FUNDAMENTALS OF MODIFIED RELEASE FORMULATIONS

1. Dr. Basavraj K. NanjwadeM. Pharm., Ph. D Professor of Pharmaceutics Department of Pharmaceutics KLE University College of Pharmacy BELGAUM – 590010, Karnataka, INDIA FUNDAMENTALS OF MODIFIED RELEASE FORMULATIONS

2. CONTENTS: • Diffusion controlled • Dissolution controlled • Erosion controlled and hybrid system in drug delivery • Mathematical models • Design and optimization of release rates based desired pharmacokinetic profile

3. In these type of system the rate controlling step is not dissolution rate but the diffusion of dissolved drug through a polymeric barrier. • Since the diffusional path length increases with time as the insoluble matrix is gradually depleted by the drug and the release of drug is never zero order. • This system are broadly classified into two categories reservoir system and monolithic system. DIFFUSION CONTROLLED

4. There are following type of diffusion controlled system • Reservoir devices • Matrix devices 1. Reservoir devices:- • Drug will partition in to the membrane and exchange with fluid surrounding the particle or tablet. • The water soluble polymer material encases a core of drug. • Additional drug will enter the membrane, diffuse to the periphery and exchange with the surrounding media. DIFFUSIONCONTROLLED

5. These systems are hollow in which core of drug is surrounded in water insoluble polymer membrane. • Coating or microencapsulation technique are used to apply polymer. • The permeability of membrane depend on thickness of the coat/concentration of coating solution & on the nature of polymer, ethyl cellulose and polyvinyl acetate are the commonly used polymer in such devices. reservoir diffusion controlled system

6. The mechanism of drug release across the membrane involves partitioning into the membrane with subsequent release into the surrounding fluid by diffusion. • The rate of drug release from the reservoir system can be explained by Fick ’s Law of diffusionas per the following equation. dm/dt = DSK(ΔC)/l reservoir diffusion controlled system

7. dm/dt = DSK(ΔC)/l Where, S= is the active diffusion area. D = is the diffusion coefficient of the drug across the coating membrane. l = is the diffusional path length (thickness of polymer coat) ΔC= is the concentration difference across l. K= is the partition coefficient of the drug between polymer and the external medium.

8. There are 2 processes used to apply insoluble polymeric materials to enclose drug containing core in tablets. Press coating & Air suspension techniques • Microencapsulation process is commonly used. • In most cases drug is incorporated in coating film as well as in the microcapsule. • Care should be taken during placement into tablet or capsule dosage forms to minimize fragmentation or fusion of the particle both effects will alter release characteristics. Methods to develop the Reservoir devices

9. In these system the drug is dispersed in insoluble matrix of rigid non swellable hydrophobic materials or swellable hydrophilic substances. • Insoluble plastics such as PVC and fatty materials like stearic acid, beeswax etc are the material used for rigid matrix. • The drug is generally kneaded within the solution of plastic material such as PVC in an organic solvent and granulated. The wax drug matrix is prepared by dispersing the drug in molten fat followed by congealing. 2. Matrix diffusion controlled system

10. Matrix diffusion controlled system

11. The equation describing drug release for this system is given by T. Higuchi. Q=[Dἐ/T (La-ἐCs)Cs t]1/2 Q = weight in gram of drug release/unit surface area D = diffusion coefficient Cs = solubility of drug in the release medium ἐ= Porosity of matrix T = tourtuosity of matrix A = Concentration of drug in the tablet express as g/ml Matrix diffusion controlled system

12. Assumptions made in the previous equations : • A pseudo-steady state is maintained during release . • A>>Cs , i.e. , excess solute is present . • C=0 in solution at all times ( perfect sink ) . • Drug particles are much smaller than those in the matrix . • The diffusion coefficient remains constant . • No interaction between the drug and the matrix occurs . Matrix diffusion controlled system

13. The release of highly water soluble drug can be sustained by using swellable matrix systems. • Hydrophilic gums may be of natural origin (Guar gum, tragacanth), semi synthetic (HPMC, CMC, Xanthan gum) or synthetic (poly acryl amides) are the material generally used for such matrices. • In the solvent such as alcohol the gum and drug are granulated together and compressed into tablet. Matrix diffusion controlled system

14. The mechanism of drug release from this system involves initial dehydration of hydrogel followed by absorption of water and desorption of drug via swelling controlled diffusion mechanism. • As the gum swells and the drug diffuses out of it, the swollen mass devoid of drug appear transparent or glass like and so the system is sometimes called as glassy hydrogel. Matrix diffusion controlled system

15. Matrix system Reservoir system Suitable for both non- Degradable reservoir systems degradable and degradable system. may be difficult to design No danger of ‘dose dumping’ Rupture can result in dangerous in case of rupture. Dose dumping. Achievement of ‘zero order’ Achievement of zero order release is difficult. release is easy. Advantages and Disadvantages of Matrix and Reservoir system

16. These system are easiest to design. • The drug with slow dissolution rate is inherently sustained. E.g. Griseofulvin, Digoxin and Saliyclamide & they act as natural prolonged release products. DISSOLUTION CONTROLLED RELEASE

17. Aluminum aspirin and ferrous sulfate produce slow dissolving form when it comes in contact with GI fluids. • Drugs having high aqueous solubility & dissolution rate E.g. Pentoxifylline steroid undergo transformation into less soluble polymorphs during dissolution in absorption pool. DISSOLUTION CONTROLLED RELEASE

18. The basic principle of dissolution control is as follows: If the dissolution process is diffusion layer controlled where the rate of diffusion from the solid surface through a unstirred liquid film to the bulk solution is rate limiting, the flux‘J’is given by J= -D(dc/dx) Where, D = Diffusion coefficient. Dc/ dx = Concentration gradient between the solid surface and bulk of solution. DISSOLUTION CONTROLLED RELEASE

19. In terms of flow rate of material (dm/dt) through unit area (A), the flux can be given as J = (1/A) dm/dt  • For the system with linear concentration gradient and thickness of the diffusion layer ‘h’ dc/ dx = (Cb - Cs) • Where Cs represents the concentration at the solid surface and Cb is the bulk solution concentration. A combined equation for rate of material is given as dm/dt = - (DA/h) (Cb - Cs) = kA (Cs - Cb) Where, k is intrinsic dissolution rate constant. DISSOLUTION CONTROLLED RELEASE

20. Dissolution controlled release products are divided in two classes: 1) Encapsulation dissolution control. 2) Matrix dissolution control. • Encapsulation/Coating dissolution controlled system (Reservoir Devices): • Encapsulation involves coating of individual particles, or granules of drug with the slowly dissolving material. • The particles obtained after coating can be compressed directly into tablets as in spacetabs or placed in capsules as in the spansule products.

21. As the time required for dissolution of coat is a function of its thickness and the aqueous solubility of the polymer one can obtain the coated particles of varying thickness in the range of 1- 200 micron. Encapsulation/Coating dissolution controlled system (Reservoir Devices):

22. By using one of several microencapsulation techniques the drug particles are coated or encapsulated with slowly dissolving materials like cellulose, PEGs, olymethacrylates, waxes etc. Two methods of preparation are employed : • Seed or granule coating • Microencapsulation Encapsulation/Coating dissolution controlled system (Reservoir Devices):

23. Seed or Granule Coated Products : Procedure: • Non pareil seeds are coated with drug • This followed with by a coat of slowly dissolving material such as carbohydrate sugars & cellulose , PEG , polymeric material & wax. • Coated granules can be placed in a capsule for administration. E.g. amobarbital & dextroamphetamine sulfate Microencapsulation : • This method can be used to encase liquids , solids , or gases. E.g. aspirin & potassium chloride • Advantage of this method is that sustained drug release can be achieved with taste abatement & better GI tolerability. Encapsulation/Coating dissolution controlled system (Reservoir Devices):

24. MICROENCAPSULATION PROCESSES

25. 2. Matrix (or Monolith)/ Embedded dissolution controlled system. • Since the drug is homogeneously dispersed throughout a rate controlling medium matrix system are also called monoliths. • The waxes used for such system are beeswax, carnauba wax, hydrogenated castor oil etc. • These waxes control the drug dissolution by controlling the rate of dissolution fluid penetration into the matrix by altering the porosity of tablet, decreasing its wettability or by itself dissolved at a slower rate.

26. The dispersion of drug wax is prepared by dispersing the drug in the molten wax followed by congealing and granulating the same. • The process, compression parameters and size of particles formed determine the release rate from this system. The drug release is often first order from such matrices. Matrix (or Monolith)/ Embedded dissolution controlled system.

27. Matrix (or Monolith)/ Embedded dissolution controlled system.

28. MARKETED FORMULATIONS

29. MARKETED FORMULATIONS

30. Erosion is defined as the disintegration of the polymer/ wax matrix, as a result of degradation and is characterized by material loss from the polymer generally in the physical state. • Polymer or wax degradation or hydrolysis is brought by enzyme, pH change or due to osmotic pressure or hydrodynamic pressure that causes fragmentation. • Erosion is effected by external stimuli, such systems can be classified under stimuli activated drug delivery system. Erosion controlled drug delivery system

31. It is classified on the type of stimuli: • Physical e.g. (osmotic pressure) • Chemical e.g.(pH) • Biological e.g. (enzyme) • Examples of erodible matrices include hydrophobic materials ethyl cellulose and waxes. • Depending on the erosion mechanism, polymer or waxes undergo either surface erosion or bulk erosion Erosion controlled drug delivery system

32. SURFACE EROSION: • It occurs from the surface layers of the device only. • It results in gradual decrease in the size of the device while the bulk phase remain un-degraded. • There is a difference in erosion rate between the surface and centre of matrix, the process is also called as heterogeneous erosion. • Surface erosion occurs when water penetration is restricted to device surface. Erosion controlled drug delivery system

34. b) BULK EROSION: • it occurs throughout the polymer bulk and the process is thus called as homogenous erosion. • Bulk erosion occurs when the water is readily able to penetrate the matrix of the device. Erosion controlled drug delivery system

35. They are also called as membrane cum matrix drug delivery system. • These systems are those where the drug in matrix of release- retarding material is further coated with a release controlling polymer membrane. • It combines constant release kinetics of reservoir system with mechanical robustness of matrix system. Hybrid system in drug delivery

36. Degradation by erosion normally takes place in devices that are prepared from soluble polymers. • In such instances, the device erodes as water is absorbed into the systems causing the polymer chains to hydrate, swell, and ultimately dissolved away from the dosage form. • Degradation can also result from chemical changes to the polymer including cleavage of covalent bonds, ionization and protonation either along the polymer backbone or on pendent side chains. Erosion controlled drug delivery system

37. There are various mathematical models • Zero order kinetics • First order kinetics • Weibull model • Higuchi model • Hixson Crowell model • Korsmeyer Peppas model • Baker- Lonsdale model • Hopfenberg model MATHEMATICAL MODELS

39. This model is used for dosage forms that do not disaggregate and release the drug slowly (assuming that area does not change and no equilibrium conditions are obtained). • It can be represented by the following equation: Wo - Wt = Kt Zero order kinetics

40. Where W is the initial amount of drug in the pharmaceutical dosage form, W is the amount of drug in the pharmaceutical dosage form at time t and K is a proportionality constant. Dividing this equation by W0 and simplifying. ft= kot Where ft = 1-(Wt –W0) and f represents the fraction of drug dissolved in time t and k0 the apparent dissolution rate constant or zero order release constant. Wo - Wt = Kt

41. This model is applied for dissolution studies, and also describe the absorption and elimination of some drugs. ln Qt = lnQ0 + Kt Qt = Drug amounts remaining to be released at time t Q0 = Drug amounts remaining to be released at zero hr Kt = First order release constant. A graph of drug release versus time will be linear. First order kinetics

42. A general empirical equation adopted by Weibull was used to describe the release process. • Erodible matrix formulations follow this model. M = 1- e[-(t-Ti)b/a Weibull model

43. Diffusion matrix formulations follow this model. • This model is used to study the release of water soluble and low soluble drugs incorporated in semisolid and / or solid matrixes. • It is denoted by the following equation ft = KHt1/2 ft =fraction of drug released at time t KH = Higuchi release rate constant t = time Higuchi model

44. Erodible matrix systems follow this model. • When this model is used, it is assumed that release rate is limited by the drug particles dissolution rate, and not by the diffusion that may occur through polymeric matrix. • It is represented by the following equation Wo1/3 – Wt1/3= Kst Hixson – crowell model

45. Wo1/3 – Wt1/3= Kst Where, Wo = initial amount of drug present in the matrix. Wt = amount of drug released in time t. Ks = release rate constant. Hixson – crowell model

46. Swellable polymer devices follow this model. • This model is generally used to analyze the release of pharmaceutical polymeric dosage forms, when the release mechanism is not well known or when more than one type of release phenomena could be involved. • It is denoted by the following equation. Mt/M∞ = Ktn Korsmeyer- Peppa’s model

47. Mt/M∞ = Ktn Where, Mt = amount released at time t M∞= amount released at infinite time K = release rate constant n = release exponents Korsmeyer- Peppa’s model

48. This model is suitable for microcapsules or microspheres. • It describes the drug controlled release from a spherical matrix. ft = 3/2[1-(1-Mt/M∞)2/3] – Mt/M∞= Kt Where, Ft = fraction of drug released at time t Mt = amount released at time t M∞ = amount released at infinite time Baker- lansdale model

49. This model was used for the release of drugs from surface- eroding devices with several geometries. • This equation describes drug release from slabs, spheres and infinite cylinders displaying heterogeneous erosion. • It is given by the following the equation. Mt/M∞ 1 – [1-k1t(t-l)]n Hopfenberg model

50. Mt = amount released at time t M∞ = amount released at infinite time K = rate constant Mt/M∞ 1 – [1-k1t(t-l)]n Hopfenberg model