Factors Influencing the Design and Act of Controlled Release Products

Physiological Properties

(1) Aqueous solubility: Most of the active pharmaceutical moieties (API) are weakly acidic or basic in nature, which affects the water solubility of the API. Weak water-soluble drugs are difficult to design controlled-release formulations. High aqueous solubility drugs show burst release followed by a rapid increment in plasma drug concentration. These types of drugs are good candidates 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, which is a significant factor that affects the passive diffusion of the drug across the biological membrane. The drugs have a high or low P value, not suitable for CR; it should be appropriate to dissolve in both phases.

The partition coefficient is defined as "the concentration ratio of unionised drug distributed between two phases at equilibrium".

• Given by the Noyes-Whitney's Equation:

P = [A] / ([A]∞)

• The logarithm (base 10) of the partition coefficient (log 10 P) is often used.
• For ionizable drugs, where the ionised 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:

1. Either low flux into the tissues 
2. 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 ionisation of the drug at physiological pH in the GIT. Generally, the highly ionised drugs are poor candidates for CRDDS. The absorption of the unionised drug occurs rapidly compared to ionised drugs from the biological membranes. The pKa range for an acidic drug whose ionisation depends on the pH is 3.0 to 7.5, and for a basic drug it lies 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: The molecular size and molecular weight are two important factors which affect the molecular diffusibility across a biological membrane. Molecular size less than 400D is easily diffused, but greater than 400D creates a problem in drug diffusion.

(i) In addition to diffusion through a variety of biological membranes, drugs in many CRDDS must diffuse through a rate-controlling membrane or matrix.

(ii) The ability of a drug to pass through membranes is called diffusivity.

(iii) An important influence upon the value of diffusivity-D, in polymers, is the molecular size of the diffusing species.

(iv) 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.

(v) 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 the therapeutic effect of such an 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 (may be 95%), thus the need to formulate 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 is drug release from the dosage form. The absorption rate should be rapid the release rate to prevent the dose dumping. The various factors, like; aqueous solubility, log P, and acid hydrolysis, which affect the absorption of drugs.

(2) Distribution: Distribution of the drug from the conventional dosage form directly gets distributed throughout the body, and gets accumulated at 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 prevent accumulation in other sites.

It also enables the complete drug to reach 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 can become fatal sometimes. Removal of such an unwanted accumulated portion 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 its action and then gets eliminated safely.

(4) Biological half-life (t1/2): In general, a drug having a short half-life requires frequent dosing and suitable candidate for a controlled release system. A drug with a long half-life requires dosing after a long time interval. Ideally, the drugs with having t1/2 of 2-3 hours are a suitable candidate for CRDDS. Drugs having a t 1/2 of more than 7-8 hours are not used for a controlled release system.

(5) Dose size: The CRDDS are formulated to eliminate repetitive dosing, so they must contain a larger dose than conventional dosage forms. But the dose used in a conventional dosage form gives an indication of the dose to be used in CRDDS. The volume of sustained dose should be as large as possible under the 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 less 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 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 the GIT are poor candidates for CRDDS. Drugs which are absorbed throughout the GIT are good candidates for controlled release.

(8) Patient physiology: The physiological condition of the patient, like gastric emptying rate, residence time, and GI diseases, influences the release of the drug from the dosage form directly or indirectly.

Pharmacokinetic parameters considered during the drug selection are listed as follows:

Table: Pharmacokinetic Parameters for Drug Selection

Parameter	Comment
Biological or elimination half-life.	It should be between 2 to 6 hours.
Elimination rate constant (KE).	Required for design.
Total clearance (CLT).	Doesn't depend on.
Intrinsic absorption rate.	It should be greater than the release rate.
Apparent volume of distribution (Vd).	Vd affects the required amount of the drug.
Absolute bioavailability.	Should be 75% or more.
Steady state concentration (Css).	Lower Css and smaller Vd.
Toxic concentration.	The therapeutic window should be broader.