INTRODUCTION:

A pharmaceutical dosage form designed to delay the release of a therapeutic agent such that its appearance in the systemic circulation is delayed and/or prolonged and its plasma profile is sustained in duration is referred to as sustained release.²

A controlled release is one that extends beyond the sustained drug’ action. Additionally, it suggests a predictability and reproducibility in the drug release kinetics, meaning that the drug ingredient(s) will release from a controlled release drug delivery system according to a rate profile that is both kinetically predictable and repeatable from one unit to the next.²

To improve patient adherence, convenience, and satisfaction, pharmaceutical makers are focusing on developing controlled release dosage forms.³ A controlled release drug delivery system delivers the medication over a certain length of time at a predefined rate, either locally or systemically. A suitable delivery profile that can result in therapeutic plasma levels is the aim of these devices.⁴ In order to preserve drugs against physiological deterioration or elimination, promote patient compliance, and strengthen quality control in the production of pharmaceutical products, controlled release systems have been developed.⁵

Advantages of CRDDS:

Fig 1. Advantages of CRDDS

Disadvantages of CRDDS:

Fig. 2: Disadvantages of CRDDS

Factors affecting the formulation of oral controlled release drug delivery system:

I) Physicochemical factors:

1) Aqueous solubility:

The quantity of a substance that stays in solution in a specific volume of solvent that contains undissolved substance is known as its solubility. It is a compound’s thermodynamic property. The amount of drug in the solution in G.I. tract or the drug’s intrinsic permeability, determines the fraction of the drug absorbed into the portal blood. A drug needs to partition into the absorbing membrane after dissolving in the aqueous phase surrounding the delivery site in order to be absorbed. A drug’s aqueous solubility affects its dissolution rate, which determines its concentration in solution and, ultimately which acts as driving force for diffusion through membranes. Dissolution rate is related to aqueous solubility, as shown by the Noyes-Whitney equation that, under sink conditions, is

dC/dt = kD A. Cs

where dc/dt is the dissolution rate, kD is the dissolution rate constant, A is the total surface area of the drug particles, and Cs is the aqueous saturation solubility of the drug.⁹

The majority of drugs are weak bases or acids. It will be challenging to include medications with limited water solubility into a sustained release mechanism. It might be challenging to slow down the rate of dissolution if it has a high solubility and rapid dissolution rate. When compared to less soluble drugs, those with high water solubility can dissolve in water or gastrointestinal fluid more easily, release their dosage form in a burst, and absorb faster, increasing the drug’s concentration in the bloodstream. A highly water-soluble medication might be challenging to include into the dosage form and to delay the drug’s release, particularly at high doses.

The three main factors—intestinal permeability, dissolution, and solubility—can be estimated for their potential contributions using the biopharmaceutical classification system (BCS). Compounds with solubility < 0.1 mg/ml face significant solubilization obstacles, and frequently compounds with solubility 10 mg/ml present difficulties to solubilization dosing formulation. Class III (high solubility-low permeability) and Class IV (low solubility-low permeability) drugs are poor candidates for controlled release dosage forms. Generally speaking, it is not ideal to formulate highly soluble medications into a controlled release product.¹⁰

2) Partition coefficient:

The ratio of fraction of drug in an oil phase to that of an aqueous phase is termed as the partition coefficient.¹⁰ The partition coefficient affects drug diffusion across the rate-controlling membrane or matrix as well as drug penetration across biological membranes.⁹ A drug’s rate and extent of absorption increase with its apparent partition coefficient. These drugs are more likely to pass through even the BBB and other more selective barriers. Due to enhanced partitioning into fatty tissues, which always have lower blood flow rates than aqueous tissues like the liver, these drugs also have an increased apparent volume of distribution. As a result, these tissues may resemble models with two or more compartments. The metric holds significance in ascertaining the drug’s release rate from a lipophilic matrix or device.¹¹

3) Molecular weight of the drug:

The absorption is more rapid and complete the smaller the molecular weight. The molecular size threshold for pharmaceuticals absorbed by pore transport mechanism is 400 daltons for linear compounds and 150 daltons for spherical compounds. On the other hand, passive diffusion accounts for almost 95% of drugs absorption. The ability of a drug to permeate through membranes is known as diffusivity, and it is inversely correlated with molecular size. For passive diffusion, a drug’s molecular size cannot be larger than 600 daltons. Peptides and proteins are examples of drugs with enormous molecular sizes that are not good candidates for oral controlled release systems.¹¹

4) Drug pKa and ionization at physiological pH:

The strength of an acid or a base can be determined using the pKa value. Thus, a drug molecule’s charge at a certain pH can be ascertained using its pKa value. Only in their unionized form does drug molecules have therapeutic activity, and in this state, they can readily pass through the lipoidal membrane. The drug’s dissociation constant and the pH of the fluid at the site of absorption determine how much of the drug stays in unionized form. Therefore, the medicine is not appropriate for SR/CR dosage form if it remains in ionized form at its absorption site. The drugs should be non-ionized at the site to a degree of 0.1–5% for the best passive absorption. Medications like hexamethonium, which are mostly found in ionized form, are not good choices for controlled delivery system.¹²

5) Drug stability:

Drugs which are not stable in g.i. environment cannot be administered as oral controlled release formulation because of bioavailability problems, e.g., nitroglycerine. In such a case a different route of administration should be selected like the transdermal route.

6) Mechanism and site of absorption:

Controlled release methods are not suitable choices for drugs absorbed by windows or carrier-mediated transport pathways. e.g. several B vitamins.¹¹

II) Biological factors:

1) Absorption:

The way a drug absorbs can have an impact on whether or not it works well as an extended-release product. The goal of developing a product with controlled release is to establish a control on delivery system. It is necessary that the release rate be substantially slower than the absorption rate. (10) When administered orally, Kr<<<Ka is the most crucial. Maximum absorption half-life should be 3–4hours, assuming that the medication transits through the gastrointestinal tract’s absorptive region in 9–12hours. This translates to a minimal absorption rate constant Ka value of 0.17–0.23/hr required for about 80–95% absorption during a transit period of 9–12hours. For a medication with a very slow rate of absorption (Ka<<0.17/hr), the first order release rate constant Kr less than 0.17/hr results in unacceptably poor bioavailability in many patients. Consequently, it will be challenging to construct slowly absorbed drugs into extended-release systems where the Kr<<<Ka requirement must be satisfied.⁹ Potent drugs that are soluble in water but have low absorption rates, such as decamithonium, are likewise not good candidates because even a small change in absorption could lead to possible toxicity.¹¹

2) Distribution:

The distribution of a drug in the body’s vascular and extravascular areas is a significant aspect to be taken into account in total elimination kinetics. The apparent volume of distribution and the ratio of the drug in tissues to the drug in plasma (T/P) are used to express a drug’s distribution characteristic. The greater volume of distribution indicates that a comparatively smaller amount of drug is present in the circulation and a greater amount of the drug is bound to the tissues. The drug in the bloodstream is subject to renal or hepatic clearance. That is, the majority of a drug is in the blood and subject to hepatic or renal clearance if its apparent volume of distribution is lower.¹² In contrast, this mechanism will have to work with less drug if the volume of distribution is high.

Table: drugs with apparent volume of distribution higher than total volume of distribution⁹

Sr. No.	Drug	Apparent volume of distribution (L)
1	Amiodarone	4620
2	Azithromycin	2170
3	Chloroquine	12950
4	Doxepin	1400
5	Digoxin	500
6	Flurazepam	1540
7	Haloperidol	1400

3) Absorption window:

Some medications only absorb from a particular area of the gastrointestinal tract when taken orally. The “absorption window” refers to this section. Furthermore, these candidates are unfit for CRDDS.¹⁰

4) Metabolism:

As long as the rate of metabolism is not excessively high, a medicine that is extensively metabolized can be used in a controlled release system. Drug’s metabolism can either turn an inactive drug into an active metabolite or deactivate an active drug. Complex metabolic patterns would greatly complicate the S.R./C.R. design, especially in cases where a metabolite, such as isosorbide 2, 5-dinitrate, is entirely or partially responsible for biological activity.⁹ A drug with the ability to induce or inhibit metabolism is not a good fit for this kind of product since it would be hard to keep blood levels at a steady state.¹¹

5) Elimination half life:

Half life, which is influenced by both clearance (Cl) and volume of distribution (V_d), is the period of time it takes for the drug’s concentration in the body (or the plasma concentration) to decrease half.

T_1/2 = 0. 693.Vd/C (9)

The amount of drug must be included in the controlled release dosage form increases with decreasing t1/2. To maintain the rapid release rate, a very large dose of medicines having a half-life of less than two hours may be necessary. Drugs with half-lives between two and four hours are suitable choices for such a system.¹¹

6) Therapeutic dose:

Controlled release formulations should not contain drugs with low therapeutic indices. In the event that the body’s system fails, dose dumping might happen, which would be dangerous.¹⁰

II) METHODOLOGY:

Classification of CRDDS:

Based on mechanism of drug release these are further classified as follows:

1. Diffusion controlled products

2. Dissolution controlled products

3. Erosion products

4. Osmotic pump system

5. Ion exchange resins

1) Diffusion controlled products:

Diffusion is the process of movement of drug molecules from a region of higher concentration to one of lower concentration. The flux of the drug (in amount/area.time) across the membrane in the direction of decreasing concentration gradient. These is given by Fick’s first law

J= - D dc/dx

Where, D = diffusion coefficient in area/ time, dc/dx = change of concentration ‘c’ with distance ‘x’

Drug release rates in diffusion systems are determined by the drug’s ability to diffuse through an inert water-insoluble membrane. There are two types of diffusion devices

a) Reservoir type

b) Matrix type

a) Reservoir type:

The drug’s release rate is regulated by a polymeric substance that is insoluble in water, which surrounds the drug’s core. After partitioning into the membrane, the drug will exchange with the fluid surrounding the particle or tablet. More drug will seep into the polymer, spread to the edges, and interact with the surrounding components. Commonly utilized polymers in these devices are poly-vinyl acetate and ethylene cellulose.¹³

Fig 3: Schematic Representation of Reservoir Diffusion Controlled Drug Delivery Device¹³

b) Matrix type:

For the rapidly released drugs the matrix system is the commonest controlled release delivery system. In these systems the drugs are uniformly distributed or dissolved in appropriate polymeric materials.¹⁴

Fig 4: Schematic Representation of Matrix Diffusion Controlled Drug Delivery System ¹³

2) Dissolution controlled products:

It can be difficult to manage the dissolution rate of drugs with high water solubility and dissolution rate. It is possible to achieve dissolution-controlled release by covering drug particles or granules with polymeric materials of different thickness or encapsulating the drug in an insoluble polymer delaying the drug’s rate of dissolution in the GI medium . Diffusion via the aqueous boundary layer is the step that limits the rate at which a drug dissolves. The drug’s solubility serves as the energy source for drug release, which is impeded by the diffusional boundary layer between stagnant fluid and liquid. The dissolution rate (dm/dt) can be roughly calculated using (15)

dM/dt = DS/h (Cs-C) Or

dC/dt = DS/Vh (Cs-C)

Where M is the mass of solute dissolved in time t, dM/dt is the mass rate of dissolution (mass/time), D is the diffusion coefficient of the solute in solution, S is the surface area of The exposed solid, h is the thickness of the diffusion layer, Cs is the solubility of the solid (i.e., concentration of a saturated solution of the compound at the surface of the solid and at the temperature of the experiment), and C is the concentration of solute in the bulk solution and at time t. The quantity dC/dt is the dissolution rate, and V is the volume of solution.¹⁶

There are two common Formulation system relying on dissolution rate to determine the drug release rates, these are as follows,

a) Encapsulated dissolution system

b) Matrix dissolution system

a) Encapsulated Dissolution System:

The term “Coating dissolution-controlled system” is another name for this. The stability and thickness of the coating determine the pace of coat dissolution. It reduces GI discomfort and hides flavor, odor, and color. Drugs that are highly water soluble can be made into controlled release products by slowing down their rate of dissolution. This can be achieved by making the appropriate salt or derivatives, covering the drug with a substance that dissolves slowly, or integrating the drug into a carrier that dissolves slowly. Examples: Ornade spansules, Chlortrimeto Repetabs.¹⁷

Fig 5: Schematic Representation of Encapsulated Dissolution System¹⁵

b) Matrix Dissolution System:

The drug is uniformly distributed throughout a rate-controlling medium in matrix systems. They use waxes such hydrogenated castor oil, beeswax, and carnauba wax, among others, which regulate the rate at which the dissolution fluid enters the matrix by changing the tablet’s porosity, making it less wettable, or dissolving more slowly on its own. The drug release is often first order from such a matrices. Typically, the medicine that is embedded in wax is made by distributing the drug in melted wax, then granulating and solidifying the mixture.¹⁵

3) Erosion products:

In this system drug or active agents are mixed with biodegradable polymers. These materials degrade within the body as a result of natural biological processes and drug release occurs at constant rate. Most biodegradable polymers are designed to degrade as a result of hydrolysis of the polymer chains into biologically acceptable and progressively smaller compounds. The release if drug from these products is controlled by the erosion rate of a carrier matrix. The rate of release is determined by the rate of erosion. Biodegradable polymers and drugs or active agents are combined in this system.¹⁸

4) Osmotic pump systems:

Osmogen and a drug-containing core make up the majority of osmotic delivery devices, often known as osmotic pumps. These are covered in a semi-permeable membrane with one or more drug delivery pores, allowing the drug to be released gradually as a suspension or solution.

Basic components of osmotic pumps:

1. Drug

2. Osmotic agent

3. Semipermeable membrane

4. Plasticizer

5. Hydrophilic and lipophilic polymer

6. Wicking agent

7. Surfactant

8. Coating solvent¹⁹

5) Ion exchange resins:

Ion exchange resins are insoluble polymers containing functional groups that are either basic or acidic and that may exchange counter ions with the aqueous solutions surrounding them.²⁰ The low operating cost of the ion exchange system is a significant benefit. It uses minimal energy, and the chemicals that are regenerated are inexpensive. Moreover, resin beds have a long lifespan before needing to be replaced if they are properly maintained. The drawback is that the rate of release is directly correlated with the amount of ions in the administered area. Furthermore, variations in dietary habits, hydration levels, and gut microbiota can all impact the drug’s release rate.²¹

III) CONCLUSION:

By optimizing the biopharmaceutics, pharmacokinetic, and pharmacodynamic properties of drugs, oral sustained release (S.R.) and controlled release (C.R.) products offer an advantage over conventional dosage forms. This is because a single daily dose is sufficient for therapeutic management through uniform plasma concentration, maximizing drug utility with a reduction in local and systemic side effects, and curing or controlling conditions in the shortest amount of time with the least amount of drug to ensure greater patient compliance. This review describes the various physicochemical and biological factors affecting the formulation and performance of CRDDS along with the various formulation approaches i.e., types of controlled release systems.

IV) REFERENCES:

1. Muhammad Mustafa Swaleh, Zeb-un-Nisa, Syed Imran Ali, Maqsood Ahmed Khan and S. Saira Shehnaz. A Detailed Review on Oral Controlled Release Matrix Tablets. International Journal of Pharmaceutical Sciences Review and Research. 2020; 64(2): 27-38, DOI: 10.47583/ijpsrr. 2020.v64i02.005.

2. Yie W. Chien. Novel Drug Delivery System. Informa Healthcare, Second edition, 1991,1-42, http://dx.doi.org/10.47583/ijpsrr.2020.v64i02.005.

3. Aqsa Siraj, Muhammad Iqbal Nasiri, Syed Baqir S. Naqvi, Tariq Ali, Rabia Ismail Yousaf, Humera Sarwar and Muhammad Arif Asghar. Formulation development and evaluation of highly water-soluble drug-loaded controlled release matrix tablets. Bulletin of Pharmaceutical Sciences Assiut. 2021; 44(1): 15-29, https://dx.doi.org/10.21608/bfsa.2021.174122.

4. Ali Nokhodchi, Shaista Raja, Pryia Patel and Kofi Asare-Addo. The Role of Oral Controlled Release Matrix Tablets in Drug Delivery Systems. Bioimpacts. 2012; 4(2): 175-187, doi: 10.5681/bi.2012.027.

5. Ronald A. Siegel and Michael J. Rathbone. Overview of controlled release mechanism, Fundamentals and Applications of Controlled Release. Drug Delivery, Springer. 2012; 19-42. https://doi.org/10.1007/978-1-4614-0881-9_2

6. Shivakalyani Adepu and Seeram Ramakrishna. Controlled Drug Delivery Systems: Current Status and Future Directions. Molecules. 2021; 26(19); 5905, DOI: 10.3390/molecules26195905.

7. Leon Lachman, Herbert A. Liberman. The Theory and practice of Industrial Pharmacy, CBS Publishers. Fourth Edition. 2013: 597-628.

8. Jeganath S., Asha D., Sathesh Kumar S., Keerthi S Nair and Senthil Kumaran K. Oral Controlled Drug Delivery System – A Review. Research Journal of Pharmacy and Technology. 2018; 11(2): 797-804, DOI: 10.5958/0974-360X.2018.00151.8

9. Ranjith Kumar Mamidala, Vamshi Ramana, Sandeep G, Meka Lingam, Ramesh Gannu and Madhusudan Rao Yamsani. Factors Influencing the Design and Performance of Oral Sustained/Controlled Release Dosage Forms. International Journal of Pharmaceutical Sciences and Nanotechnology. 2009; 2(3): 583-594, https://doi.org/10.37285/ijpsn.2009.2.3.1

10. Kushal Modi, Monali Modi, Durgavati Mishra, Mittal Panchal, Umesh Sorathiya and Pragna Shelat. Oral controlled release drug delivery system: An overview. International Research Journal of Pharmacy. 2013; 4(3): 70-76, DOI:10.7897/2230-8407.04312

11. D. M. Brahmankar and Sunil B. Jaiswal. Biopharmaceutics and Pharmacokinetics- A treatise, Vallabh Prakashan, Third edition, 2015, 400-518.

12. Vijay Patel, Arvind Singh Jadon, Prateek Jain, Basant Khare, Bhupendra Singh Thakur, Rubeena Khan, Deepshikha Ray and Anushree Jain. Controlled Drug Delivery System: An overview on advances and new technologies. World Journal of Pharmaceutical and Life Sciences. 2022; 8(12): 85-92,

13. Nidhi Patel, Anamika Chaudhary, Twinkle Soni, Mehul Sambyal, Hitesh Jain and Umesh Upadhyay. Controlled Drug Delivery System: A Review. Indo American Journal of Pharmaceutical Sciences. 2016; 3(3): 227-233, DOI: 10.48175/5681.

14. Mosab Arafat. Approaches to achieve an Oral controlled release drug delivery system using polymers: A Recent Review. International Journal of Pharmacy and Pharmaceutical Sciences. 2015; 7(7): 16-22.

15. Sukanya Patil and Jaya Agnihotri. Sustained and Controlled Drug Delivery System: A Review. International Journal of Pharmacy and Pharmaceutical Research. 2022; 23(4): 258-282.

16. Alfred N. Martin, Martin’s Physical Pharmacy and Pharmaceutical Sciences, Lippincott Williams & Wilkins, a Wolters Kluwer buisness, Sixth edition, 2011; 223-257: 300-317.

17. Manisha Gahlyan and Saroj Jain. Oral controlled release drug delivery system – A Review. Pharma Tutor. 2014; 2(8): 170-178.

18. Sathish Ummadi, B. Shravani, N. G Raghavendra Rao, M. Srikanth Reddy, B. Sanjeev Nayak. Overview on Controlled Release Dosage Form. International Journal of Pharma Sciences. 2013; 3(4): 258-269.

19. Yosif Almoshari. Osmotic Pump Drug Delivery Systems: A Comprehensive Review. Pharmaceuticals. 2022; 15(11): 1430.

20. D. Belsare, Suparna S. Bakhle, Kanchan P. Upadhye, Gouri R. Dixit and Ninad A Mahakulkar. A Review on Ion Exchange Resins as Drug Delivery System. International Journal of Pharmaceutical Sciences Review and Research. 2020; 62(2): 90-96.

21. Dhiraj Marathe, Samadhan Mali, S. Talele, Rajendra Mogal and A.G. Jadhav. Ion Exchange Resins Drug Delivery System: A Review. International Journal of Pharmacy and Pharmaceutical Research. 2020; 18(2): 1-10.

Received on 20.03.2025 Revised on 23.04.2025

Accepted on 07.06.2025 Published on 08.07.2025

Available online from July 12, 2025

Asian J. Pharm. Tech. 2025; 15(3):271-276.

DOI: 10.52711/2231-5713.2025.00041

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.