been shown that the value of n is indicative of the drug release mechanism (10-14). For
`n = 0.5, drug release follows a Fickian diffusion mechanism that is driven by a chemical po-
`tential gradient. For n = 1, drug release occurs via the relaxational transport that is associated
`with stresses and phase transition in hydrated polymers. For 1 > n > 0.5, non-Fickian diffusion (cid:9)
`behavior is often observed as a result of contributions from diffusion and polymer erosion (10). (cid:9)
`In order to describe relaxational transport, Peppas and Sahlin derived the following equa- (cid:9)
`tion by introducing a second term into Eq. 1 (12): (cid:9)
`Q = ki r + k2t2" (cid:9)
`
`(2)
`
`where k3 and k2 are constants reflecting the relative contributions of Fickian and relaxation
`mechanisms. In the case where surface area is fixed, the value of n should be 0.5. Thus, Eq. 2 (cid:9)
`becomes:
`
`where the first and second terms represents drug release due to diffusion and polymer erosion,
`respectively. This equation was later successfully applied to describe drug release from the hy-
`drophilic matrices (14,15). (cid:9)
`In a hydrophobic inert matrix system, the drug is dispersed throughout a matrix that in-
`volves essentially negligible movement of the device surface. For a homogeneous monolithic (cid:9)
`matrix system, the release behavior can be described by the Higuchi equation subject to the ma- (cid:9)
`trix boundary conditions (16):
`
`M, = [DC,(2A CA112 (cid:9)
`
`(4)
`
`where M, is the drug released per unit area at time t, A is the drug loading per unit volume, CS
`is the solubility, and 1) is the diffusion coefficient in the matrix phase. Equation 4 was derived
`based on the assumptions that (a) a pseudo-steady state exists, (b) the drug particles are small
`compared to the average distance of diffusion, (c) diffusion coefficient is constant, (d) perfect
`sink conditions exist in the external media, (e) only the diffusion process occurs, (f) the drug
`
`CD
`
`0_
`Q
`
`ci)
`
`a)
`1)
`as
`
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`
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`ti)
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`(cid:9)
`(cid:9)
`(cid:9)
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`468 (cid:9)
`
`Qiu and Zhang
`
`concentration in the matrix is greater than the drug solubility in the polymer, and (g) no inter- (cid:9)
`action between drug and matrix takes place. In the case of A >> > C„ Eq. 4 reduces to: (cid:9)
`M, = [2DAC5t]1/2 (cid:9)
`Thus, the amount of drug released is proportional to the square root of time, A, D, and C.,.. (cid:9)
`Drug release from a porous monolithic matrix system involves the simultaneous penetra- (cid:9)
`tion of surrounding liquid, dissolution of drug, and leaching out of the drug through interstitial (cid:9)
`channels or pores. The volume and length of the openings in the matrix must be accounted for (cid:9)
`in the diffusion equation, leading to a second form of the Higuchi equation (17): (cid:9)
`D ili2
`M, = [ec (2A — eC5)—a-t
`7 (cid:9)
`
`(6)
`
`(5) (cid:9)
`
`where E and r are the porosity and tortuosity of the matrix, respectively, and Da is the drug dif- (cid:9)
`fusion coefficient in the aqueous phase. Similarly, Eq. 7 can be derived based on pseudo-steady- (cid:9)
`
`state approximation (A >> Ca (cid:9): (cid:9)
`
`M
`, = (2DaAC, --e- tY2
`7 (cid:9)
`The porosity, e, in Eqs. 6 and 7, is the fraction of matrix that exists as pores or channels into (cid:9)
`which the surrounding liquid can penetrate. It is the total porosity of the matrix after the drug (cid:9)
`has been extracted. The total porosity consists of the initial porosity, ea, due to air, or void space (cid:9)
`in the matrix before the leaching process begins, and the porosity created by extracting the (cid:9)
`drug, Ed, and the water-soluble excipients, Ee, (18, 18a): (cid:9)
`A A, (cid:9)
`'---- ea + Ed + c, = ta + — + (cid:9)
`P
`Pex (cid:9)
`where p is the drug density, and p„ and A„ are the density and the concentration of water-
`soluble excipient, respectively. In a case where no water-soluble excipient is used in the for-
`mulation and initial porosity, ea, is smaller than the porosity, ed, Eq. 8 becomes: (cid:9)
`
`E
`
`(7) (cid:9)
`
`(8)
`
`A (cid:9)
`e ''''' ed = — (cid:9)
`P (cid:9)
`Hence, the Eqs. 6 and 7 yield: (cid:9)
`
`M, = AR2 -- -s•C' ) D' 's tr (cid:9)
`
`P 1 TP j (cid:9)
`
`M, — A( 2Dacs (cid:9) t)112 (cid:9)
`\ rp 1 (cid:9)
`
`(9)
`
`(10) (cid:9)
`
`(11)
`
`In contrast to the homogeneous monolithic matrix system, the release from a porous monolith
`is expected to be directly proportional to the drug concentration in the matrix, A. (cid:9)
`It should be noted that the Higuchi equation was originally derived for planar diffusion
`into a perfect sink. More recently, a simple exponential relation was introduced by Ritger and
`Peppas to describe the general release behavior from hydrophobic matrices in the form of slabs,
`spheres, and cylinders (19):
`Q = M,= (cid:9)
`
`(12)
`
`§
`
`1 -= cr.
`0
`o
`ui
`
`r.
`
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`
`13 w
`2
`2
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` co 0.
`12
`_E
`co
`›-.
`_c
`a)
`7.5
`'-cp co
`0
`_-a- c-Ti
`__Ti
`= .5
`0
`co
`,.= a)
`
`0
`0'
`t
`co
`
`--, (cid:9)
`
`' 0
`1 -c
`.,.t E
`
`- i (cid:9)
`
`-c)
`o.) a
`8
`ci)
`co
`o
`trn
`co Q
`co
`=
`W3
`co
`E
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`The material on this page was copied from the collection of the National Library of Medicine by a third party and may be protected by U.S. Copyright law.
`
`Research and Development of Oral Forms (cid:9)
`
`469
`
`where Q is the fractional release, k is a constant, and n is the diffusional exponent. In the case
`of pure Fickian release, the exponent n has a limiting values of 0.50 for smooth slabs, 0.45 for
`smooth spheres, and 0.43-0.50 for smooth cylinders depending on the aspect ratio.
`
`2. Reservoir Polymeric Systems
`In developing reservoir polymeric systems, commonly used methods include microencapsula-
`tion of drug particles, coating of tablets or multiparticulates, and press coating of tablets. A
`polymeric membrane offers a predetermined resistance to drug diffusion from the reservoir to
`the sink. The driving force of such systems is the concentration gradient of active molecules be-
`tween reservoir and sink. The resistance provided by the membrane is a function of film thick-
`ness and characteristic of both the film and the migrating species in a given environment. The
`mechanisms of drug release from the film-coated dosage forms may be categorized into (a)
`transport of the drug through a network of capillaries filled with dissolution media; (b) trans-
`port of the drug through the homogeneous film barrier by diffusion; (c) transport of the drug
`through a hydrated swollen film; and (d) transport of the drug through flaws, cracks, and im-
`perfections within the coating matrix (20-22).
`Based on Fick's first law of diffusion, the release rate of a drug from a reservoir poly-
`meric system at steady state is given by:
`
`dM,DSK 0
`dt = (cid:9)
`A
`L
`where M, is the total amount of drug released at time t, D is the diffusion coefficient of the drug,
`S is the effective membrane or barrier surface area for drug diffusion, L is the diffusional path-
`length (such as thickness of the film), K is the partition coefficient of drug between the barrier
`and aqueous phases, and AC is the concentration gradient. In a case where D, S, K, L, and AC
`are constant in Eq. 13, the amount of drug released as a function of time can be obtained by in-
`tegration:
`
`(13)
`
`M, (DSK AC )
`
`t = kt
`
`(14)
`
`where k is the release rate constant. The apparent zero-order release from this type of system is
`often desired for a controlled release dosage form in many situations.
`
`3. Osmotic Pump Systems
`In an osmotic pump system, a tablet core is encased by a semipermeable membrane with an ori-
`fice. When the system is exposed to body fluids, water will penetrate through the semiperme-
`able membrane into the tablet core containing osmotic excipients and the active drug. There are
`two types of osmotic pump systems that have been described: a one-chamber elementary os-
`motic pump (EOP) and a two-chamber system (e.g., push-pull). In both systems, drug release
`via the orifice of the dosage form is controlled by an osmotic pressure formed in the device. The
`rate of water penetration into the system in terms of volume can be expressed as:
`
`dV
`Ak
`(Alr — AP) (cid:9)
`dt = I
`where dVIdt is the rate of water flow, k is the hydraulic permeability, A is the membrane area,
`is the thickness, Aar is the osmotic pressure difference, and AP is the hydrostatic pressure
`
`(15)
`
`ing (cid:9)
`
`ter- (cid:9)
`
`(5)
`
`tra- (cid:9)
`tial (cid:9)
`for (cid:9)
`
`(6)
`
`dy- (cid:9)
`
`(7)
`
`nto (cid:9)
`rug (cid:9)
`ace
`the
`
`(8)
`ter- (cid:9)
`for-
`
`(9)
`
`;10) (cid:9)
`
`11) (cid:9)
`
`dith
`
`;ion (cid:9)
`and (cid:9)
`abs, (cid:9)
`
`:12) (cid:9)
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`IF
`
`Q
`
`w
`
`_o
`
`Medicine by a third party and
`
`Yr.
`
`.4 0
`A 2
`
`
`s..g
`
`"CS
`
`CD_
`S
`
`'
`
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`
`(Ts
`
`(1)
`
`cn
`
`C171
`
`I a)
`
`470 (cid:9)
`
`Diu and Zhang
`
`difference. Since the system is usually rigid, the volume of the device is constant during oper-
`ation, the amount of drug released at time t can be expressed by: (cid:9)
`
`dM _ dV
`dt (cid:9)
`dt
`
`u"" (cid:9)
`
`(16) (cid:9)
`
`where [5] is the drug solubility. When the hydrostatic pressure difference is negligible, Eq. 16
`becomes:
`
`dM kA
`dt (cid:9)
`1
`
`On[S] (cid:9)
`
`(17)
`
`In summary, the osmotic delivery systems can be more readily programmed to obtain var-
`ious desired release profiles, such as zero-order and pulsatile release. For most drug molecules,
`the release rate is independent of the drug properties and release environment. However, the
`manufacturing of this type of system often requires specialized equipment and processes.
`
`4. (cid:9) Other Systems
`Other controlled release systems include ion exchange systems, such as, Biphetamine capsules
`containing amphetamine and dextroamphetamine, manufactured by Penwalt (23). Ion exchange
`systems generally utilize resins composed of water-insoluble crosslinked polymers. These poly-
`mers contain salt-forming functional groups in repeating positions on the polymer chain. The
`drug is bound to the resin and released by exchanging with appropriately charged ions in con-
`tact with the ion exchange groups.
`
`B. Materials Used for Controlling Drug Release (cid:9)
`Materials used for controlling drug release from oral tablets and capsules include polymers
`from natural products, chemically modified natural products, and synthetic products. Some of
`the common materials that have regulatory clearance are discussed briefly in this section based
`on their applications in different types of controlled release systems. The list is not intended to
`be comprehensive but rather serves as a starting point for interested readers. (cid:9)
`
`1. (cid:9) Materials Used for Matrix Systems (cid:9)
`The materials most widely used in preparing matrix systems include both hydrophilic and hy-
`polymers. Commonly available hydrophilic polymers include hydroxypropylmethyl- (cid:9)
`drophobic
`cellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), xantham gum, (cid:9)
`sodium alginate, poly(ethylene oxide), and crosslinked homopolymers and copolymers of
`acrylic acid. They are usually supplied in micronized forms because small particle size is criti-
`cal to the rapid formation of gelatinous layer on the tablet surface.
`Hydroxypropylmethylcellulose is a nonionic water-soluble cellulose ether made by Dow (cid:9)
`Chemical under the brand name Methocel. Methocel is available in four different chemistries (cid:9)
`(E, F, J, and K series) based on varying degrees of hydroxypropyl and methyl substitution. The
`specially produced Methocel of ultrafine particle size for controlled release formulations in-
`clude KIOOLV, K4M, K 15M, K100M, E4M, and EIOM. When dissolved at a concentration of
`2% in water, the viscosity ranges from 100 to 100,000 cps. Similar grades of HPMC (Metolose
`SR) are also available from ShinEtsu of Japan.
`Both HPC and HEC are also nonionic water-soluble cellulose ethers made by the Aqualon
`division of Hercules Inc. under the brand names Klucel and Natrosol, respectively. For controlled
`
`(cid:9)
`(cid:9)
`

`

`hang
`
`n per-
`
`(16)
`
`q. 16
`
`(17)
`
`var-
`:Ades,
`r, the
`
`)rules
`-lane
`poly-
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`I con-
`
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`me of
`based
`led to
`
`td hy-
`ethyl-
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`criti-
`
`Dow
`istries
`3. The
`ns in-
`ion of
`tolose
`
`malon
`Tolled
`
`Research and Development of Oral Forms
`
`471
`
`release applications, they are available in high- and low-viscosity grades, such as Klucel HXF,
`EXF, and Natrosol 250HX.
`Xanthan gum is a water-soluble polysaccharide gum produced by the Kelco division of
`Monsanto Co. under the brand name of Keltrol. It is composed of D-glucosyl, D-mannosyl, and
`D-glucosyluronic acid residues and differing proportions of 0-acetyl and pyruvic acid acetal.
`The primary structure consists of a cellulose backbone with trisaccharide side chains.
`Sodium alginate is a water-soluble gelling polysaccharide also made by Kelco under the
`brand name Keltone. Keltone HVCR and LVCR are forms that are used in controlled release
`products.
`Polyethylene oxide) polymer is a nonionic water-soluble resins made by Union Carbide
`under the brand name of Polyox. Its common structure is —(OCH2CH2)n—OH. For controlled re-
`lease applications it is available in a variety of viscosity grades. Examples include Polyox WSR
`N-12K, WSR N-60K, WSR-301, WSR-coagulant, WSR-303, WSR-308 with molecular weights
`ranging from 100,000 to 8 million.
`Crosslinked homopolymers and copolymers of acrylic acid are water-swellable, but insol-
`uble, resins made by the B. F. Goodrich Company under the brand name Carbopol. Carbopol
`971P NE 974P, and 934P NF are specifically designed for preparing hydrogel controlled release
`systems.
`Hydrophobic and monolithic polymer matrix systems usually use waxes and water-insolu-
`ble polymers in their formulation. Many waxes are long carbon chain wax esters, glycerides, and
`fatty acids. Natural and synthetic waxes of differing melting points have been used as controlled
`release matrix materials. Examples include camauba wax, beeswax, candelilla wax, microcrys-
`talline wax, ozokerite wax, paraffin waxes, and low molecular weight polyethylene, to name a
`few. Insoluble polymers used in preparing controlled release matrices include fine powders of
`ammoniomethacrylate copolymers (Eudragit RL100, PO, RS100, PO) by Rohm America, Inc.,
`ethylcellulose (Ethocel FP7, FPIO, FP100) by Dow Chemical Co., cellulose acetate (CA-398-
`10), cellulose acetate butyrate (CAB-381-20), cellulose acetate propionate (CAP-482-20) by
`Eastman Chemical Co., and latex dispersion of methacrylic ester copolymers (Eudragit NE30D).
`
`2. (cid:9) Materials Used for Reservoir Systems
`The most common materials to form a drug release barrier surrounding a core tablet, drug par-
`ticles, beads, or pellets for diffusion-controlled reservoir systems include water-insoluble
`acrylic copolymers and ethylcellulose. These film-coating polymers have historically been used
`in an organic solution. In recent years, they have been• mostly applied as aqueous dispersions
`that form films by a process of coalescence of submicrometer polymer particles. Ammo-
`niomethacrylate copolymers (Eudragit RL 30D, RS 30D) are water-permeable and swellable
`film formers based on neutral methacrylic esters with a small proportion of trimethylarnmo-
`nioethyl methacrylate chloride. Methacrylic ester copolymers (Eudragit, NE30D) is a neutral
`ester without any functional groups. They are supplied by Rohm America as 30% aqueous dis-
`persions without the need of plasticizers unless improved film flexibility is desired. Ethylcellu-
`lose for film coating is available as an aqueous polymeric dispersion containing plasticizers un-
`der the brand name of Surelease (Colorcon) and as pseudolatex dispersion, Aquacoat ECD
`(FMC), which requires addition of plasticizers to facilitate film formation during coating.
`Enteric polymers may also be incorporated into the coating film to modify release rate,
`such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate (HPMCP),
`methacrylic acid and methacrylic esters (Eudragit L and S). Enteric polymers are pH-dependent
`polymers. At high pH (e.g., >5.5), the polymer dissolves. At low pH, the polymer is imperme-
`able and insoluble.
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`472 (cid:9)
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`Qiu and Zhang
`
`3. (cid:9) Polymers Used for Osmotic Pump Systems
`Cellulose acetate comprising a certain percentage of acetyl content can be used together with
`other pH-dependent and pH-independent soluble cellulose derivatives to form a semipermeable
`film. Other polymers including polyurethane, ethylcellulose, poly(ethylene oxide) polymers,
`PVC, and PVA may be used in the osmotic pump systems.
`
`C. (cid:9) Development Technologies
`
`Most oral controlled release systems are in the forms of tablets and capsules. Development
`technologies for these dosage forms include tableting, spheronization (or pelletization), and
`film coating of single unit or multiparticulates.
`
`1. Tableting Process
`Controlled release tablet dosage forms are usually manufactured using conventional processes
`of granulation, blending, compression, and coating where necessary. Each unit operation of the
`development technologies has been extensively addressed (24). In manufacturing matrix for-
`mulations, precompression may have to be considered to ensure product quality because high
`concentrations of polymers are often used in these systems.
`
`2. Spheronization/Pelletization Process
`Controlled release pellets, beads, or spheres may offer certain advantages over single unit
`dosage forms in that they minimize the risk of unexpected drug release (e.g., dose dumping)
`which may occur when a single-unit device is defective (25). In addition, multiparticulate
`dosage forms can be designed to provide customized release profiles by combining beads with
`different release rates or to deliver incompatible drugs in the same dosage unit (26).
`The basic methods for pellet or bead production include (a) microencapsulation, (b)
`spray congealing, (c) formation of particles from a plastic mass, and (d) agglomeration. Most
`microencapsulation techniques are based on processes by which coatings of natural or syn-
`thetic polymers are applied to solid or liquid agents via coacervation or polymerization
`(27,28). The spray-congealing process consists of embedding the active drug in an excipient,
`such as wax or plastic. Formation of particles from a plastic mass is achieved using a machine
`known as a marumerizer or a spheronizer (29,30). The spheronization process in the marumer-
`izer involves partial shaping of pellets followed by utilization of friction and surface forces to
`form spheres. Powdered raw materials are converted into a plastic mass using water or solvents
`in conjunction with binding agents. This mass is extruded under pressure through a perforated
`screen or die. The cylindrical, spaghetti-like extrudates are then broken down by spinning in
`the marumerizer until the length is equal to the diameter. Tice process continues until they are
`rolled into spheres by centrifugal and frictional forces. To produce solid spheres, the extrudate
`must break into short segments and short cylinders must be sufficiently plastic to be rounded
`by spheronization. The materials that break into short cylinders without sufficient plastic prop-
`erties do not yield a spherical product (31). Microcrystalline cellulose is found to exhibit the
`elasticity required for extrusion and spheronization. Thus, it is an excipient most commonly
`used for pelletization/spheronization (32).
`Agglomeration is one of the oldest processes for manufacturing spherical particles. It is
`based on the layering technology derived from sugar coating in a coating pan. Traditionally, these
`spheronization processes involving surface forces can be divided into two stages: nucleation (seed
`growth) and sphere growth (bead preparation). With the layering technique, the active drug or
`
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`Research and Development of Oral Forms (cid:9)
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`other ingredients in the form of either a dry powder or solution/dispersion are agglomerated to
`form seeds. There are commercially available nonpareil seed or seeds containing active drugs.
`This process can be performed in a coating pan, a rotary granulator, or a fluidized bed.
`
`3. Coating Technologies
`In the pharmaceutical industry, significant advances have been achieved in polymer coating of
`solid dosage forms over the last two decades. Polymer coating involves deposition of a uniform
`membrane of polymer onto the surface of the substrates, such as tablets, spheres, or pellets, and
`drug particles. Coating techniques that are used in developing controlled release reservoir or os-
`motic systems include (a) film coating, (b) layering coating, and (c) compressed coating. The
`properties of the resulting functional coating are influenced by coating formulations as well as
`processing variables.
`The film coating process is performed in a coating pan, a fluidized bed or a rotary gran-
`ulator. Ethylcellulose, methacrylic ester copolymers, methacryl ester copolymers, cellulose ac-
`etate, and enteric polymers are widely used either alone or in combination with water-soluble
`polymers for the preparation of controlled release films. Since the integrity of the film and the
`absence of flaws or cracks are important factors in controlling the drug release from such prepa-
`ration, it is imperative that the film formulation be optimized. Plasticizers are often added to
`such films to increase the film flexibility and minimize the incidence of flaws. Other factors af-
`fecting film coating and drug release include formulation (e.g., pigment, plasticizer, solvent)
`and process variables (e.g., equipment, batch scale, airflow, spray rate, temperature.).
`The layering coating process is often performed in a sugar coating pan or a fluidized bed.
`This type of coating process is noncontinuous. For example, in coating beads, the seeds may
`first be coated with one layer of active drug, then coated with one layer of polymer followed by
`another active drug layer. The process is repeated until multiple layers are completed to meet
`the predetermined requirement. In some cases, the active drug may be dissolved or dispersed
`with the coating materials. Factors affecting coating quality and performance of the final prod-
`uct are similar to those discussed in the film coating process.
`The compression coating process is performed using a tablet press to make a compress
`coat surrounding a tablet core (tablet-in-tablet). The compress coat may function as a barrier to
`drug release or as part of formulation to provide biphasic release. The process involves initial
`compression of the core formulation to produce a relatively soft tablet followed by transferring
`to a larger die for final compression of the comp