Controlled Drug Delivery Systems

Controlled Drug Delivery Systems: Oral administration of drugs has been the most common and preferred route for the delivery of most therapeutic agents. It remains the preferred route of administration investigated in the discovery and development of new drug candidates and formulations. The popularity of the oral route is attributed to patient acceptance, ease of administration, accurate dosing, cost-effective manufacturing methods, and generally improved shelf-life of the product. For many drugs and therapeutic agents, conventional, multiple dosing of immediate-release formulations provides satisfactory clinical performance with an appropriate balance of efficacy and safety. 

The rationale for the development of an extended-release formulation of a drug is to enhance its therapeutic benefits, minimizing its side effects while improving the management of the diseased condition. Besides its clinical advantages, an innovative extended-release formulation provides an opportunity for a pharmaceutical company to manage its product life-cycle. The dearth of new chemical entities is forcing many pharmaceutical companies to reformulate an existing conventional formulation to an extended-release product as a strategy of life-cycle management and retaining market share. To imagine the ideal drug delivery system, two prerequisites would be required:

1. It would be a single dose for the duration of treatment. 
2. It should deliver the active entity directly to the site of action, thereby minimizing or eliminating side effects. Thus, the goal of sustained/controlled release dosage form is to maintain therapeutic blood or tissue levels of the drug over an extended period.

Figure.1 shows comparative blood drug level profiles obtained from the administration of conventional, controlled as well as sustained release dosage forms. Thus, the conventional tablet provides only a single and transient burst of the drug. A Pharmacological effect is seen as long as the amount of drug is within the therapeutic range. The pharmacological effect is altered when the peak concentration is above or below the therapeutic range. The main purpose of controlled release is to improve safety and minimize side effects of the drug by reducing fluctuation in drug levels.

Different Terms Used Under Novel Drug Delivery Systems 

1. Delayed-Release
2. Extended-Release 
3. Sustained Release
4. Controlled Release 
5. Site-Specific Targeting
6. Receptor Targeting 
7. Fast Dissolve Drug Delivery System (Flash) 

Delayed-Release 

A dosage form that releases a discrete fraction of drug at a time or times other than administration, although one portion may be released immediately after administration.  Examples include; enteric-coated tablets, where a timed-release is achieved by barrier coating repeated action tablets or spansules.

Extended-Release 

When absorption of the drug is greater than its elimination, the release is known as extended-release. A dosage form should allow at least a twofold reduction in dosage frequency as compared to that drug presented as an immediate release dosage form.  These include; any dosage form that maintains the therapeutic blood or tissue level of the drug for a prolonged time.

Sustained Release 

It includes the drug delivery systems that achieve and ensure a slow release of drugs over an extended/prolonged period or at a constant release rate to attain and maintain therapeutically effective levels of drug concentration in the circulation. Here the absorption rate is equal to the elimination rate over an extended period.

Controlled Release 

It includes any drug delivery system from which the drug is delivered at a predetermined rate over a prolonged period.

Site-Specific Targeting 

It is a dosage form that releases drugs at or near the intended physiologic site of action.  Targeted release dosage forms may have either immediate or extended-release characteristics. Targeted drug delivery is implicated by using carriers either meant for passive preprogrammed or active preprogrammed or self-programmed drug release approach. Thus, they are usually appended with suitable site directing molecules, which recognize their receptor or molecular determinants at the target.

Receptor Targeting 

In such a system, the target is a particular receptor within an organ or tissue.

Fast Dissolve Drug Delivery System (Flash) 

It is a type of solid dosage form that dissolves or disintegrates in the oral cavity without the help of water or chewing. Fast dissolution is achieved by forming a loose network (Zydis,  Eli Lilly), or by effervescent agent (Oraslav, Cima), or with a mixture of disintegrating agent and swelling (Flash Tab, Prographarm).

The rationale of Controlled Drug Delivery 

The basic rationale of controlled drug delivery is to alter the pharmacokinetics and pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by modifying the molecular structure and/or physiological parameters inherent in a selected route of administration.  The primary objectives of controlled drug delivery are to ensure safety and to improve the efficacy of drugs as well as patient compliance. For conventional dosage forms, only the dose and dosing interval can vary and for each drug, there exists a therapeutic window of plasma concentration below which therapeutic effect is insufficient and above which undesirable or toxic side effects are elicited. This is often defined as, “the ratio of median lethal dose (LD₅₀) to median effective dose (ED₅₀)”.

Advantages of Controlled Drug Delivery 

• Maintenance of drug levels within the desired range.
• Delivery of “difficult” drugs: slow release of water-soluble drugs, fast release of low solubility drugs.
• Less dosing and increased patient compliance.
• Eliminate overdosing or underdosing.
• Prevention of side effects.
• Reduction in health care cost.
• Improved efficiency in treatment.
• Reduction in adverse side effects and improvement intolerability.

Disadvantages of Controlled Drug Delivery

• Dumping is a major disadvantage of CRDDS, which refers to the rapid release of a relatively large quantity of drug from a controlled release formulation. This phenomenon becomes hazardous with potent drugs.
• Poor in-vivo and in-vitro correlations.
• Difficult to optimize the accurate dose and dosing interval.
• Patient variability affects the release rate like GI emptying rate, residential time, fasting or non-fasting condition, etc.

Factors Influencing the Design and Act of Controlled Release Products 

Physiological Properties 

(1) Aqueous solubility: Most of the active pharmaceutical moiety (API) are weakly acidic or basic that affect the water solubility of API. Weak water-soluble drugs are difficult to design the controlled release formulations. High aqueous solubility drugs show burst release followed by a rapid increment in plasma drug concentration. These types of drugs are a good candidate for CRDDS. The pH-dependent solubility also creates a problem in formulating CRDDS. BCS class-III and IV drugs are not suitable candidates for this type of formulation. 

Determination of Solubility: 

1. Semi-quantitative method.
2. Accurate-quantitative method. 
3. pH change method. 

Absorption of poorly soluble drugs is often dissolution rate-limited. Such drugs do not require any further control over their dissolution rate and thus may not seem to be good candidates for oral controlled release formulations. Controlled release formulations of such drugs may be aimed at making their dissolution more uniform rather than reducing it.

(2) Partition coefficient (P-value): P-value denotes the fraction of the drug into oil and aqueous phase that is a significant factor that affects the passive diffusion of the drug across the biological membrane. The drugs are having high or low P values not suitable for CR, it should be appropriate to dissolve in both phases. 

The partition coefficient is defined as “the concentration ratio of the unionized drug distributed between two phases at equilibrium”. 

Given by the Noyes-Whitney’s Equation: 

• The logarithm (base 10) of the partition coefficient (log 10 P) is often used.
• For ionizable drugs, where the ionized species does not partition into the organic phase, the apparent partition coefficient, (D), can be calculated as: 
  • Acids: log 10 D = log 10 P – log 10 (1 + 10 (pH − pKa)
  • Bases: log 10 D = log 10 P – log 10 (1 + 10 (pKa − pH)
• The octanol-water partition coefficient has been widely used as a measurement for determining the relative lipophilicity of a drug. Drugs that are very lipid-soluble or very water-soluble i.e., extremes in partition coefficient, will demonstrate: 
  • Either low flux into the tissues or
  • Rapid flux followed by accumulation in tissues.
• Both cases are undesirable for a controlled release system. 

(3) Drug pKa: pKa is the factor that determines the ionization of the drug at physiological pH in GIT. Generally, the high ionized drugs are poor candidates for CRDDS. The absorption of the unionized drug occurs rapidly as compared to ionized drugs from the biological membranes. The pKa range for an acidic drug that ionization depends on the pH is 3.0 to 7.5 and for a basic drug, it lay between 7 and 11. 

(4) Drug stability: Drugs that are stable in acid/base, enzymatic degradation, and other gastric fluids are good candidates for CRDDS. If a drug is degraded in the stomach and small intestine, it is not suitable for controlled release formulations because it will decrease in bioavailability of the concerned drug. 

(5) Molecular size and molecular weight: Molecular size and molecular weight are two important factors that affect molecular diffusibility across a biological membrane.  The molecular size less than 400D is easily diffused but greater than 400D creates a problem in drug diffusion. 

1. In addition to diffusion through a variety of biological membranes, drugs in many CRDDS must diffuse through a rate-controlling membrane or matrix. 
2. The ability of the drug to pass through membranes is called diffusivity. 
3. An important influence upon the value of diffusivity-D, in polymers, is the molecular size of the diffusing species.
4. The value of D thus is related to the size and shape of the cavities as well as the size and shape of the drugs.
5. The molecular size of the drug plays a major role when it comes to the diffusion of the drug through a biological membrane. 

(6) Protein binding: The drug-protein complex acts as a reservoir in plasma for the drug.  Drugs showing high plasma protein binding are not a good candidate for CRDDS because the protein binding increases the biological half-life. So, there is no need to sustain the drug release. 

This complex leads to:

• Inhibition of therapeutic effect of such amount.
• Half-life is increased (compared to in vitro studies).
• Toxicity profiles elevated. 

Thus, in most cases, protein binding is undesirable. Many drugs are highly protein-bound (maybe 95%), thus the need of formulating a modified drug or drug delivery system starts. 

Biological Properties 

(1) Absorption: Uniformity in rate and extent of absorption is an important factor in formulating the CRDDS. However, the rate-limiting step in drug release from the dosage form. The absorption rate should rapid the release rate to prevent dose dumping. The various factors like; aqueous solubility, log P, acid hydrolysis, which affect the absorption of drugs. 

(2) Distribution: Distribution of drug from the conventional dosage form directly gets distributed throughout the body, and gets accumulated to some of the off-sites, which may lead to toxicity. Such instances can be prevented by CRDDS, which can be site-targeted and specific towards the disease’s condition area and thus preventing accumulation in other sites.  It also enables the complete drug to be reached to the required site, unlike the conventional forms. 

(3) Elimination: There are so many drugs available, which accumulate in the organs like; liver, pancreas, etc., and become fatal sometimes. Removal of such unwanted accumulated portions is quite hectic for the system due to the slow elimination rate. In such cases, CRRDS again plays a major role as the accumulation in off-sites is comparatively negligible, and also the released drug easily expresses the action and then gets eliminated safely. 

(4) Biological half-life (t1/2): In general, the drug having a short half-life requires frequent dosing and is a suitable candidate for a controlled release system. A drug with a long half-life requires dosing after a long-time-interval. Ideally, the drugs having t_1/2 2-3 hours, are a suitable candidate for CRDDS. Drugs having t_1/2 more than 7-8 hours are not used for a controlled release system.

(5) Dose size: The CRDDS are formulated to eliminate the repetitive dosing, so it must contain a large dose than the conventional dosage form. But the dose used in conventional dosage form indicates the dose to be used in CRDDS. The volume of sustained dose should be as large as it comes under acceptance criteria.

• The size of the drug plays a major role in determining the size of the final finished product.
• In case, the dose is already high, then formulating the same into controlled release will further increase the overall dosage size and thereby reduce patient compliance.
• For drugs with an elimination half-life of fewer than 2 hours, as well as those administered in large doses, a controlled release dosage form may need to carry a prohibitively large quantity of the drug. 

(6) Therapeutic window: The drugs with a narrow therapeutic index are not suitable for CRDDS. If the delivery system failed to control release, it would cause dose dumping and ultimate toxicity. 

(7) Absorption window: The drugs which show absorption from the specific segment in GIT are a poor candidate for CRDDS. Drugs that are absorbed throughout the GIT are good candidates for controlled release.

(8) Patient physiology: The physiological condition of the patient like gastric emptying rate, residential time, and GI diseases influence the release of the drug from the dosage form directly or indirectly.  Pharmacokinetic parameters considered during the drug selection are listed as follow: 

Table.1: Pharmacokinetic Parameters for Drug Selection

Formulation Aspects Influencing the Design of Oral Controlled Release Drug Delivery Systems 

Drug Properties 

Drug solubility and dose are the most important factors to be considered in the design of ER matrices. In general, extended-release formulation of extreme drug solubility coupled with a high dose is challenging. Drugs with very low solubility (e.g. <0.01 mg/ml) may dissolve slowly and have slow diffusion through the gel layer of a hydrophilic matrix.  Therefore, the main mechanism of release would be through erosion of the surface of the hydrated matrix. In these cases, the control over matrix erosion to achieve consistent extended release throughout the GI tract is critical. For drugs with very high-water solubility, the drug dissolves within the gel layer (even with a small amount of free water) and diffuses out into the media. Therefore, it is important to control the factors that affect drug diffusivity (e.g. pH, gel strength, and availability of free water) within the gel layer and parameters that ensure the integrity of the gel layer after the drug has been dissolved and released from the gel layer. For poorly soluble drugs, the particle size of the drug has a major influence on its release profile. A decrease in particle size of the drug causes an increase in solubility and hence a faster drug release rate.

Polymer Considerations 

Depending on dosage size and desired release rate, the typical use level can vary from 20 to 50% (w/w). For drugs with high water solubility, there is a threshold level of polymer for achieving controlled release, and a further increase in polymer level may not decrease the drug release rate. However, for obtaining a robust formulation with consistent performance and insensitivity to minor variations in raw materials or manufacturing processes, a usage level of 30% (w/w) has been recommended. 

The particle size of the polymer is also an important factor. The finer the particle size, the faster the rate of hydration of the polymer and hence better the control of drug release.  Coarser polymer particles used in a direct compression formulation have been reported to result in faster drug release than finer particles. The coarser the particle size, the slower the hydration rate and gel layer formation.

Presence of Other Excipients 

Fillers:  Soluble fillers (e.g. lactose), insoluble fillers (e.g. microcrystalline cellulose, dicalcium phosphate), and/or partially soluble (e.g. partially pregelatinized starch). Fillers are generally used in hydrophilic matrices to enhance the pharmaco-technical properties of tablets (improve compressibility, flow, and mechanical strength) or to modify the drug release profile. The inclusion of fillers affects the dissolution performance of a matrix by a “dilution effect” on the polymer. The magnitude of the effect on the performance of matrices is dependent on the drug, the polymer level, and the level of excipient itself. The presence of water-soluble fillers in high concentrations in the matrix leads to faster and greater water uptake by the matrix, resulting in weaker gel strength, higher erosion of the gel layer, and therefore faster drug release. Insoluble but weakly swellable fillers such as; microcrystalline cellulose remain within the gel structure and generally result in decreased release rate. The presence of partially pregelatinized starch such as; Starch 1500® in HPMC matrices has been reported to decrease the drug release rate. For a highly soluble or sparingly soluble drug, the rank order of release rate was as follows: 

Lactose > Microcrystalline cellulose > Partially pregelatinized starch.

Release Modifiers and Stabilizers 

Drugs with pH-dependent aqueous solubility (weak acids or bases) are formulated in HPMC matrices, they may exhibit pH-dependent drug release. Formulating CR matrices of such drugs may lead to lower drug release due to exposure of the dosage form to increasing pH media of the GI tract (from pH 1.2 to 7). Formulating pH-independent CR matrices for such drugs would not only ensure adequate release throughout the physiological pH but also lower intra- and inter-patient variability. Development of such pH-independent matrices for weakly basic drugs has been shown with the incorporation of acidic excipients (weak acids or salts of strong acids) that lower the micro-environmental pH within the gel layer and thus maintain high local solubility of the drug independent of the external release media.

Effect of Salts and Electrolytes 

In general, as the concentration of ions in a polymer solution increases polymer hydration or solubility decreases. The amount of water available to hydrate the polymer is reduced because more water molecules are required to keep the ions in the solution. Moreover, the types of ions in the solution affect the polymer hydration to varying degrees. The susceptibility of cellulose ethers to ionic effects follows the lyotropic series of the ions (chloride < tartrate < phosphates and potassium < sodium). Changes in the hydration state of a polymer in solution are manifested primarily by changes in solution viscosity and turbidity or cloud point. At low ionic strengths, the polymer hydration is unaffected, but higher ionic strengths may lead to a loss of gel integrity of the matrix. The extent of this influence depends on the polymer type and lyotropic series of the ions. The effect of electrolytes or salts is important only in cases where high concentrations of salts or electrolytes are present as tablet components or as constituents of dissolution media.  In vivo conditions, however, have fairly low ionic strength (ionic strength of gastrointestinal fluids, (0.01-0.15)) to affect the polymer hydration and have a significant impact on release rate.

Characteristics of Dosage Form 

Variation in tablet shape and size may cause changes in surface area available for drug release and hence influences drug release profiles from HPMC matrices. A constant surface area to volume ratio (S/V) of different sizes and shape tablets for an HPMC formulation would lead to similar drug release profiles. The size of the tablet may also dictate the polymer level requirement. Smaller tablets have been reported to require higher polymer content because of their higher surface area to volume ratio and thus shorter diffusion pathways.  One technology proposed for modifying the matrix surface area to volume ratio was by physical restriction of the swelling of hydrophilic matrix by partially coating the matrix with insoluble polymers or multi-layered tablets (Geomatrix® technology). 

Presence of Coating 

The application of film coatings to tablet formulations is a common practice in the pharmaceutical industry. Tablets are coated for a variety of reasons such as improving the stability of the formulation, taste masking, enhancing the aesthetic appearance, identification, and branding, improving the packaging process, or modifying the drug release profile. Coating of hydrophilic matrices with water-soluble polymers such as; Opadry® or low-viscosity HPMC generally does not alter drug release profiles. Coating with water-insoluble polymers such as ethylcellulose with or without permeability modifiers (e.g., low viscosity grades of HPMC or Opadry) may be used for modulating the drug release profile from HPMC matrices.

Classification of Oral Controlled Drug Delivery System 

1. Dissolution controlled systems 
2. Diffusional systems: (a) Reservoir devices (b) Matrix devices 
3. Bio erodible and combination of diffusion and dissolution systems 
4. Osmotically controlled systems 
5. Ion-exchange systems 
6. pH-independent formulations 
7. Altered density formulations: (a) High-density approach (b) Low-density approach 

The majority of oral controlled release systems rely on dissolution, diffusion, or a combination of both mechanisms, to generate a slow release of drug to the gastrointestinal tract. 

Dissolution-Controlled Systems 

Controlled release preparations of drugs could be made by decreasing their rate of dissolution. The approaches to achieve this include preparation of appropriate salts or derivatives, coating the drug with a slowly dissolving material, or incorporating it into a tablet with a slowly dissolving carrier. 

Dissolution-controlled systems can be made in several different ways: By alternating layers of drug with rate controlling coats, a pulsed delivery can be achieved. If the outer layer is a quickly releasing bolus of drug, initial levels of the drug in the body can be quickly established with pulsed intervals following. An alternative method is to administer the drug as a group of beads that have coatings of different thicknesses. Since the beads have different coating thicknesses, their release will occur progressively. Those with the thinnest layers will provide the initial dose. The maintenance of drug levels at later times will be achieved from those with thicker coatings. This is the principle of spansule technology or microencapsulation. 

The dissolution process at a steady state is described by Noyes Whitney equation: 

where,

• dC/dt = Dissolution rate 
• D = Diffusion coefficient of the drug through pores 
• h = Thickness of the diffusion layer 
• A = Surface area of the exposed solid 
• C_s = Saturated solubility of the drug 
• C = Concentration of drug in the bulk solution 

Based on the technical sophistication, it is classified as: 

1. Matrix type
2. Encapsulation type 

Matrix Type 

Matrix dissolution devices are prepared by compressing the drug with a slowly dissolving carrier into a tablet. 

Controlled dissolution by: 

1. Altering porosity of tablet
2. Decreasing its wettability 
3. Dissolving at a slower rate 

The drug release is determined by the dissolution of the polymer. 

Examples: Dimetane extencaps, Dimetapp extents. 

Encapsulation Type 

The drug particles are coated or encapsulated by the microencapsulation technique. The pellets are filled in hard gelatin capsules, popularly called ‘spansules’. Once the coating material dissolves, the entire drug inside the microcapsule is immediately available for dissolution and absorption.

Here the drug release is determined by dissolution rate and thickness of polymer membrane which may range from 1 to 200 µ.  The dissolution rate of the coat depends upon the stability and thickness of the coating.

Examples: 

1. Ornade spansules. 
2. Chlortrimeton repetabs.

Diffusional Systems 

Diffusion systems are characterized by the release rate of a drug being dependent on its diffusion through an inert membrane barrier. Usually, this barrier is an insoluble polymer. In general, two types of diffusional systems are recognized. They are reservoir devices and matrix devices. 

The released drug from a reservoir device follows Fick’s first law of diffusion.

Where,

• J = Flux, amount/area-time 
• D = Diffusion coefficient of the drug in the polymer, area/time 
• dc/dx = Change in concentration with respect to polymer distance 

Reservoir Devices 

Reservoir devices are characterized by a core of the drug, the reservoir, surrounded by a polymeric membrane. The nature of the membrane determines the rate of release of drugs from the system.

The advantages of reservoir diffusional systems are, zero-order delivery is possible and release rate will vary with polymer type. The disadvantages of reservoir diffusional systems are, a system must be physically planted site, difficult to deliver high-molecular-weight compounds, rupture can result in dangerous dose dumping.

Matrix Devices 

A matrix device consists of drugs dispersed homogeneously throughout a polymer matrix. In this model, the drug in the outside layer exposed to the bathing solution is dissolved first and then diffuses out of the matrix. This process continues with the interface between the bathing solution and the solid drug moving towards the interior. Obviously, for this system to be diffusion controlled, the rate of dissolution of drug particles within the matrix must be much faster than the diffusion rate of the dissolved drug leaving the matrix.

Bio Erodible and Combination of Diffusion and Dissolution Systems 

These systems can combine the diffusion and dissolution of both the matrix material and the drug. Drugs not only can diffuse out of the dosage form, as with some previously described matrix systems but the matrix itself undergoes a dissolution process. The complexity of the system varies from the fact that, as the polymer dissolves the diffusional path length for the drug may change. This usually results in a moving boundary diffusion system. Zero-order release can occur only if surface erosion occurs and the surface area does not change with time. The inherent advantage of such a system is that the bio erodible property of the matrix does not result in a ghost matrix and removal from implant sites is not necessary. The disadvantages of this system include difficulty to control kinetics owing to multiple processes of release, the potential toxicity of degraded polymer must be considered.

Another method of bio-erodible system is to attach the drug directly to the polymer by a chemical bond. Generally, the drug is released from the polymer by hydrolysis or enzymatic reaction. A third type, which in this case utilizes a combination of diffusion and dissolution, is that of a swelling-controlled matrix. 

Here the drug is dissolved in the polymer, but instead of an insoluble or eroding polymer, as in previous systems, swelling of the polymer occurs. This allows entrance of water, which causes dissolution of the drug and diffusion out of the swollen matrix. In these systems, the release rate is highly dependent on the polymer swelling rate, drug solubility, and the amount of soluble fraction in the matrix. This system usually minimizes burst effects, since polymer swelling must occur before drug release.

Osmotically Controlled Systems 

In these systems, osmotic pressure provides the driving force to generate a controlled release of the drug. Consider a semi-permeable membrane that is permeable to water, but not to drugs. A tablet containing a core of the drug is surrounded by such a membrane and when this device is exposed to water or any other body fluid, water will flow into the tablet owing to the osmotic pressure difference. 

These systems generally appear in two different forms. The first one contains the drug as a solid core together with electrolyte, which is dissolved by the incoming water. The electrolyte provides a high osmotic pressure difference. The second system contains the drug in solution in an impermeable membrane within the device. The electrolyte surrounds the bag. Both systems have single or multiple holes bored through the membrane to allow drug release. In the first example, high osmotic pressure can be relieved only by pumping a solution, containing the drug, out of the hole. Similarly in the second example, the high osmotic pressure causes compression of the inner membrane, and the drug is pumped out through the hole. 

The advantages of osmotically controlled devices are, a zero-order release is obtainable.  Reformulation is not required for different drugs and the release of drugs is independent of the environment of the system. The disadvantages of these systems include, systems can be much more expensive than conventional counterparts and quality control is more extensive than conventional tablets.

Ion-Exchange Systems 

Ion-exchange systems generally use resins composed of water-insoluble, cross-linked polymers. These polymers 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 contact with the ion-exchange groups. 

Resin⁺ − Drug⁻ + X⁻ → resin⁺ − X⁻ + Drug⁻ 

Conversely, 

Resin⁻ − Drug⁺ + Y⁺ → Resin⁻ − Y⁺ + Drug⁺ 

Where, X⁻ and Y⁺ are ions in the GI tract. The free drug then diffuses out of the resin. The drug-resin complex is prepared by mixing the resin with drug solution either by repeated exposure of the resin to the drug in a chromatography column or by prolonged contact in the solution. 

The date of drug diffusing out of the resin is controlled by the area of diffusion, diffusional path length, and rigidity of the resin, which is a function of the amount of crosslinking agent used to prepare the resin. 

This system is advantageous for drugs that are highly susceptible to degradation by enzymatic processes since it offers a protective mechanism by temporarily altering the substrate. This approach to controlled release, however, has the limitation that the release rate is proportional to the concentration of the ions present in the area of administration.

Although the ionic concentration of the GI tract remains rather constant with limits, the release rate of the drug can be affected by variability in diet, water intake, and individual intestinal content. 

An improvement in this system is to coat the ion-exchange resin with a hydrophobic rate-limiting polymer, such as ethylcellulose or waxes. These systems rely on the polymer coat to govern the rate of drug availability.

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